text
stringlengths
2.15k
1.18M
url
stringlengths
26
510
(PDF) Ultrathin Al2O3 Coating on LiNi0.8Co0.1Mn0.1O2 Cathode Material for Enhanced Cycleability at Extended Voltage Ranges PDF | Ni-rich LiNi0.8Co0.1Mn0.1O2 oxide has been modified by ultrathin Al2O3 coatings via atomic layer deposition (ALD) at a growth rate of 1.12... | Find, read and cite all the research you need on ResearchGate Ultrathin Al2O3 Coating on LiNi0.8Co0.1Mn0.1O2 Cathode Material for Enhanced Cycleability at Extended Voltage Ranges DOI: 10.3390/coatings9020092 Zhiqiang Xie Abstract and Figures Ni-rich LiNi0.8Co0.1Mn0.1O2 oxide has been modified by ultrathin Al2O3 coatings via atomic layer deposition (ALD) at a growth rate of 1.12 Å/cycle. All characterizations results including TEM, SEM, XRD and XPS together confirm high conformality and uniformity of the resultant Al2O3 layer on the surface of LiNi0.8Co0.1Mn0.1O2 particles. Coating thickness of the Al2O3 layer is optimized at ~2 nm, corresponding to 20 ALD cycles to enhance the electrochemical performance of Ni-rich cathode materials at extended voltage ranges. As a result, 20 Al2O3 ALD-coated LiNi0.8Co0.1Mn0.1O2 cathode material can deliver an initial discharge capacity of 212.8 mAh/g, and an associated coulombic efficiency of 84.0% at 0.1 C in a broad voltage range of 2.7–4.6 V vs. Li+/Li in the first cycle, which were both higher than 198.2 mAh/g and 76.1% of the pristine LiNi0.8Co0.1Mn0.1O2 without the Al2O3 protection. Comparative differential capacity (dQ/dV) profiles and electrochemical impedance spectra (EIS) recorded in the first and 100th cycles indicated significant Al2O3 ALD coating effects on suppressing phase transitions and electrochemical polarity of the Ni-rich LiNi0.8Co0.1Mn0.1O2 core during reversible lithiation/delithiation. This work offers oxide-based surface modifications with precise thickness control at an atomic level for enhanced electrochemical performance of Ni-rich cathode materials at extended voltage ranges. (a) Schematics illustration of the Al2O3 ALD growth at the surface of NCM811 particles; FESEM images of (b) bare NCM811, and (c) 20 Al2O3 ALD NCM811; EDS mapping of (d) 20 Al2O3 ALD NCM811; TEM images of (e) bare NCM811, (f) 20 Al2O3 ALD NCM811, and (g) 50 Al2O3 ALD NCM811; and HRTEM images of (h) bare NCM811, (i) 20 Al2O3 ALD NCM811, and (j) 50 Al2O3 ALD NCM811. … Characteristics XPS spectra captured on the 10 Al 2 O 3 ALD NCM811, 20 Al 2 O 3 ALD NCM811, and 50 Al 2 O 3 ALD NCM811 materials compared to the bare NCM811: (a) Al 2p, (b) Ni 2p, (c) Co 2p, and (d) Mn 2p peaks. … Figures - available via license: Creative Commons Attribution 4.0 International 160+ million publication pages coatings Article Ultrathin Al 2 O 3 Coating on LiNi 0.8 Co 0.1 Mn 0.1 O 2 Cathode Material for Enhanced Cycleability at Extended V oltage Ranges Wenchang Zhu 1,2 , Xue Huang 1,2 , T ingting Liu 3 , Zhiqiang Xie 4 , Ying Wang 4 , Kai T ian 1,2 , Liangming Bu 1,2 , Haibo Wang 1,2,5 , Lijun Gao 1 , 2, * and Jianqing Zhao 1, 2, * 1 College of Energy , Soochow Institute for Energy and Materials InnovationS, Soochow University , Suzhou 215006, China; [email protected] (W .Z.); [email protected] (X.H.); [email protected] (K.T.); [email protected] (L.B.); [email protected] (H.W .) 2 Key Laboratory of Advanced Carbon Materials and W earable Energy Technologies of Jiangsu Pr ovince, Soochow University , Suzhou 215006, China 3 Suzhou University of Science and T echnology & Jiangsu Key Laboratory of Environmental Science and Engineering, Suzhou 215001, China; [email protected] 4 Department of Mechanical & Industrial Engineering, Louisiana State University , Baton Rouge, LA 70803, USA; [email protected] (Z.X.); [email protected] (Y .W.) 5 Institute of Chemical Power Sources, Soochow University , Suzhou 215600, China * Correspondence: [email protected] (L.G.); [email protected] (J.Z.); T el.: +86-512-6522-9905 (L.G. & J.Z.) Received: 20 December 2018; Accepted: 31 January 2019; Published: 3 February 2019     Abstract: Ni-rich LiNi 0.8 Co 0.1 Mn 0.1 O 2 oxide has been modified by ultrathin Al 2 O 3 coatings via atomic layer deposition (ALD) at a growth rate of 1.12 Å/cycle. All characterizations results including TEM, SEM, XRD and XPS together confirm high conformality and uniformity of the resultant Al 2 O 3 layer on the surface of LiNi 0.8 Co 0.1 Mn 0.1 O 2 particles. Coating thickness of the Al 2 O 3 layer is optimized at ~2 nm, corresponding to 20 ALD cycles to enhance the electrochemical performance of Ni-rich cathode materials at extended voltage ranges. As a result, 20 Al 2 O 3 ALD-coated LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathode material can deliver an initial discharge capacity of 212.8 mAh/g, and an associated coulombic efficiency of 84.0% at 0.1 C in a broad voltage range of 2.7–4.6 V vs. Li + /Li in the first cycle, which were both higher than 198.2 mAh/g and 76.1% of the pristine LiNi 0.8 Co 0.1 Mn 0.1 O 2 without the Al 2 O 3 protection. Comparative differential capacity (d Q /d V ) profiles and electrochemical impedance spectra (EIS) recorded in the first and 100th cycles indicated significant Al 2 O 3 ALD coating effects on suppressing phase transitions and electrochemical polarity of the Ni-rich LiNi 0.8 Co 0.1 Mn 0.1 O 2 core during reversible lithiation/delithiation. This work offers oxide-based surface modifications with precise thickness control at an atomic level for enhanced electrochemical performance of Ni-rich cathode materials at extended voltage ranges. Keywords: Al 2 O 3 oxide; atomic layered deposition; LiNi 0.8 Co 0.1 Mn 0.1 O 2 ; Ni-rich cathode material; lithium ion battery 1. Introduction Lithium ion batteries have been dominantly applied in hybrid electric vehicles (HEVs) and pure electric vehicles (EVs) [ 1 , 2 ], which significantly enhances our living environment. In particular for electric transportation systems and future large-scale applications of stationary grid energy storage, lithium ion batteries are required to provide higher ener gy and power densities, together with excellent long-term service life and acceptable cost [ 3 ]. Performance of lithium ion batteries Coatings 2019 , 9 , 92; doi:10.3390/coatings9020092 www.mdpi.com/journal/coatings Coatings 2019 , 9 , 92 2 of 12 critically depends on the electrochemical properties and behaviors of electrode materials both in cathodes and anodes [ 4 – 6 ]. Because of the rapid development of practical Si–C composite anode materials, developing high-performance cathode materials with high specific capacity , high working potential, excellent cycle life, reliable safety , and low cost has become an urgent requirement [ 7 – 9 ]. Li-excess and Ni-rich layered oxides have been extensively investigated as high-energy cathode materials for superior lithium ion batteries [ 10 , 11 ]. Despite delivering an attractive discharge capacity of ~250 mAh/g, Li-excess layered cathode materials have been suffering from two crucial issues. One is the layered-to-spinel phase transition during prolonged electrochemical cycles, leading to continuous voltage fading. The other is low coulombic efficiency in the first cycle that r esults from the initial electrochemical activation of the Li + -inactive Li 2 MnO 3 component [ 10 , 12 , 13 ]. These two problems impede practical applications of Li-excess cathode materials. Alternatively , Ni-rich layered oxides have been considered as feasible cathode materials by offering a reversible capacity of ~200 mAh/g and a stable working voltage at ~3.8 V vs. Li + /Li. It is well-known that the resultant electrochemical performance of Ni-rich cathode materials is essentially determined on the specific composition of Ni, Co, and Mn elements within these ternary transition metal oxides, LiNi 1 − x − y Co x Mn y O 2 ( x + y < 0.5) [ 11 , 14 , 15 ]. Higher Ni content results in higher lithium storage capacity of LiNi 1 − x − y Co x Mn y O 2 , but leads to the undesired formation of Li + /Ni 2+ cation mixing in the layered structure; the expense of safety in material usage and more complexity in the material preparation [ 16 , 17 ]. Mn and Co dopants have been demonstrated to enhance the structural robustness and cationic ordering for LiNi 1 − x − y Co x Mn y O 2 variants, respectively . However, the specific capacity has to be sacrificed, when Mn and Co contents are increased. In order to rapidly promote practical applications of Ni-rich cathode materials for superior lithium ion batteries, poor cycling and thermal stabilities of LiNi 1 − x − y Co x Mn y O 2 should be urgently addressed, especially for materials with high Ni content. Capacity fading can be exacerbated, when these Ni-rich LiNi 1 − x − y Co x Mn y O 2 cathodes are cycled at broad voltage ranges with a high upper cut-off voltage above 4.3 V vs. Li + /Li. One reason is that the intensive oxidation capability of Ni 3+/4+ redox could aggravate parasitic side reactions during lithiation/delithiation of LiNi 1 − x − y Co x Mn y O 2 cathode materials, leading to undesired electrolyte decomposition and solid electrolyte interphase (SEI) formation at the surface of the cathode. The other reason is the induced phase transition from the initial layered structur e to spinel-like and/or NiO-like rock-salt phases at the surface of LiNi 1 − x − y Co x Mn y O 2 particles, because the formation of Li + vacancies in high concentration at deep charge destabilizes the initial layered structure of LiNi 1 − x − y Co x Mn y O 2 [ 18 ]. These unfavorable structural transformations are consecutive, and gradually overspread from the surface to bulk Ni-rich layered oxides [ 17 , 19 ]. In addition, the formation of impure phases definitely brings about structural degradation and increased kinetic barrier for lithium ion diffusion, causing capacity fading and inferior rate capability of LiNi 1 − x − y Co x Mn y O 2 cathode materials [ 20 , 21 ]. Surface modifications, either on particles of active cathode materials or at the surface of the entire cathode, have been demonstrated to improve electrochemical performance for various cathode materials even in harsh operation conditions, such as elevated working temperatures and broad voltage ranges [ 22 , 23 ]. Oxides are considered common coating materials, because of their low material cost, simple synthetic procedure, and high effectiveness in protecting internal electrode materials. V arious examples have been reported in the literature [ 24 – 28 ], involving Al 2 O 3 , ZrO 2 , ZnO, TiO 2 , Cr 2 O 3 , SnO 2 , etc. However, associated electrochemical performance of modified cathode materials is sensitively determined by qualities of the coated oxides in terms of thickness, conformality , uniformity , and integrity . Oxide coatings prepared by atomic layer deposition (ALD) have been demonstrated to considerably enhance electrochemical performance for various cathode materials, involving layered LiCoO 2 [ 29 , 30 ], spinel LiMn 2 O 4 , and LiMn 1.5 Ni 0.5 O 4 [ 31 , 32 ]; Ni-rich LiNi 1 − x − y Co x Mn y O 2 and LiNi 0.8 Co 0.15 Al 0.05 O 2 [ 33 , 34 ]; and Li-excess Li[Li 1 − x M x ]O 2 oxides [ 35 ]. The ALD technique can result in highly conformational and uniform oxide coating layers at the entire surface of the underlying substrates, and thus has been considered as an effective method for surface modifications of different Coatings 2019 , 9 , 92 3 of 12 cathode materials. Ni-rich cathode materials have been dominantly used for lithium ion batteries to power currently-developed electric automobiles, but still suffer from poor service life, especially in harsh operation conditions, such as at elevated working temperatures and/or in extended voltage ranges. As reported in the literature [ 33 , 34 ], Al 2 O 3 ALD coatings contribute to enhanced cycling stabilities of LiNi 0.5 Co 0.2 Mn 0.3 O 2 , LiNi 0.8 Co 0.1 Mn 0.1 O 2 , and LiNi 0.8 Co 0.15 Al 0.05 O 2 by protecting coated Ni-rich oxide particles from parasitic side reactions at the cathode’s surface. However, the insulating property of Al 2 O 3 material makes it is necessary to precisely control the coating’s thickness, in order to maximize the electrochemical performance of Ni-rich cathode materials. In addition, it is also urgent to understand structural features and chemical environments between oxide coatings and Ni-rich oxide particles. The ALD technique was employed in this work to coat ultrathin Al 2 O 3 onto Ni-rich LiNi 0.8 Co 0.1 Mn 2 target material (marked as n Al 2 O 3 ALD NCM811, then responses to the number of ALD cycles related to the thickness control of Al 2 O 3 coating layer). TEM observations were used to examine the structural characteristics of resultant Al 2 O 3 coatings and determine the ALD growth rate of Al 2 O 3 oxide. XPS spectra were used to study chemical environments of different n Al 3 ALD NCM811 ( n = 10, 20 and 50) materials. Electrochemical performance of three n Al 2 O 3 ALD NCM811 cathode materials were evaluated and compared with the bare NCM811 cathode in a broad voltage range of 2.7–4.6 V vs. Li + /Li. This work offers a high-quality oxide coating for Ni-rich cathode materials by using the ALD method, which significantly contributes to improved electrochemical performance in extended voltage ranges for superior lithium ion batteries. 2. Materials and Methods 2.1. Synthesis of Ni-Rich Layered LiNi 0.8 Co 0.1 Mn 0.1 O 2 Material In a typ ical s ol (sol utio n)-ge l rout e, sto ichio metri c amou nts of CH 3 COOL i · 2H 2 O, Ni( CH 2 · 4H 2 O, Co(CH 3 COO) 2 · 4H 2 O, and Mn(CH 3 COO) 2 · 4H 2 O were dissolved in 50 mL of distilled water . An extra 3 mol.% of the lithium source was used to compensate for the volatilization of lithium at high heating temperatures. The green sol was obtained after the solvent was completely evaporated, and was then transferred to dry in vacuum at 120 ◦ C for 5 h, under pure O 2 flow at a temperature ramp of 5 ◦ C/min. The resultant black LiNi 0.8 Mn 0.1 Co 0.1 O 2 (marked as NCM811) powder was collected after cooling to room temperature. 2.2. Al 2 O 3 Coating on LiNi 0.8 Co 0.1 Mn 0.1 O 2 Particles Through Atomic Layer Deposition The atomic layer deposition of Al 2 O 3 coating on LiNi 0.8 Mn 0.1 O 2 particles was performed in a Savannah 100 ALD system (Cambridge NanoT ech Inc., Waltham, MA, USA) at 120 ◦ C, by applying Al(CH 3 ) 3 (T rimethylalumium, TMA) and H 2 O as precursors with exposure time of 0.01 s, waiting time of 5 s, and purge time of 40 s, respectively . Nitrogen gas was used as the flow gas, and the flow rate was set at 20 sccm. The vacuum condition in the reaction chamber was controlled at 10 − 3 –10 − 2 torr, and the overpr essure threshold for the coating processes was set at 250 torr . Two self-terminating reactions involved in the ALD growth of Al 2 O 3 layer are described as follows: Al-CH 3 *+H 2 O → AlOH* + CH 4 (2) LiNi 0.8 Co 0.1 Mn 0.1 O 2 particles coated with the Al 2 O 3 layer under different ALD cycles were marked as n Al 2 O 3 ALD NCM811 (the n corresponds to the number of ALD cycles). 2.3. Characterizations Crystallographic structures of bare NCM811 and Al 2 O 3 -coated NCM811 materials were examined by X-ray diffraction (XRD), using a Bruker D8 Advance automatic diffractometer (Bruker , Billerica, MA, USA) with Cu K α radiation. Morphologies and energy dispersive spectroscopic (EDS) mappings of different samples were observed by field emission scanning electron micr oscopy (FESEM) on a Hitachi SU-8010 (Hitachi High-T ech Corp., Tokyo, Japan) and FEI Quanta FEG 250 micr oscopies (FEI, Hillsboro, OR, USA), respectively , with an acceleration voltage at 15/20 kV in a secondary electrons (SE) detection mode. The Everhart Thornley Detector (ETD) was used to collected electron signals. Detailed structural features of different specimens wer e captured by transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HR TEM) coupled with selected area electron diffraction (SAED) on a FEI T ecnai G2 T20 equipment (FEI, Hillsboro, OR, USA), at an acceleration voltage of 200 kV . Chemical environments and valent states of cations within different materials were characterized by X-ray photoelectron spectroscopic (XPS) measurements on an ESCALAB 250Xi XPS device (Thermo Fisher Scientific, W altham, MA USA). All XPS spectra were calibrated according to the binding energy of the C 1 s peak at 284.6 eV . 2.4. Electrochemical Measurements The working electrodes were composed of 80 wt.% active cathode materials, 10 wt.% super p as the conductive carbon, and 10 wt.% polyvinylidenefluoride (PVDF) as the binder. These cathodes were assembled into two-electrode CR2025-type coin cells (Shenzhen Kejing Star T echnology Co., LTD., Shenzhen, China), in an Ar -filled glove box (MBraun, Garching, Germany) for electrochemical measurements, with the metallic lithium foil as the reference, and counter electrodes with the glass microfiber (Whatman, Grade GF/B, Little Chalfont, UK) as the separator . The electrolyte was a 1 M solution dissolved in ethylene carbonate (EC) and dimethyl carbonate (DMC) at a volumetric ratio of 1:1. The real loading of active material was ~3.5 mg in the cathode with a diameter of 12 mm and a thickness of ~50 mm for all electrode materials. The electrolyte volume used during the coin cell assembly was ~0.5 mL per unit. Galvanostatic charge and discharge were performed at different current densities in a voltage range of 2.7–4.6 V vs. Li + /Li on a LAND battery testing system (Jinnuo, Wuhan, China). The current density corresponding to 1 C was 200 mA/g. Electrochemical impedance spectroscopy (EIS) was conducted in a frequency range of 10 mHz–100 kHz with an AC amplitude of 5 mV on the Autolab electrochemical workstation (PGST AT302N, Metrohm Autolab, Utrecht, The Netherlands). 3. Results and Discussion 3.1. Characteristics of Al 2 O 3 Layer Deposited on NCM811 Particles via ALD Coating As shown in the schematic illustrations in Figure 1 a, the ALD growth of Al 2 O 3 coating at the surface of NCM811 particles was subjected to a sequence of chemisorption and self-terminating surface reactions (Equations (1) and (2) in Section 2.2 ). Detailed deposition mechanisms for the different oxides, involving Al 2 O 3 , ZnO and ZrO 2 , can be found in our previous work [ 12 , 36 – 40 ]. As a result, ultrathin oxide coatings under ALD growth always reveal desirable conformality , uniformity , robustness, and pinhole-free features. Furthermore, thickness of the resultant oxide coatings can be precisely controlled at the Angstrom or atomic monolayer level, which is determined by the number of ALD cycles. Accordingly, morphologic and structural dif ferences of pristine NCM811, 20 Al 2 O 3 ALD NCM811, and 50 Al 2 O 3 ALD NCM811 materials are compared in Figure 1 b–j. The pristine NCM811 material (Figure 1 b) reveals a distinct aggregation of tremendous primary nanoparticles, which have smooth facets and sharp edges with an average particle size of ~500 nm. Such morphologic features generally indicate the high crystallinity and purity of the prepared NCM811 particles. By contrast, FESEM images of the 20 Al 2 O 3 ALD NCM811 particles showed apparent roughness at the entire surface after coating the Al 2 O 3 layer in 20 ALD cycles (Figure 1 c), implying the conformal and uniform surface modification of the NCM811 substrate. The elemental energy dispersive spectroscopic (EDS) mapping was captured on the selected 20 Al 2 O 3 ALD NCM811 particles (Figure 1 d), which revealed even distributions of Al, Ni, Co, Mn, and O elements, and thus again demonstrated desirable conformality Coatings 2019 , 9 , 92 5 of 12 and uniformity of Al 2 O 3 coatings at the surface of NCM811 particles. In order to comprehensively understand structural characteristics of the resultant Al 2 O 3 layer, 50 Al 2 O 3 ALD NCM811 particles with increased coating thickness were examined by TEM observations, and compared to bare NCM811 and the 20 Al 2 O 3 ALD NCM811 materials. As shown in Figure 1 e, TEM images of NCM811 particles showed consistent contrast throughout the whole observation area, revealing a single solid structur e without any surface modifications. HRTEM images of the selected region in Figure 1 e, marked by a blue square, showed perfect lattice fringes with a d-space of 0.47 nm (Figure 1 h), corresponding to (003) planes in the layered structure of NCM811 oxide. By contrast, TEM images of the 20 Al 2 O 3 ALD NCM811 and 50 Al 2 O 3 ALD NCM811 particles captured in Figure 1 f,g gave rise to distinct contrast differences between the dark NCM811 core and light Al 2 O 3 coating shells at the surface, respectively . It was noticeable that the ALD coating contributed to satisfactory uniformity and conformality of the resultant Al 2 O 3 layer, which was in accor dance with that coated at the surface of different cathode materials reported in the literature [ 36 , 38 ]. The precise thickness was 5.6 nm as shown in the HRTEM image of the 50 Al 2 O 3 ALD NCM811 (Figure 1 j), corresponding to an Al 2 O 3 ALD growth rate of 1.12 Å/cycle. Accordingly, 20 ALD cycles r esulted in an Al 2 O 3 coating with 2.2 nm thickness as shown in Figure 1 i for the 20 Al 2 O 3 ALD NCM811 materials. Furthermore, these two HRTEM observations indicated an amorphous feature of the Al 2 O 3 coating layer, which was distinguishable fr om the internal crystalline NCM811 particles. As a result, SEM and TEM images demonstrated the conformational and uniform coating of the Al 2 O 3 layer for the surface modification of Ni-rich NCM811 particles through ALD processes, together with thickness control at the sub-nano level. Coatings 2019 , 9 FOR PEER REVIEW 5 images of the selected region in Figure 1e, marked by a blue square, showed perfect lattice fringes with a d-space of 0.47 nm (Figure 1h), corresponding to (003) planes in the layered structure of NCM811 oxide. By contrast, TEM images of the 20 Al 2 O 3 ALD NCM811 and 50 Al 2 O 3 ALD NCM 811 particles captured in Fi gure 1f,g gave rise to distinct contrast differences between the dark NCM811 core and light Al 2 O 3 coating shells at the surface, respectively. It was noticeable that the ALD coating contributed to satisfactory uniformity and conformality of the resultant Al 2 O 3 layer, which was in accordance with that coated at the surface of differe nt cathode materials reported in the literature [36,38]. The precise thickness was 5.6 nm as shown in the HRTEM image of the 50 Al 2 O 3 ALD NCM811 (Figure 1j), corresponding to an Al 2 O 3 ALD growth rate of 1.12 Å/cycle. Accordingly, 20 ALD cycles resulted in an Al 2 O 3 coating wi th 2.2 nm thickness as shown in Figure 1i for the 20 Al 2 O 3 ALD NCM811 materials. Furthermore, these two HRTEM observations indicated an amorphous feature of the Al 2 O 3 coating layer, which was distinguishable fro m the i nternal crystalline NCM811 particles. As a result, SEM and TEM images demonstrated the conformational and uniform co ating of the Al 2 O 3 layer for the surface modification of Ni- rich NCM811 particles thro ugh ALD processes, together with thickness control at the su b-nano level. Figure 1. ( a ) Schematics illustration of the Al 2 O 3 ALD growth at the surface of NCM811 particles; FESEM images of ( b ) bare NCM811, and ( c ) 20 Al 2 O 3 ALD NCM811; EDS mapping of ( d ) 20 Al 2 O 3 ALD NCM811; TEM images of ( e ) bare NCM811, ( f ) 20 Al 2 O 3 ALD NCM811 , and ( g ) 50 Al 2 O 3 ALD NCM811; and HRTEM images of ( h ) bare NCM811, ( i ) 20 Al 2 O 3 ALD NCM811, and ( j ) 50 Al 2 O 3 ALD NCM811. Al 2 O 3 coating ef fects on changing t he crystal structure of Ni-rich NCM811 core were evaluated using XRD patterns of different coated materials, coupl ed with quantitati ve analyses fro m Rietveld refinements. As shown in Figure 2a, the XRD pattern of pri stine NCM811 material was well indexed to a layered α-NaFeO 2 structure with a R-3m space group (JCPDS No . 74-0919). It also showed a desirable intensity rati o of characteristic 003 over 104 reflectio ns, i.e., I 003 / I 104 = 1.48 and distinct peak Figure 1. ( a ) Schematics illustration of the Al 2 O 3 ALD growth at the surface of NCM811 particles; FESEM images of ( b ) bare NCM811, and ( c ) 20 Al 2 O 3 ALD NCM811; EDS mapping of ( d ) 20 Al 2 O 3 ALD NCM811; TEM images of ( e ) bare NCM811, ( f ) 20 Al 2 O 3 ALD NCM811, and ( g ) 50 Al 2 O 3 ALD NCM811; and HRTEM images of ( h ) bare NCM811, ( 2 O 3 ALD NCM811, and ( j ) 50 Al 2 O 3 ALD NCM811. Coatings 2019 , 9 , 92 6 of 12 Al 2 O 3 coating effects on changing the crystal structure of Ni-rich NCM811 core wer e evaluated using XRD patterns of different coated materials, coupled with quantitative analyses from Rietveld refinements. As shown in Figure 2 a, the XRD pattern of pristine NCM811 material was well indexed to a layered α -NaFeO 2 intensity ratio of characteristic 003 over 104 reflections, i.e., I 003 / I 104 = 1.48 and distinct peak splitting of two 006/102 and 108/110 doublets, indicating outstanding structural ordering of the layered NCM811 material. The Rietveld refinement on the XRD pattern of pristine NCM811 resulted in lattice parameters of a = 2.8746 Å, c = 14.2102 Å, and V = 101.72 Å 3 , together with a low estimated Li + /Ni 2+ cation mixing of 3.68% based on a low reliability-factor of R wp = 6.62% (T able 1 ). These XRD features all indicate an excellent layered structure of the prepar ed Ni-rich NCM811 material, in accordance with HRTEM images (Figure 1 h). XRD patterns and the associated refinement results of NCM811 particles coated with 10, 20, and 50 Al 2 ALD layers are displayed in Figure 2 b–d, respectively . The calculated lattice parameters and cation mixings of these three coated materials, with gradually-increasing coating thickness of Al 2 O 3 , are summarized in T able 1 compared to bare NCM811, together with values of standard deviations (s.d.) for the calculations. The Al 2 O 3 phase was not detectable even in the 50 Al 2 O 3 ALD NCM811 samples, owing to the amorphous phase. However, the Al 2 O 3 coating slightly suppressed the crystal structural of the internal NCM811 host. Coatings thicker than 2 nm, i.e., 20 according to the refinement results of the 20 Al 2 O 3 ALD NCM811 sample, while the 10 Al 2 O 3 ALD NCM811 showed little change in lattice parameters as compared with that in the pristine NCM811 (T able 1 ). Although the thick Al 2 O 3 coating reduced a and c values of the 50 Al 2 O 3 ALD NCM811 material, its c / a ratio was almost the same with the NCM811, again indicating high conformality and uniformity of surface modifications via oxide ALD coatings. On the other hand, XRD patterns of the O 3 -coated NCM811 materials revealed I 003 / I 104 values equal to 1.54, 1.46, and 1.45 after 10, 20, and 50 ALD cycles (Figure 2 b–d), respectively , indicating little effects of Al 2 O 3 ALD coating on the structural ordering of internal NCM811 material. The estimated cation mixings within the layered structures of these three samples wre all in an acceptable range of 3%–4%, consistent with that of the pristine NCM811 material (T able 1 ). Coatings 2019 , 9 FOR PEER REVIEW 6 splitting of two 006/102 and 108/110 doublets, indicating outstanding structural ordering of the layered NCM811 material. The Rietveld refinement on the XRD pattern of pristine NCM811 resulted in lattice parameters of a = 2.8746 Å, c = 14.2102 Å, and V = 101.72 Å 3 , together wi th a low estimated Li + /Ni 2+ cation mixing of 3.68% based on a low reliability-factor of R wp = 6.62% (Table 1). These XRD features all indicate an excellent layered structure of the prepared Ni-rich NC M811 material, in accordance with HRTEM images (Figure 1h). XRD patterns a nd the associated ref inement results of respectively. The calculated lattice para meters and cation mixings of these three coated materials, with gradual ly-increasing co ating thickness of Al 2 O 3 , are summarized in Table 1 compared to bare NCM811, together with values of standard deviations (s.d.) for the calculations. The Al 2 O 3 phase wa s not detectable even in the 50 Al 2 O 3 ALD NCM811 samples, owing to the amorphous phase. However, the Al 2 O 3 coating sli ghtly suppressed the crystal structural of the inte rnal NCM811 host. Coat ings thick er tha n 2 nm, i. e., 2 0 ALD cycles (20 cycle* 1.12 Å/cycle = 2 .24 nm), resulted in a d etectable decrease in a , c , and V values, according to the refinement results of the 20 Al 2 O 3 ALD NCM811 sample, while the 10 Al 2 O 3 ALD NCM811 showed little change in l attice parameters as compared wi th that in the pristine NCM811 (Table 1). Although the thick Al 2 O 3 coating reduced a and c values of the 50 Al 2 O 3 ALD NCM811 materi al, its c / a ratio was almost the same with the NCM811, again i ndicating high conformality and uniformity of surface modifications via oxide ALD co atings. On the other hand, XRD patterns of the three Al 2 O 3 -coated NCM811 materials revealed I 003 / I 104 values equal to 1.54, 1.46, and 1.45 after 10, 20, and 50 ALD cycles (Figure 2b–d), respectively, indicating little effects of Al 2 O 3 ALD coating on the structu ral ordering o f internal NCM811 material. The estimated cation mixings within the layered structures of these three samples wre all in an acceptable range of 3%–4%, consistent with that of the pristine NCM 811 material (Table 1). Figure 2. XRD patterns of ( a ) bare NCM8111; ( b ) 10 Al 2 O 3 ALD NCM8111; ( c ) 20 Al 2 O 3 ALD NCM8111; and ( d ) 50 Al 2 O 3 ALD NCM8111 materials, coupled with rietveld refinement results. Figure 2. XRD patterns of ( a ) 10 Al 2 O 3 ALD NCM8111; ( c ) 20 Al 2 O 3 ALD NCM8111; and ( d ) 50 Al 2 O 3 ALD NCM8111 materials, coupled with rietveld refinement results. Coatings 2019 , 9 , 92 7 of 12 T able 1. Crystal parameters of different Al 2 O 3 -coated NCM811 materials in comparison to bare NCM811, according to XRD patterns and refinement results as shown in Figure 2 . Samples a (Å) s.d. c compared. As shown in Figure 3 a, 10 Al 2 O 3 ALD NCM811, 20 Al 2 O 3 ALD NCM811, and 50 Al 2 O 3 ALD NCM811 samples all showed sharp Al 2 p XPS peaks, verifying successful Al 2 O 3 coating at the surface of NCM811 particles. These collected Al 2 p peaks slightly shifted to higher binding energies at 75.4, 75.6, and 75.7 eV , respectively, compared to 74.6 eV of pur e Al 2 O 3 Database, implying possible chemical bonding between the Al 2 O 3 coating layer and NCM811 particles. As reported in the literature [ 36 – 40 ], the oxide coating and substrate in a typical ALD growth can result in a favorable chemical bond of substrate–O–M x O y (M = Al, Zn, Zr , Sn, etc.), this process is illustrated in Figure 1 a. However, it is unexpected to see that all the characteristic of Ni 2 p , Co 2 p , and Mn 2 p XPS peaks captured on three Al 2 O 3 -coated NCM811 particles also gave rise to higher bonding O 3 was gradually increased (Figure 3 b–d). These interesting XPS results may be attributed to the tr emendous –OH groups that were left at the surface of Al 2 O 3 coating at the end of ALD growth (Figure 1 a), which are highly electronegative, and thus probably induce reduced electr on cloud densities of Al, Ni, Co, and Mn cations. The thicker Al 2 O 3 coating resulted in increased surface area of Al 2 O 3 -coated NCM811 particles as well as the quantity of residual –OH groups at the most outside surface; hence, the inductive effect was enhanced by the increased number of –OH groups, leading to binding energy 2 O 3 and NCM811, which may facilitate charge transfer and lithium ion diffusion through the oxide coating layer. Coatings 2019 , 9 FOR PEER REVIEW 7 Table 1. Crystal parameters of different Al 2 O 3 -coated NCM811 materials in comparison to bare NCM811, according to XRD patterns and refinement results as shown in Figure 2. Samples a (Å) s.d. c (Å) s.d. Volume (Å 3 ) s.d. c / a Li + at 3 b Sites s.d. R wp (%) R p (%) NCM811 2.8746 3 × 10 −5 14.2102 1.8 × 10 −3 101.72 2.87 × 10 −3 4.9432 0.9632 2.203 × 10 −3 6.62 4.81 10 Al 2 O 3 ALD NCM811 2.8745 3 × 10 −5 14.2095 3.1 × 10 −3 101.71 3.1 × 10 −3 4.9433 0.9634 2.351 × 10 −3 6.09 5.12 20 Al 2 O 3 ALD NCM811 2.8743 2 × 10 −5 14.2094 3.6 × 10 −3 101.65 3.05 × 10 −3 4.9436 0.9697 1.936 × 10 −3 6.42 5.18 50 Al 2 O 3 ALD NCM811 2.8739 4 × 10 −5 14.2071 5.2 × 10 −3 101.49 7.93 × 10 −3 4.9435 0.9666 7.725 × 10 −3 7.03 5.58 In or der to confirm Al 2 O 3 coating forma tion an d its p ossible impact s on th e chemi cal environments of transition metal catio ns at the surface o f NCM811 particles, characteristic Al 2 p , Ni 2 p , Co 2 p , and Mn 2 p XPS peaks of bare NCM811 and three Al 2 O 3 -coated NCM811 materials were measured and compared. As shown in Figure 3a, 10 Al 2 O 3 ALD NCM811, 20 Al 2 O 3 ALD NCM811, and 50 Al 2 O 3 ALD NCM811 samples all showed sharp Al 2 p XPS peaks, verifying successful Al 2 O 3 coating at the surface of NCM8 11 particles. These coll ected Al 2 p peaks sl ightly shifted to higher binding energies at 75.4, 75.6, and 75.7 eV, respectively, compared to 74.6 eV of pure Al 2 O 3 oxide reported in NIST XPS Database, implying possible chemical bonding between the Al 2 O 3 coating layer and NCM811 particles. As reported in the literature [36–40], the ox ide coating and substrate in a typical ALD growth can result in a favorable chemical bond of substrate–O–M x O y (M = Al, Zn, Zr, Sn, etc.), this process is illustrated in Figure 1a. However, it is unexpected to see that all the characteristic of Ni 2 p , Co 2 p , an d Mn 2 p XPS peaks captured on three Al 2 O 3 -coated NCM811 particles also gave rise to higher bonding energies compared to those of pristine NCM811 particles, when the coating thickness of Al 2 O 3 was gradually increased (Figure 3b–d). These interesting XPS results may be attributed to the tremendous –OH groups that were left at the surface of Al 2 O 3 coating at the end of ALD growth (Figure 1a), which are highly el ectronegative, and thus probably induce reduced e lectron cloud densities of Al, Ni, Co, and Mn cations. The t hicker Al 2 O 3 coa ting resulted in increased surface area of Al 2 O 3 -coated NCM 811 particles as well as the quantity of residual –OH groups at the most outside surface; hence, the inducti ve effect was enhanced by the increased number of –OH groups, leadi ng to binding energy shifts of different cations to higher values. XPS results indicate a probable chemical bonding between Al 2 O 3 and NCM811, which may facilitate charge transfer and lithium ion diffusion through the oxide coating layer. Figure 3. Characteristics XPS spectra captured o n the 10 Al 2 O 3 ALD NCM811, 20 Al 2 O 3 ALD NCM811, and 50 Al 2 O 3 ALD NCM811 materials compared to the bare NCM811: ( a ) Al 2 p , ( b ) Ni 2 p , ( c ) Co 2 p , and ( d ) Mn 2 p peaks. Figure 3. Characteristics XPS spectra captured on the 10 Al 2 O 3 ALD NCM811, 20 Al 2 O 3 ALD NCM811, and 50 Al 2 O 3 ALD NCM811 materials compared to the bare NCM811: ( a ) Al 2 p , ( b ) Ni 2 p , ( c ) Co 2 p , and ( d ) Mn 2 p peaks. Coatings 2019 , 9 , 92 8 of 12 3.2. Enhanced Electrochemical Performance of Ni-Rich NCM811 Cathode Materials by Al 2 O 3 ALD Coating Effects of Al 2 O 3 ALD coating on improving electrochemical performance of Ni-rich NCM811 cathode material are evaluated in Figure 4 , where different cathode materials were subjected to a broad voltage range of 2.7–4.6 V vs. Li + /Li. Figure 4 a compares resultant cycling performance of the Al 2 O 3 -coated NCM811 cycled at 0.1 C with bare NCM811 material. The coating thickness of Al 2 O 3 layer was optimized at ~2 nm, corresponding to 20 ALD cycles. As a result, the 20 Al 2 O 3 ALD NCM811 cathode delivered an impressive discharge capacity of 212.8 mAh/g and an associated initial columbic efficiency of 84.0% in the first cycle, which were both higher than 198.2 mAh/g and 76.1% of the pristine NCM811 without Al 2 O 3 protection. Accordingly , the charge/discharge curves of these two cathode materials cycled at 1st and 100th cycles are shown in Figure 4 b. The improved electrochemical reversibility with increased specific capacity of the 20 Al 2 O 3 ALD NCM811 in the first cycle can be attributed to the conformal surface modification from the Al 2 O 3 coating (Figure 1 a), which effectively suppressed detrimental side reactions even when the NCM811 cathode material was cycled in an extended voltage range up to 4.6 V . In addition to protecting the internal Ni-rich core material from the HF attack in electrolytes as reported in the literature [ 29 , 41 ], the conformational and uniform Al 2 O 3 coating also reduced the electrolyte decomposition induced by high oxidation of Ni 3+ /Ni 4+ redox, especially under the deeply-charged condition at a high cut-off voltage of 4.6 V . As shown in Figure 4 a,b, the pristine NCM811 cathode material suffered from distinct capacity decay to 127.5 mAh/g after 100 electrochemical cycles, while the 20 Al 2 O 3 ALD NCM811 retained a much higher capacity of 157.2 mAh/g in the 100th cycle. Furthermore, the NCM811 also encountered an obvious working voltage fading from 3.80 initially to 3.76 V in the 100th cycle. By contrast, electrochemical polarity was effectively inhibited in the 20 Al 2 O 3 ALD NCM811 cathode material, resulting in a well-preserved working voltage from 3.84 V in the first cycle to 3.83 V after 100 cycles. The 10 Al 2 O 3 ALD NCM811 delivered moderate cycling performance as shown in Figure 4 a, between the NCM811 and 20 Al 2 O 3 ALD NCM811, which was attributed to the thinner Al 2 O 3 coating around 1 nm. On the other hand, the much thicker coating of Al 2 O 3 layer (>5 nm) after 50 ALD cycles resulted in satisfactory cycling stability , but the lithium storage capacity had to be sacrificed (Figure 4 a), owing to the inferior conductivity of insulating Al 2 O 3 oxide [ 42 , 43 ]. According to reports in the literature [ 13 , 44 ], Ni-rich cathode materials undergo inevitable phase transitions among three hexagonal (H1, H2, and H3) and one monoclinic (M) phases in their layered structures during lithiation/delithiation, which further aggravate undesired capacity fading in long-term electrochemical cycles. In order to examine possible phase transitions, related differential capacity (d Q /d V ) profiles ar e shown in Figure 4 c, which were transferred from charge/discharge curves in Figur e 4 b. The initial anodic peak of pristine NCM811 showed the much higher intensity by contrast with 20 Al 2 O 3 ALD NCM811, indicating severe parasitic side reactions that occurred during the first phase transformation from the hexagonal H1 to monoclinic M phases. Subsequent M to H2, and H2 to H3 took place around at 4.0 and 4.2 V as marked in Figure 4 c, respectively , when the Ni-rich cathode materials were charged to a high cutoff voltage. In successive discharge processes, phase transitions from H3 to H2 to M were reduced, resulting in dominant cathodic peaks around 3.75 V both in NCM811 and 20 Al 2 O 3 ALD NCM811 cathodes. However, two r edox pairs at higher voltages around 4.0 and 4.2 V were detected in the 100th cycle of pristine NCM811 cathode (peak voltages of detected anodic and cathodic peaks are marked by underlines), while the 20 Al 2 O 3 ALD NCM811 gave rise to the smoother d Q /d V curves above 3.9 V , revealing significantly suppressed phase transitions for its enhanced cycling stability after the optimal Al 2 O 3 ALD coating. Furthermore, total resistance changes of these two cathodes after 100 cycles were determined by EIS spectra as shown in Figure 4 d. These measurements were conducted on their fully-discharged states after prolonged electrochemical cycles. EIS spectra of fresh cells were also recorded at open circuit voltage states for the comparison. It is worth noting that two fresh cells of NCM811 and the 20 Al 2 O 3 ALD NCM811 cathodes both showed small resistances around 25 Ω . However, two Nyquist cir cles with larger diameters were captured in both cathodes after 100 cycles. The selected equivalent circuit, as the inset, was used to calculate the associated resistances based on Coatings 2019 , 9 , 92 9 of 12 fitting solid lines. For the pristine NCM811, one Nyquist circle in high frequency may be attributed to impure phases, such as spinel-like and/or rock-salt phases formed during prolonged cycles as reported in the literature [ 45 , 46 ], and others in low frequency were assigned to the solid electrolyte interphase (SEI) film. By contrast, two Nyquist circles in 20 Al 2 O 3 ALD NCM811 resulted from the Al 2 O 3 coating and SEI film at the surface of cycled cathode material, respectively . It is noticeable that introduction of 2 nm Al 2 O 3 coating led to acceptable resistance at 29 Ω , which was smaller than the 35 Ω caused by the secondary impure structure that formed at the surface of NCM811 without surface modification. Moreover, the 20 Al 2 O 3 ALD NCM811 resulted in considerable decrease (160 Ω ) corresponding to SEI film resistance, while the pristine NCM811 brought about larger SEI r esistance (250 Ω ). Electrochemical performance demonstrated significant effects of the optimized Al 2 O 3 ALD coating on reducing electrochemical polarity and improving r eversibility of Ni-rich cathode materials for superior lithium ion batteries. Coatings 2019 , 9 FOR PEER REVIEW 9 prolonged cycles as reported in the literature [45 ,46], and others in low frequency were assigned to the solid electrolyte interphase (SEI) film. By contrast, two Nyquist c ircles in 20 Al 2 O 3 ALD NCM811 resulted from the Al 2 O 3 coating and SEI film at the sur face of cycled cathode material, respectively. It is noticeable that introduction of 2 nm Al 2 O 3 coating led to acceptable resistance at 29 Ω, which was smaller than the 35 Ω c aused by the secondary impure structure that formed at the surface of NCM811 without surface modification . Moreover, the 20 A l 2 O 3 ALD NCM811 result ed in con siderable decrease (160 Ω) corresponding to SEI fil m resistance, while the pristine NCM811 brought about larger SEI resistance (250 Ω) . Electrochemical performance demonstrated significant effects of the optimized Al 2 O 3 ALD coating on reducing electrochemical polarity and improving reversi bility of Ni-rich cathode materials for superi or lithium ion batteries. Figure 4 Electrochemical performance of different cathode materials in a broad voltage range of 2.7– 4.6 V vs. Li + /Li: ( a ) cycling performance at 0.1 C for 100 cycles; ( b ) charge/discharge curves of bare NCM811 and 20 Al 2 O 3 ALD NCM811 in the first and 100th cycles at 0.1 C; ( c ) d Q /d V profiles of bare NCM811 and 20 Al 2 O 3 ALD NCM811 in the first and 100th cycles; and ( d ) EIS spectra captured on fresh cells (solid patterns) at open circuit voltage states and after 100 cycles at fully-discharged states (hollow patterns). 4. Conclusions Enhanced cycling stability of Ni-rich LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathode material in an extended voltage range has been reali zed by surface modification of ultrathin Al 2 O 3 coating through atomic layer deposition. The o xide ALD growth leads to impressive conformality and uniformity of resultant Al 2 O 3 layer, and the coating thickness can be precisely controlled at 1.12 Å per ALD cycle. The optimal thickness of the Al 2 O 3 coating for LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathode material is in 2 nm level through performing 20 ALD cycles. Ei ther the thicker or thinner coating thi ckness leads to decreased lithium storage capacity together with inferior cycling performance of different Al 2 O 3 coated LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathodes. The optimized 20 Al 2 O 3 ALD modified LiNi 0.8 Co 0.1 Mn 0. 1 O 2 cathode material di stinctly shows increased discharge capacity a nd columbic efficiency in the first cycle, as well as improved capacity retention after successive 100 cycles in comparison with the pristine Figure 4. Electrochemical performance of different cathode materials in a broad voltage range of 2.7–4.6 V vs. Li + /Li: ( a ) cycling performance at 0.1 C for 100 cycles; ( b ) charge/discharge curves of bare NCM811 and 20 Al 2 O 3 ALD NCM811 in the first and 100th cycles at 0.1 C; ( c ) d Q /d V profiles of bare NCM811 and 20 Al 2 O 3 ALD NCM811 in the first and 100th cycles; and ( d ) EIS spectra captured on fresh cells (solid patterns) at open circuit voltage states and after 100 cycles at fully-discharged states (hollow patterns). 4. Conclusions Enhanced cycling stability of Ni-rich LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathode material in an extended voltage range has been realized by surface modification of ultrathin Al 2 O 3 coating through atomic layer deposition. The oxide ALD growth leads to impressive conformality and uniformity of resultant Al 2 O 3 layer, and the coating thickness can be pr ecisely controlled at 1.12 Å per ALD cycle. The optimal thickness of the Al 2 O 3 coating for LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathode material is in 2 nm level through performing 20 ALD cycles. Either the thicker or thinner coating thickness leads to decreased lithium storage capacity together with inferior cycling performance of different Al 2 O 3 Coatings 2019 , 9 , 92 10 of 12 coated LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathodes. The optimized 20 Al 2 O 3 ALD modified LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathode material distinctly shows increased discharge capacity and columbic efficiency in the first cycle, as well as improved capacity retention after successive 100 cycles in comparison with the pristine material. Electrochemical features in the first and 100th cycle of cathode materials, with and without Al 2 O 3 protection were compared, involving charge/dischar ge curves, differential capacity profiles, and electrochemical impedance spectra. The Al 2 O 3 coating has been demonstrated to suppress parasitic side reactions and phase transitions during prolonged lithiation/delithiation of the LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathode, resulting in reduced electrochemical polarity and enhanced cycling stability for Ni-rich cathode materials cycled in broad voltage ranges. Author Contributions: Conceptualization, J.Z.; Methodology, W .Z., T.L., Z.X., and X.H.; Software, L.B.; Data Curation, W .Z., X.H., L.B., and K.T.; W riting—Original Draft Preparation, W .Z.; Writing—Review and Editing, Y .W., H.W ., J.Z., and L.G.; Project Administration, L.G. and J.Z.; Funding Acquisition, L.G. and J.Z. Funding: This research was funded by the National Natural Science Foundation of China (Nos. 21703147 and U1401248); the Jiangsu Provincial Natural Science Foundations for the Y oung Scientist (No. BK20170338); the General Financial Grant from the China Postdoctoral Science Foundation (No. 2016M601876); and the Open Fund of Jiangsu Key Laboratory of Materials and T echnology for Energy Conversion (No. MTEC-2017M01). Acknowledgments: The authors acknowledge Suzhou Key Laboratory for the Advanced Carbon Materials and W earable Energy Technologies, Suzhou 215006, China. Conflicts of Interest: The authors declare no conflicts of interest. References 1. Poizot, P .; Laruelle, S.; Grugeon, S.; Grugeon, L.; T arascon, J.M. Nano-sized transition-metal oxides as negative-electrode materials for Lithium-ion batteries. Nature 2000 , 407 , 496–499. [ CrossRef ] 2. Mizushima, K.; Jones, P .C.; Wiseman, P .J.; Goodenough, J.B. Li x CoO 2 (0 < x < − 1): A new cathode material for batteries of high energy density . Mater. Res. Bull. 1980 , 15 , 783–789. [ CrossRef ] 3. Thackeray , M.M.; Wolverton, C.; Isaacs, E.D. Electrical ener gy storage for transportation-approaching the limits of, and going beyond, Lithium-ion batteries. Energy Environ. Sci. 2012 , 5 , 7854–7863. [ CrossRef ] 4. T ang, Y.; Deng, J.; Li, W .; Malyi, O.I.; Zhang, Y .; Zhou, X.; Pan, S.; W ei, J.; Cai, Y.; Chen, Z. W ater-soluble sericin protein enabling stable solid-electrolyte interphase for fast charging high voltage battery electrode. Adv. Mater . 2017 , 29 , 1701828. [ CrossRef ] 5. T ang, Y.; Zhang, Y .; Malyi, O.I.; Bucher, N.; Xia, H.; Xi, S.; Zhu, Z.; Lv, Z.; Li, W .; Wei, J. Identifying the origin and contribution of surface storage in TiO 2 (B) nanotube electrode by in situ dynamic valence state monitoring. Adv. Mater . 2018 , 36 , 1802200. [ CrossRef ] 6. Zhang, Y .; Malyi, O.I.; Tang, Y .; Wei, J.; Zhu, Z.; Xia, H.; Li, W .; Guo, J.; Zhou, X.; Chen, Z. Reducing the charge carrier transport barrier in functionally layer-graded electrodes. Angew. Chem. 2017 , 56 , 14847. [ CrossRef ] 7. Yi, R.; Dai, F.; Gordin, M.L.; Chen, S.; Wang, D. Lithium-ion batteries: micro-sized Si–C composite with interconnected nanoscale building blocks as high-performance anodes for practical application in Lithium-ion batteries. Adv. Energy Mater. 2013 , 3 , 273. [ CrossRef ] 8. Fergus, J.W . Recent developments in cathode materials for Lithium ion batteries. J. Power Sources 2010 , 195 , 939–954. [ CrossRef ] 9. Lee, J.; Kitchaev, D.A.; Kwon, D.H.; Lee, C.W .; Papp, J.K.; Liu, Y .S.; Lun, Z.; Cl é ment, R.J.; Shi, T.; Mccloskey , B.D. Reversible Mn 2+/ Mn 4+ double redox in Lithium-excess cathode materials. Nature 2018 , 556 , 185–190. [ CrossRef ] 10. Jiang, K.C.; Wu, X.L.; Yin, Y .X.; Lee, J.S.; Kim, J.; Guo, Y.G. Superior hybrid cathode material containing Lithium-excess layered material and graphene for Lithium-ion Batteries. ACS Appl. Mater . Interfaces 2012 , 4 , 4858–4863. [ CrossRef ] 11. Zhao, J.; Zhang, W .; Huq, A.; Misture, S.T.; Zhang, B.; Guo, S.; W u, L.; Zhu, Y .; Chen, Z.; Amine, K. In situ probing and synthetic control of cationic ordering in Ni-Rich layered oxide cathodes. Adv. Energy Mater. 2017 , 7 , 1601266. [ CrossRef ] 12. Zhao, J.; Aziz, S.; Wang, Y . Hierarchical functional layers on high-capacity Lithium-excess cathodes for superior Lithium ion batteries. J. Power Sources 2014 , 247 , 95–104. [ CrossRef ] Zhao, J.; Huang, R.; Gao, W .; Zuo, J.M.; Zhang, X.F.; Misture, S.T .; Chen, Y.; Lockard, J.V .; Zhang, B.; Guo, S. An Ion-exchange promoted phase transition in a Li-excess layered cathode material for high-performance Lithium ion batteries. Adv. Energy Mater. 2015 , 5 , 1401937. [ CrossRef ] 14. Martha, S.K.; Sclar, H.; Framowitz, Z.S.; Kovacheva, D.; Saliyski, N.; Gofer, Y .; Sharon, P .; Golik, E.; Markovsky , B.; Aurbach, D. A comparative study of electrodes comprising nanometric and submicron particles of LiNi 0.5 Mn 0.5 O 2 , LiNi 0.33 Mn 0.33 Co 0.33 O 2 , and LiNi 0.4 Mn 0.4 Co 0.2 O 2 layered compounds. J. Power Sources 2009 , 189 , 248–255. [ CrossRef ] 15. Li, X.; Cheng, F .; Guo, B.; Chen, J. Template-synthesized LiCoO 2 , LiMn 2 O 4 , and LiNi 0.8 Co 0.2 O 2 nanotubes as Liu, W .; Oh, P .; Liu, X.; Lee, M.J.; Cho, W.; Chae, S.; Kim, Y .; Cho, J. Nickel-rich layered Lithium transition-metal oxide for high-energy Lithium-ion batteries. Angew. Chem. 2015 , 54 , 4440–4457. [ CrossRef ] 17. Zhong, S.; Lai, M.; Yao, W .; Li, Z. Synthesis and electrochemical properties of LiNi 0.8 Co x Mn 0.2 − x O 2 positive-electrode material for Lithium-ion batteries. Electrochim. Acta 2016 , 212 , 343–351. [ CrossRef ] 18. Zou, Y .; Yang, X.; Lv , C.; Liu, T.; Xia, Y .; Shang, L.; Waterhouse, G.I.; Y ang, D.; Zhang, T. Multishelled Ni-Rich Li(Ni x Co y Mn z particles coated by Al 2 O 3 using atomic layer deposition for Lithium-ion batteries. J. Power Sources 2015 , 274 , 1254–1262. [ CrossRef ] 32. Guan, D.; W ang, Y. Ultrathin surface coatings to enhance cycling stability of LiMn 2 O 4 cathode in Lithium-ion batteries. Ionics 2013 , 19 , 1–8. [ CrossRef ] 33. Mohanty , D.; Dahlberg, K.; King, D.M.; David, L.A.; Sefat, A.S.; W ood, D.L.; Daniel, C.; Dhar, S.; Mahajan, V .; Lee, M. Modification of Ni-rich FCG NMC and NCA cathodes by atomic layer deposition: preventing surface phase transitions for high-voltage Lithium-ion batteries. Sci. Rep. 2016 , 6 , 26532. [ CrossRef ] Coatings 2019 , 9 , 92 12 of 12 34. O 3 coatings for improved cycling performance and thermal stability of LiNi 0.5 Co 0.2 Mn 0.3 O 2 cathode material. Electrochim. Acta 2016 , 203 , 154–161. [ CrossRef ] 35. Zhang, X.; Belharouak, I.; Li, L.; Lei, Y .; Elam, J.W .; Nie, A.; Chen, X.; Yassar , R.S.; Axelbaum, R.L. Structural and electrochemical study of Al 2 O 3 and TiO 2 Coated Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 Adv. Energy Mater . 2013 , 3 , 1299–1307. [ CrossRef ] 36. Zhao, J.; W ang, Y. Atomic layer deposition of epitaxial ZrO 2 coating on LiMn 2 O 4 nanoparticles for high-rate lithium ion batteries at elevated temperature. Nano Energy 2013 , 2 , 882–889. [ CrossRef ] 37. Aziz, S.; Zhao, J.; Cain, C.; W ang, Y. Nanoar chitectured LiMn 2 O 4 /Graphene/ZnO composites as electrodes for Lithium ion batteries. J. Mater. Sci. T echnol. 2014 , 30 , 427–433. [ CrossRef ] 38. Zhao, J.; W ang, Y. Surface modifications of Li-ion battery electr odes with various ultrathin amphoteric oxide coatings for enhanced cycleability . J. Solid State Electrochem. 2013 , 17 , 1049–1058. [ CrossRef ] 39. Zhao, J.; Ying, W . Ultrathin surface coatings for improved electrochemical performance of Lithium ion 40. Zhao, J.; W ang, Y. High-capacity full Lithium-ion cells based on nanoar chitectured ternary manganese-nickel- cobalt carbonate and its lithiated derivative. J. Mater. Chem. A 2014 , 2 , 14947–14956. [ CrossRef ] 41. Aykol, M.; Kirklin, S.; W olverton, C. Thermodynamic aspects of cathode coatings for Lithium-ion batteries. Adv. Energy Mater . 2015 , 4 , 1400690. [ CrossRef ] 42. Zhao, F .; Tang, Y .; Wang, J.; T ian, J.; Ge, H.; Wang, B. V apor-assisted synthesis of Al 2 O 3 -coated LiCoO 2 for high-voltage lithium ion batteries. Electrochim. Acta 2015 , 174 , 384–390. [ CrossRef ] 43. Araki, K.; Taguchi, N.; Sakaebe, H.; Tatsumi, K.; Ogumi, Z. Electrochemical pr operties of LiNi 1/3 Co 1/3 Mn 1/3 cathode material modified by coating with Al 2 O 3 nanoparticles. J. Power Sources 2014 , 269 , 236–243. [ CrossRef ] 44. Kalluri, S.; Yoon, M.; Jo, M.; Liu, H.K.; Dou, S.X.; Cho, J.; Guo, Z. Feasibility of cathode surface coating technology for high-energy Lithium-ion and beyond-Lithium-ion batteries. Adv. Mater . 2017 , 29 , 1605807. 45. Liu, S.; Xiong, L.; He, C. Long cycle life lithium ion battery with lithium nickel cobalt manganese oxide (NCM) cathode. J. Power Sources 2014 , 261 , 285–291. [ CrossRef ] 46. Jung, S.K.; Gwon, H.; Hong, J.; Park, K.Y .; Seo, D.H.; Kim, H.; Hyun, J.; Yang, W .; Kang, K. Understanding the degradation mechanisms of LiNi 0.5 Co 0.2 Mn 0.3 O 2 cathode material in Lithium ion batteries. Adv. Energy Mater . 2014 , 4 , 1300787. [ CrossRef ] ... Al2O3 is an attractive material due to its excellent dielectric properties, good adhesion to many surfaces, and thermal and chemical stability [13][14][15]. Al2O3 ultra-thin films have many potential applications in diverse areas such as the passivation of electrical contacts, as a protective layer against corrosion by oxygen, and as a gas diffusion layer in polymers, among others [16][17] [18] [19][20][21][22][23][24][25][26][27]. ... ... Al 2 O 3 is an attractive material due to its excellent dielectric properties, good adhesion to many surfaces, and thermal and chemical stability [13][14][15]. Al 2 O 3 ultra-thin films have many potential applications in diverse areas such as the passivation of electrical contacts, as a protective layer against corrosion by oxygen, and as a gas diffusion layer in polymers, among others [16][17] [18] [19][20][21][22][23][24][25][26][27]. ... Al2O3 Ultra-Thin Films Deposited by PEALD for Rubidium Optically Pumped Atomic Magnetometers with On-Chip Photodiode Article Full-text available Florival M. Cunha Manuel F. Silva Nuno M. Gomes José H. Correia This communication shows the recipe for plasma-enhanced atomic layer deposition (PEALD) Al2O3 ultra-thin films with thicknesses below 40 nm. Al2O3 ultra-thin films were deposited by PEALD to improve the rubidium optically pumped atomic magnetometers’ (OPMs) cell lifetime. This requirement is due to the consumption of the alkali metal (rubidium) inside the vapor cells. Moreover, as a silicon wafer was used, an on-chip photodiode was already integrated into the fabrication of the OPM. The ALD parameters were achieved with a GPC close to 1.2 Å/cycle and the ALD window threshold at 250 °C. The PEALD Al2O3 ultra-thin films showed a refractive index of 1.55 at 795 nm (tuned to the D1 transition of rubidium for spin-polarization of the atoms). The EDS chemical elemental analysis showed an atomic percentage of 58.65% for oxygen (O) and 41.35% for aluminum (Al), with a mass percentage of 45.69% for O and 54.31% for Al. A sensitive XPS surface elemental composition confirmed the formation of the PEALD Al2O3 ultra-thin film with an Al 2s peak at 119.2 eV, Al 2p peak at 74.4 eV, and was oxygen rich. The SEM analysis presented a non-uniformity of around 3%. Finally, the rubidium consumption in the coated OPM was monitored. Therefore, PEALD Al2O3 ultra-thin films were deposited while controlling their optical refractive index, crystalline properties, void fraction, surface roughness and thickness uniformity (on OPM volume 1 mm × 1 mm × 0.180 mm cavity etched by RIE), as well as the chemical composition for improving the rubidium OPM lifetime. ... The survey spectrum (Figure 2a) clearly indicates similar binding energies for all species in both samples, which indicating that the chemical states of the transition metal elements in the layered NCM811 structure did not change upon coating with Ag. The Ni 2p spectrum ( Figure 2b) shows that the Ni 2p 3/2 peak appearing at BE of 855.16 eV for pristine NCM811 is slightly shifted towards higher binding energy (855.55 eV) for Ag-NCM811, which can be attributed to a decreased Ni 2+ /Ni 3+ ratio [34] . This result reveals that more Ni 3+ ions appear on the Ag-NCM811 electrode surface than in pristine NCM811. ... Silver Nanocoating of LiNi0.8Co0.1Mn0.1O2 Cathode Material for Lithium-Ion Batteries Article Xintong Li Kai Chang Somia Abbas Christian M. Julien Surface coating has become an effective approach to improve the electrochemical performance of Ni-rich cathode materials. In this study, we investigated the nature of an Ag coating layer and its effect on electrochemical properties of the LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode material, which was synthesized using 3 mol.% of silver nanoparticles by a facile, cost-effective, scalable and convenient method. We conducted structural analyses using X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy, which revealed that the Ag nanoparticle coating did not affect the layered structure of NCM811. The Ag-coated sample had less cation mixing compared to the pristine NMC811, which could be attributed to the surface protection of Ag coating from air contamination. The Ag-coated NCM811 exhibited better kinetics than the pristine one, which is attributed to the higher electronic conductivity and better layered structure provided by the Ag nanoparticle coating. The Ag-coated NCM811 delivered a discharge capacity of 185 mAh·g−1 at the first cycle and 120 mAh·g−1 at the 100th cycle, respectively, which is better than the pristine NMC811. ... Surface modification is an effective approach to improve the electrochemical performance and overcome the limitations of NCM electrode materials [13,[18][19][20]. Thus far, metal oxides, fluorides, phosphates, and other coatings, such as MgO [21], ZrO 2 [16], SiO 2 [22], Al 2 O 3 [23, 24] , Nd 2 O 3 [25], LaFeO 3 [26], LiNbO 3 [27], LiAlO 2 [28], LBO (Li 2 O-2B 2 O 3 ) [16], Li 2 TiO 3 [29], Li 2 ZrO 3 [30], Li 2 WO 4 /WO 3 [12], Li 3 VO 4 [31], Li 4 Ti 5 O 12 [32], LiF [33], CaF 2 [34], FePO 4 [11], Li 3 PO 4 [35], polysiloxane [36], polyaniline [37], and dual coatings such as Li 3 PO 4 with polypyrrole (PPy) [38] have been applied to the surface of NCM811 to improve its electrochemical performance. Surface modification of bulk materials can segregate the bulk materials from the electrolyte, thus protecting the material surface from being attacked by the electrolyte during (de)lithiation [16]. ... Artificial Interface Modification of Ni-rich Ternary Cathode Material to Enhance Electrochemical Performance for Li-ion Storage through RF-Plasma-assisted Technique Article Mar 2023 CHEM ENG J Rasu Muruganantham Tzu-Hsin Tseng Meng-Lun Lee Wei-Ren Liu Ni-rich LiNi0.8Co0.1Mn0.1O2 (NCM811) is a promising high-performance cathode material for large-scale Li-ion storage applications. However, devices consisting of Ni-rich materials are less thermally stable, and several factors hinder their use in practical high-energy-density applications. Herein, an approach for plasma-modified NCM811 with TiN is proposed to effectively improve the electrochemical performance and stabilize the cathode–electrolyte interface reaction. In addition, the following aspects are systematically investigated using different techniques: (i) physicochemical properties; (ii) Li storage performance, particularly, cyclic/rate capacity, kinetic behavior of the lithium-ion diffusivities, and electrical conductivity; and (iii) key factor for improving the electrochemical performance through ex-situ/in-situ investigations. The NCM811- TiN/graphite pouch cell displays a high reversible capacity of 17.5 mAh and sustains over 200 cycles at 1 C. Comprehensive characterization and probes indicate that the TiN interface with the NCM electrode enhances thermal stability, cyclic capacity, and rate stability without changing the bulk structure and morphology. Hence, these findings facilitate the practical use of safe and high- energy-density Li-ion batteries. ... When the content of Ni reaches to 80%, the capacity fading during cycling becomes more severe. Many researches have also reported that Al2O3 coatings on high Ni-content cathode materials can improve the capacity retention by suppressing phase transition and hydrofluoric acid-induced transition metal dissolution [130, 131, 132,133]. With the higher electrical conductivity than metal oxide, ultra-thin TiN layer was coated on LiNi0.8Co0.1Mn0.1O2 ... Atomic-scale engineering of advanced catalytic and energy materials via atomic layer deposition for eco-friendly vehicles Article Full-text available Mar 2023 Xiao Liu Yu Su Rong Chen Highlights Recent process of atomic layer deposition on catalytic and energy materials is summarized. The enhanced catalytic and electrochemical performances are presented. Atomic layer deposition reactors for mass production are highlighted. The challenges on future applications of atomic layer deposition are discussed. View ... Nano-particle coatings are effective in improving structural stability and cycling performance of micron-sized CAM particles. Different coating materials like Al 2 O 3 [91,117, 118] , LiAlO 2 [119], CeO 2 [120], ZnO [121], ZrO 2 [121] have been coated on the surface of CAM particles through the sol-gel [119], dry mechanofusion (figure 10(b)) [122], and ALD [123,124] techniques. ALD has advantages over other coating methods in terms of regulating film thickness in the Angstrom range, allowing a uniform coating and good conformality [124]. ...
https://www.researchgate.net/publication/330896173_Ultrathin_Al2O3_Coating_on_LiNi08Co01Mn01O2_Cathode_Material_for_Enhanced_Cycleability_at_Extended_Voltage_Ranges
Life | Free Full-Text | L-DOPA and Droxidopa: From Force Field Development to Molecular Docking into Human & beta;2-Adrenergic Receptor The increasing interest in the molecular mechanism of the binding of different agonists and antagonists to β2-adrenergic receptor (β2AR) inactive and active states has led us to investigate protein–ligand interactions using molecular docking calculations. To perform this study, the 3.2 Å X-ray crystal structure of the active conformation of human β2AR in the complex with the endogenous agonist adrenaline has been used as a template for investigating the binding of two exogenous catecholamines to this adrenergic receptor. Here, we show the derivation of L-DOPA and Droxidopa OPLS all atom (AA) force field (FF) parameters via quantum mechanical (QM) calculations, molecular dynamics (MD) simulations in aqueous solutions of the two catecholamines and the molecular docking of both ligands into rigid and flexible β2AR models. We observe that both ligands share with adrenaline similar experimentally observed binding anchor sites, which are constituted by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Moreover, both L-DOPA and Droxidopa molecules exhibit binding affinities comparable to that predicted for adrenaline, which is in good agreement with previous experimental and computational results. L-DOPA and Droxidopa OPLS AA FFs have also been tested by performing MD simulations of these ligands docked into β2AR proteins embedded in lipid membranes. Both hydrogen bonds and hydrophobic interaction networks observed over the 1 μs MD simulation are comparable with those derived from molecular docking calculations and MD simulations performed with the CHARMM FF. L-DOPA and Droxidopa: From Force Field Development to Molecular Docking into Human β 2 -Adrenergic Receptor by Andrea Catte *,†,§ , Akash Deep Biswas ‡,§ , Giordano Mancini and Vincenzo Barone * Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126 Pisa, Italy Authors to whom correspondence should be addressed. ‡ Current address: Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy. These authors contributed equally to this work. Life 2022 , 12 (9), 1393; https://doi.org/10.3390/life12091393 Received: 29 June 2022 / Revised: 10 August 2022 / Accepted: 1 September 2022 / Published: 6 September 2022 (This article belongs to the Special Issue Advances in G Protein-Coupled Receptors Biophysical and Medicinal Chemistry ) Abstract : The increasing interest in the molecular mechanism of the binding of different agonists and antagonists to β 2 -adrenergic receptor ( β 2 AR) inactive and active states has led us to investigate protein–ligand interactions using molecular docking calculations. To perform this study, the 3.2 Å X-ray crystal structure of the active conformation of human AR in the complex with the endogenous agonist adrenaline has been used as a template for investigating the binding of two exogenous catecholamines to this adrenergic receptor. Here, we show the derivation of L-DOPA and Droxidopa OPLS all atom (AA) force field (FF) parameters via quantum mechanical (QM) calculations, molecular dynamics (MD) simulations in aqueous solutions of the two catecholamines and the molecular docking of both ligands into rigid and flexible β 2 AR models. We observe that both ligands share with adrenaline similar experimentally observed binding anchor sites, which are constituted by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Moreover, both L-DOPA and Droxidopa molecules exhibit binding affinities comparable to that predicted for adrenaline, which is in good agreement with previous experimental and computational results. L-DOPA and Droxidopa OPLS AA FFs have also been tested by performing MD simulations of these ligands docked into β 2 AR proteins embedded in lipid membranes. Both hydrogen bonds and hydrophobic interaction networks observed over the 1 μ s MD simulation are comparable with those derived from molecular docking calculations and MD simulations performed with the CHARMM FF. Keywords: catecholamines ; drugs ; adrenergic receptors ; L-DOPA ; Droxidopa ; force field parameterization ; quantum mechanical calculations ; molecular docking ; molecular dynamics simulations 1. Introduction The Guanine Nucleotide-Binding Protein Coupled Receptors (GPCRs) form the largest family of human trans-membrane proteins and take part in a wide range of critical biological functions including sight, sensation and neurological transmission [ 1 , 2 , 3 ]. There are several activities of the GPCRs in the body, including cognitive responses [ 4 ], cardiovascular functions [ 5 ] and the growth and development of cancer [ 6 ]. Thirty-five percent of all commercially available drugs in the United States and throughout the world target GPCRs because of their relevance in many human disorders [ 7 , 8 , 9 ]. In all GPCRs there are seven transmembrane α helices (TM-I-TM- VII), which are linked by extracellular (ECL1-ECL3) and intracellular (ICL1-ICL3) loops [ 10 , 11 ]. In addition to hormones and therapeutics, a large variety of other extracellular molecules can act as agonists or antagonist on GPCRs, with the former often causing conformational changes in proteins associated with specific activities [ 12 ]. Furthermore, GPCRs are being viewed as the allosteric machinery that can be triggered by ions, lipids, cholesterol and water [ 13 , 14 ]. Moreover, due to technological breakthroughs in crystallization technologies during the last two decades, new X-ray crystal structures of GPCRs are being reported with an exponential rate [ 3 , 15 ]. In addition, over 150 GPCR X-ray structures published in the www.rcsb.org Protein Data Bank (accessed on 5 January 2020) are in complex with ligands [ 16 ]. At the same time, homology models of GPCRs have provided a molecular representation of more than 10% of the GPCR super-family. Structure-based drug discovery (SBDD) relies on understanding receptor-drug interactions at the atomic level, so molecular docking and molecular dynamics simulations have become widespread tools for drug design, measuring binding affinity, revealing reaction mechanisms and protein-ligand interactions, in addition to understand the GPCR structure and dynamics [ 17 , 18 , 19 , 20 , 21 , 22 ]. To activate the class A GPCR β 2 -adrenergic receptor (ADRB2 or β 2 AR), which is found in pulmonary and cardiac myocyte tissues, hormones, such as adrenaline and noradrenaline together with the neurotransmitter dopamine, are required. There has been some progress in understanding the inactive state of adrenergic receptors thanks to the identification of the first high resolution X-ray crystal structures of β 2 AR bound to inverse agonist (-)-carazozol (PDB ID: 2RH1) [ 23 , 24 ] and antagonist (-)-timolol (PDB ID: 3D4S) [ 25 ]. In addition, β 2 AR stabilized with a nanobody and a nucleotide-free Gs protein heterotrimer has its first agonist-bound active-state X-ray crystal structure determined [ 26 , 27 ]. Moreover, the 2 AR X-ray crystal structure, released in 2013 (PDB ID: 4LDO) [ 28 ], has served as a structural template for the investigation of the binding conformations and affinity of several endogenous agonists and antagonists. Studies using fluorescence spectroscopy have shown that catecholamines, including adrenaline, noradrenaline and dopamine may modify the 2 AR’s conformation, leading to the formation of distinct adrenergic receptor intermediate states [ 29 , 30 , 31 , 32 ]. There have been more recent confirmations of the β 2 AR’s structural heterogeneity by NMR spectroscopy, which reveals that it may exist in three different states: active, intermediate and inactive [ 33 ]. Human β 2 AR structures in association with 1365 ligands, 75 of which are drugs, may be found in the biggest database of GPCR structures and mutations ( www.gpcrdb.org (accessed on 20 December 2019)) [ 7 ]. Among the drugs that interact with β 2 AR is droxidopa (L-DOPS), which is an L-serine with a 3,4-dihydroxyphenyl group replaced at the beta position [ 34 ]. The amino acid levodopa (L-DOPA) is structurally identical to L-DOPS and a cathecolamine L-tyrosine derivative, which is an intermediate product of the biosynthesis of dopamine [ 35 ]. Since the symptoms of Parkinson’s disease (PD) are related to a progressive reduction of dopamine levels in the brain, dopamine and drugs able to safely cross the blood–brain barrier have been used to increase the dopaminergic function in patients with PD. Due to the inability of dopamine to cross the blood–brain barrier, L-DOPA in combination with carbidopa, which is an inhibitor of extracerebral dopa decarboxylase (IEDD), has also been employed in the treatment of PD [ 35 ]. Recently, PD and neurogenic orthostatic hypotension have been both treated with droxidopa, a noradrenaline precursor, which has been authorized in Japan and is now being tested in Europe, the United States, Australia and Canada. More recently, prodrugs of L-DOPA and carbidopa, namely levodopa-4 ′ -phosphate (foslevodopa) and carbidopa-4’-phosphate (foscarbidopa), have been employed in successful clinical trials on patients with advanced PD in the United States [ 36 , 37 ] and are going to be tested in the United States and Australia [ 38 ]. Here, we report the results of the force field (FF) development of L-DOPA and Droxidopa molecules, and their MD simulations in water. All FF parameters were obtained through high-level QM calculations, according to the procedure implemented in the JOYCE program [ 39 ]. All MD simulations were performed using an FF parameterized ad hoc for each solute of interest to increase the accuracy of the conformational sampling. In addition, we show the results of the molecular dockings of these exogenous catecholamines into the human 2 AR X-ray crystal structure released by Ring et al., in 2013 (PDB ID: 4LDO) and their comparison with observations from the full agonist adrenaline. Each wholly flexible ligand was docked into the 2 AR binding pocket following two different approaches: (1) a rigid receptor model derived from the PDB coordinates of the 2 AR X-ray crystal structure (PDB ID: 4LDO), and (2) a 2 AR receptor with flexible side chains of key amino acids in its binding site. Both approaches show and confirm that the pocket conformation is compatible with the binding of adrenaline, suggesting that a similar binding mode can be predicted for L-DOPA and Droxidopa. The characteristic network of hydrogen bonds of catecholamines is also preserved, showing the equal importance of 2 AR amino acids interacting with head (Ser203/Ser204/Ser207) and tail (Asp113/Asn312) moieties of every analyzed ligand. However, other β 2 AR residues, such as Thr118 and Tyr316, also play a remarkable role in the binding of L-DOPA and Droxidopa. Moreover, the binding affinities calculated from the molecular docking of adrenaline are in good agreement with experimental values, allowing a more reliable comparison of this property estimated for L-DOPA and Droxidopa non-natural ligands. The findings of this article are presented in the following sections starting from the development and validation of a new FF for L-DOPA and Droxidopa, and then proceeding to a discussion of the molecular docking results. 2. Materials and Methods 2.1. Force Field Development Protocol The FF parameter set of adrenaline, L-DOPA and Droxidopa ligands were obtained by fitting energies, gradients and Hessian to the results of Electronic Structure calculations, as described in the Joyce/Ulysses procedure [ 39 , 40 ]. Electronic structure calculations were carried out with the Gaussian16 suite of programs [ 41 , 42 ], using Density-Functional Theory (DFT) [ 43 ] with the hybrid Becke3LYP functional (B3LYP) [ 44 ] in conjunction with the jul–cc-pVDZ basis set [ 45 ], taking into account solvent effects by means of the Conductor-like Polarizable Continuum Model (C-PCM) [ 46 , 47 ] and setting water as a reference solvent ( Figure S1 ). The CM5 method based on Hirschfeld partitioning [ 48 ] was used to determine atomic charges in view of its near invariance for different quantum chemical models, remarkable reproduction of molecular dipole moments consistence with the latest revisions of the OPLS all atom (AA) force field [ 49 , 50 , 51 , 52 ] used for dispersion–repulsion interactions ( Tables S1 and S2 ). Dihedral angles were assigned using GaussView version 6 [ 53 ]. Fitting of QM torsional profiles by linear combinations of cosine functions ( Figure 1 ), were performed with Grace version 5.1.25 (Paul J. Turner, Portland, OR, USA). Dihedral angles γ and θ of adrenaline, γ of L-DOPA and η of Droxidopa were refined manually after the initial estimate. Molecular dynamics (MD) simulations of protonated adrenaline, zwitterionic L-DOPA and Droxidopa in water were performed using Gromacs [ 54 , 55 , 56 ]. The SPC model [ 57 ] was used to describe water molecule (adrenaline or L-DOPA or Droxidopa) interactions. All the systems were simulated in the NVT ensemble with periodic boundary conditions, with an integration time step of 2 fs. The temperature was kept constant at 300 K with velocity-rescaling temperature coupling [ 58 ]. The LINCS algorithm was used to constrain all bonds [ 59 ]. The Particle Mesh Ewald (PME) method was used to compute long-range electrostatic interactions with grid search and a cut-off radius of 1.1 nm [ 60 ]. For each molecule, 20 ns NVT MD simulations in vacuum were performed using JOYCE-derived topology. Then, MD simulation production runs of adrenaline, L-DOPA and Droxidopa in SPC water were performed for 100 ns at 300 K. The analysis of MD simulations was performed with Gromacs analytical tools (gmx angle, gmx distance etc.). Then, 20 ns structures of each ligand simulated in water were used as starting conformations for the molecular docking into rigid and flexible β 2 AR models. 2.2. β 2 AR Molecular Modeling The atomistic model of the TMD of human β 2 AR was built up from the X-ray crystal structure of the protein active state conformation (PDB ID: 4LDO) [ 28 ]. Amino acid residues 1–28 and 343–413, which are not present in the X-ray structure, were not included following an approach similar to the one employed by Rosenbaum et al., 2011 [ 61 ]. The ICL3 domain intracellular residues 232–262, which were not employed by Rosenbaum et al., in 2011 and modeled by Dror et al., 2009 [ 61 , 62 ], were taken from a β 2 AR homology model built up using 2RH1 as a template and reported in the Sali Laboratory ModBase database of comparative protein structure ( Figure 2 ) [ 63 ]. 2RH1 is an excellent template structure for β 2 AR due to its high sequence identity (90%) and a good RMSD of C α s of residues 29–231 and 263–342 (2.5 Å) with respect to 4LDO. T4 lysozyme (T4L) and Nanobody 6B9 (Nb6B9) amino acids were removed, and N- and C- termini were made neutral using acetyl and methylamino groups, as reported in previous studies [ 61 , 62 , 64 , 65 ]. Water molecules and adrenaline ligands were not included in the AA model. The sequence of human β 2 AR ( https://www.uniprot.org/uniprot/P07550 (accessed on 20 December 2019)) was also reproduced by mutating the four engineered mutations (Met96Thr, Met98Thr, Asn187Glu and Cys265Ala) present in the receptor’s X-ray crystal structure released by Ring et al., in 2013 to their native amino acid forms [ 28 ]. All lysines and arginines were protonated, while all aspartates, glutamates and histidines (HSD) were deprotonated except for Glu122 (GLH), Asp130 (ASH) and His172 (HSP) residues, as previously reported by Dror et al., in 2009 and 2011 [ 62 , 64 ]. Since the β 2 AR all atom structure is in its active conformation, Asp79 was deprotonated because the protonation state has been suggested to be stable upon activation [ 66 , 67 ]. The cysteine residues located in ECL2 (Cys184- Cys190) and TM-III (Cys106-Cys191) domains of the β 2 AR model were modified to form disulfide bonds by deleting hydrogens bound to SG atoms [ 68 ]. The building up of the final β 2 AR all atom structure was performed using VMD 1.9.4 and its psfgen plugin [ 69 ]. 2.3. Molecular Docking Protocol Initially, we performed an alignment of the geometry optimized structures of L-DOPA (DAH) and Droxidopa (DRO) molecules to adrenaline (ALE) in the 2 AR X-ray crystal structure (PDB ID: 4LDO), modified as described above, to produce an improved docking grid box around the receptor’s binding pocket. The 2 AR model shown in Figure 2 was used as a rigid receptor. In the flexible model of β 2 AR, protein residues of the binding pocket (Asp113, Val117, Thr118, Phe193, Thr195, Ser203, Ser204, Ser207, Asn293, His296, Asn301, Tyr308, Asn312 and Tyr316: see ref. [ 28 ]) forming polar and apolar interactions with adrenaline were considered flexible, using a similar approach to that reported by Tosso et al., 2020 in the molecular docking of dopamine to the D 2 DR receptor [ 70 ]. In the case of L-DOPA, His296 and Asn301 were excluded from the list of flexible residues because the total number of torsional degrees of freedom, including those of the ligand (6), would have exceeded the maximum number allowed by AutoDock Tools 1.5.6, the graphical user interface of AutoDock 4.2.6 (AD4) for generating consistent docking results [ 71 ]. For Droxidopa His296, Asn301 and Val117 were not included in the list of flexible amino acids because of the additional torsional degree of freedom of this ligand as compared to L-DOPA. In both receptor models, the X-, Y-, and Z-axes dimensions of the docking box grid were 50, 50 and 50, respectively, and a resolution of 0.375 Å was employed in the active site region. The grid box size was 18.75 Å, which is more than 2.9 times the radius of gyration of both L-DOPA (2.77 Å) and Droxidopa (2.91 Å) molecules, in good agreement with recommendations by Feinstein et al., in 2015 [ 72 ]. Non-polar hydrogen atoms were merged into heavy atoms and Gasteiger charges were assigned to each molecule. During each docking run, all torsion angles of flexible amino acids and ligands were free to rotate. Four-hundred poses were generated using the maximum number of generations and energy evaluation of 27,000 and 5e7, respectively, for both rigid and flexible 2 AR models, as previously reported for the molecular docking of dopamine to the D 2 DR receptor [ 70 ]. The Virtual Screening analysis of the final docked conformations was performed with the AD4 pythonsh command using a tolerance of 2 Å root mean square deviation (RMSD) for the clustering [ 73 , 74 ]. The binding free energy ( Δ G bind = − RTlnK i ) (BFE) and inhibition constants (K i ) of lowest energy structures, estimated by AD4 with the Virtual Screening method, were employed to calculate the binding affinities of each ligand [ 73 ]. Since experimental binding affinities of adrenaline and other endogenous catecholamines were measured at 310.15 K, AD4 BFEs estimated at 298.15 K were also corrected, resulting in an increase of 0.2 units for the corresponding binding affinity (pK d ) of each ligand at the physiological temperature [ 75 ]. Two sets of ligand heavy atom RMSDs were calculated using the X-ray crystal structure of adrenaline as a reference: one employed the original coordinates of the ligand and the other, defined as superimposed RMSD, involved a structural alignment of the ligand with the X-ray structure of adrenaline. Superimposed RMSDs were also calculated using the lowest energy conformations derived from rigid and flexible molecular dockings for each ligand. To validate the molecular docking protocol, adrenaline was redocked into the β 2 AR X-ray crystal structure (PDB ID: 4LDO). Two sets of redocking experiments were performed using 2 AR rigid and flexible models. From the rigid docking set, the lowest energy structures of each cluster were selected to perform ten independent runs. The consistency of the docking results was considered achieved when at least 70% of the individual runs generated conformations clustered within an RMSD of < 0.5 Å relative to the overall best energy pose of the ligand. For both protonation states of adrenaline, rigid docking runs using the same coordinates of the receptor X-ray crystal structure produced conformations (heavy atoms superimposed RMSD of 0.2 Å) and BFEs (−6.4 kcal/mol and −8.1 kcal/mol for neutral and protonated adrenaline, respectively) similar to those of the lowest energy conformations from ten independent runs [ 76 ]. The BFE of adrenaline in the X-ray crystal structure was estimated with the epdb option of AD4. In order to improve the performance of AD4 runs, the multilevel parallel version of AutoDock 4.2 was also employed to perform multiple independent runs of various ligands [ 77 ]. RMSDs of ligand heavy atoms were calculated using AutoDock Tools 1.5.7 [ 78 ]. The number of hydrogen bonds and hydrophobic interactions between a ligand and the receptor were measured using the protein–ligand interaction profiler (PLIP) [ 79 ]. Images were prepared using VMD 1.9.4, AutoDock Tools 1.5.6 and LigPlot+ version 2.2 [ 80 ]. 2.4. MD Simulations of 2 AR-Catecholamine Complexes In order to test the quality of FFs developed for the different ligands, we also performed 1 s AA MD simulations of β 2 AR-catecholamine complexes embedded in solvated lipid bilayers composed of 260 palmitoyloleoylphosphatidylcholine (POPC) and 65 cholesterol (CHOL) molecules (20% CHOL) using the OPLS AA FFs for proteins [ 52 ] and lipids [ 81 , 82 , 83 ], following an approach similar to that reported by Biswas et al., in 2021 [ 76 ]. The contact maps of β 2 AR residues with each ligand were generated with the Timeline plugin version 2.3 of VMD 1.9.4 [ 69 ]. A ligand-protein contact was counted only when at least one atom of each catecholamine was within 5 Å of any atom of the receptor. BFEs of ligands were extracted from MD simulations of β 2 AR-catecholamine complexes using Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations [ 84 ]. 3. Results 3.1. Force Field Parameterization and Md Simulations of L-Dopa and Droxidopa Following the protocol described in the methods section, the QM torsional profiles of each dihedral angle of the zwitterionic L-DOPA were accurately reproduced by the corresponding JOYCE FF functions ( Figure 3 ). It is worth noting that both QM and JOYCE torsional profiles of α , β , γ and δ dihedrals were very similar to those of zwitterionic Tyrosine reported by Del Galdo et al., in 2018 [ 85 ]. Concerning the torsions of the charged groups ( α and β dihedrals) in the zwitterionic condition, the agreement between QM and JOYCE torsional profiles was better than the already satisfactory one reported by Del Galdo et al., in 2018 for the closely related L-Tyrosine amino acid, indicating the good quality of the FF parameterization of L-DOPA [ 85 ]. Similar to L-DOPA, the QM torsional profiles of the dihedrals of zwitterionic Droxidopa were in good agreement with JOYCE FF functions ( Figure 4 ). In particular, QM and JOYCE torsional profiles of α , β , γ , δ , ϵ and η dihedrals of Droxidopa were very similar to those observed for L-DOPA ( Figure 3 ). Moreover, we also generated OPLA AA FF parameters for adrenaline, whose QM torsional profiles were accurately reproduced by the corresponding JOYCE FF parameters for all dihedral angles. QM and JOYCE torsional profiles of α , γ , δ , ϵ and η dihedrals of adrenaline were very similar to those observed for L-DOPA and Droxidopa ligands ( Figure S2 ). A complete list of the most representative bond lengths, bond angles and dihedral angles of each ligand is provided in the SI of this work ( Tables S1–S3, Figures S3–S11 ). To test the FFs of adrenaline, L-DOPA and Droxidopa, we performed MD simulations of each parameterized ligand both in vacuum and in aqueous solution. It is worth noting that all the dihedral distributions are comparable in the gas phase and in aqueous solution for both L-DOPA and Droxidopa molecules ( Figure 5 and Figure 6 ). Similar results were also observed for adrenaline ( Figure S12 ). Additionally, we also observed a good agreement between the fittings of QM torsional energy profiles subjected to the subtraction of electrostatic and Lennard–Jones contributions ( Table S4 ) and correspondent QM and JOYCE for each dihedral of adrenaline ( Figure S13 ), L-DOPA ( Figure S14 ) and Droxidopa ( Figure S15 ). The profiles of the Helmoltz free energy variation as a function of each of the dihedral angles were also similar to the corresponding QM energy for both L-DOPA and Droxidopa ( Figure 7 and Figure 8 ). Similar behavior of Helmholtz free energy variations was also found for each dihedral of adrenaline ( Figure S16 ). The Helmholtz free energy variation ( Δ A ) was computed from the MD ensemble probability distribution of the generic θ dihedral coordinate, according to the equation: Δ A ( θ ) = − k T ( ρ ( θ ) / ρ 0 ) where k is the Boltzmann constant, T is the temperature, ρ ( θ ) is the dihedral probability distribution having ρ 0 as a maximum value (missing A points in the figures imply that no sampling could be found for the corresponding geometry). Each profile obtained using as a statistical ensemble the MD simulation performed employing Joyce-derived FF parameters is also compared with the one obtained with the use of the OPLS AA FF (see Methods). The differences between QM energy and MD A profiles can be ascribed to the entropic contribution, which is only present in the free energy, as previously observed by Del Galdo et al., in 2018 for zwitterionic Tyrosine [ 85 ]. Despite these discrepancies, this comparison can be used to analyze, at least qualitatively, the accuracy of the FF for the different dihedral angles. 3.2. Validation of the 2 AR Model: Redocking of Adrenaline In our recent work, we verified the ability of the 2 AR X-ray crystal structure (PDB ID: 4LDO) to generate biologically relevant binding conformations of adrenaline by redocking the endogenous ligand into rigid and flexible receptor models, employing a similar approach to the one reported by Katritch et al., in 2009 [ 76 , 86 ]. At the physiological pH of 7.4, adrenaline is mostly present in its protonated form (94.7%); however, due to an experimental pKa of 8.52, the percentage of neutral forms is not negligible (5.3%) [ 87 ]. The effect of the protonation state of this endogenous ligand on its interaction with 2 AR has been recently investigated by performing the redocking using both species [ 76 ]. We have shown that the neutral form of adrenaline is about 2 kcal/mol less stable than its more biologically relevant protonated form. This energy difference arises from the higher number of hydrogen bonds formed by the protonated species with residues in the 2 AR binding pocket as compared to the neutral form of the ligand [ 76 ]. Hereafter, adrenaline refers to the protonated form of the endogenous catecholamine. In particular, the redocking of adrenaline into rigid and flexible 2 AR models generates conformations different from that of the ligand in the X-ray crystal structure, exhibiting ligand heavy atoms RMSDs of 2.2 Å and 2.4 Å, respectively ( Figure 9 A,B). Although ligand–receptor hydrogen bonds of the ethanolamine tail of the redocked adrenaline with the anchor site formed by amino acids Asp113/Asn312 are similar to those observed in the X-ray crystal structure, the catechol head of the molecule interacts with different residues, namely Ser203/Asn293 and Thr118/Ser207 in crystal and redocked structures, respectively ( Figure 9 A,B). These results mainly arise because there is a substantial energetic difference between the free energies of binding of redocked and crystal structure ligands. According to experiments, the BFE of adrenaline ranges from −8.3 kcal/mol to −8.9 kcal/mol, as calculated from binding affinities of adrenaline reported by Del Carmine et al., in 2004 and 2002, indicating that the structure of adrenaline from the rigid redocking is almost in its more energetically stable conformation [ 75 , 88 ]. Interestingly, rigid and flexible docking lowest energy conformations of adrenaline are also structurally similar, as shown by the ligand heavy atom RMSD of 0.6 Å (superimposed RMSD = 0.3 Å). However, the average BFE of adrenaline for the lowest energy structure from the Virtual Screening of the flexible docking is −12.5 kcal/mol, indicating that this conformation of the ligand is not only much more stable than the one obtained from the rigid docking but it also has a pK d better than the experimental values reported in the literature ( Table 1 ) [ 75 , 88 ]. 3.3. L-DOPA Binding to the 2 AR Receptor The docking of L-DOPA to a rigid 2 AR model generated 70% of the largest cluster conformations from ten independent runs showing an adrenaline-like interaction of catechol and ethanolamine moieties of the ligand with the binding pocket anchor sites Ser203/Ser204/Ser207 and Asp113/Asn312, respectively ( Figure 10 A and Table 2 ). These conformations of the catecholamine displayed a pK d of 4.7 and an average BFE of −6.4 kcal/mol, which were similar to the values we recently reported for neutral adrenaline [ 76 ]. Interestingly, we also observed that the docking of L-DOPA to a rigid model of the receptor also yielded the lowest energy conformations unable to form hydrogen bonds in an adrenaline-like fashion [ 76 ]. The molecular docking of L-DOPA into a flexible 2 AR model yielded more ligand–receptor hydrogen bonds than those observed in the lowest energy conformation of the catecholamine produced by the rigid docking ( Figure 10 B and Table 2 ). In particular, the catechol head of the ligand also formed an additional hydrogen bond with the binding site amino acid Thr118. The lowest energy conformations showed an average BFE of −12.8 kcal/mol, corresponding to a pK d of 9.4 and being comparable to that observed for the endogenous ligand adrenaline docked into a flexible 2 AR model ( Table 1 ). We have recently observed that Autodock Vina (Vina) [ 89 ] generated best conformations of L-DOPA docked into rigid and flexible β 2 AR models displaying average BFEs of −7.3 and −7.9 kcal/mol, respectively, which were different from correspondent AD4 results (−6.4 and −12.8 kcal/mol, respectively) ( Figures S17 and S18 ) [ 76 ]. In the flexible β 2 AR model, this difference in the stability of the ligand is due to the higher number of hydrogen bonds formed by the best AD4 conformation as compared to the best Vina structure ( Figure S18A,B ). However, the Vina conformation, as observed in the docking to a rigid β 2 AR model, was still structurally closer to adrenaline’s conformation in the X-ray crystal structure than the best AD4 pose ( Figure S18C ). 3.4. Droxidopa Binding to the 2 AR Receptor The rigid docking of Droxidopa to β 2 AR generated the lowest energy binding poses comparable to those observed for adrenaline, in which the ethanolamine moiety of the ligand was bound to the Asp113/Asn312 anchor site and its catechol moiety formed bonds only with Ser207 in the TM-V domain of the receptor ( Figure 11 A). It is worth noting that the lowest energy pose showed an average BFE of −7.4 kcal/mol (best conformations resulting from ten independent docking runs), which is very similar to the one we recently observed for noradrenaline (−7.6 kcal/mol), of which Droxidopa is a precursor, confirming the validity of the molecular docking protocol [ 76 ]. Moreover, the pK d of Droxidopa (5.4) is also in good agreement with experimental and computational values available for noradrenaline [ 75 , 76 , 86 , 88 ]. Similarly to L-DOPA, the best binding poses of Droxidopa docked in the flexible 2 AR model formed more hydrogen bonds with both anchor sites of the binding pocket of the receptor as compared to the ligand bound to the rigid model ( Figure 11 B). The lowest energy binding pose of Droxidopa in the flexible receptor model is associated with an average BFE of −14.0 kcal/mol, corresponding to a pK d of 10.3 ( Table 1 ), and hydrogen bond interactions comparable to those observed in the best binding conformation of the ligand in a rigid 2 AR model ( Figure 11 A). Moreover, this structure is characterized by a hydrogen bond network showing an additional polar interaction with Asn312 in the Asp113/Asn312 anchor site ( Figure 11 B and Table 2 ). Additionally, this best binding pose of Droxidopa is likely a representative ligand’s conformation because its orientation is similar to that of catecholamines in 2 AR models reported in the literature [ 76 , 86 ]. In analogy with L-DOPA, the lowest energy Vina conformations of Droxidopa docked into rigid and flexible β 2 AR models displayed less hydrogen bond contacts and average BFEs of −7.5 and −7.9 kcal/mol, respectively, corresponding to binding affinities similar to the rigid AD4 value and comparable with noradrenaline computational and experimental results ( Figures S19 and S20 ) [ 75 , 76 , 86 , 88 ]. These results implicate that hydrophobic interactions could also play a crucial role in the stability of this catecholamine. 3.5. Hydrogen Bonds in β 2 AR-Adrenaline Complexes The lowest energy conformation of adrenaline from the docking into a rigid β 2 AR model displayed a hydrogen bond network essentially similar to the one of the ethanolamine tail of the ligand in the X-ray crystal structure ( Figure 9 and Table 2 ). The ethanolamine moiety of established hydrogen bond interactions with both anchor site amino acids Asp113 and Asn312, is in good agreement with experimental and computational findings [ 28 , 86 , 90 ]. Moreover, hydrogen bond interactions were observed between the Asn312 side chain and the β -OH of the ligand, in good agreement with biochemical results [ 91 ]. Furthermore, the H-bond distance between Tyr316 and β -OH of adrenaline present in the X-ray crystal structure was partially disrupted and increased from 3.5 to 3.9 Å in the redocked adrenaline. Additionally, Tyr316 was still found to be involved in the formation of hydrogen bonds with the N amino of adrenaline. The Asn293 side chain was located too far away from acceptor and donor atoms of the catecholamine to form hydrogen bonds, which were previously proposed and reported for β 2 AR agonists experimentally and computationally [ 75 , 86 , 88 , 92 , 93 ]. At the same time, this conformational model of the β 2 AR-adrenaline complex presented marked differences in the ligand catechol head of the ligand. Hydrogen bonds of catechol hydroxyls with side chains of serines of the TM-V helical domain are considered the most specific interactions for β 2 AR agonists [ 75 , 88 , 94 , 95 , 96 , 97 ]. In particular, the H-bonding of both meta-OH and para-OH hydroxyl groups with both Ser203 and Ser207 side chains was not reproduced as in the X-ray crystal structure, the only exception being represented by a decrease of the donor-acceptor Ser207-para-OH distance from 3.5 to 2.6 Å ( Table 2 ). While the distance between hydroxyl groups of the catechol head and the Ser204 side chain increased, additional hydrogen bond interactions arose between both meta-OH and para-OH with Thr118 side chain ( Table 2 ). The involvement of Thr118 in the β 2 AR hydrogen bond network has been recently found in wild type and mutated (T164I) forms of the receptor bound to salbutamol using molecular docking and MD simulations [ 98 ]. Similar hydrogen bond interactions were essentially observed for the neutral form of the ligand, the only exception being the loss of the Tyr316-N-amino H-bond [ 76 ]. Moreover, the presence of hydrogen bond interactions between residue Thr118 and different β 2 AR ligands has previously been reported in MD simulation studies [ 98 , 99 , 100 , 101 , 102 ]. It is worth noting that adrenaline formed more stable hydrogen bonds on average, as evidenced by shorter distances reported in Table 2 , with both its ethanolamine tail and catechol head when docked into a flexible 2 AR model as compared to conformations of the ligand bound to a rigid model both to the X-ray crystal structure of the receptor. Moreover, two additional hydrogen bonds were found between the catechol head hydroxyls and serines S203 and S207, namely Ser203-para-OH and Ser207-meta-OH, which contributed to the observed dramatic decrease of the BFE ( Table 1 ). The hydrogen bond between the meta hydroxyl group of the catechol ring of adrenaline and residue Asn293 of 2 AR reported in the X-ray crystal structure (PDB ID: 4LDO) was not reproduced in the lowest energy binding poses of protonated and neutral adrenaline docked in both receptor models [ 28 , 76 ]. 3.6. Hydrogen Bonds in 2 AR in Complex with L-DOPA and Droxidopa The docking of L-DOPA and Droxidopa in both flexible and rigid 2 AR models produced ligand conformations similar to the best binding poses of adrenaline. It is worth noting that the hydrogen bonds of both L-DOPA and Droxidopa docked in different 2 AR models displayed some similarities and remarkable differences with the network of polar interactions of the endogenous catecholamine ( Figure 10 , Figure 11 , Figure 12 A and Table 2 ). The main similarity with polar interactions observed for the endogenous ligand was represented by a reduction in hydrogen bond distances when using flexible receptor models ( Table 2 ). Both ligands formed hydrogen bonds with anchor sites Asp113 and Asn312 through their ethanolamine moieties. In Droxidopa, as observed for adrenaline, the presence of the -OH group in the ethanolamine tail of the ligand strengthened these polar interactions, resulting in the formation of H-bonds with Asp113 and Asn312 residues in both rigid and flexible 2 AR models ( Table 2 ). In both receptor models, L-DOPA also showed a hydrogen bond interaction with Asn312 through one oxygen of its carboxylic acid moiety. A similar polar interaction was only present in Droxidopa docked to a flexible 2 AR receptor ( Table 2 ). In analogy with adrenaline and despite the receptor model, the ethanolamine N of both exogenous ligands developed hydrogen bonds with Tyr316, which also behaved as an anchor site interacting with the -OH group of Droxidopa docked only in the rigid receptor model ( Table 2 ). In the rigid receptor, L-DOPA displayed hydrogen bond interactions with 2 AR residues Ser203 and Ser207 through its catechol moiety para-OH and meta-OH hydroxyls, respectively ( Table 2 ). These polar interactions are different from those reported by experimental and computational studies that predict the formation of hydrogen bonds of meta-OH and para-OH hydroxyl groups of the catechol head of various catecholamines with Ser203 and Ser 207, respectively [ 86 , 95 , 97 ]. It is interesting to note that the docking of L-DOPA to a rigid 2 AR model also leads to hydrogen bonding with Ser204 through the para-OH of its catechol head, displaying an additional polar interaction not observed in experiments and computational investigations [ 86 , 95 , 97 ]. However, the hydrogen bond interaction of the para-OH hydroxyl group of L-DOPA’s catechol with Ser 207 is observed when the exogenous ligand is docked into a flexible 2 AR model, in good agreement with previous experimental and computational studies [ 86 , 95 , 97 ] ( Table 2 ). In addition, in the flexible 2 AR model, both hydroxyl groups of L-DOPA’s catechol head formed hydrogen bonds with Thr118, as observed for the endogenous catecholamine ( Table 2 ). As opposed to L-DOPA, the catechol moiety of Droxidopa was involved in hydrogen bonding only with 2 AR residues Ser207 and Thr118 in both receptor models ( Table 2 ). In the case of Droxidopa, the para-OH-Ser207 hydrogen bond was found to be particularly stable in rigid and flexible β 2 AR models. Furthermore, both hydroxyl groups of the catechol moiety of Droxidopa formed hydrogen bonds with Thr118 in the flexible β 2 AR model ( Table 2 ). Similar to the endogenous catecholamine, both exogenous ligands did not display hydrogen bonds with Asn293, which has been found to form a stabilizing polar interaction with adrenaline bound to β 2 AR using different experimental techniques [ 28 , 93 , 96 ]. In our recent work, we performed the shifting of the grid box center in order to observe the formation of this hydrogen in both endogenous and exogenous ligands [ 76 ]. In particular, AD4 lowest energy conformations of L-DOPA and Droxidopa obtained with the shifted grid box center did not exhibit hydrogen bond interactions of the catechol head of the ligand with residue Asn293 of flexible β 2 AR systems, while both ligands showed polar interactions with Thr118 [ 76 ]. As observed with adrenaline, the hydrogen bond with residue Asn293 of β 2 AR was instead formed in both L-DOPA and Droxidopa lowest energy binding poses docked into flexible β 2 AR models obtained by Vina calculations [ 76 ]. 3.7. Hydrophobic Contacts of β 2 AR Agonists The adrenaline ligand exhibited hydrophobic contacts with Val117 and Phe289 residues when docked to a rigid β 2 AR model ( Figure 12 B). Phe289 was also reported to be a key residue in the formation of hydrophobic interactions with different catecholamines in a previous computational study [ 86 ]. When adrenaline was docked in a flexible β 2 AR model, the endogenous ligand also exhibited hydrophobic interactions with Phe290 ( Figure 12 B). We recently found that neutral adrenaline displayed similar hydrophobic contacts with Val117 and Phe289 residues in rigid β 2 AR models subjected to AD4 and Vina calculations [ 76 ]. In flexible β 2 AR models, neutral adrenaline presented the same apolar contacts generated by Vina docking runs of the ligand docked in a rigid receptor, while AD4 calculations showed hydrophobic interactions with Val114 and Val117 residues [ 76 ]. Interestingly, L-DOPA exhibited hydrophobic contacts with β 2 AR residues Val114 and Phe193 in rigid receptor models ( Figure 12 B). It is worth noting that the Vina L-DOPA’s lowest energy conformation in a rigid β 2 AR model also displayed an additional apolar interaction with residue Val117 [ 76 ]. In flexible β 2 AR models, the lowest energy binding poses of L-DOPA displayed hydrophobic contacts with Val117 and Phe289 ( Figure 12 B and Figure 13 A). In our recent work, the Vina best binding poses showed the same hydrophobic contacts of the rigid docking approach, namely with Val114, Val117 and Phe193 residues [ 76 ]. In rigid β 2 AR models, the lowest energy binding pose of Droxidopa formed hydrophobic interactions with residues Val117 and Phe289 ( Figure 12 B). We have also recently observed that the Vina best binding pose exhibited apolar contacts with Val114, Val117 and Phe193, as noted for L-DOPA [ 76 ]. When 2 AR binding pocket residues were flexible, the Droxidopa lowest energy conformation displayed hydrophobic contacts with Val114, Val117 and Phe289 ( Figure 12 B and Figure 13 B). In our recent study, the Vina best binding pose of Droxidopa showed more apolar interactions with amino acids Val114, Phe193 and Phe289 [ 76 ]. 3.8. Protein–Ligand Interactions in MD Simulations of 2 AR-Catecholamine Complexes Additionally, we performed one microsecond-long AA MD simulations of 2 AR-catecholamine complexes embedded in POPC:CHOL lipid membranes, which allowed us to determine whether or not the lowest energy binding poses were stable. After 300 ns, the receptor C-alpha atoms RMSDs reached a plateau value of less than 4 Å in the 2 AR-adrenaline complex, indicating that the endogenous ligand provided structural stability to the entire protein ( Figure 14 A). This stability persisted until 700 ns into the simulation period, when there were fewer changes in protein conformation. When compared to 2 AR adreanline’s lower RMSD values and stability at 300 ns, Droxidopa and L-Dopa show less fluctuation after 300ns, suggesting that these exogenous ligands might induce more conformational changes within the protein than adrenaline ( Figure 14 A). The RMSDs of the ligand’s heavy atoms are shown in Figure 14 B. It is worth noting that the stability of each ligand is achieved after 300 ns of the simulation time, which is in line with prior findings. The conformational variations in L-Dopa and Droxidopa were found to be larger than in the 2 AR-adrenaline system; however, after 300 ns, all simulations achieved stability with less changes in the conformational state of each exogenous ligand. The hydrogen bond network of L-DOPA and Droxidopa with 2 AR residues during MD simulations was very similar to the one observed with the CHARMM FF ( Figure 15 ) and comparable to that of adrenaline ( Figure S22 ), supporting the results obtained with molecular docking calculations. The contact maps illustrated in Figure 16 for the L-Dopa and Droxidopa molecules indicate excellent interactions between ligands and the 2 AR residues. In the green to red shades, while analyzing the 1000 ns simulation, we observe that the L-Dopa forms stronger connections with V114, F193, F289, F290 and N293 and loose or fading interactions with D113, V117, S203, S204, S207, Y308 and N312, which may also include the hydrophobic interaction component of the binding site. When analyzing the Droxidopa, we found that it forms strong connections with D113, V114, V117, F289, F290, N312 and Y316, and fading bonds with T118, S203, S204, S207, W286 and N293 throughout the 1000 ns simulation time. In addition, Droxidopa has a greater affinity for binding than L-Dopa, which is convincing evidence that it may be more effective. We observed that Adrenaline’s probability contact map with 2 AR residues is comparable to L-Dopa’s ( Figure S23 ), displaying excellent contacts with D113, V114, V117, F193, F289 and N312 and fading bonds for T110, T118, S203, S207, F290, N293, Y308 and Y316. Furthermore, we can see that Adrenaline’s interaction profile is extremely comparable to that of L-Dopa, while that of Droxidopa’s interaction profile is rather higher. BFE calculations using the MM-PBSA method indicate this as well. Droxidopa has a stronger interaction with the β 2 AR receptor than L-Dopa or Adrenaline, as evidenced by its BFE reported in Table 1 , indicating that all three interaction profiles and residue characterizations can be trusted. Interestingly, MM-PBSA calculations over a 1 s MD simulation of the β 2 AR-adrenaline complex yielded a BFE of −4.5 +/− 0.4 kcal/mol (pK d = 3.3), which was higher than the experimental value of the endogenous ligand (−8.2 kcal/mol pK d = 6.1–6.5) ( Table 1 ). More interestingly, in the simulated receptor–ligand complex, L-DOPA displayed a BFE of −5.4 +/− 0.4 kcal/mol (pK d = 3.9), which was lower than the adrenaline ligand value ( Table 1 ). Furthermore, MD simulations of the 2 AR-Droxidopa complex exhibited a catecholamine BFE of −12.5 +/−0.4 kcal/ mol, corresponding to a pK d of 9.3 ( Table 1 ), better than noradrenaline experimental values (i.e., 5.0 and 5.4). On the contrary, the adrenaline and L-DOPA BFEs estimated for each ligand parameterized with the OPLS FF were more positive than not only those obtained by both rigid and flexible docking calculations, but also those from MD simulations performed with the CHARMM FF [ 76 ], suggesting that this FF might better reproduce the conformational space of these ligands. We examined the contributions of 2 AR residues to the BFE of each catecholamine, in order to better understand protein–ligand interactions ( Figure 17 ). For the most part, the hydrogen bond and hydrophobic interactions of the receptor residues (particularly D113, Y308, N312, S203, S204, S207, T118, N293, V114, V117 and F193) were shown to have a positive effect on adrenaline’s BFE, confirming both experimental and computational results [ 75 , 76 , 86 , 88 , 94 , 97 ]. Intriguingly, six negatively charged amino acids (E107, E180, E188, D192, D300, E306) and two positively charged residues (R175 and K305) had a stabilizing and destabilizing influence on the 2 AR-adrenaline complex, despite being positioned on the periphery of the 2 AR binding pocket. Figure 17 shows that L-DOPA substantially interacted with the same residues as adrenaline and, particularly, with hydrophilic (S203, S204, T118, N293, Y308) and hydrophobic (V114, V117, F193 and F289) residues. Furthermore, we found that D113 had a poor contact with the ligand, which may have been owing to the ligand’s carboxilic group being in an unfavorable position relative to the aspartic acid equivalent moiety. The 2 AR residues that contributed more to the Droxidopa’s BFE were similar to those found for L-DOPA and adrenaline, and those that bound more strongly to the catecholamine were V114, V117 and F289, in good agreement with the interaction pattern described above and our previous findings with the CHARMM FF [ 76 ]. D113, similar to L-DOPA, had a modest interaction with Droxidopa, although its energetic contribution was less favorable. 4. Discussion To study the interaction of the adrenergic receptor 2 AR with endogenous and exogenous catecholamines, we have recently used molecular docking calculations and MD simulations [ 76 ]. Rigid docking calculations produced the lowest energy conformations of all investigated ligands with pK d s similar to experimental values. In contrast, all catecholamines docked into flexible 2 AR models had pK d s exceeding experimental values, which were also confirmed by BFEs obtained from MM-PBSA calculations performed on MD simulations of 2 AR-catecholamine complexes. In particular, the molecular docking of endogenous ligands, such as adrenaline, noradrenaline and dopamine, into both rigid and flexible 2 AR models led to the discovery of novel binding poses. These new conformations differ from experimental and computationally anticipated structures, indicating that catecholamines can adopt more energetically stable binding modes. The best binding poses of exogenous ligands L-DOPA and Droxidopa were similar to endogenous catecholamines dopamine and noradrenaline, respectively. Thus, to further investigate the aforementioned binding poses of endogenous and exogenous ligands through MD simulations, we parameterized the OPLS AA FFs of these small organic molecules. The JOYCE FF functions accurately reproduce the QM torsional profiles of each dihedral angle of the zwitterionic L-DOPA. These dihedral torsional profiles resemble those of zwitterionic L-Tyrosine, as reported by Del Galdo et al., in 2018 [ 85 ]. The agreement between QM and JOYCE torsional profiles for charged groups in zwitterionic condition was better than that found by Del Galdo et al., in 2018 [ 85 ] for the comparable amino acid L-Tyrosine, confirming the excellent quality of the FF parameterization of L-DOPA. Similar to L-DOPA, the QM torsional profiles of zwitterionic Droxidopa dihedrals matched JOYCE FF characteristics. The QM and JOYCE torsional profiles of Droxidopa dihedrals are very close to those of L-DOPA. In addition, QM and JOYCE torsional profiles of protonated adrenaline were similar and in good agreement with those observed for the two exogenous ligands. To evaluate the L-DOPA and Droxidopa FFs, we performed MD simulations of each ligand in both vacuum and aqueous solution. Notably, both L-DOPA and Droxidopa showed similar dihedral distributions in vacuum and water for each dihedral angle. The Helmholtz free energy variation patterns were identical to the QM energy profiles for both L-DOPA and Droxidopa. Each profile created using the JOYCE program as a statistical ensemble is compared to the OPLS AA FF profile. The entropic contribution is only present in the free energy, as reported by Del Galdo et al., in 2018 [ 85 ] for zwitterionic Tyrosine. Despite this difference, the comparison has allowed us to qualitatively assess the accuracy of the developed FFs for various dihedral angles of each ligand. Since adrenaline is predominantly protonated at a physiological pH, we initially employed this form of the ligand to perform its redocking into rigid and flexible 2 AR models, yielding conformations distinct from that of the X-ray crystal structure (ligand heavy atom RMSDs of 2.2 and 2.4 Å, respectively) ( Figure 9 ) [ 28 ]. While the ethanolamine tail of the redocked adrenaline binds to anchor site amino acids Asp113/Asn312, the catechol head interacts with different residues in the crystal and redocked structures, respectively. According to experimental studies, the BFE of adrenaline varies from −8.3 kcal/mol to −8.9 kcal/mol, showing that the rigid redocking structure of adrenaline is almost in its more energetically stable conformation (BFE = −8.1 kcal/mol). The lowest energy conformation of adrenaline in flexible receptor models is not only more stable than the rigid docking conformation, but also has a pK d better than the experimental values reported in the literature ( Table 1 ) [ 75 , 88 ]. This remarkable result is most probably a consequence of the larger conformational space sampled by the flexible redocking as compared to the rigid docking calculation [ 76 ]. Taking into account the variety of 2 AR active states in physiological [ 103 ] and tumoral [ 104 ] conditions, it is plausible to predict that the endogenous catecholamine could interact with the receptor adopting conformations more similar to those described by flexible docking calculations and MD simulations. Interestingly, the docking of L-DOPA to a rigid receptor model generated best binding poses unable to create hydrogen bonds in an adrenaline-like manner. As a consequence, the average BFE of L-DOPA docked into a rigid 2 AR model was −6.4 kcal/mol, higher than the Vina finding (−7.3 kcal/mol), corresponding to a pK d of 4.7 ( Figure S10 and Table 1 ) [ 76 ]. The docking of L-DOPA into the flexible 2 AR model induced more ligand–receptor hydrogen bond interactions than docking into the rigid receptor model. The ligand’s catechol head formed hydrogen bonds with the binding site residue Thr118. Moreover, L-DOPA docked into a flexible 2 AR model has a pK d of 9.4, which is comparable to the value observed for adrenaline (9.2) ( Table 1 ). The lowest energy conformation of Droxidopa bound to a rigid receptor showed a BFE of −7.4 kcal/mol, which is comparable to the one we observed for noradrenaline (−7.6 kcal/mol) [ 75 , 76 , 88 ], demonstrating the validity of the molecular docking protocol. Droxidopa, similar to L-DOPA, docked into the flexible β 2 AR model resulted in lowest energy conformations having stronger hydrogen bond interactions with both anchor sites of the binding pocket of the receptor ( Table 2 ). Droxidopa’s lowest energy conformation in the flexible receptor model had a BFE of −14.0 kcal/mol (pK d = 10.3), polar interactions similar to the ligand’s best binding pose in the rigid β 2 AR model ( Table 1 and Table 2 ) and an orientation similar to that of catecholamines in 2 AR models [ 86 ]. Although the contribution of hydrophobic interactions has to be taken into account, this favorable BFE is due to a hydrogen bond network larger than those observed for adrenaline and L-DOPA [ 76 ]. When docked into a rigid 2 AR model, the lowest energy conformation of adrenaline revealed a hydrogen bond network similar to that of the ligand’s ethanolamine tail in the X-ray crystal structure, showing polar interactions with Asp113 and Asn312. In particular, the Asn312 side chain formed hydrogen bonds with the ligand’s -OH, as expected biochemically [ 91 ]. Tyr316 was also involved in the formation of hydrogen bonds with adrenaline’s ethanolamine tail ( Figure 9 and Table 2 ). However, the most specific polar interactions for β 2 AR agonists are hydrogen bonds between catechol hydroxyls and serines in the TM-V helical domain [ 94 , 95 , 96 ]. We only observed the conservation of the hydrogen bond between S207 and the para-OH of the ligand, as compared to the β 2 AR X-ray structure ( Table 2 ). Interestingly, both catechol hydroxyls formed polar interactions with Thr118. Molecular docking and MD simulations have recently revealed the role of Thr118 in the β 2 AR hydrogen bond network [ 76 ]. Furthermore, MD simulations studies have reported hydrogen bond interactions between residue Thr118 and several 2 AR ligands [ 98 , 99 , 100 , 101 , 102 ]. When docked into a flexible β 2 AR model, adrenaline established more stable hydrogen bonds with its ethanolamine tail and catechol head, as compared to conformations of the ligand bound to a rigid receptor model or the X-ray crystal structure ( Figure 9 and Table 2 ). We observed the formation of additional hydrogen bonds between catechol head hydroxyls and serines S203 and S207 (Ser203-para-OH and Ser207-meta-OH), which contributed to the BFE decrease. The Asn293 side chain did not form hydrogen bonds with the meta-OH of adrenaline, as in Ring et al.’s X-ray structure [ 28 ] and a previous computational study of β 2 AR agonists [ 86 ]. L-DOPA and Droxidopa conformations were similar to adrenaline’s best binding poses in both flexible and rigid 2 AR models. The tail moieties of both ligands formed hydrogen bond interactions with anchor sites Asp113 and Asn312 ( Figure 10 , Figure 11 and Table 2 ). In the rigid β 2 AR model, the catechol head of L-DOPA formed hydrogen bonds with Ser203 and Ser207 through its para- and meta-OH hydroxyl groups, respectively, in good agreement with experimental and computational results [ 86 , 94 , 95 , 96 ]. Additionally, L-DOPA docked into a rigid receptor model formed hydrogen bonds with Ser204 through the para-OH of its catechol moiety, an interesting polar interaction not supported by previous experimental and computational investigations ( Table 2 ). Both hydroxyl groups of L-DOPA and Droxidopa catechol heads formed hydrogen bonds with Thr118 in flexible β 2 AR models. In both receptor models, Droxidopa’s catechol head also displayed polar interactions with Ser207, as shown by the quite stable para-OH-Ser207 hydrogen bond ( Figure 11 and Table 2 ). Although we shifted the grid box center toward Asn293 of flexible β 2 AR systems [ 76 ], the catechol heads of both L-DOPA and Droxidopa did not form hydrogen bonds with Asn293 and displayed polar interactions with Thr118 in AD4 lowest energy conformations. Interestingly, the L-DOPA and Droxidopa lowest energy binding poses docked into flexible β 2 AR models produced by Vina simulations created a hydrogen bond with Asn293 of β 2 AR [ 76 ]. It is worth noting that the hydrogen bond network of L-DOPA and Droxidopa observed through molecular docking calculations was also reproduced during MD simulations of β 2 AR-catecholamine complexes performed with CHARMM [ 76 ] and OPLS AA FFs ( Figure 15 , Table S5 and Figure S22 ). The OPLS AA FF of both ligands were less successful in keeping stable hydrogen bonds with Ser203 and Ser207, but generated similar percentages of hydrogen bond formation with other key amino acids, such as Asp113, N312, Thr118 and Y316, especially in the case of Droxidopa, as compared to corresponding results obtained with the CHARMM AA FF ( Figure 15 and Table S5 ) [ 76 ]. In rigid and flexible β 2 AR models, adrenaline showed hydrophobic interactions with Val117 and Phe289 residues. In recent computational studies, Phe289 has been found to be a critical residue in the formation of hydrophobic interactions with catecholamines [ 76 , 86 ]. However, adrenaline docked in a flexible β 2 AR model also revealed hydrophobic interactions with Phe290. Molecular docking calculations employing rigid receptor models showed that L-DOPA had hydrophobic interactions with β 2 AR residues Val114 and Phe193. When L-DOPA was docked into flexible β 2 AR models, the exogenous ligand formed apolar interactions with Val117 and Phe289, the same residues were observed for the endogenous ligand. Similarly to adrenaline, Droxidopa’s lowest energy conformation interacted with Val117 and Phe289 in rigid β 2 AR models. When β 2 AR binding pocket residues were flexible, the Droxidopa best binding pose exhibited hydrophobic contacts with Val114, Val117 and Phe289. It is remarkable that MD simulations of β 2 AR-catecholamine complexes performed with CHARMM and OPLS AA FFs displayed the formation of hydrophobic interactions with the same amino acids obtained by molecular docking calculations ( Figure 16 , Figure 17 , Figures S21 and S23 ), confirming the quality of both ligands’ FFs and their ability to reproduce these important apolar interactions [ 76 ]. Due to the broader conformational space sampled by MD simulations, this methodology usually provides better and more reliable binding poses of ligands than lowest energy conformations obtained by flexible and rigid molecular docking using both AD4 and Vina calculations. In order to validate the hypothesis that drugs employed in the treatment of PD could display binding conformations similar to those observed for L-DOPA and Droxidopa, we also performed the molecular docking of carbidopa, foslevodopa and foscarbidopa to a rigid 2 AR model using the latest version of Vina (v. 1.2.3) ( Figure S24 ) [ 105 ]. The lowest energy conformations of carbidopa, foslevodopa and foscarbidopa are structurally similar to those observed for adrenaline, L-DOPA and Droxidopa, respectively, displaying BFEs of −7.5, −6.4 and −7.2 kcal/mol, respectively, comparable with the values obtained for the endogenous and exogenous ligands. Moreover, the hydrogen bond network of these drugs is also characterized by polar interactions with the same amino acids, including Thr118, observed in best binding poses of adrenaline, L-DOPA and Droxidopa ( Figure S24 ). The main motivation of our study was to provide a step-by-step perspective guide for the investigation of 2 AR-catecholamine complexes, including the development of FF parameters of ligands, molecular docking calculations of each ligand to both flexible and rigid receptor models and MD simulations of lowest energy binding poses of ligands docked to protein models embedded in lipid membranes. Future objectives will include the FF parameterization of additional related drugs (see above) and MD simulations of 2 AR-drug complexes embedded in membranes with more physiological lipid composition at atomistic and coarse grained levels. 5. Conclusions OPLS AA FFs have been developed and tested for protonated adrenaline, and zwitterionic L-DOPA and Droxidopa molecules by performing QM calculations and MD simulations in water. QM torsional profiles of all ligands resembled those of zwitterionic L-Tyrosine [ 85 ]. Moreover, QM and JOYCE torsional profiles of α , β , , δ , ϵ and η dihedrals of Droxidopa were similar to those observed for L-DOPA. Molecular docking calculations have highlighted that the binding of exogenous catecholamines to 2 AR is favored by the formation of hydrogen bonds between their catechol head and ethanolamine tail moieties and key amino acids, such as Ser203, Ser204, Ser207, Asp113 and Asn312, as reported in previous experimental and computational studies [ 75 , 86 , 88 , 94 , 97 ]. This network of polar interactions involves Tyr316 and Thr118 residues of β 2 AR and ethanolamine and catechol moieties, respectively, increasing the stability of lowest energy binding poses of each investigated ligand. Additionally, each catecholamine also formed hydrophobic interactions with 2 AR residues Val114, Val117, Phe193, Phe289 and Phe290, previously observed to interact with similar agonists [ 86 ]. Furthermore, OPLS AA FF parameters of adrenaline, L-DOPA and Droxidopa were also applied in 1 s long MD simulations of 2 AR-catecholamine complexes embedded in lipid membranes. MD simulations of these 2 AR-catecholamine complexes exhibited hydrogen bond and hydrophobic interactions comparable to those derived from molecular docking calculations and MD simulations performed with the CHARMM AA FF [ 76 ]. Since we have recently shown how L-DOPA and Droxidopa drugs interact with 2 AR [ 76 ], our preliminary molecular docking and latest MD simulations findings strengthen the hypothesis that similar binding modes could also be predicted for the other drugs in use for treating patients with Parkinson’s disease. Supplementary Materials The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/life12091393/s1 , Figure S1. Geometry optimized chemical structures of protonated adrenaline, zwitterionic L-DOPA and Droxidopa. Figure S2. Torsional profiles derived from QM calculations and JOYCE for protonated adrenaline. Figure S3. OPLS AA force field parameters of adrenaline: bond lengths and force constants. Figure S4. OPLS AA force field parameters of adrenaline: bond angles and force constants. Figure S5. OPLS AA force field parameters of adrenaline: dihedral angles, force constants and multiplicity. Figure S6. OPLS AA force field parameters of L-DOPA: bond lengths and force constants. Figure S7. OPLS AA force field parameters of L-DOPA: bond angles and force constants. Figure S8. OPLS AA force field parameters of L-DOPA: dihedral angles, force constants and multiplicity. Figure S9. OPLS AA force field parameters of Droxidopa: bond lengths and force constants. Figure S10. OPLS AA force field parameters of Droxidopa: bond angles and force constants. Figure S11. OPLS AA force field parameters of Droxidopa: dihedral angles, force constants and multiplicity. Figure S12. Comparison of Dihedrals distributions in vacuum and water to torsional profiles obtained by QM calculations and JOYCE for protonated adrenaline. Figure S13. Comparison of protonated adrenaline dihedral angles torsional energy profiles from QM, JOYCE, QM after the subtraction of electrostatic and LJ energy contributions and fittings calculations. Figure S14. Comparison of zwitterionic L-DOPA dihedral angles torsional energy profiles from QM, JOYCE, QM after the subtraction of electrostatic and Lennard-Jones (LJ) energy contributions and fittings calculations. Figure S15. Comparison of zwitterionic Droxidopa dihedral angles torsional energy profiles from QM, JOYCE, QM after the subtraction of electrostatic and LJ energy contributions and fittings calculations. Figure S16. Comparison of protonated adrenaline QM torsional energy profiles with Helmholtz free energy variations obtained from MD simulations performed using JOYCE and OPLS FFs. Figure S17. Comparison of lowest energy binding poses obtained from AD4 and Vina molecular docking calculations for L-DOPA docked into rigid 2 AR models. Figure S18. Comparison of lowest energy binding poses obtained from AD4 and Vina molecular docking calculations for L-DOPA docked into flexible 2 AR models. Figure S19. Comparison of lowest energy binding poses obtained from AD4 and Vina molecular docking calculations for Droxidopa docked into rigid 2 AR models. Figure S20. Comparison of lowest energy binding poses obtained from AD4 and Vina molecular docking calculations for Droxidopa docked into rigid 2 AR models. Figure S21. Percentage of contacts of ligands with the receptor hydrophobic residues extracted from MD simulations of 2 AR-catecholamine complexes performed with CHARMM and OPLS AA FFs. Figure S22. Hydrogen bond network of adrenaline with key amino acids of 2 AR binding pocket using CHARMM and OPLS AA FFs. Figure S23. Normalized number of contacts of adrenaline with 2 AR residues. Figure S24. Comparison of lowest energy binding poses from Vina molecular docking calculations for carbidopa, foslevodopa and foscarbidopa. Table S1. Partial atomic charges and OPLS AA force field Lennard-Jones parameters of adrenaline. Table S2. Partial atomic charges and OPLS AA force field Lennard-Jones parameters of L-DOPA. Table S3. OPLS AA force field Lennard-Jones parameters of Droxidopa. Table S4. Coulomb and Lennard-Jones energies of adrenaline, L-DOPA and Droxidopa. Table S5. Percentage of hydrogen bond formation for different β 2 AR-Ligand complexes from 1 μ s all atom MD simulations performed with CHARMM and OPLS AA FF parameters. adrenaline.itp: OPLS AA force field parameters of adrenaline generated with JOYCE. dopa.itp: OPLS AA force field parameters of L-DOPA generated with JOYCE. droxidopa.itp: OPLS AA force field parameters of Droxidopa generated with JOYCE. Author Contributions Conceptualization, A.C. and V.B.; methodology, A.C. and A.D.B.; software, A.C. and A.D.B.; validation, A.C. and A.D.B.; formal analysis, A.C. and A.D.B.; investigation, A.C. and A.D.B.; resources, V.B.; data curation, A.C. and A.D.B.; writing—original draft preparation, A.C. and A.D.B.; writing—review and editing, A.C., A.D.B., G.M. and V.B.; visualization, A.C. and A.D.B.; supervision, G.M.; project administration, V.B.; funding acquisition, V.B. All authors have read and agreed to the published version of the manuscript. Funding This research was funded by the Italian MIUR (PRIN 2017; Project PHANTOMS - Physico-chemical Heuristic Approaches: Nanoscale Theory Of Molecular Spectroscopy; grant number 2017A4XRCA) and by the Italian Space Agency (ASI; project ‘Life in Space’, N. 2019-3-U.0). Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Data can be found with A.C. Acknowledgments We are grateful to Sara Del Galdo for contributing to the force field development of L- DOPA and Droxidopa molecules. We are thankful to Alberto Coduti and all the staff of the high-performance computer facilities of the SMART Laboratory ( https://smart.sns.it ) for providing assistance with software installation and computer resources. Conflicts of Interest The authors declare no conflict of interest. Abbreviations The following abbreviations are used in this manuscript: AA All Atom β 2 AR Beta2 Adrenergic Receptor pK d Binding Affinity BFE Binding Free Energy GPCR Guanine Nucleotide-Binding Protein Coupled Receptor DFT Density-Functional Theory FF Force Field L-DOPA Levodopa MD Molecular Dynamics PD Parkinson’s Disease QM Quantum Mechanical References Lee, Y.; Lazim, R.; Macalino, S.J.Y.; Choi, S. Importance of protein dynamics in the structure-based drug discovery of class A G protein-coupled receptors (GPCRs). Curr. Opin. Struct. Biol. 2019 , 55 , 147–153. [ Google Scholar ] [ CrossRef ] [ PubMed ] Latorraca, N.R.; Venkatakrishnan, A.; Dror, R.O. GPCR dynamics: Structures in motion. Chem. Rev. 2017 , 117 , 139–155. [ Google Scholar ] [ CrossRef ] [ PubMed ] Gacasan, S.B.; Baker, D.L.; Parrill, A.L. G protein-coupled receptors: The evolution of structural insight. AIMS Biophys. 2017 , 4 , 491–527. [ Google Scholar ] [ CrossRef ] [ PubMed ] Chien, E.Y.; Liu, W.; Zhao, Q.; Katritch, V.; Han, G.W.; Hanson, M.A.; Shi, L.; Newman, A.H.; Javitch, J.A.; Cherezov, V.; et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 2010 , 330 , 1091–1095. [ Google Scholar ] [ CrossRef ] Yang, J.; Villar, V.A.M.; Armando, I.; Jose, P.A.; Zeng, C. G protein–coupled receptor kinases: Crucial regulators of blood pressure. J. Am. Heart Assoc. 2016 , 5 , e003519. [ Google Scholar ] [ CrossRef ] Bar-Shavit, R.; Maoz, M.; Kancharla, A.; Nag, J.K.; Agranovich, D.; Grisaru-Granovsky, S.; Uziely, B. G protein-coupled receptors in cancer. Int. J. Mol. Sci. 2016 , 17 , 1320. [ Google Scholar ] [ CrossRef ] Hauser, A.S.; Attwood, M.M.; Rask-Andersen, M.; Schiöth, H.B.; Gloriam, D.E. Trends in GPCR drug discovery: New agents, targets and indications. Nat. Rev. Drug Discov. 2017 , 16 , 829–842. [ Google Scholar ] [ CrossRef ] Hauser, A.S.; Chavali, S.; Masuho, I.; Jahn, L.J.; Martemyanov, K.A.; Gloriam, D.E.; Babu, M.M. Pharmacogenomics of GPCR drug targets. Cell 2018 , 172 , 41–54. [ Google Scholar ] [ CrossRef ] Sriram, K.; Insel, P.A. G protein-coupled receptors as targets for approved drugs: How many targets and how many drugs? Mol. Pharmacol. 2018 , 93 , 251–258. [ Google Scholar ] [ CrossRef ] Fredriksson, R.; Lagerström, M.C.; Lundin, L.G.; Schiöth, H.B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 2003 , 63 , 1256–1272. [ Google Scholar ] [ CrossRef ][ Green Version ] Pierce, K.L.; Premont, R.T.; Lefkowitz, R.J. Seven-transmembrane receptors. Nat. Rev. Mol. Cell Biol. 2002 , 3 , 639–650. [ Google Scholar ] [ CrossRef ] Tyndall, J.D.; Sandilya, R. GPCR agonists and antagonists in the clinic. Med. Chem. 2005 , 1 , 405–421. [ Google Scholar ] [ CrossRef ] Chattopadhyay, A. GPCRs: Lipid-dependent membrane receptors that act as drug targets. Adv. Biol. 2014 , 2014 , 1–12. [ Google Scholar ] [ CrossRef ] Chattopadhyay, A.; Paila, Y.D. Lipid–protein interactions, regulation and dysfunction of brain cholesterol. Biochem. Biophys. Res. Commun. 2007 , 354 , 627–633. [ Google Scholar ] [ CrossRef ] Katritch, V.; Cherezov, V.; Stevens, R.C. Structure-function of the G protein–coupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol. 2013 , 53 , 531–556. [ Google Scholar ] [ CrossRef ] Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res. 2000 , 28 , 235–242. [ Google Scholar ] [ CrossRef ] Nakliang, P.; Lazim, R.; Chang, H.; Choi, S. Multiscale Molecular Modeling in G Protein-Coupled Receptor (GPCR)-Ligand Studies. Biomolecules 2020 , 10 , 631. [ Google Scholar ] [ CrossRef ] Basith, S.; Cui, M.; Macalino, S.J.; Park, J.; Clavio, N.A.; Kang, S.; Choi, S. Exploring G protein-coupled receptors (GPCRs) ligand space via cheminformatics approaches: Impact on rational drug design. Front. Pharmacol. 2018 , 9 , 128. [ Google Scholar ] [ CrossRef ] Heifetz, A.; James, T.; Morao, I.; Bodkin, M.J.; Biggin, P.C. Guiding lead optimization with GPCR structure modeling and molecular dynamics. Curr. Opin. Pharmacol. 2016 , 30 , 14–21. [ Google Scholar ] [ CrossRef ] Yuan, X.; Xu, Y. Recent trends and applications of molecular modeling in GPCR–ligand recognition and structure-based drug design. Int. J. Mol. Sci. 2018 , 19 , 2105. [ Google Scholar ] [ CrossRef ][ Green Version ] Lee, Y.; Basith, S.; Choi, S. Recent advances in structure-based drug design targeting class AG protein-coupled receptors utilizing crystal structures and computational simulations. J. Med. Chem. 2018 , 61 , 1–46. [ Google Scholar ] [ CrossRef ] [ PubMed ] Rodríguez-Espigares, I.; Torrens-Fontanals, M.; Tiemann, J.K.S.; Aranda-García, D.; Ramírez-Anguita, J.M.; Stepniewski, T.M.; Worp, N.; Varela-Rial, A.; Morales-Pastor, A.; Medel-Lacruz, B.; et al. GPCRmd uncovers the dynamics of the 3D-GPCRome. Nat. Methods 2020 , 17 , 777–787. [ Google Scholar ] [ CrossRef ] Cherezov, V.; Rosenbaum, D.M.; Hanson, M.A.; Rasmussen, S.G.; Thian, F.S.; Kobilka, T.S.; Choi, H.J.; Kuhn, P.; Weis, W.I.; Kobilka, B.K.; et al. High-resolution crystal structure of an engineered human β2-adrenergic G protein–coupled receptor. Science 2007 , 318 , 1258–1265. [ Google Scholar ] [ CrossRef ] [ PubMed ] Rosenbaum, D.M.; Cherezov, V.; Hanson, M.A.; Rasmussen, S.G.; Thian, F.S.; Kobilka, T.S.; Choi, H.J.; Yao, X.J.; Weis, W.I.; Stevens, R.C.; et al. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 2007 , 318 , 1266–1273. [ Google Scholar ] [ CrossRef ] [ PubMed ] Hanson, M.A.; Cherezov, V.; Griffith, M.T.; Roth, C.B.; Jaakola, V.P.; Chien, E.Y.; Velasquez, J.; Kuhn, P.; Stevens, R.C. A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor. Structure 2008 , 16 , 897–905. [ Google Scholar ] [ CrossRef ] [ PubMed ] Rasmussen, S.G.; Choi, H.J.; Fung, J.J.; Pardon, E.; Casarosa, P.; Chae, P.S.; DeVree, B.T.; Rosenbaum, D.M.; Thian, F.S.; Kobilka, T.S.; et al. Structure of a nanobody-stabilized active state of the β 2 adrenoceptor. Nature 2011 , 469 , 175–180. [ Google Scholar ] [ CrossRef ] Rasmussen, S.G.; DeVree, B.T.; Zou, Y.; Kruse, A.C.; Chung, K.Y.; Kobilka, T.S.; Thian, F.S.; Chae, P.S.; Pardon, E.; Calinski, D.; et al. Crystal structure of the β 2 adrenergic receptor–Gs protein complex. Nature 2011 , 477 , 549–555. [ Google Scholar ] [ CrossRef ] Ring, A.M.; Manglik, A.; Kruse, A.C.; Enos, M.D.; Weis, W.I.; Garcia, K.C.; Kobilka, B.K. Adrenaline-activated structure of β 2 -adrenoceptor stabilized by an engineered nanobody. Nature 2013 , 502 , 575–579. [ Google Scholar ] [ CrossRef ] Swaminath, G.; Xiang, Y.; Lee, T.W.; Steenhuis, J.; Parnot, C.; Kobilka, B.K. Sequential binding of agonists to the β 2 adrenoceptor: Kinetic evidence for intermediate conformational states. J. Biol. Chem. 2004 , 279 , 686–691. [ Google Scholar ] [ CrossRef ] Swaminath, G.; Deupi, X.; Lee, T.W.; Zhu, W.; Thian, F.S.; Kobilka, T.S.; Kobilka, B. Probing the β 2 adrenoceptor binding site with catechol reveals differences in binding and activation by agonists and partial agonists. J. Biol. Chem. 2005 , 280 , 22165–22171. [ Google Scholar ] [ CrossRef ][ Green Version ] Kobilka, B.K.; Deupi, X. Conformational complexity of G-protein-coupled receptors. Trends Pharmacol. Sci. 2007 , 28 , 397–406. [ Google Scholar ] [ CrossRef ] Kobilka, B. The structural basis of G-protein-coupled receptor signaling (Nobel Lecture). Angew. Chem. Int. Edit. 2013 , 52 , 6380–6388. [ Google Scholar ] [ CrossRef ] Nygaard, R.; Zou, Y.; Dror, R.O.; Mildorf, T.J.; Arlow, D.H.; Manglik, A.; Pan, A.C.; Liu, C.W.; Fung, J.J.; Bokoch, M.P.; et al. The dynamic process of β 2 -adrenergic receptor activation. Cell 2013 , 152 , 532–542. [ Google Scholar ] [ CrossRef ] Katsube, J.; Narabayashi, H.; Hayashi, A.; Tanaka, C.; Suzuki, T. Development of L-threo-DOPS, a norepinephrine precursor amino acid. Yakugaku Zasshi 1994 , 114 , 823–846. [ Google Scholar ] [ CrossRef ] Goole, J.; Amighi, K. Levodopa delivery systems for the treatment of Parkinson’s disease: An overview. Int. J. Pharm. 2009 , 380 , 1–15. [ Google Scholar ] [ CrossRef ] Rosebraugh, M.; Voight, E.A.; Moussa, E.M.; Jameel, F.; Lou, X.; Zhang, G.G.Z.; Mayer, P.T.; Stolarik, D.; Carr, R.A.; Enright, B.P.; et al. Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson’s Disease. Ann. Neurol. 2021 , 90 , 52–61. [ Google Scholar ] [ CrossRef ] Rosebraugh, M.; Liu, W.; Neenan, M.; Facheris, M.F. Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion. J. Park. Dis. 2021 , 11 , 1695–1702. [ Google Scholar ] [ CrossRef ] Facheris, M.; Robieson, W.; Fisseha, N.; Standaert, D. Efficacy and safety of foslevodopa/foscarbidopa versus oral carbidopa/levodopa in advanced Parkinson’s disease patients: Design of a phase 3, randomized, double-blind, double-dummy, active controlled 12-week trial. J. Neurol. Sci. 2021 , 429 , 331. [ Google Scholar ] [ CrossRef ] Barone, V.; Cacelli, I.; De Mitri, N.; Licari, D.; Monti, S.; Prampolini, G. J oyce and U lysses: Integrated and user-friendly tools for the parameterization of intramolecular force fields from quantum mechanical data. Phys. Chem. Chem. Phys. 2013 , 15 , 3736–3751. [ Google Scholar ] [ CrossRef ] Cacelli, I.; Prampolini, G. Parametrization and Validation of Intramolecular Force Fields Derived from DFT Calculations. J. Chem. Theory Comput. 2007 , 3 , 1803–1817. [ Google Scholar ] [ CrossRef ] Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; et al. Gaussian 09 Revision E.01 ; Gaussian, Inc.: Wallingford, CT, USA, 2009. [ Google Scholar ] Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Petersson, G.A.; Nakatsuji, H.; et al. Gaussian 16 Revision C.01 ; Gaussian, Inc.: Wallingford, CT, USA, 2016. [ Google Scholar ] Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 1988 , 37 , 785–789. [ Google Scholar ] [ CrossRef ] Becke, A.D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A 1988 , 38 , 3098–3100. [ Google Scholar ] [ CrossRef ] Papajak, E.; Zheng, J.; Xu, X.; Leverentz, H.R.; Truhlar, D.G. Perspectives on Basis Sets Beautiful: Seasonal Plantings of Diffuse Basis Functions. J. Chem. Theory Comput. 2011 , 7 , 3027–3034. [ Google Scholar ] [ CrossRef ] [ PubMed ] Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J. Comput. Chem. 2003 , 24 , 669–681. [ Google Scholar ] [ CrossRef ] [ PubMed ] Barone, V.; Cossi, M. Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model. J. Phys. Chem. A 1998 , 102 , 1995–2001. [ Google Scholar ] [ CrossRef ] Marenich, A.V.; Jerome, S.V.; Cramer, C.J.; Truhlar, D.G. Charge Model 5: An Extension of Hirshfeld Population Analysis for the Accurate Description of Molecular Interactions in Gaseous and Condensed Phases. J. Chem. Theory Comput. 2012 , 8 , 527–541. [ Google Scholar ] [ CrossRef ] [ PubMed ] Vilseck, J.Z.; Tirado-Rives, J.; Jorgensen, W.L. Evaluation of CM5 charges for condensed-phase modeling. J. Chem. Theory Comput. 2014 , 10 , 2802–2812. [ Google Scholar ] [ CrossRef ] Jorgensen, W.L.; Maxwell, D.S.; Tirado-Rives, J. Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids. J. Am. Chem. Soc. 1996 , 118 , 11225–11236. [ Google Scholar ] [ CrossRef ] Damm, W.; Frontera, A.; Tirado–Rives, J.; Jorgensen, W.L. OPLS all-atom force field for carbohydrates. J. Comput. Chem. 1997 , 18 , 1955–1970. [ Google Scholar ] [ CrossRef ] Kaminski, G.A.; Friesner, R.A.; Tirado-Rives, J.; Jorgensen, W.L. Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides. J. Phys. Chem. B 2001 , 105 , 6474–6487. [ Google Scholar ] [ CrossRef ] Dennington, R.; Keith, T.A.; Millam, J.M. GaussView Version 6 ; Semichem Inc.: Shawnee Mission, KS, USA, 2019. [ Google Scholar ] Abraham, M.J.; Murtola, T.; Schulz, R.; Páll, S.; Smith, J.C.; Hess, B.; Lindahl, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 2015 , 1–2 , 19–25. [ Google Scholar ] [ CrossRef ] Spoel, D.V.D.; Lindahl, E.; Hess, B.; Groenhof, G.; Mark, A.E.; Berendsen, H.J.C. GROMACS: Fast, flexible, and free. J. Comput. Chem. 2005 , 26 , 1701–1718. [ Google Scholar ] [ CrossRef ] Berendsen, H.J.C.; van der Spoel, D.; van Drunen, R. GROMACS: A message-passing parallel molecular dynamics implementation. Comput. Phys. Comm. 1995 , 91 , 43–56. [ Google Scholar ] [ CrossRef ] Berendsen, H.J.C.; Grigera, J.R.; Straatsma, T.P. The missing term in effective pair potentials. J. Phys. Chem. 1987 , 91 , 6269–6271. [ Google Scholar ] [ CrossRef ] Bussi, G.; Donadio, D.; Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 2007 , 126 , 014101. [ Google Scholar ] [ CrossRef ] Hess, B.; Bekker, H.; Berendsen, H.J.C.; Fraaije, J.G.E.M. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 1997 , 18 , 1463–1472. [ Google Scholar ] [ CrossRef ] Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald: An N.log(N) method for Ewald sums in large systems. J. Chem. Phys. 1993 , 98 , 10089–10092. [ Google Scholar ] [ CrossRef ] Rosenbaum, D.M.; Zhang, C.; Lyons, J.; Holl, R.; Aragao, D.; Arlow, D.H.; Rasmussen, S.G.F.; Choi, H.J.; DeVree, B.T.; Sunahara, R.K.; et al. Structure and Function of an Irreversible Agonist-β 2 Adrenoceptor complex. Nature 2011 , 469 , 236–240. [ Google Scholar ] [ CrossRef ] Dror, R.O.; Arlow, D.H.; Borhani, D.W.; Jensen, M.Ø.; Piana, S.; Shaw, D.E. Identification of two distinct inactive conformations of the β 2 -adrenergic receptor reconciles structural and biochemical observations. Proc. Natl. Acad. Sci. USA 2009 , 106 , 4689–4694. [ Google Scholar ] [ CrossRef ] Pieper, U.; Webb, B.M.; Dong, G.Q.; Schneidman-Duhovny, D.; Fan, H.; Kim, S.J.; Khuri, N.; Spill, Y.G.; Weinkam, P.; Hammel, M.; et al. ModBase, a database of annotated comparative protein structure models and associated resources. Nucleic Acids Res. 2014 , 42 , D336–D346. [ Google Scholar ] [ CrossRef ][ Green Version ] Dror, R.O.; Arlow, D.H.; Maragakis, P.; Mildorf, T.J.; Pan, A.C.; Xu, H.; Borhani, D.W.; Shaw, D.E. Activation mechanism of the β 2 -adrenergic receptor. Proc. Natl. Acad. Sci. USA 2011 , 108 , 18684–18689. [ Google Scholar ] [ CrossRef ] Dilcan, G.; Doruker, P.; Akten, E.D. Ligand-binding affinity of alternative conformers of human β 2 -adrenergic receptor in the presence of intracellular loop 3 (ICL3) and their potential use in virtual screening studies. Chem. Biol. Drug Des. 2019 , 93 , 883–899. [ Google Scholar ] [ CrossRef ] Vanni, S.; Neri, M.; Tavernelli, I.; Rothlisberger, U. A Conserved Protonation-Induced Switch can Trigger “Ionic-Lock” Formation in Adrenergic Receptors. J. Mol. Biol. 2010 , 397 , 1339–1349. [ Google Scholar ] [ CrossRef ] Ranganathan, A.; Dror, R.O.; Carlsson, J. Insights into the Role of Asp792.50 in β 2 Adrenergic Receptor Activation from Molecular Dynamics Simulations. Biochemistry 2014 , 53 , 7283–7296. [ Google Scholar ] [ CrossRef ] [ PubMed ] Bang, I.; Choi, H.J. Structural Features of β 2 Adrenergic Receptor: Crystal Structures and Beyond. Mol. Cells 2015 , 38 , 105–111. [ Google Scholar ] [ CrossRef ] Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph. Model. 1996 , 14 , 33–38. [ Google Scholar ] [ CrossRef ] Tosso, R.D.; Parravicini, O.; Zarycz, M.N.C.; Angelina, E.; Vettorazzi, M.; Peruchena, N.; Andujar, S.; Enriz, R.D. Conformational and electronic study of dopamine interacting with the D2 dopamine receptor. J. Comput. Chem. 2020 , 41 , 1898–1911. [ Google Scholar ] [ CrossRef ] Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. J. Comput. Chem. 2009 , 30 , 2785–2791. [ Google Scholar ] [ CrossRef ] Feinstein, W.P.; Brylinski, M. Calculating an optimal box size for ligand docking and virtual screening against experimental and predicted binding pockets. J. Cheminform. 2015 , 7 , 1–10. [ Google Scholar ] [ CrossRef ] [ PubMed ] Cosconati, S.; Forli, S.; Perryman, A.L.; Harris, R.; Goodsell, D.S.; Olson, A.J. Virtual Screening with AutoDock: Theory and Practice. Expert. Opin. Drug. Discov. 2010 , 5 , 597–607. [ Google Scholar ] [ CrossRef ][ Green Version ] Cosconati, S.; Marinelli, L.; Di Leva, F.S.; La Pietra, V.; De Simone, A.; Mancini, F.; Andrisano, V.; Novellino, E.; Goodsell, D.S.; Olson, A.J. Protein Flexibility in Virtual Screening: The BACE-1 Case Study. J. Chem. Inf. Model. 2012 , 52 , 2697–2704. [ Google Scholar ] [ CrossRef ] [ PubMed ] Del Carmine, R.; Ambrosio, C.; Sbraccia, M.; Cotecchia, S.; Ijzerman, A.P.; Costa, T. Mutations inducing divergent shifts of constitutive activity reveal different modes of binding among catecholamine analogues to the β 2 -adrenergic receptor. Br. J. Pharmacol. 2002 , 135 , 1715–1722. [ Google Scholar ] [ CrossRef ] [ PubMed ] Biswas, A.D.; Catte, A.; Mancini, G.; Barone, V. Analysis of L-DOPA and Droxidopa binding to Human β 2 -Adrenergic Receptor. Biophys. J. 2021 , 7 , 1–18. [ Google Scholar ] [ CrossRef ] Norgan, A.P.; Coffman, P.K.; Kocher, J.P.A.; Katzmann, D.J.; Sosa, C.P. Multilevel Parallelization of AutoDock 4.2. J. Cheminform. 2011 , 3 , 12. [ Google Scholar ] [ CrossRef ] Sanner, M.F. Python: A programming language for software integration and development. J. Mol. Graph. Model. 1999 , 17 , 57–61. [ Google Scholar ] Salentin, S.; Schreiber, S.; Haupt, V.J.; Adasme, M.F.; Schroeder, M. PLIP: Fully automated protein–ligand interaction profiler. Nucleic Acids Res. 2015 , 43 , W443–W447. [ Google Scholar ] [ CrossRef ] Laskowski, R.A.; Swindells, M.B. LigPlot+: Multiple Ligand–Protein Interaction Diagrams for Drug Discovery. J. Chem. Inf. Model. 2011 , 51 , 2778–2786. [ Google Scholar ] [ CrossRef ] Maciejewski, A.; Pasenkiewicz-Gierula, M.; Cramariuc, O.; Vattulainen, I.; Róg, T. Refined OPLS All-Atom Force Field for Saturated Phosphatidylcholine Bilayers at Full Hydration. J. Phys. Chem. B 2014 , 118 , 4571–4581. [ Google Scholar ] [ CrossRef ] Kulig, W.; Pasenkiewicz-Gierula, M.; Róg, T. Topologies, structures and parameter files for lipid simulations in GROMACS with the OPLS-aa force field: DPPC, POPC, DOPC, PEPC, and cholesterol. Data Brief 2015 , 5 , 333–336. [ Google Scholar ] [ CrossRef ] Kulig, W.; Pasenkiewicz-Gierula, M.; Róg, T. Cis and trans unsaturated phosphatidylcholine bilayers: A molecular dynamics simulation study. Chem. Phys. Lipids 2016 , 195 , 12–20. [ Google Scholar ] [ CrossRef ] Kumari, R.; Kumar, R.; Lynn, A.; Open Source Drug Discovery Consortium. g_mmpbsa–A GROMACS tool for high-throughput MM-PBSA calculations. J. Chem. Inf. Model. 2014 , 54 , 1951–1962. [ Google Scholar ] [ CrossRef ] [ PubMed ] Del Galdo, S.; Mancini, G.; Daidone, I.; Polzi Zanetti, L.; Amadei, A.; Barone, V. Tyrosine absorption spectroscopy: Backbone protonation effects on the side chain electronic properties. J. Comput. Chem. 2018 , 39 , 1747–1756. [ Google Scholar ] [ CrossRef ] [ PubMed ] Katritch, V.; Reynolds, K.A.; Cherezov, V.; Hanson, M.A.; Roth, C.B.; Yeager, M.; Abagyan, R. Analysis of Full and Partial Agonists Binding to β 2 -Adrenergic Receptor Suggests a Role of Transmembrane Helix V in Agonist-Specific Conformational Changes. J. Mol. Recognit. 2009 , 22 , 307–318. [ Google Scholar ] [ CrossRef ] [ PubMed ] Álvarez Diduk, R.; Galano, A. Adrenaline and Noradrenaline: Protectors against Oxidative Stress or Molecular Targets? J. Phys. Chem. B 2015 , 119 , 3479–3491. [ Google Scholar ] [ CrossRef ] Del Carmine, R.; Molinari, P.; Sbraccia, M.; Ambrosio, C.; Costa, T. “Induced-Fit” Mechanism for Catecholamine Binding to the β 2 -Adrenergic Receptor. Mol. Pharmacol. 2004 , 66 , 356–363. [ Google Scholar ] [ CrossRef ] Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem. 2010 , 31 , 455–461. [ Google Scholar ] [ CrossRef ] Strader, C.D.; Sigal, I.S.; Candelore, M.R.; Rands, E.; Hill, W.S.; Dixon, R.A. Conserved aspartic acid residues 79 and 113 of the beta-adrenergic receptor have different roles in receptor function. J. Biol. Chem. 1988 , 263 , 10267–10271. [ Google Scholar ] [ CrossRef ] Suryanarayana, S.; Kobilka, B.K. Amino acid substitutions at position 312 in the seventh hydrophobic segment of the beta 2-adrenergic receptor modify ligand-binding specificity. Mol. Pharmacol. 1993 , 44 , 111–114. [ Google Scholar ] Hannawacker, A.; Krasel, C.; Lohse, M. Mutation of Asn293 to Asp in transmembrane helix VI abolishes agonist-induced but not constitutive activity of the beta(2)-adrenergic receptor. Mol. Pharmacol. 2002 , 62 , 1431–1437. [ Google Scholar ] [ CrossRef ] Wieland, K.; Zuurmond, H.M.; Krasel, C.; Ijzerman, A.P.; Lohse, M.J. Involvement of Asn-293 in stereospecific agonist recognition and in activation of the beta 2-adrenergic receptor. Proc. Natl. Acad. Sci. USA 1996 , 93 , 9276–9281. [ Google Scholar ] [ CrossRef ] Ambrosio, C.; Molinari, P.; Cotecchia, S.; Costa, T. Catechol-binding serines of β 2 -adrenergic receptors control the equilibrium between active and inactive receptor states. Mol. Pharmacol. 2000 , 57 , 198–210. [ Google Scholar ] Liapakis, G.; Ballesteros, J.A.; Papachristou, S.; Chan, W.C.; Chen, X.; Javitch, J.A. The forgotten serine. A critical role for Ser-2035.42 in ligand binding to and activation of the beta 2-adrenergic receptor. J. Biol. Chem. 2000 , 275 , 37779–37788. [ Google Scholar ] [ CrossRef ] Liapakis, G.; Chan, W.C.; Papadokostaki, M.; Javitch, J.A. Synergistic contributions of the functional groups of epinephrine to its affinity and efficacy at the beta2 adrenergic receptor. Mol. Pharmacol. 2004 , 65 , 1181–1190. [ Google Scholar ] [ CrossRef ][ Green Version ] Strader, C.D.; Candelore, M.R.; Hill, W.S.; Sigal, I.S.; Dixon, R.A. Identification of two serine residues involved in agonist activation of the beta-adrenergic receptor. J. Biol. Chem. 1989 , 264 , 13572–13578. [ Google Scholar ] [ CrossRef ] Bandaru, S.; Alvala, M.; Nayarisseri, A.; Sharda, S.; Goud, H.; Mundluru, H.P.; Singh, S.K. Molecular dynamic simulations reveal suboptimal binding of salbutamol in T164I variant of β 2 adrenergic receptor. PLoS ONE 2017 , 12 , e0186666. [ Google Scholar ] [ CrossRef ] Isin, B.; Estiu, G.; Wiest, O.; Oltvai, Z.N. Identifying Ligand Binding Conformations of the β 2 -Adrenergic Receptor by Using Its Agonists as Computational Probes. PLoS ONE 2012 , 7 , e50186. [ Google Scholar ] [ CrossRef ] Plazinska, A.; Kolinski, M.; Wainer, I.W.; Jozwiak, K. Molecular interactions between fenoterol stereoisomers and derivatives and the β 2 -adrenergic receptor binding site studied by docking and molecular dynamics simulations. J. Mol. Model. 2013 , 19 , 4919–4930. [ Google Scholar ] [ CrossRef ] Dickson, C.J.; Hornak, V.; Velez-Vega, C.; McKay, D.J.J.; Reilly, J.; Sandham, D.A.; Shaw, D.; Fairhurst, R.A.; Charlton, S.J.; Sykes, D.A.; et al. Uncoupling the Structure–Activity Relationships of β 2 Adrenergic Receptor Ligands from Membrane Binding. J. Med. Chem. 2016 , 59 , 5780–5789. [ Google Scholar ] [ CrossRef ] Manna, M.; Niemelä, M.; Tynkkynen, J.; Javanainen, M.; Kulig, W.; Müller, D.J.; Rog, T.; Vattulainen, I. Mechanism of allosteric regulation of β 2-adrenergic receptor by cholesterol. Elife 2016 , 5 , e18432. [ Google Scholar ] [ CrossRef ] Zocher, M.; Fung, J.J.; Kobilka, B.K.; Müller, D.J. Ligand-specific interactions modulate kinetic, energetic, and mechanical properties of the human β 2 adrenergic receptor. Structure 2012 , 20 , 1391–1402. [ Google Scholar ] [ CrossRef ] Cole, S.W.; Sood, A.K. Molecular pathways: Beta-adrenergic signaling in cancer. Clin. Cancer Res. 2012 , 18 , 1201–1206. [ Google Scholar ] [ CrossRef ] [ PubMed ] Eberhardt, J.; Santos-Martins, D.; Tillack, A.F.; Forli, S. AutoDock Vina 1.2.0: New docking methods, expanded force field, and Python bindings. J. Chem. Inf. Model. 2021 , 61 , 3891–3898. [ Google Scholar ] [ CrossRef ] [ PubMed ] Figure 1. Chemical structures of protonated adrenaline and zwitterionic L-DOPA and Droxidopa ligands. Carbon, hydrogen, nitrogen and oxygen atoms are shown in cyan, white, blue and red, respectively. Non-polar hydrogens are not shown for clarity. Dihedral angles of each ligand are highlighted by green arrows. Figure 1. Chemical structures of protonated adrenaline and zwitterionic L-DOPA and Droxidopa ligands. Carbon, hydrogen, nitrogen and oxygen atoms are shown in cyan, white, blue and red, respectively. Non-polar hydrogens are not shown for clarity. Dihedral angles of each ligand are highlighted by green arrows. Figure 2. ( A ) A side view of the β 2 AR model shows the main changes applied to the 4LDO original structure with adrenaline (ALE) in its crystallographic binding site highlighted by a green square. β 2 AR TM α -helices and the ICL3 domain are in gray and red, respectively. M96, M98, N187 and C265 residues, which are mutated in the X-ray crystal structure, and Q231 and K263 residues connecting 4LDO to the ICL3 domain are shown in licorice representation. ( B ) β 2 AR residues of the binding pocket interacting with crystallographic adrenaline (green) are shown in purple without hydrogens. TM α -helices III, V, VI and VII are displayed in grey. ( C ) Chemical structures of protonated adrenaline and zwitterionic L-DOPA and Droxidopa molecules employed in the molecular docking to rigid and flexible β 2 AR receptor models. Figure 2. ) A side view of the β 2 AR model shows the main changes applied to the 4LDO original structure with adrenaline (ALE) in its crystallographic binding site highlighted by a green square. β 2 AR TM α -helices and the ICL3 domain are in gray and red, respectively. M96, M98, N187 and C265 residues, which are mutated in the X-ray crystal structure, and Q231 and K263 residues connecting 4LDO to the ICL3 domain are shown in licorice representation. ( B ) β 2 AR residues of the binding pocket interacting with crystallographic adrenaline (green) are shown in purple without hydrogens. TM α -helices III, V, VI and VII are displayed in grey. ( C ) Chemical structures of protonated adrenaline and zwitterionic L-DOPA and Droxidopa molecules employed in the molecular docking to rigid and flexible β 2 AR receptor models. Figure 3. Torsional profiles derived from QM calculations (dots) and JOYCE (lines) for zwitterionic L-DOPA. Each panel refers to dihedral angles defined in Figure 1 . Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 3. Torsional profiles derived from QM calculations (dots) and JOYCE (lines) for zwitterionic L-DOPA. Each panel refers to dihedral angles defined in Figure 1 . Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 4. Torsional profiles derived from QM calculations (dots) and JOYCE (lines) for zwitterionic Droxidopa. Each panel refers to one of the dihedral angles defined in Figure 1 . Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 4. Torsional profiles derived from QM calculations (dots) and JOYCE (lines) for zwitterionic Droxidopa. Each panel refers to one of the dihedral angles defined in Figure 1 . Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 5. ( Top ) Dihedral distributions in vacuum (green) and water (cyan) are compared to torsional profiles obtained by QM calculations (dots) and JOYCE (lines) for zwitterionic L-DOPA. Each panel refers to one of the dihedral angles defined in Figure 1 . ( Bottom ) L-DOPA structures simulated for 20 ns and 100 ns in vacuum and water, respectively. Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 5. ( Top ) Dihedral distributions in vacuum (green) and water (cyan) are compared to torsional profiles obtained by QM calculations (dots) and JOYCE (lines) for zwitterionic L-DOPA. Each panel refers to one of the dihedral angles defined in Figure 1 . ( Bottom ) L-DOPA structures simulated for 20 ns and 100 ns in vacuum and water, respectively. Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 6. ( Top ) Dihedral distributions in vacuum (green) and water (cyan) compared to torsional profiles obtained by QM calculations (dots) and JOYCE (lines) for zwitterionic Droxidopa. Each panel refers to one of the dihedral angles defined in Figure 1 . ( Bottom ) Droxidopa structures simulated for 20 ns and 100 ns in vacuum and water, respectively. Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 6. ( Top ) Dihedral distributions in vacuum (green) and water (cyan) compared to torsional profiles obtained by QM calculations (dots) and JOYCE (lines) for zwitterionic Droxidopa. Each panel refers to one of the dihedral angles defined in Figure 1 . ( Bottom ) Droxidopa structures simulated for 20 ns and 100 ns in vacuum and water, respectively. Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 7. ( Top ) Zwitterionic L-DOPA QM torsional energy profiles (circles) compared with Helmholtz free energy variations as a function of the dihedral angle, as obtained from MD simulations performed using JOYCE (magenta dots) and OPLS (cyan dots) FFs. ( Bottom ) 100 ns structures of L-DOPA from MD simulations using JOYCE and OPLS (Fittings) FF parameters, respectively. Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 7. ( Top ) Zwitterionic L-DOPA QM torsional energy profiles (circles) compared with Helmholtz free energy variations as a function of the dihedral angle, as obtained from MD simulations performed using JOYCE (magenta dots) and OPLS (cyan dots) FFs. ( Bottom ) 100 ns structures of L-DOPA from MD simulations using JOYCE and OPLS (Fittings) FF parameters, respectively. Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 8. ( Top ) Zwitterionic Droxidopa QM torsional energy profiles (circles) compared with Helmholtz free energy variations as a function of the dihedral angle, as obtained from MD simulations performed using JOYCE (magenta dots; for clarity, red dots are used for the dihedral θ ) and OPLS AA FFs (cyan dots); ( Bottom ) 100 ns structures of Droxidopa from MD simulations using JOYCE and OPLS (Fittings) FF parameters, respectively. Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 8. ( Top ) Zwitterionic Droxidopa QM torsional energy profiles (circles) compared with Helmholtz free energy variations as a function of the dihedral angle, as obtained from MD simulations performed using JOYCE (magenta dots; for clarity, red dots are used for the dihedral θ ) and OPLS AA FFs (cyan dots); ( Bottom ) 100 ns structures of Droxidopa from MD simulations using JOYCE and OPLS (Fittings) FF parameters, respectively. Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 9. Conformations of adrenaline from the 2 AR X-ray crystal structure (PDB ID: 4LDO) and the redocking of the ligand to rigid ( A ) and flexible ( B ) models of the receptor are shown in yellow and green, respectively. Lowest energy binding poses of adrenaline from the molecular docking to rigid (yellow) and flexible (green) 2 AR models are compared to the ligand’s conformation in the X-ray crystal structure (dark green). The protein is shown as grey ribbons and β 2 AR side chains in contact with adrenaline are shown as sticks and balls. Carbon atoms of rigid and flexible side chains of 2 AR amino acid residues interacting with adrenaline are shown in purple and green, respectively. Hydrogen bonds are shown with cyan spheres. All non-polar hydrogens are not shown. Figure 9. Conformations of adrenaline from the 2 AR X-ray crystal structure (PDB ID: 4LDO) and the redocking of the ligand to rigid ( A ) and flexible ( B ) models of the receptor are shown in yellow and green, respectively. Lowest energy binding poses of adrenaline from the molecular docking to rigid (yellow) and flexible (green) β 2 AR models are compared to the ligand’s conformation in the X-ray crystal structure (dark green). The protein is shown as grey ribbons and 2 AR side chains in contact with adrenaline are shown as sticks and balls. Carbon atoms of rigid and flexible side chains of β 2 AR amino acid residues interacting with adrenaline are shown in purple and green, respectively. Hydrogen bonds are shown with cyan spheres. All non-polar hydrogens are not shown. Figure 10. Binding poses of L-DOPA obtained from the molecular docking into ( A ) rigid and ( B ) flexible models of the β 2 AR receptor. The largest cluster conformation of L-DOPA (salmon) in a β 2 AR rigid model displays more hydrogen bonds with anchor sites as compared to the lowest energy binding pose of the ligand in a flexible receptor. Carbon atoms of flexible side chains in the binding site are in green. View point and color code as in Figure 9 . Figure 10. A ) rigid and ( B ) flexible models of the β 2 AR receptor. The largest cluster conformation of L-DOPA (salmon) in a β 2 AR rigid model displays more hydrogen bonds with anchor sites as compared to the lowest energy binding pose of the ligand in a flexible receptor. Carbon atoms of flexible side chains in the binding site are in green. View point and color code as in Figure 9 . Figure 11. Conformations from the molecular docking of Droxidopa to ( A ) rigid and ( B ) flexible models of the β 2 AR receptor. The lowest energy binding pose of Droxidopa (violet) in a rigid receptor displays more hydrogen bond interactions with anchor sites when compared to the lowest energy binding conformation of the ligand in a flexible β 2 AR model. Carbon atoms of flexible side chains in the binding site are in green. View point and color code as in Figure 9 . Figure 11. Conformations from the molecular docking of Droxidopa to ( A ) rigid and ( B ) flexible models of the β 2 AR receptor. The lowest energy binding pose of Droxidopa (violet) in a rigid receptor displays more hydrogen bond interactions with anchor sites when compared to the lowest energy binding conformation of the ligand in a flexible β 2 AR model. Carbon atoms of flexible side chains in the binding site are in green. View point and color code as in Figure 9 . Figure 12. Number of ( A ) hydrogen bond and ( B ) hydrophobic contacts between β 2 AR amino acids and different catecholamines docked into rigid and flexible receptor models obtained by molecular docking calculations. Figure 12. Number of ( A ) hydrogen bond and ( B ) hydrophobic contacts between β 2 AR amino acids and different catecholamines docked into rigid and flexible receptor models obtained by molecular docking calculations. Figure 13. Receptor hydrophobic residues in contact with lowest energy binding poses of ( A ) L-DOPA and ( B ) Droxidopa docked into flexible β 2 AR models are shown in yellow. View point and color code as in Figure 9 . Figure 13. Receptor hydrophobic residues in contact with lowest energy binding poses of ( A ) L-DOPA and ( B ) Droxidopa docked into flexible β 2 AR models are shown in yellow. View point and color code as in Figure 9 . Figure 14. ( A ) RMSDs of β 2 AR C α atoms in receptor complexes with adrenaline (green), L-DOPA (blue) and Droxidopa (red). ( B ) RMSDs of ligands heavy atoms. Figure 14. ( A ) RMSDs of β 2 AR C α atoms in receptor complexes with adrenaline (green), L-DOPA (blue) and Droxidopa (red). ( B ) RMSDs of ligands heavy atoms. Figure 15. Snapshots of MD simulations of β 2 AR-catecholamine complexes show the hydrogen bond network of ( top ) L-DOPA and ( bottom ) Droxidopa ligands with key amino acids of the receptor binding pocket using CHARMM and OPLS AA FFs. Hydrogen bonds are highlighted with dashed blue lines. View point and color code as in Figure 5 of ref. [ 76 ]. Figure 15. Snapshots of MD simulations of β 2 AR-catecholamine complexes show the hydrogen bond network of ( top ) L-DOPA and ( bottom ) Droxidopa ligands with key amino acids of the receptor binding pocket using CHARMM and OPLS AA FFs. Hydrogen bonds are highlighted with dashed blue lines. View point and color code as in Figure 5 of ref. [ 76 ]. Figure 16. Normalized number of contacts of ( A ) L-DOPA and ( B ) Droxidopa with the receptor residues extracted from 1 μ s AA MD simulations of the β 2 AR-catecholamine complexes performed with the OPLS AA FF. Snapshots from MD simulations show β 2 AR hydrophilic (cyan) and hydrophobic (yellow) residues interacting with ( top ) L-DOPA and ( bottom ) Droxidopa ligands. For clarity, only β 2 AR residues displaying the largest percentages of contacts with the ligand are shown. Side chains of some residues are indicated by green arrows. This analysis was performed over the whole 1 μ s trajectory. Figure 16. Normalized number of contacts of ( A ) L-DOPA and ( B ) Droxidopa with the receptor residues extracted from 1 μ s AA MD simulations of the β 2 AR-catecholamine complexes performed with the OPLS AA FF. Snapshots from MD simulations show β 2 AR hydrophilic (cyan) and hydrophobic (yellow) residues interacting with ( top ) L-DOPA and ( bottom ) Droxidopa ligands. For clarity, only β 2 AR residues displaying the largest percentages of contacts with the ligand are shown. Side chains of some residues are indicated by green arrows. This analysis was performed over the whole 1 μ s trajectory. Figure 17. The mapping of energy contributions on the structure of β 2 AR-catecholamine complexes and contribution energies of β 2 AR residues for ( top ) adrenaline, ( middle ) L-DOPA and ( bottom ) Droxidopa ligands. Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Figure 17. The mapping of energy contributions on the structure of β 2 AR-catecholamine complexes and contribution energies of β 2 ) adrenaline, ( middle ) L-DOPA and ( bottom ) Droxidopa ligands. Energies are reported in kilojoules per mole (1 kJ/mol = 0.24 kcal/mol). Table 1. Calculated binding affinities, pK d , of different ligands for rigid and flexible β 2 AR models obtained by molecular docking calculations in comparison with experimental values. Table 1. Calculated binding affinities, pK d , of different ligands for rigid and flexible β 2 AR models obtained by molecular docking calculations in comparison with experimental values. Ligand Calculated Binding Affinity pK d a Experimental Binding Affinity pK d Rigid Model Flexible Model Adrenaline 5.9 9.2 6.1 b –6.5 c (3.3) d L-DOPA 4.7 9.4 NA (3.9) Droxidopa 5.4 10.3 NA (9.2) Table 2. Hydrogen bond distances for different β 2 AR-Ligand complexes from AD4 calculations. This analysis was performed on the following ligands: adrenaline (ALE), L-DOPA (DAH) and Droxidopa (DRO). Distances not compatible with hydrogen bonding are shown in bold characters. Table 2. Hydrogen bond distances for different β 2 AR-Ligand complexes from AD4 calculations. This analysis was performed on the following ligands: adrenaline (ALE), L-DOPA (DAH) and Droxidopa (DRO). Distances not compatible with hydrogen bonding are shown in bold characters. Hydrogen Bonds ( β 2 AR-Ligand) Donor-Acceptor Distance (Å) Rigid Model Flexible Model ALE DAH DRO ALE DAH DRO OD1 (D113)-N (amino) 3.7 ( 4.1 ) a 3.0 3.4 2.8 2.8 2.8 OD2 (D113)-N (amino) 2.7 (2.8) 2.5 2.4 2.6 2.5 2.3 OD1 (D113)-O ( β -OH) 3.0 (2.8) - c 2.7 3.1 - 2.9 OG1 (T118)-O (para) 3.3 ( 4.4 ) 6.2 3.6 3.4 3.1 3.1 OG1 (T118)-O (meta) 3.2 ( 7.0 ) 3.7 3.3 2.6 2.7 3.1 OG (S203)-O (para) 4.7 ( 3.7 ) 2.8 4.3 2.7 2.6 4.7 OG (S203)-O (meta) 7.1 (3.2) 7.1 5.1 5.1 4.9 7.5 OG (S204)-O (para) 6.5 ( 5.7 ) 3.5 6.3 6.2 5.5 6.9 OG (S204)-O (meta) 8.7 ( 4.8 ) 6.2 8.7 8.0 7.8 8.8 OG (S207)-O (para) 2.6 (3.5) 4.5 2.9 3.1 2.5 2.7 OG (S207)-O (meta) 4.0 (6.0) 2.9 4.1 2.8 3.1 3.9 OD1 (N312)-N (amino) 2.8 (2.8) 2.9 2.7 3.0 3.0 2.9 ND2 (N312)-O ( β -OH) 2.9 (2.8) - 2.8 4.9 - 3.0 ND2 (N312)-O1 (-COO − ) - b 2.7 4.6 - 2.5 3.5 ND2 (N312)-O2 (-COO − ) - 4.0 5.3 - 4.0 5.0 OH (Y316)-N (amino) 3.4 (3.5) 3.0 2.9 3.3 2.4 2.4 OH (Y316)-O ( β -OH) 3.9 (3.5) - 3.5 4.1 - 3.9 a Hydrogen bonds of adrenaline’s conformation in the β 2 AR X-ray crystal structure (PDB ID: 4LDO) are shown in parentheses. b COO− group is absent in the adrenaline ligand. c β-OH group is absent in the L-DOPA ligand. MDPI and ACS Style Catte, A.; Biswas, A.D.; Mancini, G.; Barone, V. L-DOPA and Droxidopa: From Force Field Development to Molecular Docking into Human β 2-Adrenergic Receptor. Life 2022, 12, 1393. https://doi.org/10.3390/life12091393 AMA Style Catte A, Biswas AD, Mancini G, Barone V. L-DOPA and Droxidopa: From Force Field Development to Molecular Docking into Human β 2-Adrenergic Receptor. Life. 2022; 12(9):1393. https://doi.org/10.3390/life12091393 Chicago/Turabian Style Catte, Andrea, Akash Deep Biswas, Giordano Mancini, and Vincenzo Barone. 2022. "L-DOPA and Droxidopa: From Force Field Development to Molecular Docking into Human β 2-Adrenergic Receptor" Life12, no. 9: 1393. https://doi.org/10.3390/life12091393 Article Metrics
https://www.mdpi.com/2075-1729/12/9/1393
IJERPH | Free Full-Text | Willingness to Take COVID-19 Vaccines in Ethiopia: An Instrumental Variable Probit Approach This paper analyzed the factors influencing the willingness of Ethiopia’s population to take COVID-19 vaccines. The data included the COVID-19 High Frequency Phone Survey of Households in Ethiopia that were collected in 2021. This paper relied on the 10th round of the survey, which was comprised of 2178 households. The Instrumental Variable Probit regression model was used to analyze the data. The results showed that majority of the respondents (92.33%) would receiveCOVID-19 vaccines, while 6.61% and 1.06% were, respectively, unwilling and unsure. Across the regions of Ethiopia, Southern Nations, Nationalities, and Peoples’ Region (SNNPR) (99.30%), Oromia (97.54%), Tigray (97.04%) and Gambela (95.42%) had the highest proportions of respondents willing to have the vaccine. Vaccine safety concern was the topmost reason for those unwilling to receive the vaccine. The results of the Instrumental Variable Probit regression showed that currently working, age, engagement with non-farm businesses and region of residence significantly influenced the population’s willingness to take the vaccine (p < 0.05). It was concluded that although the willingness be vaccinated was impressive, without everyone being receiving the COVID-19 vaccine, infection risk can still be high; this is due to the persistent mutation of the viral strains. Thus, there is a need to intensify efforts toward addressing the safety issues of COVID-19 vaccines, while efforts to enhance acceptability should focus on the youth population and those who are unemployed. Willingness to Take COVID-19 Vaccines in Ethiopia: An Instrumental Variable Probit Approach Int. J. Environ. Res. Public Health 2021 , 18 (17), 8892; https://doi.org/10.3390/ijerph18178892 Received: 7 July 2021 / Revised: 18 August 2021 / Accepted: 19 August 2021 / Published: 24 August 2021 Abstract This paper analyzed the factors influencing the willingness of Ethiopia’s population to take COVID-19 vaccines. The data included the COVID-19 High Frequency Phone Survey of Households in Ethiopia that were collected in 2021. This paper relied on the 10th round of the survey, which was comprised of 2178 households. The Instrumental Variable Probit regression model was used to analyze the data. The results showed that majority of the respondents (92.33%) would receiveCOVID-19 vaccines, while 6.61% and 1.06% were, respectively, unwilling and unsure. Across the regions of Ethiopia, Southern Nations, Nationalities, and Peoples’ Region (SNNPR) (99.30%), Oromia (97.54%), Tigray (97.04%) and Gambela (95.42%) had the highest proportions of respondents willing to have the vaccine. Vaccine safety concern was the topmost reason for those unwilling to receive the vaccine. The results of the Instrumental Variable Probit regression showed that currently working, age, engagement with non-farm businesses and region of residence significantly influenced the population’s willingness to take the vaccine ( p < 0.05). It was concluded that although the willingness be vaccinated was impressive, without everyone being receiving the COVID-19 vaccine, infection risk can still be high; this is due to the persistent mutation of the viral strains. Thus, there is a need to intensify efforts toward addressing the safety issues of COVID-19 vaccines, while efforts to enhance acceptability should focus on the youth population and those who are unemployed. Keywords: COVID-19 ; viral strain ; vaccine ; vaccination ; Ethiopia 1. Introduction Judging by the intensity of its morbidity and mortality, COVID-19 has proved to be one of the worst pandemics the world has recently witnessed. Having been declared as a Public Health Emergency of International Concern (PHEIC), addressing COVID-19 requires the proper administration of medical services, among which effective vaccination cannot be over-emphasized [ 1 ]. This is in alignment with conventional wisdom derived from the fact that, aside from access to safe drinking water, no other interventions in the history of mankind have had significant impacts on reducing incidences of morbidity and mortality as vaccinations [ 2 ]. The World Health Organization (WHO) is therefore advocating for speedy interventions that would ensure access of every individual to COVID-19 vaccines, as a way of securing our collective existence given the severity of the ongoing pandemic. Generally, vaccines are meant to enhance the immune system through their extraordinary ability in responding to and remembering certain encounters with pathogenic antigens [ 3 ]. More importantly, over the past few decades, a number of success stories in addressing many pandemics of worrisome morbidity and fatality have been directly associated with development and effective utilization of vaccines. It has been estimated that, annually, vaccines prevent about 6 million deaths that could have resulted from vaccine-preventable diseases [ 4 ]. Therefore, healthcare professionals and policymakers are now advocating for development of vaccines in sufficient quantities, in order to address the ongoing COVID-19 pandemic. Vaccines can be classified as live or non-live. Live vaccines are used with certain restrictions since they can replicate uncontrollably in individuals whose immune systems are compromised as a result of underlying medical conditions [ 3 ]. However, individuals with compromised immune systems can access non-live vaccines without risk, although their efficacy may be substantially sub-optimal [ 5 ]. However, due to several factors, addressing COVID-19 through vaccination presents some peculiar challenges. The first borders on several speculations on the emergence of the virus, many of which may influence acceptability of global efforts in addressing its spread. Specifically, there have been a number of conspiracy theories advancing the hidden international agendas throughout the COVID-19 saga, many of which are precipitating fears and vaccine hesitancy [ 6 ]. The emergence of social media as major platform for information-sharing has rendered an individual of the 21st century more informed, whether rightly or wrongly. Specifically, it should be reemphasized that the acceptability of polio vaccines in Nigeria, Pakistan and Afghanistan was affected by misinformation on its tendency to inhibit fertility [ 7 , 8 ]. Presently, the information around COVID-19 vaccines has been diverse, and much of this information is spreading misleading rumors [ 9 ]. There have been underlying notions that COVID-19 vaccines may contain deliberate poisons that are meant to control global population [ 10 ]. In a recent study, 91% of the information obtained from several countries on the internet was classified as rumors [ 10 ]. These include the fear of being sick or dying after receiving the COVID-19 vaccination and that the vaccine is a messenger Ribonucleic acid (mRNA) that may distort the sequence of human deoxyribonucleic acid (DNA), thereby turning them into mere prototypic beings whose genetic compositions may have been silently modified [ 10 ]. Several factors may influence an individual’s conception or belief in medical procedures for disease prevention. People also the fundamental right to decline whatever options are presented to them by healthcare professionals [ 11 ]. Except by legislative means, many countries cannot force individuals to be vaccinated against their will. More importantly, some authors have highlighted the factors that can influence the decision to comply with government’s vaccination programs. These include possession of proper education on health-related issues, an individual’s perception of the level of risk [ 10 , 12 , 13 , 14 ], race [ 15 ], perceived risk of infection [ 16 ], perceived benefits [ 17 ], age [ 15 , 18 , 19 , 20 , 21 ], educational level [ 18 ], gender [ 15 , 19 , 21 ], chronic medical condition [ 19 ], access to health insurance [ 19 ], ethnicity, income and employment [ 22 ] and previously being tested for the virus [ 18 ]. It should be emphasized that most of these studies have been conducted in the United States of America and China. There are currently very few studies on African countries and Ethiopia in particular. Studies on the willingness to partake in the COVID-19 vaccination program are not only important but essentially timely. Such studies can enhance the understanding of health policymakers on socio-economic and demographic factors that influence vaccination compliance. This is going to assist public health practitioners in evaluating the expected effectiveness of resources that are being committed to the procurement of vaccines and the expected impacts on the control and management of COVID-19 pandemic. 2. Materials and Methods 2.1. The Data This study used the data from the COVID-19 High Frequency Phone Survey of Households in Ethiopia that commenced in 2020 [ 23 ]. The World Bank leveraged the Living Standards Measurement Study (LSMS) to implement this survey based on existing long-term collaboration with the Central Statistical Agency (CSA) of Ethiopia [ 23 ].The survey is therefore a subsample of the Ethiopia Socioeconomic Survey (ESS) that was conducted by the CSA in 2018/2019. ESS is a long-term project that is being implemented by the CSA, which is constitutionally mandated according to Ethiopia’s Proclamation No. 442/2005 to coordinate the National Statistical System (NSS) in order to provide time-responsive datasets for informed policy decisions [ 24 ]. The survey was telephonically conductedbetween 1st and 23rd of February 2021 and the World Bank has implemented similar collaborations between national statistical agencies of five other African countries, including Tanzania, Malawi, Nigeria, Uganda and Kenya [ 23 ]. The respondents were contacted through the phone numbers that were provided during the previous ESS. The sampling frame was therefore formed by the list of all the households that supplied their phone numbers, because correctly addressing the COVID-19 pandemic necessitates social distancing and intermittent lockdowns within Ethiopia [ 25 ]. Specifically, out of the 7527 households that formed the sampling frame for wave 4 of the 2018/2019 ESS [ 26 ], valid phone numbers were obtained for 5374 households, with 4626 being phone-owners and 995 providing reference phone numbers. The first round of the survey targeted 3300 households for an interview in order to ensure national representativeness. Specifically, 1300 rural households and 2000 urban households were targeted. It should also be noted that 1413 rural households had phones and 771 provided reference phone numbers. Additionally, 3213 urban households had phones and 224 could be reached through reference phone numbers. In the first round, the survey was implemented by calling all of the phone numbers that were provided in order to account for non-response and attrition [ 25 ]. A household is flagged as non-response only after being called at least three times in three days [ 25 ]. The consent to participate in the survey was sought from those who were reached on their phones after the objectives of the survey had been clearly explained to them. Most of the respondents were the heads of the household. However, in few cases where the heads were indisposed, a representative with adequate information on the contents of the questionnaire stood for them. The survey used the modular approach of the Computer Assisted Telephone Interview (CATI) techniques. The questionnaire was loaded with Survey CTO (Dobility, Inc., Cambridge, MA, USA). This is a CATI software that has been noted as one of the most reliable software for collecting data in offline settings [ 23 ]. Tablets were given to every enumerator along with sufficient data bundles which were loaded on their personal mobile phone devices. The collected data were daily sent to the central server and Senior Field Supervisors were designated to review the survey with the enumerators twice-a-day through phone calls in order to address quality concerns. Audio recordings of the interviews were also logged in order to reconcile outliers or non-response issues [ 23 ]. The interviews were carried out in six languages: Wolayita, Afan Oromo, Amharic, Afar, Somali and Tigrigna [ 25 ]. During the first round in 2020, 3249 households were successfully interviewed (2271 from urban areas and 978 from rural areas). At each round of data collection, the consents of the interviewed households were sought for inclusion in the next survey [ 25 ]. However, during the 10th round, only 2178 households completed the survey, with 537 from rural areas and 1641 from urban areas. 2.2. Limitations of the Data The survey suffers from limitations because intermittent lockdowns prevented the conduction of face-to-face interviews with the respondents. In addition, using a sampling frame that was based on those whose phone numbers or references phone numbers were provided during the 2018/2019 ESS also undermines the representativeness of the data. This is a result of the low penetration of telecommunication in rural Ethiopia. This is more evidently revealed by the low proportion of rural respondents in the dataset, unlike the results from ESS that were conducted via face-to-face interviews in 2018/2019 [ 26 ]. Dropout of respondents, as characterized by panel data, is also a matter of concern. Specifically, the first round of the survey had 3249 respondents, compared to 2178 in the tenth round. 2.3. Instrumental Variable Probit Model The Instrumental Variable Probit regression model was used to analyze the data. Conventionally, the Probit model is used when the dependent variable is binary in nature. The Probit model uses the cumulative Gaussian normal distribution function to calculate the probability of belonging to any of the categories.The standard Probit model is not applicable for this study because of the suspicion that the “currently working” variable could be endogenous, thereby implying that the estimated parameters would be biased. Therefore, an extension of the Probit model, in the form of the Instrumental Variable Probit regression, was used. The model is ideal for a situation whereby a dichotomous dependent variable, estimated as dummy variable, is suggested to be influenced by some independent variables, among which there is a variable that had been suspected to be endogenous [ 27 ]. (1) 1 z X i k + π G i + ϵ i (2) In Equation (1), the dependent variable ( Y i ) was coded as 1 for willing to take COVID-19 vaccines and 0 (0) for otherwise. X i k are the explanatory variables which include urban area (yes = 1, 0 otherwise), occupation—unemployed is the base variable—[agriculture (yes = 1, 0 otherwise), industry/manufacturing (yes = 1, 0 otherwise), wholesale and retail trade (yes = 1, 0 otherwise), transport services (yes = 1, 0 otherwise), restaurant (yes = 1, 0 otherwise), public administration (yes = 1, 0 otherwise), personal service like beauty salon (yes = 1, 0 otherwise), construction (yes = 1, 0 otherwise) and education/health (yes = 1, 0 otherwise)], regional variables—Tigray is the base variable—[Afar region (yes = 1, 0 otherwise), Amhara (yes = 1, 0 otherwise), Oromia (yes = 1, 0 otherwise), Somali (yes = 1, 0 otherwise), Benishangul-Gumuz (yes = 1, 0 otherwise), SNNPR (yes = 1, 0 otherwise), Gambela (yes = 1, 0 otherwise), Harar (yes = 1, 0 otherwise), Addis Ababa (yes = 1, 0 otherwise) and Dire Dawa (yes = 1, 0 otherwise)], age of household head (years), farming income (yes = 1, 0 otherwise) and business income (yes = 1, 0 otherwise). W i is the endogenous explanatory variable coded as 1 for currently working and 0 (0) otherwise. Equation (2) estimates the determinants of being currently working with gender of the respondents ( G i ) , which was coded as 1 for males and 0 otherwise representing the instrumental variable. If W i is not endogenous, then C o v ( X i ε i ) = 0 ]. The analyses for this study were carried out with STATA 13 software. The software generated the Wald test of exogeneity statistic, which, if shown to be statistically significant, implies the adequacy of the instrumental variable(s) and the use of IV Probit is thus justified. 3. Results 3.1. Socioeconomic Characteristics of Respondents Table 1 shows the distribution of the respondents’ socioeconomic factors based on their decision to receive the vaccination. It shows that majority of the respondents (92.33%) would get a COVID-19 vaccination if the approved vaccines are freely available. The results in the Table further reveal that respondents from urban areas accounted for 75.34% of the respondents and majority of those who were not willing to be vaccinated came from urban areas. Based on gender, 62.21% of the respondents were males, but more females were unwilling to be vaccinated. In addition, 69.65% of the respondents were working at the time of the survey. The majority of the respondents were in their active age brackets of 25 < 45 years, while 4.64% were over 59 years of age. Table 1. Respondents’ Demographic Characteristics. Figure 1 and Figure 2 further reveal the distribution of the respondents’ decisions to get a COVID-19 vaccine across different regions and occupational groups in Ethiopia. Figure 1 shows that SNNPR (99.30%), Oromia (97.54%), Tigray (97.04%) and Gambela (95.42%) had the highest proportions of vaccine-willing respondents while Dire Dawa (83.69%), Addis-Ababa (87.94%) and Harar (90.34%) had the lowest percentages. Figure 2 also shows that the respondents who occupied public administration positions constituted the highest frequencies of those that were willing and unwilling to be vaccinated. Figure 3 presents the reasons that were provided by the respondents for being unwilling to be vaccinated, coming from the different regions across Ethiopia. This Figure reveals that the safety of the vaccines was the topmost reason provided by the respondents across the different regions. In the Dire Dawa region, however, the second most important reason that was provided for the rejection of COVID-19 vaccine was based on side effects it might have, while second most important factor in Addis Ababa was the fear that it would not work. Figure 1. Distribution of respondents based on willingness to get COVID-19 vaccines across the Ethiopia’s regions. Figure 2. Frequencies of respondents willing to get COVID-19 vaccines across occupational groups in Ethiopia. Figure 3. Frequencies of respondents’reasons for not willing to get COVID-19 vaccines across the regions in Ethiopia. 3.2. IV Probit Model Results Table 2 presents the results of data analysis with the Instrumental Variable (IV) Probit regression approach. The model produced a good fit for the data based on the statistical significance ( p < 0.01) of the computed Chi-square statistics (101.75). Additionally, the use of the Instrumental Variable Probit was justified by the statistical significance of the computed Wald test of exogeneity ( p < 0.05). This implies that the currently working variable was truly endogenous and the instrumental variable was adequate. Table 2. Determinants of Willingness to Take COVID-19 Vaccines. The results further show that the parameter of the “currently working” variable is statistically significant ( p < 0.01). This result implies that respondents who were currently working were far more likely to be willing to receive the vaccine. The parameter of age is also showed a positive sign and was statistically significant ( p < 0.01). This also implies that old respondents were more likely to have a COVID-19 vaccine. The parameter of non-farm businesses showed a negative sign and was therefore statistically significant ( p < 0.05). This shows that those respondents whose households opened non-farm businesses some four weeks before the survey had a significantly lower probability of receiving a COVID-19 vaccine. Additionally, the regional variables for Afar, Amhara, Somali, Harar, Addis Ababa and Dire Dawa showed a negative sign and were also statistically significant ( p < 0.05). These results imply that compared with respondents from Tigray, residents from Afar, Amhara, Somali, Harar, Addis Ababa and Dire Dawa were less likely to have a COVID-19 vaccine. 4. Discussion The results of data analyses show that most of the respondents (92.3%) indicated that they would be willing to have a COVID-19 vaccination if approved vaccines are available. This represents a large proportion of the population given that in some previous studies, lower proportions had been reported. Specifically, in the USA, 75% reported a willingness to be vaccinated [ 15 ]; in China, 28.7% indicated yes and 54.6% said probably [ 17 ]; in a survey in Philadelphia, 63.7% of employees indicated yes and 26.3% were unsure [ 18 ]. In Africa, 71% [ 29 ] and 59% [ 30 ] were willing to be vaccinated in South Africa and the Democratic Republic of the Congo, respectively. However, given the high-mutant property of COVID-19, a higher vaccination coverage would likely guarantee the attainment of herd immunity. This is due to a recent emergence of different variant strains of COVID-19 due to a progressive mutation that is rendering certain developed vaccines to be less effective [ 31 , 32 ]. The results further revealed that a higher proportion of urban dwellers were unwilling to be vaccinated compared to rural dwellers. However, the parameter of urban residence did not significantly influence the probability of willingness to receive a COVID-19 vaccine. This is expected because urban residents may have access to a high level of misinformation on the COVID-19 vaccine [ 9 , 12 , 13 ]. The results also show that more males were willing to be vaccinated than their female counterparts. This result reveals the gender factor that can impact efforts by government in addressing COVID-19 in Ethiopia. In some previous studies [ 15 , 19 , 21 ], gender was found to influence decisions around the COVID-19 vaccination. Older respondents were also far more likely to be willing to have a COVID-19 vaccine. This is expected because age is one of the major factors affecting COVID-19 infection, with elderly people having weaker immune systems and thus at a higher risk of infection. A similar finding had been reported in some previous studies [ 15 , 18 , 19 , 20 , 21 ]. Furthermore, the “currently working” variable significantly increased the probability of willingness to be vaccinated. This can be explained by the desirability of good health for individuals that are working, since being sick with COVID-19 would reduce their productivity and thus their income. However, the results show that engagement with non-farm businesses reduced the probability of willingness to have a COVID-19 vaccine. This points to the fact that self-employed individuals may be less likely to see the need to get COVID-19 vaccines because they are not subjected to the operational contents of any formal contracts. The results also indicate that willingness to get vaccinated is influenced by some regional variables. This reemphasizes the need to factor in regional differences when addressing the COVID-19 pandemic in Ethiopia. The reasons for individuals’ unwillingness to get COVID-19 vaccines were also revealed. Specifically, pertinent issues surrounding the safety and the side effects of the vaccines were of the topmost concern to the respondents. In certain previous vaccination interventions that were meant to address prior epidemic outbreaks, safety had been a fundamental determinant of acceptance. Good examples include the polio vaccination in northern Nigeria [ 10 ], the H1N1 vaccine in Sweden and Finland [ 32 ], and the measles, mumps and rubella (MMR) vaccine in the United Kingdom and United States [ 33 ]. 5. Conclusions Understanding the expected behavior of the population in relation to the uptake of COVID-19 vaccination is a vital subject demanding thorough investigations and analyses. This is now more important, given the intermittent upsurge of infections, in what have been described as viral waves in many African countries. The consensus among policymakers is that addressing COVID-19 requires adequate vaccination of the entire population, based on the speed of infections, seriousness of morbidity and mutative features of the virus that are now undermining the effectiveness of the developed vaccines. Based on the findings of this study, some recommendations can be made. It should be emphasized that several socioeconomic variables are of fundamental relevance in addressing the willingness to have a COVID-19 vaccine. Specifically, although older people would be more willing to receive COVID-19 vaccines, efforts to address the pandemic also require younger individuals to take adequate protective responsibilities, especially because they tend to be asymptomatic. In addition, there are some gender issues that should be taken cautiously in the ongoing efforts at promoting the effective management of COVID-19. Specifically, Ethiopian women are to be targeted with information to facilitate their responsiveness to COVID-19 vaccination. It is also important to ensure that occupational factors that are relevant for promoting COVID-19 acceptance in Ethiopia are addressed, understanding that informally engaged people would need to be specifically targeted with compelling information to address their hesitancy around the vaccine. Furthermore, ongoing research efforts and international initiatives to provide workable vaccines against COVID-19 are commendable. However, more efforts are still needed in addressing the effectiveness of vaccines with significantly minimized side effects. Meanwhile, the provision of honest communication by healthcare practitioners on effectiveness and expected side effects of available COVID-19 vaccines would go a long way in helping individuals to make informed decisions on being vaccinated. Informed consents were obtained from all subjects involved in the study. Data Availability Statement Conflicts of Interest References Nueangnong, V.; Subih, A.A.S.H.; Al-Hattami, H.M. The 2020’s world deadliest pandemic: Corona Virus (COVID-19) and International Medical Law (IML). Cogent Soc. Sci. 2020 , 6 , 1818936. [ Google Scholar ] [ CrossRef ] Plotkin, S.A.; Mortimer, E.A. Vaccines ; Saunders: Philadelphia, PA, USA, 1988. [ Google Scholar ] Pollard, A.J.; Bijker, E.M. A guide to vaccinology: From basic principles to new developments. Nat. Rev. Immunol. 2021 , 21 , 83–100. [ Google Scholar ] [ CrossRef ] Rodrigues, C.M.C.; Plotkin, S.A. Impact of Vaccines; Health, Economic and Social Perspectives. Front. Microbiol. 2020 , 11 , 1526. [ Google Scholar ] [ CrossRef ] [ PubMed ] Rubin, L.G.; Levin, M.J.; Ljungman, P.; Davies, E.G.; Avery, R.K.; Tomblyn, M.; Bousvaros, A.; Dhanireddy, S.; Sung, L.; Keyserling, H.; et al. Executive Summary: 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host. Clin. Infect. Dis. 2014 , 58 , 309–318. [ Google Scholar ] [ CrossRef ] [ PubMed ] Freeman, D.; Loe, B.S.; Chadwick, A.; Vaccari, C.; Waite, F.; Rosebrock, L.; Jenner, L.; Petit, A.; Lewandowsky, S.; Vanderslott, S.; et al. COVID-19 vaccine hesitancy in the UK: The Oxford coronavirus explanations, attitudes, and narratives survey (Oceans) II. Psychol. Med. 2020 , 11 , 1–15. [ Google Scholar ] [ CrossRef ] Aylward, R.B.; Heymann, D.L. Can we capitalize on the virtues of vaccines? Insights from the polio eradication initiative. Am. J. Public Health 2005 , 95 , 773–777. [ Google Scholar ] [ CrossRef ] [ PubMed ] Hussain, S.F.; Boyle, P.; Patel, P.; Sullivan, R. Eradicating polio in Pakistan: An analysis of the challenges and solutions to this security and health issue. Glob. Health 2016 , 12 , 1–9. [ Google Scholar ] [ CrossRef ][ Green Version ] Islam, S.; Kamal, A.-H.M.; Kabir, A.; Southern, D.L.; Khan, S.H.; Hasan, S.M.M.; Sarkar, T.; Sharmin, S.; Das, S.; Roy, T.; et al. COVID-19 vaccine rumors and conspiracy theories: The need for cognitive inoculation against misinformation to improve vaccine adherence. PLoS ONE 2021 , 16 , e0251605. [ Google Scholar ] [ CrossRef ] Jegede, A.S. What led to the Nigerian boycott of the polio vaccination campaign? PLoS Med. 2007 , 4 , e73. [ Google Scholar ] [ CrossRef ][ Green Version ] Calitz, T. Constitutional Rights in South Africa Protect Against Mandatory COVID-19 Vaccination. 2012. Available online: https://www.hhrjournal.org/2021/04/constitutional-rights-in-south-africa-protect-against-mandatory-covid-19-vaccination/ (accessed on 25 June 2021). Donzelli, G.; Palomba, G.; Federigi, I.; Aquino, F.; Cioni, L.; Verani, M.; Carducci, A.; Lopalco, P.L. Misinformation on vaccination: A quantitative analysis of YouTube videos. Hum. Vaccines Immunother. 2018 , 14 , 1654–1659. [ Google Scholar ] [ CrossRef ][ Green Version ] Scheufele, D.A.; Krause, N.M. Science audiences, misinformation, and fake news. Proc. Natl. Acad. Sci. USA 2019 , 116 , 7662–7669. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Wiyeh, A.B.; Cooper, S.; Jaca, A.; Mavundza, E.; Ndwandwe, D.; Wiysonge, C.S. Social media and HPV vaccination: Unsolicited public comments on a Facebook post by the Western Cape Department of Health provide insights into determinants of vaccine hesitancy in South Africa. Vaccine 2019 , 37 , 6317–6323. [ Google Scholar ] [ CrossRef ] [ PubMed ] Kelly, B.J.; Southwell, B.G.; McCormack, L.A.; Bann, C.M.; MacDonald, P.D.; Frasier, A.M.; Bevc, C.A.; Brewer, N.T.; Squiers, L.B. Predictors of willingness to get a COVID-19 vaccine in the U.S. BMC Infect. Dis. 2021 , 21 , 338. [ Google Scholar ] [ CrossRef ] Ehde, D.M.; Roberts, M.K.; Herring, T.E.; Alschuler, K.N. Willingness to obtain COVID-19 vaccination in adults with multiple sclerosis in the United States. Mult. Scler. Relat. Disord. 2021 , 49 , 102788. [ Google Scholar ] [ CrossRef ] Lin, Y.; Hu, Z.; Zhao, Q.; Alias, H.; Danaee, M.; Wong, L.P. Understanding COVID-19 vaccine demand and hesitancy: A nationwide online survey in China. PLoS Negl. Trop. Dis. 2020 , 14 , e0008961. [ Google Scholar ] [ CrossRef ] Seale, H.; Heywood, A.E.; Leask, J.; Sheel, M.; Durrheim, D.N.; Bolsewicz, K.; Kaur, R. Examining Australian public perceptions and behaviors towards a future COVID-19 vaccine. BMC Infect. Dis. 2021 , 21 , 1–9. [ Google Scholar ] [ CrossRef ] Kourlaba, G.; Kourkouni, E.; Maistreli, S.; Tsopela, C.-G.; Molocha, N.-M.; Triantafyllou, C.; Koniordou, M.; Kopsidas, I.; Chorianopoulou, E.; Maroudi-Manta, S.; et al. Willingness of Greek general population to get a COVID-19 vaccine. Glob. Health Res. Policy 2021 , 6 , 1–10. [ Google Scholar ] [ CrossRef ] Tobin, E.A.; Okonofua, M.; Adeke, A.; Obi, A. Willingness to Accept a COVID-19 Vaccine in Nigeria: A Population-based Cross-sectional Study. Central Afr. J. Public Health 2021 , 7 , 53. [ Google Scholar ] [ CrossRef ] Bell, S.; Clarke, R.; Mounier-Jack, S.; Walker, J.L.; Paterson, P. Parents’ and guardians’ views on the acceptability of a future COVID-19 vaccine: A multi-methods study in England. Vaccine 2020 , 38 , 7789–7798. [ Google Scholar ] [ CrossRef ] [ PubMed ] World Bank. Ethiopia—COVID-19 High Frequency Phone Survey of Households 2020. Available online: https://microdata.worldbank.org/index.php/catalog/3716 (accessed on 1 May 2021). Central Statistical Agency of Ethiopia. Ethiopian Data Quality Assessment Framework (EDQAF). 2011. Available online: https://unstats.un.org/unsd/methodology/dataquality/references/Ethiopia_edqaf.pdf (accessed on 11 August 2021). Ambel, A.A.; Bundervoet, T.; Haile, A.; Wieser, C. Monitoring COVID-19 Impacts on Households in Ethiopia. 2020. Available online: https://microdata.worldbank.org/index.php/catalog/3716/related-materials (accessed on 11 August 2021). Central Statistical Agency and World Bank. Ethiopia Socioeconomic Survey (ESS) ESS Panel II 2018/2019 Refreshed Sample: Baseline Basic Information Document. 2021. Available online: https://microdata.worldbank.org/index.php/catalog/3823/related-materials (accessed on 11 August 2021). Li, C.; Poskitt, D.S.; Zhao, X. The Bivariate Probit Model, Maximum Likelihood Estimation, Pseudo True Parameters and Partial Identification. Monash Business School Working Paper 16/16. 2016. Available online: https://www.monash.edu/business/econometrics-and-business-statistics/research/publications/ebs/wp16-16.pdf (accessed on 2 February 2021). Wooldridge, J.M. Econometric Analysis of Cross Section and Panel Data , 2nd ed.; MIT Press: Cambridge, MA, USA, 2010. [ Google Scholar ] Burger, R.; Buttenheim, A.; English, R.; Maughan-Brown, B.; Köhler, T.; Tameris, M. COVID-19 Vaccine Hesitancy in South Africa: Results from NIDS-CRAM Wave 4. Available online: https://www.researchgate.net/publication/351515147_COVID-19_vaccine_hesitancy_in_South_Africa_Results_from_NIDS-CRAM_Wave_4 (accessed on 2 July 2021). Ditekemena, J.; Nkamba, D.; Mavoko, A.; Fodjo, J.S.; Luhata, C.; Obimpeh, M.; Van Hees, S.; Nachega, J.; Colebunders, R. COVID-19 Vaccine Acceptance in the Democratic Republic of Congo: A Cross-Sectional Survey. Vaccines 2021 , 9 , 153. [ Google Scholar ] [ CrossRef ] [ PubMed ] Savulescu, J. Good reasons to vaccinate: Mandatory or payment for risk? J. Med. Ethics 2021 , 47 , 78–85. [ Google Scholar ] [ CrossRef ] [ PubMed ] Sarkanen, T.O.; Alakuijala, A.P.; Dauvilliers, Y.; Partinen, M. Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis. Sleep Med. Rev. 2017 , 38 , 177–186. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Kaye, J.A.; del Mar Melero-Montes, M.; Jick, H. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: A time trend analysis. BMJ 2001 , 322 , 460–463, PMCID:PMC26561. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Figure 1. Distribution of respondents based on willingness to get COVID-19 vaccines across the Ethiopia’s regions. Figure 2. Frequencies of respondents willing to get COVID-19 vaccines across occupational groups in Ethiopia. Figure 3. Frequencies of respondents’reasons for not willing to get COVID-19 vaccines across the regions in Ethiopia. Table 1. Respondents’ Demographic Characteristics. Variables Not Willing/Not Sure Willing Total Sector Freq % Freq % Freq % Urban 148 6.80 1493 68.55 1641 75.34 Rural 19 0.87 518 23.78 537 24.66 Gender Female 93 4.27 730 33.52 823 37.79 Male 74 3.40 1281 58.82 1355 62.21 Currently Working No 51 2.34 610 28.01 661 30.35 Yes 116 5.33 1401 64.33 1517 69.65 Age of Respondents <20 3 0.14 38 1.74 41 1.88 20 < 25 21 0.96 183 8.40 204 9.37 25 < 30 39 1.79 366 16.80 405 18.60 30 < 35 24 1.10 342 15.70 366 16.80 35 < 40 33 1.52 321 14.74 354 16.25 40 < 45 24 1.10 371 17.03 395 18.14 45 < 50 6 0.28 132 6.06 138 6.34 50 < 55 9 0.41 96 4.41 105 4.82 55 < 60 5 0.23 64 2.94 69 3.17 >=60 3 0.14 98 4.50 101 4.64 Total 167 7.67 2011 92.33 2178 100.00 Table 2. Determinants of Willingness to Take COVID-19 Vaccines.
https://www.mdpi.com/1660-4601/18/17/8892/xml
Tissue expression of OR4C6 - Staining in thymus - The Human Protein Atlas Expression of OR4C6 in thymus tissue. Antibody staining with in immunohistochemistry. Fields » Search result ANDNOT Field AllGene nameProtein classUniprot keywordChromosomeExternal idTissue expression (IHC)Patient ID (IHC)Tissue category (RNA)Tissue expression cluster (RNA)Reliability score tissue (IHC)Brain region category (RNA)Mouse brain category (RNA)Pig brain category (RNA)Reliability score mouse brainCell type category (RNA)Single cell type expression cluster (RNA)Cell type enrichment (RNA)Prognostic cancerCancer category (RNA)Immune cell category (RNA)Immune cell lineage category (RNA)Immune cell expression cluster (RNA)Secretome annotationPan-cancer panelSubcellular location (ICC)Subcellular location - cell line (ICC)Subcellular Cell Cycle Peak PhaseReliability score cells (ICC)Cell line category (RNA)Cell line expression cluster (RNA)Metabolic pathwayEvidence summaryUniProt evidenceNeXtProt evidenceHPA evidenceProtein array (PA)Western blot (WB)Immunohistochemistry (IHC)Immunocytochemistry (ICC)With antibodiesProtein structuresHas protein dataSort by Term Gene name Class Blood group antigen proteinsCancer-related genesCandidate cardiovascular disease genesCD markersCitric acid cycle related proteinsDisease related genesEnzymesFDA approved drug targetsG-protein coupled receptorsHuman disease related genesImmunoglobulin genesMapped to neXtProtMapped to UniProt SWISS-PROTMetabolic proteinsNuclear receptorsPlasma proteinsPotential drug targetsPredicted intracellular proteinsPredicted membrane proteinsPredicted secreted proteinsProtein evidence (Ezkurdia et al 2014)Protein evidence (Kim et al 2014)RAS pathway related proteinsRibosomal proteinsRNA polymerase related proteinsT-cell receptor genesTranscription factorsTransportersVoltage-gated ion channels Subclass Class Biological processMolecular functionDisease Keyword Chromosome 12345678910111213141516171819202122MTUnmappedXY External id Tissue AnyAdipose tissueAdrenal glandAppendixBone marrowBreastBronchusCartilageCaudateCerebellumCerebral cortexCervixChoroid plexusColonDorsal rapheDuodenumEndometriumEpididymisEsophagusEyeFallopian tubeGallbladderHairHeart muscleHippocampusHypothalamusKidneyLactating breastLiverLungLymph nodeNasopharynxOral mucosaOvaryPancreasParathyroid glandPituitary glandPlacentaProstateRectumRetinaSalivary glandSeminal vesicleSkeletal muscleSkinSmall intestineSmooth muscleSoft tissueSole of footSpleenStomachSubstantia nigraTestisThymusThyroid glandTonsilUrinary bladderVagina Cell type Expression Patient ID Tissue AnyAdipose tissueAdrenal glandBone marrowBrainBreastCervixChoroid plexusEndometriumEpididymisEsophagusFallopian tubeGallbladderHeart muscleIntestineKidneyLiverLungLymphoid tissueOvaryPancreasParathyroid glandPituitary glandPlacentaProstateRetinaSalivary glandSeminal vesicleSkeletal muscleSkinSmooth muscleStomachTestisThyroid glandTongueUrinary bladderVagina Category Tissue enrichedGroup enrichedTissue enhancedLow tissue specificityNot detectedDetected in allDetected in manyDetected in someDetected in singleIs highest expressed Cluster 82:Adipose tissue - ECM organization17:Adrenal gland - Steroid metabolism14:B-cells - Humoral immune response75:Bone marrow - mRNA splicing & Cell cycle65:Brain - Ion transport70:Brain - Nervous system development10:Brain - Neuronal signaling73:Brain - Neuropeptide signaling6:Brain - Smell perception58:Brain - Synaptic function76:Brain & Bone marrow - Chromatin organization32:Brain & Lymphoid tissue - Unknown function27:Brain & Skin - Unknown function5:Breast - Unknown function69:Cerebellum - Gene expression regulation88:Choroid plexus - Transmembrane transport42:Ciliated cells - Cilium & Cell projection49:Ciliated cells - Cilium organization30:Epididymis - Antimicrobial activity68:Epididymis - Unknown function84:Esophagus - Epithelial cell function89:Fibroblasts - ECM organization44:Heart - Cardiac muscle contraction38:Heart - Muscle contraction16:Immune cells - Immune response45:Intestine - Brush border56:Intestine - Transmembrane transport37:Intestine - Unknown function87:Intestine & Kidney - Transmembrane transport41:Intestine & Liver - Lipid metabolism7:Kidney - Transmembrane transport81:Kidney & Liver - Metabolism62:Liver - Hemostasis60:Liver - Hemostasis & Lipid metabolism85:Liver - Metabolism86:Liver & Placenta - Transport via ER19:Lung - Lung function66:Lymphoid tissue - Immune response regulation64:Macrophages - Immune response67:Neutrophils - Humoral immune response40:Neutrophils - Inflammatory response57:Non-specific - Angiogenesis53:Non-specific - Cell cycle regulation54:Non-specific - Microtubule organization39:Non-specific - Mitochondria55:Non-specific - Mitochondria & Proteasome52:Non-specific - Ribosome72:Non-specific - Transcription59:Non-specific - Translation51:Non-specific - Unknown function29:Non-specific - Vesicular transport25:Pancreas - Digestion48:Parathyroid gland - membrane proteins26:Pituitary gland - Hormone signaling28:Placenta - Pregnancy79:Retina - Phototransduction77:Retina - Visual perception20:Retina & Lymphoid tissues - Unknown function24:Salivary gland - Salivary secretion61:Skin - Cornification31:Skin - Epidermis development12:Smooth muscle tissue - Mixed function11:Squamous epithelial cells - Epithelial cell function4:Stomach - Digestion33:Striated muscle - Muscle contraction80:Striated muscle - Unknown function63:T-cells - Adaptive immune response23:Testis - Cell cycle regulation71:Testis - DNA repair83:Testis - Spermatogenesis43:Testis - Unknown function1:Thyroid gland - Transcription Reliability EnhancedSupportedApprovedUncertain Brain region AnyAmygdalaBasal gangliaCerebellumCerebral cortexHippocampal formationHypothalamusMedulla oblongataMidbrainPonsSpinal cordThalamusWhite matter Category Region enrichedGroup enrichedRegion enhancedLow region specificityNot detectedDetected in allDetected in manyDetected in someDetected in singleIs highest expressed Brain region AnyAmygdalaBasal gangliaCerebellumCerebral cortexHippocampal formationHypothalamusMidbrainOlfactory bulbPituitary glandPons and medullaRetinaThalamusWhite matter Category Region enrichedGroup enrichedRegion enhancedLow region specificityNot detectedDetected in allDetected in manyDetected in someDetected in singleIs highest expressed Brain region AnyAmygdalaBasal gangliaCerebellumCerebral cortexHippocampal formationHypothalamusMedulla oblongataMidbrainOlfactory bulbPituitary glandPonsRetinaSpinal cordThalamusWhite matter Category Region enrichedGroup enrichedRegion enhancedLow region specificityNot detectedDetected in allDetected in manyDetected in someDetected in singleIs highest expressed Reliability SupportedApproved Cell type AnyAdipocytesAlveolar cells type 1Alveolar cells type 2AstrocytesB-cellsBasal keratinocytesBasal prostatic cellsBasal respiratory cellsBasal squamous epithelial cellsBipolar cellsBreast glandular cellsBreast myoepithelial cellsCardiomyocytesCholangiocytesClub cellsCollecting duct cellsCone photoreceptor cellsCytotrophoblastsDendritic cellsDistal enterocytesDistal tubular cellsDuctal cellsEarly spermatidsEndometrial ciliated cellsEndometrial stromal cellsEndothelial cellsEnteroendocrine cellsErythroid cellsExcitatory neuronsExocrine glandular cellsExtravillous trophoblastsFibroblastsGastric mucus-secreting cellsGlandular and luminal cellsGranulocytesGranulosa cellsHepatocytesHofbauer cellsHorizontal cellsInhibitory neuronsIntestinal goblet cellsIonocytesKupffer cellsLangerhans cellsLate spermatidsLeydig cellsMacrophagesMelanocytesMicroglial cellsMonocytesMucus glandular cellsMuller glia cellsNK-cellsOligodendrocyte precursor cellsOligodendrocytesPancreatic endocrine cellsPaneth cellsPeritubular cellsPlasma cellsProstatic glandular cellsProximal enterocytesProximal tubular cellsRespiratory ciliated cellsRod photoreceptor cellsSalivary duct cellsSchwann cellsSerous glandular cellsSertoli cellsSkeletal myocytesSmooth muscle cellsSpermatocytesSpermatogoniaSquamous epithelial cellsSuprabasal keratinocytesSyncytiotrophoblastsT-cellsTheca cellsThymic epithelial cellsUndifferentiated cells Category Cell type enrichedGroup enrichedCell type enhancedLow cell type specificityNot detectedDetected in allDetected in manyDetected in someDetected in singleIs highest expressed Cluster 20:Airway & Pancreas - Proteolysis41:Alveolar cells - Lung function63:Astrocytes - Nervous system maintenance62:B-cells - B-cell activation70:Basal prostatic cells - Lipid metabolism35:Bipolar cells - Visual perception30:Breast - Lactation5:Bronchus - Unknown function77:Cardiomyocytes - Muscle contraction56:Ciliated cells - Cilium assembly53:Connective tissue cells - ECM organization28:Cytotrophoblasts - Unknown function57:Early spermatids - Flagellum & Golgi organization49:Early spermatids - Spermatogenesis55:Endocrine cells - Hormone signaling52:Endometrial stromal cells - ECM organization14:Endometrium - Transcription regulation66:Endothelial cells - Angiogenesis50:Enterocytes - Absorption71:Erythroid cells - Oxygen transport54:Extravillous trophoblasts - Unknown function65:Fibroblasts - ECM organization58:Gastric mucus-secreting cells - Digestion46:Granulocytes - Mast cell degranulation17:Granulosa cells - Transcription regulation29:Hepatocytes - Metabolism13:Hepatocytes - Oxidoreductase activity26:Intestinal epithelial cells - Absorption23:Langerhans cells - Immune response51:Late spermatids - Spermatogenesis33:Macrophages - Degranulation69:Macrophages - Innate immune response68:Muller glia cells - Visual perception75:Myeloid cells - Innate immune response9:Neurons - Nervous system development38:Neurons - Neuronal signaling32:Neurons - Synaptic function10:Neurons & Oligodendrocytes - Nervous system development7:NK-cells - Immune response regulation43:Non-specific - Cell proliferation12:Non-specific - Chromatin organization18:Non-specific - Mixed function16:Non-specific - RNA binding64:Non-specific - Transcription39:Non-specific - Translation8:Oligodendrocytes - Myelin sheath organization74:Pancreatic cells - Mixed function44:Photoreceptor cells - Visual perception45:Plasma cells - Humoral immune response48:Plasmacytoid dendritic cells - Unknown function4:Platelets - Platelet activation73:Prostatic glandular cells - Transcription59:Proximal enterocytes - Transmembrane transport60:Proximal tubular cells - Absorption25:Schwann cells & Melanocytes - Mixed function21:Serous glandular cells - Salivary secretion27:Skeletal myocytes - Muscle contraction72:Smooth muscle cells - ECM organization15:Smooth muscle cells - Muscle contraction36:Spermatids - Spermatogenesis24:Spermatids - Unknown function31:Spermatocytes - Spermatogenesis42:Spermatocytes & Spermatids - Spermatogenesis76:Spermatocytes & Spermatogonia - Spermatogenesis47:Spermatogonia - Spermatogenesis22:Squamous epithelial cells - Keratinization3:Suprabasal keratinocytes - Cornification67:Syncytiotrophoblasts - Pregnancy1:T-cells - Immune response2:T-cells - T-cell receptor Tissue Adipose subcutaneousAdipose visceralBreastColonHeart muscleKidneyLiverLungPancreasProstateSkeletal muscleSkinStomachTestisThyroid Cell type Enrichment Very highHighModerate Cancer Breast cancerCervical cancerColorectal cancerEndometrial cancerGliomaHead and neck cancerLiver cancerLung cancerMelanomaOvarian cancerPancreatic cancerProstate cancerRenal cancerStomach cancerTestis cancerThyroid cancerUrothelial cancer Prognosis FavorableUnfavorable Cancer AnyBreast cancerCervical cancerColorectal cancerEndometrial cancerGliomaHead and neck cancerLiver cancerLung cancerMelanomaOvarian cancerPancreatic cancerProstate cancerRenal cancerStomach cancerTestis cancerThyroid cancerUrothelial cancer Category Cancer enrichedGroup enrichedCancer enhancedLow cancer specificityNot detectedDetected in allDetected in manyDetected in someDetected in singleIs highest expressed Cell type AnyBasophilClassical monocyteEosinophilGdT-cellIntermediate monocyteMAIT T-cellMemory B-cellMemory CD4 T-cellMemory CD8 T-cellMyeloid DCNaive B-cellNaive CD4 T-cellNaive CD8 T-cellNeutrophilNK-cellNon-classical monocytePlasmacytoid DCT-regTotal PBMC Category Immune cell enrichedGroup enrichedImmune cell enhancedLow immune cell specificityNot detected in immune cellsNot detectedDetected in allDetected in manyDetected in someDetected in singleIs highest expressed Cell lineage AnyB-cellsDendritic cellsGranulocytesMonocytesNK-cellsT-cells Category Lineage enrichedGroup enrichedLineage enhancedLow lineage specificityNot detectedDetected in allDetected in manyDetected in singleIs highest expressed Cluster 23:Antigen presenting cells - Antigen presentation21:B-cells - Adaptive immune response43:B-cells - Humoral immune response37:B-cells - Transcription24:B-cells - Unknown function41:Basophils - Cellular respiration46:Basophils - DNA binding38:Basophils - Unknown function18:Basophils - Vesicular transport45:Eosinophils - Innate immune response52:Eosinophils - Transcription49:Eosinophils - Unknown function36:GdT-cells - Adaptive immune response5:Granulocytes - Unknown function16:MAIT-cells - Unknown function25:Monocytes - Inflammatory response51:Monocytes - Innate immune response14:Monocytes - Unknown function28:Myeloid DCs - Unknown function50:Neutrophils - Cellular senescence33:Neutrophils - Chromatin organization8:Neutrophils - Inflammatory response9:Neutrophils - Innate immune response1:Neutrophils - Mixed function15:NK-cells - Transcription48:NK-cells - Unknown function12:Non-specific - Basic cellular processes27:Non-specific - Gene expression31:Non-specific - Inflammatory response26:Non-specific - Mitochondria39:Non-specific - mRNA processing44:Non-specific - Transcription30:Non-specific - Translation47:Plasmacytoid DCs - Protein folding29:Plasmacytoid DCs - Unknown function20:T-cells - T-cell receptor32:T-cells - Unknown function4:T-regs - Cell cycle regulation35:T-regs - Unknown function Annotation Immunoglobulin genesIntracellular and membraneSecreted - unknown locationSecreted in brainSecreted in female reproductive systemSecreted in male reproductive systemSecreted in other tissuesSecreted to bloodSecreted to digestive systemSecreted to extracellular matrix Disease AnyAcute myeloid leukemiaBreast cancerCervical cancerChronic lymphocytic leukemiaColorectal cancerDiffuse large B-cell lymphomaEndometrial cancerGliomaLung cancerMyelomaOvarian cancerProstate cancer Location Actin filamentsAggresomeCell JunctionsCentriolar satelliteCentrosomeCleavage furrowCytokinetic bridgeCytoplasmic bodiesCytosolEndoplasmic reticulumEndosomesFocal adhesion sitesGolgi apparatusIntermediate filamentsKinetochoreLipid dropletsLysosomesMicrotubule endsMicrotubulesMidbodyMidbody ringMitochondriaMitotic chromosomeMitotic spindleNuclear bodiesNuclear membraneNuclear specklesNucleoliNucleoli fibrillar centerNucleoli rimNucleoplasmPeroxisomesPlasma membraneRods & RingsVesicles Searches EnhancedSupportedApprovedUncertainIntensity variationSpatial variationCCD protein mitotic structureCCD protein interphaseCell cycle dependent proteinCell cycle independent proteinCell cycle dependent transcriptCell cycle independent transcriptMultilocalizingLocalizing 1Localizing 2Localizing 3Localizing 4Localizing 5Localizing 6Main locationAdditional location Location AnyActin filamentsAggresomeCell JunctionsCentriolar satelliteCentrosomeCleavage furrowCytokinetic bridgeCytoplasmic bodiesCytosolEndoplasmic reticulumEndosomesFocal adhesion sitesGolgi apparatusIntermediate filamentsKinetochoreLipid dropletsLysosomesMicrotubule endsMicrotubulesMidbodyMidbody ringMitochondriaMitotic chromosomeMitotic spindleNuclear bodiesNuclear membraneNuclear specklesNucleoliNucleoli fibrillar centerNucleoli rimNucleoplasmPeroxisomesPlasma membraneRods & RingsVesicles Cell line AnyA-431A-549AF22ASC52teloBJ [Human fibroblast]CACO-2EFO-21FHDF/TERT166GAMGHaCaTHAP1HBEC3-KTHBF/TERT88HDLM-2HEK293HELHeLaHep-G2HTCEpiHTEC/SVTERT24-BHTERT-HME1HTERT-RPE1HTERT-RPE1 (serum starved)HUVEC/TERT2JURKATK-562LHCN-M2MCF-7NB4OE19PC-3REHRh30RPTEC/TERT1RT-4SH-SY5YSiHaSK-MEL-30SuSaTHP-1U-251MGU2OS Type ProteinRna Phase G1SG2 Reliability EnhancedSupportedApprovedUncertain Cancer type AnyBile duct cancerBladder cancerBone cancerBrain cancerBreast cancerCervical cancerColorectal cancerEsophageal cancerGallbladder cancerGastric cancerHead and neck cancerKidney cancerLeukemiaLiver cancerLung cancerLymphomaMyelomaNeuroblastomaNon-cancerousOvarian cancerPancreatic cancerProstate cancerRhabdoidSarcomaSkin cancerTestis cancerThyroid cancerUncategorizedUterine cancer Category Cancer enrichedGroup enrichedCancer enhancedLow cancer specificityNot detectedDetected in allDetected in manyDetected in someDetected in singleIs highest expressed Cluster 23:B-cell cancers - Adaptive immune response6:BEWO - Unknown function69:BICR 18 - Unknown function14:Bone cancer - Transcription28:Bone cancer CADO-ES1 - Glutamate signalling65:Breast cancer - Unknown function20:Connective tissue cells - ECM organization2:DU4475 - Unknown function59:Fibroblasts - Metabolism62:Granulocytes - Innate immune response3:HUVEC & TIME - Signal transduction60:Keratinocytes - Epithelial cell function68:Kidney - Mixed function50:L-1236 & L-428 - Unknown function61:Liver - Metabolism35:Liver cancer - Metabolism12:Lymphoid cancers - Adaptive immune response9:Lymphoid cancers - Immune response11:Lymphoma - Adaptive immune response54:Lymphoma - Cytokine signaling64:Lymphoma - Humoral immune response66:Myeloid cells - Innate immune response32:Myeloid leukemia - Oxygen transport51:Myeloma - Humoral immune response26:NCI-H716 - Unknown function21:Neuroblastoma - Neuronal signaling7:Neuronal cell lines - Stereocilium56:Neurons - Neuronal signaling30:Non-specific - Antiviral immune response58:Non-specific - Basic cellular processes45:Non-specific - Cell proliferation41:Non-specific - Cilium assembly40:Non-specific - Enzymes43:Non-specific - Mitochondria67:Non-specific - Mitochondria & RNA binding53:Non-specific - mRNA processing13:Non-specific - Nuclear processes1:Non-specific - Nucleosome assembly15:Non-specific - Protein binding48:Non-specific - RNA binding31:Non-specific - Transcription57:Non-specific - Translation63:Non-specific - Unknown function10:Ovarian & Endometrial cancers - Unknown function37:Ovarian cancer RMG-I - Cellular stress response24:Prostate cancer - Lipid metabolism34:Rabdoid cancer - Embryonic development47:Retina - Visual perception22:Rhabdoid cancers - Neuronal signaling17:RS4;11 - Unknown function42:Sarcoma - Muscle contraction16:Skin cancer - Melanocyte processes33:Skin cancer - Membrane components52:Spermatids - Smell perception19:Stomach & Colon cancer - Absorption27:TE 441.T - Unknown function29:TT & NCI-H1385 - Synaptic signal transduction Pathway Acyl-CoA hydrolysisAcylglycerides metabolismAlanine; aspartate and glutamate metabolismAmino sugar and nucleotide sugar metabolismAminoacyl-tRNA biosynthesisAndrogen metabolismArachidonic acid metabolismArginine and proline metabolismAscorbate and aldarate metabolismBeta oxidation of branched-chain fatty acids (mitochondrial)Beta oxidation of di-unsaturated fatty acids (n-6) (mitochondrial)Beta oxidation of di-unsaturated fatty acids (n-6) (peroxisomal)Beta oxidation of even-chain fatty acids (mitochondrial)Beta oxidation of even-chain fatty acids (peroxisomal)Beta oxidation of odd-chain fatty acids (mitochondrial)Beta oxidation of phytanic acid (peroxisomal)Beta oxidation of poly-unsaturated fatty acids (mitochondrial)Beta oxidation of unsaturated fatty acids (n-7) (mitochondrial)Beta oxidation of unsaturated fatty acids (n-7) (peroxisomal)Beta oxidation of unsaturated fatty acids (n-9) (mitochondrial)Beta oxidation of unsaturated fatty acids (n-9) (peroxisomal)Beta-alanine metabolismBile acid biosynthesisBile acid recyclingBiopterin metabolismBiotin metabolismBlood group biosynthesisButanoate metabolismC5-branched dibasic acid metabolismCarnitine shuttle (cytosolic)Carnitine shuttle (endoplasmic reticular)Carnitine shuttle (mitochondrial)Carnitine shuttle (peroxisomal)Cholesterol biosynthesis 1 (Bloch pathway)Cholesterol biosynthesis 2Cholesterol biosynthesis 3 (Kandustch-Russell pathway)Cholesterol metabolismChondroitin / heparan sulfate biosynthesisChondroitin sulfate degradationCoA synthesisCysteine and methionine metabolismDrug metabolismEicosanoid metabolismEstrogen metabolismEther lipid metabolismFatty acid activation (cytosolic)Fatty acid activation (endoplasmic reticular)Fatty acid biosynthesisFatty acid biosynthesis (even-chain)Fatty acid biosynthesis (odd-chain)Fatty acid biosynthesis (unsaturated)Fatty acid desaturation (even-chain)Fatty acid desaturation (odd-chain)Fatty acid elongation (even-chain)Fatty acid elongation (odd-chain)Fatty acid oxidationFolate metabolismFormation and hydrolysis of cholesterol estersFructose and mannose metabolismGalactose metabolismGlucocorticoid biosynthesisGlutathione metabolismGlycerolipid metabolismGlycerophospholipid metabolismGlycine; serine and threonine metabolismGlycolysis / GluconeogenesisGlycosphingolipid biosynthesis-ganglio seriesGlycosphingolipid biosynthesis-globo seriesGlycosphingolipid biosynthesis-lacto and neolacto seriesGlycosphingolipid metabolismGlycosylphosphatidylinositol (GPI)-anchor biosynthesisHeme degradationHeme synthesisHeparan sulfate degradationHistidine metabolismInositol phosphate metabolismIsolatedKeratan sulfate biosynthesisKeratan sulfate degradationLeukotriene metabolismLinoleate metabolismLipoic acid metabolismLysine metabolismMetabolism of other amino acidsMiscellaneousN-glycan metabolismNicotinate and nicotinamide metabolismNucleotide metabolismO-glycan metabolismOmega-3 fatty acid metabolismOmega-6 fatty acid metabolismOxidative phosphorylationPantothenate and CoA biosynthesisPentose and glucuronate interconversionsPentose phosphate pathwayPhenylalanine metabolismPhenylalanine; tyrosine and tryptophan biosynthesisPhosphatidylinositol phosphate metabolismPool reactionsPorphyrin metabolismPropanoate metabolismProstaglandin biosynthesisProtein assemblyProtein degradationProtein modificationPurine metabolismPyrimidine metabolismPyruvate metabolismRetinol metabolismRiboflavin metabolismROS detoxificationSerotonin and melatonin biosynthesisSphingolipid metabolismStarch and sucrose metabolismSteroid metabolismSulfur metabolismTerpenoid backbone biosynthesisThiamine metabolismTransport reactionsTricarboxylic acid cycle and glyoxylate/dicarboxylate metabolismTryptophan metabolismTyrosine metabolismUbiquinone synthesisUrea cycleValine; leucine; and isoleucine metabolismVitamin A metabolismVitamin B12 metabolismVitamin B2 metabolismVitamin B6 metabolismVitamin C metabolismVitamin D metabolismVitamin E metabolismXenobiotics metabolism Category Evidence at protein levelEvidence at transcript levelNo human protein/transcript evidence Score Evidence at protein levelEvidence at transcript levelNo human protein/transcript evidence Score Evidence at protein levelEvidence at transcript levelNo human protein/transcript evidence Score Evidence at protein levelEvidence at transcript levelNo human protein/transcript evidence Validation SupportedApprovedUncertain Validation Enhanced - CaptureEnhanced - GeneticEnhanced - IndependentEnhanced - OrthogonalEnhanced - RecombinantSupportedApprovedUncertain Validation Enhanced - IndependentEnhanced - OrthogonalSupportedApprovedUncertain Validation Enhanced - GeneticEnhanced - IndependentEnhanced - RecombinantSupportedApprovedUncertain Antibodies YesNo Protein structure ExperimentalPrediction In atlas TissueCellPathologyBrainBlood - conc. immunoassayBlood - conc. mass spectrometryBlood - detected peaDisease - peaDisease - mass spectrometry Column GenePositionTissue specific scorePrognosticReliability (IF)Reliability (IH)
https://www.proteinatlas.org/ENSG00000181903-OR4C6/tissue/thymus
Institute for Poverty, Land and Agrarian Studies (PLAAS) Institute for Poverty, Land and Agrarian Studies (PLAAS) TheInstitute for Poverty, Land and Agrarian Studies (PLAAS)engages in research, training, policy development and advocacy in relation to land and agrarian reform, rural governance and natural resource management. It is committed to social change that empowers the poor, builds democracy and enhances sustainable livelihoods. Lockdown, resilience and emergency statecraft in the Cape Town food system  Kroll, Florian ; Adelle, Camilla ( Cities , 2022 ) Well before the Covid-19 pandemic, rapidly growing cities of the global South were at the epicenter of multiple converging crises affecting food systems. Globally, government lockdown responses to the disease triggered ... Life on the land: New lives for agrarian questions  Shattuck, Annie ; Grajales, Jacobo ; Hall, Ruth ( Taylor and Francis Group , 2023 ) The politics of food, climate, energy, and the yet unfinished work ofending colonialism run square through questions of land. Theclassical agrarian question has taken on new forms, and a newintensity. We look at four ... Intra-party cohesion in Zimbabwe’s ruling party after Robert Mugabe  Zamchiya, Phillan ( Journal of Asian and African Studies , 2023 ) Some mainstream political scientists apply the trilogy of exit, voice and loyalty in studying intra-party cohesion. This approach applies more neatly in liberal than in repressive contexts. I therefore make three modifications ... Smallholder views on Chinese agricultural investments in Mozambique and Tanzania in the context of VGGTS  Pointer, Rebecca ; Sulle, Emmanuel ; Ntauazi, Clemente ( MDPI , 2023 ) Based on a case study in each country, this study documents the views of Mozambican and Tanzanian smallholders regarding Chinese agricultural investments and the extent to which investors abide by their legitimate land ... Resisting agrarian neoliberalism and authoritarianism: Struggles towards a progressive rural future in Mozambique  Monjane, Boaventura ( Wiley , 2022 ) After nearly two and a half decades with a Land Law widely considered progressive, Mozambique is preparing to revise its legal framework for land. Land activists accuse the government of pursuing an authoritarian approach, ... Covid-19 Impacts: Household Food Production, Agroecology, Rural Livelihoods and Alternative Food Systems  Building leaders for the UN Ocean Science Decade: A guide to supporting early career women researchers within academic marine research institutions  Shellock, Rebecca J ; Cvitanovic, Christopher ; Isaacs, Moenieba ( Oxford University Press , 2023 ) Diverse and inclusive marine science is now recognized as essential for addressing the complex and accelerating challenges facing marine social-ecological systems (Blythe and Cvitanovic, 2020; Lawless et al., 2021). The ... Changing customary land tenure regimes in Zambia, implications for women’s land rights  Zamchiya, Phillan ; Musa, Chilombo ( Institute for Poverty Land and Agrarian Studies (PLAAS) , 2023-03 ) This paper argues that the formalisation of customary land through a rural certification programme in Nyimba District, Zambia, has triggered the establishment of a new tenure regime that transcends the dualism between ... Securing Tenure for Customary Land Rights Holders in Southern Africa  Zamchiya, Phillan ( Institute for Poverty Land and Agrarian Studies (PLAAS) , 2023-02 ) The Land and Its People: the land question and the South African political order  Du Toit, Andries ( Institute for Poverty Land and Agrarian Studies (PLAAS) , 2023-03 ) This paper examines the disjuncture between the discourses of policy deliberation and contentious politics in debates about ‘the land question’ in South Africa. It argues that the South African land debate as it unfolds ... Gender, generation and the experiences of farm dwellers resettled in the Ciskei Bantustan, South Africa, ca 1960–1976  Evans, Laura ( Wiley , 2013 ) This paper examines the experiences of farm dwellers resettled in rural townships in theCiskei Bantustan during the decades of the 1960s and 1970s. Drawing on the oraltestimonies of elderly residents ... South Africa’s Bantustans and the dynamics of “decolonisation”: Reflections on writing histories of the homelands  Evans, Laura ( Taylor and Francis Group , 2012 ) From the late 1950s, as independent African polities replaced formal colonialrule in Africa, South Africa’s white minority regime set about its own policy ofmimicry in the promotion of self-governing homelands, which ... Zambia’s Customary Landholding Certificate and Tenure Options for Women  Zamchiya, Phillan ; Musa, Chilombo ( Institute for Poverty Land and Agrarian Studies (PLAAS) , 2023-02 ) Women’s Lived Realities Under Customary Tenure in Rural South Africa and Policy Implications  Zamchiya, Phillan ; Lebepe, Shula ( Institute for Poverty Land and Agrarian Studies (PLAAS) , 2023-02 ) Securing Land Tenure for Women and Men Living on Customary Land in Zimbabwe  This policy brief reports on findings from a study investigating the impact of the formalisation of customary land on tenure relations and livelihoods for women and men living in rural Zimbabwe. The research was conducted ... Securing Land Tenure for Women Under Mozambique’s Land Administration Programme (Terra Segura)  Musa, Chilombo ; Zamchiya, Phillan ; Ntauazi, Clemente ; Noyes, Joana ( Institute for Poverty Land and Agrarian Studies (PLAAS) , 2023-01 ) This policy brief reports findings from a study undertaken by researchers at the Institute for Poverty, Land and Agrarian Studies (PLAAS) at the University of the Western Cape (UWC) investigating the formalisation of ... More than socially embedded: The distinctive character of ‘communal tenure’ regimes in South Africa and its implications for land policy  Cousins, Ben ( Wiley , 2007 ) This article analyzes debates over tenure reform policy in post-apartheid South Africa, with a particular focus on the controversial Communal Land Rights Act of 2004. Land tenure systems in the ... The next great Trek? South African commercial farmers move north  Hall, Ruth ( Taylor and Francis Group , 2012 ) This paper analyses the shifting role of South African farmers, agribusiness andcapital elsewhere in the Southern African region and the rest of the continent. Itexplores recent trends in this expansion, and investigates ... Smallholder Aagriculture and land reform in South Africa  Lahiff, Edward ; Cousins, Ben ( Institute of Development Studies , 2005 ) How canland reformcontribute toa revitalisationof smallholder agriculture inSouthernAfrica?Thisquestion remains important despitenegativeperceptions of land reformas a result of the impactofZimbabwe’s “fast-track” resettlement ... Institutions and Co-Management in East African Inland and Malawi Fisheries: A Critical Perspective  Nunan, Fiona ; Hara, Mafaniso ; Onyango, Paul ( Elsivier , 2015 ) Institutions matter within natural resource management. While there are many examples of analyses of the nature and influence of institutions within fisheries, there are fewer examples of how institutions inform the practice ...
https://repository.uwc.ac.za/handle/10566/18
Observational study of the development and evaluation of a fertility preservation patient decision aid for teenage and adult women diagnosed with cancer: the Cancer, Fertility and Me research protocol | BMJ Open Observational study of the development and evaluation of a fertility preservation patient decision aid for teenage and adult women diagnosed with cancer: the Cancer, Fertility and Me research protocol G L Jones 1 , J Hughes 1 , N Mahmoodi 1 , D Greenfield 2 , G Brauten-Smith 3 , J Skull 4 , J Gath 5 , D Yeomanson 6 , E Baskind 7 , J A Snowden 8 , 9 , http://orcid.org/0000-0001-6710-5403 R M Jacques 10 , G Velikova 11 , K Collins 12 , D Stark 13 , R Phillips 14 , S Lane 15 , H L Bekker 16 (On behalf of the Cancer, Fertility and Me research team) 1 Department of Psychology, School of Social Sciences, Leeds Beckett University, City Centre Campus , Leeds , UK 3 Breast Cancer Care , London , UK 4 Jessop Wing, Sheffield Teaching Hospitals NHS Foundation Trust , Sheffield , UK 5 Independent Cancer Patients’ Voice , London , UK 6 Sheffield Children's Hospital NHS Foundation Trust , Sheffield , UK 7 Seacroft Hospital, Leeds Teaching Hospitals , Leeds , UK 8 Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield 9 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK 10 School of Health and Related Research, University of Sheffield , Sheffield , UK 11 University of Leeds, St James Hospital, Leeds Teaching Hospitals , Leeds , UK 12 Centre for Health and Social Care Research, Sheffield Hallam University , Sheffield , UK 13 University of Leeds, St James Hospital, Leeds Teaching Hospitals , Leeds , UK 14 Center for Review and Dissemination, University of York, Leeds General Infirmary, Leeds Teaching Hospitals , York , UK 15 Oxford Radcliffe Hospitals NHS Trust , Oxford , UK 16 Leeds Institute of Health Sciences, School of Medicine, University of Leeds , Leeds , UK Correspondence to Professor GL Jones; [email protected] Abstract IntroductionWomen diagnosed with cancer and facing potentially sterilising cancer treatment have to make time-pressured decisions regarding fertility preservation with specialist fertility services while undergoing treatment of their cancer with oncology services. Oncologists identify a need for resources enabling them to support women's fertility preservation decisions more effectively; women report wanting more specialist information to make these decisions. The overall aim of the ‘Cancer, Fertility and Me’ study is to develop and evaluate a new evidence-based patient decision aid (PtDA) for women with any cancer considering fertility preservation to address this unmet need. Methods and analysisThis is a prospective mixed-method observational study including women of reproductive age (16 years +) with a new diagnosis of any cancer across two regional cancer and fertility centres in Yorkshire, UK. The research involves three stages. In stage 1, the aim is to develop the PtDA using a systematic method of evidence synthesis and multidisciplinary expert review of current clinical practice and patient information. In stage 2, the aim is to assess the face validity of the PtDA. Feedback on its content and format will be ascertained using questionnaires and interviews with patients, user groups and key stakeholders. Finally, in stage 3 the acceptability of using this resource when integrated into usual cancer care pathways at the point of cancer diagnosis and treatment planning will be evaluated. This will involve a quantitative and qualitative evaluation of the PtDA in clinical practice. Measures chosen include using count data of the PtDAs administered in clinics and accessed online, decisional and patient-reported outcome measures and qualitative feedback. Quantitative data will be analysed using descriptive statistics, paired sample t-tests and CIs; interviews will be analysed using thematic analysis. Ethics and disseminationResearch Ethics Committee approval (Ref: 16/EM/0122) and Health Research Authority approval (Ref: 194751) has been granted. Findings will be published in open access peer-reviewed journals, presented at conferences for academic and health professional audiences, with feedback to health professionals and program managers. The Cancer, Fertility and Me patient decision aid (PtDA) will be disseminated via a diverse range of open-access media, study and charity websites, professional organisations and academic sources. External endorsement will be sought from the International Patient Decision Aid Standards (IPDAS) Collaboration inventory of PtDAs and other relevant professional organisations, for example, the British Fertility Society. Trial registration numberNCT02753296; pre-results. Fertility preservation Cancer Decision-making Decision aid Protocol This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:http://creativecommons.org/licenses/by-nc/4.0/ http://dx.doi.org/10.1136/bmjopen-2016-013219 Fertility preservation Cancer Decision-making Decision aid Protocol Strengths and limitations of this study To the best of our knowledge, this research will develop the first, open access, evidence-based fertility preservation decision aid that is suitable for women of reproductive age (16 years+) and diagnosed with anycancer. The research will provide evidence of its acceptability and utility to women and healthcare professionals in usual practice across cancer and fertility care pathways. The research will provide evidence for the causal assumptions of its effectiveness and issues for implementation in usual care practice. This research will not provide evidence of its effectiveness on healthcare outcomes. However, our findings will provide the evidence to inform the study design for evaluating the effectiveness of this complex intervention on health outcomes in the future. Introduction The impact of cancer treatment on female fertility Approximately 50% of people in the UK will be diagnosed with cancer at some point in their lifetime.1Owing to rising survival rates, the importance of addressing the late effects of cancer treatment, such as the risk of infertility, has increased.2Chemotherapy, radiotherapy, hormonal, medical and surgical interventions may all affect female fertility. Although, the degree to which chemotherapy and radiotherapy impacts on gonadal function depends on the treatment agent administered, the dose, as well as the woman's age and levels of ovarian reserve at the time,3–5loss of fertility is considered one of the most significant late effects of cancer treatment3and cancer survivors often report it as one of the most distressing outcomes of their cancer treatment.6 The rationale for the study Women diagnosed with cancer have to make time-pressured decisions about fertility preservation while simultaneously planning their cancer treatment. These decisions are stressful as women are having to trade-off the immediate consequences of starting cancer treatment with the long-term chances of having a biological child in the future, post cancer treatment. For those contemplating fertility preservation, women are required to move between two medical services (oncology and fertility services) to make care planning decisions collaboratively with fertility preservation and cancer teams. In the initial stages of treatment for cancer, the American Society of Clinical Oncology and the American Society for Reproductive Medicine recommend options to preserve fertility which are discussed with each patient of reproductive age about to undergo cancer treatment which may affect their fertility.7 ,8The current National Institute for Clinical Excellence (NICE) pathway for preserving fertility in people diagnosed with cancer presents similar guidelines for the UK.9However, the evidence suggests that many women do not feel well supported in their choices, with many missing out on having fertility preservation at this crucial time. A recent UK survey by Breast Cancer Care found that as little as 12% of 170 women were referred to a fertility consultant, with many being unaware that infertility was a consequence following chemotherapy.10 Evidence from the medical and psychological literature examining aspects of fertility, pregnancy and decision-making following a cancer diagnosis have identified a range of factors which may hinder decision-making for this patient population.11–25The barriers identified are diverse including financial concerns (especially in those countries where fertility preservation is not covered by insurance), fear associated with aggravating a hormone-sensitive cancer or a future pregnancy (in terms of a cancer recurrence and/or implications for the health of a future child) and lack of referral to fertility services (eg, due to reasons such as the oncologist prioritising cancer survival). However, lack of fertility preservation information is also a key reason cited. The need for more evidence-based information that is integrated into the cancer care pathway early, and prior to transition to fertility services, has been identified as an important factor to facilitate women's decision-making at this time.26 ,27It has been found that oncologists lack specific fertility preservation information for patients, and have only moderate confidence in their knowledge about fertility and the preservation options available.28Therefore, they have also expressed the need for more evidence-based fertility preservation information to enable them to support women's decision-making more effectively.29 Patient decision aids Patient decision aids (PtDAs) are information resources supporting people to make decisions between healthcare options.30They are evidence-based resources, drawing on clinical effectiveness of healthcare options data, studies of patients' decision-making and illness experiences and evidence from the decision sciences on how people make healthcare choices.31PtDAs support people to make reasoned decisions, that is, ones based on accurate information about the consequences of all options, in accordance with their beliefs, and trade-offs between their treatment preferences.32–34Compared with usual care, receiving a PtDA helps people participate with their health professionals in making personalised choices between healthcare options.32 ,33They have been shown to improve patients' knowledge of the risks and benefits of options, value of consequences to their lives and efficacy in making informed decisions.30 While there are many fertility preservation resources publically available for women with cancer,35few exist to support the fertility preservation decision process in women of reproductive age.35Of those publishing their development studies, two PtDAs were designed for women with breast cancer specifically, and none for women in the UK,36 ,37despite women with a range of different cancers facing fertility preservation treatment decisions. It is therefore likely a new PtDA supporting women diagnosed with anycancer to make fertility preservations decisions will meet patient, service and practice needs.25 ,26 ,35 Aims and objectives The aim of this research is to develop a fertility preservation PtDA enabling cancer and fertility services to support effectively women's fertility preservation decisions following a diagnosis of any cancer type. Our objectives are to: develop a PtDA for use by oncology and haematology teams to support women making fertility preservation choices, while having a recent cancer diagnosis; assess the face validity of the PtDA to support women making informed decisions about fertility preservation before starting their cancer treatment and evaluate the acceptability of the PtDA using qualitative and quantitative methods to 1) women making fertility preservation decisions while planning their cancer treatment and 2) oncology, haematology and fertility health professionals supporting women's cancer and fertility treatment choices. Evaluation of the PtDA should enable us to determine whether the provision of a PtDA early in the cancer care pathway better supports women, especially in the stressful intervening period between planning their cancer treatment and referral to the fertility expert. We also anticipate that the provision of this PtDA will enable women to make more informed fertility preservation treatment decisions, have more focused consultations with the fertility experts and a better opportunity to ask the right questions for them at the right time. Methods and analysis All aspects of the research are discussed with the steering group, and all stakeholders comment on all the materials. There has been patient and public involvement in the development of the research protocol and initial needs assessment. The PtDA is being developed across two regional cancer (adult, and teenage and young adult services) and fertility centres in Yorkshire. Ethics approval was granted on 5 April 2016. Design The Cancer, Fertility and Me PtDA was developed over a year using systematic and evidence-based methods (table 1—stages 1 and 2).33 ,38 ,39A prospective, observational study using interview and questionnaire methods to evaluate the PtDA will be conducted (table 1—stage 3) informed by Medical Research Council Guidance for Developing Complex Interventions.40 Table 1 The three stages of the Cancer, Fertility and Me study Stage 1: Development of the PtDA (November 2015—July 2016) Stage 1 has used evidence to develop a PtDA supporting women to make informed decisions about fertility preservation options before starting cancer treatment. This will be for use alongside usual cancer and fertility care pathways. The PtDA has used guidance from the International Patient Decision Aid Standards (IPDAS) collaboration34on balance of options,41 ,42risk presentation,43–45eliciting values,46 ,47use of patient stories,30enabling readability48and understanding illness.49 ,50The guidance helps information to be structured so that it encourages people to evaluate all decision options, and their consequences, in accordance with their values and without bias, thus, enabling decision-making to be based on their trade-offs between these evaluations, that is, to make a reasoned decision.34 The aim is for women to receive the PtDA from their cancer health care professionals as part of usual care during the patient's first consultation to discuss cancer and/or fertility treatment options (this could be at cancer diagnosis), before referral to fertility services. The PtDA is being disseminated as a leaflet and PDF on a website, and evaluated accordingly. The content of the PtDA will be informed by evidence from the following: Clinical guidelines on infertility and cancer prognosis, risks and benefits of cancer and fertility preservation treatment.8–9 ,35 Systematic narrative review of women's values, treatment preferences and decision-making experiences about fertility preservation when diagnosed with cancer, completed in June 2016. This was carried out as part of the previous PreFer study which was a 3-year mixed-methods prospective study exploring fertility preservation decision-making and quality of life in women with cancer.25 Environmental scan using systematic methods to synthesise evidence about open access resources for women with cancer about fertility preservation (patient information and clinical guidelines) and critically evaluate their ability to support informed decision-making, completed in May 2016.35 Observations of local service delivery, referral pathways within and across services and integration of research practices across regional National Health Service (NHS) centres for cancer and infertility services, completed by June 2016. Regular meetings with the study steering group to decide the content and design of the PtDA. During this time web and graphic designers were involved in developing the PtDA's identity for use in health and patient forums, completed by July 2016. Stage 2: Face validity study (July 2016–December 2016) Stage 2 assesses the face validity of the PtDA for stakeholders. During the development of decision aids, this process is sometimes referred to as Learner Verification (LV).51The aim is to assess the PtDA across stakeholders for attractiveness, comprehension, cultural acceptability, self-efficacy and persuasion.52 ,53 Sample A purposive sample of eligible women and health professionals will be invited to participate from the study sites. All women of reproductive age (16 years +), diagnosed with any cancer and undergoing or has undergone cancer treatment(s) which may impact fertility will be eligible. The sample of health professionals will consist of adult and paediatric oncologists and haematologists, cancer surgeons, cancer nurse specialists and fertility specialists (clinicians, nurses and counsellors). There is no statistical guidance for undertaking LV methods using qualitative methods. Prior literature and our research experience suggest a sample size of 20 participants in total across both sites to be appropriate.54Therefore, 10 women and 10 health professionals from the two clinical centres will be invited to participate. In addition to the 20 participants, women and key health professionals will be invited to participate from relevant user groups/forums and professional organisations identified by the Cancer, Fertility and Me steering group and our systematic reviews (eg, National Cancer Research Initiative, Breast Cancer Care and British Fertility Society among others). Recruitment To recruit the women to stage 2, the nurses/clinicians will make the initial approach (for those women recruited from the two clinical centres). For the women recruited through the service user groups/forums, the lead contacts for the service user groups will make the initial approach. Following this, the contact details of the interested women will be passed to a trained researcher and those willing to participate will be sent the PtDA and associated documents to review by post. Recruitment of health professionals will be obtained from the study sites and through purposive and snowball sampling for the key stakeholders. The PtDA will be sent by post or via a PDF online depending on the request of the health professional. Appropriate consenting procedures and guidelines prescribed by the British Psychological Society55and NHS research protocols will be followed. Data collection All the women and health professionals will be asked to complete a study questionnaire which includes the LV questionnaire, and the Preparation for Decision-making questionnaire.56The LV questionnaire will consist of four items taken from the QQ-10,57but will also comprise of three open-ended questions relating to the acceptability and utility of the PtDA from women's and health professional's perspective. The Preparation for Decision-making scale56is a 10-item measure which assesses an individual's perception of how useful a PtDA is in preparing the respondent to communicate with their practitioner at a consultation focused on making a health decision. High scores on the overall scale (range 0–100) indicate higher perceived levels of preparation for decision-making. Second, all the health professionals and women who completed the questionnaire and consent form, will be asked to take part in a follow-up telephone interview. An interview schedule will be used to seek their feedback and understanding of the purpose of the PtDA and study measures.51 ,53Interviews will be audio recorded, digitalised and transcribed for analysis. Data analysis Telephone interviews will be coded and managed using NVivo 10 qualitative data analysis software. Analysis will use a practical, thematic approach outlined by Braun and Clarke58using a systematic five-step approach: familiarisation, generating initial codes, searching for themes, reviewing themes and defining and naming themes. Stage 3: Evaluation study (January 2017–May 2018) Stage 3 evaluates the acceptability, feasibility and usefulness of the PtDA in clinical practice with women and health professionals. The study design employs mixed methods, using quantitative (stage 3a) and qualitative methods (stage 3 b). Stage 3a Quantitative sample All women receiving a new diagnosis of cancer from two regional centres will be eligible for participation. Inclusion criteria are women of a reproductive age (16 years +) with a new diagnosis of any cancer, and facing cancer treatment(s) with curative intent, which may impact fertility. We anticipate that the majority will be women with breast cancer, although women with lymphoma and leukaemia, head and neck cancers and cervical cancers are also likely to be represented in this research. From the results of our previous PreFer study,13we have found that ∼90 women, across both hospital sites, aged between 16 and 40 years are diagnosed with cancer and face chemotherapy treatment annually and are eligible to receive the new PtDA. We identified around 17% of women from this group do not wish to consider fertility preservation as they already have children or never wanted children. During the 12-month period we hope to recruit ∼78 women in total, taking into account a 20% non-response rate from our previous data. Using a paired t-test to compare the outcome measures before and after the implementation of the PtDA, with 78 participants, we have 80% power at 5% two-sided significance to detect a minimum standardised effect size of 0.32. Stage 3a Quantitative recruitment We will adopt the ‘referral model’ for implementing the PtDA59that is, the PtDA will be mentioned and discussed by their healthcare professional with any woman fitting the eligibility criteria during the patient's first consultation to discuss treatment options. The referral model proposes that these tools are ‘adjuncts’ that support decision-making, when used ahead of visits, or shortly afterwards.59Eligible women will be invited to participate by the researchers working with the clinical care team, immediately following this consultation. Stage 3a Quantitative data collection Quantitative data will be collected at three time-points (figure 1). Questionnaire packs will be given to women at the same time as the PtDA (baseline); the timing of their attendance at the fertility clinic or cancer treatment starting point if not going to fertility services (time 1) and after their first session of chemotherapy (time 2a). The measures chosen for this study have been decided on following recommended guidance from the Patient Decision Aid International Research Group,60and will assess the use of the PtDA and decisional preparedness. Figure 1 Process flow chart for stage 3 evaluation study. Baseline: questionnaire pack includes: The State Trait Anxiety Inventory—STAI-6,61the EuroQol five dimensions questionnaire (EQ-5D),62the Stage of Decision-making63and the Decisional Conflict Scale.64Women are instructed not to open and read the PtDA (or access it online) until they have completed the questionnaires. The State Trait Anxiety Inventory—6 item45is a brief 6-item version used to measure of state anxiety. All items are rated on a 4-point scale (1-Almost never, 4-Almost always). Higher scores indicate greater anxiety. The EQ-5D62is a standardised instrument for use as a measure of health outcome. It consists of five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has three levels: no problems, some problems and extreme problems. The Stage of Decision-making63is a 6-category tool to assess the individual's readiness to engage in decision-making, progress in making a choice and receptivity to considering or reconsidering options. The tool is rated on a 6-point scale (1-not thinking about it at all; 6-considered the options). The Decisional Conflict Scale64is a 16-item scale which measures the patient's reported experience of making a reasoned and/or conflicted decision. Scores >37.5 on the overall scale (range 0–100) indicate high decisional conflict, which is characterised by decision delay and/or uncertainty about decision. Time 1: Questionnaire pack includes: the STAI-6,45the Stage of Decision-making63and the Preparation for Decision-making.56 Time 2a: Questionnaire pack includes: the STAI-6,45the Stage of Decision-making63and the Decisional Conflict Scale.64 Stage 3a Quantitative data analysis We will report summary statistics for the count data and other service indicators. For the decisional outcome measures and other patient-reported outcomes we will use paired sample t-tests to calculate mean change in scores from baseline to time 1 and from baseline to time 2. 95% CIs for the mean changes will also be calculated. All statistical tests will be two-tailed with significance determined at p≤0.05. Stage 3b Qualitative sample Qualitative, semistructured interviews with a purposive sample of ∼30 women from the stage 3a evaluation (15 women from each site) and 30 health professionals including cancer surgeons, adult and paediatric oncologists and haematologists, nurse specialists and fertility experts (15 from each site) will be carried out. The purpose of the interviews are to gain a deeper sight into service user and healthcare professionals experiences of using the PtDA and its impact on the decision- making process and clinical care, within the context of this complex intervention.40Although a total of ∼30 interviews are estimated, this will be guided by data saturation, following established protocols in qualitative research.58 ,65 ,66 Stage 3b Qualitative recruitment The sample will consist of the women recruited into the stage 3 quantitative study, and the clinical sample will be obtained through snowball sampling methods. Women and health professionals will be issued with a study pack, including a study information sheet and the PtDA. On the day of the interview, an interview consent form will be completed. As shown in Figure 1, the interview with women and the health professionals will be carried out after the first round of chemotherapy has been completed (time 2b) at a place that is most preferred. Stage 3b Qualitative data collection The interview schedule will comprise of the telephone interview LV schedule used in stage 2, with additional open-ended questions to add depth and breadth to the interpretation of the quantitative results enabling further insight into their experiences. It will also focus on LV and the PtDAs clarity and usefulness in planning care and making decisions between treatment options. However, additional areas we will explore include the PtDAs likelihood of use, barriers to use in practice, whether or not the women and health professionals benefit from their delivery, usefulness of the PtDA in aiding service transition and how the women used the PtDA. All interviews will be audio-recorded and transcribed verbatim for analysis. Following the interview, the women will be given a final study pack questionnaire to complete, which comprises of the EQ-5D62and the Decisional Regret Scale.67The Decisional Regret Scale is a brief five-item scale which measures ‘distress or remorse after a health care decision’ using a 5-point Likert scale (1- strongly agree; 5- strongly disagree). A score of 0 on the overall scale (range 0–100) indicates no regret; scores of 100 mean high regret. Stage 3b Qualitative data analysis Interviews will be coded and managed using NVivo 10. Framework analysis will be carried out to identify recurrent themes which have been specifically developed for applied health and policy research.68Independent analysis of the transcribed data by members of the study team and steering group will take place. Interdisciplinary analysis meetings will include critical appraisal of the literature, systematic data and coding framework verification and challenging of interpretive analysis. We will map the data against the themes identified from the existing literature as well as allow new themes to emerge. We will adhere to established quality criteria for qualitative research.58 ,65 ,66 Other questionnaires and outcome measures Demographic information about women's age, ethnicity, employment and treatment status will be collected through a questionnaire during stage 2 (face validity) and at stage 3 baseline. Demographic information about health professionals will also be collected through a questionnaire, during stage 2 and at stage 3 (time 2b). Details of patients' cancer treatment(s) will be recorded at the end of the study using a study ‘cancer treatment proforma’. This proforma has been ethically approved and used to record the cancer treatment details in the previously mentioned PreFer Study.26 Count data will be collected of the number of PtDAs given to women and health professionals, counts of use and number of clicks on the ‘Cancer, Fertility and Me’ website and downloads of the online PDF version will be recorded. In addition, we will record length of oncology, haematology and fertility consultations and length of time to fertility and cancer treatment. Using count data is a common method for evaluating a decision aid.69 Ethics and dissemination Ethical considerations Written, signed consent will be obtained from all participants. Issues particularly pertinent to this study will include participants' right to withdraw from the research process, informed consent and their right to confidentiality and anonymity. Usual NHS care will be provided by the health professionals involved, which includes referral to support and counselling services available within the oncology, haematology and fertility services at the NHS study sites, if any of the women wish. In line with good practice, across both sites, the young women aged 16–17 years and their parents/guardians will be asked to sign for consent. Dissemination This research will involve rigorous methods and evaluation in a clinical context.40The multidisciplinary and collaborative nature of this proposal will enable us to disseminate the research and its milestones to the study participants and into the NHS and wider healthcare community through a variety of local, national and international channels regularly throughout the duration of this research. During the development and evaluation phases of the research, we are engaging with patients and the public through the North Trent Consumer Research Panel group, NHS England's Patient Involvement Team, International Cancer Patient Voices, the service user research partnership of Breast Cancer Care as well as presenting our findings at INVOLVE national conferences. A study website is currently under development (http://www.leedsbeckett.ac.uk/cancerfertilityandme.ac.uk). It will be used to provide an evidence-based portal on the study, team and links with our international partners. It will enable access to the web-based version of the instrument and provide two-way links into other relevant organisations, charities signposted on our webpage and the other social media planned to be used in the study, for example, twitter/blogs. We plan to impact the academic and clinical community more widely through conference presentations and publications in peer-reviewed journals that are open access. Findings on the quality of the PtDA and study outcomes will be used to provide feedback to health professionals and programme managers. Audit and feedback is an effective intervention for changing the behaviour of health professionals (Cochrane Effective Practice and Organisation of Care Group). The study will be widely and regularly disseminated throughout its duration. We will develop links with NHS England patient information teams and other UK and international bodies who endorse patient education materials for use/dissemination by service teams. We will also seek assessment by the international criteria of PtDAs to be included in their A to Z inventory.60 The primary output of this study will be the final version of the PtDA. Once evaluated, it will be promoted widely and made available free through a diverse range of media (ie, social and print), charity websites, professional organisations, academic sources and posted to all key stakeholders and participants. Discussion It is anticipated that this research will provide evidence about the effectiveness of a PtDA to support cancer patients' decision-making in relation to fertility preservation. Currently, fertility preservation PtDAs for women of reproductive age only exist to support women with breast cancer. A unique feature of this research is that we hope to provide evidence that one open-access PtDA can be used effectively across a range of women's cancer types. Another strength of this research is that it will be administered early into the cancer care pathway, thus providing clinical cancer care teams with an evidence-based resource to provide to all women diagnosed with cancer, therefore meeting a current unmet need. It is anticipated that this will encourage more cancer specialists to have fertility related discussions with women, help raise fertility awareness and provide a resource that will improve the care, support and management of the women. While this might result in more women choosing to see the fertility expert (Breast Cancer Care alone estimated that around 5000 women per year who should be having this consultation are missing out), it should also reduce the number of women with cancer who are inappropriately referred for fertility preservation and unsuitable for this treatment. In trying to create a resource that is suitable for women with any cancer, this undoubtedly creates a number of challenges (in terms of synthesising the evidence on cancer treatment on female reproduction and the fertility preservation choices available). We have tried to prepare for this and included an extensive face validity stage during which the PtDA will undergo review from a large number of patients, service users and key stakeholders from a variety of oncology and fertility specialities. The overall aim of the ‘Cancer, Fertility and Me’ study is to develop and evaluate a new evidence-based PtDA for women with any cancer considering fertility preservation. The data generated as part of this study should help us identify factors associated with its implementation in practice, and/or integration in care. During its evaluation, the cancer care clinical teams will hand out information about the study and the PtDA. We will capture data on the acceptability of this method of integration within care from the clinical teams. It may be our clinical teams think a short skills training session on using our PtDA within cancer and fertility services will support its implementation in usual practice. It is likely future research evaluating our PtDA's impact on health outcomes may therefore also need to include an assessment of shared decision-making training within an implementation study's process evaluation. References ↵ Sasieni PD , Shelton J , Ormiston-Smith N , et al . What is the lifetime risk of developing cancer?: the effect of adjusting for multiple primaries . Br J Cancer 2011 ; 105 : 460 – 5 . doi:10.1038/bjc.2011.250 ↵ Cancer Research UK . Cancer Stats for the UK (retrieved 26 Jan 2016). http://www.cancerresearchuk.org/health-professional/cancer-statistics#heading-Zero Google Scholar ↵ Meirow D , Nugent D . The effects of radiotherapy and chemotherapy on female reproduction . Hum Reprod Update 2001 ; 7 : 535 – 43 . doi:10.1093/humupd/7.6.535 ↵ Meirow D , Biederman H , Anderson RA , et al . Toxicity of chemotherapy and radiation on female reproduction . Clin Obstet Gynecol 2010 ; 53 : 727 – 39 . doi:10.1097/GRF.0b013e3181f96b54 ↵ Maltaris T , Seufert R , Fischl F , et al . The effect of cancer treatment on female fertility and strategies for preserving fertility . Eur J Obstet Gynecol Reprod Biol 2007 ; 130 : 148 – 55 . doi:10.1016/j.ejogrb.2006.08.006 OpenUrl CrossRef PubMed Web of Science Google Scholar ↵ Peate M , Meiser B , Hickey M , et al . The fertility-related concerns, needs and preferences of younger women with breast cancer: a systematic review . Breast Cancer Res Treat 2009 ; 116 : 215 – 23 . doi:10.1007/s10549-009-0401-6 ↵ Lee SJ , Schover LR , Partridge AH , et al . American Society of Clinical Oncology recommendations on fertility preservation in cancer patients . J Clin Oncol Res 2006 ; 24 : 2917 – 31 . doi:10.1200/JCO.2006.06.5888 ↵ The Ethics Committee of the American Society for Reproductive Medicine . Fertility preservation and reproduction in patients facing gonadotoxic therapies: a committee opinion Fertil Steril 2013 ; 100 : 1224 – 3 . ↵ National Institute for Health and Care Excellence . Cryopreservation to preserve fertility in people diagnosed with cancer. http://pathways.nice.org.uk/pathways/fertility#path=view%3A/pathways/fertility/cryopreservation-to-preserve-fertility-in-people-diagnosed-with-cancer.xml&content=view-index (accessed 26 Jan 2016 ). ↵ Breast cancer care study ‘Standards of Care for Younger Women; Results from the survey of healthcare professionals’ by Grete Brauten- Smith and Jennifer Finnegan-John. https://www.breastcancercare.org.uk/about-us/media/press-releases/approximately-5000-breast-cancer-patients-missing-out-fertility-care (accessed 26 Jan 2016 ). ↵ Kuhn D . Fertility options in young breast cancer survivors: a review of the literature . Oncol Nurs Forum 2004 ; 31 : E46 – 53 . doi:10.1188/04.ONF.E46-E53 ↵ Goossens J , Delbaere I , Van Lancker A , et al . Cancer patients’ and professional caregivers’ needs, preferences and factors associated with receiving and providing fertility-related information: a mixed-methods systematic review . Int J Nurs Stud 2014 ; 51 : 300 – 19 . doi:10.1016/j.ijnurstu.2013.06.015 ↵ Gonçalves V , Sehovic I , Quinn G . Childbearing attitudes and decisions of young breast cancer survivors: a systematic review . Hum Reprod Update 2014 ; 20 : 279 – 92 . doi:10.1093/humupd/dmt039 ↵ Holton BA , Kirkman M , Rowe H , et al . The childbearing concerns and related information needs and preferences of women of reproductive age with a chronic, noncommunicable health condition: a systematic review . Womens Health Issues 2014 ; 22 : e541 – 52 . doi:10.1016/j.whi.2012.08.001 ↵ Ganz PA , Bower JE , et al . Quality of life, fertility concerns, and behavioural health outcomes in younger breast cancer survivors: a systematic review . J Natl Cancer Inst Monogr 2012 ; 104 : 386 – 405 doi:10.1093/jnci/djr541 ↵ Jensen JR , Morbeck DE , Coddington CC . Fertility preservation . Mayo Clinical Procedure 2011 ; 86 : 45 – 9 . doi:10.4065/mcp.2010.0564 ↵ Loren AW , Mangu PB , Beck LN , et al . Fertility preservation for patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update . J Clin Oncol 2013 ; 31 : 2500 – 10 . doi:10.1200/JCO.2013.49.2678 ↵ Quinn GP , Murphy D , Knapp C , et al . Who decides? Decision making and fertility preservation in teens with cancer: a review of the literature . J Adolesc Health 2011 ; 49 : 337 – 46 . doi:10.1016/j.jadohealth.2011.01.005 Schmidt R , Richter D , Sender A , et al . Motivations for having children after cancer--a systematic review of the literature . Eur J Cancer Care (Engl) 2016 ; 25 : 6 – 17 . doi:10.1111/ecc.12276 ↵ Sobota A , Ozakinci G . Fertility and parenthood issues in young female cancer patients—a systematic review . J Cancer Surviv 2014 ; 8 : 707 – 21 . doi:10.1007/s11764-014-0388-9 ↵ Penrose R , Beatty L , Mattiske J , et al . The psychosocial impact of cancer-related infertility on women . Clin J Oncol Nurs 2012 ; 17 : 188 – 93 . doi:10.1188/13.CJON.188-193 ↵ Tschudin S , Bitzer J . Psychological aspects of fertility preservation in men and women affected by cancer and other life-threatening diseases . Hum Reprod Update 2009 ; 15 : 587 – 97 . doi:10.1093/humupd/dmp015 ↵ Butow P , Tesson S , et al . Systematic review of decision aids for patients making a decision about treatment for early breast cancer . Breast 2016 ; 26 : 31 – 45 . doi:10.1016/j.breast.2015.12.007 OpenUrl Google Scholar ↵ Lee MC , Gray J , Han HS , et al . Fertility and reproductive considerations in female premenopausal patients with breast cancer . Cancer Control 2010 ; 17 : 162 – 72 . ↵ Jones GL , Hughes J , Mahmoodi N , et al . What factors influence the decision-making process for women with cancer contemplating fertility preservation? A systematic review. RCOG World Congress : Birmingham, UK . Abstract , July 2016 . Google Scholar ↵ Jones GL , Hughes J , Greenfield D , et al . What factors influence the fertility preservation treatment decision-making process in women with cancer? the qualitative findings of the PreFer study. European Shared Medical Decision Making conferences , London, UK : Abstract , July 2016 . Google Scholar ↵ Wilkes S , Coulson S , Crosland A , et al . Experience of fertility preservation among younger people diagnosed with cancer . Hum Fertil (Camb) 2010 ; 13 : 151 – 8 . doi:10.3109/14647273.2010.503359 ↵ Duffy C , Allen SM , Dube C , et al . Oncologists’ confidence in knowledge of fertility issues for young women with cancer . J Cancer Educ 2012 ; 27 : 369 – 76 . doi:10.1007/s13187-011-0304-1 ↵ Adams E , Hill E , Watson E . Fertility Preservation in Cancer Survivors: a national survey of oncologists’ current knowledge, practice and attitudes . Br J Cancer 2013 ; 108 : 1602 – 15 . doi:10.1038/bjc.2013.139 ↵ Stacey D , Bennett CL , Barry MJ , et al . Decision aids for people facing health treatment or screening decisions . Cochrane Database Syst Rev 2011 ; 5 : CD001431 . OpenUrl Google Scholar ↵ Bekker HL , Winterbottom AE , Butow P , et al . Do personal stories make patient decision aids more effective: a critical review of evidence and theory? BMC Med Inform Decis Mak 2013 ; 13 (Suppl 2 ): S9 . doi:10.1186/1472-6947-13-S2-S9 ↵ Rothert ML , Holmes-Rovner M , Rovner D , et al . An educational intervention as decision support for menopausal women . Res Nurs Health 1997 ; 20 : 377 – 87 . doi:10.1002/(SICI)1098-240X(199710)20:5<377::AID-NUR2>3.0.CO;2-L ↵ O'Connor A , Edwards AG . The role of decision aids in promoting evidence-based patient choice . In: Edwards AG , Elwyn G , eds . Evidence-based patient choice: inevitable or impossible? Oxford : Oxford University Press , 2001 : 220 – 43 . Google Scholar ↵ Bekker HL , Thornton JG , Airey CM , et al . Informed decision making: an annotated bibliography and systematic review . Health Technol Assess 1999 ; 3 : 1 – 156 . OpenUrl PubMed Google Scholar ↵ Mahmoodi N , Bekker HL , King N , et al . Decision aids’ efficacy to support women's fertility preservation choices before cancer treatment: an environmental scan. European Society of Medical Decision Making Society Bi-Annual Conference . London: UK . June 2016 . Google Scholar ↵ Peate M , Meiser B , Friedlander M , et al . Development and pilot testing of a fertility decision aid for young women diagnosed with early breast cancer . Breast J 2011 ; 17 : 112 – 14 . doi:10.1111/j.1524-4741.2010.01033.x OpenUrl CrossRef PubMed Google Scholar ↵ Garvelink MM , ter Kuile MM , Fischer MJ , et al . Development of a decision aid about fertility preservation for women with breast cancer in The Netherlands . J Psychosom Obstet Gynecol 2013 ; 34 : 170 – 8 . doi:10.3109/0167482X.2013.851663 OpenUrl CrossRef PubMed Google Scholar ↵ Coulter A , Stilwell D , Kryworuchko J , et al . A systematic development process for patient decision aids . BMC Med Inform Decis Mak 2013 ; 13 (Suppl 2 ): S2 . doi:10.1186/1472-6947-13-S2-S2 OpenUrl CrossRef PubMed Google Scholar ↵ Winterbottom AE , Gavaruzzi T , Bekker HL . Patient acceptability of the Yorkshire Dialysis Decision Aid (YoDDA) Booklet: a prospective non-randomised comparison study across 6 predialysis services . Pert Dial Int 2016 ; 36 : 374 – 81 . doi:10.3747/pdi.2014.00274 OpenUrl Google Scholar ↵ Craig P , Dieppe P , Macintyre S , et al . Developing and evaluating complex interventions: the new Medical Research Council guidance . BMJ 2008 ; 337 : a1655 . doi:10.1136/bmj.a1655 OpenUrl FREE Full Text Google Scholar ↵ Purva Abhyankar P , Volk RJ , Blumenthal-Barby J , et al . Balancing the presentation of information and options in patient decision aids: an updated review . BMC Med Inform Decis Mak 2013 ; 13 (Suppl 2 ): S6 doi:10.1186/1472-6947-13-S2-S6 OpenUrl Google Scholar ↵ Stalmeier P , Volk RJ , Abhyankar P , et al . Balancing the presentation of information and options . In: Volk R , Llewellyn-Thomas H . eds . Update of the International Patient Decision Aids Standards (IPDAS) Collaboration's background document . Chapter I , 2012 . http://ipdas.ohri.ca/resources.html (accessed 20 Mar 2016 ) Google Scholar ↵ Trevena LJ , Davey HM , Barratt A , et al . A systematic review on communicating with patients about evidence . J Evaluation Clin Pract 2006 ; 12 : 13 – 23 . doi:10.1111/j.1365-2753.2005.00596.x OpenUrl CrossRef PubMed Web of Science Google Scholar ↵ Trevena LJ , Zikmund-Fisher BJ , Edwards A , et al . Presenting quantitative information about decision outcomes: a risk communication primer for patient decision aid developers . BMC Med Inform Decis Mak 2013 ; 13 (Suppl 2 ): S7 . doi:10.1186/1472-6947-13-S2-S7 OpenUrl CrossRef Google Scholar ↵ Barratt A , Trevena L , Davey HM , et al . Use of decision aids to support informed choices about screening . BMJ 2004 ; 329 : 507 – 10 . doi:10.1136/bmj.329.7464.507 OpenUrl FREE Full Text Google Scholar ↵ O'Connor AM , Stacey D , Tugwell P , et al . Incorporating patient values . In: DiCenso A , Guyatt G , Ciliska D , eds . Evidence-based nursing: a guide to clinical practice . Toronto : Mosby , 2005 ; 490–507. Google Scholar ↵ Fagerlin A , Pignone M , Abhyankar P , et al . Clarifying values: an updated review . BMC Med Inform Decis Mak 2013 ; 13 (Suppl 2 ): S8 . doi:10.1186/1472-6947-13-S2-S8 OpenUrl CrossRef Google Scholar ↵ Ley P , Florio T . The use of readability formulas in health care . Psychol Health Med 1996 ; 1 : 7 – 28 . doi:10.1080/13548509608400003 OpenUrl CrossRef Google Scholar ↵ Leventhal H , Diefenbach M , Leventhal EA . Illness cognition: using common sense to understand treatment adherence and affect cognition interactions . Cognit Ther Res 1992 ; 16 : 143 – 63 . doi:10.1007/BF01173486 OpenUrl CrossRef Web of Science Google Scholar ↵ Leventhal H , Benyamini Y , Bownlee S , et al . Illness Representations: Theoretical Foundations . In: Petrie KJ , Weinman JA , eds . Perceptions of health and illness: current research and applications . The Netherlands : Harwood Academic Publisher , 1997 ;19–46. Google Scholar ↵ Doak LG , Doak CC , Meade CD . Strategies to improve cancer education materials . Oncol Nurse Forum 1996 ; 23 : 1305 – 12 . OpenUrl PubMed Google Scholar ↵ Knapp CA , Quinn GP , Murphy DM . Assessing the reproductive concerns of children and adolescents with cancer: challenges and potential solutions . J Adolesc Young Adult Oncol 2011 ; 1 : 31 – 5 . doi:10.1089/jayao.2010.0003 OpenUrl Google Scholar ↵ Quinn P , Vadaparampil ST , Sehovic I , et al . Patient and Family Tools to Aid in Education and decision Making About Oncofertility . In: Woodruff TK , Clayman ML , Waimey KE , eds . Oncofertility communication: sharing information and building relationships across disciplines . Springer : New York , 2014 ; 35–47 . Google Scholar ↵ Jones G , Kennedy S , Barnard A , et al . Development of an endometriosis quality-of-life instrument: the endometriosis health profile-30 . Obstet Gynecol 2001 ; 98 : 258 – 64 . OpenUrl CrossRef PubMed Web of Science Google Scholar ↵ The British Psychological Society . Professional Practice Guidelines 1995. Report . Leicester, UK , 2001 . https://www.bps.org.uk (accessed 22 Jun 2016 ). Google Scholar ↵ Bennett C , Graham ID , Kristjansson E , et al . Validation of a preparation for decision making scale . Patient Educ Couns 2010 ; 78 : 130 – 3 . doi:10.1016/j.pec.2009.05.012 OpenUrl CrossRef PubMed Google Scholar ↵ Moores KL , Jones GL , Radley SC . Development of an instrument to measure face validity, feasibility and utility of patient questionnaire use during health care: the QQ-10 . Int J Qual Health Care 2012 ; 24 : 517 – 24 . doi:10.1093/intqhc/mzs051 OpenUrl Abstract / FREE Full Text Google Scholar ↵ Braun V , Clarke V . Using thematic analysis in psychology . Qual Res in Psychol 2006 ; 3 : 77 – 101 . doi:10.1191/1478088706qp063oa OpenUrl CrossRef Google Scholar ↵ Elwyn G , Scholl I , Tietbohl C , et al . ‘Many miles to go…’: a systematic review of the implementation of patient decision support interventions into routine clinical practice . BMC Med Inform Decis Mak 2013 ; 13 (Suppl 2 ): S14 . doi:10.1186/1472-6947-13-S2-S14 OpenUrl CrossRef PubMed Google Scholar ↵ Ottawa Hospital Research Institute . Patient Decision Aids Research Group. 2014 . https://decisionaid.ohri.ca/cochinvent.php (a ccessed 27 Jan 2016 ). Google Scholar ↵ Marteau TM , Bekker HL . The development of a six-item short-form of the state scale of the Spielberger State-Trait Anxiety Inventory (STAI) . Br J Clin Psychol 1992 ; 31 (Pt 3 ): 301 – 6 . doi:10.1111/j.2044-8260.1992.tb00997.x OpenUrl CrossRef PubMed Web of Science Google Scholar ↵ The Euroqol Group . Euroqol- a new facility for the measurement of health-related quality-of-life . Health Policy 1990 ; 16 : 199 – 208 . doi:10.1016/0168-8510(90)90421-9 OpenUrl CrossRef PubMed Web of Science Google Scholar ↵ O'Connor AM . Stage of decision making . Ottawa : Ottawa Hospital Research Institute . 2000 . https://decisionaid.ohri.ca/eval_stage.html (Accessed 27 Jan 2016 ). Google Scholar ↵ O'Connor AM . Validation of a decisional conflict scale . Med Decis Making 1995 ; 15 : 25 – 30 . doi:10.1177/0272989X9501500105 ↵ Chamberlain K . Using grounded theory in health psychology . In: Murray M , Chamberlain K , eds . Qualitative health psychology . London : Sage , 1999 : 183 – 201 . Google Scholar ↵ Miles MB , Huberman AM . Qualitative data analysis: an expanded sourcebook . Los Angeles : Sage , 1994 . Google Scholar ↵ Brehaut JC , O'Connor AM , Wood TJ , et al . Validation of a decision regret scale . Med Decis Making 2003 ; 23 : 281 – 92 . doi:10.1177/0272989X03256005 ↵ Ritchie J , Spencer L , O'Connor W . Carrying out qualitative analysis . In: Ritchie J , Lewis J , eds . Qualitative research practice: a guide for social science students and researchers . London : SAGE Publications Ltd , 2003 : 220 – 62 . Google Scholar ↵ Elwyn G , Kreuwel I , Durand MA , et al . How to develop web-based decision support interventions for patients: a process map . Patient Educ Couns 2011 ; 82 : 260 – 5 . doi:10.1016/j.pec.2010.04.034 OpenUrl CrossRef PubMed Google Scholar Footnotes ContributorsGLJ conceived the idea, secured funding and is the chief investigator. The first REC approval was made by GLJ. GLJ, JH, HLB, KC, DG, JAS, GV, GB-S, RMJ, JG provided intellectual input into the protocol for the grant application. GLJ, JH, HLB, NM, KC, DG, GV, GB-S, RMJ, JAS, EB, DY, SL, DS, JG, SL, RP provided intellectual input and study design for the final protocol of the study. FundingThis work is funded by Yorkshire Cancer Research, grant number (S391). Competing interestsNone declared. Ethics approvalThe study protocol was approved by the East Midlands NHS Research Ethics for the Protection of Persons of Bordeaux University (approval number 2015-A00778-41). It was also approved by the National Commission for Data Processing and Freedoms (approval number 1838811). Provenance and peer reviewNot commissioned; externally peer reviewed.
https://bmjopen.bmj.com/content/7/3/e013219
v>>VV>LLi`V>i*> >`- *]>ivi>>iV> with the SHBP vendor or change drug stores. U iVii`i}>`}L>>iV> 24 important notice decision guide 2008 October 1, 2007 Two Peachtree Street Atlanta, GA 30303 {{xUnn Important Notice from the SHBP for Medicare Eligible Members About Your Prescription Drug Coverage with BlueChoice HMO, BlueCross BlueShield Lumenos HRA, Kaiser Permanente, Indemnity, PPO, UnitedHealthcare Choice HMO, UnitedHealthcare Definity HRA and Medicare For Plan Year: January 1December 31, 2008 Please read this notice carefully and keep it where you can find it. This notice has information about your current prescription drug coverage with the SHBP and about your options under Medicare's prescription drug coverage. This information can help you decide whether or not you want to join a Medicare drug plan. Information about where you can get help to make decisions about your prescription drug coverage is at the end of this notice. 1. Medicare prescription drug coverage became available in 2006 to everyone with Medicare. You can get this coverage if you join a Medicare Prescription Drug Plan or join a Medicare Advantage Plan (like an HMO or PPO) that offers prescription drug coverage. All Medicare drug plans provide at least a standard level of coverage set by Medicare. Some plans may also offer more coverage for a higher monthly premium. 2. The SHBP has determined that the prescription drug coverage offered by BlueChoice HMO, i i-i`i,]>i*i>ii]`i]**"]1i`i>V>i Choice HMO and UnitedHealthcare Definity HRA Options under SHBP are, on average for all plan participants, expected to pay out as much as standard Medicare prescription drug coverage pays and is considered Creditable Coverage. Because your existing coverage is, on average, at least as good as standard Medicare prescription drug coverage, you can keep this coverage and not pay a higher premium (a penalty) if you later decide to join a Medicare drug plan. You can join a Medicare drug plan when you first become eligible for Medicare and each year from November 15th through December 31st. This may mean that you may have to wait to join a Medicare drug plan and that you may pay a higher premium (a penalty) if you join later. You may pay that higher premium (a penalty) as long as you have Medicare prescription drug coverage. However, if you lose creditable prescription drug coverage, through no fault of your own, you will be eligible for a sixty (60) day Special Enrollment Period (SEP) because you lost creditable coverage to join a Part D plan. In addition if you lose your SHBP coverage, you will be eligible to join a Part D plan at that time using an Employer Group Special Enrollment Period. You should compare your current coverage, including which drugs are covered at what cost, with the coverage and costs of the plans offering Medicare prescription drug coverage in your area. If you decide to join a Medicare drug plan, your SHBP coverage will be affected. See below for more information about what happens to your current coverage if you join a Medicare drug plan. If you elect Part D and keep your SHBP coverage under BlueChoice HMO, BlueCross BlueShield i,]>i*i>ii]`i]**"]1i`i>V>i Vi">` UnitedHealthcare Definity HRA Options, these plans will coordinate with Part D coverage. important notice 25 decision guide 2008 If you do decide to join a Medicare drug plan and drop your BlueChoice HMO, BlueCross i-i`i,]>i*i>ii]`i]**"]1i`i>V>i Vi" UnitedHealthcare Definity HRA coverage, be aware that you and your dependents will not be able to get your SHBP coverage back. You should also know that if you drop or lose your coverage with SHBP and don't join a Medicare drug plan within 63 continuous days after your current coverage ends, you may pay a higher premium (a penalty) to join a Medicare drug plan later. If you go 63 continuous days or longer without prescription drug coverage that's at least as good as Medicare's prescription drug coverage, your monthly premium may go up by at least 1% of the base beneficiary premium per month for every month that you did not have that coverage. For example, if you go nineteen months without coverage, your premium may consistently be at least 19% higher than the base beneficiary premium. You may have to pay this higher premium (a penalty) as long as you have Medicare prescription drug coverage. In addition, you may have to wait until the following November to join. For More Information about this Notice or Your Current Prescription Drug Coverage... Contact the SHBP Call Center at (404) 656-6322 or (800) 610-1863 for further information. NOTE: You'll get this notice each year. You will also get it before the next period you can join a Medicare drug plan, and if your SHBP coverage changes. You also may request a copy. For More Information about Your Options under Medicare Prescription Drug Coverage... More detailed information about Medicare plans that offer prescription drug coverage is in the Medicare & You handbook. You will get a copy of the handbook in the mail every year from Medicare. You may also be contacted directly by Medicare drug plans. For more information about Medicare prescription drug coverage: U6i`V>i} U >->ii>>Vi>Vi*}>iii`iL>VVivVvi Medicare & You handbook for their telephone number) for personalized help U >n , n{//9i`V>n{n{n If you have limited income and resources, extra help paying for Medicare prescription drug coverage is available. For information about this extra help, visit Social Security on the web at www.socialsecurity.gov, or call them at 1-800-772-1213 (TTY 1-800-325-0778). Remember: Keep this Creditable Coverage notice. If you decide to join one of the Medicare drug plans, you may be required to provide a copy of this notice when you join to show whether or not you have maintained creditable coverage and whether or not you are required to pay a higher premium (a penalty). Date: October 1, 2007 Name of Entity/Sender: State Health Benefit Plan Office: Call Center Address: P. O. Box 38342, Atlanta, GA 30334 Phone Number: (404) 656-6322 or (800) 610-1863 26 important notice decision guide 2008 Two Peachtree Street Atlanta, GA 30303 {{xUnn October 1, 2007 Important Notice from the SHBP for Medicare Eligible Members About Your Prescription Drug Coverage with the High Deductible Health Plan and Medicare For Plan Year: January 1December 31, 2008 Please read this notice carefully and keep it where you can find it. This notice has information about your current prescription drug coverage with the State Health Benefit Plan (SHBP) and about your options under Medicare's prescription drug coverage. This information can help you decide whether you want to join a Medicare drug plan. Information about where you can get help to make decisions about your prescription drug coverage is at the end of this notice. 1. Medicare prescription drug coverage became available in 2006 to everyone with Medicare. You can get this coverage if you join a Medicare Prescription Drug Plan or join a Medicare Advantage Plan (like an HMO or PPO) that offers prescription drug coverage. All Medicare drug plans provide at least a standard level of coverage set by Medicare. Some plans may also offer more coverage for a higher monthly premium 2. The SHBP has determined that the prescription drug coverage under the High Deductible Health Plan (HDHP) Option, is, on average for all plan participants, NOT expected to pay out as much as standard Medicare prescription drug coverage pays and is considered NonCreditable Coverage. This is important, because most likely, you will get more help with your drug costs if you join a Medicare drug plan, than if you only have prescription drug coverage through the HDHP offered by the SHBP 3. You have decisions to make about Medicare prescription drug coverage that may affect how much you pay for that coverage, depending on if and when you join. Read this notice carefully as it explains your options Consider joining a Medicare drug plan. You can keep your HDHP coverage offered by the SHBP. You can keep the coverage regardless of whether it is as good as Medicare drug plan. However, because your existing coverage is, on average, NOT at least as good as standard Medicare prescription drug coverage, you may pay a higher premium (a penalty) if you later decide to join a Medicare drug plan. You can join a Medicare drug plan when you first become eligible for Medicare and each year from November 15th through December 31st. This may mean that you may have to wait to join a Medicare drug plan and that you may pay a higher premium (a penalty) if you join later. You may pay that higher premium (a penalty) as long as you have Medicare prescription drug coverage. However, if you lose *Vi>}i`ii- *Lii}Li>*> >>>i}> Employer Group Special Enrollment Period. You Need to Make a Decision When you make your decision, you should compare your current coverage, including which drugs are covered, with the coverage and cost of the plans offering Medicare prescription drug coverage in your area. If you decide to join a Medicare drug plan, your HDHP coverage under SHBP will be affected. See below for more information about what happens to your current coverage if you join a Medicare drug plan. important notice 27 decision guide 2008 Uvii`V>i*> iLiVii}Livi`V>i*> ]V>ii your HDHP coverage even if you elect Part D and the HDHP will coordinate benefits with Part D coverage. Uv``iV`i>i`V>i`}>>`` *Vi>}i`i- *]Li aware that you and your dependents will not be able to get your SHBP coverage back. U9`>>v`i *Vi>}i- *>``> Medicare drug plan within 63 continuous days after your current coverage ends, you may pay a higher premium (a penalty) to join a Medicare drug plan later. Uv}V`>}iiV`}Vi>}i>>i>>}`> Medicare's prescription drug coverage, your monthly premium may go up by at least 1% of the base beneficiary premium per month for every month that you did not have that coverage. For example, if you go nineteen months without coverage, your premium may consistently be at least 19% higher than the base beneficiary premium. You may have to pay this higher premium (penalty) as long as you have Medicare prescription drug coverage. In addition, you may have to wait until the following November to join. For More Information about this Notice or Your Current Prescription Drug Coverage... Contact the SHBP Call Center at (404) 656-6322 or (800) 610-1863 for further information. NOTE: You will get this notice each year. You will also get it before the next period you can join a Medicare drug plan, and if your SHBP coverage changes. You also may request a copy. For More Information about Your Options under Medicare Prescription Drug Coverage... More detailed information about Medicare plans that offer prescription drug coverage is in the Medicare & You handbook. You will get a copy of the handbook in the mail every year from Medicare. You may also be contacted directly by Medicare drug plans. For more information about Medicare prescription drug coverage: U6i`V>i} U >->ii>>Vi>Vi*}>iii`iL>VVivVvi Medicare & You handbook for their telephone number) for personalized help U >n , n{//9i`V>n{n{n If you have limited income and resources, extra help paying for Medicare prescription drug coverage is available. For information about this extra help, visit Social Security on the web at www.socialsecurity.gov, or call them at 1-800-772-1213 (TTY 1-800-325-0778). Date: October 1, 2007 Name of Entity/Sender: State Health Benefit Plan Office: Call Center Address: P. O. Box 38342, Atlanta, GA 30334 Phone Number: (404) 656-6322 or (800) 610-1863 decision guide 2008 28 %FQBSUNFOUPG$PNNVOJUZ)FBMUI 1SJWBDZ/PUJDF /Vi`iVLii`V>v>>L>Lii`>``Vi`>`V> }i>VViv>*i>iiiV>iv 5IF1MBOT1SJWBDZ$PNNJUNFOUUP:PV /ii}> i>iv i> `i>`>v>>L>` v>i> Vi`iV}v>/Vii i>``Viv>>Li}>`i*>iii >Lv> 6OEFSTUBOEJOHUIF5ZQFPG*OGPSNBUJPOUIBUUIF1MBO)BT S9HBPirecordisindi>caite>}tihatVy]ouVhavepreiviou>slyprovi]diedVinfoirmativonto>us. T>hLisinformatio n inclu/ded yovurna>me,addVres`si,`birthdat>e, ip]h>o`n`enium]Lber,S`o>ciia]lSecuriityNuLmib]e-r,gVe>nd-eirVandM edicaLrie]in}fior`miation i>fa`pplicaible.i>Itmayals>ohViaveinVcliuded>healthin>form>aition.W>he>nyou>rihealVth`ciar`epir>ovidervssen>dclaim s to t7heiPlan'sclaiim>sadVm>iinistrato`riforipa`ymVe>ntmthecilai*m>sincVlu>de yo>u`rdiagno>sesavndt>hemied]icalitrVea>tments yoVur`ecieived.`Fo>}r somie>me`dicailtreia`tmV>entsi,>youirhealthciarVeipiro`viderssendiadid`itVio>nalim>ediicali]nformation toi>thePVl>anisucha`sidocito`r's>`st`ateme>nts, ix`-rVa>ysorvlab >testresults.i*>V>`V>ii]> >Lii :PVS)FBMUI*OGPSNBUJPO3JHIUT 9>iiv}}i}>`}ii>v>> >>L\ U9>ii}ii>`L>>Vvi>v>iViVi> iiiViv>>ii`i`v>i}>>Vi>} U9>ii}> V>}ii>v>>ViVVii >`iii`iVi>VV>Vi U9>ii}ii>vi`Vi> >>`ivi>v> Li}} U9>ii}ii>iVVi>i`Vivi>v> ii`>}iiii U9>ii}ii> VV>i>Li>>>>> V>>iiiv>Vv`i> U9>ii}iVii>>iVvVi9>> >vv}i>i VvVi]>L>>Vv 7iLi]`V}i}>} V **>V Vi decision guide 2008 29 1SJWBDZ-BXT3FRVJSFNFOUT ii`L>\ U>>i>Vvv> UiViv i}>`i>`>V>VVii}>`}iv>> >>L UiivVi U i`Vi>v>>Lii]iVivi i>}iVi9>>i>>i>>i]}]iViv iv>> `Vi`Livii`ivV>}i i`i>ii}iV] >ii>iiv>vLiii v>>Li>viii>}iv> Intheifvuturei,]D C Hma>ycVha>ng}eiitspriva>cVypra>cVticVeis,Ifvitspriva>cVypra>cVticVeiscVha>ng}eisig}nifivcVa>ntly,]D C H willprovid`eia>neiwnoticVeitoyou.D C HwillposttheineiwnoticVei.onitsW7eibLsiteia>twww.d`cVh.g}eiorg}ia>.g}ov. C licVkonHIP*PAP*riva>cVyNoticVeis.T/hisnoticVeiwasivevfifVectiiveApril1{4],2003 . )PX%$)6TFTBOE%JTDMPTFT)FBMUI$BSF*OGPSNBUJPO /ii>iiiVii*>`i}V>V>iV>ii>i]> i>>ViV>>i`V>V>i>V>i`i7iiVi>i V>Vi`]i*>>`Vii>vv>iV>>iV> iviLi*>>>i`i`/iVv>]i*>iii V>>vi}>`v>>VV`>Vii> /iv}V>i}i`iVLi`vvii>>i*>i>``Vii>v> i>VV>i}]ii>>ii>>`}i>i>i *>i /i*>>i>``Viv>>L>V>>i>ivii> iVi>iVii`i>i]iiVii>iViVii`Li*>]i> V>i`ii`>V>v>iiV>>`>/iV>V`iv>> `ivi]>i>`>}i>`i>i i`V>/i>i /i*>>i`Viv>>Lii>iViiiVi>i`V> i>i>`iVii>i]v>V>i> i>i->i>>}ii*}>]i*> >i`v>>LV` /"i>i6>*>*}> /i*>>i`Viv>>L>*>}>>`ii> iVii>V>ii>i]i*>>V>V>V>>ii>iV` ViVi>vV>i>iVii`>`iVivV>i /"iii}iVi*`} iiv-iVi /i*>>}iv>>Li}ii>}iVi>>i}}Liiv iVi/iv>LiiVi>viViiiLiiviVi>`Li >i`LL> decision guide 2008 30 /ii9vi` /i*>>>v>>Li>>`iLi} >i>iv>>L >>}}>`i>i>>i]v>>L>>}i`V>iVVi]>`v>>L iV`}>i>} "iii}i> >i*`i /i*>>`Viv>>Li}ii>}iVi>Vii>`iV i`V>v>Vi]V>>]>ii`L> ,ii>V /i*>>`Viv>>Lv>ii>ViV>>Lii>i`L>ii L>`/iiiL>`iiiii>ViV>`iiii>Vv v>/iii>VLiviivi}i*> ,ii`L> /i*>`Viv>>L>ii`L> 1`ii**>V>]>>ii*>ii>i*i>i>v> *>i``>v>i>i`iii>iv*>i``>]ii> iii>iv>}iii>iv*>vii`Liii/vi iVv>VvVi`i}>i>i``>>viV>}}i> ]>Li>i`Vii>ii>iii>iv 'PS.PSF*OGPSNBUJPOPSUP3FQPSUB1SPCMFN v>ii>``i>``>v>]>V>Vi- *>{{x >>V>}>i>nn`iv>>V>}>i> vLiii>V}>iLii>i`\ U9V>vi>V>i*>LV>}i- *>{{x>>V>}>i> nn`iv>>V>}>i>]L}\- *q*1]*" n{] >>]{ U9V>vi>V>ii>>`>-iVi"vvViv ,}L}\ 1- i>ivi>>`>-iVi"vvViv ,}],i}6]>>i`i> ii]-ii-7]-i ]>>] /iiLii>>vv}>V> decision guide 2008 31 Health Insurance Portability And Accountability Act (HIPAA) Annual Notice This section describes certain rights available to you under the Health Insurance Portability and Accountability Act (HIPAA) when you add a dependent to your SHBP coverage. The PPO, PPO CCO and Indemnity Options contain a pre-existing condition (PEC) limitation. Specifically, the Health Plan will not pay charges that are over $1,000 for the treatment of any pre-existing condition during the first 12 months of a patient's coverage, unless the patient gives satisfactory documentation that he or she has been free of treatment or medication for that condition for at least six consecutive calendar months. However, a preexisting condition limitation does not apply to coverage for: U*i}>V U iLV`i`i>}in>i>`i`>Vi`v>`]viV` becomes covered within 31 days after birth, adoption or placement for adoption. In certain situations, SHBP dependents can reduce the 12-month pre-existing condition limitation period. The reduction is possible by using what is called "creditable coverage" to offset a pre-existing condition period. Creditable coverage generally includes the health coverage a family member had immediately prior to joining the SHBP. Coverage under most group health plans, as well as coverage under individual health policies and governmental health programs, qualifies as creditable coverage. To reduce the pre-existing condition limitation period for your dependents (including your spouse), you must provide the SHBP with a certificate of creditable coverage stating when coverage started and ended for each dependent that you want to cover. Any period of prior coverage for that dependent will reduce the 12-month limitation period if no more than 63 days have elapsed between the dependent's loss of prior coverage and the first day of coverage under the SHBP. If your dependent (including a spouse) had any break in coverage lasting more than 63 days, your dependent will receive creditable coverage only for the period of time after the break ended. Within two years after your dependent's former coverage terminated, he or she has the right to obtain a certificate of creditable coverage from his or her former employer(s) to offset the preexisting condition limitation period under the SHBP. The SHBP will evaluate the certificate of creditable coverage or other documentation to determine whether any of the pre-existing condition limitation period will be reduced or eliminated. After completing the evaluation, the SHBP will notify you as to how the pre-existing condition limitation period will be reduced or eliminated. Please submit the certificate of creditable coverage to the Plan with your dependent's enrollment paperwork. decision guide 2008 32 8PNFOT)FBMUIBOE$BODFS3JHIUT"DU /i*>Vii7ii>>` >Vi,}Vvn>iV]V`} iVVi}i]Vii`i>i>i}i`i*> }V>Vi}i]i- *Vi\ U>}iviVVviLi>Vi>iV>Liiivi` U,iVVviiLi>>Vii>iV>>i>>Vi U*ii>`>iVL> U/i>ivV>VV>v>iV]V`}i`i> "/ \,iVVi}iii>>]>`>>i>`ii vV> i`i>i`v>i>iVi>i`Liiv>>>Li`ii*>]V>V>V iiLi-iVivVi>}i/iiiLi>ii`ivVi 4UBUFNFOUTPG3JHIUT6OEFSUIF/FXCPSOT BOE.PUIFST)FBMUI1SPUFDUJPO"DU i>>>`i>>Vii}ii>>]`ivi`i>>]iV iivv >>i}v>ViVV`LviiiLV`i>{n v}>>}>`ii]i>v}>Vi>i>iVii]vi`i> >}ii>`iLiiiL>i`}`i]>viV}i i]v`V>}}iiiiLi>i>{n>>V>Li >V>i]>>`i>]`ivi`i>>]ii>>`iL>>>vi >i>ViiviVL}>i}v>iViv{n 1FOBMUJFTGPS.JTSFQSFTFOUBUJPO v>- *>V>iiii}Lv>i>}vVi>}i]`}V>}i vVi>}iiv}vLiiv]i- *>>i>`ii>V>}>i>V>] V`}Li`i>}Vi>}ivi>V>>`i`ii`iQR }>Li- *vv>``ivV>i}>ivLiivV i>V>iLiivV>iiiii`*i>i>V`i>>]V> i>ivV>}ii*>V>iV>Vv> `i>`ivViivii>i]i>V>vi- *i`>iv> `ii`i}ii}LivVi>}ivi>V>>iii>>Li i}Lv>`ii`i/V>LiivVi`iviiivi> i>iii>iiV>}ii>i}vV>ViiVi9 >>V>i- *Vi>}ivLi}}i`>i>v>iii `Vii` Helping Georgians Stay Healthy
https://dlg.usg.edu/record/dlg_ggpd_y-ga-bc900-pe4-bs1-bh4-b2008-belec-p-btext/fulltext.text
(PDF) Impacts of Hurricanes Irma and Maria on Aedes aegypti Populations, Aquatic Habitats, and Mosquito Infections with Dengue, Chikungunya, and Zika Viruses in Puerto Rico PDF | Puerto Rico was severely impacted by Hurricanes Irma and Maria in September 2017. The island has been endemic for dengue viruses (DENV) and... | Find, read and cite all the research you need on ResearchGate Impacts of Hurricanes Irma and Maria on Aedes aegypti Populations, Aquatic Habitats, and Mosquito Infections with Dengue, Chikungunya, and Zika Viruses in Puerto Rico June 2019 The American journal of tropical medicine and hygiene 100(6):1413-1420 DOI: 10.4269/ajtmh.19-0015 CC BY 4.0 Authors: Veronica Acevedo Abstract and Figures Puerto Rico was severely impacted by Hurricanes Irma and Maria in September 2017. The island has been endemic for dengue viruses (DENV) and recently suffered epidemics of chikungunya (CHIKV 2014) and Zika (ZIKV 2016) viruses. Although severe storms tend to increase the number of vector and nuisance mosquitoes, we do not know how they influence Aedes aegypti populations and arboviral transmission. We compared the abundance of female Ae. aegypti in autocidal gravid ovitraps (AGO traps), container habitats, and presence of RNA of DENV, CHIKV, and ZIKV in this vector before and after the hurricanes in Caguas city and in four communities in southern Puerto Rico. Two of these communities were under vector control using mass AGO trapping and the other two nearby communities were not. We also investigated mosquito species composition and relative abundance (females/trap) using Biogents traps (BG-2 traps) in 59 sites in metropolitan San Juan city after the hurricanes. Mosquitoes sharply increased 5 weeks after Hurricane Maria. Ensuing abundance of Ae. aegypti was higher in Caguas and in one of the southern communities without vector control. Aedes aegypti did not significantly change in the two areas with vector control. The most abundant mosquitoes among the 26 species identified in San Juan were Culex (Melanoconion) spp., Culex quinquefasciatus, Culex nigripalpus, and Ae. aegypti. No arboviruses were detected in Ae. aegypti following the hurricanes, in contrast with observations from the previous year, so that the potential for Aedes-borne arboviral outbreaks following the storms in 2017 was low. Number of female pupae of Aedes aegypti collected from containers in houses (A) and number of positive containers of each type per 100 houses (Breteau container index) (B) before and after Hurricanes Irma and Maria in Caguas city, Puerto Rico in 2017. … Average number of female Aedes aegypti per sentinel autocidal gravid ovitraps per week and accumulated rainfall (mm) during the third and second weeks before each mosquito-sampling week in 2016, and comparable results observed in 2017 after Hurricanes Irma and Maria in Caguas city, Puerto Rico. Rainfall was lag-forwarded 1.5 weeks to facilitate visual comparisons with mosquito numbers. … Map of the metropolitan area of San Juan city showing the average number of mosquitoes per BG-S trap per day of the four more abundant mosquito species across major landscape elements (forests, high-density housing, low-density housing, non-forested vegetation, and wetlands) after Hurricanes Irma and Maria hit Puerto Rico in 2017. … Am. J. Trop. Med. Hyg. , 100(6), 2019, pp. 1413 – 1420 doi:10.4269/ajtmh.19-0015 Impacts of Hurricanes Irma and Maria on Aedes aegypti Populations, Aquatic Habitats, and Mosquito Infections with Dengue, Chikungunya, and Zika Viruses in Puerto Rico Roberto Barrera, 1 * Gilberto Felix, 1 Veronica Acevedo, 1 Manuel Amador, 1 Damaris Rodriguez, 1 Luis Rivera, 1 Orlando Gonzalez, 1 Nicole Nazario, 2 Marianyoly Ortiz, 2 Jorge L. Muñoz-Jordan, 3 Stephen H. Waterman, 1 and Ryan R. Hemme 1 1 Entomology and Ecology Team, Dengue Branch, Centers for Disease Control and Prevention, San Juan, Puerto Rico; 2 Vector Control Unit of Puerto Rico, Puerto Rico Science Trust, San Juan, Puerto Rico; 3 Molecular Diagnostic Laboratory, Dengue Branch, Centers for Disease Control and Prevention, San Juan, Puerto Rico Abstract. Puerto Rico was severely impacted by Hurricanes Irma and Maria in September 2017. The island has been endemic for dengue viruses (DENV) and recently suffered epidemics of chikungunya (CHIKV 2014) and Zika (ZIKV 2016) viruses. Although severe storms tend to increase the number of vector and nuisance mosquitoes, we do not know how they in fl uence Aedes aegypti populations and arboviral transmission. We compared the abundance of female Ae. aegypti in autocidal gravid ovitraps (AGO traps), container habitats, and presence of RNA of DENV, CHIKV, and ZIKV in this vector before and after the hurricanes in Caguas city and in four communities in southern Puerto Rico. Two of these communities were under vector control using mass AGO trapping and the other two nearby communities were not. We also investigated mosquito species composition and relative abundance (females/trap) using Biogents traps (BG-2 traps) in 59 sites in metropolitan San Juan city after the hurricanes. Mosquitoes sharply increased 5 weeks after Hurricane Maria. Ensuing abundance of Ae. aegypti was higher in Caguas and in one of the southern communities without vector control. Aedes aegypti did not signi fi cantly change in the two areas with vector control. The most abundant mosquitoes among the 26 species identi fi ed in San Juan were Culex ( Melanoconion ) spp., Culex quinquefasciatus , Culex nigripalpus , and Ae. aegypti . No arboviruses were detected in Ae. aegypti following the hurricanes, in contrast with observations from the previous year, so that the potential for Aedes -borne arboviral outbreaks following the storms in 2017 was low. INTRODUCTION Severe storms disturb aquatic habitats where mosquitoes undergo immature development and affect the spatial dis- persal of both mosquitoes and vertebrate hosts, including displacement of people. New aquatic habitats for vector or nuisance mosquitoes appear after severe storms, such as the thousands of abandoned swimming pools in New Orleans following Hurricane Katrina. 1 Increases in the relative abun- dance of several mosquito species that develop in ground- water habitats after hurricanes have been reported, including important vectors of arboviruses, such as West Nile, Saint Louis encep halitis, and Ea stern equin e encephalit is viruses. 2 – 8 Communicable diseases are generally not common after natural disasters, with the exception of events resulting in the displacement of people without adequate sanitation, access to shelter, and primary health care. 9 Nasci and Moore 4 reviewed the impact of storms and fl oods in the continental United States from 1975 to 1997 and concluded that with one exception, these natural events did not increase trans- mission of arboviruses to humans or domestic animals. No signi fi cant increases of arboviral diseases after storms and fl oods were observed in other studies despite heightened mosquito abundance 2,10 or the presence of arboviruses in mosquitoes. 11,12 The Pan American Health Organization 13 reported that neither dengue nor malaria cases increased over previous values after Hurricane Mitch swept through Central America. Hurricane Georges hit Puerto Rico as a category 3 hurricane in 1998 in the midst of a large dengue epidemic, yet the storm did not exacerbate the epidemic. 14 Similarly, Hur- ricane Hortense hit Puerto Rico on September 10, 1996, causing heavy rains and fl ooding, but did not change the usual seasonal pattern of dengue transmission. 15 Nevertheless, several reports do account for increased risk of arbovirus transmission after severe storms or fl ooding. Surges in West Nile neuro-invasive disease cases were re- ported during the 3 weeks following Hurricane Katrina in areas directly impacted by the hurricane in Louisiana and Mis- sissippi. 16 These authors also suggested that increased in- cidence of the disease the following year was possibly caused by increased exposure to mosquito bites where people had substandard living conditions and during reconstruction ac- tivities. Increased dengue and leptospirosis incidence was reported after a severe fl ood in southern Thailand, 17 although the mechanism how the fl ood caused an increase in dengue incidence was not investigated. An association between in- creased dengue incidence and high river levels in Bangladesh was explained by accumulation of garbage, including plastic containers along water bodies. 18 Although hur ricanes are freq uent in many tropic al countrie s where dengueviruses (DENV) are endemic , no previous studi es assessed ho w hurrican es affect the m ain dengue ve ctor Aedes aegypti (L.) . Here, we inv estigated c hanges in ad ult Ae. aegypt i and its aquatic habi tats, abund ance of other urbanmosquitoes, and the prese nce of chiku ngunya, den gue, and Zika v iruses in Ae. aegypti fol lowing the im pacts of cat egory 4 Hurric anes Irma and Maria in Septem ber 2017 in Puerto Ric o. Maria, which ha s been the thir d costliest h urricane in th e U.S. histor y, traverse d the island on Se ptember 20 , 2017. Wind s near 250 km/ho urs, heavy rains, and fl oods devast ated the islands . 19 METHODS We compared adult Ae. aegypti populations before and immediately following the hurricanes in two areas where we have been conducting vector surveillance and control activities: the city of Caguas, Caguas municipality, and four * Address correspondence to Roberto Barrera, Entomology and Ecology Team, Dengue Branch, Centers for Disease Control and Prevention, 1324 Calle Canada, San Juan 00920, Puerto Rico. E-mail: [email protected] 1413 communities in southern Puerto Rico. We also initiated adult mosquito surveillance of other mosquito species, including Ae. aegypti , in the metro area of San Juan city 1 month after Hurricane Maria. Immature surveys in Caguas city before and after the hurricanes were conducted to understand how the storms affected the composition and abundance of con- tainers producing Ae. aegypti . Caguas city study. We compared female Ae. aegypti per trap per week in 360 surveillance autocidal gravid ovitraps (SAGO traps) placed at fi xed stations throughout the city from the second week of October to December 2016 (non-hurricane year) and f rom the second week of October to De cember 2017 (hurricane year). Hurricanes Irma and Maria interrupted weekly sampling from the fi rst week in September to the fi rst week in October 2017. In- tegrated vector management, including community awareness, source reduction, larviciding, and mass trapping using three autocidal gravid ovitraps (AGO traps)per building in most of the buildings, slowly started in late November 2016 and continued through August 2017, when control traps began to be withdrawn (CDC, unpublished data). Results fr om that investigation are being published elsewhere (CDC, unpublished data). We conducted pupal surveys in 395 and 677 buildings in June/July 20 17 (before) and November/December 2017 (after hurricanes), respectively. The sites selected for the pupal surveys were areas around SAGO traps with above average numbers of female Ae. aegypti .W e searched for all containers with water per building to record the abundance of Ae. aegypti pupae and identi fi ed the most pro- ductive types of containers. Co llected pupae were preserved in 80% ethanol and taken to the laboratory for identi fi cation under a stereoscopic microscope. We also calculated the house index (HI; percentage of houses with at least one container with immature Ae. aegypti ), container index (CI; percentage of containers with water that had immatures), Breteau index (BI; no. of positive containers per 100 houses), and container Breteau index (no. of positive containers of each type per 100 houses). Southern Puerto Rico study. We have been conducting Ae. aegypti surveillance in four communities (241 – 397 houses each) in Salinas and Guayama municipalities for several years. 20 Two communities (La Margarita and Villodas) were initially treated with source reduction and larvicing, and La Margarita received three AGO traps per home in most homes in December 2011. In February 2013, we treated Villodas with three AGO traps per home and simultaneously we started monitoring two untreated, nearby communities (Arboleda and Playa) to compare Ae. aegypti populations with the two treated areas. Mosquito surveillance has been conducted using 28 – 44 SAGO traps per community since then. We compared the abundance of Ae. aegypti in the study areas from August 2016 through January 2017 (non-hurricane year) with data from August 2017 through January 2018 (hurricane year). Weekly sampling was interrupted for 2 weeks (last week in September and fi rst week in October 2017) in all four areas following Hurricane Maria. Hurricane Irma did not signi fi cantly affect surveillance or control in these southern areas. San Juan city study. We deployed 59 BG-2 Sentinel (BG-S) traps throughout San Juan city from October 17 to November 17, 2017. Most BG-S traps were operated for four consecutive days for o ne or two con secut ive week s per site . The samp ling sites were selected based on a previous study in 2005, where we trapped in various types of land covers within the city (for- ests, high-density housing, low-density housing, non-forested vegetation, and wetlands). 21 W e d i dn o tu s eC D Cm i n i a t u r el i g h t traps as in the previous study because our CDC light traps used D-batteries, which were in short supply immediately after the hurricane, and because no dry ice was available. BG-S traps were operated with BS-lure using rechargeable batteries that we had in stock (sealed lead-acid 12V 18 ampere hour). Collected mosquitoes were transported to the laboratory and stored at − 20 ° C until they were enumerated and identi fi ed. Weather. Meteorological stations (HOBO data loggers; Onset Computer Corporation, Boume, MA) during these studies recorded rainfall, air temperature, and relative hu- midity in Caguas city (eight stations) and in the southern Puerto Rico communities (three stations). We calculated ac- cumulated rainfall during the third and second weeks before mosquito sampling because rainfall during the preceding week should not contribute to new adult Ae. aegypti at the time of sampling. We used average temperature and relative hu- midity during 3 weeks before sampling because these pa- rameters could in fl uence the number of adult mosquitoes present at the moment of sampling, assuming that mosqui- toes do not live longer than 3 weeks. To compare weather between years, we used average weekly rainfall, average daily air temperature, and average daily relative humidity. Hurricane Maria knocked down most of our weather stations, and it took us several weeks to obtain spare parts to fi x them (January 2018). We obtained missing weather data from nearby weather stations th at kept record ing during tha t time in Cagu as (HSWHQ ICAGU ASC5 Station 18 ° 22 3 9 N, − 66 ° 044 9 W), Sa linas (Camp Santia go Station 18 ° 00 4 9 N, − 66.283 9 W), and Guay ama (Jobos Bay Stati on 17 ° 956 9 N, − 66 ° 223 9 W). Arbovirus detections in Ae. aegypti . To understand if in- creased mosquito abundance following the 2017 hurricanes were associated with increased arbovirus transmission, we used a trioplex real time, reverse transcription polymerase chain reaction (RT-PCR) to simultaneously detect RNA of DENV, CHIKV, and ZIKV in pools (1 – 20 specimens per vial) of female Ae. aegypti collected in SAGO traps in Caguas city and in the four communities in southern Puerto Rico. 22,23 Pools of female Ae. aegypti from Caguas were collected, analyzed, and compared for the following periods: October – December 2016 and October – December 2017. Pools from the four southern communities were collected, analyzed, and compared for October 2016 – January 2017 and October 2017 – January 2018. Data collected during 2016 on arbovirus detections in the four southern communities were recently published. 22 Statistical methods. We compared females of Ae. aegypti per trap per week during similar periods (October – December or January) between the year before (2016) and after the hur- ricanes (2017) using generalized estimating equations (GEE). We used the following weather parameters as covariates: accumulated rainfall 2 – 3 weeks before mosquito sampling, and average temperature and relative humidity for 3 weeks, including the sampling week. A negative binomial model with log link was used for the analyses and a fi rst-order autore- gressive function as the covariance structure for repeated measures. We reported results as means and standard errors. Statistical analyses were carried out with IBM SPSS Statistics 25 software (IBM Corporation, Armonk, NY). RESULTS Caguas city. We found 441 Ae. aegypti pupae in 35 of 395 buildings (1.1 pupae/building) in the pupal survey before the 1414 BARRERA AND OTHERS hurricanes (June/July 2017) and 1962 pupae in 140 of 677 buildings (2.9 pupae/building) after the hurricanes (November/ December 2017). The containers producing more Ae. aegypti pupae during the fi rst survey were discarded tires, other dis- carded containers, 19-L pails, 10-L buckets, and fl ooded water meters (Figure 1). After the hurricanes, the most pro- ductive containers were cavities in building structures (e.g., inundated fl oors of houses with damaged or missing roofs, hollow bricks, and tubes), discarded containers (damaged appliances, rubble, and trash), plant pots (trivets), fl ooded water meters, 19-L pails, 10-L buckets, and discarded tires (Figure 1). The BI per type of container (positive containers per 100 houses) indicated that the most common containers with Ae. aegypti immatures before the hurricanes were fl ooded F IGURE 1. Number of female pupae of Aedes aegypti collected from containers in houses ( A ) and number of positive containers of each type per 100 houses (Breteau container index) ( B ) before and after Hurricanes Irma and Maria in Caguas city, Puerto Rico in 2017. IMPACT OF HURRICANES ON AEDES AEGYPTI 1415 water meters, discarded containers, 19-L pails and 10-L buckets, discarded tires, and plant pots (Figure 1). After the hurricanes, the most common positive containers were dis- carded containers, plant pots, containers for water storage (drums, 19-L pails, 10-L buckets, and pail lids), water meters, and cavities in structures (Figure 1). The HI, CI, and BI (HI = 14%, CI = 3%, BI = 19) before the hurricanes were lower than those after the hurricanes (HI = 33%, CI = 12, BI = 62). The average number of female adults of Ae. aegypti per AGO trap per week after the hurricanes in October – December 2017 (16.8 ± 0.2; N = 4,242 trap × weeks) was signi fi cantly different (Wald χ 1 2 = 220; P < 0.001) from the previous, non- hurricane year (October – December 2016; 8.4 ± 0.1; N = 4,309). There were signi fi cant effects of the covariates: ac- cumulated rainfall (Wald χ 1 2 = 380; P < 0.001), average tem- perature (Wald χ 1 2 = 30; P < 0.001), and average relative humidity (Wald χ 1 2 =2 4 ; P < 0.001). The number of female mos- quit oes peaked in October and by the end of November 2017 (Figure 2). The rela tive ab unda nce of Ae. aegypti (1.4 – 2.1 ± 0.04; CDC, unpublished data) prevailing in Caguas city a few months (May – August 2017) before removing the control traps in August – September 2017 was several times lower than that observed in October – December 2017 (16.8 ± 0.2), showing that the population of Ae. aegypti rapidly recovered after re- moving control measures and following the hurricanes. Average weekly rainfall from the second week in October – December 2016 (37.8 ± 8.1 mm) was similar to that registered for the same time interval in 2017 (41.5 ± 9.1; Figure 2) in Caguas city. Weekly rainfall distribution varied between years, with one peak in November 2016 and two peaks in October and November 2017 (Figure 2). Average temperature and relative humidity in 2016 (25.9 ± 0.3 ° C; 85.2 ± 0.6%) and 2017 (26.2 ± 0.2 ° C; 80.8 ± 1.1%) were comparable. We found one DENV-, three CHIKV-, and 44 ZIKV-positive pools of female Ae. aegypti in October – December 2016, the year of the Zika epidemic in Puerto Rico (4,385 pools). No arboviruses were detected in Ae. aegypti in Caguas city after the hurricanes in October – December 2017 (5,257 pools). Southern Puerto Rico. Hurricane Maria directly affected all four study sites, bringing down power lines and trees, and partially or totally destroying many buildings. Yet, few control AGO traps were lost (20 – 37) in the two communities under mass trapping, but many were toppled or dry (95 of 498 in Villodas and 145 of 568 in La Margarita). There were simulta- neous sharp increases in Ae. aegypti in all four communities 5 weeks after Hurricane Maria (Figure 3). Average Ae. aegypti abundance at each of the four sites during the fi fth week after the hurricane was the largest ever recorded for those sites since 2013 (CDC, unpublished data). Abundance of Ae. aegypti in the two communities with control AGO traps (Vil- lodas and La Margarita) has been small and steady for several years, 22 at or below two females per trap per week. These low numbers were observed for most of 2016/2017 and 2017/ 2018 (Figure 3A and B), except following Hurricane Maria when abundance increased to 10 – 14 mosquitoes per trap per week. Despite these temporary abundance peaks, the GEE analyses showed lack of signi fi cant differences (Wald χ 1 2 = 0.4; P > 0.05) in the average abundance of Ae. aegypti per trap per week for the months of the study between years (non- hurricane 1.7 ± 0.1 versus hurricane 2.21 ± 0.1) and a signi fi - cant effect of rainfall (Wald χ 1 2 = 88.4; P < 0.001) in Villodas. Similarly, average mosquito numbers in La Margarita did not signi fi cantly (Wald χ 1 2 = 0.4; P < 0.001) change between years (1.3 ± 0.1 versus 2.2 ± 0.1). Covariates rainfall (Wald χ 1 2 = 155.9; P < 0.001) and temperature (Wald χ 1 2 = 117.6; P < 0.001) were signi fi cant. Mosquito abundance after the hurricanes in one of the two communities without vector control (Arboleda 10.0 ± 0.3 females/trap/week; Figure 3C) was steadily more than ob- served levels in the previous year from October to December (6.5 ± 0.2). The GEE analysis showed signi fi cant differences between years (Wald χ 1 2 = 39.1; P < 0.001) and signi fi cant F IGURE 2. Average number of female Aedes aegypti per sentinel autocidal gravid ovitraps per week and accumulated rainfall (mm) during the third and second weeks before each mosquito-sampling week in 2016, and comparable results observed in 2017 after Hurricanes Irma and Maria in Caguas city, Puerto Rico. Rainfall was lag-forwarded 1.5 weeks to facilitate visual comparisons with mosquito numbers. 1416 BARRERA AND OTHERS effects of rainfall (Wald χ 1 2 = 155.3; P < 0.001) and temperature (Wald χ 1 2 = 6.6; P < 0.05). Average mosquito abundance in the other community without vector control (Playa 13.8 ± 0.6) was actually lower than in the previous, non-hurricane year (16.6 ± 0.6). Results from the GEE analysis showed that those differ- ences were signi fi cant (Wald χ 1 2 = 20.0; P < 0.001) despite the fact that the peak in mosquito abundance that was observed 5 weeks after the hurricane reached its largest value ever (42 females/trap/week; Figure 3D). Effects of covariates rainfall (Wald χ 1 2 = 122.6; P < 0.001) and temperature (Wald χ 1 2 = 29.1; P < 0.001) were signi fi cant. Average weekly rainfall for all sites after the hurricanes from August 2017 to January 2018 (40.4 ± 6.5 mm) was double than that registered for August 2016 – January 2017 (19.5 ± 2.5; Figure 3). Overall, average temperature and relative humidity in August 2016 – January 2017 (26.9 ± 0.2 ° C; 76.3 ± 0.5%) and August 2017 – January 2018 (26.8 ± 0.1 ° C; 76.5 ± 0.6%) were similar. No pools of Ae. aegypti females tested positive for DENV, CHIKV, or ZIKV in either August 2016 – January 2017 or August 2017 – January 2018 in the two communities treated with AGO traps (La Margarita 213 pools and Villodas 148 pools). We found fi ve and eight positive pools of female Ae. aegypti with ZIKV in the untreated communities (Arboleda 265 pools and Playa 626 pools, respectively), in August 2016 – January 2017, and no arboviruses were detected in Ae. aegypti from these communities in August 2017 – January 2018 (382 and 480 pools, respectively). Thus, no arbovirus activity was evident in Ae. aegypti in any of these communities following Hurricanes Irma and Maria in 2017. San Juan city. We placed BG-S traps at 59 locations in the following municipalities of the metro area of San Juan city: Bayam ´ on, Carolina, Cataño, Guaynabo, San Juan, and Trujillo Alto (Figure 4). We collected 11,797 females of 26 species of mosquitoes in 451 trap days (Table 1). There were 17 trap failures, including some stolen batteries or traps, wire prob- lems, and ants. The most common female adult mosquito species in the traps were Culex atratus , Culex quinque- fasciatus , Ae. aegypti , and Culex nigripalpus . More Cx. atratus were captured in non-forest vegetation areas and in forests. Culex quinquefasciatus was more abundant in wetland areas followed by low-density housing areas. Aedes aegypti was F IGURE 3. Comparing average numbers of female Aedes aegypti and accumulated rainfall (mm) during the third and second weeks before each mosquito-sampling week in four communities in southern Puerto Rico. Two communities ( A and B ) were under vector control interventions using three autocidal gravid ovitraps per house in most houses in 2016 and in 2017 when the Hurricanes Irma and Maria hit Puerto Rico. The other two communities ( C and D ) were nearby sites without vector-control interventions. Rainfall was forwarded 1.5 weeks to facilitate comparisons with mosquito numbers. IMPACT OF HURRICANES ON AEDES AEGYPTI 1417 more common in low-density housing areas, but like Cx. quinquefasciatus , this species was widely distributed across landscapes in the metro area. Culex nigripalpus was more abundant in wetlands and forests (Table 1). The average numbers of Ae. aegypti per trap per day in the various land- scapes were as follows: low-density housing 9.8 ± 1.1, high- density housing 3.4 ± 0.4097, non-forest vegetation 2.7 ± 0.5, forests 2.6 ± 1.0, and wetlands 2.1 ± 0.3. DISCUSSION Severe storms are expected to increase the number of mosquitoes by increasing or decreasing the edge surface of groundwater habitats, fi lling cavities/containers with rainwa- ter, and generating additional container aquatic habitats in destroyed or abandoned properties (damaged appliances, inundated fl oors/roofs, and rubble). The latter two events are relevant to the ecology of Ae. aegypti because this species does not use groundwaters but used water- fi lled containers for immature development. This study showed large numbers of containers and pupae of Ae. aegypti in the weeks following Hurricane Maria in Caguas city, including highly productive, fl ooded fl oors and rubble resulting from wind/ fl ood damage. Adult female of Ae. aegypti doubled in numbers after the hurricanes in this city. Surprisingly, the amount of rainfall from October to December in 2016 and 2017 was similar in Caguas, which may indicate that the increase in the number of adult mosquitoes was mainly a result of more containers holding water. Year 2016 was a rather wet year itself. 22 The numeric response of the Ae. aegypti population to in- creased rainfall in 2017 as compared with 2016 in southern Puerto Rico was heterogeneous, although mosquito numbers in all four study sites sharply increased exactly 5 weeks after Hurricane Maria. The only signi fi cant average increase in adults of Ae. aegypti from October 2017 through January 2018 in comparison with the same period in 2016/2017 was ob- served in one of the two locations without vector control. The other location without vector control actually showed signi fi - cantly lower mosquito numbers than in the previous year when rainfall was about half. Contributing to the heterogeneity of responses, the two sites with vector control (three AGO traps per home in most homes plus surveillance AGO traps) did not F IGURE 4. Map of the metropolitan area of San Juan city showing the average number of mosquitoes per BG-S trap per day of the four more abundant mosquito species across major landscape elements (forests, high-density housing, low-density housing, non-forested vegetation, and wetlands) after Hurricanes Irma and Maria hit Puerto Rico in 2017. 1418 BARRERA AND OTHERS show any signi fi cant difference in mosquito captures in comparison with the previous year. We were able to continue vector surveillance in the four southern areas 3 weeks after Maria and to reset or replace lost AGO control traps within 5 weeks in the two communities with vector control, despite pervasive limited living conditions at the time. Wherever sig- ni fi cant increases in Ae. aegypti captures were observed after the hurricanes, they returned to pre-hurricane levels during December 2017 or shortly thereafter. Although monitoring unusual increases in mosquitoes after natural disasters is important, some areas may already con- tain enough mosquitoes to cause local arbovirus outbreaks without any additional increases caused by the storms. For example, average Ae. aegypti captures before or after the hurricanes in Caguas city and in the two sites without vector control in southern Puerto Rico were several times higher than two female Ae. aegypti per trap per day; the relative abun- dance associated with 50% less prevalence of anti- chikungunya IgG antibodies in areas with mass-trapping vector control. 24 Whether vector control needs to be applied after natural disasters, such as after severe storms, should be decided based on assessments of abundance of key vector or nui- sance mosquito species, virus infection rates in mosquitoes, and seroprevalence in sentinel or wild vertebrate hosts. 4 Emergency vector control has been practiced in the United States after severe storms due to signi fi cant increases in ground-water mosquitoes. 3,5,6,8 Our study of mosquito cap- tures in the metro area of San Juan could not be directly compared with a previous study 21 because we did not have the same traps available after the hurricanes. However, we obtained similar results to the previous study conducted during a wette r than normal year (20 05) when we used CDC miniature li ght traps with CO 2 : high numbers of Cu lex ( Mela- noconion ) spp. mosqui toes in less d isturbed a reas with ta ll or short vegeta tion and wetlands, 26 mosqu ito species ve rsus 28 in 2005, and wide spread distr ibution of Cx. nigripalpus ;a ni m - portant West Ni le virus vector . 25 The two other wi despread species fou nd were Ae. aegy pti and Cx. quinq uefascia tus ,b o t h of which were mor e abundant in are as with low-de nsity hous- ing. People in the metro area we re mostly exposed to thes e urban mosqu ito species an d to a lesser extent to Cx. ni g- ripalpus . Because of lack of power, pi ped water, dama ged houses, and re construc tion activ ities, the peop le in Puerto Rico were expos ed to increa sed mosqui to bites aft er the hurric anes. Dengue, chikungunya, and Zika viruses were not detected in Ae. aegypti in Caguas city or in the four southern commu- nities after the hurricanes. In contrast, we detected all of these viruses in Ae. aegypti the previous year in Caguas city and in two of the communities without vector control in southern Puerto Rico. No viruses were found during comparable pe- riods before or after the hurricanes in the two communities under vector control with mass AGO trapping. Because Ae. aegypti adults do not fl y far, the presence of arboviruses in these mosquitoes indicates the presence of local infectious persons. 26 Our results suggest that these arboviruses were not being actively transmitted in the study areas. Lack of arboviruses in Ae. aegypti after the hurricanes in 2017 is consistent with the paucity of human cases during the same periods. For example, less than 20 Zika cases per week were reported from Puerto Rico from October 2017 to January 2018, whereas up to 1,000 cases per week were reported during the same time period during the Zika outbreak in 2016/2017. 27,28 Thus, the potential for outbreaks after the T ABLE 1 Composition and abundance of female adult mosquitoes collected in BG-S traps in the metro area of San Juan city, Puerto Rico, after Hurricanes Irma and Maria (October – November 2017) Mosquito species Forest High-density housing Low-density housing Non-forest vegetation Wetlands Total Culex (Mel.) atratus Theo. 1.302 1 11 3.884 137 5.335 ... This study provides the opportunity to examine how interannual climate variability may impact domestic populations of Ae. aegypti that were managed by applying sustained, area-wide mass trapping. We previously reported on the effectiveness of mass trapping with sticky gravid ovitraps on reductions of Ae. aegypti populations and arbovirus prevalence in both mosquitoes and people (Barrera et al. 2014a, 2019a , 2019b . Data from 2014 and 2016 during the outbreaks of chikungunya and Zika viruses, respectively were previously analyzed to compare mosquito densities, weather, and infection rates of Ae. aegypti (Barrera et al. 2019a). ... ... We also reported on the impact of category 4 hurricanes Irma and Maria that hit Puerto Rico in September 2017 on Ae. aegypti populations and arbovirus circulation in the study areas. These results showed heterogeneity of impacts on Ae. aegypti density in unmanaged study sites, limited effects in managed sites, and absence of arboviruses in Ae. aegypti before and after the hurricanes in 2017 (Barrera et al. 2019b ). This study expands published knowledge by examining long term trends in mosquito populations and the impact of climate in managed and unmanaged scenarios. ... ... The impact of major hurricanes during La Niña conditions (Hurricanes Irma and Maria, September 2017) on mosquito populations in various municipalities in Puerto Rico that included data from the 4 study sites was previously published (Barrera et al. 2019b ). There was a sharp increase in Ae. aegypti populations 5 weeks after the hurricanes in the 4 study sites and in a city in central Puerto Rico. ... El Niño Southern Oscillation (ENSO) effects on local weather, arboviral diseases, and dynamics of managed and unmanaged populations of Aedes aegypti (Diptera: Culicidae) in Puerto Rico Roberto Barrera Veronica Acevedo Manuel Amador Gabriela Paz-Bailey We investigated the effects of interannual El Niño Southern Oscillation (ENSO) events on local weather, Aedes aegypti populations, and combined cases of dengue (DENV), chikungunya (CHIKV), and Zika (ZIKV) viruses in 2 communities with mass mosquito trapping and 2 communities without mosquito control in southern Puerto Rico (2013–2019). Gravid adult Ae. aegypti populations were monitored weekly using Autocidal Gravid Ovitraps (AGO traps). Managing Ae. aegypti populations was done using 3 AGO traps per home in most homes. There were drought conditions in 2014–2015 concurrent with the emergence of a strong El Niño (2014–2016), wetter conditions during La Niña (2016–2018), a major hurricane (2017), and a weaker El Niño (2018–2019). The main factor explaining differences in Ae. aegypti abundance across sites was mass trapping. Populations of Ae. aegypti reached maximum seasonal values during the wetter and warmer months of the year when arbovirus epidemics occurred. El Niño was significantly associated with severe droughts that did not impact the populations of Ae. aegypti. Arbovirus cases at the municipality level were positively correlated with lagged values (5–12 mo.) of the Oceanic El Niño Index (ONI), droughts, and abundance of Ae. aegypti. The onset of strong El Niño conditions in Puerto Rico may be useful as an early warning signal for arboviral epidemics in areas where the abundance of Ae. aegypti exceeds the mosquito density threshold value. ... In the Caribbean region, events of heavy rainfall may occur repeatedly in the same year, increasing the risk of epidemics of new and emerging VBZD [29]. The occurrence of adverse events, such as hurricanes and storms, poor infrastructure and population mobility also influence mosquito population and dengue transmission [13, [30] [31][32]. The relationship between population mobility, relative to space/distance and time, and the implications for dengue and other infectious diseases transmission need to be better studied, particularly, within the context of Caribbean societies. ... Climate and dengue transmission in Grenada for the period 2010–2020: Should we be concerned? Kinda Francis Odran Edwards Lindonne Telesford The impacts of climate change on vector-borne and zoonotic diseases (VBZD) are well founded in some countries but remain poorly understood in Caribbean countries. VBZD impose significant burdens on individuals and healthcare systems, heightening the need for studies and response measures to address epidemics and persistent high prevalence of these diseases in any region. This study analyses the pattern of dengue case distribution in Grenada between 2010–2020 and investigates the relationship between rainfall and cases. The total number of dengue cases in the wet seasons (June to December) and dry seasons (January to May) were 1741 and 458, respectively, indicating higher prevalence of the disease in wet periods. The data also shows that rainfall was not consistently higher during the typical rainy season months. The observed patterns in 2013, 2018 and 2020 show, while these were the driest years, the number of cases were higher than in other years. Two factors may explain high number of cases in the drier years (1) frequent sporadic heavy rainfall and (2) poor water storage practices in dry season. With each 30 mm unit decrease in annual rainfall, the incidence rate ratio of dengue was reduced by a factor of .108 (89.2%). The work of the Vector Control Unit is shown to be effective in managing dengue in Grenada. The study highlights the need for year-round surveillance and interventions to control the mosquito population and dengue transmission. ... Flooding events due to Hurricanes Maria and Irma (both made landfall on USVI in September 2017) did not increase ZIKV disease cases in USVI (Fig. 1). In neighboring Puerto Rico, increased mosquito populations were observed 5 weeks after Hurricanes Maria and Irma, but there was no increased detection of dengue, chikungunya, or ZIKV in mosquitoes (Barrera et al, 2019) . Other hurricane-or flood-related disasters have not been shown to increase transmission of arboviruses to humans or domestic animals in the United States, with the exception of the Red River flood of 1975 (Nasci and Moore, 1998). ... Spatial, Sociodemographic, and Weather Analysis of the Zika Virus Outbreak: U.S. Virgin Islands, January 2016–January 2018 A. Springer Browne David S. Rickless C. Reed Hranac Esther Ellis Background: The first Zika virus outbreak in U.S. Virgin Islands identified 1031 confirmed noncongenital Zika disease (n = 967) and infection (n = 64) cases during January 2016-January 2018; most cases (89%) occurred during July-December 2016. Methods and Results: The epidemic followed a continued point-source outbreak pattern. Evaluation of sociodemographic risk factors revealed that estates with higher unemployment, more houses connected to the public water system, and more newly built houses were significantly less likely to have Zika virus disease and infection cases. Increased temperature was associated with higher case counts, which suggests a seasonal association of this outbreak. Conclusion: Vector surveillance and control measures are needed to prevent future outbreaks. ... lifespan, extrinsic incubation period, positive rate of dengue virus), thus hindering the inference of the association mechanism between tropical cyclones and dengue incidence. A study in Puerto Rico found that the abundance of Aedes aegypti did not increase significantly in vector-controlled communities after the hurricane, and dengue virus was not detected in Aedes aegypti, while dengue virus was detected in communities without vector control [42] . It explicitly supports vector control as the primary public health intervention for reducing dengue transmission at the community level [43]. ... Short-term effects of tropical cyclones on the incidence of dengue: a time-series study in Guangzhou, China Chuanxi Li Zhe Zhao Yu Yan Wei Ma Background Limited evidence is available about the association between tropical cyclones and dengue incidence. This study aimed to examine the effects of tropical cyclones on the incidence of dengue and to explore the vulnerable populations in Guangzhou, China. Methods Weekly dengue case data, tropical cyclone and meteorological data during the tropical cyclones season (June to October) from 2015 to 2019 were collected for the study. A quasi-Poisson generalized linear model combined with a distributed lag non-linear model was conducted to quantify the association between tropical cyclones and dengue, controlling for meteorological factors, seasonality, and long-term trend. Proportion of dengue cases attributable to tropical cyclone exposure was calculated. The effect difference by sex and age groups was calculated to identify vulnerable populations. The tropical cyclones were classified into two levels to compare the effects of different grades of tropical cyclones on the dengue incidence. Results Tropical cyclones were associated with an increased number of dengue cases with the maximum risk ratio of 1.41 (95% confidence interval 1.17–1.69) in lag 0 week and cumulative risk ratio of 2.13 (95% confidence interval 1.28–3.56) in lag 0–4 weeks. The attributable fraction was 6.31% (95% empirical confidence interval 1.96–10.16%). Men and the elderly were more vulnerable to the effects of tropical cyclones than the others. The effects of typhoons were stronger than those of tropical storms among various subpopulations. Conclusions Our findings indicate that tropical cyclones may increase the incidence of dengue within a 4-week lag in Guangzhou, China, and the effects were more pronounced in men and the elderly. Precautionary measures should be taken with a focus on the identified vulnerable populations to control the transmission of dengue associated with tropical cyclones. Graphical Abstract View ... Although our results suggest that DENV-1 and DENV-2 lineages that emerged in the country could have originated in Veracruz, we do not have samples prior to 2012, and we cannot exclude an origin in another location. Veracruz was affected by hurricane Ernest in 2012, creating favorable conditions for vector development (Barrera et al., 2019) . Concurrently, a significant increase in the number of confirmed DF cases (12,572 in total) was reported (Salud, 2022), thus a higher representation, compared to those from other sites, was reflected in our sampling. ... Genetic diversity and spatiotemporal dynamics of DENV-1 and DENV-2 infections during the 2012–2013 outbreak in Mexico Eduardo D. Rodríguez-Aguilar Jesús Martinez Barnetche Lilia Juarez Mario Henry Rodríguez Dengue fever is caused by four related dengue virus serotypes, DENV-1 to DENV-4, where each serotype comprises distinct genotypes and lineages. The last major outbreak in Mexico occurred during 2012 and 2013, when 112,698 confirmed cases were reported (DENV-1 and DENV-2 were predominant). Following partial E, NS2A and NS5 gene sequencing, based on the virus genome variability, we analyzed 396 DENV-1 and 248 DENV-2 gene sequences from serum samples from dengue acute clinical cases from 13 Mexican states, Mutations were identified, and their genetic variability estimated, along with their evolutionary relationship with DENV sequences sampled globally. DENV-1 genotype V and DENV-2 Asian-American genotype V were the only genotypes circulating during the outbreak. Mutations in NS2A and NS5 proteins were widely disseminated and suggested local emergence of new lineages. Phylogeographic analysis suggested viral spread occurred from coastal regions, and tourist destinations, such as Yucatan and Quintana Roo, which played important roles in disseminating these lineages. ... Culex quinquefasciatus takes advantage of improper disposal of sewage water above-or belowground in urban areas to oviposit and undergo immature development (Barrera et al. 2008, Chaves et al. 2009, Mackay et al. 2009, Burke et al. 2010, Correia et al. 2012. Culex quinquefasciatus and Aedes aegypti (L.) have widespread distribution in urban areas and some studies have shown that the abundance of these species is correlated , Ng et al. 2018, Barrera et al. 2019) . Given the public health importance of these mosquitoes and the need to monitor their presence and abundance, it would be advantageous to use the same monitoring device that could efficiently track both species. ... Surveillance and Control of Culex quinquefasciatus Using Autocidal Gravid Ovitraps Roberto Barrera Veronica Acevedo Manuel Amador We monitored trap captures of Culex quinquefasciatus using an interrupted time-series study to determine if autocidal gravid ovitraps (AGO traps) were useful to control the population of this mosquito species in a community in southern Puerto Rico. Data for this report came from a previous study in which we used mass trapping to control Aedes aegypti, resulting in a significant 79% reduction in numbers of this species. The AGO traps used to monitor and control Ae. aegypti also captured numerous Cx. quinquefasciatus. Culex quinquefasciatus was monitored in surveillance AGO traps from October 2011 to February 2013, followed by a mosquito control intervention from February 2013 to June 2014. Optimal captures of this mosquito occurred on the 2nd wk after the traps were set or serviced, which happened every 8 wk. Changes in collection numbers of Cx. quinquefasciatus were positively correlated with rainfall and showed oscillations every 8 wk, as revealed by sample autocorrelation analyses. Culex quinquefasciatus was attracted to and captured by AGO traps, so mass trapping caused a significant but moderate reduction of the local population (31.2%) in comparison with previous results for Ae. aegypti, possibly resulting from female mosquitoes flying in from outside of the study area and decreased attraction to the traps past the 2nd wk of trap servicing. Because Ae. aegypti and Cx. quinquefasciatus are frequently established in urban areas, mass trapping to control the former has some impact on Cx. quinquefasciatus. Control of the latter could be improved by locating and treating its aquatic habitats within and around the community. ... Nevertheless, after interviewing cancer patients and health providers in this research, a fair assumption would be to consider the combination of stressors, including environmental factors promoting unhealthy and unpleasant conditions not only to cancer patients but also for many vulnerable communities in the aftermath of Hurricane María. Such conditions are solar radiation (in a warm-humid tropical environment), elevated air surface temperature + relative humidity (increasing heat index), floods, deforestation and canopy destruction, the lack of electricity and essential services, poor air quality (due to portable electric generators), vector-borne diseases and rodents, (rats and mosquitos [39] ), potable water accessibility and water sanitation. ... Environmental Stressors Suffered by Women with Gynecological Cancers in the Aftermath of Hurricanes Irma and María in Puerto Rico Int J Environ Res Publ Health Pablo A. Mendez-Lazaro Yanina M. Bernhardt William A Calo Ana P. Ortiz-Martinez Background: Hurricanes are the immediate ways that people experience climate impacts in the Caribbean. These events affect socio-ecological systems and lead to major disruptions in the healthcare system, having effects on health outcomes. In September 2017, Puerto Rico (PR) and the United States Virgin Islands (USVI) experienced one of the most catastrophic hurricane seasons in recent history (Hurricane Irma was a Category 5 and Hurricane María was a Category 4 when they hit PR). Objective: This study examines environmental stressors experienced by women with gynecologic (GYN) cancers from PR and USVI who received oncologic cancer care in PR, in the aftermath of the hurricanes. Methods: A descriptive qualitative study design was used to obtain rich information for understanding the context, barriers, knowledge, perspectives, risks, vulnerabilities, and attitudes associated to these hurricanes. We performed focus groups among GYN cancer patients (n = 24) and key-informant interviews (n = 21) among health-care providers and administrators. Interviews were conducted from December 2018-April 2019. Results: Environmental health stressors such as lack of water, heat and uncomfortable temperatures, air pollution (air quality), noise pollution, mosquitos, and rats ranked in the top concerns among cancer patients and key-informants. Conclusions: These findings are relevant to cancer patients, decision-makers, and health providers facing extreme events and disasters in the Caribbean. Identifying environmental secondary stressors and the most relevant cascading effects is useful for decision-makers so that they may address and mitigate the effects of hurricanes on public health and cancer care. Outbreaks of Vector-borne Infectious Disease Following a Natural Disaster Norma Quintanilla Introduction Over the past century, global disaster deaths have averaged approximately 45,000 people annually. Vector-borne pathogens are susceptible to climatic conditions influencing vector survival, gonotrophic cycle, and transmission efficiency in human hosts. However, the literature has not collectively analyzed the relationship between natural disasters and vector-borne disease (VBD) outbreaks over decades. Objective This literature review identifies and examines published papers documenting VBD outbreaks associated with natural disasters. Additionally, information was gathered about the kinds of natural disasters commonly associated with VBD outbreaks and which diseases typically occur post- disasters. Methods A literature review was performed using two search strategies with terms for natural disasters and vector-borne infectious diseases as identified in the title, keywords, or abstract. Observational studies and systematic review papers were screened on the occurrence of a VBD post-disaster. Results A total of 30 studies were captured. Eight disaster types were captured: flood, hurricane, tropical cyclone, typhoon, tsunami, drought, monsoon, and earthquake. Floods (n=21), hurricanes (n=20), tsunamis (n=8), and drought (n=8) account for the top four disaster events commonly associated with VBDs. Of the VBDs identified, malaria outbreaks were identified in 16 papers, while dengue outbreaks were captured in 11. Conclusion The literature reveals a predominance of floods, malaria and dengue. While there is increasing acknowledgment that disasters can lead to outbreaks of VBDs, there is limited research and consistent data available. Future research should rely on well-defined, consistent case detection and enrollment procedures, preferably at various lag periods following a disaster event. Background: Climate change is expected to increase the frequency of flooding events. Although rainfall is highly correlated with mosquito-borne diseases (MBD) in humans, less research focuses on understanding the impact of flooding events on disease incidence. This lack of research presents a significant gap in climate change-driven disease forecasting. Objectives: We conducted a scoping review to assess the strength of evidence regarding the potential relationship between flooding and MBD and to determine knowledge gaps. Methods: PubMed, Embase, and Web of Science were searched through 31 December 2020 and supplemented with review of citations in relevant publications. Studies on rainfall were included only if the operationalization allowed for distinction of unusually heavy rainfall events. Data were abstracted by disease (dengue, malaria, or other) and stratified by post-event timing of disease assessment. Studies that conducted statistical testing were summarized in detail. Results: From 3,008 initial results, we included 131 relevant studies (dengue n=45, malaria n=61, other MBD n=49). Dengue studies indicated short-term (<1 month) decreases and subsequent (1-4 month) increases in incidence. Malaria studies indicated post-event incidence increases, but the results were mixed, and the temporal pattern was less clear. Statistical evidence was limited for other MBD, though findings suggest that human outbreaks of Murray Valley encephalitis, Ross River virus, Barmah Forest virus, Rift Valley fever, and Japanese encephalitis may follow flooding. Discussion: Flooding is generally associated with increased incidence of MBD, potentially following a brief decrease in incidence for some diseases. Methodological inconsistencies significantly limit direct comparison and generalizability of study results. Regions with established MBD and weather surveillance should be leveraged to conduct multisite research to a) standardize the quantification of relevant flooding, b) study nonlinear relationships between rainfall and disease, c) report outcomes at multiple lag periods, and d) investigate interacting factors that modify the likelihood and severity of outbreaks across different settings. https://doi.org/10.1289/EHP8887.
https://www.researchgate.net/publication/333657654_Impacts_of_Hurricanes_Irma_and_Maria_on_Aedes_aegypti_Populations_Aquatic_Habitats_and_Mosquito_Infections_with_Dengue_Chikungunya_and_Zika_Viruses_in_Puerto_Rico
Latest content added for The Portal to Texas History Title: The Groom News (Groom, Carson County, Tex.) 1926-current <feed xmlns=" http://www.w3.org/2005/Atom" xmlns:georss=" http://www.georss.org/georss" xmlns:media=" http://search.yahoo.com/mrss/" xml:lang=" en-us"> Latest content added for The Portal to Texas History Title: The Groom News (Groom, Carson County, Tex.) 1926-current <link href=" https://texashistory.unt.edu/explore/titles/t00495/browse/?sort=added_d&t=untl_agent" rel=" alternate"/> <link href=" https://texashistory.unt.edu/explore/titles/t00495/feed/?sort=added_d&t=untl_agent" rel=" self"/> <link href=" https://texashistory.unt.edu/explore/titles/t00495/feed/?sort=added_d&t=untl_agent&start=50" rel=" next"/> <link href=" https://texashistory.unt.edu/explore/titles/t00495/feed/?sort=added_d&t=untl_agent&start=0" rel=" first"/> <link href=" https://texashistory.unt.edu/explore/titles/t00495/feed/?sort=added_d&t=untl_agent&start=1950" rel=" last"/> <id> https://texashistory.unt.edu/explore/titles/t00495/browse/?sort=added_d&t=untl_agent </id> <updated> 2023-01-10T09:07:31-06:00 </updated> <author> <name> UNT Libraries </name> </author> <subtitle> This is a custom feed for browsing The Portal to Texas History Title: The Groom News (Groom, Carson County, Tex.) 1926-current </subtitle> <entry> <title> The Groom News (Groom, Tex.), Vol. 25, No. 27, Ed. 1 Thursday, September 27, 1951 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1532257/" rel=" alternate"/> <id> https://texashistory.unt.edu/ark:/67531/metapth1532257/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1532257/"><img alt="The Groom News (Groom, Tex.), Vol. 25, No. 27, Ed. 1 Thursday, September 27, 1951" title="The Groom News (Groom, Tex.), Vol. 25, No. 27, Ed. 1 Thursday, September 27, 1951" src="https://texashistory.unt.edu/ark:/67531/metapth1532257/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1532257/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 23, No. 47, Ed. 1 Thursday, February 16, 1950 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1532256/" rel=" alternate"/> <id> https://texashistory.unt.edu/ark:/67531/metapth1532256/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1532256/"><img alt="The Groom News (Groom, Tex.), Vol. 23, No. 47, Ed. 1 Thursday, February 16, 1950" title="The Groom News (Groom, Tex.), Vol. 23, No. 47, Ed. 1 Thursday, February 16, 1950" src="https://texashistory.unt.edu/ark:/67531/metapth1532256/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1532256/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 21, No. 42, Ed. 1 Thursday, December 25, 1947 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1532252/" rel=" alternate"/> <id> https://texashistory.unt.edu/ark:/67531/metapth1532252/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1532252/"><img alt="The Groom News (Groom, Tex.), Vol. 21, No. 42, Ed. 1 Thursday, December 25, 1947" title="The Groom News (Groom, Tex.), Vol. 21, No. 42, Ed. 1 Thursday, December 25, 1947" src="https://texashistory.unt.edu/ark:/67531/metapth1532252/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1532252/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 20, No. 22, Ed. 1 Thursday, September 26, 1946 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1532249/" rel=" alternate"/> <id> https://texashistory.unt.edu/ark:/67531/metapth1532249/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1532249/"><img alt="The Groom News (Groom, Tex.), Vol. 20, No. 22, Ed. 1 Thursday, September 26, 1946" title="The Groom News (Groom, Tex.), Vol. 20, No. 22, Ed. 1 Thursday, September 26, 1946" src="https://texashistory.unt.edu/ark:/67531/metapth1532249/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1532249/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 20, No. 25, Ed. 1 Thursday, October 17, 1946 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1532250/" rel=" alternate"/> <id> https://texashistory.unt.edu/ark:/67531/metapth1532250/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1532250/"><img alt="The Groom News (Groom, Tex.), Vol. 20, No. 25, Ed. 1 Thursday, October 17, 1946" title="The Groom News (Groom, Tex.), Vol. 20, No. 25, Ed. 1 Thursday, October 17, 1946" src="https://texashistory.unt.edu/ark:/67531/metapth1532250/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1532250/small/"/> <entry> <title> The Groom News (Groom, Tex.), Vol. 55, No. 17, Ed. 1 Thursday, July 10, 1980 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517777/" rel=" alternate"/> <published> 2022-10-29T05:19:00-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517777/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517777/"><img alt="The Groom News (Groom, Tex.), Vol. 55, No. 17, Ed. 1 Thursday, July 10, 1980" title="The Groom News (Groom, Tex.), Vol. 55, No. 17, Ed. 1 Thursday, July 10, 1980" src="https://texashistory.unt.edu/ark:/67531/metapth1517777/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517777/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 42, Ed. 1 Thursday, December 31, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517814/" rel=" alternate"/> <published> 2022-10-28T22:54:40-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517814/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517814/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 42, Ed. 1 Thursday, December 31, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 42, Ed. 1 Thursday, December 31, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517814/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517814/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 40, Ed. 1 Thursday, December 17, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517813/" rel=" alternate"/> <id> https://texashistory.unt.edu/ark:/67531/metapth1517813/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517813/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 40, Ed. 1 Thursday, December 17, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 40, Ed. 1 Thursday, December 17, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517813/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517813/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 39, Ed. 1 Thursday, December 10, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517812/" rel=" alternate"/> <published> 2022-10-28T22:54:23-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517812/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517812/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 39, Ed. 1 Thursday, December 10, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 39, Ed. 1 Thursday, December 10, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517812/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517812/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 38, Ed. 1 Thursday, December 3, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517811/" rel=" alternate"/> <published> 2022-10-28T22:54:12-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517811/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517811/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 38, Ed. 1 Thursday, December 3, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 38, Ed. 1 Thursday, December 3, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517811/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517811/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 37, Ed. 1 Thursday, November 26, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517810/" rel=" alternate"/> <published> 2022-10-28T22:54:04-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517810/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517810/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 37, Ed. 1 Thursday, November 26, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 37, Ed. 1 Thursday, November 26, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517810/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517810/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 36, Ed. 1 Thursday, November 19, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517809/" rel=" alternate"/> <published> 2022-10-28T22:54:03-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517809/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517809/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 36, Ed. 1 Thursday, November 19, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 36, Ed. 1 Thursday, November 19, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517809/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517809/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 35, Ed. 1 Thursday, November 12, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517808/" rel=" alternate"/> <published> 2022-10-28T22:54:02-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517808/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517808/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 35, Ed. 1 Thursday, November 12, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 35, Ed. 1 Thursday, November 12, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517808/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517808/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 33, Ed. 1 Thursday, October 29, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517806/" rel=" alternate"/> <published> 2022-10-28T22:53:46-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517806/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517806/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 33, Ed. 1 Thursday, October 29, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 33, Ed. 1 Thursday, October 29, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517806/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517806/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 34, Ed. 1 Thursday, November 5, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517807/" rel=" alternate"/> <published> 2022-10-28T22:53:46-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517807/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517807/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 34, Ed. 1 Thursday, November 5, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 34, Ed. 1 Thursday, November 5, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517807/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517807/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 32, Ed. 1 Thursday, October 22, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517805/" rel=" alternate"/> <published> 2022-10-28T22:53:42-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517805/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517805/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 32, Ed. 1 Thursday, October 22, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 32, Ed. 1 Thursday, October 22, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517805/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517805/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 31, Ed. 1 Thursday, October 15, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517804/" rel=" alternate"/> <published> 2022-10-28T22:53:25-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517804/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517804/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 31, Ed. 1 Thursday, October 15, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 31, Ed. 1 Thursday, October 15, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517804/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517804/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 30, Ed. 1 Thursday, October 8, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517803/" rel=" alternate"/> <published> 2022-10-28T22:53:16-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517803/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517803/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 30, Ed. 1 Thursday, October 8, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 30, Ed. 1 Thursday, October 8, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517803/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517803/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 29, Ed. 1 Thursday, October 1, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517802/" rel=" alternate"/> <published> 2022-10-28T22:53:09-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517802/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517802/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 29, Ed. 1 Thursday, October 1, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 29, Ed. 1 Thursday, October 1, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517802/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517802/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 28, Ed. 1 Thursday, September 24, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517801/" rel=" alternate"/> <published> 2022-10-28T22:53:08-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517801/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517801/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 28, Ed. 1 Thursday, September 24, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 28, Ed. 1 Thursday, September 24, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517801/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517801/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 27, Ed. 1 Thursday, September 17, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517800/" rel=" alternate"/> <published> 2022-10-28T22:53:07-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517800/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517800/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 27, Ed. 1 Thursday, September 17, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 27, Ed. 1 Thursday, September 17, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517800/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517800/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 26, Ed. 1 Thursday, September 10, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517799/" rel=" alternate"/> <published> 2022-10-28T22:52:50-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517799/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517799/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 26, Ed. 1 Thursday, September 10, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 26, Ed. 1 Thursday, September 10, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517799/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517799/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 25, Ed. 1 Thursday, September 3, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517798/" rel=" alternate"/> <published> 2022-10-28T22:52:47-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517798/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517798/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 25, Ed. 1 Thursday, September 3, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 25, Ed. 1 Thursday, September 3, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517798/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517798/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 24, Ed. 1 Thursday, August 27, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517797/" rel=" alternate"/> <published> 2022-10-28T22:52:38-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517797/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517797/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 24, Ed. 1 Thursday, August 27, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 24, Ed. 1 Thursday, August 27, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517797/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517797/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 23, Ed. 1 Thursday, August 20, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517796/" rel=" alternate"/> <published> 2022-10-28T22:52:31-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517796/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517796/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 23, Ed. 1 Thursday, August 20, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 23, Ed. 1 Thursday, August 20, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517796/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517796/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 22, Ed. 1 Thursday, August 13, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517795/" rel=" alternate"/> <published> 2022-10-28T22:52:14-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517795/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517795/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 22, Ed. 1 Thursday, August 13, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 22, Ed. 1 Thursday, August 13, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517795/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517795/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 21, Ed. 1 Thursday, August 6, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517794/" rel=" alternate"/> <published> 2022-10-28T22:52:14-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517794/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517794/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 21, Ed. 1 Thursday, August 6, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 21, Ed. 1 Thursday, August 6, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517794/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517794/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 20, Ed. 1 Thursday, July 30, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517793/" rel=" alternate"/> <published> 2022-10-28T22:52:11-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517793/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517793/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 20, Ed. 1 Thursday, July 30, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 20, Ed. 1 Thursday, July 30, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517793/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517793/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 56, No. 7, Ed. 1 Thursday, April 30, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517792/" rel=" alternate"/> <published> 2022-10-28T22:52:10-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517792/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517792/"><img alt="The Groom News (Groom, Tex.), Vol. 56, No. 7, Ed. 1 Thursday, April 30, 1981" title="The Groom News (Groom, Tex.), Vol. 56, No. 7, Ed. 1 Thursday, April 30, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517792/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517792/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 55, No. 50, Ed. 1 Thursday, February 26, 1981 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517791/" rel=" alternate"/> <published> 2022-10-28T22:52:02-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517791/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517791/"><img alt="The Groom News (Groom, Tex.), Vol. 55, No. 50, Ed. 1 Thursday, February 26, 1981" title="The Groom News (Groom, Tex.), Vol. 55, No. 50, Ed. 1 Thursday, February 26, 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1517791/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517791/small/"/> </entry> <entry> <title> The Groom News (Groom, Tex.), Vol. 55, No. 40, Ed. 1 Thursday, December 18, 1980 </title> <link href=" https://texashistory.unt.edu/ark:/67531/metapth1517789/" rel=" alternate"/> <published> 2022-10-28T22:51:53-05:00 </published> <id> https://texashistory.unt.edu/ark:/67531/metapth1517789/ </id> <summary type=" html"> <p><a href="https://texashistory.unt.edu/ark:/67531/metapth1517789/"><img alt="The Groom News (Groom, Tex.), Vol. 55, No. 40, Ed. 1 Thursday, December 18, 1980" title="The Groom News (Groom, Tex.), Vol. 55, No. 40, Ed. 1 Thursday, December 18, 1980" src="https://texashistory.unt.edu/ark:/67531/metapth1517789/small/"/></a></p><p>Weekly newspaper from Groom, Texas that includes local, state, and national news along with extensive advertising.</p> </summary> <media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1517789/small/"/> </entry>
https://texashistory.unt.edu/explore/titles/t00495/feed/?sort=added_d&t=untl_agent
Italy's Pilgrim Route-La Via Francigena [Archive] - Eupedia Forum Well, it's one of them. It's the ancient pilgrim route from France, hence the name, or more broadly, northern Europe, to Rome. It was analogous, I think, with the pilgrim route to Santiago de Compostela. See: https://en.wikipedia.org/wiki/Via_Francigena " The name Via Francigena is first mentioned in the Actum Clusio, a parchment of 876 in the Abbey of San Salvatore al Monte Amiata (Tuscany).At the end of the 10th century Sigeric the Serious, the Archbishop of Canterbury, used the Via Angela 28-08-17, 16:49 Well, it's one of them. It's the ancient pilgrim route from France, hence the name, or more broadly, northern Europe, to Rome. It was analogous, I think, with the pilgrim route to Santiago de Compostela. See: https://en.wikipedia.org/wiki/Via_Francigena "The name Via Francigena is first mentioned in the Actum Clusio, a parchment of 876 in the Abbey of San Salvatore (https://en.wikipedia.org/wiki/Abbey_of_San_Salvatore) al Monte Amiata (https://en.wikipedia.org/wiki/Monte_Amiata) (Tuscany (https://en.wikipedia.org/wiki/Tuscany)).[2] (https://en.wikipedia.org/wiki/Via_Francigena#cite_note-2)At the end of the 10th century Sigeric the Serious (https://en.wikipedia.org/wiki/Sigeric_the_Serious), the Archbishop of Canterbury (https://en.wikipedia.org/wiki/Archbishop_of_Canterbury), used the Via Francigena to and from Rome in order to receive his pallium (https://en.wikipedia.org/wiki/Pallium);[3] (https://en.wikipedia.org/wiki/Via_Francigena#cite_note-3) he recorded his route and his stops on the return journey,[4] (https://en.wikipedia.org/wiki/Via_Francigena#cite_note-4) but nothing in the document suggests that the route was then new. Later itineraries to Rome include the Leiðarvísir og borgarskipan (https://en.wikipedia.org/wiki/Lei%C3%B0arv%C3%ADsir_og_borgarskipan) of the Icelandic (https://en.wikipedia.org/wiki/Iceland) traveller Nikolás Bergsson (https://en.wikipedia.org/w/index.php?title=Nikol%C3%A1s_Bergsson&action=edit&redlink=1) (in 1154) and the one from Philip Augustus (https://en.wikipedia.org/wiki/Philip_Augustus) of France (in 1191).[5] (https://en.wikipedia.org/wiki/Via_Francigena#cite_note-5) Two somewhat differing maps of the route appear in manuscripts of Matthew Paris (https://en.wikipedia.org/wiki/Matthew_Paris), Historia Anglorum, from the 13th century." http://www.goodwalkingbooks.com/images/assets/via%20fran/vf%20map%20walk.gif I initially became interested in it because it passed quite literally in front of the house where I was born, and in later years I've walked parts of it myself. Unfortunately, stretches of it have been overlaid by modern roads, which is the case in the part that goes past my door, and no side paths have been provided, and parts of it aren't very well marked. Also, unlike the better known pilgrimage route to Santiago de Compostela, convenient accommodations don't exist everywhere, which means hikers have to camp out, but as it is getting more and more known, and more people are hiking it, I think it may change. "Due to the scarcity of dedicated pilgrims' accommodation along the Via Francigena, pilgrims often camp out rather than staying in hotels or pensions (https://en.wikipedia.org/wiki/Pension_(lodging)), both options which would turn out expensive when used for weeks on end. However increasingly in Italy, some monasteries and religious houses offer dedicated pilgrim's accommodation. These are called spedali and — like the refugios found on the Way of St. James (https://en.wikipedia.org/wiki/Way_of_St._James) in France and Spain — they offer cheap and simple dormitory-style accommodation. Spedali accept pilgrims who bear a valid credenziale (pilgrim's passport), usually for one night only. Some places offer meals as well. Only a few decades ago, interest in the Via Francigena was limited to scholars. This began to change in recent years when many who, after travelling the Way of St.James (https://en.wikipedia.org/wiki/Way_of_St._James) in Spain, wanted to make the pilgrimage to Rome on foot as well. In Italy, this gave birth to a network of lovers of the Via Francigena, who with paint and brush, began to mark its trails and paths. These people were joined by religious and local government agencies who also tried to recover the original route. Where possible today's route follows the ancient one but sometimes it deviates from the historical path in favour of paths and roads with low traffic." http://ac4fa7708134a70c34d3-66da2307b23609a8f8a6d8a13d2f16e2.r38.cf1.rackcdn.c om/1241/2/default.jpg http://www.gonews.it/wp-content/uploads/2014/03/via_francigena.jpg Sigerico, Archbishop of Canterbury, stayed here, in Aulla, my municipal center, around 990 AD, and the Abbey and guest house are part of the very little of ancient Aulla which remains following the destruction during World War II. https://upload.wikimedia.org/wikipedia/commons/d/db/Pic-VF4-IT23_Ponteromli-Aulla_08_%28abad%C3%ADa_San_Caprasio%29.JPG People do it following guides, and there are also starting to be guided excursions. http://www.viefrancigene.org/en/
https://www.eupedia.com/forum/archive/index.php/t-34500.html?s=68570bdd38a314f7c3475865624a5e4b
Luke 13:3 (AFV) - Robertson's Book Notes (NT) No, I tell you; but if you do not repent, you shall all likewise perish. Luke 13:3  ( A Faithful Version ) A.F.VA.S.V.Amplified®DarbyI.S.V.K.J.V.N.A.S.B.NASB E-PrimeYoung'sCompare all Book Notes: Robertson's Book Notes (NT) Luke There is not room here for a full discussion of all the interesting problems raised by Luke as the author ofthe Gospeland Acts. One can find them ably handled in the Introduction to Plummer's volume on Luke's Gospel in the International and Critical Commentary, in the Introduction to Ragg's volume on Luke's Gospel in the Westminster Commentaries, in the Introduction to Easton's Gospel According to St. Luke, Hayes' Synoptic Gospels and the Book of Acts, Ramsay's Luke the Physician, Harnack's Date of the Acts and the Synoptic Gospels, Foakes-Jackson and Kirsopp Lake's Beginnings of Christianity, Carpenter's Christianity According to St. Luke, Cadbury's The Making of Luke-Acts, McLachlan's St. Luke: The Man and His Work, Robertson's Luke the Historian in the Light of Research, to go no further. It is a fascinating subject that appeals to scholars of all shades of opinion. The Same Author For Gospel And ActsThe author of Acts refers to the Gospel specifically as "the first treatise," \ton pr"ton logon\, (Acts 1:1) and both are addressed to Theophilus (Luke 1:3;Acts 1:1). He speaks of himself in both books as "me" (\kamoi\,Luke 1:3) and (I made) (\epoiˆsamˆn\,Acts 1:1). He refers to himself with others as "we" and "us" as inActs 16:10, the "we" sections of Acts. The unity of Acts is here assumed until the authorship of Acts is discussed in Volume III. The same style appears in Gospel and Acts, so that the presumption is strongly in support of the author's statement. It is quite possible that the formal Introduction to the Gospel (Luke 1:1-4) was intended to apply to the Acts also which has only an introductory clause. Plummer argues that to suppose that the author of Acts imitated the Gospel purposely is to suppose a literary miracle. Even Cadbury, who is not convinced of the Lucan authorship, says: "In my study of Luke and Acts, their unity is a fundamental and illuminating axiom." He adds: "They are not merely two independent writings from the same pen; they are a single continuous work. Acts is neither an appendix nor an afterthought. It is probably an integral part of the author's original plan and purpose." The Author Of Acts A Companion Of PaulThe proof of this position belongs to the treatment of Acts, but a word is needed here. The use of "we" and "us" inActs 16:10and fromActs 20:6to the end of chapter Acts 28 shows it beyond controversy if the same man wrote the "we" sections and the rest of the Acts. This proof Harnack has produced with painstaking detail in his Date of the Acts and the Synoptic Gospelsand in his volume The Acts of the Apostlesand in his Luke the Physician. This Companion Of Paul A PhysicianThe argument for this position lies in the use of medical terms throughout the Gospel and the Acts. Hobart in his Medical Language of St. Lukeproves that the author of both Gospel and Acts shows a fondness for medical terms best explained by the fact that he was a physician. Like most enthusiasts he overdid it and some of his proof does not stand the actual test of sifting. Harnack and Hawkins in his Horae Synopticaehave picked out the most pertinent items which will stand. Cadbury in his Style and Literary Method of Lukedenies that Luke uses Greek medical words more frequently in proportion than Josephus, Philo, Plutarch, or Lucian. It is to miss the point about Luke merely to count words. It is mainly the interest in medical things shown in Luke and Acts. The proof that Luke is the author of the books does not turn on this fact. It is merely confirmatory. Paul calls Luke "the beloved physician" (\ho iatros ho agapˆtos\,Colossians 4:14), "my beloved physician." Together they worked in the Island of Malta (Acts 28:8-10) where many were healed and Luke shared with Paul in the appreciation of the natives who "came and were healed (\etherapeuonto\) who also honoured us with many honours." The implication there is that Paul wrought miracles of healing (\iasato\), while Luke practised his medical art also. Other notes of the physician's interest will be indicated in the discussion of details like his omitting Mark's apparent discredit of physicians (Mark 5:26) by a milder and more general statement of a chronic case (Luke 8:43). This Companion And Author LukeAll the Greek manuscripts credit the Gospel to Luke in the title. We should know that Luke wrote these two books if there was no evidence from early writers. Irenaeus definitely ascribes the Gospel to Luke as does Clement of Alexandria, Tertullian, the Muratorian Fragment. Plummer holds that the authorship of the four great Epistles of Paul (I and II Corinthians, Galatians, Romans) which even Baur accepted, is scarcely more certain than the Lukan authorship of the Gospel. Even Renan says: "There is no very strong reason for supposing that Luke was not the author of the Gospel which bears his name." A Sketch Of LukeHis name is not a common one, and is probably a shortened form of \Lukios\ and \Lukanos\. Some of the manuscripts of the Gospel actually have as the title \Kata Lukanon\. Dean Plumptre suggests that the Latin poet Lucanus was named after Luke who probably was the family physician when he was born. That is conjecture as well as the notion of Hayes that, since the brothers Gallio and Seneca were uncles of Lucanus they were influenced by Luke to be friendly toward Paul both in Corinth and in Rome. It is probable that Luke was a Greek, certainly a Gentile, possibly a freedman. So this man who wrote more than one-fourth of the New Testament was not a Jew. It is not certain whether his home was in Antioch or in Philippi. It is also uncertain whether he was already converted when Paul met him at Troas. The Codex Bezae has a "we" passage afterActs 11:27which, if genuine, would bring Luke in contact with Paul before Troas. Hayes thinks that he was a slave boy in the family of Theophilus at Antioch, several conjectures in one. We do not know that Theophilus lived at Antioch. It may have been Rome. But, whether one of Paul's converts or not, he was a loyal friend to Paul. If he lived at Antioch, he could have studied medicine there and the great medical temple of Aesculapius was at Aegae, not far away. As a Greek physician, Luke was a university man and in touch with the science of his day. Greek medicine is the beginning of the science of medicine as it is known today. Tradition calls him a painter, but of that we know nothing. Certainly he was a humanist and a man of culture and broad sympathies and personal charm. He was the first genuine scientist who faced the problem of Christ and of Christianity. It must be said of him that he wrote his books with open mind and not as a credulous enthusiast. The Date Of The GospelThere are two outstanding facts to mark off the date of this Gospel by Luke. It was later than the Gospel of Mark since Luke makes abundant use of it. It was before the Acts of the Apostles since he definitely refers to it inActs 1:1. Unfortunately the precise date of both terminiis uncertain. There are still some scholars who hold that the author of the Acts shows knowledge of the Antiquitiesof Josephus and so is after AD85, a mistaken position, in my opinion, but a point to be discussed when Acts is reached. Still others more plausibly hold that the Acts was written after the destruction of Jerusalem and that the Gospel of Luke has a definite allusion to that event (Luke 21:20f.), which is interpreted as a prophecy post eventuminstead of a prediction by Christ a generation beforehand. Many who accept this view hold to authorship of both Acts and Gospel by Luke. I have long held the view, now so ably defended by Harnack, that the Acts of the Apostles closes as it does for the simple and obvious reason that Paul was still a prisoner in Rome. Whether Luke meant the Acts to be used in the trial in Rome, which may or may not have come to pass, is not the point. Some argue that Luke contemplated a third book which would cover the events of the trial and Paul's later career. There is no proof of that view. The outstanding fact is that the book closes with Paul already a prisoner for two years in Rome. If the Acts was written about AD63, as I believe to be the case, then obviously the Gospel comes earlier. How much before we do not know. It so happens that Paul was a prisoner a little over two years in Caesarea. That period gave Luke abundant opportunity for the kind of research of which he speaks inLuke 1:1-4. In Palestine he could have access to persons familiar with the earthly life andteachings of Jesusand to whatever documents were already produced concerning such matters. Luke may have produced the Gospel towards the close of the stay of Paul in Caesarea or during the early part of the first Roman imprisonment, somewhere between AD59 and 62. The other testimony concerns the date of Mark's Gospel which has already been discussed in volume I. There is no real difficulty in the way of the early date of Mark's Gospel. All the facts that are known admit, even argue for a date by AD60. If Mark wrote his Gospel in Rome, as is possible, it would certainly be before AD64, the date of the burning of Rome by Nero. There are scholars, however, who argue for a much earlier date for his gospel, even as early as AD50. The various aspects of the Synoptic problem are ably discussed by Hawkins in his Horae Synopticae, by Sanday and others in Oxford Studies in the Synoptic Problem, by Streeter in his The Four Gospels, by Hayes in his The Synoptic Gospels and the Book of Acts, by Harnack in his Date of the Acts and the Synoptic Gospels, by Stanton in his The Gospels as Historical Documents, and by many others. My own views are given at length in my Studies in Mark's Gospeland in Luke the Historian in the Light of Research. The Sources Of The GospelIn his Preface or Prologue (Luke 1:1-4) the author tells us that he had two kinds of sources, oral and written, and that they were many, how many we have no way of telling. It is now generally accepted that we know two of his written sources, Mark's Gospel and Q or the Logia of Jesus (written by Matthew, Papias says). Mark is still preserved and it is not difficult for any one by the use of a harmony of the Gospels to note how Luke made use of Mark, incorporating what he chose, adapting it in various ways, not using what did not suit his purposes. The other source we only know in the non-Markan portions of Matthew and Luke, that is the material common to both, but not in Mark. This also can be noted by any one in a harmony. Only it is probable that this source was more extensive than just the portions used by both Matthew and Luke. It is probable that both Matthew and Luke each used portions of the Logia not used by the other. But there is a large portion of Luke's Gospel which is different from Mark and Matthew. Some scholars call this source L. There is little doubt that Luke had another document for the material peculiar to him, but it is also probable that he had several others. He spoke of "many." This applies especially to chapters 9 to 21. But Luke expressly says that he had received help from "eye-witnesses and ministers of the word," in oral form this means. It is, then, probable that Luke made numerous notes of such data and used them along with the written sources at his command. This remark applies particularly to chapters 1 and 2 which have a very distinct Semitic (Aramaic) colouring due to the sources used. It is possible, of course, that Mary the mother of Jesus may have written a statement concerning these important matters or that Luke may have had converse with her or with one of her circle. Ramsay, in his volume, Was Christ Born at Bethlehem?shows the likelihood of Luke's contact with Mary or her circle during these two years at Caesarea. Luke handles the data acquired with care and skill as he claims in his Prologue and as the result shows. The outcome is what Renan called the most beautiful book in the world. The Character Of The BookLiterary charm is here beyond dispute. It is a book that only a man with genuine culture and literary genius could write. It has all the simple grace of Mark and Matthew plus an indefinable quality not in these wonderful books. There is a delicate finish of detail and proportion of parts that give the balance and poise that come only from full knowledge of the subject, the chief element in a good style according to Dr. James Stalker. This scientific physician, this man of the schools, this converted Gentile, this devoted friend of Paul, comes to the study of the life of Christ with a trained intellect, with an historian's method of research, with a physician's care in diagnosis and discrimination, with a charm of style all his own, with reverence for and loyalty toJesus Christas Lord and Saviour. One could not afford to give up either of the Four Gospels. They each supplement the other in a wonderful way. John's Gospel is the greatest book in allthe world, reaching the highest heights of all. But if we had only Luke's Gospel, we should have an adequate portrait of Jesus Christ as Son ofGodand Son of Man. If Mark's is the Gospel for the Romans and Matthew's for the Jews, the Gospel of Luke is for the Gentile world. He shows the sympathy of Jesus for the poor and the outcast. Luke understands women and children and so is the universal Gospel of mankind in all phases and conditions. It is often called the Gospel of womanhood, of infancy, of prayer, of praise. We have in Luke the first Christian hymns. With Luke we catch some glimpses of the child Jesus for which we are grateful. Luke was a friend and follower of Paul, and verbal parallels with Paul's Epistles do occur, but there is no Pauline propaganda in the Gospel as Moffatt clearly shows ( Intr. to Lit. of the N.T., p. 281). The Prologue is in literary Koin‚and deserves comparison with those in any Greek and Latin writers. His style is versatile and is often coloured by his source. He was a great reader of the Septuagint as is shown by occasional Hebraisms evidently due to reading that translation Greek. He has graciousness and a sense of humour as McLachlan and Ragg show. Every really great man has a saving sense of humour as Jesus himself had. Ramsay dares to call Luke, as shown by the Gospel and Acts, the greatest of all historians not even excepting Thucydides. Ramsay has done much to restore Luke to his rightful place in the estimation of modern scholars. Some German critics used to citeLuke 2:1-7as a passage containing more historical blunders than any similar passage in any historian. The story of how papyri and inscriptions have fully justified Luke in every statement here made is carefully worked out by Ramsay in his various books, especially in The Bearing of Recent Discovery on the Trustworthiness of the New Testament. The main feature of this proof appears also in my Luke the Historian in the Light of Research. So many items, where Luke once stood alone, have been confirmed by recent discoveries that the burden of proof now rests on those who challenge Luke in those cases where he still stands alone. The Berean: Daily Verse and CommentSign up for the Berean: Daily Verse and Comment, and have Biblical truth delivered to your inbox. This daily newsletter provides a starting point for personal study, and gives valuable insight into the verses that make up the Word of God. See whatover 150,000 subscribersare already receiving each day.Email Address: Subscribe A Faithful Version King James Version New International Version New King James Version Leave this field empty We respect your privacy . Your email address will not be sold, distributed, rented, or in any way given out to a third party. We have nothing to sell . You may easily unsubscribe at any time.
https://www.bibletools.org/index.cfm/fuseaction/Bible.show/sVerseID/25522/eVerseID/25522/opt/bn/RTD/rbn/version/AFV
Exodus 35:3 (RSV) - Forerunner Commentary you shall kindle no fire in all your habitations on the sabbath day." Exodus 35:3  ( Revised Standard Version ) Exodus 35:1-3 Even though the Israelites were constructing an important edifice devoted to the worship ofGod, they were not to desecrate this holy time by working on it. John W. RitenbaughThe Fourth Commandment Exodus 35:3 There is an interesting example in the way Orthodox Jews keep theSabbathand the 39 forbidden Sabbath activities ( melachot) that they have come up with. Rather than learn the principles involved in Sabbath-keeping, the attitude seems to be, “Let's just have a rule to cover every conceivable development.” The command inExodus 35:3directly follows a command not to workon the Sabbath, so in saying not to kindle a fire,Godwas speaking of a fire employed in work, such as one used by a smith to shape metal, not a home heating fire. However, the Orthodox Jews take it to an extreme, teaching that it includes the modern analogy of moving electricity through a circuit. If a person opens his refrigerator door on the Sabbath and the light inside comes on, in their judgment, he has “kindled a fire.” So, the Orthodox Jewish solution is to unscrew the bulb in the refrigerator on the Preparation Day so that no light comes on when the door is opened on the Sabbath. On the Sabbath, a Jew cannot turn the lights on in the house or the burner on the stove. To get around this, Jews use timers. Note that they do these things to “get around” the law. To this end, their sages have come up with the concept of grama, and this has nothing to do with the nice older lady who gave you cookies as a child. In Jewish law, there is a difference in direct and indirect action on the Sabbath. For instance, a Jew cannot intentionally extinguish a flame, but if he opens a window and the wind blows out the candle, he has not violated Sabbath law. Such an indirect action, whose result is not guaranteed, is called grama, which comes from the Hebrew root meaning “to cause [something to happen].” If a fire breaks out on the Sabbath, a Jew cannot put it out, but he can fill water jugs and place them in the path of the fire. When—or if—the heat bursts the jugs, the water may put the fire out. There are more subtleties to grama, but that is the short explanation. So, in this modern, technological world, the Jews use the grama principle in numerous ways. Opening and closing electrical circuits would be work. But if the switch has a delay so that, when a Jew presses or turns it, nothing immediately happens, yet a few seconds later something does happen, that is not considered work. Some manufacturers have installed “Sabbath” modes on their appliances. On some new refrigerators, unscrewing the light bulb is not so easy. So now, more than 300 types of ovens, stoves, and refrigerators can be set to “Sabbath” mode, which, when enabled, means lights stay off, displays are blank, tones are silenced, fans are stilled, compressors slowed, etc. To quote WIREDmagazine's Michael Erard in “The Geek Guide to Kosher Machines”: In a kosher fridge, there's no light, no automatic icemaker, no cold-water dispenser, no warning alarm for spoiled food, no temperature readout. Basically, [Sabbath mode] converts your fancy—and expensive—appliance into the one your grandma bought after World War II. If we have to jump through these mental and physical hoops to follow God's laws, have we really learned the principles involved?
https://www.bibletools.org/index.cfm/fuseaction/Bible.show/sVerseID/2535/eVerseID/2535/version/RSV
Social Sciences | Free Full-Text | Do Data from Large Personal Networks Support Cultural Evolutionary Ideas about Kin and Fertility? The fertility decline associated with economic development has been attributed to a host of interrelated causes including the rising costs of children with industrialization, and shifts in family structure. One hypothesis is that kin may impart more pro-natal information within their networks than non-kin, and that this effect may be exacerbated in networks with high kin-density where greater social conformity would be expected. In this study, we tested these ideas using large personal networks (25 associates of the respondent) collected from a sample of Dutch women (N = 706). Kin (parents) were perceived to exert slightly more social pressure to have children than non-kin, although dense networks were not associated with greater pressure. In contrast, women reported talking to friends about having children to a greater extent than kin, although greater kin-density in the network increased the likelihood of women reporting that they could talk to kin about having children. Both consanguineal and affinal kin could be asked to help with child-care to a greater extent than friends and other non-kin. Overall, there was mixed evidence that kin were more likely to offer pro-natal information than non-kin, and better evidence to suggest that kin were considered to be a better source of child-care support. Do Data from Large Personal Networks Support Cultural Evolutionary Ideas about Kin and Fertility? by Gert Stulp 1,* and Louise Barrett 2,3 1 Department of Sociology & Inter-University Center for Social Science Theory and Methodology, Grote Rozenstraat 31, 9712 TS Groningen, The Netherlands 2 Department of Psychology, Science Commons, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada 3 Applied Behavioral Ecology and Ecosystems Research Unit, University of South Africa, Private Bag X6, Florida 1710, South Africa * Author to whom correspondence should be addressed. Soc. Sci. 2021 , 10 (5), 177; https://doi.org/10.3390/socsci10050177 Received: 14 April 2021 / Revised: 11 May 2021 / Accepted: 13 May 2021 / Published: 18 May 2021 (This article belongs to the Special Issue The Behavioral Ecology of the Family ) Abstract The fertility decline associated with economic development has been attributed to a host of interrelated causes including the rising costs of children with industrialization, and shifts in family structure. One hypothesis is that kin may impart more pro-natal information within their networks than non-kin, and that this effect may be exacerbated in networks with high kin-density where greater social conformity would be expected. In this study, we tested these ideas using large personal networks (25 associates of the respondent) collected from a sample of Dutch women ( N = 706). Kin (parents) were perceived to exert slightly more social pressure to have children than non-kin, although dense networks were not associated with greater pressure. In contrast, women reported talking to friends about having children to a greater extent than kin, although greater kin-density in the network increased the likelihood of women reporting that they could talk to kin about having children. Both consanguineal and affinal kin could be asked to help with child-care to a greater extent than friends and other non-kin. Overall, there was mixed evidence that kin were more likely to offer pro-natal information than non-kin, and better evidence to suggest that kin were considered to be a better source of child-care support. Keywords: kin ; affinal kin ; density ; personal network ; social support ; social pressure ; fertility 1. Introduction Why do (post)industrial humans have so few children? This question has occupied economists, demographers, quite a few historians, and many evolutionarily-minded social scientists (see Sear et al. 2016 ). Over time, it has become clear that any explanation must combine both individual level and societal factors, and that industrial societies cannot be treated as monolithic, but have their own distinct reproductive ecologies ( Stulp et al. 2016 ; Sear 2015 ; Burger and DeLong 2016 ). Identifying how and why reproductive decision-making shifts across space and time thus requires consideration of the diverse range of changes associated with economic development—from increased mobility to improved hygiene, and from ideas on contraception to child labor laws—any number of which could influence family size, whether alone or through potentially complex intersections ( Newson et al. 2005 ). Evolutionary approaches to the issue of fertility decline have included both individual-level explanations concerning the costs and benefits of producing children (see Lawson and Mulder ( 2016 ) for review) as well as more complex models that consider how cultural norms evolve, both within and outside the reproductive domain (see Colleran ( 2016 ) for review). With respect to behavioral ecology-inspired, individual-based models, early work by Turke ( 1989 ), for example, suggested that reductions in the size of extended kin networks during modernization meant that people could no longer call on kin for help with child-care (and/or their perceptions of the likelihood of such help declined), which served to raise the relative costs of children; family size therefore shifted downward to reflect the number of children that could be raised adequately by a smaller family unit. In this view, family size limitation reflects a rational, potentially adaptive response to ecological circumstances. Other authors, in contrast, have suggested that family size decline resulted from the misperception of child-rearing cues in a novel environment ( Kaplan 1996 ); specifically, parents assume that greater investment per child is required than is strictly necessary to promote offspring survival and success. As a result, parents engage in an extreme quality–quantity trade-off that accords with life history considerations, but is functionally maladaptive. Although these individually-oriented optimality models offer genuine insight into how and why reproductive decision-making may have shifted with modernization, such models cannot account for why particular social norms regarding family size arise and take hold in ways that continue to influence behavior independently of changes in an individual’s ecological circumstances (see e.g., Lesthaeghe and Surkyn 1988 ). There has, therefore, been an enduring interest in developing models that consider fertility decline from a cultural evolutionary perspective (see Colleran ( 2016 ) for review). Models that incorporate social norms in addition to individual cost-benefit analyses have often considered how particular kinds of learning biases can shape decision-making such as imitating highly successful or prestigious individuals. An early example is Boyd and Richerson ’s ( 1985 ) suggestion that fertility decline is a culturally evolved process that reflects shifts in prestige and who people imitate. Under non-industrial conditions, Boyd and Richerson ( 1985 ) argued that prestige and success would be associated with high reproductive success, as individuals afforded prestige would likely be the matriarchs or patriarchs of large families. Modernization then generated new forms of success and associated prestige, often in roles associated with education and work outside the domestic sphere, such as teachers. As such high-investment social roles were likely to cause the individuals fulfilling these roles to limit family size, this would then result in smaller family sizes among those imitating high-prestige individuals, thus creating new reproductive norms. As Newson et al. ( 2005 ) point out, however, the manner by which prestige is determined is itself a product of social values and group norms. Thus, this prestige influence model leaves unexplained why norms of social prestige should have changed to favor “the exotic expertise” of school teachers and the like. Newson and colleagues thus suggest we also need to incorporate teaching biases into cultural evolutionary models in order to generate a more complete explanation. Specifically, they suggest that kin and non-kin are likely to differ in the kinds of information they convey, with kin more likely to encourage behavior that leads to reproductive success. If modernization leads to shifts in the composition of networks, possibly along the lines Turke ( 1989 ) suggested, then this, in itself, would be sufficient to explain why family limitation took hold as pro-natal kin influence waned, and new cultural norms for small family sizes could develop. Newson et al. ( 2005 ) offer evidence in favor of their hypothesis from the ethnographic literature, and also by reference to close-knit religious sects like the Amish and Hutterites. They offer further suggestive evidence from a study of family planning in Mozambique, where conversations about family limitation were more likely to occur between friends than relatives. More specific tests of their model require attention to the following two hypotheses: (a) among individuals in the same culture, those with more kin-based networks should be more inclined to behave in ways likely to lead to reproductive success, and (b) in conversations about reproduction, relatives should be more likely to condone or encourage pro-natal behavior. Of course, one has to keep in mind that the hypothesis is concerned with the kinds of teaching biases that serve to initiate a demographic transition and it is possible that these may have changed over time, such that kin and non-kin may converge much more closely in the present day. This is an empirical issue, however, and so it remains valid to test whether different kinds of teaching biases are conveyed via kin versus non-kin. Here, we use data on the personal networks of Dutch women to investigate (i) whether kin-rich networks are associated with higher levels of social pressure to reproduce, and whether women feel they can talk to kin about having children to a greater extent than the non-kin members of their networks (that is, kin-related teaching bias may come about through both unsolicited and solicited advice). This speaks directly to Newson et al. ’s ( 2005 ) ideas regarding teaching biases. We also consider (ii) whether people perceive kin as more likely to help with child-care than non-kin, as this may also increase receptiveness to pro-natal information, and so factor into kin-based influences on reproductive success (more in line with Turke ’s ( 1989 ) behavioral ecological approach). In addition, we consider network density (i.e., the proportion of all possible ties between alters in the network that are present) as this has the potential to influence both the degree to which novel information is transmitted, and the extent to which social norms are adhered to and policed ( Montgomery and Casterline 1996 ; Marsden 1987 ; Kohler et al. 2001 ). If kin-rich networks are also denser, this could amplify the influence of kin as proposed by Newson et al. ( 2005 ), because close kin relationships within the network could potentially enable close monitoring and maintenance of pro-natal norms and resist outside influence. This adds a further twist to Newson et al.’s ideas, as kin influence could potentially weaken with modernization due to changes in internal network structure in addition to changes in network composition. In line with this, Colleran ( 2020 ), using data from a large sample of Polish women across 22 villages, found that greater market integration was associated with a loosening of kin ties in women’s networks (i.e., the proportion of all possible ties that were kin-based was lower), even though network size did not change. Interestingly, in an earlier study on the same population, Colleran et al. ( 2014 ) found that less educated women, when living among more highly educated neighbors, had fewer children than expected and more highly educated social networks. This effect was not due to a greater presence of non-kin in the network, nor to horizontal transmission between strong ties in the network; rather, it seemed to reflect more frequent interactions with highly educated women. This suggests that reproductive decision-making was partly driven by cultural dynamics beyond the individual (i.e., women’s personal circumstances alone could not fully account for their reproductive decisions). Taken together, these findings suggest either that prestige-based copying of educated women may, in fact, drive decision-making contra Newson et al., and/or greater contact with highly educated women combined with reduced kin density allows new social norms to diffuse more easily due to a reduced capacity for personal networks to resist change. One limitation of this earlier work is that, despite an impressive sample size in general, ego-networks were small, with respondents asked to name up to five other women to whom they could talk about important personal matters (mean network size was 3.11 individuals); such small networks may not be fully representative. Women in our sample were asked to name 25 alters (of either sex, kin and non-kin). In what follows, we therefore begin by establishing whether network density relates to the proportion of kin in large networks, and whether network structure in our sample varies in ways that would reinforce or undermine Newson et al. ’s ( 2005 ) hypotheses concerning kin-related teaching biases. We then go on to test our two main hypotheses. In our analyses, we consider the influence of both consanguineal and affinal kin, in line with Bogin et al. ’s ( 2012 ) characterization of human reproduction as biocultural, rather than as cooperative per se; that is, unlike non-human cooperative breeders, the provision of care and resource transfers among humans is often decoupled from genetic relatedness—a distinction that is worth making explicit. In addition, the blood relatives of an individual’s partner obviously have a vested interest in the reproduction of the couple ( Burton-Chellew and Dunbar 2011 ; Hughes 1988 ). In our view, then, support, information, and pressure are likely to be exerted by both consanguineal and affinal kin in similar fashion (although it should be remembered that the interests of kin and affinal kin may diverge: Sear et al. 2003 ). 2. Results 2.1. Descriptives Overall, we obtained data from 706 Dutch women between the ages of 18 and 41. Each woman reported on exactly 25 alters with whom they had been in contact within the last year and with whom they would be able to communicate if needed. This gave us information on 17,650 alters. On average, respondents reported seven kin in their personal networks, which equates to 28% (SD = 15%), although there was substantial variation with 16 respondents reporting no kin and five reporting 80% or more ( Figure 1 ). The proportion of affinal kin was considerably lower at 10% (SD = 11%) (if we exclude women’s partners this declines to 7% (SD = 10%) for those women who named their partner as an alter). This implies that, on average, networks consisted mostly of non-kin (62%; SD = 18%). Those who reported more kin reported slightly fewer affinal kin ( r = −0.05), but many fewer non-kin ( r = −0.80). Similarly, reporting more affinal kin meant reporting fewer non-kin ( r = −0.56). Figure 1. The number of people in the network that are consanguineal kin; affinal kin; non-kin; that can help you with child-care; or that you could talk to about having children. % refers to percentage of respondents ( N = 706). 2.2. Are More Kin-Heavy Networks More Densely Connected? Respondents were asked to indicate whether each alter in their network was in contact with each of the other alters, where contact referred to both face-to-face interactions as well as other forms of contact. This meant that respondents had to evaluate 300 alter-alter-ties. The nature of our question means that it need not be the case that all kin are connected (e.g., divorced parents may not be in contact) as is often assumed in kin networks (e.g., Colleran 2020 ; David-Barrett 2019 ). The average density of the network across respondents was 24% (SD = 11%), which means that, on average, 24% of the possible 300 ties between all 25 alters exist ( Figure 2 ). Density was positively but weakly associated with the number of consanguineal kin that people reported in their network ( r = 0.30; Figure 2 ), and even more weakly with the number of affinal kin ( r = 0.16). A linear regression predicted a density of 23% with five kin alters in the network, which increased to 27% with 10 kin alters in the network. The number of non-kin was negatively associated with density ( r = −0.35; Figure 2 ; combining the number of consanguineal and affinal kin would lead to an identical, but positive correlation with density of r = 0.35). Figure 2. ( a ) The association between the number of consanguineal kin in the network and density ( r = 0.30); ( b ) The association between the number of non-kin in the network and density ( r = −0.35); ( c ) histogram of density (binwidth = 2.5%). Shaded band is 95% confidence interval around linear regression line. 2.3. Are Kin More Supportive with Respect to Child-Care and Communication? For each alter, respondents were asked whether they could (i) ask the alter for help with child-care, and (ii) talk to the alter about having children. On average, 35% (SD = 21%) of alters were available for help with child-care and respondents stated they could talk to 28% (SD = 24%) of alters about having children. Respondents reported that approximately 55% of consanguineal and affinal kin could help with child-care ( Figure 3 ), but only 24% of non-kin. Non-kin were further broken down into those that were or were not considered friends: 37% of friends were able to help with child-care, whereas this was true for only 7% of non-friends. Figure 3. Percentage of kin, affinal kin, and non-kin (which are divided into friends and not friends) that respondents can ask for help with child-care or talk to about having children. Estimates presented in white are those for affinal kin excluding the respondent’s partner ( N = 1316). Approximately 40% of affinal kin were reported as approachable for discussions about having children, compared to approximately 25% for consanguineal kin and non-kin. However, when partners were excluded from affinal kin, this percentage dropped to 21%. Thus, for kin beyond the potential reproductive partnership, respondents talk to affinal kin to the same degree that they talk to consanguineal kin or non-kin. Again, if we split non-kin into friends and non-friends, talking about children was more likely with friends (41%) than non-friends (9%). Thus, respondents were likely to speak to friends about having children to a greater extent than both kin categories, and most unlikely to talk about such things with non-friends. We modeled these data with a binomial mixed model, controlling for respondent age, partnership status, and whether the respondent had children, and corroborated these results ( Appendix A , Table A1 ). Compared to non-kin, non-friend alters, the odds of being able to ask for help with child-care was 10.2 (95% CI: 8.8–11.8) times higher for friends, 32.9 (95% CI: 28.3–38.3) times higher for consanguineal kin, and 36.6 (95% CI: 30.7–43.8) times higher for affinal kin. When examining whether respondents could talk to the alter about having children, weaker but still strong patterns emerged: compared to non-kin, non-friend alters, the odds of talking about children were 6.0 (95% CI: 5.2–6.9) times higher for consanguineal kin, 11.6 (95% CI: 9.7–13.7) for affinal kin, and 12.4 (95% CI: 10.8–14.2) for friends. We then considered both the composition and density of the network on respondent perceptions. In order to do so, we needed to consider ties between groups of alters, and among kin in particular. We therefore modeled the four alter categories separately (i.e., consanguineal kin, affinal kin, friends, and non-friends). With respect to network composition (i.e., the number of alters in the network belonging to a given category), an increase in the number of consanguineal kin, affinal kin, and non-friends decreased the probability of being able to ask an alter to help with child-care ( Figure 4 ; Table A2 ; controlling for the density among that group, the age of the respondent, partnership status, and whether the respondent has children). Specifically, the predicted odds of being able to ask an alter to help with child-care decreased by 8.1 (95% CI: 5.4–12.1) for consanguineal kin as we moved from no consanguineal kin alters in the network (composition of 0%) to all individuals in the network being consanguineal kin (composition of 100%). For affinal kin, the odds declined by 3.7 (95% CI: 1.5–9.5), and for non-kin/non-friend alters, the odds declined by 11.6 (95% CI: 5.6–24.1). For non-kin friends, in contrast, the odds increased very slightly by 1.4 (95% CI: 1.1–1.9). Figure 4. Predicted percentages (95% confidence band based on binomial regressions; see Table A2 ) of responses to the questions “can ask alter for help with child-care” and “can talk to alter about having children” depending on composition for consanguineal kin ( N = 676 respondents), affinal kin ( N = 339), friends ( N = 668), and non-friend alters ( N = 606). Composition refers the percentage of alters in the network belonging to that particular group. Darker shades represent the middle 50% of data. Sample sizes vary because density (which is included in the models) could only be calculated for particular groups when the respondent listed at least two of that group. An increase of 4% in composition means one extra alter is listed in the network of 25. Models were evaluated for 29 year-old women with a partner and children, and average density among the particular groups. On top of the panels, histograms of composition for each group are displayed (binwidth = 4%). Reporting more consanguineal and affinal kin in the network also decreased the probability of being able to talk to these categories of alters about having children, whereas this was less pronounced for friends and non-friends ( Figure 4 ). For consanguineal kin, the predicted odds of talking to an alter about children decreased by 11.1 (95% CI: 6.8–18.0) when moving from no consanguineal kin alters in the network (composition of 0%) to all individuals being consanguineal kin (composition of 100%). For affinal kin, the odds decreased by 4.4 (95% CI: 1.7–11.5), and for non-friend alters by 1.5 (95% CI: 0.8–2.7). The number of friends in the network produced no change in the odds of talking to an alter about having children (i.e., the predicted odds had a value of 1.0 (95% CI: 0.8–1.4), Table A2 ). With respect to density, we also found a strong impact on whether an individual could be asked for help with child-care but, in this case, the relationship was positive for both kin categories in addition to friends (controlling for the number of alters in the network of that particular group, the age of the respondent, partnership status, and whether the respondent has children). That is, for consanguineal kin, affinal kin, and non-kin friends, increased network density was associated with a higher probability of women being able to ask for help with child-care, but there was no such relationship for non-friend alters ( Figure 5 ). The predicted odds of being able to ask an alter to help with child-care increased by 5.6 (95% CI: 4.2–7.4) for consanguineal kin as we moved from no ties between the alters (density of 0%) to all ties existing between the alters (density of 100%), while for affinal kin, the odds increased by 10.7 (95% CI: 6.2–18.6). For friends, the odds increased by 2.0 (95% CI: 1.5–2.5), and for non-friends, the odds increased by only 1.1 (95% CI: 0.7–1.6) ( Table A2 ). Figure 5. Predicted percentages (95% confidence band based on binomial regressions; see Table A2 ) of responses to the questions “can ask alter for help with child-care” and “can talk to alter about having children” depending on density for consanguineal kin ( N = 676 respondents), affinal kin ( N = 339), friends ( N = 668), and non-friend alters ( N = 606). Darker shades represent middle 50% of data. Sample sizes vary because density could only be calculated for particular groups when the respondent listed at least two of that group. Models were evaluated for 29 year-old women with a partner and children, and average composition among the particular groups. On top of the panels, histograms of density for each group are displayed (binwidth = 5%). Different patterns, however, emerged for talking about having children. With respect to consanguineal and affinal kin, increased density was associated with being able to talk about children, whereas the relationship was reversed and weaker for friends ( Figure 5 ): higher friend-density was associated with a lower probability that women could talk about having children. Density had little impact among non-kin/non-friend alters. The predicted odds of talking to an alter about children were raised by 3.0 (95% CI: 2.2–4.2) for consanguineal kin and 2.6 (95% CI: 1.5–4.4) affinal kin, when moving from no ties between the alters (density of 0%) to all ties existing between the alters (density of 100%), while they decreased by 1.3 (95% CI: 1.0–1.6) for friends, and by 1.1 (95% CI: 0.7–1.6) for non-friend alters ( Table A2 ). 2.4. Do Women with Kin-Heavy Networks Feel More Pressure to Have Children? In order to assess whether kin and non-kin differed in the kinds of information they passed to respondents, we investigated the extent to which respondents reported feeling pressure from their parents (or caretakers) and the pressure they felt from friends to have children (on a 7-point scale; ranging from strongly disagree to strongly agree). Excluding women that responded with “I don’t know” ( N = 92 for pressure from parents and N = 162 for pressure from friends) and “not applicable” ( N = 38 for pressure from parents), respondents reported slightly higher levels of pressure to reproduce from parents (mean = 4.21; SD = 2.19; N = 576) than from friends (mean = 3.97; SD = 2.12; N = 544; t -test: t(1118) = 1.92; p = 0.056; d = 0.11; paired t -test: mean difference = 0.14; t (510) = 3.00; p = 0.0028; d = 0.13) ( Figure 6 ). About half (53%) of respondents felt at least some pressure to reproduce from parents—defined as those responding with “somewhat agree”, “agree”, and “strongly agree”—whereas the rest (47%) did not (i.e., those responding with “neither agree/disagree” up to “strongly disagree”). Slightly less than half of respondents (46%) felt at least some pressure from friends. Figure 6. Do you feel pressure to have (more) children from parents and friends? Each stacked bar chart is of equivalent width, covering all responses, and centered on the response “neither agree/disagree”. Responses “I don’t know” and “not applicable” were excluded from the counts. Perceived pressure was very different for women with and without children ( Figure 6 ). Among those with children, only 25% felt some pressure to reproduce from parents and only 22% reported pressure from friends, whereas this increased to 67% and 59% among those women without children. Moreover, the most frequent response among those with children was “completely disagree”, whereas for women without children it was “agree”. The overall pattern of responses to pressure from parents and friends was very similar within women with children and within women without children ( Figure 6 ). This resemblance is also apparent from the strong correlation between the pressure felt from friends and from parents ( r = 0.88; N = 511). Neither the number of kin nor the density among kin had a substantive impact on the degree of pro-natal pressure that women reported ( Figure 7 ; Table A3 ). The strongest effect was observed for the number of kin, but the effect was negligible (and the 95% confidence interval included zero): more than 20 extra kin were predicted to be required to move the scale up by one point up (e.g., from somewhat agree to agree). Adding the number of kin to the model increased the explained variance by 0.5% in perceived pressure from parents, whereas kin-density increased this by 0.001%. Density among friends had a negative effect on perceived pressure from friends, but again, the effect was negligible (again, the 95% confidence interval included zero): moving from no ties between friends (density of 0%) to all friends being connected (density of 100%) decreased the perceived pressure on average by about half a point. Adding density to the model increased the explained variance by 0.4% in perceived pressure from friends, whereas the number of friends increased this by 0.002%. Figure 7. ( a ) The association between network composition (percentage of kin) (top) and density among kin (bottom) and the pressure felt to have children by parents. ( b ) The association between network composition (percentage of friends) (top) and density among friends and the pressure felt to have children by friends. The shaded band is the 95% confidence interval around predictions from linear regressions (see Table A3 ). Darker shades represent middle 50% of data. Models were evaluated for 29 year-old women with a partner and without children, and for average composition or density. 3. Discussion Overall, we did not find strong support for the idea that kin and non-kin differ in the level of pro-natal information they impart and the degree of social pressure they exert. Although women, on average, experienced slightly more pressure from parents than from friends, the similarity in response was more striking than the differences. There were, however, stark differences in perceived pressure from both family and friends for women with and without children, with the latter reporting higher levels of pressure. This is no doubt to be expected: the decision to have any children at all is likely to be seen as more consequential from the point of view of parents, and so most pressure may be felt at this point in the life course. We found a negligible influence of overall network composition (proportion of kin and friends in the network) and structure (kin-density and friend-density) on the extent to which respondents reported experiencing social pressure. When we considered respondents themselves seeking advice on having children, we found that women reported that they could talk about having children with their friends to a greater extent than either their consanguineal or affinal kin. In this case, there was an effect of network density: for both kin categories, denser networks meant that women could talk more to their kin about having children compared to those with sparser networks. This was not the case for friends, where more ties between friends reduced the probability of talking to friends about children. One limitation of our study is that we asked only about pressure from parents, rather than from all categories of kin. Thus, we did not capture how other categories of kin may reinforce pro-natal pressure received from parents—it may be that pro-natal social influence is a form of complex contagion (e.g., Hodas and Lerman 2014 ), and asking about parents alone fails to pick up on this. However, our findings showed a positive (if weak) relationship between density and the number of kin and a negative relationship with the number of non-kin. This implies that kin-dense networks should show more social conformity and relay more similar information than the more diffuse networks associated with larger numbers of non-kin, but we found no evidence that this was the case. It could also be true that the norms transmitted and sustained within kin networks relate to the support and encouragement of any expressed desire to reproduce on the part of respondents, or a general emphasis on the happiness and fulfilment that children bring, rather than exerting a pressure to have children per se; the particular phrasing of our question cannot distinguish between different kinds of pro-natal sentiment, plus the word “pressure” may have been interpreted in wholly negative terms. The idea that density among kin increased women’s perceptions that kin could help with child-care and that they could talk to kin about having children gives some support to this idea. Overall, then, we cannot rule out the possibility that a more fine-grained analysis would identify kin-based teaching biases, but our current analyses offer no consistent evidence that, in this sample at least, kin and non-kin differ in the kinds of information they are likely to pass on and circulate within networks. We should also note that Newson et al. ’s ( 2005 ) hypothesis focuses on the origins of low fertility norms, which are potentially distinct from the processes that maintain such norms in the population once established. More generally, our data show that, even in a low-fertility population like the Netherlands, personal networks contain a substantial number of kin: on average, seven consanguineal kin are reported plus an additional 2.5 affinal kin. This means that some 40% of people’s self-reported personal networks can be considered kin. This reinforces the idea that, while the size of (extended) kin networks may have diminished ( Murphy 2011 ), kin nevertheless remain important social contacts in contemporary populations (e.g., Marsden 1987 ; Höllinger and Haller 1990 ; Allan 2008 ). Again, it is worth noting that our findings come from much larger personal networks than is often the case. This is important because structural and compositional aspects of networks are only reliably estimated with a large number of alters (>15–20; McCarty et al. 2007a , 2007b ; Stadel and Stulp 2021 ). With 25 alters, we can thus be fairly confident that we have reliable estimates of the density and the composition of the networks, and that we are tapping into weak links, meaning that people are not simply calling to mind the most readily available members of their network. Of course, 25 alters remains a low number compared to people’s total social network size, and our estimates of density are thus confined to respondents’ personal networks and will not hold for entire sociocentric networks. These findings raise the further question of whether this level of kin representation would be sufficient to resist the influence of new norms being introduced into the network by non-kin and weak ties, and whether it would be sufficient to provide the level of support needed to act as an incentive for women to reproduce rather than postpone birth (or produce a smaller family size than they desire). With respect to the first issue, our answer is only speculative, but we consider this unlikely, given our finding that women talk to their friends about having children much more than their kin; if kin are not sought out for their advice, then their ability to influence decisions will be reduced, no matter how well they are represented (although, as noted above, density may need to be factored in here). With respect to the latter question, consanguineal kin and affinal kin were equally likely to contribute to child-care if needed, and did so at a higher level than non-kin friends and non-friends, which corroborates the idea that networks with many kin are able to ease the burden of child-rearing in ways that might open up opportunities for further reproduction ( Turke 1989 ). The fact that women also reported a substantial likelihood of asking friends for help with child-care means that kin-based help is likely to be augmented by that from friends, and confirms that human reproduction should be considered to be biocultural ( Bogin et al. 2012 ), where affinal kin and non-kin are important for raising children, in addition to biological kin. One surprising finding was that women reported that they could ask for support from their consanguineal and affinal kin to a much greater extent than they could talk to them about having children. Compared to both categories of kin, friends were somewhat less likely to be asked for help, but they were spoken to about children to a greater extent. This suggests that there are certain social expectations around kin-based help with child-care, which makes it easy to request such help from a large proportion of kin, but that conversations about having children may be limited to network members with whom one shares a close relationship. This is supported to some degree by our findings on network composition: as the number of consanguineal and affinal kin in the network increased, women reported being less likely to ask for help and to talk about children, which suggests that we are perhaps capturing more distantly related kin, who are less approachable for help. Overall, these findings are in line with the notion that kin can be asked for more practical support, while people turn to friends for emotional support (e.g., Allan 2008 ; Voorpostel and Lippe 2007 ). Modernization has dramatically changed personal networks, and people in contemporary populations experience greater freedom in their choice of interaction partners. Friends have taken a prominent role in people’s social environment, but this does not mean that kin have lost their importance. The strong reciprocity that is considered important for (maintaining) friendships, does not hold to the same extent for family relations. Novel information and norms may spread more freely in a world with fewer kin, but help with raising children—a service that is not easily reciprocated—seemingly continues to fall predominantly on kin. 4. Materials and Methods 4.1. Participants Here, we make use of data from the LISS (Longitudinal Internet Studies for the Social sciences) panel administered by CentERdata (Tilburg University, The Netherlands). This is a representative sample of Dutch individuals who participate in monthly Internet surveys. The panel is based on a true probability sample of households drawn from the population register by Statistics Netherlands (CBS). Households that could not otherwise participate are provided with a computer and Internet connection. Only households in which at least one household member spoke Dutch are included. A longitudinal study consisting of 10 core surveys are fielded in the panel every year, covering a large variety of topics. The representativeness of the LISS-panel is similar to those from traditional surveys based on probability sampling ( Knoef and de Vos 2009 ; Scherpenzeel and Bethlehem 2011 ). Initial selection biases were substantially corrected by refreshment samples, and further refreshment samples were planned for attrition biases ( Scherpenzeel 2011 ). The LISS-panel has information on over 10,000 individuals. 4.2. Social Networks and Fertility Survey The LISS-panel allows researchers to do their own survey within the panel. We added a study named the Social Networks and Fertility survey (for further details see Stulp 2021 ; Buijs and Stulp 2019 ). This research involves investigating social influences on fertility desires and outcomes (i.e., how many children people have or would like to have). All women in the LISS panel between the ages of 18 and 40 ( N = 1332) were invited to participate in this survey between 20 February and 27 March 2018. Due to constraints on our budget for renumerating respondents and concerns about statistical power, we focused on women only, rather than collecting data on smaller samples for both men and women. In total, 758 women completed the survey with a mean age of 29.2 (SD = 6.5). Respondents were similar to non-respondents based on a comparison of a range of measures that are collected for all respondents and are continuously updated including birth year, position in household, number of children, marital status, region of living, income, educational level, and (migration) background ( Stulp 2021 ). For this study, we only selected respondents that listed 25 alters. We excluded respondents that gave problematic responses to alter relationship questions, who did the survey on their phone (against explicit instructions), that had more than 10 missing values, and the one respondent that reported no alter-alter-ties (see Stulp 2021 ). This led to a final sample of 706 respondents. Ethical approval for this particular study was obtained through the ethical committee of sociology at the University of Groningen (ECS-170920). For information on the ethical approval on the LISS-panel as a whole, see https://www.lissdata.nl/faq-page#n5512 (accessed on 17 May 2021). The survey was in Dutch. For the full survey in Dutch, an English translation of the questionnaire, further description of the survey, and code to clean and correct the LISS survey data, please visit: https://doi.org/10.34894/EZCDOA (accessed on 17 May 2021). R-code to produce the results in the current manuscript can be found here: https://doi.org/10.34894/DTCZWA (accessed on 17 May 2021). Data will become available on https://www.lissdata.nl (accessed on 17 May 2021). 4.3. Procedure Respondents were invited to participate in a study on “social networks and fertility” and instructed that the survey would probably take around 25–30 min and that they would receive €12.50 for completing the survey. The first block of questions was about the fertility intentions and desires of the respondents and their partners if they had one. The second part of the questionnaire involved generating 25 names. Respondents were asked: “Please list 25 names of individuals 18 years or older with whom you have had contact in the last year. This can be face-to-face contact, but also contact via phone, Internet, or email. You know these people and these people also know you by your name or face (think of friends, family, acquaintances, etcetera). You could reach out to these people if you would have to. Please name your partner in case you have one. The names do not have to match perfectly; you can also use nicknames. It is important that you would recognize these names in a future survey. For this research, it is important that you actually name 25 individuals!”. This phrasing was based on the studies by McCarty and colleagues ( McCarty et al. 2007a , 2007b ). When a respondent proceeded with the questionnaire without listing 25 names, a pop-up screen appeared, reminding respondents that listing 25 alters was important for this study, and that if they had difficulties coming up with names, they could use a contact list. They were also informed that if they still wanted to continue without listing 25 names, that this was also possible. The choice to ask respondents to list exactly 25 names, rather than allowing respondents to freely name as many network members as they liked, was deliberate: allowing respondents a free choice of how many alters to report could lead to variation in network size that reflects motivation to complete the questionnaire and/or differences in how the question was interpreted. Some respondents may have found listing 25 alters hard, others may have found it easy, and this will be reflected in the characteristics of the alters. It is this latter kind of variation that is of interest to network researchers ( McCarty et al. 2019 ). We chose 25 alters because people can easily do so ( McCarty 2002 ; McCarty and Govindaramanujam 2005 ), because this size of the network is large enough to consist of weak(er) ties, and because networks smaller than 25 individuals reduce the reliability of estimates of the composition and structure of the network ( McCarty et al. 2007b ; Stadel and Stulp 2021 ). In total, 738 respondents (97%) listed exactly 25 alters, and 632 of those (90%) came up with the names from memory ( Stulp 2021 ). Subsequently, 16 alter characteristics were asked about (see Stulp 2021 ). Here we only list those relevant for this study: (i) type of relationship, with the choice of partner, parent, siblings, other relative, relative of partner, acquaintance/friend of partner, from primary school, from high school, from college/university, from work, from a social activity, through a mutual acquaintance/friend, from the neighborhood, and other. These categories were reduced to kin, affinal kin, and non-kin; (ii) whether the alter was considered a friend; (iii) which of these individuals could the respondent ask for help with the care of the child; and (iv) with whom of these individuals did the respondent discuss having children. Nineteen alters were not given a relationship and we assumed these to be non-kin. The final question about the alters concerned ties between alters. The following question was asked: “With whom does the alter have contact? With contact, we meant all forms of contact including face-to-face contact, contact via (mobile) phone, letters, emails, texts, and other forms of online and offline communication”. The survey ended with some additional questions among which two were about the pressure felt to have children. Respondents were asked to state their agreement with the statement “Most of my friends think that I should have (more) children” (scale from completely agree (1) to completely disagree (7) and a “I don’t know” option). They were then asked the same but for parents/caretakers (similar answer options except the possibility “Not applicable” was also added). 4.4. Data Analysis In all our models, we control for respondent age (centered on 29), whether the respondent has a partner, and whether the respondent has children, all of which are important predictors for network composition and structure, and fertility behavior. For analyses where the dependent variable is a characteristic of the alter (e.g., can talk to this alter about having children, or can ask this alter for help with child-care), we presented results from binomial mixed models to accommodate the nested structure of the data (alters nested in ego; van Duijn et al. 1999 ). We performed linear regressions in the case of the pressure felt to reproduce from parents and friends. To examine the effects of composition and density on the probability of talking to alters about having children or being able to ask them for help with child-care, we used binomial models. We used R ( R Core Team 2018 ) for cleaning, transforming, analyzing, and visualizing all data and to write the manuscript. We made use of the following R-packages: ggplot2 ( Wickham 2016 ), tidyverse ( Wickham 2017 ), patchwork ( Pedersen 2017 ), ggtext ( Wilke 2020 ), rmarkdown ( Xie et al. 2018 ), broom ( Robinson et al. 2021 ), and kableExtra ( Zhu 2019 ). We report on how we determined our sample size, all data exclusions (if any), all manipulations, and all measures in the study. The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Appendix A Table A1. Binomial mixed model parameter estimates (95% CI) for the effect of type of alter on whether alter can help with child-care or can be talked to about having children while controlling for age, partnership status, and parenthood. Table A1. Binomial mixed model parameter estimates (95% CI) for the effect of type of alter on whether alter can help with child-care or can be talked to about having children while controlling for age, partnership status, and parenthood. Estimate Can Help with Child-Care Can Talk to about Children Intercept −3.069 (−3.298; −2.839) −3.126 (−3.386; −2.865) Age −0.024 (−0.043; −0.005) 0.018 (−0.004; 0.041) Has partner −0.055 (−0.284; 0.175) 0.139 (−0.138; 0.416) Has child −0.091 (−0.353; 0.172) −0.102 (−0.417; 0.212) Friend 2.321 (2.177; 2.465) 2.517 (2.377; 2.656) Affinal kin 3.601 (3.423; 3.779) 2.447 (2.275; 2.618) Consanguineal kin 3.495 (3.343; 3.646) 1.786 (1.644; 1.929) SD random intercept 1.180 1.443 Age was centered around 29; women without partners or children were the reference category. Alters ( N = 17,650) are nested within respondents ( N = 706). Table A2. Binomial regression estimates (95% confidence interval) for the effect of density on whether alters can help with child-care or can be talked to about having children while controlling for age, partnership status, and parenthood. Table A2. Binomial regression estimates (95% confidence interval) for the effect of density on whether alters can help with child-care or can be talked to about having children while controlling for age, partnership status, and parenthood. Outcome Estimate Consanguineal Kin Affinal Kin Friends Non-Friends Can help with child-care Intercept −0.415 (−0.739; −0.090) −1.441 (−2.567; −0.315) −0.723 (−0.914; −0.531) −1.676 (−2.076; −1.276) Age −0.034 (−0.046; −0.023) −0.065 (−0.088; −0.042) 0.005 (−0.006; 0.016) 0.039 (0.017; 0.061) Has partner 0.067 (−0.074; 0.209) 0.050 (−0.964; 1.065) −0.201 (−0.321; −0.081) −0.273 (−0.549; 0.002) Has child −0.107 (−0.268; 0.053) −0.112 (−0.373; 0.149) −0.043 (−0.199; 0.113) 0.231 (−0.063; 0.525) Composition −0.084 (−0.100; −0.068) −0.053 (−0.090; −0.015) 0.015 (0.003; 0.026) −0.098 (−0.127; −0.069) Density 1.721 (1.439; 2.004) 2.372 (1.823; 2.922) 0.672 (0.411; 0.933) 0.061 (−0.365; 0.488) Can talk to about having children Intercept −1.218 (−1.599; −0.836) −2.028 (−3.393; −0.663) −0.238 (−0.426; −0.050) −2.259 (−2.62; −1.898) Age 0.001 (−0.012; 0.014) −0.011 (−0.034; 0.012) 0.026 (0.015; 0.037) 0.023 (0.004; 0.042) Has partner 0.163 (0.004; 0.323) 0.988 (−0.281; 2.256) −0.065 (−0.184; 0.055) 0.119 (−0.121; 0.360) Has child 0.014 (−0.165; 0.193) −0.120 (−0.388; 0.147) 0.104 (−0.047; 0.255) 0.054 (−0.201; 0.308) Composition −0.096 (−0.116; −0.077) −0.059 (−0.098; −0.020) −0.001 (−0.013; 0.011) −0.016 (−0.040; 0.008) Density 1.101 (0.771; 1.431) 0.937 (0.390; 1.484) −0.240 (−0.500; 0.020) −0.078 (−0.469; 0.314) # respondents 676 339 668 606 # in group 4891 1624 5961 4915 # help 2649 899 2232 329 # talk 1276 561 2454 445 Age was centered around 29; women without partners or children were the reference category. Composition refers to the number of alters in the network for that particular group (e.g., affinal kin). Density refers to the density among the particular group. The number of respondents vary, because density can only be calculated when respondents list at least two alters of that particular group. “# in group” refers to the number of alters in that group, “# help” refers to how many alters in that group can help with child-care, and “# talk” refers to how many alters in that group can be talked to about having children. Table A3. Linear regression parameter estimates (95% CI) for the number of kin/friends and density among alters on the pressure felt to reproduce by parents and friends while controlling for age, partnership status, and parenthood. Table A3. Linear regression parameter estimates (95% CI) for the number of kin/friends and density among alters on the pressure felt to reproduce by parents and friends while controlling for age, partnership status, and parenthood. Estimate Pressure from Parents Pressure from Friends Intercept 4.044 (3.100; 4.989) 4.266 (3.677; 4.854) Age −0.045 (−0.076; −0.013) −0.064 (−0.096; −0.031) Has partner 0.581 (0.190; 0.973) 0.583 (0.175; 0.991) Has child −1.948 (−2.386; −1.511) −1.546 (−1.991; −1.102) Composition 0.049 (0.000; 0.097) −0.002 (−0.040; 0.036) Density 0.036 (−0.769; 0.840) −0.562 (−1.237; 0.113) N 557 521 R 2 24 22 Age was centered around 29; women without partners or children were the reference category. “Composition” and “Density” refer to number of kin and density among kin in the model on pressure felt from parents and the number of friends and density among friends in the model on pressure felt from friends. Analysis samples include respondents with minimally two kin or friends in their networks. References Allan, Graham. 2008. Flexibility, Friendship, and Family. Personal Relationships 15: 1–16. [ Google Scholar ] [ CrossRef ] Bogin, Barry, Jared Bragg, and Christopher Kuzawa. 2012. Humans Are Not Cooperative Breeders but Practice Biocultural Reproduction. Annals of Human Biology 41: 368–80. [ Google Scholar ] [ CrossRef ] [ PubMed ] Boyd, R., and P. J. Richerson. 1985. Culture and the Evolutionary Process . Chicago: The University of Chicago Press. [ Google Scholar ] Buijs, Vera L., and Gert Stulp. 2019. Friends, Family, and Family Friends: Predicting Friendships of Dutch Women. Open Science Framework . [ Google Scholar ] [ CrossRef ] Burger, Oskar, and John P. DeLong. 2016. What If Fertility Decline Is Not Permanent? The Need for an Evolutionarily Informed Approach to Understanding Low Fertility. Philosophical Transactions of the Royal Society B: Biological Sciences 371: 20150157. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Burton-Chellew, M. N., and R. I. M. Dunbar. 2011. Are Affines Treated as Biological Kin? A Test of Hughes’s Hypothesis. Current Anthropology 52: 741–46. [ Google Scholar ] [ CrossRef ] Colleran, Heidi. 2016. The Cultural Evolution of Fertility Decline. Philosophical Transactions of the Royal Society B: Biological Sciences 371: 20150152. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Colleran, Heidi. 2020. Market Integration Reduces Kin Density in Women’s Ego-Networks in Rural Poland. Nature Communications 11. [ Google Scholar ] [ CrossRef ][ Green Version ] Colleran, Heidi, Grazyna Jasienska, Ilona Nenko, Andrzej Galbarczyk, and Ruth Mace. 2014. Community-Level Education Accelerates the Cultural Evolution of Fertility Decline. Proceedings of the Royal Society B: Biological Sciences 281: 20132732. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] David-Barrett, Tamas. 2019. Network Effects of Demographic Transition. Scientific Reports 9: 2361. [ Google Scholar ] [ CrossRef ] Hodas, Nathan O., and Kristina Lerman. 2014. The Simple Rules of Social Contagion. Scientific Reports 4: 4343. [ Google Scholar ] [ CrossRef ][ Green Version ] Höllinger, Franz, and Max Haller. 1990. Kinship and Social Networks in Modern Societies: A Cross-Cultural Comparison among Seven Nations. European Sociological Review 6: 103–24. [ Google Scholar ] [ CrossRef ] Hughes, Austin L. 1988. Evolution and Human Kinship . Oxford: Oxford University Press. [ Google Scholar ] Kaplan, Hillard S. 1996. A Theory of Fertility and Parental Investment in Traditional and Modern Human Societies. American Journal of Physical Anthropology 101: 91–135. [ Google Scholar ] [ CrossRef ] Knoef, Marike, and Klaas de Vos. 2009. The Representativeness of LISS, an Online Probability Panel . Tilburg: CentERdata. [ Google Scholar ] Kohler, H. P., J. R. Behrman, and Susan Cotts Watkins. 2001. The Density of Social Networks and Fertility Decisions: Evidence from South Nyanza District, Kenya. Demography 38: 43–58. [ Google Scholar ] [ CrossRef ] [ PubMed ] Lawson, David W., and Monique Borgerhoff Mulder. 2016. The Offspring Quantity-Quality Trade-off and Human Fertility Variation. Philosophical Transactions of the Royal Society B: Biological Sciences 371: 20150145. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Lesthaeghe, Ron, and Johan Surkyn. 1988. Cultural Dynamics and Economic Theories of Fertility Change. Population and Development Review 14: 1–45. [ Google Scholar ] [ CrossRef ] Marsden, Peter V. 1987. Core Discussion Networks of Americans. American Sociological Review 52: 122–31. [ Google Scholar ] [ CrossRef ] McCarty, Christopher. 2002. Structure in Personal Networks. Journal of Social Structure 3. Available online: http://www.cmu.edu/joss/content/articles/volume3/McCarty.html (accessed on 17 May 2021). McCarty, Christopher, and Sama Govindaramanujam. 2005. A Modified Elicitation of Personal Networks Using Dynamic Visualization. Connections 26: 9–17. [ Google Scholar ] McCarty, Christopher, J. L. Molina, C. Aguilar, and L. Rota. 2007a. A Comparison of Social Network Mapping and Personal Network Visualization. Field Methods 19: 145–62. [ Google Scholar ] [ CrossRef ][ Green Version ] McCarty, Christopher, Peter D. Killworth, and James Rennell. 2007b. Impact of Methods for Reducing Respondent Burden on Personal Network Structural Measures. Social Networks 29: 300–15. [ Google Scholar ] [ CrossRef ] McCarty, Christopher, Miranda J. Lubbers, Raffaele Vacca, and José Luis Molina. 2019. Conducting Personal Network Research: A Practical Guide . New York: The Guilford Press. [ Google Scholar ] Montgomery, M. R., and J. B. Casterline. 1996. Social Learning, Social Influence, and New Models of Fertility. Population and Development Review 22: 151–75. [ Google Scholar ] [ CrossRef ] Newson, Lesley, Tom Postmes, S. E. G. Lea, and Paul Webley. 2005. Why Are Modern Families Small? Toward an Evolutionary and Cultural Explanation for the Demographic Transition. Personality and Social Psychology Review 9: 360–75. [ Google Scholar ] [ CrossRef ] [ PubMed ] Pedersen, Thomas Lin. 2017. Patchwork: The Composer of Ggplots. Available online: https://github.com/thomasp85/patchwork (accessed on 17 May 2021). R Core Team. 2018. R: A Language and Environment for Statistical Computing . Vienna: R Foundation for Statistical Computing, Available online: https://www.R-project.org/ (accessed on 17 May 2021). Robinson, David, Alex Hayes, and Simon Couch. 2021. Broom: Convert Statistical Objects into Tidy Tibbles. Manual. Available online: https://CRAN.R-project.org/package=broom (accessed on 17 May 2021). Scherpenzeel, Annette C. 2011. Data Collection in a Probability-Based Internet Panel: How the Liss Panel Was Built and How It Can Be Used. BMS: Bulletin of Sociological Methodology/Bulletin de Méthodologie Sociologique 109: 56–61. [ Google Scholar ] [ CrossRef ] Scherpenzeel, Annette C., and Jelke G. Bethlehem. 2011. How Representative Are Online Panels? Problems of Coverage and Selection and Possible Solutions. In Social and Behavioral Research and the Internet. Advances in Applied Methods and Research Strategies . Edited by Marcel Das, Peter Ester and Lars Kaczmirek. Abingdon: Routledge. [ Google Scholar ] [ CrossRef ] Sear, Rebecca. 2015. Evolutionary Contributions to the Study of Human Fertility. Population Studies 69: S39–S55. [ Google Scholar ] [ CrossRef ] Sear, Rebecca, Ruth Mace, and Ian A McGregor. 2003. The Effects of Kin on Female Fertility in Rural Gambia. Evolution and Human Behavior 24: 25–42. [ Google Scholar ] [ CrossRef ][ Green Version ] Sear, Rebecca, David W Lawson, Hillard S. Kaplan, and Mary K Shenk. 2016. Understanding Variation in Human Fertility: What Can We Learn from Evolutionary Demography? Philosophical Transactions of the Royal Society B 371: 20150144. [ Google Scholar ] [ CrossRef ][ Green Version ] Stadel, Marie, and Gert Stulp. 2021. Balancing Bias and Burden in Personal Network Studies. PsyArXiv . [ Google Scholar ] [ CrossRef ] Stulp, Gert. 2021. Collecting Large Personal Networks in a Representative Sample of Dutch Women. Social Networks 64: 63–71. [ Google Scholar ] [ CrossRef ] Stulp, Gert, Rebecca Sear, and Louise Barrett. 2016. The Reproductive Ecology of Industrial Societies, Part I: Why Measuring Fertility Matters. Human Nature 27: 422–44. [ Google Scholar ] [ CrossRef ][ Green Version ] Turke, Paul W. 1989. Evolution and the Demand for Children. Population and Development Review 15: 61–90. [ Google Scholar ] [ CrossRef ] van Duijn, Marijtje A. J., Jooske T. van Busschbach, and Tom A. B. Snijders. 1999. Multilevel Analysis of Personal Networks as Dependent Variables. Social Networks 21: 187–210. [ Google Scholar ] [ CrossRef ] Voorpostel, Marieke, and Tanja Van Der Lippe. 2007. Support Between Siblings and Between Friends: Two Worlds Apart? Journal of Marriage and Family 69: 1271–82. [ Google Scholar ] [ CrossRef ][ Green Version ] Wickham, Hadley. 2016. Ggplot2: Elegant Graphics for Data Analysis . New York: Springer, Available online: http://ggplot2.org (accessed on 17 May 2021). Wickham, Hadley. 2017. Tidyverse: Easily Install and Load the “Tidyverse”. Available online: https://CRAN.R-project.org/package=tidyverse (accessed on 17 May 2021). Wilke, Claus O. 2020. Ggtext: Improved Text Rendering Support for ‘Ggplot2.’ Manual. Available online: https://CRAN.R-project.org/package=ggtext (accessed on 17 May 2021). Xie, Yihui, J. J. Allaire, and Garrett Grolemund. 2018. R Markdown: The Definitive Guide . Boca Raton: Chapman and Hall/CRC, Available online: https://bookdown.org/yihui/rmarkdown (accessed on 17 May 2021). Zhu, Hao. 2019. KableExtra: Construct Complex Table with ‘kable’ and Pipe Syntax. Manual. Available online: https://CRAN.R-project.org/package=kableExtra (accessed on 17 May 2021). Figure 1. The number of people in the network that are consanguineal kin; affinal kin; non-kin; that can help you with child-care; or that you could talk to about having children. % refers to percentage of respondents ( N = 706). Figure 2. ( a ) The association between the number of consanguineal kin in the network and density ( r = 0.30); ( b ) The association between the number of non-kin in the network and density ( r = −0.35); ( c ) histogram of density (binwidth = 2.5%). Shaded band is 95% confidence interval around linear regression line. Figure 4. Predicted percentages (95% confidence band based on binomial regressions; see Table A2 ) of responses to the questions “can ask alter for help with child-care” and “can talk to alter about having children” depending on composition for consanguineal kin ( N = 676 respondents), affinal kin ( N = 339), friends ( N = 668), and non-friend alters ( N = 606). Composition refers the percentage of alters in the network belonging to that particular group. Darker shades represent the middle 50% of data. Sample sizes vary because density (which is included in the models) could only be calculated for particular groups when the respondent listed at least two of that group. An increase of 4% in composition means one extra alter is listed in the network of 25. Models were evaluated for 29 year-old women with a partner and children, and average density among the particular groups. On top of the panels, histograms of composition for each group are displayed (binwidth = 4%). Figure 5. Predicted percentages (95% confidence band based on binomial regressions; see Table A2 ) of responses to the questions “can ask alter for help with child-care” and “can talk to alter about having children” depending on density for consanguineal kin ( N = 676 respondents), affinal kin ( N = 339), friends ( N = 668), and non-friend alters ( N = 606). Darker shades represent middle 50% of data. Sample sizes vary because density could only be calculated for particular groups when the respondent listed at least two of that group. Models were evaluated for 29 year-old women with a partner and children, and average composition among the particular groups. On top of the panels, histograms of density for each group are displayed (binwidth = 5%). Figure 6. Do you feel pressure to have (more) children from parents and friends? Each stacked bar chart is of equivalent width, covering all responses, and centered on the response “neither agree/disagree”. Responses “I don’t know” and “not applicable” were excluded from the counts. Figure 7. ( a ) The association between network composition (percentage of kin) (top) and density among kin (bottom) and the pressure felt to have children by parents. ( b ) The association between network composition (percentage of friends) (top) and density among friends and the pressure felt to have children by friends. The shaded band is the 95% confidence interval around predictions from linear regressions (see Table A3 ). Darker shades represent middle 50% of data. Models were evaluated for 29 year-old women with a partner and without children, and for average composition or density.
https://www.mdpi.com/2076-0760/10/5/177/htm
My dogs brought home a chicken... | Page 2 | BackYard Chickens - Learn How to Raise Chickens Yes, I'm aware of this mentality and am trying to avoid it. Is it advisable to go talk to other surrounding farms to find out where the flocks are and to... My dogs brought home a chicken... <here is a image 501994e5e6106d8f-47cd7c94ac30277b> grammaC said: Yes, I'm aware of this mentality and am trying to avoid it. Is it advisable to go talk to other surrounding farms to find out where the flocks are and to explain that we're not purposely letting our dogs roam? Let them know to call us and we'll come get the dogs if they end up in a neighbor's yard? We are new (6 months) to the "neighborhood" and I want to be on friendly terms. Yes on all accounts. Give them your phone number and get them to associate your name and face with your dogs. Still folks with threatened stock will vary wildly in respect to how they will react. With repeated visits by problem causing dogs, virtually all will take action against your dogs and in most areas killing your dogs will be within their rights. You gotta confine your dogs until they have been proven to not be a threat to livestock. Some folks will kill dogs regardless of threat presented. Remember livestock can include other animals. I have 18 acres and dog does not restrict his activities to it. He also patrols neighbors place where geese and ducks are kept. Scoob is not a threat to those birds but something(s); coyotes, bobcats, other dogs have been taking a few. As a result those birds get stressed when Scoob visits which concerns me. grammaC said: Yes, I'm aware of this mentality and am trying to avoid it. Is it advisable to go talk to other surrounding farms to find out where the flocks are and to explain that we're not purposely letting our dogs roam? Let them know to call us and we'll come get the dogs if they end up in a neighbor's yard? We are new (6 months) to the "neighborhood" and I want to be on friendly terms. Nothing wrong with that mentality, what is "not purposely letting our dogs roam"? You don't fence them, you let them roam full stop. We're on 14 acres, all fenced with multiple layers. Any dogs manage to walk/ sneak/ climb/ squeeze itself in here either will be greeted with by my dogs or if they're lucky, shot by me. We don't take chances with our animals, and we don't believe in any excuses offered for roaming dogs. As a farmer and dog lover it bothers me that multiple neighbors allow their dogs to roam. I love dogs and the neighbors all have very friendly non-aggressive dogs, but my rat terrier (who loves people) will attack intruding animals. I also have many small farm animals from chickens to rabbits that are fair game to most dogs. I have been lucky so far that a few gun shots in the air seem to have caused the roamers to bypass us, but if they do come back as mutch as I love dogs they will be shot. It's not really a "mentality" as much as a necessity. I have in the past had to put down two of my own dogs who I could not break from chasing (not killing) chickens and cows I sure as heck am not going to tolerate someone elses animal doing it. grammaC said: Yes, I'm aware of this mentality and am trying to avoid it. Is it advisable to go talk to other surrounding farms to find out where the flocks are and to explain that we're not purposely letting our dogs roam? Let them know to call us and we'll come get the dogs if they end up in a neighbor's yard? We are new (6 months) to the "neighborhood" and I want to be on friendly terms. There are several things that you need to think about here. 1. You want to be on "Friendly " terms - Strong fences make good neighbors, no kidding. Fence an acre to turn them out in. 2. You don't want to have to worry about your dogs getting hurt - your neighbor does not want to have to worry that he may not be home when your dogs come to call, that he may find them to late or come home to find birds missing and wonder if your dogs have been there. 3. You say you are not "purposely letting our dogs roam"- If your dogs go out the door and you are not supervising them at ALL times while they are outside then you ARE letting them roam. You know that your dogs are not Boundry Trained, fenced, chained or otherwise restrained. It would be like your neighbor letting his goats run loose and eat your wifes prize roses or jump up on your car. (call me if you come out to find my goat standing on your car) 4. An ounce of prevention is worth a pound of cure - If you don't allow your dogs to roam you don't have to worry about them harrassing someones stock, so the neighbor doesn't have to worry about his stock and you don't have to worry about your dogs getting shot. This makes for some very "Friendly" neighbors. By all means visit and get to know your neighbors, take your well behaved leashed dogs with you so your neighbors will know who they belong to "IF" they happen to see them out. Do not make your neighbors responsible for your dogs. Least you think I don't like dogs. I raise and show a large mastiff breed and have 5 to 8 at any one time. We also do lots of rescue of large and small dogs, we own 3 chi mix rescues, and 2 Cavaliers, several fixed barn cats, 2 horses, about 70 free range chickens, a few guineas, and boarded dogs in training. Our back pastures are field/livestock fence and kennel/training areas are fenced. Our front is not fenced at all and several of our personal dogs run loose at any given time, they are boundry trained and here to protect our stock. Livestock fence won't stop the big or small dogs, ours or yours. You say you are "aware of this mentality". Are you refering to protecting ones property from a dangerous intruder? (FYI in a rural area any dog off it's property and in proximity to someone else's stock could legally be considered just that, especially ones found with dead chickens in their mouths.) nzpouter said: Nothing wrong with that mentality, what is "not purposely letting our dogs roam"? You don't fence them, you let them roam full stop. We're on 14 acres, all fenced with multiple layers. Any dogs manage to walk/ sneak/ climb/ squeeze itself in here either will be greeted with by my dogs or if they're lucky, shot by me. We don't take chances with our animals, and we don't believe in any excuses offered for roaming dogs. if you haven't confined your dogs, then you ARE letting them roam. Sorry, but dogs, especially a pack of dogs, are always going to be a danger. Even if you train them to never touch YOUR flock, they will be a danger to other farmers' livestock. Dogs know the difference between "their" animals and everyone elses. Not to mention, that even if they are innocently passing through a farm, it's very likely that a farmer will view them as a threat and employ the popular SSS. Fence your dogs, allow them outside only with supervision, whatever it takes to insure that they stay at home 100% of the time. If you want to be on friendly terms, then this is the way to do it. <here is a image 91b81d5f230b96a0-1a538c33bc3698d0> <here is a image bd90bae6ed750916-3535435cd24ac3b0> <here is a image daed566a286cb928-567fb6e761efe8f6> <here is a image 501994e5e6106d8f-47cd7c94ac30277b> grammaC said: Thought about a fence, but it's not practical to fence in the 11 acres. Invisible fencing is not all that expensive. Trust me when I tell you that it has saved the life of my neighbor's pit/chessie X -- 'nough said. Regardless of whther or not your dogs killed the chicken if they are visiting other farms they will be shot. Sorry, but that is just a fact. Need to fence them in, get rid of them or at least chain them up. I know too many people, myself included, that have lost numerous livestock due to dogs at large. If hubby let his hunting dogs roam, eventually they would get into trouble. Maybe they wouldn't kill livestock, they never have, but to just be let loose, there would be trouble. Even if your dogs just happened to find that chicken as a carcass, they will probably become a problem over time. Good luck. No to mention if you have intact dogs, males are very good at getting other dogs pregnant, even through a fence. It has happened to use a few times and having to put down an entire littler of puppies is no fun. It also trashes prized hunting stock. Every unwanted pregnancy costs us money and time. I hate dogs that run loose and mess with our contained animals. <here is a image 9ecac2ebe8784b0a-b23613ff6d296905> Quote: If you're still turning them loose, and they are not fenced, then you ARE "purposely" letting them roam, since you already know they do it Talking to the neighbors doesn't do anything to solve the actual problem If your dogs showed up at myhouse, and were killing my chickens, I'd only be calling you to come pick up the bodies I feel certain the owner of the Rottweiler that killed my neighbor's goats is still wondering why his dog never came home Quote: Invisible fencing is not all that expensive. No to mention if you have intact dogs, males are very good at getting other dogs pregnant, even through a fence. Jeeze, you guys are scaring me. I'm always amazed by the "shoot first ask questions later" line of thinking. I understand if there are repeated issues, but dogs/goats/cows/horses/chickens/sheep do get loose unintentionally sometimes. What if I shot the sheep in the middle of the road or ran them over instead of calling the deputies to help round them up for the farmer? Or the goat that gets into my garden? Seems a bit extreme to me. But anyway... The invisible fence won't work, because we already have a shock collar on the dog and if he's chasing a squirrel, he'll run right through the zap. Typically, he comes back with just the vibration, but he can take a lot of zap if he's otherwise engaged. The neighbor dogs come over almost every day and my dogs will run across the road and romp with them if I don't nip it in the bud. I guess we'll have to think about a fenced area for the dogs as well as a fenced run for the chickens. And, I highly agree with spaying/neutering. Both our dogs are neutered and, the barn cat who was already living here, we took to the vet and vaccinated and dewormed.
https://www.backyardchickens.com/threads/my-dogs-brought-home-a-chicken.630218/page-2
OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-13:50:08.055 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-13:53:43.063 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-13:57:02.070 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-14:00:37.078 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-14:03:56.086 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-14:07:31.094 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-14:10:51.102 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-14:14:26.109 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-14:17:45.117 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-14:21:20.125 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-14:24:39.133 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-14:28:14.141 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN 14/220-14:31:33.148 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN O
https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20170308T174344/anc/eng/usm4/sci_anc_usm414_219_220.drf
STATE v. BERWALD | 186 S.W.3d 349 (2005) | sw3d3491512 | Leagle.com Motion for Rehearing and or Transfer to Supreme Court Denied January 31 2006. JOSEPH M. ELLIS Judge. Appellant Allen B. Berwald...sw3d3491512 STATE v. BERWALD No. WD 64445. View Case Cited Cases Citing Case 186 S.W.3d 349 (2005) STATE of Missouri, Respondent, v. Allen B. BERWALD, Appellant. Missouri Court of Appeals, Western District. https://leagle.com/images/logo.png December 27, 2005. Motion for Rehearing and/or Transfer Denied January 31, 2006. Application for Transfer Denied April 11, 2006. Attorney(s) appearing for the Case Jeremy S. Weis, Kansas City, MO, for appellant. Shaun J. Mackelprang, Assistant Attorney General, Jefferson City, MO, for respondent. Before RONALD R. HOLLIGER, Presiding Judge, ROBERT G. ULRICH, Judge and JOSEPH M. ELLIS, Judge. Missouri Court of Appeals, Western District. Motion for Rehearing and/or Transfer to Supreme Court Denied January 31, 2006. [186 S.W.3d 353] JOSEPH M. ELLIS, Judge. Appellant, Allen B. Berwald, was convicted by a Bates County jury of one count of statutory rape in the first degree and one count of statutory sodomy in the second degree, both of which concerned N.B., his adopted minor daughter. Mr. Berwald was sentenced to concurrent terms of imprisonment in the custody of the Missouri Department of Corrections of twenty-five years and seven years, respectively. We reverse his convictions and remand for a new trial. Before stating the facts of this case, it is helpful to review its relevant procedural history. On October 20, 2003, Mr. Berwald was charged by information with three counts of statutory rape in the first degree (section 566.032); 1one count of statutory rape in the second degree (section 566.034); two counts of statutory sodomy in the first degree (section 566.062); two counts of statutory sodomy in the second degree (section 566.064); and three counts of endangering the welfare of a child in the first degree (section 568.045). He entered pleas of not guilty to all eleven charges. Pursuant to Rule 23.04, Mr. Berwald subsequently moved for an order directing the State to file a bill of particulars, which was granted after a hearing. On June 29, 2004 (the morning of the first day of trial), the State filed an amended information dismissing both counts of first-degree statutory sodomy, leaving nine charges intact. These nine charges were as follows. In Count I, the State alleged that in the summer or fall of 2000, when N.B. was less than fourteen years old, Mr. Berwald committed the crime of statutory rape in the first degree by having sexual intercourse with N.B. in front of the television in the living room of the Berwald family home. Count II alleged that Mr. Berwald committed statutory rape in the first degree by having sexual intercourse with N.B., who was then less than fourteen years old, by the fireplace in the living room of the Berwald family home in winter 2000 or spring 2001, while Count III alleged that Mr. Berwald committed statutory rape in the first degree by having sexual intercourse with N.B., who was then less than fourteen years old, on her bed in the Berwald family home in summer 2001. In Count IV, the State alleged that in winter 2002, when N.B. was less than seventeen years old, Mr. Berwald committed statutory rape in the second degree by having sexual intercourse with N.B. on her bed in the Berwald family home. In Count V, the State alleged that sometime in winter 2002, when N.B. was less than seventeen years old, Mr. Berwald committed statutory sodomy in the second degree by having deviate sexual intercourse with N.B. in the Berwald family home, during which he inserted his fingers into N.B.'s vagina. Count VI was similar to Count V, and alleged that sometime in 2003, Mr. Berwald committed statutory sodomy in the second degree by having deviate sexual intercourse with N.B., who was then less than seventeen years old, in the Berwald family home, during which he inserted his fingers into N.B.'s vagina. Finally, in Counts VII, VIII, and IX, the State alleged that in summer 2001, winter 2002, and sometime in 2003, respectively, when N.B. was less than seventeen years old and he was her parent, Mr. Berwald committed endangerment of the welfare of a child in the first degree by having deviate sexual intercourse with N.B. in the Berwald family home, during which he inserted his fingers into N.B.'s vagina. The State's case-in-chief was presented over the course of a day and a half. At [186 S.W.3d 354] the conclusion of the State's case, Mr. Berwald filed a Motion for Judgment of Acquittal at the Close of the State's Evidence. The trial court entered a directed verdict of acquittal on one of the second-degree statutory sodomy counts against Mr. Berwald (Count V), but denied his motion as to the other eight counts. Mr. Berwald's case-in-chief also required a day and a half to present. At the close of all the evidence, Mr. Berwald filed a Motion for Judgment of Acquittal at the Close of all the Evidence. The trial court entered a directed verdict of acquittal on two of the three counts of endangering the welfare of a child in the first degree (Counts VII and VIII), but denied his motion as to the remaining six counts, which were submitted to the jury. 2 The jury found Mr. Berwald guilty on Counts III and VI, but found him not guilty on Counts I, II, IV, and IX. His motion for new trial was overruled, and he was sentenced to concurrent terms of imprisonment in the custody of the Missouri Department of Adult Institutions of twenty-five years on Count III and seven years on Count VI. This appeal followed. Set forth in the light most favorable to the State, the State's evidence showed the following as to Counts III and VI. N.B., who was born on November 24, 1987, was a sixteen-year-old junior at Butler High School at the time of trial. She is the natural child of Kelly Berwald, who married Mr. Berwald in 1991. In 1992, Mr. Berwald, who was sixty-seven years old at the time of trial, adopted N.B. and her brother M.B. The Berwald family resided in a home located in rural Bates County, Missouri. In the summer of 2001, N.B. was thirteen years old. Mr. Berwald came into her room one night while she was lying on her bed. He pulled N.B. over to the edge of the bed, so that she was lying across the bed with her legs hanging over the edge. He pulled off her jeans, stood between her legs, and used his hands to open the "folds" around her vagina. Mr. Berwald then rubbed his flaccid penis on N.B.'s vagina and attempted to insert his penis into her vagina, penetrating it slightly. On one occasion in 2003, prior to the end of March, while N.B. was less than seventeen years old and he was her parent, Mr. Berwald inserted his finger into N.B.'s vagina while they were in the Berwald family home. N.B. and only N.B. was the source of all this testimony. On March 21, 2003, Mr. and Ms. Berwald separated, and Ms. Berwald moved out of the family home to live in the offices of Mr. Berwald's business. N.B. continued living in the Berwald family home for a week or two, and then went to stay with her mother. On or about April 29, 2003, N.B., who feared that her mother was going to get back together with Mr. Berwald, told Ms. Berwald for the first time about being sexually abused by Mr. Berwald, and further revealed, for the first time as well, that she was also involved in a sexual relationship with a boyfriend, B.I. Shortly after hearing these allegations, which were consistent with a "dream sequence" she had experienced a few months earlier during which she dreamed that Mr. Berwald was sexually abusing N.B. while N.B. was asleep, Ms. Berwald used a microcassette tape recorder she had found in the office to audiotape N.B.'s initial account of the abuse. Ms. Berwald then [186 S.W.3d 355] took N.B. to the circuit clerk's office to obtain a child protection order. A hotline call was placed to the Division of Family Services, and N.B. was subsequently interviewed by various law enforcement, juvenile justice, and family services personnel about the abuse prior to Mr. Berwald's eventual arrest. The rest of the State's evidence against Mr. Berwald (in fact, the vast majority of the evidence against him) did not relate directly to the criminal acts with which he had been charged. Instead, it pertained to other instances of alleged sexual contact between Mr. Berwald and either N.B. or other persons at various other times, all of which were uncharged offenses. That evidence, all of which was admitted over Mr. Berwald's objections in a motion in limine and during trial as it was introduced, was as follows. N.B. testified that when she was ten or eleven years old and in the fifth grade, Mr. Berwald told her that her legs were "sexy" when she "would stand on [her] tippy toes." N.B. also testified that a few years later, while she was in the seventh and eighth grades, Mr. Berwald began touching her breasts and/or rubbing her vagina with his hand about four to five times a week. She testified that, when he would rub her breasts, he would rub them just above the nipple and tell her that he was doing that to make them grow faster and mature more quickly. N.B. further testified about one time during her seventh-grade year, when Mr. Berwald placed her hand in his pants and had her touch his penis and masturbate him. N.B. also testified that, at least on one occasion in the summer following her eighth-grade year, Mr. Berwald had her lie on a counter and spread her legs, then used his hands to open her vagina so that he could examine it, claiming to be checking to see if she was still a virgin, if she was pregnant, and if tampons were hurting her. She said that, during her ninth-grade year, he would also hide in her closet and watch her getting dressed. According to N.B., these acts continued through her ninth-grade year, and Mr. Berwald would often come into her room at night to molest her. Finally, N.B. testified that during 2002 and 2003, while she was in ninth grade, Mr. Berwald did not have any sexual contact with her involving his penis, but did touch her breasts and rub her vagina with his hand between two and four times a week. When Mr. Berwald touched her during this time, N.B. testified, he would tell her that he was "working her hormones." The State also presented testimony from Jane Howe and Vicki Twedt, two of Mr. Berwald's adult children from his first marriage. Ms. Howe was forty-five years old at the time of trial and Ms. Twedt was forty-three. Ms. Howe testified that, during the nine-year period when she was six to fifteen years old, Mr. Berwald touched her vagina thirty or more times. According to Howe, he would have her get on the bed with her panties off, lie on her stomach, and raise her buttocks in the air with her legs spread apart. Ms. Howe testified that he would insert his fingers "[j]ust inside the lips" of her vagina "a little bit" and would look into her vagina, claiming he was doing that to check for hernias, to see if she was pregnant, or to see if she had begun having sex yet. Ms. Twedt testified that she was scared of Mr. Berwald and that on numerous occasions between the fifth and eleventh grades, he rubbed her breasts, telling her that if she rubbed the muscle above her breasts, they would get larger. On two occasions, said Ms. Twedt, Mr. Berwald told her to get in the bathtub so that he could check her for a hernia, and when she did so, he opened her vagina with his fingers and looked [186 S.W.3d 356] inside it. The events described by Ms. Howe and Ms. Twedt had allegedly occurred from twenty to thirty years prior to the charged offenses, and their testimony was admitted over specific and continuing objections by counsel for Mr. Berwald both before trial (in a motion in limine) and during trial that it was inadmissible under State v. Bernard, 849 S.W.2d 10 (Mo. banc 1993), and its progeny. The State also presented the testimony of four witnesses regarding various incriminating statements they purportedly heard Mr. Berwald make in their presence. Ralph Manuel, who had once worked for Mr. Berwald's trucking company as a driver before being fired by him in August 2001, testified that Mr. Berwald told Manuel on one occasion that Berwald had "felt [N.B.'s] breasts for knots." Manuel further testified that Mr. Berwald was always "giddish" [sic] about N.B., not like a proud parent, but like a teenage kid who was "satiated" with her. Kim Abney, Ms. Berwald's sister, testified that Mr. Berwald called her on April 30, 2003, to tell her that N.B. and Ms. Berwald had accused him of molesting N.B., and that the only thing he could think of that might have led to their accusations was that he "used to rub her buttocks to help her develop more fully." When she asked him what that meant, Mr. Berwald told Abney that "it loosens the muscles, tendons and ligaments, and it makes their — them develop more fully into a woman as he had done with his own children." Bates County Chief Deputy Sheriff Gary Martin testified that, after criminal charges had been filed against Mr. Berwald, he went to Berwald's home and spoke with him about the accusations. According to Martin, during the course of their hour-long conversation, Berwald denied the allegations but told Martin that once, while he and N.B. were lying on the floor watching television together, he was rubbing a cramp on N.B.'s leg and his hand had gone too far up her leg, prompting her to say, "Dad, that's not my leg." The State also presented the testimony of Roger Farrell, Ms. Berwald's former stepfather. Farrell testified that, on one occasion in July 2003 when they were talking together at Farrell's business, Mr. Berwald told Farrell that N.B. would "wake up when she wanted me to stop." According to Farrell, Mr. Berwald did not offer any additional details regarding the meaning of that statement, and Farrell conceded on cross-examination that it was possible that Mr. Berwald was merely repeating some of the allegations that had been made against him. Since there was a conviction, we normally would not present a detailed summary of the evidence presented by the defendant. However, we do so here because, as will soon be seen infra,it is important in establishing whether Mr. Berwald suffered sufficient prejudice to be entitled to reversal and remand for a new trial. See State v. Driscoll,55 S.W.3d 350, 357-58 (Mo. banc 2001) (conducting detailed review of defendant's evidence to assist in determining whether the jury would likely have convicted the defendant absent the inadmissible evidence adduced by the State). Mr. Berwald presented a vigorous defense, during which he and fourteen other witnesses testified in support of his theory of the case, which was that the charged acts of sexual abuse never actually occurred (in whole or in part), but had been fabricated by N.B. and her mother. Mr. Berwald adamantly denied all of the charged (and uncharged) allegations of sexual abuse that had been leveled against him and insisted that he had never touched N.B. in an inappropriate way. He presented numerous witnesses to support [186 S.W.3d 357] his defense theory, including: (1) expert medical evidence to show that due to his various health problems (including, as acknowledged at trial by N.B. herself) impotence, congestive heart disease, and knee replacement surgery, he was physically incapable of performing some of the sexual acts alleged by N.B. and was out of the home in the hospital during part of the charged time frames; (2) evidence that N.B. was involved in a forbidden sexual relationship with her boyfriend B.I. and was motivated to fabricate the abuse charges "so that her mom wouldn't be so mad at her" for having sex with B.I. and to be able to keep seeing him; (3) evidence that he was often on the road or working late as a truck driver and was not home often enough for him to have molested N.B. nearly as often as she claimed he did; (4) evidence that Ms. Berwald was motivated to fabricate the allegations against him to gain leverage in her pending divorce action against him and to draw attention from the fact that she and several of the State's witnesses against him had been involved in stealing or concealing several thousand dollars in company funds from his business after they separated (including Mr. Manuel and Ms. Abney, who admitted their complicity in Ms. Berwald's scheme at trial); and (5) evidence that Ms. Berwald had started to plant the idea of the molestation in people's minds well before leaving him for another employee of his business, John Freed, with whom she had had an affair during the marriage. Mr. Berwald also presented substantial impeachment evidence, including: (1) testimony from a female friend of N.B.'s who said N.B. had told her that Mr. Berwald never molested her; (2) testimony from N.B.'s brother to the effect that he never observed anything that would corroborate N.B.'s testimony, never saw Mr. Berwald and N.B. alone and never saw him in her bedroom, that N.B.'s story kept changing when he communicated with her about the allegations, and that he felt pressured by a State Technical Assistance Team (STAT) investigator, Larry Wyrick, to "help his sister out" by confirming her allegations; (3) testimony that N.B. kept in close contact with Mr. Berwald after leaving the family home to live with her mother and attended a birthday dinner for Mr. Berwald at the Berwald family home on April 9, 2003; (4) testimony that Ms. Howe told a detective that she was concerned the information from N.B. about the claimed molestations was fabricated; (5) testimony that there were often various overnight guests at the family home, making N.B.'s allegations as to the pervasive scope and extent of the alleged sexual abuse unlikely to be true; (6) testimony from Ms. Berwald that on one occasion before N.B. first told her she had been sexually abused by Mr. Berwald, when Ms. Berwald had asked N.B. if Mr. Berwald had sexually abused her, N.B. said "no"; (7) testimony from DFS investigator Rhonda Talley that, during N.B.'s initial interview with Talley, N.B. told Talley that Mr. Berwald had never put his penis into her vagina; (8) a stipulation that the SAFE exam performed on N.B. at Children's Mercy Hospital revealed no physical signs of sexual abuse; and (9) testimony from several different witnesses to attempt to impeach or discredit the accounts of Ms. Howe and Ms. Twedt. As noted supra, at the close of the evidence, instructions, and arguments of counsel, Mr. Berwald was found guilty of one count of first-degree statutory rape and one count of second-degree statutory sodomy, and not guilty of the two remaining counts of first-degree statutory rape, one count of second-degree statutory sodomy, and one count of endangering the welfare of a child. Jury sentencing having been waived by Mr. Berwald, on August 6, [186 S.W.3d 358] 2004, the trial court, after overruling his motion for new trial, sentenced Mr. Berwald to concurrent terms of twenty-five years' imprisonment for first-degree statutory rape and seven years' imprisonment for second-degree statutory sodomy in the custody of the Department of Corrections. This appeal followed. Any additional facts necessary to the disposition of the appeal will be supplied as needed later in this opinion. In his first point, Mr. Berwald contends that the trial court prejudicially erred and abused its discretion in admitting the trial testimony of Jane Howe and Vicki Twedt regarding uncharged acts of sexual abuse he purportedly committed against them as children some twenty to thirty years before trial because it was neither logically nor legally relevant to the issues before the jury in that their testimony did not relate to any criminal offense for which he was on trial and its prejudicial effect far outweighed its probative value. "A trial court typically has broad discretion in deciding whether to admit evidence and, as such, its decision will not be disturbed unless a clear abuse of discretion is shown." State v. Danikas,11 S.W.3d 782, 788 (Mo.App. W.D.1999). It has long been established, though, that "a defendant has the right to be tried only for the offense for which he is on trial, and that evidence of other crimes committed by [the] defendant is normally inadmissible." State v. Edwards,116 S.W.3d 511, 533 (Mo. banc 2003). Such uncharged crimes evidence carries with it several significant risks, including: (1) that the introduction of evidence of other crimes will mislead or confuse the jury, (2) that the jury will give undue weight to the if he did it once, he'll do it again inference, (3) that the defendant will be made to defend, not just against the charges brought, but against all of his prior, similar behavior which, for whatever reason, was not prosecuted by the State, and (4) that the jury, in its rush to punish the defendant for his past acts — which the jury must infer have gone unpunished — may overlook the fact that the State has failed to prove the defendant was guilty of the charges brought. State v. Bernard,849 S.W.2d 10, 22 (Mo. banc 1993) (Robertson, C.J., concurring in part). "If, however, evidence of prior misconduct is both logically and legally relevant to prove the charged crime, it is admissible." State v. Barriner,34 S.W.3d 139, 144 (Mo. banc 2000). "Evidence is logically relevant if it has some legitimate tendency to establish directly the accused's guilt of the charges for which he is on trial." Id.In this regard, "[e]vidence of prior uncharged misconduct generally has a legitimate tendency to prove the specific crime charged when it tends to establish motive, intent, the absence of mistake or accident, a common scheme or plan, or the identity of the person charged with the commission of the crime on trial." Id.at 145. With regard to identity as a basis for logical relevance, in State v. Bernard, 849 S.W.2d 10 (Mo. banc 1993), the Missouri Supreme Court expressly recognized a closely-related exception for certain prior uncharged misconduct that falls within the "signature modus operandi /corroboration" category. Id. at 17. "The signature modus operandi /corroboration exception approximates the long established, well recognized exception that allows evidence of prior uncharged misconduct for the purpose of proving the identity of the wrongdoer." Id. "In the context of corroboration, evidence of prior crimes is logically relevant [if] it has a legitimate tendency to [186 S.W.3d 359] prove a material fact in the case by corroborating the testimony of the victim as to the sexual assault." Id. Nevertheless: For the prior conduct to fall within the identity exception, there must be more than mere similarity between the crime charged and the uncharged crime. The charged and uncharged crimes must be nearly identical and their methodology so unusual and distinctive that they resemble a signature of the defendant's involvement in both crimes. Id(internal quotation marks omitted); see also State v. Frey,897 S.W.2d 25, 31 (Mo. App. W.D.1995) (holding that the uncharged crime must be "so unusual and distinctive as to be a `signature' (similar to a fingerprint) of the defendant's conduct.") "This is a threshold requirement that must be met before the trial court can proceed to weigh any additional factors in determining the question of admissibility." Bernard,849 S.W.2d at 17. Of course, to be admissible, evidence must also be legally relevant. Id.Evidence is legally relevant if its probative value outweighs its costs. State v. Barriner,111 S.W.3d 396, 401 (Mo. banc 2003). This determination "involves a process through which the probative value of the evidence (its usefulness) is weighed against the dangers of unfair prejudice, confusion of the issues, misleading the jury, undue delay, waste of time or needless presentation of cumulative evidence (the cost of the evidence)." State v. Sladek,835 S.W.2d 308, 314 (Mo. banc 1992). Since Bernardwas decided, the appellate courts of this state have been quite reluctant to sanction the admission of evidence relating to a defendant's prior uncharged misconduct under the signature modus operandi/corroboration exception to the general rule of exclusion. As our Supreme Court observed in State v. Gilyard,979 S.W.2d 138, 141 (Mo. banc 1998), "[b]ecause of the stringent standard for legal relevance, however, most cases addressing the corroboration exception have held the evidence of prior uncharged misconduct inadmissible." In particular, "the passage of time between incidents [may be] so lengthy that the prejudice or other `cost' of the evidence outweighs the probative value of the signature modus operandi." Bernard,849 S.W.2d at 19. Indeed, this court has held that "[b]ecause evidence of other crimes is highly prejudicial, such evidence should be admitted only when there is `strict necessity.'" State v. Pennington,24 S.W.3d 185, 190 (Mo.App. W.D.2000). In admitting the trial testimony of Jane Howe and Vicki Twedt, the trial court found it to be both logically and legally relevant. As to logical relevance, the trial court ruled that because the allegations they planned to make if allowed to testify were "so similar to what occurred, or what [N.B.] has said," their testimony "goes to motive, to intent, to absence of mistake or accident, and to a, potentially, a common scheme or plan." As to legal relevance, the trial court ruled, without any further explanation: "Of course, this is prejudicial. I believe its probative value outweighs its prejudicial effect." The State does not even attempt to defend the trial court's ruling on the logical relevance of the testimony of Ms. Howe and Ms. Twedt on the grounds that it was probative as to motive, intent, the absence of mistake or accident, or a common scheme or plan. Instead, the State argues solely that the evidence was logically relevant to identify Mr. Berwald as the person who committed the charged crimes under the signature modus operandi/corroboration exception recognized in Bernard. While formally recognizing the signature modus operandi /corroboration exception [186 S.W.3d 360] in Missouri, the Court in Bernard cautioned against the indiscriminate admission of such evidence at trial, noting that it was "`particularly important that the requirement for a signature modus operandi be strictly enforced'" to ensure that the exception does not "`become so broad that it swallows up the underlying rule of exclusion.'" Bernard, 849 S.W.2d at 16, 17 (quoting Sladek, 835 S.W.2d at 315 (Thomas, J., concurring)). Thus, the Court required that any evidence of prior uncharged sexual misconduct that corroborates the testimony of the victim "be nearly identical to the charged crime and so unusual and distinctive as to be a signature of the defendant's modus operandi. " Id. at 17. Although both are threshold requirements "that must be met before the trial court can proceed to weigh any additional factors in determining the question of admissibility," id.,such as assessing whether the evidence's probative value exceeds its costs, including "the dangers of unfair prejudice, confusion of the issues, misleading the jury, undue delay, waste of time or needless presentation of cumulative evidence," Sladek,835 S.W.2d at 314, the factual summary provided supramakes it clear that, with regard to the trial testimony of Ms. Howe and Ms. Twedt, the State did not make the first of these two essential showings — namely, that the charged and uncharged crimes were "nearly identical." Mr. Berwald went to trial accused of nine separate criminal offenses alleged to have been committed against N.B. between the fall of 2001 and the spring of 2003. Counts I-IV were all statutory rape charges involving allegations of sexual intercourse between Mr. Berwald and N.B., including actual penetration of her vagina by Mr. Berwald's penis. However, neither Ms. Howe nor Ms. Twedt alleged that Mr. Berwald ever had sexual intercourse of any kind with them, with or without successful penetration. And while Counts V-IX all charged that Mr. Berwald had deviate sexual intercourse with N.B. during which he inserted his fingers into N.B.'s vagina, the record shows that the testimony of Ms. Howe and Ms. Twedt clearly did not involve uncharged sexual misconduct which was "nearly identical" to one or more of those charged crimes, as both women described digital-vaginal contact during which Mr. Berwald spread the lips of their vaginas and peered inside, either to check for hernias, to see if they were pregnant, or to see if they had begun having sex yet. In stark contrast, N.B.'s trial testimony pertaining to the crimes charged in Counts V-IX described overtly sexual digital-vaginal contact which did notinvolve any such distinctive conduct by Mr. Berwald. Finally, Ms. Twedt's testimony that Mr. Berwald rubbed her breasts, telling her that if she rubbed the muscle above her breasts, they would get larger, also had no relationship whatsoever to any of the criminal conduct alleged in Counts I-IX, in that none of the counts contained allegations that Mr. Berwald rubbed N.B.'s breasts. The State nevertheless insists that the trial testimony of Ms. Howe and Ms. Twedt was logically relevant since it had a legitimate tendency to prove a material fact in the case by corroborating the testimony of N.B. as to the sexual abuse Mr. Berwald had inflicted on her. Pointing to N.B.'s trial testimony that, during the summer after she completed the eighth grade, Mr. Berwald had her lie on a counter and spread her legs, then used his hands to open her vagina so that he could examine it (claiming to be checking to see if she was still a virgin, if she was pregnant, and if tampons were hurting her), and that Mr. Berwald would "work her hormones" by rubbing her breasts just [186 S.W.3d 361] above the nipple to make them grow faster and mature more quickly, the State argues that Mr. Berwald's practice of allegedly conducting bogus do-it-yourself medical examinations in order to overcome his daughters' concerns about inappropriate sexual contact was "so unusual and distinctive as to be a signature of the defendant's modus operandi. " Bernard, 849 S.W.2d at 17. Had the trial testimony of N.B. cited by the State concerned a charged offenseagainst Mr. Berwald, we might consider entertaining the State's argument. However, it did not. Rather, it concerned unchargedcriminal acts alleged by N.B. which were supposedly "corroborated" by the testimony of Ms. Howe and Ms. Twedt regarding events which allegedly occurred some two or three decades before. Since the narrow signature modus operandi/corroboration exception to the general rule of inadmissibility recognized in Bernardrequires that "[t]he similarity must be between the prior uncharged act and the present crime," Frey,897 S.W.2d at 31 (emphasis added); see also Bernard,849 S.W.2d at 17 (emphasis added) (noting that "[f]or corroboration evidence to be of sufficiently increased probative value so as to outweigh its prejudicial effect, the evidence must be more than merely similar in nature to the sexual assault for which the defendant is charged."), the trial testimony of Ms. Howe and Ms. Twedt was logically irrelevant in that it did not corroborate the testimony of N.B. as to any of the criminal offenses for which Mr. Berwald was on trial. Accordingly, that testimony was inadmissible and the trial court erred and abused its discretion in admitting it over repeated objections by Mr. Berwald. 3We now proceed to the question of prejudice. "With regard to trial court errors that have been preserved, we review for prejudice, not mere error, and will reverse only if the error was so prejudicial that it deprived the defendant of a fair trial." State v. Hutchison,957 S.W.2d 757, 761 (Mo. banc 1997). This rule is generally applicable when we review issues pertaining to the admission of evidence. See, e.g., State v. Churchill,98 S.W.3d 536, 538 (Mo. banc 2003) (internal quotation marks omitted) ("When this Court is asked to review the admissibility of evidence, it reviews for prejudice, not mere error, and will reverse only if the error was so prejudicial that it deprived the defendant of a fair trial."); State v. Anderson,76 S.W.3d 275, 277 (Mo. banc 2002) (same). In particular, our Supreme Court has held that it is to be applied in cases where, as here, a criminal defendant alleges on direct appeal that a trial court erred in admitting evidence of prior uncharged crimes over timely and specific objection that "the offenses were not logically relevant nor necessary to prove the charged crimes." State v. Morrow,968 S.W.2d 100, 105, 106 (Mo. banc 1998). 4 [186 S.W.3d 362] In criminal cases involving the improper admission of evidence, the test for prejudice "is whether the improper admission was outcome-determinative." State v. Black, 50 S.W.3d 778 , 786 (Mo. banc 2001). When the prejudice from the improper admission of evidence is outcome-determinative, reversal is required. A finding of outcome-determinative prejudice expresses a judicial conclusion that the erroneously admitted evidence so influenced the jury that, when considered with and balanced against all evidence properly admitted, there is a reasonable probability that the jury would have acquitted but for the erroneously admitted evidence. Id.(internal citation omitted); see also State v. Bell,950 S.W.2d 482, 484 (Mo. banc 1997); Case,140 S.W.3d at 87. In judicially determining whether "there is no reasonable probability that the jury would have acquitted but for the erroneously admitted evidence," Black,50 S.W.3d at 786, we must keep in mind that the State is "not entitled to the benefit of all reasonable inferences from the evidence, as in a review for the sufficiency of the evidence." Driscoll,55 S.W.3d at 357. In Bernard,the Court held that the prior uncharged crimes evidence which did not meet the narrow signature modus operandi/corroboration exception to the general rule of inadmissibility because it bore "no similarity to the conduct with which [the defendant] is charged in the present case ... is prejudicial, and its admission requires reversal and remand for a new trial." 849 S.W.2d at 20. Moreover, "[t]he amount of evidence that was erroneously admitted and the extent to which the evidence was referred during the trial" may also be considered in determining the existence of reversible, outcome-determinative error. Barriner,34 S.W.3d at 151. In this regard, the record shows that the evidence in question (considered together with that which Mr. Berwald was forced to present in an attempt to rebut the allegations of Ms. Howe and Ms. Twedt) was extensive, covering well over 200 printed pages of the transcript. The transcript also demonstrates that the prosecutor [186 S.W.3d 363] took full advantage of the trial court's erroneous rulings permitting the State to present the testimony of Ms. Howe and Ms. Twedt over proper objection by Mr. Berwald. The prosecutor actually began his closing argument to the jury by specifically referring to that evidence, and also repeatedly mentioned it throughout his rebuttal argument, claiming that Ms. Howe and Ms. Twedt were especially credible witnesses since, unlike some of the other witnesses the jury had heard testify, "[t]heir stories are consistent" and "[t]hey never had their stories rehearsed." The prosecutor also contended that what happened to N.B. was "a recreation of what happened" to Ms. Howe and Ms. Twedt, even though that was clearly not the case as to any of the crimes with which Mr. Berwald was charged and for which he was on trial. The transcript further shows that the prosecutor's last words to the jury before it retired to begin its deliberations were: "And Jane [Twedt] and Vicki Howe came into this courtroom and testified that they still loved him [Mr. Berwald]. They still loved him. They still love him. Man, if you ever saw raw emotion and a family in hurt and turmoil, this is it. There's something going on here." Thus, the State's belated claim on appeal that this evidence did not contribute to the jury's guilty verdicts on Counts III and VI in any way is totally inconsistent with what it argued to the jury at trial. "Because of the volume of testimony devoted to the improperly admitted evidence, as well as the number of references highlighting the improperly admitted evidence, the likelihood that this evidence had a lasting impact on the jury is great." Id. Nevertheless, the State maintains that there was no outcome-determinative prejudice. First, the State argues that Mr. Berwald was not prejudiced since the jury was given a limiting instruction, which stated: If you find and believe from the evidence that the defendant was involved in offenses other than the one [sic] for which he is now on trial and other than the offenses mentioned in Instructions Nos. 9, 11, 13, 15, 17, and 195 you may consider that evidence on the issues of motive, intent and absence of mistake or accident. You may not consider such evidence for any other purpose. This argument is disingenuous, because as noted supra,the State does not even attempt to justify the admission of the testimony of Ms. Howe and Ms. Twedt on the grounds that it was probative as to Mr. Berwald's motive, intent, or the absence of mistake or accident. Furthermore, even if it had any such evidentiary value, it would still have been inadmissible because where, as here, "evidence of other crimes is unnecessary because motive, intent,... or absence of mistake were not issues, the probative value of such evidence is far outweighed by its prejudicial effect." State v. Conley,938 S.W.2d 614, 621 (Mo.App. E.D.1997). Since the challenged testimony was inadmissible for any purpose, the limiting instruction was wholly ineffective to protect Mr. Berwald's right to be tried only for the offenses with which he had been charged and for which he was on trial. Second, the State claims Mr. Berwald was not prejudiced because, if the testimony of Ms. Howe and Ms. Twedt had played a decisive role in its deliberations, "the jury would likely have convicted [him] on all possible counts." As illustrated by the cases cited supra, that is not the appropriate [186 S.W.3d 364] inquiry to determine the existence of outcome-determinative prejudice. Instead, the appropriate inquiry is whether there is a substantial likelihood that the jury would have acquitted Mr. Berwald on five or all six charges (rather than on only four) had the trial court properly excluded the highly prejudicial testimony of Ms. Howe and Ms. Twedt, which undoubtedly (but impermissibly) bolstered the rest of the State's case against Mr. Berwald. Given the overall weakness of the State's case against Mr. Berwald and the large amount of defense evidence he presented tending to show his innocence, 6 this is not a particularly close call. We therefore reject the State's speculative claim that the erroneously admitted evidence played little or no role in producing the jury's guilty verdicts on Counts III and VI due to his acquittal by the jury on Counts I, II, IV, and XI. To summarize, after thoroughly reviewing the record and the law, we can only conclude that the trial court erred and abused its discretion in admitting the evidence in question. Moreover, Mr. Berwald has demonstrated to our satisfaction that when considered with and balanced against all evidence properly admitted, there is a reasonable probability that the jury would have acquitted Mr. Berwald on Counts III and VI but for the error committed by the trial court in admitting the testimony of Ms. Howe and Ms. Twedt. Accordingly, the point is granted, and Mr. Berwald's convictions on Counts III and VI must be reversed and the case remanded for a new trial. In his second point, Mr. Berwald argues that the trial court prejudicially erred and abused its discretion in admitting the trial testimony of N.B. herself regarding multiple uncharged acts of sexual abuse he purportedly committed against her because it was neither logically nor legally relevant to the issues before the jury in that her testimony as to those acts did not relate to any criminal offense for which he was on trial and its prejudicial effect far outweighed its probative value. Since Mr. Berwald has been granted a new trial on Counts III and VI and it is unclear whether and how such other crimes evidence from N.B. will be introduced in a retrial not involving Counts I, II, IV, V, VII, VIII, and IX, we need not decide the point in this appeal. The same applies to Mr. Berwald's fourth point, in which he argues that, due to the trial court's erroneous admission of N.B.'s vague and overlapping trial testimony concerning a host of similar charged and uncharged criminal sexual acts which she said took place at or around the time of the events charged in Count VI, the jury was unable to reasonably distinguish between the charged and uncharged acts and he was effectively denied his constitutional right to a unanimous verdict of guilt by all twelve jurors on Count VI. Should either or both of these issues arise on retrial, in deciding whether to admit or exclude N.B.'s uncharged crimes testimony (in whole or in part), the trial court is to be guided by the applicable portions of our analysis supra,as well as the proper exercise of its sound discretion. In his third and final point, Mr. Berwald argues the trial court abused its discretion in denying his motion to dismiss all charges against him or to grant him a new trial based on the State's failure to preserve a microcassette audiotape of N.B.'s initial allegations which had been [186 S.W.3d 365] recorded by Ms. Berwald. We disagree, because, although the State's handling of this evidence was sloppy and perhaps negligent, Mr. Berwald has not shown that the audiotape in question was exculpatory or that the State acted in bad faith in failing to preserve it. To properly understand this contention, it is necessary to set forth some additional facts. As mentioned supra,Ms. Berwald created the audiotape in question on or about April 29, 2003, when N.B. told Ms. Berwald for the first time about being sexually abused by Mr. Berwald. On March 15, 2004, Mr. Berwald took the deposition of his estranged wife. While testifying regarding the initial allegations lodged by her daughter, Ms. Berwald let slip the fact that she had audiotaped her conversation with N.B. The record shows that, although Mr. Berwald was not, the State was well aware of the existence of the tape before Ms. Berwald's deposition, because, as conceded by the State in its brief, it had been delivered by her to five different state investigators involved in the criminal investigation a few days after she recorded it, including DFS investigator Rhonda Talley, Bates County Chief Deputy Juvenile Officer Deborah Powell, STAT investigator Larry Wyrick, and two members of the Bates County Sheriff's Department (Justin Moreland and Gary Martin), none of whom preserved or attempted to electronically enhance the tape before giving it back to Ms. Berwald. Mr. Berwald subsequently filed a motion to dismiss the amended information in its entirety, seeking to establish a violation of Arizona v. Youngblood,488 U.S. 51, 109 S.Ct. 333, 102 L.Ed.2d 281 (1988), based on his claim that the State failed to preserve potentially exculpatory evidence. In particular, Mr. Berwald alleged that the State had acted in bad faith by (1) failing to preserve the tape; and (2) failing to attempt to have the audio electronically enhanced to determine if it contained any exculpatory evidence before returning it to Ms. Berwald, "a woman who is actively engaged in divorce proceedings from Mr. Berwald and has an interest in seeing him sentenced to prison." The motion further alleged that Mr. Berwald had retained an audio expert who believed that "the tape could, in all likelihood, have been enhanced to obtain the complete statements" from N.B. and Ms. Berwald. During a brief hearing on the motion a few days before the start of trial, the prosecutor stated that Ms. Berwald had advised him she could not find the tape and that she may have discarded it. The prosecutor also stated that Talley and Powell both explained to him that they gave the tape back to Ms. Berwald because it "is of no use to us, or you can't hear it, or some words to the effect that this isn't any good," explaining: "That may be negligence, but I don't see that as bad faith. And it's just like police not taking fingerprints at the scene of a crime. I mean, you know, if they — if they are sloppy and don't do it, I think it's more akin to that than it is a discovery violation." The trial court postponed ruling on the motion, waiting to see if the tape would be found before trial began, but made a preliminary finding of no bad faith on the State's part. Immediately before swearing the jury, the trial court overruled Mr. Berwald's motion to dismiss. At trial, seven witnesses testified about the tape. N.B. testified that when she had listened to it, "you couldn't hardly understand very much." Ms. Berwald testified that she made the tape, which she subsequently "got rid of" or misplaced, so N.B. wouldn't have to repeat her allegations against Mr. Berwald, but that the various [186 S.W.3d 366] law enforcement officials she took it to "couldn't understand it." Powell, for whom Ms. Berwald evidently played the tape first, testified that the first three minutes of the tape were "inaudible," stating that she could not hear anyone's voices and that there was "absolutely not one word that I could understand on the tape." She further stated that all she heard on the tape was "scratching and banging" and that the tape was "completely useless as any kind of tool." However, Powell acknowledged that she'd never fast-forwarded the tape to check to see if the quality improved later on. Talley also heard the first few minutes of the tape, describing it as "inaudible," stating that the voices were "muddled" and "muffled." Like Powell, Talley acknowledged that she never attempted to fast-forward through the tape to see if other portions were audible. Detective Justin Moreland of the Bates County Sheriff's Department testified that he was given the tape by Ms. Berwald, but that he "couldn't understand anything on it," because all he could hear was "mumbling." He testified that he made no report about the tape because it had no apparent evidentiary value and was of no benefit to either party. Deputy Martin testified that he hardly remembered the tape and did not recall listening to it, but said that Detective Moreland had told him that it was inaudible. Finally, STAT investigator Wyrick testified that he was given the tape by Ms. Berwald and tried to play it, but couldn't understand what was being said because "it wasn't a very good recording." Although he could hear voices, testified Wyrick, they were "staticky" and "garbley" [sic] so he gave the tape back to Ms. Berwald, explaining that because he found the tape to be a "fairly insignificant" piece of evidence, he didn't bother to mention it in his written report. Asked whether he attempted to fast-forward through the tape to see if other portions were audible, Wyrick stated that he couldn't remember. Wyrick further testified that he did not have the tape analyzed by an audio expert to try to filter out the static and background noise because he relied on the Missouri State Highway Patrol laboratory for such services, which had been unable to successfully filter tapes that were "a lot better than" this tape. A trial court's refusal to dismiss a charging instrument is reviewed for abuse of discretion. See State v. Burns,112 S.W.3d 451, 454 (Mo.App. W.D.2003). "Whatever duty the Constitution imposes on the States to preserve evidence, that duty must be limited to evidence that might be expected to play a significant role in the suspect's defense." California v. Trombetta,467 U.S. 479, 488, 104 S.Ct. 2528, 2534, 81 L.Ed.2d 413, 422 (1984). Therefore, in assessing whether a trial court abused its discretion in refusing to impose dismissal as a sanction for the State's failure to preserve evidence that is potentially useful to the defense, this court must determine "whether the evidence was of such significance to create a reasonable likelihood that the outcome of the trial would be affected." Burns,112 S.W.3d at 454-55. Moreover, even if the evidence might be expected to play such a role in the outcome of the trial, a defendant must also show that "the State acted in bad faith in destroying the evidence or that the exculpatory value of the evidence was apparent before it was destroyed." at 455. "Absent a showing of bad faith on the part of the police or prosecutor, the failure to preserve even potentially useful evidence does not constitute a denial of due process." State v. Ferguson, 20 S.W.3d 485 , 504 (Mo. banc 2000). In this context, bad [186 S.W.3d 367] faith is the destruction of the evidence by a state actor "for the purpose of depriving the defendant of exculpatory evidence[.]" State v. Armentrout, 8 S.W.3d 99 , 110 (Mo. banc 1999). Thus, to merit relief on a claim of failure to preserve evidence, the defendant must also show that the evidence had an exculpatory value that was apparent to the State before it was destroyed. Trombetta, 467 U.S. at 489, 104 S.Ct. at 2534, 81 L.Ed.2d at 422. Accordingly, for due process purposes, bad faith turns on law enforcement's "`knowledge of the exculpatory value of the evidence at the time it was lost or destroyed.'" State v. Smith, 157 S.W.3d 687 , 691 (Mo.App. W.D.2004) (quoting Youngblood, 488 U.S. at 56 n.*, 109 S.Ct. at 336 n.*, 102 L.Ed.2d at 288 n.*). The trial testimony recited supramakes it abundantly clear that Mr. Berwald failed to show that the tape in question contained exculpatory evidence significant enough to create a reasonable likelihood that the outcome of the trial would have been affected. Indeed, in his brief, he articulates no specific basis for doing anything more than speculating that something exculpatory might possibly have been found had the tape been electronically enhanced to filter out the static and background noise. Furthermore, even if the evidence was potentially useful, Mr. Berwald also failed to make a showing that the State acted in bad faith in failing to preserve the evidence since he did not demonstrate that its exculpatory value was apparent to the State before the tape was lost or destroyed or that the tape was not preserved for the purpose of depriving him of access to exculpatory evidence. Point denied. Mr. Berwald's convictions on Count III (statutory rape in the first degree, section 566.032) and Count VI (statutory sodomy in the second degree, section 566.064) are reversed and the case is remanded for a new trial. All concur. FootNotes 1. All statutory references are to RSMo 2000. 2. Because Counts VI and IX charged essentially the same underlying conduct, the trial court required the State to submit Count IX in the alternative to Count VI. Therefore, Mr. Berwald could have been convicted on either none or one of those two counts, but not both of them. 3. Since evidence must be both logically and legally relevant to be admissible, we need not decide the issue of its legal relevance. We note, however, that the events described by Ms. Howe and Ms. Twedt had allegedly occurred from twenty to thirty years prior to the charged offenses and that several hundred pages of the transcript were devoted either to their testimony or the related testimony of Mr. Berwald's opposing witnesses. During all this, the jury no doubt focused its attention more on the stale sexual abuse allegations of Mr. Berwald's adult daughters than on the allegations of N.B. herself, thereby setting the stage for possible confusion of the issues, misleading the jury, undue delay, and waste of time. 4. "In most cases of trial court error, the issue is whether the evidence was `outcome determinative,' that is, whether `the erroneously admitted evidence so influenced the jury that, when considered with and balanced against all the evidence properly admitted, there is a reasonable probability that the jury would have reached a different conclusion but for the erroneously admitted evidence.'" Driscoll, 55 S.W.3d at 356 (quoting Barriner, 34 S.W.3d at 150). However, when a properly preserved error is so serious that it rises to the magnitude of a federal or state constitutional violation, including "due process, confrontation clause, right to present a defense, right to access justice through the courts of Missouri, right to a reliable verdict and sentencing, [or] cruel and unusual punishment," State v. Wolfe, 13 S.W.3d 248 , 263 (Mo. banc 2000), it is presumed to be prejudicial and "the judgment of guilt can be affirmed only if it is shown [by the State] that the error was harmless beyond a reasonable doubt" in accordance with the "heightened standard" of review set forth in Chapman v. California, 386 U.S. 18 , 87 S.Ct. 824, 17 L.Ed.2d 705 (1967) and Neder v. United States, 527 U.S. 1 , 119 S.Ct. 1827, 144 L.Ed.2d 35 (1999). Driscoll, 55 S.W.3d at 356; State v. Case, 140 S.W.3d 80 , 87 (Mo.App. W.D.2004) (noting that when the error complained of rises to the level of a constitutional violation, "[t]he State must prove beyond a reasonable doubt that [it] did not contribute to the verdict obtained.") See also State v. Whitfield, 107 S.W.3d 253 , 262 (Mo. banc 2003) (internal quotation marks omitted) ("Under this test, the beneficiary of a constitutional error, the State, must prove beyond a reasonable doubt that the error complained of did not contribute to the verdict obtained.") Although there is some older Missouri authority to the contrary, as demonstrated by Morrow, in which our Supreme Court employed the general test for prejudice when the defendant alleged trial court error in the admission of evidence of prior uncharged crimes over his timely and specific objection at trial, this case does not involve a federal or state constitutional violation, so the harmless-beyond-a-reasonable-doubt standard of Chapman and Neder does not apply here. 5. These instructions were the verdict directors on Counts I, II, III, IV, VI, and IX, respectively. 6. The State dropped two of the original eleven charges against Mr. Berwald immediately prior to trial and he was acquitted on seven of the nine remaining charges, either by the trial court or the jury. Comment
https://www.leagle.com/decision/2005535186sw3d3491512
Ruptured pulmonary hydatid cyst | Changeset | Radiopaedia.org Ruptured pulmonary hydatid cyst Diagnosis almost certain Updates to Study Attributes Findings was changed: There is extensive air density seen in the soft tissues of the anterior, lateral and posterior chest wall, dissecting into the deep soft tissue and muscle planes, and which extends superiorly and inferiorly to involve the left neck and left lateral abdominal wall, respectively. The emphysema even crosses over to the right side at the level of the thoracic inlet. Within the lung fields, there is a large, well defined, cystic lesion measuring 16 cm (AP) x 9 cm (Trans) x 19 cm (CC) seen in the left lung, occupying almost the entire lung field. Within the dependant portion of this lesion, there is a heterogeneous, serpinginous serpiginous or onion peel like nodule density. This is representative of the spin or cumbo Cumbo sign of detached or ruptured hydatid cyst membranes. Pleural reaction posteriorly, as well as lung atelectasis medial to the cyst, are also seen, in keeping with the rupture. Surrounding the hydatid cyst there are multiple smaller cystic cavities interspersed with areas of severe panlobular interstitial emphysema. Midline shift to the right is also seen, likely secondary to mass effect. The right lung field is unaffected. Updates to Case Attributes Body was changed: Subcutaneous or Surgical surgical emphysema often occurs in the chest wall secondary to a malpositioned chest tube. This is not a life threatening complication and will resolve given time. Clinically may be perceived as crepitus of the soft tissues on the affected side. It is also known as surgical emphysema due to the dissection of the air into the deep soft tissues and intramuscular planes. In this case, the underlying pulmonary pathology is that of a ruptured (complicated) cyst from a pulmonary hydatid infection. This is the second most common site of hydatid disease after the liver (hepatic hydatid cyst), and may infect the lungs through either transdiaphragmatic or haematogenous spread. Concurrent infection in both the liver and the lungs however, is rare. In this case, the liver is visualized and has normal parenchyma. These hydatid cysts can grow very large and can be uni or multiloculated. They can also have odd shapes and rupture (as in this case) due to pressures from adjacent broncho-vascular structures, as well as the continuous production of hydatid fluid and increase in intracystic pressure. The imaging characteristics of these cysts include various radiological signage devised to help with its diagnosis, including the Cumbo/ Onion peel/ Double arch sign seen here. It is worth noting that patients with underlying pleural pathology (such as in this case where the adjacent hydatid cyst causes pleural reaction) may be prone to malpositioning of a chest tube due to the chronic pleural inflammation. - <p>Subcutaneous or Surgical emphysema often occurs in the chest wall secondary to a malpositioned chest tube. This is not a life threatening complication and will resolve given time. Clinically may be perceived as crepitus of the soft tissues on the affected side. It is also known as surgical emphysema due to the dissection of the air into the deep soft tissues and intramuscular planes.</p><p>In this case, the underlying pulmonary pathology is that of a ruptured (complicated) cyst from a pulmonary hydatid infection. This is the second most common site of hydatid disease after the liver (hepatic hydatid cyst), and may infect the lungs through either transdiaphragmatic or haematogenous spread. Concurrent infection in both the liver and the lungs however, is rare. In this case, the liver is visualized and has normal parenchyma. </p><p>These hydatid cysts can grow very large and can be uni or multiloculated. They can also have odd shapes and rupture (as in this case) due to pressures from adjacent broncho-vascular structures, as well as the continuous production of hydatid fluid and increase in intracystic pressure. The imaging characteristics of these cysts include various radiological signage devised to help with its diagnosis, including the Cumbo/ Onion peel/ Double arch sign seen here.</p><p>It is worth noting that patients with underlying pleural pathology (such as in this case where the adjacent hydatid cyst causes pleural reaction) may be prone to malpositioning of a chest tube due to the chronic pleural inflammation.</p><p> </p><p> </p> + <p>Subcutaneous or surgical emphysema often occurs in the chest wall secondary to a malpositioned chest tube. This is not a life threatening complication and will resolve given time. Clinically may be perceived as crepitus of the soft tissues on the affected side. It is also known as surgical emphysema due to the dissection of the air into the deep soft tissues and intramuscular planes.</p><p>In this case, the underlying pulmonary pathology is that of a ruptured (complicated) cyst from a pulmonary hydatid infection. This is the second most common site of hydatid disease after the liver (hepatic hydatid cyst), and may infect the lungs through either transdiaphragmatic or haematogenous spread. Concurrent infection in both the liver and the lungs however, is rare. In this case, the liver is visualized and has normal parenchyma. </p><p>These hydatid cysts can grow very large and can be uni or multiloculated. They can also have odd shapes and rupture (as in this case) due to pressures from adjacent broncho-vascular structures, as well as the continuous production of hydatid fluid and increase in intracystic pressure. The imaging characteristics of these cysts include various radiological signage devised to help with its diagnosis, including the Cumbo/ Onion peel/ Double arch sign seen here.</p><p>It is worth noting that patients with underlying pleural pathology (such as in this case where the adjacent hydatid cyst causes pleural reaction) may be prone to malpositioning of a chest tube due to the chronic pleural inflammation.</p> References changed: 1. Al Mosa AFH, Ishaq M, Ahmed MHM. Unusual Malposition of a Chest Tube, Intrathoracic but Extrapleural. (2018) Case reports in radiology. 2018: 8129341. <a href="https://doi.org/10.1155/2018/8129341">doi:10.1155/2018/8129341</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/30174979">Pubmed</a> <span class="ref_v4"></span> 2. R. Morar, C. Feldman. Pulmonary echinococcosis. (2003) European Respiratory Journal. 21 (6): 1069. <a href="https://doi.org/10.1183/09031936.03.00108403">doi:10.1183/09031936.03.00108403</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/12797504">Pubmed</a> <span class="ref_v4"></span> 3. Peter M. Jones, Robert D. Hewer, Hugh D. Wolfenden, Paul S. Thomas. Subcutaneous emphysema associated with chest tube drainage. (2001) Respirology. 6 (2): 87. <a href="https://doi.org/10.1046/j.1440-1843.2001.00317.x">doi:10.1046/j.1440-1843.2001.00317.x</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/11422886">Pubmed</a> <span class="ref_v4"></span> 4. Sarkar M, Pathania R, Jhobta A, Thakur BR, Chopra R. Cystic pulmonary hydatidosis. (2016) Lung India : official organ of Indian Chest Society. 33 (2): 179-91. <a href="https://doi.org/10.4103/0970-2113.177449">doi:10.4103/0970-2113.177449</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/27051107">Pubmed</a> <span class="ref_v4"></span> Al Mosa AFH, Ishaq M, Ahmed MHM. Unusual Malposition of a Chest Tube, Intrathoracic but Extrapleural. (2018) Case reports in radiology. 2018: 8129341. <a href="https://doi.org/10.1155/2018/8129341">doi:10.1155/2018/8129341</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/30174979">Pubmed</a> <span class="ref_v4"></span> R. Morar, C. Feldman. Pulmonary echinococcosis. (2003) European Respiratory Journal. 21 (6): 1069. <a href="https://doi.org/10.1183/09031936.03.00108403">doi:10.1183/09031936.03.00108403</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/12797504">Pubmed</a> <span class="ref_v4"></span> Peter M. Jones, Robert D. Hewer, Hugh D. Wolfenden, Paul S. Thomas. Subcutaneous emphysema associated with chest tube drainage. (2001) Respirology. 6 (2): 87. <a href="https://doi.org/10.1046/j.1440-1843.2001.00317.x">doi:10.1046/j.1440-1843.2001.00317.x</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/11422886">Pubmed</a> <span class="ref_v4"></span> Sarkar M, Pathania R, Jhobta A, Thakur BR, Chopra R. Cystic pulmonary hydatidosis. (2016) Lung India : official organ of Indian Chest Society. 33 (2): 179-91. <a href="https://doi.org/10.4103/0970-2113.177449">doi:10.4103/0970-2113.177449</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/27051107">Pubmed</a> <span class="ref_v4"></span> Add cases to playlists Share cases with the diagnosis hidden Use images in presentations Use them in multiple choice question Creating your own cases is easy. Case creation learning pathway
https://radiopaedia.org/cases/ruptured-pulmonary-hydatid-cyst-1/changesets/250519/edits?from_revision_history=true&lang=gb
(PDF) The Digital Divide Among College Students: Lessons Learned From the COVID-19 Emergency Transition PDF | This report examines the meaning and impact of the digital divide-the gap between those who can and cannot access the Internet-on college students... | Find, read and cite all the research you need on ResearchGate Research The Digital Divide Among College Students: Lessons Learned From the COVID-19 Emergency Transition Abstract and Figures This report examines the meaning and impact of the digital divide-the gap between those who can and cannot access the Internet-on college students during the COVID-19 emergency shift to remote learning. The assessment is based on several national surveys conducted in the spring or summer of 2020, as well as results from a large-scale survey the authors conducted at Indiana University and The Ohio State University during the same time period. Key findings of the report are previewed below. Prevalence of Inadequate Technology Approximately 16%-19% of college students reported technology barriers (inadequate computer hardware or Internet connection) that inhibited participation in online learning. Higher rates of technology inadequacy were observed among lower-income students (20%-30%) than higher-income students (10%-12%); Black (17%-29%) and Hispanic (23%-28%) students relative to White students (12%-17%); and students living in a rural area (14%-25%) compared to those living in a suburban (16%) or urban area (16%-20%). Inadequate Technology and Student Success Compared to students with robust Internet access and reliable devices, college students with inadequate technology struggled more with the transition to remote learning. For example, they reported a sharper increase in difficulty meeting deadlines and a steeper decline in their sense of success as college students. In addition, regardless of their academic or demographic background, students with inadequate technology were substantially more likely to opt for a "Pass / No-Pass" grade in spring 2020, which signaled that students were struggling with their online coursework. Institutional and State Approaches In order to support students with inadequate technology during the emergency transition, most colleges across the U.S. loaned laptops or hotspots to students who needed them or negotiated with vendors to provide free or discounted equipment. At the same time, states leveraged recent legislation or passed new legislation to help bridge the digital divide, particularly in terms of broadband access. Four types of recent broadband policy are evident in the Midwest: streamlining bureaucratic and regulatory models, supporting community and private sector engagement and training, leveraging state resources, and making other financial investments in broadband access. Percentage of Indiana-Ohio Respondents with Inadequate Technology by Race/Ethnicity, Residence, Class Standing, and Institutional Type … Figures - uploaded by The Digital Divide Among Coll ege Students: L essons L earned F r om the CO VID- 19 E merg ency T ransition The Ohio State University Benjamin A . Motz Indiana University Marcos D. Rivera The Ohio State University Andrew Heckler The Ohio State University Joshua D. Quick Indiana University Elizabeth A . Hance The Ohio State University Caroline Karwisch The Ohio State University EDITOR Aaron Horn Associate Vice President of Research, MHEC [email protected] ( * ) Recommended Citation Jaggars, S. S., Motz, B. A., Rivera, M. D ., Heckler , A., Quick, J.D., Hance, E. A., & Karwischa, C. (2021). The Digital Divide Among Colleg e Students: Lessons Learned F rom the 1 The Digital Divide Among College Students This report examines the meaning and impact of the digital divide — the gap between those who can and cannot access the Internet — on college students during the COVID- 19 emergency shift to remote learning. The assessment is based on several national surveys conducted in the spring or summer of 2020, as well as results from a large-scale survey the authors conducted at Indiana University and The Ohio State University during the same time period. Key findings of the report are previewed below. Prevalence of Inadequate T echnolog y Approximately 16% - 19% of college students reported technology barriers (inadequate computer hardware or Internet connection) that inhibited participation in online learning. Higher rates of technology inadequacy were observed among lower-income students (20%-30%) than higher-income students (10%-12%); Black (17%-29%) and Hispanic (23%-28%) students relative to White students (12%-17%); and students living in a rural area (14%- 25%) compared to those living in a suburban (16%) or urban area (16%-20%). Inadequate T echnology and Student Success Compared to students with robust Internet access and reliable devices, college students with inadequate technology struggled more with the transition to remot e learning. For example, they reported a sharper increase in difficulty meeting deadlines and a steeper decline in their sense of success as college students. In addition, regardless of their academic or demographic background, students with inadequate technology were substantially more likely to opt for a “Pass / No-P ass” grade in spring 2020, which signaled that students were struggling with their online coursework. Institutional and State Approaches In order to support students with inadequate technology during the emergency transition, most colleges across the U.S. loaned laptops or hotspots to students who needed them or negotiated with vendors to provide fr ee or discounted equipment. At the same time, states lever aged recent legislation or passed new legislation to help bridge the digital divide, particularly in terms of broadband access. Four types of recent broadband policy are e vident in the Midwest: streamlining bureaucratic and regulatory models, supporting community and private sector engagement and training, leveraging stat e resources, and making other financial investments in broadband access. EXECUTIVE SUMMARY POLICY OPTIONS u Support community and private sector engagement and training, by bolstering the efforts of Community Anchor Institutions and creating broadband certifications and trainings for communities. u Leverage state administration t o strategically allocate indirect feder al funding to support technology access and to streamline, coordinate, and support the administration of broadband progr ams through a centralized state office. u Invest directly in broadband through programs that inc entivize or match private and local investment. u In broadband expansion efforts, place a particular emphasis on wireless broadband in order to maximize ac cess for students who rely on portable wireless devices. u Incentivize or support colleges in efforts to provide tablets, lapt ops, and wireless access to students who would otherwise have inadequate technology . 2 The Digital Divide Among College Students The Digital Divide Among Coll ege Students: Lessons L earned Fr om the COVID- 19 Emergency T ransition D uring spring 2020, the entirety of U.S. higher education moved online in response to the COVID-19 pandemic. V er y quickly, c olleges learned that the “digital divide” is a real challenge for their students. The digital divide refers to the gap between those who can readily access and use the Internet versus those who cannot. In particular, about 2 7% of U.S. adults do not have broadband Internet at home and thus may find it difficult to conduct critical activities online, such as shopping, seeking employment, or doing academic work (Pew Research Center , 2019). College students might be assumed to be on the “good side” of the digital divide and to enjoy seamless technology access; however , the emergency transition to online learning quickly called that assumption into question. This report first provides background on the extent of the digital divide within the U.S. in general, and within American colleges and universities in specific, prior to the emergency shift to online learning in spring 2020. T o understand the meaning and impact of the digital divide on college students during the emergency shift, results are presented from sever al national surveys conducted in the spring or summer of 2020, as well as a large-scale survey at Indiana University and The Ohio State University. Using these national and Midw estern- specific data, digital inequities are linked with college students’ academic experiences and outcomes during the COVID- 19 period. Finally, an analysis of recent state legislation in the Midwest highlights key policy approaches to bridge the digital divide for college students and their communities. BACKGROUND ON THE U.S. DIGITAL DIVIDE The digital divide is defined as the “gap between individuals, households, businesses and geographic areas at different socio-economic levels with regard to both their opportunities to access information and communication technologies (ICT s) and to their use of the Internet for a wide variety of activities” (OECD, 2006). An important indicator of the digital divide is the extent to which individuals from different income, r acial/ ethnic, and geographical groups lack broadband internet at home. The higher speeds of a broadband connection do not just provide greater convenienc e and efficiency relative to a dial-up connection; many data-intensive applications require broadband capability to function properly , such as videoconferencing and live streaming. Nationally , survey data collected in 2019 indicates that 27 percent of adults lack a broadband connection at home (Pew Research Center , 2019). Moreover , as F igure 1 illustrates, lo w-income, underrepresented minority, and rur al populations in the United States are most likely to lack at-home broadband Internet. For example, only 63% of rural r esidents have broadband, in comparison to 79% of suburban residents. In order to use the Internet effectively , individuals need not only robust Internet access but also devices which can connect to the Internet and efficiently manage the task at hand (Fernandez et al., 2019; OECD, 2006). Howev er, 17% of U.S. adults are “cellphone dependent”: they rely on a mobile phone for activities such as shopping, finding health information, seeking employment, or doing academic work. Users may turn to cellular data when they lack reliable high- speed Internet or do not have a reliable larger-format device such as a tablet, laptop, or desktop computer (Fernandez et al., 2019; Perrin, 2019; Perrin & T urner, 2019). As Figure 2 shows, cellphone dependency levels are highest among low-income, Black or Hispanic, and rural populations. While smartphones are helpful with basic online tasks, they are inadequate for complex tasks such as completing homework (Fernandez et al., 2019). For example, in a large-scale study of 8th to 11th graders in Michigan, cellphone dependency substantially hindered students’ academic progress and success (Hampton et al., 2020). 1 When a cellphone is insufficient, users without at-home Internet turn to the homes of friends and family, coff ee shops and restaurants, libraries, and community center s (Perrin & Turner , 2019). However, in c ommunities without widespread broadband infrastructure, public and private alternatives to at-home access are scarce (Hampton et al., 2020). 2 Rural residents may be most likely to suffer from a conv ergence of limited at-home broadband, spotty cell phone cover age, and lack of nearby alternative access locations. Indeed, 24% of rural adults say access to high-speed Internet is a “major problem” in their local community , compared to 13% of urban and 9% of suburban adults (Anderson, 2018). 3 The Digital Divide Among College Students Source: Pew Research Center . (2019). Internet/Broadband Fact Sheet. I FIGURE 1. Percentage of U.S. Adults Who are Home Broadband Users, by Family Income, R ace/Ethnicity, and Residential Setting 92% 87% 72% 56% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% By income $75K+ $50K-$75K $30K-$50K < $30K 79% 66% 61% By race White Black Hispanic 79% 75% 63% By residential setting Suburban Urban Rural Source: Pew Research Center . (2019). Internet/Broadband Fact Sheet. I FIGURE 2. Percentage of Cellphone-Dependent Adults in the U.S. by Family Income, Race/Ethnicity, and Residential Setting 6% 10% 20% 26% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% By income $75K+ $50K-$75K $30K-$50K < $30K 12% 23% 25% By race White Black Hispanic 13% 17% 20% By residential setting Suburban Urban Rural 4 The Digital Divide Among College Students DIGITAL DIVIDES IN COLLEGE Although the overall U.S. digital divide was clearly observable and widely discussed prior to COVID- 19, college students were rarely mentioned in the digital divide research because most colleges offer robust Internet access acr oss campus libraries, classrooms, and residence halls, and many off-campus students live in highly-wired neighborhoods near campus (Galanek et al., 2018; Gierdowski, 2019). For students who cannot afford well-performing laptops or desktops, campus computer labs and libraries also provide free ac cess to these devices (e.g., see Regalado & Smale, 2014). Despite these advantages, some college students remained “underconnected. ” For example, among college students who commuted in 2018, 28% reported having subpar Internet access (Galanek et al., 2018). Other studies found that some college students had difficulty paying their Internet bill on time, struggled with data caps or outdated connection hardware, or could not complete academic work due t o computer performance issues (Gonzalez et al., 2020; Rideout & Katz, 2016). These studies suggested that having reliable high-speed Internet and a well-performing tablet, laptop, or desktop is critical to college students’ academic success (Gonzalez et al., 2020; Reisdorf et al., 2020). For example, a study of students at a Midwestern university found that, after controlling for socioeconomic status and other demographic factors, students with more poorly-functioning laptops had lower GP As (Gonzalez et al., 2020). The potential for growing digital divides in college became evident as institutions responded to the COVID- 19 pandemic. In March 2020, colleges across the country pivoted to r emote learning for students in traditionally face-to-face cour ses. In a nationally-representative survey of undergraduate students who experienced the online transition (Means & Neisler , 2020), students described several features of their online courses which require robust Internet access, including live discussion sessions (67%), recorded lectures (65%), frequent quizzes (64%), live lectures (60%), pre-recorded videos (55%), and live breakout groups (25%). At the same time, students lost access to several key sourc es of broadband Internet and desktop computing, as campus libraries, computer labs, and residence halls were emptied, and coffee shops, public libraries, and community centers closed their doors. To under stand the extent and impact of the digital divide on college students during this period, multi-institutional surveys of colleges or their students are reviewed and discussed below. T o provide a lens specific to the Midwest, results are also presented from a survey of over 9 ,500 undergraduates and over 2,300 instructors across all 14 campuses of Indiana University and The Ohio State University (the “Indiana-Ohio” survey), which was conducted from April to June 2020. 3 T aken together , the survey results indicate that many students had inadequate technology – including poor Internet access or lack of access to a device necessary to complet e academic work online – which thwarted students’ academic experience and success. T echnology use statistics are disaggregated by race/ ethnicity, family income, and residential setting when possible. Prevalence of Inadequate T echnolog y National and Midwestern surveys of technology use among college students suggest that inadequate technology has been a common barrier during the COVID- 19 pandemic. In May 2020, the Congressionally-authorized non-profit organization Digital Promise conducted a nationwide survey of around a thousand undergraduates, including both two- and four-year colleg e students (Means & Neisler , 2020). Digital Promise found that 16% of undergraduates had Internet connectivity issues which “often” or “very often” hindered their ability to participate in coursework. These rates were higher among Black and Hispanic students (17% and 23%, respectively) than among White students (12%). Connectivity problems were also higher among students from households earning under $50,000 (20%) than from households earning over $100,000 (12%) but did not differ statistically between students from suburban/ urban communities (16%) and those from rural communities (14%). In terms of computer hardware, nearly 80 percent of students in the Digital Promise study reported using a laptop for remote learning during the pandemic, whereas other students relied on a desktop computer (15%), a tablet (3%), or a smartphone (2%). About 8% of students reported experiencing serious hardware or software problems that interfered with their coursework often or very often, though these rates were higher among Black and Hispanic students (15% and 10%, respectively) than among White students (6%); and they were higher among students from households earning under $50,000 (11%) than among students from households earning over $100,000 (4%) (Means & Neisler , 2020). 5 The Digital Divide Among College Students The Indiana-Ohio survey found similar levels of technology inadequacy across students. Approximately 19% of undergraduates reported having inadequate technology of some type for full participation in online learning, with students reporting inadequate Internet access (11%), inadequate hardware (8%), or primary reliance on a cellphone (8%). 4 Similar to the Digital Promise findings, the Indiana-Ohio survey found that students from underrepresented racial and ethnic groups were substantially more likely than White students to deal with inadequate technology (see T able 1). For example, the rate of technol ogy inadequacy was around ten percentage points higher among Black students (28%) than among White students (18%). 5 Levels of inadequate technology were also higher among students from small-town or rural areas (21%) in comparison to those from suburban areas (16%). In addition to technology gaps by race/ ethnicity and residential setting, the Indiana-Ohio survey revealed digital divides by academic class and institutional type. T able 1 shows that freshmen and sophomores were more likely to experience inadequate technology than upperclassmen. 6 Regarding institutional type, the results indicated that technology barriers were more common at regional or comprehensive universities, which tend to serve more students from disadvantaged backgrounds than do flagship research universities. I TABLE 1. Percentage of Indiana- Ohio Respondents with Inadequate Techno logy by Race/Ethnicity, Residence, Cass Standing, and Institutional Type Ohio State University Indiana University Combined All Students 20% 18% 19% Race / Ethnicity African-American 29% 28% 28% Asian-American 20% 17% 19% Hispanic 28% 24% 25% White 19% 17% 18% Other 15% 15% 15% Residential Setting Urban 20% 16% 18% Suburban 16% 16% 16% Small Town/Rur al 25% 20% 21% Class Standing Freshman 23% 25% 24% Sophomore 23% 21% 21% Junior 20% 17% 18% Senior 18% 15% 16% Type of Campus Flagship 19% 17% 18% Regional 26% 21% 22% Source: Authors’ analysis of Indiana-Ohio COVID- 19 survey data. Table excludes international students; the cat egory “Other” combines domestic U.S. race/ ethnicity groups which had a low number of responses to the survey, including Native American students and those who identified with Two or Mor e Races. 6 The Digital Divide Among College Students Inadequate T echnology and Student Success Several surveys fielded during the pandemic rev ealed that many students experienced multiple academic challenges while engaging in online learning. For example, a survey by the SERU university consortium, conducted from May to July 2020 with over 30,000 undergraduates across nine public resear ch universities (Soria et al., 2020; Soria & Horgos, 2020), found that 76% lacked motivation for online learning (see T able 2). More than half of students also reported a lack of interaction with other students, the inability to learn effectively , and a lack of access to an appropriate study space as obstacles to success. SERU did not report these data by race or residential setting; however , they did divide respondents into five categories of social class and found that low-income students were significantly more likely than higher-income students to lack necessary technology (30% versus 10%) (Soria & Horgos, 2020). I TABLE 2. Obs tacles to Online Learning during the COV ID- 19 Pandemic Among Undergraduate Students at Public Research Universities in the U.S. Type of Obstacle Percentage of Students who Experienced Obstacle Lack of motivation for online learning 76% Lack of interaction/ communication with other students 64% Inability to learn effectively in an online format 61% Distracting home environment or lack of access to an appropriat e study space 56% Course content that is not appropriate for online learning 43% Lack of clear expectations for online learning from instructor(s) 39% Lack of access to your instructor(s) 28% Lack of access to academic advising 19% Inability to attend classes at their scheduled online meeting time 18% Inability to access learning support services 16% Lack of access to technology necessary for online learning 16% Lack of familiarity with technical tools necessary for online learning 14% Source: Soria et al. (2020) The obstacles to remote learning f or undergraduate, graduate, and professional students. 7 The Digital Divide Among College Students T echnology Adequacy Strongly Agree or Agree Neither Agree nor Disagree Strongly Disagree or Disagree 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Adequate Inadequate I found my coursew ork more challenging Adequate Inadequate It took more effort to complete my coursework Adequate Inadequate It was harder to meet deadlines Adequate Inadequate I felt successful as a college student Source: Authors’ analysis of Indiana-Ohio COVID- 19 survey data. I FIGURE 3. Reationship between T echnology Adequacy and Student Perceptions of Success Among students without adequate technology, the academic experience was likely even more problematic. As noted earlier, r esearch prior to COVID- 19 suggested that inadequate technology is negatively associated with overall college perf ormance, even when controlling for socioeconomic background (Reisdorf et al., 2020). Across the multi-institutional and national surveys conducted during the COVID- 19 emergency transition, only the Indiana-Ohio survey examined how technology access influenced students’ academic experience and success during this period. 7 As Figure 3 shows, Indiana-Ohio survey respondents with inadequate technology were more likely than their peers t o agree that after the switch to online learning, coursew ork became more challenging, took more effort, and that they had a harder time meeting deadlines. Moreover , only 28% of students without adequate t echnology felt successful as a college student, compared to 46% of students with adequate technology. 8 8 The Digital Divide Among College Students During the COVID- 19 crisis, students dealt with a wide variety of financial and personal challenges; having inadequate technology seemed to exacerbate the impact of those challenges on students’ academic success. For example, a student in the Indiana-Ohio survey commented: I think everyone, instructors, university , students had the rug pulled out from under them, but I couldn’t devote the focus to schoolwork bec ause half my brain was busy having fits wondering if I can afford to keep living. I used the food banks and got some resources without spending money , but it didn’t feel like enough especially since my internet plans and configurations depended on using/ being on campus…. There was so much insecurity and instability during this time. My grades and schoolwork reflect that. While students’ subjective assessment of their success is important, more objective measures are also critical to inform policy and practice. In order to understand whether technology inadequacy interfered with students’ academic performance, an analysis was conducted to determine which students at Ohio State chose to switch to a “Pass / No P ass” (P/NP) gr ading option for their Spring 2020 courses. 9 Students who opt for a P /NP grading option may do so for various reasons, but poor course performance was the most common reason in Spring 2020. 10 The analysis showed that Ohio State students with inadequate technology were more likely to switch to P /NP for at least one course: 43% of students with inadequate technology did so, compared to 34% of students with acceptable technology (a difference of 9 per centage points). After controlling for the student’s prior GP A as well as the background variables listed in T able 1, a difference of 7 percentage points persisted across all demographic gr oups. 11 Yet because A frican-American and Hispanic students were disproportionately likely to face inadequate technology , they were also more likely to switch t o P /NP: overall, 46% of African-American students and 39% of Hispanic students switched to P /NP in Spring 2020, compared with 35% of White students. (See the Appendix for more detailed results.) THE IMP ACT OF INSTITUTIONAL TECHNOLOGY PROGRAMS College and university administrator s are well aware that students have encountered technology barriers during the pandemic. In April 2020, Educause – a non-profit association of colleges and companies focused on higher education information technology – conducted a poll of 267 two-y ear and four-year colleges in order to understand whether students had the technology necessary for remote learning. Across colleges, 36% of administrator s reported that students were having “moderate or extreme difficulty” with Int ernet access, and 26% reported that students had the same level of difficulty with equipment and devices. In response, 81% of colleges were loaning laptops to students, 4 7% were loaning hotpots, and 28% were negotiating with vendors to pro vide free or discounted equipment to students (Grajek, 2020). Such lending programs tend to operat e on a small scale, as it is time- and cost-intensive to identify individual students who are truly in need, and to procure and deliver equipment to them. Furthermore, little research exists regarding whether investments in a large-scale technology progr am would have a significant impact on the various digital divides in college. .12 Data from the Ohio-Indiana study were thus analyzed to help address this issue. In contrast to Indiana University , Ohio State already had a large-scale technology pro vision program in place: since 2018, Ohio State has pro vided iPad Pros to every new first-year student. 13 Thus, one might expect Ohio State students to report substantially lower levels of technology inadequacy, compar ed to similar students at Indiana University. Indeed, in their open-ended comments on the survey, many Ohio State students indicat ed that the university-provided iPad was their primary devic e for completing coursework. One student commented: The university iPad was much needed as it is my only computer-like device available right now with libraries closed and I am living at home with no computer access and no laptop. Its tools were therefore vital for me to be abl e to perform coursework, and very helpful in general. While student comments provided important qualitative evidence supporting Ohio State’s technology program, a quantitative analysis of rates of technology inadequacy between Ohio State and Indiana University revealed mixed results. Specifically, a c omparison of Ohio State and Indiana University students found no differences in rat es of technology inadequacy, y et Ohio State students were significantly more likely to “strongly agree” that their device was adequate (67% vs. 57%, respectively). 14 The absence of a larger difference in the rate of technol ogy inadequacy may 9 The Digital Divide Among College Students be due to the fact that Ohio State’s iPads are WiFi only. F or example, one student commented: There is no internet provider where I live who services the area, so my family couldn’t get internet connection even if we could afford it. A hotspot provided either in the software of the iPad or just a hotspot device would have been extremely helpful to allow me to work on my assignments in my home. In general, for students who returned home to a residence without broadband wireless, the WiFi-only iPad would not be very useful for academic work. 15 STA TE POLICY APPRO ACHES IN THE MIDWEST When the COVID- 19 pandemic struck, several Midwestern states had already taken steps to expand broadband Internet access, and the pandemic has further heightened the need to move forward with those legislative efforts. Over the past two years, Midwestern states’ policies regar ding broadband have clustered into four key ar eas: streamlining bureaucratic and regulatory models, supporting community and private sector engagement and training, lever aging state resources, and making other financial investments in broadband access. Below we provide an ov erview of each area, along with illustrative examples. Streamlining Bureaucratic and Reguator y Models Across the country, regulat ory frameworks for telecommunications and electricity were devel oped prior to the advent of broadband, and these frameworks may need updates to reflect the critical role of broadband in daily life. Several Midwestern states hav e recently passed legislation to remove barriers for collabor ation with telecommunications companies or broadband service providers to construct or improve telecommunications facilities (Cash, 2019). These la ws recognize the importance of leveraging electric c orporations and incentivizing electric cooperatives to work with the Stat e to improve broadband. For e xample, Missouri’s Electrical Corporation Broadband Authorization Act authorizes an electrical corporation to own, construct, install, maintain, repair, and r eplace broadband infrastructure, and to enter int o contracts with broadband affiliates with shortened approval processes. The Act also reduces administrative barrier s to expedite expansions of broadband access (Morton, 2020). Several states in the Midwest have also pr oposed legislation to limit contract awards or procur ements to service providers which adhere to principles of net neutrality (Morton, 2019). 16 As part of their regulatory reforms, states have put a particular emphasis on wireless broadband. For example, Wisconsin passed legislation to facilitate the deployment of wireless equipment by wireless service companies, 17 and Nebraska gave wireless providers public rights-of-wa y access to provide services. 18 Supporting Community and Private Sector Engagement and T raining In many underserved areas, Community Anchor Institutions (CAIs) play a key role in broadband adoption and education. According to the Feder al Communications Commission (2011), CAIs are entities such as government offices, schools, colleg es, or libraries that “provide outreach, access, equipment, and support services to facilitate greater use of broadband service by vulnerable populations, including low-income, the unemployed, and the aged” (p. 17700). T argeted legislation can help bolster CAI efforts. For example, Michigan’s MERIT Network is a non-profit organization governed by Michigan’s public universities that operates almost 4,000 miles of fiber-optic infrastructure in the state. The state’s Broadband Technol ogy Opportunities Program provided funding for MERIT to extend critical broadband service to community anchor institutions in rural and underserved communities (Sallet, 2019). In addition to partnerships with CAIs, states have supported community efforts through the creation of broadband certifications and trainings. For example, Indiana now offer s Community Broadband Certifications, which send a signal to stakeholders that the community is ready for infrastructur e investment (Office of Lieutenant Governor Suzanne Crouch, 2020). However , the onus is on the community to seek out and acquire the investment. CAIs can help communities assess the costs and benefits of broadband investment and support communities through the planning process. For example, the University of Missouri has developed a toolkit for community broadband assessment and planning and is currently piloting its implementation with Bollinger County (Denkler et al., 2020). 10 The Digital Divide Among College Students Leveraging Federal F unding and State Administration During the COVID- 19 crisis, states used CARES Act funds, other COVID- 19 relief funds, and other federal funding to provide devices and hot spots to students without access. For example, North Dakota allocated 10% of its CARES Act Elementary and Secondary School Emergency Relief Fund to K-12 schools that needed support with technol ogical capacity, remote learning, and other emergency needs (North Dakota Department of Public Instruction, 2020). Ohio allocated $50 million of the state CARES Act funding to provide hotspots and Internet-enabled devices to K -12 students (Ohio Department of Education, 2020). While states have been creative with the ways they navigate restrictions on federal funding to narro w the digital divide during COVID- 19, many cities, colleges, and companies have implemented their own strat egies to expand broadband access. However , such efforts were not always coordinated with each other or with the state’s larger strategy. C onsequently, some states creat ed a centralized state office to streamline, coordinate, and support the administration of state and local regulation, programs, and funding to expand broadband (Morton, 2019, 2020; Stauffer et al., 2020). For example, in 2019 Illinois created the Office of Broadband within the state’s Department of Commerce and Economic Opportunity, which implements the Connect Illinois broadband infrastructure grant progr am and related programing. Such offices provide a valuable opportunity to create a statewide vision for broadband and to coordinat e the implementation of that vision through multiple public and private entities within the state. Making Direct Investments States are beginning to invest directly in broadband through grant programs, tax incentives, and user subsidies. F or example, Minnesota’s Border-to-Border Broadband Grant Program provides resourc es to motivate new and existing providers to invest in building br oadband infrastructure in unserved and underserved parts of the state. The grant provides up to 50% of a project’s infrastructure costs. Thus far it has connected 3,400 households, 5,200 businesses, and 300 community institutions across the state to ensure equitable access (Minnesota Office of Broadband Development, 2018, 2020). Some states are also providing tax incentives f or broadband service providers and subsidies for low-income househol ds. 19 For example, Wisconsin exempt ed from the telephone company tax any property used to provide br oadband service to a rural or underserved area. 20 Illinois is working to pass the Low-Income Broadband Assistance Program, which woul d directly pay a portion of the monthly broadband bill for low- income households. 21 CONCLUSION Whether classes are interrupted by a pandemic, a climate event, or other public emergency, the ability of students to continue their studies and maintain academic progress depends on access to computer hardware and robust Int ernet access. However , in colleges across the country, including in the Midwest, approximately 16% - 19% of students lack the technology necessary to fully participate in online learning. Further, this report documented significant digital divides by family income, race and ethnicity , and residential setting. Higher rates of technology inadequacy during the CO VID-19 pandemic were observed among lower-income students (20%-30%) than higher-income students (10%-12%); Black (17%-29%) and Hispanic (23%-28%) students relative to White students (12%-17%); and students living in a rural area (14%- 25%) compared to those living in a suburban (16%) or urban area (16%-20%). Regardless of demographic or academic background, technology inadequacy creates an academic struggle for students and threatens their academic success. As a result, current continuity planning may have the unintended consequence of magnifying inequities among students who are already marginalized. In order to strengthen academic continuity planning, states and institutions can work together to ensure that all students have access to adequate hardware and br oadband Internet. Institutions might consider putting an emphasis on the provision of large-format, WiFi-enabled mobile devices (such as iPads or Surface tablets) which can remain with each student regardless of where they may find themselves in an emergency. For e xample, colleges might consider including this hardware as part of the standard financial aid package for students who receive need-based institutional aid. Colleges should also maintain a formal program for short- and long- term loans of tablets, laptops, and wireless hotspots for students who have a demonstrated need for these devices. In turn, states would better serve all students by reviewing 11 The Digital Divide Among College Students their current broadband policies and legislation with an eye to equity to ensure that policies are expanding broadband access for rural, African-American, Hispanic, and other underserved populations. For example, states might consider investing in ubiquitous wireless broadband that would all ow students to use mobile devices effectively from any l ocation. Many colleges have already work ed to make this vision a reality on and around their own campuses and are well- positioned to partner with community and state leaders to craft larger-scale implementations, such as citywide wireless broadband. Based on an overview of legislation in the Midwest, several state policy options are worth considering: J Streamline bureaucratic and regulatory models for telecommunications, including removing barriers for collaboration with broadband service providers. J Support community and private sector engagement and training, by bolstering the efforts of Community Anchor Institutions and creating broadband certifications and trainings for communities. J Leverage state administration t o strategically allocate indirect federal funding to support technology access and to streamline, coordinate, and support the administration of broadband programs through a centralized stat e office. J Invest directly in broadband through programs that incentivize or match private and local investment. J In broadband expansion efforts, place a particular emphasis on wireless broadband to minimize infrastructure costs. J Incentivize or support colleges in efforts to provide tablets, laptops, and wireless access to students who would otherwise have inadequate technology . 12 The Digital Divide Among College Students REFERENCES Anderson, M. (2018). About a quarter of rural Americans say access to high-speed internet is a major problem. Washington, D.C.: P ew Research Center . Cash, C. (2019). New State Laws Clear Hurdles for Co-ops That Choose to Pursue Broadband . National Rural Electric Cooperative Association. https://www.electric. coop/ new-state-laws-clear-hurdles-for-co-ops-that-choose-to- pursue-broadband/ Dickert-Conlin, S., Fitzpatrick, K., & Hanson, A. (2005). Utilization of income tax credits by low-income individuals. National Tax Journal, 58 (4), 7 43 – 785. Denkler, S., Luppino , T ., Gupta, L., Shannon, K., Boots. B., McCarty, M., Canfield, C., & Prewitt, W. (2020). R eport of a June 1, 2020 workshop: Bringing broadband to a Missouri community. Columbia, MO: Missouri Broadband R esource Rail, University of Missouri System. Federal Communications Commission . (2011). 11- 161. (pp. 17700). http://fjallfoss.fcc.gov /edocs_public/attachmatch/FCC -11- 161A 1_Rcd.pdf Fernandez, L., Reisdorf, B. C., & Dutton, W . H. (2019). Urban Internet myths and realities: A Detroit case study . Information, Communication & Society, online ahead of print, 1 - 22 . Fridley , D., & Rogers-Adkinson, D . (2015). Implementing a one-to-one technology initiative in higher education. Administrative Issues Journal: Connecting Education, Practice, and Research, 5 (2), 38 - 50. Galanek, J. D., Gierdowski, D. C., & Brooks, D . C. (2018). ECAR study of undergraduate students and information technology, 2018 . Louis ville, CO: ECAR. Gierdowski, D. C. (2019). ECAR Study of undergraduate students and information technology, 20 19. Louisville, CO: ECAR. Gonzales, A. L., Calarco, J.M., and Lynch, T . K. (2020). Technology problems and student achievement gaps: A Validation and extension of the technology maintenance construct. Communication Research, 47 (5), 750 – 770. Grajek, S. (2020). EDUCAUSE COVID- 19 QuickPoll results: Help for students. EDUCAUSE Review , Data Bytes, April 3, 2020. Hampton, K. N., Fernandez, L., Robertson, C. T ., & Bauer, J. M. (2020). Broadband and student performance gaps. East Lansing, MI: James H. and Mary B. Quello Center , Michigan State University. Hargis, J., Cavanaugh, C., Kamali, T ., & Soto, M. (2014). A federal higher education iPad mobile learning initiativ e: Triangulation of data t o determine early effectiveness. Innovative Higher Education, 39 (1), 45-57 . Jaggars, S. S., Rivera, M., Hance, E., & Heckler , A. (2020). COVID- 19 teaching and learning survey. Columbus, OH: The Ohio State University. Kontos, G. (2002). Laptops and university Students: A review and survey. Educational T echnology, 42 (4), 55-59. Lundgren, Z. P . T. (2020). The four horsemen of the Internet apocalypse: The revelation of state net neutrality laws. Georgia Law Review, 54, 977 – 1014. Means, B., and Neisler , J., with Langer Research Associates. (2020). Suddenly online: A national survey of undergraduates during the COVID- 19 pandemic . San Mateo, CA: Digital Promise. Minnesota Office of Broadband Development. (2020). Broadband Grant Program . Minnesota Employment and Economic Development. https://mn.go v/ deed/programs- services/broadband/grant-pr ogram/ Minnesota Office of Broadband Development. (2018). The Minnesota Broadband Model. Minnesota Employment and Economic Development. https://mn.go v/ deed/assets/bbtf- model-infographic_tcm1045-354987 .pdf Morton, H. (2019). Net Neutrality Legislation in States . National Conference of State Legislatures. https://www. ncsl.org/research/telecommunications-and-inf ormation- technology/net-neutr ality-legislation-in-states.aspx 13 The Digital Divide Among College Students Morton, H. (2020). Broadband 2019 Legislation . National Conference of State Legislatures. https://www.ncsl. org/research/telecommunications-and-information- technology/broadband-20 19-legislation.aspx Morton, H. (2020). Broadband 2020 Legislation . National Conference of State Legislatures. https://www.ncsl. org/research/telecommunications-and-information- technology/broadband-2020-l egislation.aspx Motz, B., Jankowski, J., Snapp-Childs, W., & Quick, J. (2020). Going remote: Actionable insights from Indiana University’s transition to remote instruction due to CO VID-19. Bloomington, IN: eLearning Research and Practice Lab, Pervasive T echnology Institute, Indiana University . North Dakota Department of Public Instruction. (2020). LEA Use of Funds . https://www.nd.gov / dpi/sites/www /files/ documents/Covid- 19/ESSER%20LEA%20Use%20of%20 Funds.pdf OECD (2006). Understanding the digital divide. Paris, Fr ance: Organisation for Economic Co-Operation and Development. https://stats.oecd.org/ glossary/ detail.asp?ID=4719 Ohio Department of Education. (2020). $50 million in grant funding available to help students gain internet access . https:// education.ohio.gov /Media/Ed-Connection/ Aug-10- 2020/50-million-in-grant-funding-availabl e-to-help-stu Office of Broadband. (2020). Connect Illinois Broadband Strategic Plan . https://www2.illinois.gov /dceo/ ConnectIllinois/Documents/Broadband%20Strategic%20 Plan%202.5.20.pdf Office of Lieutenant Governor Suzanne Crouch. (2020). Indiana Statewide Broadband Strategic Plan . https://www .in.gov/ indianabroadband/files/indiana-statewide-broadband- strategic-plan-3- 24-2020.pdf Perrin, A. (2019). Digital gap between rural and nonrural America persists. Washington, D. C.: Pew Research Center Perrin, A., & T urner, E. (2019). Smartphones help blacks, Hispanics, bridge some – but not all – digital gaps with whites. Washington, D. C.: Pew Research Center . Pew Charitable T rusts (2020). How states are expanding broadband access: New research identifies tactics for connecting unserved communities. Washington, DC: Author . Pew Research Center (2019). Internet/Br oadband Fact Sheet . https://www.pewresearch.org/internet/fact-sheet/ internet-broadband/ Regalado, M. & Smale, M. A. (2014). Commuter students using technology. New Y ork, NY: City University of New Y ork. Rideout, V. J. & Katz, V .S. (2016). Opportunity for all? Technol ogy and learning in lower-income families. A report of the Families and Media Project . New Y ork, NY: The Joan Ganz Cooney Center at Sesame Workshop. Reisdorf, B. C., T riwibowo, W., & Yankelevich, A. (2020). Laptop or bust: How lack of technology affects student achievement. American Behavioral Scientist, 64 (7), 927 – 949. Sallet, J. (2019). Michigan’s MERIT Network: Connectivity T o and Through Community Anchors. Benton Institute for Broadband & Society . https://www .benton.org/blog/ michigan%E2%80%99s-merit-network-connectivity-and- through-community-anchors SchWeber , C. (2013). Survival lessons: Academic continuity, business continuity, and technology . In P. V an den Bossche, W. H. Gijselaers, & R. G. Milter (Eds.), Facilitating Learning in the 21 st Century: Leading through Technol ogy, Diversity and Authenticity (pp. 151- 163). Dordrecht, Netherlands: Springer, Dordrecht. Soria, K. M., Chirikov, I., & Jones-White, G. (2020, July). The obstacles to remote learning for undergr aduate, graduate, and professional students . Berkeley , CA: Student Experience in the Research University (SERU) Consortium, University of California – Berkeley . https:// cshe.berkeley. edu/seru-covid- survey-reports Soria, K. M., & Horgos, B. (2020, September). Social class differences in students’ experiences during the CO VID-19 pandemic . Berkeley, CA: Student Experienc e in the Research University (SERU) Consortium, University of California – Berkeley. https:// cshe.berkeley.edu/ seru-covid-survey- reports 14 The Digital Divide Among College Students Stauffer, A., de Wit, K., Read, A., & Kitson, D . (2020). How States Are Expanding Broadband Access . The P ew Charitable Trusts. https://www .pewtrusts.org/ en/research-and- analysis/reports/2020 /02/how-states-are-e xpanding- broadband-access Weston, M. E., & Bain, A. (2010). The end of techno-critique: The naked truth about 1:1 laptop initiatives and educational change. Journal of T echnology, Learning, and Assessment, 9 (6), 5 - 25. 15 The Digital Divide Among College Students APPENDIX In order to understand whether technology inadequacy continued to predict P /NP after controlling for academic and demographic background, researchers conducted a l ogistic regression model with Ohio State undergraduate survey respondents, predicting the outcome of “switched to P /NP for at least one course in Spring 2020. ” To be consistent with T able 1, international students were excluded from the model. Results are shown in T able A1. Reference categories represent the modal student: a White, Columbus-campus senior from a suburban area with a GPA of 3.40. Prior GP A is converted to a standardized scale with a standard error of 1 (or 0.56 GPA points). Inter actions between T echnology Inadequacy and other controls were not statistically significant and were dropped from the model. Predicted probabilities wer e calculated using modal values for each control. For exampl e, for the modal student, the model suggests that 34% would switch to P /NP if they had adequate technology, while 41% would switch to P /NP if they were dealing with inadequate technology; this difference of 7 percentage points is r eflected in the column “Change in Probability of P /NP. ” I TABLE A1. Logis tic Regression Predicting P/N P Grades Predictor Logit (S E) Change in Probability of P/N P Inadequate T echnology 0.28 (0.09)*** + 0.07 Ethnicity: Black 0. 13 (0. 17) + 0.03 Ethnicity: Hispanic - 0.01 (0. 17) 0.00 Ethnicity: Asian 0.07 (0. 14) + 0.02 Ethnicity: Other 0.06 (0. 14) + 0.01 Campus: Regional - 0.75 (0. 14)*** - 0.14 Home: Rural / Small T own - 0.02 (0. 10) - 0.01 Home: Urban 0. 19 (0.09) + 0.04 Prior GPA - 0.37 (0.04)*** - 0.08 Rank: Freshman 0.04 (0. 16) + 0.01 Rank: Sophomore 0.06 (0. 10) + 0.01 Rank: Junior 0.08 (0.09) + 0.02 *** p < 0.001 1 In addition to the limitations of a small-format screen, students complain that cell service is often unreliabl e or slow due to data limits or saturation of the network (Fernandez, 2019). In Hampton et al. (2020), r esearchers asked students whether they sometimes left homework unfinished due to lack of computer or Internet acc ess; 49% of cellphone-dependent students reported doing so, compared to 39% of those with slow home Internet and 17% of those with high-speed home Int ernet. Cellphone-dependent students reported an overall GP A of 2.75, compared to a GPA of 3. 18 among students with high-speed Internet access – a difference which remained statistically significant after c ontrolling for socioeconomic status and other demographic factors. 2 For example, in the Hampton et al. (2020) study of Michigan 8th to 11th gr aders, only 37% of students with no home Internet were instead able to access the Internet at a friend’s house – c ompared to 53% of students with high-speed home Internet. 16 The Digital Divide Among College Students 3 The two universities collaborated on a set of “ core” items, and each also included items unique to that university’s planning needs. This brief provides original analyses conducted by the authors. F or overall reports from each survey , see Motz et al. (2020) and Jaggars et al. (2020). The Ohio State survey was conducted from mid-April to mid-Ma y, closing just after students’ final grades were posted; the IU survey was conducted fr om mid-May to mid-June, beginning just after the spring semester ended. Analyses regarding the representativeness of Ohio State student responses suggest that surve y respondents were similar to the undergraduate population in most respects, including race/ ethnicity, first-generation status, and the lik elihood of having previously taken an online course; howe ver, r espondents were less likely to be international students and had slightly higher GPAs than the o verall undergraduate population. IU’s analysis of representativ eness is in progress; however , IU’s international students are known to be underrepresented due to an e xclusion of students who were not currently residing in the U.S. at the time of the survey. It is also possibl e that students with the most inadequate technology were least likely to respond to the survey; accordingly , our estimates of technology inadequacy may be conservative. 4 Students rated their level of agreement on a 5-point scal e (from Strongly Disagree to Strongly Agree) f or the following items: “I had adequate access to the Internet connectivity necessary to participate in remot e instruction” and “I had adequate access to computer hardware necessary to participate fully in remote instruction. ” Inadequacy of Internet or devices were defined as strongly or moderately disagreeing with the relevant it em. Responses to the two questions overlapped; for exampl e, among those who disagreed they had adequate Internet, 42% also disagreed that they had adequate hardwar e. In addition to these two questions, students also selected the “primary method of connecting to the Internet to complet e your online coursework, ” with one option being “mobile phone network data. ” Students selecting this option were defined as using a cellphone as their primary device. This question overlapped with the first two; for exampl e, among those using a cellphone as their primary device, 40% disagreed that they had adequate access to the Int ernet. Students with inadequate Internet, an inadequate device, or who used a cellphone as their primary device were defined as having “Inadequate T echnology. ” (Based on other responses on the survey regarding hardware, we suspect that the typical student with “inadequate technology” brought adequate hardware back to a family home with inadequate Internet, where they c obbled together a solution such as using their cellphone for streaming video, and using their laptop or wireless-only tablet f or mostly-offline tasks.) All other students were defined as having “Acceptable T echnology” (although not necessarily ideal technology; many of these students reported in other sections of the survey that they still had some challenges with limited Internet access). This definition of inadequacy is more strict than one used in an earlier Ohio State-specific report (which included students who “neither agree nor disagree” that they had adequate Internet/ devices, see Jaggars et al., 2020) and thus yields slightly lower estimates of inadequacy. Data in Figure 1 is pooled across Indiana University and Ohio State surveys. These proportions were not significantly different between the two universities. 5 Excludes international students; the category “Other” combines domestic U.S. race/ ethnicity groups which had a low number of responses to the survey, including Nativ e American students and those who identified with Two or Mor e Races. 6 It is not clear why underclassmen would be more likely t o suffer from inadequate technology . Perhaps students with inadequate technology are more likely to drop out bef ore graduation; or perhaps some freshmen require a few semester s to diagnose their true technology needs and to scrape together an appropriat e solution to those needs. 7 The Digital Promise analysis combined technology challenges into a larg er scale that also captured six other challenges (such as not knowing where to get help with the course, or problems sta ying motivated to do well in the course). Results found that students with multiple challenges were less likely to be satisfied with their online c ourses; for example, among students with no challenges (including no technology challenges), 81% wer e satisfied or very satisfied with their online courses, while among students with four or more challenges (which may or may not have included t echnology challenges), only 32% were satisfied or very satisfied (Means & Neisler , 2020). 8 Based on ordered probit analyses, differences in the distribution of responses f or the Adequate versus Inadequate groups were statistically significant for each item. 9 Many universities across the country offered students P /NP or similar grading options for Spring 2020. At Ohio State, the P / NP option was offered for all elective and general education c ourses, with a grade of D or above marked as “P ass, ” and a grade below D marked as “No Pass. ” Individual academic programs had the discretion to offer the P /NP option for major-specific requirements. Students were required to select the P /NP option by mid-April: four weeks after classwork pivoted to remot e learning, and approximately two weeks befor e final exams. 10 Open-ended survey comments and other qualitative feedback from students suggest that in Spring 2020, students switched to P /NP for a given course if they were struggling in that class. Relie ving GPA-r elated stress about that course allowed students to put more time and effort into their remaining courses – and in particular , to focus on courses required for admission to selective majors or graduate progr ams which may not accept a P /NP grade. Examination of administrative data shows that C and D grades were largely replaced by P ass grades in the Spring 2020 semester. 17 The Digital Divide Among College Students 11 Researchers conducted a logistic regression model pr edicting the outcome of “switched to P /NP for at least one course in Spring 2020” with the primary predictor of technology inadequacy , covariates listed in T able 1, and an additional covariate of prior GPA. F or more information, see Appendix T able A1. 12 Almost all studies examining student laptop or device provision progr ams have focused on the K- 12 sector; see Weston et al. (2010) for the most recent systematic review . In higher education, the only research summary is nearly two decades old (Kontos, 2002). Recent research is confined to case studies, with the most useful being focused on technol ogy provision initiatives in the College of Education at Southeast Missouri State (Fridley & R ogers-Adkinson, 2016) and in 17 campuses across the United Ar ab Emirates (Hargis et al., 2014). 13 Ohio State’s iPad Pro package includes a pencil, ke yboard, and a suite of learning apps. T ransfer students who first enrolled at any college in Autumn 2018 or after are also included in Ohio Stat e’s iPad program. Among survey respondents at Ohio Stat e, 98% of freshmen had a university-issued iPad, along with 94% of sophomores, 6 3% of juniors, and 11% of seniors. 14 Results are based on a comparison between the two universities when contr olling for the confounding factors listed in Tabl e 1. To be c onsistent with T able 1, international students were excluded fr om the analysis. The difference between the two universities was statistically significant at p < 0.001, with most of the difference concentr ated at the threshold between Agree and Strongly Agree. The model included interaction effects for class r ank, given that we would expect to see an institutional difference most strongly among freshmen and sophomores, and to see little or no diff erence among seniors; while the results do pattern in this direction, the interaction pattern is not statistically significant. 15 Providing a cellular-enabled device (at an additional cost of $ 150 per device) along with university payment of the student’s monthly data charge would solve this problem. Howe ver, this appr oach is cost-prohibitive at the scale of Ohio State’s progr am, which currently provides approximately 3 7,000 iP ads to students. 16 For an analysis regarding the rights of states to implement net neutr ality standards, see Lundgren (2020). For proposed legislation in the Midwest, see H.B. 5094 (I.L. 2017), H.F . 3033 & S.F . 2880 (M.N. 2018), and L.B. 856 (N.E. 2018). 17 See A.B. 235 (W.I. 2019) 18 See Small Wireless Facilities Deployment Act, Neb . Rev. Stat. §86- 1201. (2019). 19 A potential drawback of tax credits for househol ds is that many low-income individuals are not familiar enough with the tax code to leverage this kind of cr edit, see Dickert-Conlin, Fitzpatrick, & Hanson (2005). 20 See Wisconsin Stat. §76.80 (2019) 21 See H.B. 3491 (I.L. 2019) 18 The Digital Divide Among College Students Compac t Le adership, 202 0- 21 President Ms. Susan Heegaard Chair Dr. Da vid Eisler , President, Ferris State University Vice Chair Rep. Rick Carfagna, Ohio Legislature Treasur er Dr. Devinder Malhotr a, Chancellor , Minnesota State Past Chair Ms. Olivia M.A. Madison, Professor Emerita and Dean Emerita of Library Services, Iowa State University Vision MHEC members collaborate to address the region’s most pr essing challenges in higher education and transform educational opportunities so that people and communities thrive. Mission MHEC brings together midwestern states to devel op and support best practices, collaborative efforts, and cost -sharing opportunities. Through these efforts it works to ensure strong, equitable postsecondary educational opportunities and outcomes for all. Who MHE C Serves MHEC is comprised of member states from the midwestern United States. MHEC works with and for a variety of stakeholders within and across member states, including higher education system leaders, state policymakers, l egislators, and institutional leaders, while always maintaining a focus on students and their success. How MH EC W orks MHEC’s strategic approach highlights member states’ strong desire for collaboration, effectiveness, and efficiency . MHEC believes that collaborative actions informed by research and best practices are the catalyst f or improving quality , accessibility, rel evance, and affordability of postsecondary educational opportunities. MHEC does this primarily through the following approaches: convenings, pr ograms, research, and cost-savings contracts. Incr easingly, MHEC looks to l everage these approaches in conjunction with each other to serve its strategic priorities. ... They posited that technological solutions are not neutral and have the potential to reinforce and exacerbate existing problems if they are implemented without first scrutinizing, and perhaps rethinking, the objectives of higher education. In a report released by Georgetown University (2021), academics and administrators in the United States highlighted how the disruption brought about by the COVID-19 pandemic has cast a spotlight on existing inequities and has created openings for meaningful systemic changes, which is a topic highlighted in a number of other studies (Harper, 2020; Jaggars et al., 2021 ). ... Canadian Faculty Members’ Hopes and Anxieties About the Near-Future of Higher Education Article Full-text available Nicole Johnson Higher education worldwide is facing several challenges spanning from economic, social, technological, demographic, environmental, to political tensions. Calls to rethink, reimagine, and reform higher education to respond to such challenges are ongoing, and need to be informed by a wide variety of stakeholders. To inform such efforts, we interviewed thirty-seven faculty members at Canadian colleges and universities to develop a greater understanding of their hopes and anxieties about the future of higher education as they considered what higher education may look like five years into the future. Results centred on four themes: (1) anxieties and hopes are shaped by supports and resources from various sources, (2) faculty members face anxiety over matters that negatively impact them but are beyond their control, (3) faculty members hope that “good” comes from the COVID-19 pandemic, and (4) faculty members hope for a well-rounded education that will enable students to succeed both within and beyond their careers. Implications for these findings suggest a need to direct research efforts and practices toward more hopeful futures for higher education, especially in the context of online and blended learning. ... But we've also had successes stemming from efforts to involve faculty in learning technology and learning data efforts, such as through IU's faculty-driven e-text program (Abaci & Quick, 2020;Abaci et al., 2017), Center for Learning Analytics and Student Success (CLASS; Rehrey et al., 2019), Charting the Future initiative (https://chartingthefuture.iu.edu/), and eLearning Research and Practice Lab (https://pti.iu.edu/elearning-lab). For example, the eLearning Lab has facilitated the multi-institutional ManyClasses research project (Fyfe et al., 2021), population-scale investigations into the digital divide (Jaggars et al., 2021) and students' grade disclosures (Kolb et al., in press) during the COVID-19 pandemic, and a scalable model for automated nudges that is both ethically responsible (Motz, 2019) and effective , and more -none of which would have been possible without faculty leadership. Plenty of work still remains, as we continue to negotiate guiding principles and establish organizational structure to sustain inter-unit collaborations. ... Wild brooms and learning analytics Article Full-text available J Comput High Educ Benjamin Motz Anastasia S. Morrone In this commentary we present an analogy between Johann Wolfgang Von Goethe's classic poem, The Sorcerer's Apprentice, and institutional learning analytics. In doing so, we hope to provoke institutions with a simple heuristic when considering their learning analytics initiatives. They might ask themselves, "Are we behaving like the sorcerer's apprentice?" This would be characterized by initiatives lacking faculty involvement, and we argue that when initiatives fit this pattern, they also lack consideration of their potential hazards, and are likely to fail. We join others in advocating for institutions to, instead, create ecosystems that enable faculty leadership in institutional learning analytics efforts. Keywords Institutional learning analytics · Faculty involvement · Analogy Every step and saying That he used, I know, And with sprites obeying My arts I will show. Johann Wolfgang Von Goethe, The Sorcerer's Apprentice Translated by Zeydel (1955) In Goethe's classic poem, an apprentice to a sorcerer finds himself unsupervised. Hoping to demonstrate his own abilities, the apprentice recites a spell, enchanting a ... Moreover, unaffordable internet costs for students with low economic backgrounds create psychological challenges in their online learning process. In support of this idea, Jaggars et al. [87] mention that students from low socio-economic families cannot afford broadband connection and basic equipment, such as laptops/computers or tablets. One can infer from the above results that unfamiliarity with the online system and weak internet connection, among others, caused some frustration and stress among students and instructors. ... 1 Published book chapter in IntechOpen Barriers and enablers published 05 Dec 2022 Chapter Full-text available Dec 2022 Dawit Negassa Seid Golga Birhanu Kassaw Midakso The education system is one of the sectors that have been severely affected by COVID-19. As a result, a new way of teaching-learning was initiated by world's educational institutions to try to educate their students through online learning platforms. Hence, this study aims at exploring barriers and enablers of online education as well as the psychosocial well-being of university students during COVID-19 in eastern Ethiopia with a particular focus on Haramaya University. A concurrent mixed method design was employed. A total of 384 participants were selected using a stratified random sampling technique. Questionnaires, key informant interviews, and document analyses were used to collect data. Quantitative data were analyzed using descriptive statistics and qualitative data were analyzed thematically, then the analyzed data were integrated to get a holistic picture of the study result. The study revealed that university students experienced high levels of barriers, low levels of enablers, and severe levels of psychosocial problems while attending their education online during the COVID-19 pandemic. Hence, proactive measures taken for identifying and removing barriers, enhancing enablers, and creating a support system that shields the psycho-social well-being of university students are recommended as appropriate intervention strategies to adapt the online education modality in universities during the COVID-19 pandemic. ... Academically, students reported feeling overwhelmed with the shift to remote education, especially due to a lack of consistency in the technology used to deliver their courses (McDaniel et al., 2020). In one analysis that included reports from several surveys, between 16 and 19% of students reported challenges regarding access to the necessary technology to participate in remote education (Jaggars et al., 2021) . Students also reported obstacles accessing appropriate distraction free study spaces (McDaniel et al., 2020), as well as a decreased sense of belonging, opportunities for collaboration with peers, and interest in course materials after instruction moved online (Means and Neisler, 2020;Madaus et al., 2021;Tarconish et al., in press). ... What Happened Next? The Experiences of Postsecondary Students With Disabilities as Colleges and Universities Reconvened During the Pandemic Joseph W. Madaus Michael Faggella-Luby Dukes Lyman COVID-19 caused nearly every college and university in the United States to rapidly shift to remote learning during the spring 2020 semester. While this impacted all students to different degrees, students with disabilities (SWD) faced new challenges related to their mental health, the accessibility of their instruction, the receipt of accommodations, and their interactions with faculty and student support personnel. Literature is emerging that describes the experiences of SWD during the spring 2020 semester and the swift change to remote learning. However, little is currently known about what followed for these students. The present study builds from a prior investigation of SWD during the spring 2020 semester and examines student experiences and perceptions during the 2020–2021 academic year. Eighty-eight SWD from colleges across the United States completed an instrument that contained a mix of demographic, yes/no, Likert scale and open-ended items. Responses revealed most items related to accessing services and instruction showed no improvement from the spring 2020 semester, and that items related to mental health, motivation to learn, and connections with peers were perceived as worse than in spring 2020. Open-ended responses revealed similar themes, with some students describing no improvements, and others noting that accessibility service offices and faculty provided enhanced methods of communication and support. Implications for practice and future research are presented. Adult Learner Engagement, Empowerment, Faculty-Student Interaction, and Technology Strategies Theresa A. Paterra The purpose of this chapter is to provide strategies for adult learners to engage in online learning and to empower themselves to succeed in online learning. In addition, this cannot be fully accomplished without some degree of faculty-student interaction. There are some strategies that work regardless of if a course is offered synchronously or asynchronously, such as time management and presence. Technology and the use of digital tools are essential in online learning and provide high motivation and participation to adult learning in an online course. In addition, technology is extremely important in our ever-advancing global market. Some strategies previously thought to be for in-person use only can be adapted to online learning. Cross-curriculum learning provides more motivation and participation when aligned with the concepts of a course. Children’s Access to Reading Materials Relative to the Coronavirus (COVID-19) Pandemic: Preferred Formats and Resources Rita Soulen Lara Tedrow Liberal Arts Education and Online Learning: Prospects and Challenges Mar 2023 Aaron Einfeld The COVID-19 pandemic forced liberal arts educators into an unplanned dive into online learning. Though many schools had little experience with online learning, some liberal arts colleges had already begun experimenting with online learning before the pandemic. This chapter begins by examining the perceptions, practices, and lessons learned from online liberal arts education before and during the pandemic. Based on this insight, this chapter discusses the ways that liberal arts educators can leverage online environments for learning in future. As the chapter illustrates, crisis and constraints can prompt new thinking and unexpected innovation. The chapter closes with advice and suggestions for future research, theory, and practice of online liberal arts education.KeywordsOnline learningHybrid learningLiberal learning outcomesOnline learning community Shrinking the digital divide in online learning beyond the COVID-19 pandemic: A Systematic Literature Review Nov 2022 Kudakwashe Maguraushe Fine Masimba Meshack Muderedzwa Learning Management System Analytics to Examine the Behavior of Students in High Enrollment STEM Courses During the Transition to Online Instruction Oct 2022 Rob Elliott Xiao Luo Chapter Abdulsalami Ibrahim Najwa Ahmed The outbreak of COVID-19 pandemic in the spring of 2020 presents unprecedented challenges around the world. Schools, hospitals, government offices, and even transportation (both domestic and international) were put to closure. While developed countries used their monetary and technology resources to support their education systems during this trying time, digital divide is widely evident in the developing countries, which has posed a threat to the fragile educational systems across these countries. This study aimed at exploring technology professional development available to faculty during COVID-19 in the developing countries. Findings revealed a critical issue of concern, as many developing countries in Africa were not able to keep up with the impact of pandemic, which rendered universities and colleges closed. In the few countries where they could keep open, several technology professional developments were provided to educators before and during the pandemic to prepare them to navigate through virtual/remote instruction.
https://www.researchgate.net/publication/349701773_The_Digital_Divide_Among_College_Students_Lessons_Learned_From_the_COVID-19_Emergency_Transition
Acetic acid chromoendoscopy and Seattle protocol in Intestinal Metaplasia and Dysplasia and Barretts Esophagus With Low Grade Dysplasia - Clinical Trials Registry - ICH GCP Barrett& #039;s esophagus is a complication of chronic gastroesophageal reflux disease that occurs in up to 10% to 15% of patients with this pathology. Well-defined r... Acetic Acid for the Detection of Esophageal Neoplasms Barrett's esophagus is a complication of chronic gastroesophageal reflux disease that occurs in up to 10% to 15% of patients with this pathology. Well-defined risk factors have been established and are important because they are considered a precancerous lesion (intestinal metaplasia). The conventional diagnostic methods are ineffective in reliably detecting potentially treatable lesions. Investigators propose the use of vital chromoendoscopy with acetic acid using the simplified classification of Portsmouth looking for areas with loss of acetowhitening and taking targeted biopsies to increase the detection of esophageal neoplastic lesions. Study Overview Status Recruiting Conditions Intestinal Metaplasia Dysplasia Barretts Esophagus With Low Grade Dysplasia Intervention / Treatment Diagnostic test: Acetic acid chromoendoscopy Diagnostic test: Seattle protocol Detailed Description Barrett's esophagus is a complication of chronic gastroesophageal reflux disease that occurs in up to 10 to 15% of patients with this disease, well-defined risk factors have been established and are important because they are considered a precancerous condition (metaplasia intestinal). Chromoendoscopy is postulated as an effective way for the detection of esophageal precancerous lesions, early detection and timely treatment with chromoendoscopy with acetic acid being a seemingly reliable alternative, so the investigators will use with the simplified classification of Portsmouth looking for areas with loss of acetowhitening and targeted biopsy to increase the detection of esophageal neoplastic lesions, our main objective being to compare the diagnostic effectiveness of directed biopsies of dysplastic lesions with acetic acid in patients with Barrett's esophagus compared to taking non-directed protocolized biopsies. A clinical trial will be carried out, including all those patients older than 18 years who go to perform a superior endoscopy with diagnosis of Barrett's esophagus where patients will be up and B Seattle protocol group(four quadrant biopsy every 2 centimeters starting 1 centimeter from above the esophagogastric junction), then proton pump inhibitor washout and crossover allocation with the opposite corresponding manoeuver. Histopathological results of both groups will be compared. Demographic data of the participants will be collected and the evaluated areas of Barrett's esophagus with each method will be recorded in a data collection sheet detailing in a specific way the number of biopsies taken, specifying if there was loss of acetowhitening and alterations in the mucous pattern and in the case of the opposite arm, the total number of biopsies taken based on the Seattle protocol, said data will be condensed into a database for subsequent statistical analysis and publication of results. Study Type Interventional Enrollment (Anticipated) 76 Phase Not Applicable Contacts and Locations Study Contact Name : Raul Alberto Gutiérrez Aguilar, Fellow Phone Number : 21317-8 +525556276900 Email : [email protected] Study Locations Mexico Mexico City, Mexico, 06700 Recruiting Centro Medico Nacional Siglo XXI Hospital de Especialidades Contact: Raul Alberto Gutiérrez Aguilar, Fellow Phone Number : 21317-8 +525556276900 Email : [email protected] Participation Criteria Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments. Eligibility Criteria Ages Eligible for Study 17 years and older (Adult, Older Adult) Accepts Healthy Volunteers No Genders Eligible for Study All Description Inclusion Criteria: Confirmed histological diagnosis of intestinal metaplasia in follow-up protocol without dysplasia Patients whose endoscopic image is suggestive of esophageal intestinal metaplasia and is confirmed by histology Barrett's esophagus minimally 2cm Patients over 18 years of age who wish to participate in the study Signed informed consent Exclusion Criteria: Histological evidence of esophageal adenocarcinoma or known with dysplasia History of esophageal ablative therapy Known allergy or intolerance to proton pump inhibitors or acetic acid Evidence of esophageal varices Los Angeles esophagitis C or D Uncontrolled coagulopathy (INR> 1.5 or platelets <50,000) Pregnancy No authorization of informed consent Study Plan This section provides details of the study plan, including how the study is designed and what the study is measuring. How is the study designed? Design Details Primary Purpose : Diagnostic Allocation : Randomized Interventional Model : Crossover Assignment Masking : Single 2 Arms and Interventions Participant Group / Arm Intervention / Treatment Active Comparator: Chromoendoscopy with acetic acid and targeted biopsies Acetic acid is prepared at a concentration of 2.5%, after initial cleaning is done, it will be applied with a 7 French spray catheter, starting the proximal application performing a uniform application on the area of intestinal metaplasia an then will be timed for mucous visualization in search of areas of loss of acetowhitening, in case of finding such area will be registered the time in which there was loss of acetowhitening, the distance at which it is located from the upper dental arch in addition to the esophageal face on which the area is located, subsequently evaluation of the glandular pattern is performed only by classifying as normal (glands evenly distributed with normal or abnormal crypt density (compact crypts with increased density; focal irregularity or disorganized crypts; absence of a cryptic pattern), once this evaluation has been carried out, biopsies are directed to these areas to be sent to the pathology service. Diagnostic test: Acetic acid chromoendoscopy Acetic acid is prepared at a concentration of 2.5% in a 20ml syringe, it will be applied with a 7 french spray catheter compatible with a working channel 2.8mm onwards, starting the proximal application When distally performing a uniform application on the area of intestinal metaplasia and the timed time for mucous visualization in search of areas of loss of acetowhitening begins, in case of finding such area will be registered the time in which there was loss of acetowhitening, the distance at which it is located from the upper dental arch in addition to the face on which the area is located, subsequently evaluation of the glandular pattern is performed only by classifying as normal or abnormal, once this evaluation has been carried out, biopsies are directed to these areas to be sent to the pathology service. Active Comparator: Seattle protocol Take random biopsies by quadrants every 2 centimeters biopsy of the intestinal metaplasia areas 1cm above the esophagogastric junction begins, taking tissue every 2cm from the 4 quadrants, separating the biopsies in different bottles based on the length in which they were taken, to later be sent to the pathology service. Diagnostic test: Seattle protocol Take random biopsies by quadrants every 2 centimeters. Biopsy of the intestinal metaplasia areas 1cm above the esophagogastric junction will be initiated, taking tissue every 2cm from the four quadrants, separating the biopsies in different bottles based on the length in which they were taken, to later be sent to the pathology service. What is the study measuring? Primary Outcome Measures Outcome Measure Measure Description Time Frame Comparing the incidence of dysplasia by directed biopsies with acetic acid chromoendoscopy against taking non-directed protocolized biopsies( Seattle protocol) in patients with Barrett's esophagus. Time Frame: Patient will be on proton pump inhibitor (PP) for 6-8 weeks First the investigators will detect the incidence of dysplasia in Barrett esophagus in patients with acetic acid chromoendoscopy, using the Vienna Classification system by the pathologist. Patient will be on proton pump inhibitor (PP) for 6-8 weeks Comparing the incidence of dysplasia by directed biopsies with acetic acid chromoendoscopy against taking non-directed protocolized biopsies( Seattle protocol) in patients with Barrett's esophagus. Time Frame: After the wash out time of 6-8 weeks on PPI, this maneuver will be added The second maneuver consist on taking non directed biopsies by the Seattle protocol in the same patient. And the incidence of dysplasia on biopsies will be looked for using Vienna Classification system again. After the wash out time of 6-8 weeks on PPI, this maneuver will be added Collaborators and Investigators This is where you will find people and organizations involved with this study. Sponsor Coordinación de Investigación en Salud, Mexico Publications and helpful links The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study. General Publications Shaheen NJ, Falk GW, Iyer PG, Gerson LB; American College of Gastroenterology. ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus. Am J Gastroenterol. 2016 Jan;111(1):30-50; quiz 51. doi: 10.1038/ajg.2015.322. Epub 2015 Nov 3. Erratum In: Am J Gastroenterol. 2016 Jul;111(7):1077. Singh S, Sharma AN, Murad MH, Buttar NS, El-Serag HB, Katzka DA, Iyer PG. Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2013 Nov;11(11):1399-1412.e7. doi: 10.1016/j.cgh.2013.05.009. Epub 2013 May 22. Rubenstein JH, Morgenstern H, Appelman H, Scheiman J, Schoenfeld P, McMahon LF Jr, Metko V, Near E, Kellenberg J, Kalish T, Inadomi JM. Prediction of Barrett's esophagus among men. Am J Gastroenterol. 2013 Mar;108(3):353-62. doi: 10.1038/ajg.2012.446. Epub 2013 Jan 15. Sharma P, Falk GW, Weston AP, Reker D, Johnston M, Sampliner RE. Dysplasia and cancer in a large multicenter cohort of patients with Barrett's esophagus. Clin Gastroenterol Hepatol. 2006 May;4(5):566-72. doi: 10.1016/j.cgh.2006.03.001. Epub 2006 Apr 17. Chedgy F, Fogg C, Kandiah K, Barr H, Higgins B, McCord M, Dewey A, De Caestecker J, Gadeke L, Stokes C, Poller D, Longcroft-Wheaton G, Bhandari P. Acetic acid-guided biopsies in Barrett's surveillance for neoplasia detection versus non-targeted biopsies (Seattle protocol): A feasibility study for a randomized tandem endoscopy trial. The ABBA study. Endosc Int Open. 2018 Jan;6(1):E43-E50. doi: 10.1055/s-0043-120829. Epub 2018 Jan 12. Kandiah K, Chedgy FJQ, Subramaniam S, Longcroft-Wheaton G, Bassett P, Repici A, Sharma P, Pech O, Bhandari P. International development and validation of a classification system for the identification of Barrett's neoplasia using acetic acid chromoendoscopy: the Portsmouth acetic acid classification (PREDICT). Gut. 2018 Dec;67(12):2085-2091. doi: 10.1136/gutjnl-2017-314512. Epub 2017 Sep 28. Tholoor S, Bhattacharyya R, Tsagkournis O, Longcroft-Wheaton G, Bhandari P. Acetic acid chromoendoscopy in Barrett's esophagus surveillance is superior to the standardized random biopsy protocol: results from a large cohort study (with video). Gastrointest Endosc. 2014 Sep;80(3):417-24. doi: 10.1016/j.gie.2014.01.041. Epub 2014 Apr 6. Study record dates These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website. Study Major Dates Study Start (Actual) July 3, 2019 Primary Completion (Anticipated) October 1, 2022 Study Completion (Anticipated) December 1, 2022 Study Registration Dates First Submitted July 25, 2019 First Submitted That Met QC Criteria August 9, 2019 First Posted (Actual) August 13, 2019 Study Record Updates Last Update Posted (Actual) July 22, 2022 Last Update Submitted That Met QC Criteria July 21, 2022 Last Verified July 1, 2022 More Information Terms related to this study Keywords Chromoendoscopy acetic acid Dysplasia Barrett Esophagus Seattle protocol Additional Relevant MeSH Terms Digestive System Diseases Pathologic Processes Neoplasms Gastrointestinal Diseases Esophageal Diseases Precancerous Conditions Hyperplasia Barrett Esophagus Metaplasia Physiological Effects of Drugs Anti-Infective Agents Antineoplastic Agents Immunologic Factors Protective Agents Anti-Bacterial Agents Adjuvants, Immunologic Anticarcinogenic Agents Acetic Acid Retinol acetate Other Study ID Numbers R-2019-3601-143 Plan for Individual participant data (IPD) Plan to Share Individual Participant Data (IPD)? No Drug and device information, study documents Studies a U.S. FDA-regulated drug product No Studies a U.S. FDA-regulated device product No This information was retrieved directly from the websiteclinicaltrials.govwithout any changes. If you have any requests to change, remove or update your study details, please [email protected]. As soon as a change is implemented onclinicaltrials.gov, this will be updated automatically on our website as well. Clinical Trials on Intestinal Metaplasia NCT05818072 Recruiting The Prevalence, Risk Factors and Optimal Biopsy Protocol of BE Barrett's Esophagus Intestinal Metaplasia NCT05657080 Not yet recruiting Cytosponge for Gastric Intestinal Metaplasia (CyGIM) Gastric Cancer Gastric Intestinal Metaplasia Gastric Atrophy NCT05579444 Recruiting Systems Biology of Gastrointestinal and Related Diseases Obesity Gastritis Irritable Bowel Syndrome Gastric Cancer Esophageal Cancer Gastro Esophageal Reflux Crohn Disease GERD NAFLD Ulcerative Colitis NCT05464108 Recruiting Validation The Artificial Intelligence System for Automatic Evaluation of the Extent of Intestinal Metaplasia Artificial Intelligence Endoscopy Intestinal Metaplasia of Gastric Mucosa NCT05462743 Recruiting Artificial Intelligence-assisted Confocal Laser Endomicroscopy Identification of Intestinal Metaplasia Severity Artificial Intelligence Intestinal Metaplasia Confocal Laser Endomicroscopy NCT05459610 Recruiting Automatic Evaluation of the Extent of Intestinal Metaplasia With Artificial Intelligence Artificial Intelligence Endoscopy Intestinal Metaplasia of Gastric Mucosa NCT05459428 Recruiting Artificial Intelligence Confocal Laser Endomicroscopy for Real-time Assessment of Gastric Cancer Risk. Intestinal Metaplasia of Gastric Mucosa Confocal Laser Endomicroscopy NCT05447221 Recruiting Automatic Evaluation of the Severity of Gastric Intestinal Metaplasia With Pathology Artificial Intelligence Diagnosis System Gastric Cancer Artificial Intelligence Gastric Intestinal Metaplasia Pathology NCT05288153 Recruiting Metformin Efficacy and Safety for Gastric Intestinal Metaplasia Gastric Intestinal Metaplasia NCT05053945 Recruiting Helicobacter Pylori, Atrophic Gastritis and Intestinal Metaplasia Registry and Prospective Study Intestinal Metaplasia Helicobacter Pylori Atrophic Gastritis Clinical Trials on Acetic acid chromoendoscopy NCT02614703 Terminated "Acetic Acid Chromoendoscopy in Barrett's Esophagus Surveillance Barrett's Esophagus NCT01499576 Completed Acetic Acid Chromoendoscopy to Judge Gastric Intestinal Metaplasia (IM) Stomach Neoplasms Metaplasia NCT01618643 Unknown Aceto-whitening in the Assessment of Gastrointestinal Neoplasia Barrett Esophagus Barrett Adenocarcinoma Barrett Metaplasia Barrett Oesophagitis With Dysplasia Sponsors and Collaborators
https://ichgcp.net/clinical-trials-registry/NCT04054713
(PDF) Genetic Diversity of Heat-Labile Toxin Expressed by Enterotoxigenic Escherichia coli Strains Isolated from Humans PDF | The natural diversity of the elt operons, encoding the heat-labile toxin LT-I (LT), carried by enterotoxigenic Escherichia coli (ETEC) strains... | Find, read and cite all the research you need on ResearchGate Genetic Diversity of Heat-Labile Toxin Expressed by Enterotoxigenic Escherichia coli Strains Isolated from Humans May 2008 Journal of Bacteriology 190(7):2400-10 DOI: 10.1128/JB.00988-07 Authors: Abstract and Figures The natural diversity of the elt operons, encoding the heat-labile toxin LT-I (LT), carried by enterotoxigenic Escherichia coli (ETEC) strains isolated from humans was investigated. For many years, LT was supposed to be represented by a rather conserved toxin, and one derivative, produced by the reference H10407 strain, was intensively studied either as a virulence factor or as a vaccine adjuvant. Amplicons encompassing the two LT-encoding genes (eltA and eltB) of 51 human-derived ETEC strains, either LT(+) (25 strains) only or LT(+)/ST(+) (26 strains), isolated from asymptomatic (24 strains) or diarrheic (27 strains) subjects, were subjected to restriction fragment length polymorphism (RFLP) analysis and DNA sequencing. Seven polymorphic RFLP types of the H10407 strain were detected with six (BsaI, DdeI, HhaI, HincII, HphI, and MspI) restriction enzymes. Additionally, the single-nucleotide polymorphic analysis revealed 50 base changes in the elt operon, including 21 polymorphic sites at eltA and 9 at eltB. Based on the deduced amino acid sequences, 16 LT types were identified, including LT1, expressed by the H10407 strain and 23 other strains belonging to seven different serotypes, and LT2, expressed by 11 strains of six different serotypes. In vitro experiments carried out with purified toxins indicated that no significant differences in GM1-binding affinity could be detected among LT1, LT2, and LT4. However, LT4, but not other toxin types, showed reduced toxic activities measured either in vitro with cultured cells (Y-1 cells) or in vivo in rabbit ligated ileal loops. Collectively, these results indicate that the natural diversity of LTs produced by wild-type ETEC strains isolated from human hosts is considerably larger than previously assumed and may impact the pathogeneses of the strains and the epidemiology of the disease. . Serotypes and relevant phenotypic features of ETEC strains analyzed in the present study … LT structural model with locations of the polymorphic sites detected in the present study. The LT structural coordinates were retrieved from the PDB (code 1LTS). (A) Structural model of the whole toxin (A and B subunits). (B) Structural model of the A1 subunit with positions (arrows) of nine polymorphic sites with amino acid residues present in the available PDB file. (C) Structural model of the A2 subunit with positions (arrows) of seven polymorphic sites with amino acid residues present in the available PDB file. (D) Structural model of the B subunit with positions (arrows) of the five polymorphic sites with amino acid residues present in the available PDB file. Polymorphic sites are shaded dark. Three polymorphic sites (Q185R, S190L, and T193A) were located on a loop encompassing the disulfide bridge linking A1 and A2 subunits, which has not been structurally solved in the PDB file. … Unrooted phylogram constructed by the neighbor-joining method showing the sequence relationships of the concatenated amino acid sequences of the mature A and B subunits of the detected LT variants. … . Deduced amino acid compositions of variant A and B subunits obtained from sequenced elt operons of all ETEC strains analyzed in this study … Figures - uploaded by Andrea Balan Supplementary resources (14) Escherichia coli strain 4702-1 elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain 1372-1 elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain 61A-4 elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain 214-III elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain 4692-1 elt operon, complete sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain 121-I elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain PE0415 elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain 136-I elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain 63-V elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain 225-IV elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain PE0534 elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain 4321-1 elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain 2781-5 elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira Escherichia coli strain PE0615 elt operon, complete sequence Nucleotide Sequence M.A. Lasaro · Juliana Rodrigues · Célia Samarina Vilaça Santos · Beatriz Ernestina Cabilio Guth · L.C.S. Ferreira ... Although clonal and stable lineages of ETEC are spread worldwide, epidemiological studies have revealed high genetic and phenotypic diversity among ETEC strains regarding serotypes, virulence features, mainly CFs and LT types, and genotypes disclosed by molecular approaches [7,[9][10] [11] [12][13][14]. Our group previously showed the occurrence of 16 LT types among ETEC strains derived from asymptomatic and diarrheic Brazilian children [11]. ... ... Although clonal and stable lineages of ETEC are spread worldwide, epidemiological studies have revealed high genetic and phenotypic diversity among ETEC strains regarding serotypes, virulence features, mainly CFs and LT types, and genotypes disclosed by molecular approaches [7,[9][10][11][12][13][14]. Our group previously showed the occurrence of 16 LT types among ETEC strains derived from asymptomatic and diarrheic Brazilian children [11] . These LT types were grouped into four phylogenetic clusters, two of which (A and D) comprised the majority of the variants closely related to the types LT1 and LT2, respectively. ... ... More recently, these results were confirmed by further studies, and twelve additional LT variants were found among clinical strains isolated from diverse geographic areas [12]. Genetic polymorphisms in noncoding regulatory sequences and in LT-structural genes have also been ascribed to different LT types [11, 12,14]. However, considering the data available in the literature, thus far it has not been possible to correlate the ability to express LT and the natural genetic polymorphisms detected among different LT types. ... Strain-specific transcriptional and posttranscriptional regulation of heat-labile toxin expression by enterotoxigenic Escherichia coli Article Full-text available Denicar Fabris Luís C S Ferreira Enterotoxigenic Escherichia coli (ETEC) represents one of the most important etiological agents of diarrhea in developing countries and characteristically produces at least one of two enterotoxins: heat-labile toxin (LT) and heat-stable toxin (ST). It has been previously shown that the production and release of LT by human-derived ETEC strains are variable. Although the natural genetic polymorphisms of regulatory sequences of LT-encoding (eltAB) genes may explain the variable production of LT, the knowledge of the transcriptional and posttranscriptional aspects affecting LT expression among ETEC strains is not clear. To further understand the factors affecting LT expression, we evaluated the impact of the natural polymorphism in noncoding regulatory sequences of eltAB among clinically derived ETEC strains. Sequence analyses of seven clinically derived strains and the reference strain H10407 revealed polymorphic sites at both the promoter and upstream regions of the eltAB operon. Operon fusion assays with GFP revealed that specific nucleotide changes in the Pribnow box reduce eltAB transcription. Nonetheless, the total amounts of LT produced by the tested ETEC strains did not strictly correspond to the detected LT-specific mRNA levels. Indeed, the stability of LT varied according to the tested strain, indicating the presence of posttranscriptional mechanisms affecting LT expression. Taken together, our results indicate that the production of LT is a strain-specific process and involves transcriptional and posttranscriptional mechanisms that regulate the final amount of toxin produced and released by specific strains. ... The LTs that ETEC strains produce are likewise a diverse category of toxins. There are two main LT families known as LT-I and LT-II [13] . LT genes eltA and eltB produce LT-I and LT-II, respectively. ... ... LT genes eltA and eltB produce LT-I and LT-II, respectively. The ST genes are possible to express independently or in tandem with the LT genes eltA and eltB [13] . ETEC strains can express seven different toxin combinations: STh, STp, STh/LT, STp/LT, LT, and less typically, STh/STp and STh/STp [14]. ... Molecular detection of Enterotoxigenic Escherichia coli Toxins and Colonization Factors from Diarrheic Children in Pediatric Teaching Hospital, Sulaymaniyah, Iraq Article Full-text available Hezhan Faeq Rasul Sirwan Muhsin Muhammed Hunar Hiwa Arif Paywast Jalal Enterotoxigenic Escherichia coli (ETEC) is one well-established causative agent of diarrhea in the developing countries among young children. This prospective study was performed at Laboratories of University of Sulaimani (in Sulaymaniyah City/Iraq) from September to October 2021which aimed to determine the prevalence of ETEC among children and the most prevalence colonization factor (CFA/I) among ETEC. One hundred and twenty-five fresh stool samples were collected from hospitalized – children with diarrhea at Dr. Jamal Ahmed Rashid’s Pediatric Teaching Hospital. The collected samples were cultured on MacConkey and eosin methylene blue agar as selective and differential media for Gram- negative bacteria. Colonies were identified through Gram staining and biochemical tests including: Indole, methyl red, and catalase reaction test. Vitek-2 machine was depended to test some obtained isolates. Most of isolates (60%) showed positive results for E. coli – out of this percentage, 14 (18.66%) were positive for ETEC using polymerase chain reaction assay identifying stable and labile toxins (LTs). It was noticed that all of the ETEC isolates were stable toxin producer isolates whereas LT producer isolates were not identified. Colonization factor 5 (CS5) has been detected among three ETEC isolates (21.42%), meanwhile, 11 isolates (78.57%) have not expressed colonization factors at all. ... The major virulence factors of diarrhea-causing ETEC strains are enterotoxins, specifically a heat-labile toxin (LT) and a heat-stable toxin. These toxins alter the cellular signaling pathways, ultimately triggering an increase in chloride secretion and watery diarrhea (6, 7) . The LT is an AB5 toxin encoded by the eltAB operon with similarities to cholera toxin; it binds to ADP and ribosylates the guanyl-nucleotide alpha regulatory binding protein of the adenylate cyclase system, thereby increasing the levels of cyclic AMP (8,9). ... Production of monoclonal antibody of heat-labile toxin A subunit to identify enterotoxigenic Escherichia coli by epitope mapping using synthetic peptides Article Full-text available Jun Young Park Seung-Hak Cho Background Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea through two enterotoxins, a heat-labile toxin and a heat-stable toxin. These toxins alter the cellular signaling pathways, ultimately triggering an increase in chloride secretion and watery diarrhea. Objective For the development of an ETEC vaccine, we attempted to construct a peptide-specific monoclonal antibody library against heat-labile enterotoxin A subunit (LT-A) by epitope mapping using synthetic peptides. Methods Sera produced by five mice immunized with recombinant LT-A protein were examined for specific recognition with synthetic 15-mer and 34-mer peptides of LT-A proteins using enzyme-linked immunosorbent assay. The analysis revealed that the synthetic peptides number 8, 16, 24, 33, 36, 38, and 39 reacted with an anti-LT-A polyclonal antibody. For the possible prediction of LT-A epitopes, each full-length protein sequence was subjected to BCPreds analysis and three-dimensional protein structure analysis. The data showed that three peptides (synthetic peptide numbers: 33, 36, and 38–39) have identical antigenic specificities with LT-A protein, suggesting the usefulness of these linear peptide epitopes. Results Based on these peptides, we produced monoclonal antibodies to improve the specificity of LT-A detection. Monoclonal antibodies produced from two peptides (numbers 33 and 36) showed affinity for an LT-A recombinant antigen. Moreover, peptide epitope prediction analysis showed that the sites of the three peptides were identical to those exhibiting actual antigenicity. Also, it was confirmed that the amino acid sequence that actually showed antigenicity was included in the peptide predicted only by ETEC-LT-A-33. Also, the specificity of the antibody for ETEC-LT-A-33 was validated using bacterial cells, and the neutralizing effect of the antibody was determined by assessing cytokine release in infected HCT-8 cells. Conclusion The monoclonal antibodies produced in this study are useful toolsfor vaccine production against ETEC and can be used to identify peptide antigencandidates. ... Coded by Amplicons encompassing the two genes(eltA and eltB) (Lasaro et al., 2008 ) , these genes carried on plasmid (Nataro and Kaper , 1998). There are two LT serogroup LT-I and LT-II : LT-I secreted from E. coli which infected human, the other LT-II mainly isolated from E. coli animal and rarely in human but not related with disease, generally toxin with oligomeric 86 kDa and consist of 2 subunit are A (one subunit with 28-kDa) and B (five identical subunit with 11.5-kDa), B subunits arranged in ring shape (Nataro and Kaper ,1998). ... Molecular study of some virulence genes in Diarrheagenic E. coli isolated from pediatric patients with diarrhea in Wasit province Thesis Full-text available Mar 2021 Rana H. Raheema Ahmed I. Insaf Diarrheagenic Escherichia coli is still an important pathogen that cause diarrhea which lead to hospitalsadmissions and death specially in children. A total of 210 samples were collectedafrom children underafive years with diarrhea in different hospitals and private clinics, in Wasit province, south of Iraq, 40 samples as a control from healthy children during a period from 15th of September 2017 to 15th of December 2017. According to culture, biochemical testsaand API 20E the results of 100 isolates were supposed to be E. coli. The DNA were extracted from these 100 isolates from diarrheal cases and for 40 isolates of the control, concentration of DNAasamples were between (50-360 mg/µl) and theapurity between (1.8-2). All isolates studied for detection 16SrRNA gene, then detection the virulence gene of five Diarrheagenic Escherichia coli strains based on using Multiplex PolymeraseaChain Reaction technique, by amplified 13 primer (eaeA, bfpB, aggR, astA, pic, hly, stx, ,stx2, invE, ipaH, elt, estIa, estIb), the results showed the distribution of the strains and its susceptibility to antibiotics. The results appeared that only 42% (42/100) of the isolates were Diarrheagenic Escherichia Coli. The most frequent pathotypes was Enteropathogenic E. coli was 45.3% (19/42) )with 9 typical and 10 atypical(, followed by Enteroaggregative E. coli 40.5% (17/42 ), Enterotoxigenic E. coli 7.1% (3/42), Enteroinvasive E. coli 7.1% (3/42), and 0% (0/42) was Shigatoxin E. coli and no DEC in all control patients. The prevalence of Enteropathogenic E. coli and Enteroaggregative infections was high in first II and second years, while Enteroinvasive E.coli was high in third year also cause infection in first age group, all Enterotoxigenic E.coli infections were in above 1 year . The antibiotic susceptibility test for 42 of Diarrheagenic Escherichia coli isolates, were performed by disc diffusion method, using 11 antibiotics and their results showed different percentages of resistance to antibiotics as follows : the highest resistance was (95.2%) to Amoxicillin and Ampicillin, Sulfa-Trimethoprim (92.9%), followed by (85.7%) for Tetracycline and Cephalothin, Ceftriaxone (81%) and Cefotaxim ∕clavulanic acid (71.4%). While the lowest resistance was to Chloramphenicol (19 %), Ciprofloxacin (16.7%), Amikacin (7.1%) and no resistance was detected to Imipenem. We can concluded in this study, that Multiplex PCR is a rapid, and accurate procedure which can be used for aidentification and isolation of Diarrheagenic E. coli strains successfully, Enteropathogenic E. coli and Enteroaggregative E. coli are the most dominant pathotype in the studied samples, tended to occur more in children less than 2 years age, while Enterotoxigenic E. coli and Enteroinvasive E. coli tend to occur more in children more than 2 years of age. The susceptibility test showed ahigh resistance to different antibiotics in isolates which were collected from hospitalized children than isolates collected from private clinics (without history of hospital admission). The results also revealed that the most active antibiotic against Diarrheagenic E. coli was Imipenem followed by Amikacin, Ciprofloxacin and Chloramphenicol. ... Exposure to the large and immunogenic LT usually elicits a strong immune response, while ST, on the other hand, is small and nonimmunogenic. Different ETECs can produce one or both of these two toxins [71] [72] [73][74]. LT-only ETECs (i.e., ETECs that produce LT but not ST) seem to be more important contributors to travelers' diarrhea than childhood diarrhea [75][76][77]. ... Human Mucosal IgA Immune Responses against Enterotoxigenic Escherichia coli Article Full-text available Aug 2020 Saman Riaz Hans Steinsland Kurt Hanevik Infection with enterotoxigenic Escherichia coli (ETEC) is a major contributor to diarrheal illness in children in low- and middle-income countries and travelers to these areas. There is an ongoing effort to develop vaccines against ETEC, and the most reliable immune correlate of protection against ETEC is considered to be the small intestinal secretory IgA response that targets ETEC-specific virulence factors. Since isolating IgA from small intestinal mucosa is technically and ethically challenging, requiring the use of invasive medical procedures, several other indirect methods are used as a proxy for gauging the small intestinal IgA responses. In this review, we summarize the literature reporting on anti-ETEC human IgA responses observed in blood, activated lymphocyte assayss, intestinal lavage/duodenal aspirates, and saliva from human volunteers being experimentally infected with ETEC. We describe the IgA response kinetics and responder ratios against classical and noncanonical ETEC antigens in the different sample types and discuss the implications that the results may have on vaccine development and testing. View Show abstract ... Previous reports demonstrated that the TC route is a safe and efficient immunization method [15][16][17][18][27][28][29]34,35]. In particular, the TC administration route prevents the toxicity of certain adjuvants, such as LT1, which may induce local and systemic side effects when delivered via parenteral routes [23, 36] . Indeed, our results demonstrate that administration of DENV2 particles admixed with LT1 and delivered through the TC route led to the generation of specific antibody and cellular responses without any significant deleterious effects or local inflammatory reactions. ... Transcutaneous Administration of Dengue Vaccines Article Full-text available May 2020 Carla Longo Samuel Santos Pereira Alexia Adrianne Venceslau-Carvalho Sara Araujo Pereira In the present study, we evaluated the immunological responses induced by dengue vaccines under experimental conditions after delivery via a transcutaneous (TC) route. Vaccines against type 2 Dengue virus particles (DENV2 New Guinea C (NGC) strain) combined with enterotoxigenic Escherichia coli (ETEC) heat-labile toxin (LT) were administered to BALB/c mice in a three-dose immunization regimen via the TC route. As a control for the parenteral administration route, other mouse groups were immunized with the same vaccine formulation via the intradermic (ID) route. Our results showed that mice vaccinated either via the TC or ID routes developed similar protective immunity, as measured after lethal challenges with the DENV2 NGC strain. Notably, the vaccine delivered through the TC route induced lower serum antibody (IgG) responses with regard to ID-immunized mice, particularly after the third dose. The protective immunity elicited in TC-immunized mice was attributed to different antigen-specific antibody properties, such as epitope specificity and IgG subclass responses, and cellular immune responses, as determined by cytokine secretion profiles. Altogether, the results of the present study demonstrate the immunogenicity and protective properties of a dengue vaccine delivered through the TC route and offer perspectives for future clinical applications. The diverse landscape of AB5-type toxins Article Jun 2023 Paris I. Brown Adaobi Ojiakor Antonio J. Chemello Casey C. Fowler Toxin linked mobile genetic elements in major enteric bacterial pathogens Article Full-text available Mar 2023 Shruti Panwar Shashi Kumari Jyoti Verma -- Bhabatosh Das One of the fascinating outcomes of human microbiome studies adopting multi-omics technology is its ability to decipher millions of microbial encoded functions in the most complex and crowded microbial ecosystem, including the human gastrointestinal (GI) tract without cultivating the microbes. It is well established that several functions that modulate the human metabolism, nutrient assimilation, immunity, infections, disease severity and therapeutic efficacy of drugs are mostly of microbial origins. In addition, these microbial functions are dynamic and can disseminate between microbial taxa residing in the same ecosystem or other microbial ecosystems through horizontal gene transfer. For clinicians and researchers alike, understanding the toxins, virulence factors and drug resistance traits encoded by the microbes associated with the human body is of utmost importance. Nevertheless, when such traits are genetically linked with mobile genetic elements (MGEs) that make them transmissible, it creates an additional burden to public health. This review mainly focuses on the functions of gut commensals and the dynamics and crosstalk between commensal and pathogenic bacteria in the gut. Also, the review summarises the plethora of MGEs linked with virulence genes present in the genomes of various enteric bacterial pathogens, which are transmissible among other pathogens and commensals. Holotoxin disassembly by protein disulfide isomerase is less efficient for Escherichia coli heat-labile enterotoxin than cholera toxin Article Full-text available Jan 2022 Albert Serrano Jessica L. Guyette Joel B. Heim Suren Tatulian Cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) are structurally similar AB5-type protein toxins. They move from the cell surface to the endoplasmic reticulum where the A1 catalytic subunit is separated from its holotoxin by protein disulfide isomerase (PDI), thus allowing the dissociated A1 subunit to enter the cytosol for a toxic effect. Despite similar mechanisms of toxicity, CT is more potent than LT. The difference has been attributed to a more stable domain assembly for CT as compared to LT, but this explanation has not been directly tested and is arguable as toxin disassembly is an indispensable step in the cellular action of these toxins. We show here that PDI disassembles CT more efficiently than LT, which provides a possible explanation for the greater potency of the former toxin. Furthermore, direct examination of CT and LT domain assemblies found no difference in toxin stability. Using novel analytic geometry approaches, we provide a detailed characterization of the positioning of the A subunit with respect to the B pentamer and demonstrate significant differences in the interdomain architecture of CT and LT. Protein docking analysis further suggests that these global structural differences result in distinct modes of PDI-toxin interactions. Our results highlight previously overlooked structural differences between CT and LT that provide a new model for the PDI-assisted disassembly and differential potency of these toxins. Holotoxin Disassembly by Protein Disulfide Isomerase Is Less Efficient for Escherichia Coli Heat-labile Enterotoxin Than Cholera Toxin Preprint Full-text available Sep 2021 Albert Serrano Jessica L. Guyette Joel B. Heim Suren Tatulian Cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) are structurally similar AB 5 -type protein toxins. They move from the cell surface to the endoplasmic reticulum where the A1 catalytic subunit is separated from its holotoxin by protein disulfide isomerase (PDI), thus allowing the dissociated A1 subunit to enter the cytosol for a toxic effect. Despite similar mechanisms of toxicity, CT is more potent than LT. The difference has been attributed to a more stable domain assembly for CT as compared to LT, but this explanation has not been directly tested and is arguable as toxin disassembly is an indispensable step in the cellular action of these toxins. We show here that PDI disassembles CT more efficiently than LT, which provides a possible explanation for the greater potency of the former toxin. Furthermore, direct examination of CT and LT domain assemblies found no difference in toxin stability. Using novel analytic geometry approaches, we provide a detailed characterization of the positioning of the A subunit with respect to the B 5 pentamer and demonstrate significant differences in the interdomain architecture of CT and LT. Protein docking analysis further shows that these global structural differences result in distinct modes of PDI-toxin interactions. Our results highlight previously overlooked structural differences between CT and LT that provide a new molecular explanation for the PDI-assisted disassembly and differential potency of these toxins. Occurrence, distribution, and associations of O and H serogroups, colonization factor antigens, and toxins of enterotoxigenic Escherichia coli. Article Oct 1997 M K Wolf Enterotoxigenic Escherichia coli (ETEC) is a leading cause of infectious diarrhea worldwide. Four categories of antigens have been commonly studied: O serogroup, H serogroup, colonization factor antigens (CFA), and toxins. A database has been complied from published reports of nearly 1,000 ETEC isolates from 18 locations and analyzed to determine the occurrence, distribution, and associations of O serogroup, H serogroup, CFA, and toxin type. Tables listing the associations of antigens are presented. This analysis documents the widespread nature and variety of ETEC. Even the most common combination of antigens, O6:H16 CFA/II LTST, accounted for only 11% of the ETEC isolates in the database. It was isolated from 12 locations. Many phenotypes occurred only once. CFA detection based on enzyme-linked antibodies with polyclonal sera is suggested as the preferred assay. A combination of CFA and toxin-based antigens is suggested as the most practical vaccine. Random amplification of polymorphic DNA reveals serotype-specific clonal clusters among enterotoxigenic Escherichia coli strains isolated from humans Article Jun 1997 Ana Beatriz Furlanetto Pacheco Beatriz Ernestina Cabilio Guth Kelen C C Soares
https://www.researchgate.net/publication/5628903_Genetic_Diversity_of_Heat-Labile_Toxin_Expressed_by_Enterotoxigenic_Escherichia_coli_Strains_Isolated_from_Humans
Sustainability | Free Full-Text | Investigation of Small-Scale Photovoltaic Systems for Optimum Performance under Partial Shading Conditions Not only are small photovoltaic (PV) systems widely used in poor countries and rural areas where the electrical loads are low but they can also be integrated into the national electricity grid to save electricity costs and reduce CO2 emissions. Partial shading (PS) is one of the phenomena that leads to a sharp decrease in the performance of PV systems. This study provides a comprehensive performance investigation of small systems (consisting of ten modules or fewer) under all possible shading patterns that result from one shading level (300 W/m2 is chosen). The most common configurations are considered for which a performance comparison is presented. Five small systems of different sizes are studied under PS. A new simplifying method is proposed to identify the distinct PS patterns under study. Consequently, the number of cases to be studied is significantly reduced from 1862 to 100 cases only. The study is conducted using the MATLAB/Simulink& reg; environment. The simulation results demonstrate the most outperformed configuration in each case of PS pattern and the amount of improvement for each configuration. The configurations include static series-parallel (SP), static total-cross-tied (TCT), dynamic switching between SP and TCT, and TCT-reconfiguration. The study provides PV systems& rsquo; owners with a set of guidelines to opt for the best configuration of their PV systems. The optimum recommended configuration is TCT reconfiguration, rather than dynamic switching between SP and TCT. The less recommended option, which enjoys simplicity but is still viable, is the static TCT. It outperforms the static SP in most cases of PS patterns. Investigation of Small-Scale Photovoltaic Systems for Optimum Performance under Partial Shading Conditions by Mahmoud A. M. Youssef 1,* , Abdelrahman M. Mohamed 2 , Yaser A. Khalaf 3 and Yehia S. Mohamed 2 Mechanical Engineering Department, Jouf University, Sakaka 72388, Saudi Arabia Electrical Engineering Department, Jouf University, Sakaka 72388, Saudi Arabia * Author to whom correspondence should be addressed. Sustainability 2022 , 14 (6), 3681; https://doi.org/10.3390/su14063681 Received: 7 February 2022 / Revised: 13 March 2022 / Accepted: 17 March 2022 / Published: 21 March 2022 (This article belongs to the Special Issue Technology Innovation and Applications of Power Electronics of Renewable Energy Systems ) Abstract : Not only are small photovoltaic (PV) systems widely used in poor countries and rural areas where the electrical loads are low but they can also be integrated into the national electricity grid to save electricity costs and reduce CO 2 emissions. Partial shading (PS) is one of the phenomena that leads to a sharp decrease in the performance of PV systems. This study provides a comprehensive performance investigation of small systems (consisting of ten modules or fewer) under all possible shading patterns that result from one shading level (300 W/m 2 is chosen). The most common configurations are considered for which a performance comparison is presented. Five small systems of different sizes are studied under PS. A new simplifying method is proposed to identify the distinct PS patterns under study. Consequently, the number of cases to be studied is significantly reduced from 1862 to 100 cases only. The study is conducted using the MATLAB/Simulink ® environment. The simulation results demonstrate the most outperformed configuration in each case of PS pattern and the amount of improvement for each configuration. The configurations include static series-parallel (SP), static total-cross-tied (TCT), dynamic switching between SP and TCT, and TCT-reconfiguration. The study provides PV systems’ owners with a set of guidelines to opt for the best configuration of their PV systems. The optimum recommended configuration is TCT reconfiguration, rather than dynamic switching between SP and TCT. The less recommended option, which enjoys simplicity but is still viable, is the static TCT. It outperforms the static SP in most cases of PS patterns. Keywords: solar photovoltaic ; maximum power extraction ; array interconnection schemes 1. Introduction 1.1. Motivation Day by day, the demand for electric energy increases, and the need for energy sources to meet these needs increases [ 1 ]. Most of the demand for electric power is being met by fossil fuels, which are a finite viable resource, along with the catastrophic environmental problems they cause to the planet. These conditions shed light on renewable energy due to its lasting abundance, environmental friendliness, and low maintenance cost [ 2 , 3 ]. Among the various renewable energy sources, photovoltaic (PV) energy has attracted attention due to its small size and ease of installation in consumption areas, such as rooftops, over-lighting poles, and others. Consequently, it leads to saving energy loss through transmission wires from generation areas to consumption areas. By 2050, it is expected that renewable energy will contribute to 79% of the total energy demand in the world, and PV will be the largest contributor among these energies [ 4 ]. Residential small-scale PV systems are currently widely used, and many solutions have been presented to integrate the PV systems in homes. It may be a stand-alone system or with the integration with utility [ 5 , 6 ]. Many advantages have been achieved from the renewable distribution generation as saving the losses of the transmission lines and improving the network frequency [ 7 , 8 ]. However, the PV technology still faces many challenges at the present time, which needs more research, including the problem of low energy generated due to environmental conditions [ 9 ]. Usually, there are several connections in series and parallel of the PV modules to obtain the required values of voltage and current [ 10 ]. Under normal conditions, sunlight is uniformly distributed over the PV modules, and the characteristic power-voltage curve has a single maximum power point at which the highest power can be extracted [ 11 ]. However, due to the presence of many causes of shading such as trees and buildings nearby, the accumulation of dust and clouds passing, the PV modules may not receive an equal amount of solar irradiance. Such effect is known as partial shading (PS) [ 12 ]. The PS not only causes a decrease in the output power but also may cause the arising of hotspots as a result of the increased mismatch between PV modules. In order to protect the modules from this effect, bypassing diodes are added to bypass the shaded PV cells or modules. However, this addition causes the appearance of several peaks in the characteristic curve, which makes it difficult to use the traditional tracking techniques to extract the maximum power. Various techniques have been addressed in the literature to solve this problem using metaheuristic methods such as genetic algorithm, cuckoo search, particle swarm optimization, ant colony optimization, and teaching-learning-based optimization [ 13 , 14 ]. Nevertheless, almost all of these techniques require more complex calculations and processing to extract the maximum power. In [ 15 , 16 ], a simple method is proposed to detect partial shading easily in PV systems. It presents a simple and easy-to-implement controller to track the global maximum power point (MPP). It depends on estimating the voltages at the local maximum power points using only two mathematical equations to control the DC/DC converter. Recently, many researchers in this area focus on improving the performance of the PV systems under the influence of different environmental conditions, including the partial shading phenomenon. Some researchers focus on developing the internal configuration of the modules to increase their ability to face this phenomenon. For example, article [ 17 ] investigated the performance of PV modules with different bus bars configurations for cells. It analyzed seven types of poly-Si PV cells and concluded that the five Busbar cells are the most efficient under PS. Article [ 18 ] focused on the modeling and functioning of a half-cell PV module under the PS using the MATLAB software package. Unlike others, the authors of [ 19 ] inspected how to reduce the PS effect by using the half-cell modules. They concluded that half-cell modules increase the power by 1.48% in the Fill Factor because of the reduction in electrical losses of cell connectors. The module current also is enhanced by about 3%. In contrast, another team of researchers focuses on the system as a whole and how to deal with the shading of several modules within the system [ 20 , 21 ]. They investigate various systems under the influence of different PS patterns and experience new methods for static and dynamic connection. Dynamic connection means changing the connection form at the moment of shading. The attempts of this team are explained in detail in Section 1.2 . The contribution of this work concludes all the applications of small-scale PV systems (stand-alone and utility-connected systems). The study investigates the performance of small-scale PV systems for optimum performance under partial shading conditions and presents an effective solution for the PV systems’ owners with a set of guidelines to opt for the best configuration of their PV systems. The recommendations increase the output energy yield for the PV systems. Also, the study covers all the possible shading patterns, and to achieve that, a new reduction methodology to eliminate the equivalent patterns has been presented. 1.2. Literature Review To enhance the performance of solar energy under PS conditions, many efforts have been exerted in this regard. The authors of [ 20 ] tested various static configurations of the modules inside the array under 20 different PS patterns. A comparison was made to get the configuration that gives the best performance between static (series, parallel, series-parallel, bridge-linked, and total cross-tied). The study included three systems of different sizes (3 × 10), (4 × 5), and (5 × 5). In research [ 21 ], a (4 × 4) system was studied under PS conditions to extract the highest possible power using several different connections. The results were tested and verified through practical experiments. The modeling and evaluation of the performance of a system (7 × 7) under 14 shading patterns were discussed in [ 22 ]. The output power, voltage, and current at the maximum power point along with the number of local maximum points were compared. In research [ 23 ], a (2 × 4) system was studied under several shading patterns through MATLAB simulation and experimental verification. The results showed that the total-cross-tied (TCT) method provided the best performance, but the research did not include all possible shading patterns. In [ 24 ], six possible configurations for a (5 × 4) system were tested under PS. TCT was the best one when a column is entirely and unevenly shaded. Due to the demerits of the static form of the PV configuration, researchers have proposed to make a dynamic change of electrical connections according to the PS situation to give the best performance. In [ 25 ], static and dynamic reconfiguration techniques were studied to enhance a PV system’s performance. In [ 26 ], a (6 × 4) system was studied under four different levels of solar irradiance and the results were experimentally verified. In [ 27 ], a study was carried out on a (6 × 6) system under three levels of irradiance and a comparison between the TCT technique and magic square technique was introduced. In [ 28 ], the triple-tied configuration was studied and its performance was compared with the other techniques. Authors in [ 29 ] studied different reconfiguration techniques and a new scheme was presented to improve the performance of the system. Furthermore, authors in [ 30 ] presented a comprehensive study about static, reconfiguration, and metaheuristic interconnection schemes. TCT, Su-Do-Ku, Dominance square, competence square, and a proposed array configuration were studied in detail in [ 31 ]. A new Su-Do-Ku PV configuration is proposed like hyper Su-Do-Ku and compared with the already existing PV array configurations in [ 32 ]. Research [ 33 ] presented a new socio-inspired PV reconfiguration approach, called democratic political to effectively reduce the mismatching power losses. Three case studies were carried out to verify the proposed technique. On the other side, research [ 34 ] focused on large-sized systems such as (16 × 16) and (25 × 25). Also, research [ 35 ] assessed the shading losses in a large PV power plant with 2.85 MW nominal power and 10,010 modules. It introduced a methodology for the assessment of annual energy loss for the large PV stations. An improved dynamic array reconfiguration strategy was proposed based on current injection in [ 36 ]. In this strategy, the output power output and the multiple peaks in the PV array characteristic curve were also avoided. However, it needed some modifications in the power converters. A dynamic L-shaped reconfiguration was presented in [ 37 ], relying on changing each array connection to be in the form of letter L to enhance the amount of power generated from the system. In addition, a new array configuration was presented. Re-allocation of a PV module-fixed electrical connection was introduced in [ 38 ] where a new proposed “Shape-do-ku” puzzle was presented and simulated for a (4 × 4) system. 1.3. Novelty of Work Most of the past research focused on studying PV systems under the influence of a specific number of shading patterns, but the PS patterns cannot be fully evaluated. Moreover, most of the previous studies focused on large systems, and there are no comprehensive studies on small systems, despite their prevalence in the homes of low-consumption rural areas. In addition, small PV systems can be used in urban houses to partially supply the required electricity and to integrate into the public electricity grid. They can be sometimes used to energize streetlights on highways. On the other side, with the development of manufacturing technology and the use of multilayer boards, the resulting capacity of one module is increasing. That makes the PV systems need a smaller number of PV modules for the same power generated. However, the loss of electricity resulting from one module as a result of partial shading is more effective. Our study comes here as a good contributor in this area of research. It provides a comprehensive investigation of the performance of small PV systems (consisting of 10 modules or fewer) rather than for large systems as in most previous studies. PV systems are tested under all possible shading patterns as a result of a single shading level (300 W/m 2 ) for common wiring configurations rather than for a set number of patterns as in previous studies. To be able to cover all possible PS patterns, a new reduction methodology is proposed to eliminate the equivalent patterns. Consequently, the number of studied patterns is limited to a feasible value as low as 100 cases. The study affords a few recommendations for the proper choice of the PV system configuration, seeking optimum performance under PS conditions. 2. Mathematical Modeling There are several ways to model a PV cell as a single diode model (SDM), double diode model, and triple diode model. SDM does not provide highly accurate results in large systems due to inherent variations in cell characteristics [ 24 ]. However, since the study is concerned with small systems, SDM would be appropriate for both simplicity and a reasonable level of accuracy. SDM PV equivalent circuit is illustrated in Figure 1 . SDM is also available in Simulink as in Figure 2 , which makes it easier to re-study for similar systems with different variables. The current of PV cell is related to the module voltage, thermal voltage, series and parallel resistance, and diode ideality factor as: I p v = I p h 0 ( e V p v + I p v R s a V t − 1 ) − V p I p v R s R s h (1) where I PV : output current of the PV cell, I ph : light generated current, I 0 : reverse saturation current, R S : series resistance, a: diode ideality factor, R sh : shunt resistance, and V t : thermal voltage of the module which is given as: V t = K T N s q (2) where K : Boltzmann’s constant, T : absolute temperature in Kelvins, q : electron charge, N S : number of series cells. The generated current is directly related to the amount of irradiance as: I p h T C (3) where G : solar irradiance, K i : temperature coefficient of short circuit current, and T STC : reference temperature at the standard test conditions ( STC ). The standard test conditions are defined by: G STC = 1000 W/m 2 , air mass ratio = 1.5, and temperature of the module = 25 °C. Finally, the reverse saturation current can be extracted from open circuit voltage V OC at STC and temperature voltage coefficient K V as: = I S C , S T C + K i ( T − T S T C ) e V p v + I p v R s a V t − 1 (4) Suntech Power STD275-24-Vd PV module is used where its parameters and data specification are taken from the database of National Renewable Energy Laboratory (NREL) as in Table 1 . To validate the model, the simulated results are compared with the practical data (taken from the datasheet [ 39 ]) of the Suntech Power STD275-24-Vd PV module. Figure 3 a,b represents the I-V and P-V curves for the designed model and datasheet. It is observed that there is an agreement between the model results and the practical data. 3. System Description In this study, the focus is on small PV systems, which are identified as systems with 10 modules or fewer. A comprehensive study of these small systems under PS conditions is introduced. Since there are not many possible ways to connect small systems (unlike large systems), it can be considered that they are mainly limited to a small number of common static configurations as (Series, Parallel, series-parallel (SP), and total-cross-tied TCT). Since the series configuration is characterized by being the least in the number of connecting wires, it has several disadvantages such as: the low value of the current produced under normal conditions, the large value of the voltage on both ends of the system, and the significant decrease in the generated power when PS occurs [ 14 ]. In contrast, the parallel configuration is characterized by having one maximum power point under both normal conditions and PS conditions. It also gives the highest power under PS conditions. Nevertheless, it is disadvantaged by the large amount of current passing through the installation and into the inverter or batteries, as well as low output voltage levels [ 16 ]. This makes both methods unfavorable options in most cases. Therefore, it can be considered that the comparison is mainly between SP and TCT for static configurations. Also, dynamic switching between SP and TCT is proposed to be investigated in addition to TCT-reconfiguration (in which the shaded module positions are changed according to the PS pattern). PV systems can be divided into two main types: i. Symmetrical dimension systems: symmetrical systems that consist of 10 modules or fewer with equal numbers of rows and columns are mainly configured in two systems (2 × 2) and (3 × 3). ii. Asymmetrical dimension systems: asymmetrical systems are those in which the number of rows is not equal to the number of columns. Asymmetrical systems that consist of 10 modules or fewer are mainly configured in three systems (2 × 3), (2 × 4), and (2 × 5). 4. Shading Patterns Description Although the probability of some shading patterns is greater than other patterns, it is difficult to predict the typical shading pattern. Moreover, some shading patterns arise after the installation of the system. What distinguishes this research is the possibility of studying all shadow patterns that may occur in small PV systems resulting from one level of shading. A shading level of 300 W/m 2 is chosen, while the normal condition is a solar irradiance level of 1000 W/m 2 . It is also considered that the module temperature is constant at 25 °C. Because of the limited size of the system, all possible shading patterns can be identified and counted as in Table 2 . There are 1862 possibilities for the five PV systems. A simplifying method is presented to reduce the number of shading possibilities. In order to avoid repetition, it is sufficient to keep one case in which the shading pattern is similar in both connections’ SP and TCT. So, all patterns in which the number of shaded modules in all rows and columns of the first pattern is equal to all rows and columns of the second type are characterized by giving an equal performance in both configurations of SP and TCT. For example, when studying the system shown in Figure 4 , it is noticed that both patterns of PS give the same performance when connected to the two configurations under study. Consequently, it is sufficient to study only one pattern of the two. In other words, swapping a column for another column, or a row for another row does not affect the performance of the system for both SP and TCT. This limits all possible shading patterns to a limited number for comparison. From Table 2 , it is clear that the proposed method reduces the probable cases from 1862 to only 100 cases, which can be conveniently studied. 5. Performance Parameters To compare different configurations, performance assessment parameters must be determined to choose the best configuration that gives the highest performance. Selected factors are open-circuit voltage V OC , short-circuit current I SC , global maximum power point voltage V GMPP , global maximum power point current I GMPP , power losses, and the number of local maximum power points. The mismatching power loss, PL % is given by: P o w e r l o s s , P l % = P M P P − P P S C P M P P × 100 (5) where P MPP and P PSC are the maximum power point values without any shading and with PS condition, respectively. As the PL value is less, the performance of the PV system is higher. The ratio of maximum power output to the input irradiance power is called the efficiency η% and calculated by (7): E f f i c i c y , η % = V M P P × I M P P G × A × 100 (6) where G is the solar irradiance and A is the net array area. As the η value is higher, the performance of the PV system is better. To measure the difference between static SP and TCT a simple equation is used. It is considered that static TCT is better than static SP by (K T %) defined as: K T % = P T C T − P S P P T C T × 100 (7) Also, to measure the difference between static TCT and Reconfigurable TCT another simple equation is used. It is considered that reconfigurable TCT is better than static TCT by (K RT %) defined as: K R T % = P T C T m a x − P T C T P T C (8) where PTCT max is the maximum power for the same number of shaded modules using reconfigurable TCT technique 6. Simulation Results and Discussion This section evaluates systems’ performance and shows the simulation results. The diagram in Figure 5 demonstrates the research methodology. For every PS case, the results are divided according to the number of shaded modules where the highest performance data is bolded if any. The measured parameters are V OC , I SC , V GMPP , I GMPP , P GMPP , PL , efficiency, and the number of local MPPs. The comparison for every case is between static SP, static TCT, the dynamic change between them, and reconfigurable TCT. The most important performance parameter in this comparative study is the global maximum power of the PV system. For this reason, our discussion is fundamentally based on the output power of the PV system under various shading patterns to evaluate different connectivity configurations. The best connectivity configuration is the one that produces the highest power under specific shading conditions for the same system. Although other performance parameters are of less importance, they are fully reported in the tables of Appendix A for the sake of completeness. In addition, the I-V and P-V characteristic curves of the different systems under study are also included in Appendix A for full characterization of the system. 6.1. Symmetrical Dimension Systems 6.1.1. System 2 × 2 System 2 × 2 consists of five possible cases, which can be classified into four sections according to the number of shaded modules. Figure 6 explains the output power for all system 2 × 2 cases. For one shaded module (case 1), TCT presents a better performance (with 774.6 W output power) than that of SP (726.2 W). The same observation can be applied when all the modules are shaded except one (as in case 5). Reconfigurable TCT cannot add new information as there are no multiple cases to choose from for the same number of shaded modules. However, when two modules are shaded, there are three cases (Case 2, 3, and 4). In case 2, TCT has the same performance as SP (with 539.1 W output). Case 3 also has the same performance for SP and TCT (with 719.1 W output). In case 4, TCT (with 719.1 W) is better than SP (with 539.1 W). So, it is observed that dynamic change between SP and TCT is useful only for case 4 and cannot improve the performance in either case 2 or case 3. On the other hand, with reconfigurable TCT, the shade pattern can be changed from case 2 to case 3 or 4 with an improvement in output power by 25.09%. That ensures the best performance for two shaded modules. In the case of static configuration, it is clear that the TCT configuration achieves better results in terms of the amount of power generated in three out of five possible cases, while it is equal to the SP configuration in only two cases. As a result, the dynamic switching between the two configurations does not introduce any advantage. In the case of TCT-reconfiguration, the amount of improvement in the resulting power is only in one case out of the five cases, with a noticeable increase in the amount of power and a single MPP in the I-V curve. Reconfigurable TCT reduces the number of maximum power points to the least possible value among all cases of TCT. Figure A1 shows the I-V and P-V characteristic curves of the five cases, divided according to the number of shaded modules. The curves indicate the numbers and positions of local maximum power points as well as the position of the global maximum power point. V MPP of TCT in all cases (except case 2) is near to the V OC values. In contrast, with TCT reconfiguration, the V MPP of all cases is kept near to the V OC values. Table A1 presents more details about the simulated results and of the performance parameters for various shading cases. 6.1.2. System 3 × 3 Practically, system 3 × 3 is more common than 2 × 2. System 3 × 3 has 32 possible shading cases, which can be divided into eight sections according to the number of shaded modules. The bar chart of the output power for different cases is shown in Figure 7 . Again, for one shaded module (case 1), TCT presents a better performance (with 2067 W output power) than SP (1914 W). The same conclusion can be drawn for case 32 with different power levels. Thus, reconfigurable TCT cannot introduce any improvement for the first and last cases. With two shaded modules (case 2, 3, and 4), the results are similar to that of the 2 × 2 system. TCT reconfigurable ensures the best output power (with 1978 W) where the dynamic change to SP improves case 2 (to 1674 instead of 1634). However, this does not ensure the best performance for the two shaded module cases. With three shaded modules, there are six possible cases (5 to 10). TCT reconfigurable here has more effective results as it can choose from six different cases. It can change from shade pattern in (case 5, 6, or 7) to give the highest possible power (of 1905 W). The improvement ratios are 14.2%, 22.3%, 22.3% for the three cases, respectively. The same result can be observed at the state of four shaded modules, but with smaller improvement ratios (8.76%, 3.56%, and 3.56% for cases 11, 13, and 14, respectively). For the rest shading states, symmetry is observed. The states of five, six, seven, and eight shaded modules are similar to four, three, two, and one shaded modules, respectively. This is due to the symmetric dimension of the system. It can be inferred from Figure 7 , that the TCT method is superior in 24 out of 32 possible cases, while it is equal to the SP method in only four cases. Consequently, in the case of static configuration, SP configuration is not preferred, while the dynamic switching between the two configurations improves only four cases by a small percentage in most cases. The location of the same number of shaded modules significantly affects the system performance. For this reason, reconfigurable TCT has a significant effect on the performance. With the TCT reconfiguration technique, the performance is improved in 16 cases, which represents 50% of all the possible cases, and the percentage of power improvement is larger compared to the dynamic method. So, the TCT reconfiguration technique is highly recommended. Five cases (4, 7, 14, 15, and 28) have significantly smaller V MPP in SP than TCT, where only one case (27) has the opposite state. From Figure A2 b, it is observed that with TCT reconfiguration, case 3 may be the best replacement for the different shading patterns with a good position of the global MPP. The same observation can be extracted from Figure A2 a–e. The simulated results of different performance parameters are reported in Table A2 . 6.2. Asymmetrical Dimension Systems They comprise the systems in which the number of rows does not equal the number of columns, including systems 2 × 3, 2 × 4, and 2 × 5. Here, 11, 20, and 32 cases are presented for systems 2 × 3, 2 × 4, and 2 × 5, respectively. 6.2.1. System 2 × 3 The 2 × 3 system is considered one of the simplest cases of asymmetric systems and is characterized by 11 possible PS cases for one level of shading when comparing between TCT and SP. Figure 8 shows the bar chart of the output power for all system shading cases. When one module is shaded, TCT presents better output power by 5.3% than SP. The same result is found in the case of shading five modules (TCT is 4.9% better than SP). At the state of two shaded modules, TCT is better than SP in case 2 (with output power 6.61% higher) and case 4 (with output power 28.78% higher). However, TCT gives the same performance as SP in case 3. Reconfigurable TCT can change the shading pattern in case 3 to achieve an output power of 1270 W with an improvement ratio of 23.74%. Three and four shaded modules states are similar to the two shaded in the output performance but with a smaller output power owing to the wider shaded area. There is also an exception in case 8 where SP is better than TCT by a smaller ratio (0.5%). However, the optimum performance for four shaded modules can be achieved with reconfigurable TCT as in cases 9 and 10. Thorough simulation results of the performance parameters under various shading conditions can be found in Table A3 . In summary, the TCT method is superior in 7 out of 11 possible cases, while it is equal to the SP method in three cases. SP is outperformed in only one case by a very small percentage. This shows that in the case of static configuration, TCT is highly preferred over the SP configuration. The dynamic switching between the two configurations does not introduce any significant effect. In the case of TCT-reconfiguration, it is noticed that the performance improves in three cases, with a high percentage of power improvement. It is interesting to note that TCT provides higher V MPP values almost in all cases than that of the SP method. The I-V and P-V characteristic curves of the eleven cases are shown in Figure A3 , classified according to the number of shaded modules. From every figure (from Figure A3 a–e), representing a specific state, the best TCT, which is a used case for the TCT reconfiguration, can be easily extracted along with the position of the MPP location. 6.2.2. System 2 × 4 System 2 × 4 is characterized by 20 possible shading patterns for one shading level when comparing TCT and SP. The simulated output power is demonstrated in Figure 9 . One, two, and three shaded modules states are similar in the general performance to those of 2 × 3 systems with just different output power values. However, four shaded modules states have six possible cases. TCT performance is equal to SP in two cases (8 and 11 with 1078 W) and TCT is better in the rest four cases (with 1146 W for cases 9 and 10 and 1439 W for cases 12 and 13). This gives the reconfigurable TCT the ability to improve four cases to give 1439 W with an improvement ratio of 20.36% (for cases 8 and 11) and 25.1% (for cases 9 and 10). Five, six, and seven shaded modules states are similar in the general performance to three, two, and one shaded modules states, respectively. In addition, more improvement ratios are remarkable when using reconfigurable TCT with 20.73% in case 14 and 30.38% in case 17. In conclusion, the TCT method is superior in 15 cases, while it is equal to the SP method in four cases only. SP is better in only one case by a slight percentage. It is noticeable here that TCT presents higher V MPP values in seven cases than SP, while the voltage values are almost equal in the rest cases. Again, in the static configuration, the SP method is not highly preferred when compared to TCT, while the dynamic switching between the two configurations does not add any significant effect. In the case of TCT-reconfiguration, the performance improves in seven cases, with a significant percentage of power improvement. For complete characterization of the performance parameters, one may refer to Table A4 . The I-V and P-V characteristic curves of the 20 cases are shown in Figure A4 . 6.2.3. System 2 × 5 System 2 × 5 has 32 cases and can be classified into nine groups according to the number of shaded modules. Figure 10 explains the output power for all 2 × 5 system cases. The TCT method is better than SP in 23 cases with a ratio of output power improvement between 4% and 31.36%. In contrast, SP is slightly better in only three cases 16, 20, and 26 with output-power improvement percent of 0.82%, 0.26%, and 0.65%, respectively. For the remaining six cases, SP gives the same performance as TCT. Again, in the static configuration, the SP method is not preferred when compared to TCT, while the dynamic switching between the two configurations does not give any significant performance change. Reconfigurable TCT can give an output power better than TCT. The performance is improved in seven states when using TCT-reconfiguration, with a noticeable percentage of power improvement. It can improve one case, in each group of two, three, seven, and eight shaded modules, with 10.38% in case 2, 16.31% in case 5, 25% in case 26, and 25.4% in case 29, respectively. The improvement is more significant in the states of four, five, and six shaded modules. In each of the three states, there are six possible cases. Half of them have the highest possible power, where reconfigurable TCT can improve the other half to give output power as the first half. The improvement ratio can be as large as 32.26% as in case 8. Additionally, it is worth mentioning that the TCT introduces a higher V MPP value, compared to that of SP, in a quarter of the possible cases, while it is almost equal in the rest of the cases. Consequently, the TCT-reconfiguration method ensures the highest possible V MPP value in all cases. From the I-V and P-V characteristic curves of the 32 cases that are shown in Figure A5 , the best case for the TCT reconfiguration can be determined along with the location of the global MPP. Moreover, a comparison between the partial pattern and the unshaded case may be conducted. The full simulated performance parameters are reported in Table A5 . 7. Conclusions The present study presents a performance investigation of small PV systems under all possible shading patterns. Small systems are defined as those consisting of 10 modules or fewer. There are five configurations that are most commonly used; two of which are symmetrical (2 × 2 and 3 × 3) and three are asymmetrical (2 × 3, 2 × 4, and 2 × 5). The main techniques of small static systems are SP and TCT. All possible shading patterns, arising from a single shading level (300 W/m 2 ) under the two wiring techniques (SP and TCT), are studied. A new simplifying method is utilized to reduce the number of cases to be studied. The proposed method reduces the probable cases from 1862 to only 100 cases for the five systems. TCT configuration shows superiority in most cases, which makes TCT configuration the best static configuration for small PV systems. Some systems may follow the technique of dynamic switching between the (SP and TCT) according to the PS pattern to choose the best one. However, by applying this to small systems, it is notable that the amount of resultant improvement is slight or even has no value such as a 2 × 2 system. Thus, the extra complexity associated with dynamic switching does not compensate for the expected improvement. The technique of TCT-reconfiguration (in which the shaded modules positions are re-arranged in the array according to the PS pattern by changing the electrical connections) is also tested to obtain the highest possible performance. Significant improvement is observed in a large number of cases in all small PV systems. This improvement occurs with the increase in the number of shaded units in half the system. The only drawback of this method is the need for many connections. However, due to the limited size of these systems, the required cable lengths are not long. Hence, it is highly recommended to those who intend to develop their custom systems not to adopt dynamic switching configuration, but to implement TCT-reconfiguration. Furthermore, those who prefer to stick to static-configuration systems for their simplicity should follow the configurations of static TCT. Table 3 summarizes the number of cases in which TCT excelled in static configurations, in front of the number of cases that improved when transitioning to the dynamic switching between the SP and TCT configurations. The number of improved cases with TCT-reconfiguration techniques is also compared to the static TCT. Author Contributions Conceptualization, M.A.M.Y., A.M.M. and Y.S.M.; methodology, A.M.M.; software, A.M.M.; validation, M.A.M.Y., Y.A.K. and Y.S.M.; formal analysis, M.A.M.Y.; investigation, A.M.M.; writing—original draft preparation, A.M.M.; writing—review and editing, A.M.M., Y.A.K. and M.A.M.Y.; supervision, M.A.M.Y. and Y.S.M.; project administration, M.A.M.Y.; funding acquisition, M.A.M.Y. All authors have read and agreed to the published version of the manuscript. Funding This work was funded by the Deanship of Scientific Research at Jouf University under grant No. (DSR-2021-02-03102). Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Appendix A Table A1. System 2 × 2 case studies and the resulted data. Table A1. System 2 × 2 case studies and the resulted data. Case Number. Number of Shaded Modules Partial Shading Pattern Series-Parallel Total-Cross-Tied K T % K RT % V OC I SC V GMPP I GMPP P GMPP PL % Efficiency % Number of Local MPPs V OC I SC V GMPP I GMPP P GMPP PL % Efficiency % Number of Local MPPs 0 0 0 89.4 16.7 70.2 15.7 1100 0.00 14.17 1 89.4 16.7 70.2 15.7 1100 0.00 14.17 1 0.00 0.00 0 0 0 1 1 1 88.5 16.7 71.3 10.2 726.2 33.98 9.36 2 88.5 16.7 73.9 10.5 774.6 29.58 9.98 2 6.25 0.00 0 1 0 2 2 2 87.3 16.7 34.4 15.7 539.1 50.99 6.95 2 87.3 16.7 34.4 15.7 539.1 50.99 6.95 2 0.00 25.09 0 1 1 3 1 87.7 10.8 70.6 10.2 719.7 34.57 9.27 1 87.7 10.8 70.6 10.2 719.7 34.57 9.27 1 0.00 0.00 1 2 0 4 1 87.3 16.7 34.4 15.7 539.1 50.99 6.95 2 87.7 10.8 70.6 10.2 719.7 34.57 9.27 1 25.09 0.00 1 1 1 5 3 2 86.3 10.8 35 10.2 356.1 67.63 4.59 2 86.5 10.8 76 4.85 369 66.45 4.75 2 3.50 0.00 1 2 1 Figure A1. (I-V) and (P-V) characteristic curves of the PV 2 × 2 system under different numbers of shaded modules as follow: ( a ) One shaded module, ( b ) Two shaded modules, and ( c ) Three shaded modules. Figure A1. (I-V) and (P-V) characteristic curves of the PV 2 × 2 system under different numbers of shaded modules as follow: ( a ) One shaded module, ( b ) Two shaded modules, and ( c ) Three shaded modules. Table A2. System 3 × 3 case studies and the resulted data. Table A2. System 3 × 3 case studies and the resulted data. Case Number. Number of Shaded Modules Partial Shading Pattern Series-Parallel Total-Cross-Tied K T % K RT % V OC I SC V GMPP I GMPP P GMPP PL % Efficiency % Number of Local MPPs V OC I SC V GMPP I GMPP P GMPP PL % Efficiency % Number of Local MPPs 0 0 0 134.1 25 105.4 23.5 2476 0.00 14.18 1 134.1 25 105.4 23.5 2476 0.00 14.18 1 0.00 0.00 0 0 0 0 0 1 1 1 133.4 25 106.3 18 1914 22.70 10.96 2 133.5 25 110.7 18.7 2067 16.52 11.84 2 7.40 0.00 0 0 1 0 0 2 2 2 132.8 25 71.4 23.5 1674 32.39 9.59 2 132.9 25 69.6 23.5 1634 34.01 9.36 2 −2.45 17.39 0 0 1 1 0 3 1 132.9 25 106.1 18 1912 22.78 10.95 2 133 25 107.9 18.3 1978 20.11 11.33 2 3.34 0.00 1 0 2 0 0 4 1 132.8 25 71.4 23.5 1674 32.39 9.59 2 133 25 107.9 18.3 1978 20.11 11.33 2 15.37 0.00 1 0 1 1 0 5 3 3 132 25 96.6 23.5 1634 34.01 9.36 2 132 25 96.6 23.5 1634 34.01 9.36 2 0.00 14.23 0 0 1 1 1 6 2 132.1 25 108.2 12.5 1355 45.27 7.76 3 132.3 25 113.7 13 1481 40.19 8.48 3 8.51 22.26 1 0 2 1 0 7 2 132 25 96.6 23.5 1634 34.01 9.36 2 132.3 25 113.7 13 1481 40.19 8.48 3 −10.33 22.26 1 0 1 1 1 8 1 132.4 19.2 105.6 18 1905 23.06 10.91 1 132.4 19.2 105.6 18 1905 23.06 10.91 1 0.00 0.00 1 1 3 0 0 9 1 132.1 25 108.2 12.5 1355 45.27 7.76 3 132.4 19.2 105.6 18 1905 23.06 10.91 1 28.87 0.00 1 1 2 1 0 10 1 132 25 96.6 23.5 1634 34.01 9.36 2 132.4 19.2 105.6 18 1905 23.06 10.91 1 14.23 0.00 1 1 1 1 1 11 4 3 131.3 25 70.1 18 1263 48.99 7.23 3 131.5 25 72.1 18.5 1334 46.12 7.64 3 5.32 8.76 1 0 2 1 1 12 2 131.6 19.2 107.2 12.54 1345 45.68 7.70 2 131.8 19.2 112.3 13 1462 40.95 8.37 2 8.00 0.00 1 1 3 1 0 13 2 131.6 25 107.9 12.5 1353 45.36 7.75 2 131.7 25 110.2 12.8 1410 43.05 8.07 2 4.04 3.56 2 0 2 2 0 14 2 131.3 25 70.1 18 1263 48.99 7.23 3 131.7 25 110.2 12.8 1410 43.05 8.07 2 10.43 3.56 2 0 1 2 1 15 2 131.3 25 70.1 18 1263 48.99 7.23 3 131.8 19.2 112.3 13 1462 40.95 8.37 2 13.61 0.00 1 1 1 1 2 16 1 131.6 25 107.9 12.5 1353 45.36 7.75 2 131.8 19.2 112.3 13 1462 40.95 8.37 2 7.46 0.00 2 1 2 2 0 17 5 3 130.7 25 71.6 12.5 897 63.77 5.14 3 130.8 25 74.3 12.9 959.4 61.25 5.49 3 6.50 31.08 2 0 2 2 1 18 2 131 19.2 107 12.6 1343 45.76 7.69 2 131.1 19.2 108.9 12.8 1392 43.78 7.97 2 3.52 0.00 2 1 3 2 0 19 2 130.7 25 71.6 12.5 897 63.77 5.14 3 131.1 19.2 108.9 12.8 1392 43.78 7.97 2 35.56 0.00 2 1 2 1 2 20 3 130.7 25 71.6 12.5 897 63.77 5.14 3 130.9 19.2 69.8 18 1257 49.23 7.20 2 28.64 9.70 1 1 2 1 2 21 2 130.8 19.2 70.1 18 1263 48.99 7.23 2 131.1 19.2 108.9 12.8 1392 43.78 7.97 2 9.27 0.00 1 2 3 1 1 22 3 130.8 19.2 70.1 18 1263 48.99 7.23 2 130.9 19.2 69.8 18 1257 49.23 7.20 2 −0.48 9.70 1 1 3 1 1 23 6 3 129.9 25 113.2 7.2 817.3 66.99 4.68 2 129.9 25 113.2 7.2 817.3 66.99 4.68 2 0.00 38.73 3 0 2 2 2 24 2 130.5 13.3 106.3 12.6 1334 46.12 7.64 1 130.5 13.3 106.3 12.6 1334 46.12 7.64 1 0.00 0.00 2 2 3 3 0 25 3 130 19.1 71.7 12.5 896.7 63.78 5.13 3 130.3 19.2 73 12.9 941.2 61.99 5.39 3 4.73 29.45 2 1 3 2 1 26 2 129.9 25 113.2 7.2 817.3 66.99 4.68 2 130.5 13.3 106.3 12.6 1334 46.12 7.64 1 38.73 0.00 2 2 2 2 2 27 3 129.9 25 113.2 7.2 817.3 66.99 4.68 2 130.3 19.2 73 12.9 941.2 61.99 5.39 3 13.16 29.45 2 1 2 2 2 28 2 130 19.1 71.7 12.5 896.7 63.78 5.13 3 130.5 13.3 106.3 12.6 1334 46.12 7.64 1 32.78 0.00 2 2 3 2 1 29 7 3 129.3 19.2 111.1 7.2 759.2 69.34 4.35 2 129.3 19.2 112.3 7.2 811.2 67.24 4.65 2 6.41 7.92 3 1 3 2 2 30 3 129.4 13.3 71.7 12.5 896.4 63.80 5.13 2 129.6 13.3 70.2 12.6 880.8 64.43 5.04 2 −1.77 0.00 2 2 3 3 1 31 3 129.3 19.2 111.1 7.2 759.2 69.34 4.35 2 129.6 13.3 70.2 12.6 880.8 64.43 5.04 2 13.81 0.00 2 2 3 2 2 32 8 3 128.6 13.3 109.4 7.1 778.8 68.55 4.46 2 128.7 13.3 111.1 7.2 802.1 67.61 4.59 2 2.90 0.00 3 2 3 3 2 Figure A2. (I-V) and (P-V) characteristic curves of the PV 3 × 3 system under different numbers of shaded modules as follow: ( a ) One shaded module, ( b ) Two shaded modules, ( c ) Three shaded modules, ( d ) Four shaded modules, ( e ) Five shaded modules, ( f ) Six shaded modules, ( g ) Seven shaded modules, and ( h ) Eight shaded modules. Figure A2. (I-V) and (P-V) characteristic curves of the PV 3 × 3 system under different numbers of shaded modules as follow: ( a ) One shaded module, ( b ) Two shaded modules, ( c ) Three shaded modules, ( d ) Four shaded modules, ( e ) Five shaded modules, ( f ) Six shaded modules, ( g ) Seven shaded modules, and ( h ) Eight shaded modules. Table A3. System 2 × 3 case studies and the resulted data. Table A3. System 2 × 3 case studies and the resulted data. Case Number. Number of Shaded Modules Partial Shading Pattern Series-Parallel Total-Cross-Tied K T % K RT % V OC I SC V GMPP I GMPP P GMPP PL % Efficiency % Number of Local MPPs V OC I SC V GMPP I GMPP P GMPP PL % Efficiency % Number of Local MPPs 0 0 0 89.4 25 70.2 23.5 1651 0.00 14.18 1 89.4 25 70.2 23.5 1651 0.00 14.18 1 0.00 0.00 0 0 0 0 1 1 1 88.8 25 70.8 18 1276 22.71 10.96 2 88.8 25 72.8 18.5 1347 18.41 11.57 2 5.27 0.00 0 1 0 0 2 2 2 88.1 25 72.2 12.5 904.5 45.22 7.77 2 88.8 25 75 12.9 968.5 41.34 8.32 2 6.61 23.74 0 1 1 0 3 1 88.3 19.2 70.4 18 1270 23.08 10.91 1 88.3 19.2 70.4 18 1270 23.08 10.91 1 0.00 0.00 1 2 0 0 4 1 88.1 25 72.2 15.5 904.5 45.22 7.77 2 88.3 19.2 70.4 18 1270 23.08 10.91 1 28.78 0.00 1 1 1 0 5 3 3 87.3 25 34.4 23.5 808.7 51.02 6.95 2 87.7 25 34.4 23.5 808.7 51.02 6.95 2 0.00 14.89 0 1 1 1 6 2 87.6 19.2 71.5 12.5 896.3 45.71 7.70 2 87.6 19.2 73.7 12.9 950.2 42.45 8.16 2 5.67 0.00 1 2 1 0 7 2 87.3 25 34.4 23.5 807.7 51.08 6.94 2 87.6 19.2 73.7 12.9 950.2 42.45 8.16 2 15.00 0.00 1 1 1 1 8 4 3 86.7 19.2 34.8 18 625.3 62.13 5.37 2 86.8 19.2 34.6 18 622.2 62.31 5.34 2 −0.50 30.06 1 2 1 1 9 2 87 13.3 70.9 12.6 889.6 46.12 7.64 1 87 13.3 70.9 12.6 889.6 46.12 7.64 1 0.00 0.00 2 2 2 0 10 2 86.7 19.2 34.8 18 625.3 62.13 5.37 2 87 13.3 70.9 12.6 889.6 46.12 7.64 2 29.71 0.00 2 2 1 1 11 5 3 86 13.3 73.3 7.1 521 68.44 4.48 2 86.1 13.3 75.3 7.3 548.1 66.80 4.71 2 4.94 0.00 2 2 2 1 Figure A3. (I-V) and (P-V) Characteristic curves of the PV 2 × 3 system under different numbers of shaded modules as follow: ( a ) One shaded module, ( b ) Two shaded modules, ( c ) Three shaded modules, ( d ) Four shaded modules, and ( e ) Five shaded modules. Figure A3. (I-V) and (P-V) Characteristic curves of the PV 2 × 3 system under different numbers of shaded modules as follow: ( a ) One shaded module, ( b ) Two shaded modules, ( c ) Three shaded modules, ( d ) Four shaded modules, and ( e ) Five shaded modules. Table A4. System 2 × 4 case studies and the resulted data. Table A4. System 2 × 4 case studies and the resulted data. Case Number. Number of Shaded Modules Partial Shading Pattern Series-Parallel Total-Cross-Tied K T % K RT % V OC I SC V GMPP I GMPP P GMPP PL % Efficiency % Number of Local MPPs V OC I SC V GMPP I GMPP P GMPP PL % Efficiency % Number of Local MPPs 0 0 0 89.4 33.3 70.2 31.4 2201 0.00 14.18 1 89.4 33.3 70.2 31.4 2201 0.00 14.18 1 0.00 0.00 0 0 0 0 0 1 1 1 89 33.3 70.6 25.9 1826 17.04 11.76 2 89 33.3 72.9 26.5 1913 13.08 12.32 2 4.55 0.00 0 1 0 0 0 2 2 2 88.5 33.3 71.3 20.4 1452 34.03 9.35 2 88.5 33.3 73.9 21 1549 29.62 9.98 2 6.26 14.89 0 1 1 0 0 3 1 88.5 33.3 71.3 20.4 1452 34.03 9.35 2 88.6 27.5 70.4 25.9 1820 17.31 11.72 1 20.22 0.00 1 1 1 0 0 4 1 88.6 27.5 70.4 25.9 1820 17.31 11.72 1 88.6 27.5 70.4 25.9 1820 17.31 11.72 1 0.00 0.00 1 2 0 0 0 5 3 3 87.9 33.3 35.1 31.1 1097 50.16 7.07 2 88 33.3 75.5 15.3 1159 47.34 7.47 2 5.35 23.80 0 1 1 1 0 6 2 88 27.5 71 20.4 1446 34.30 9.32 2 88.2 27.5 72.7 20.9 1521 30.90 9.80 2 4.93 0.00 1 2 1 0 0 7 2 87.9 33.3 35.1 31.1 1097 50.16 7.07 2 88.2 27.5 72.7 20.9 1521 30.90 9.80 2 27.88 0.00 1 1 1 1 0 8 4 4 87.3 33.3 34.4 31.1 1078 51.02 6.94 2 87.3 33.3 34.4 31.1 1078 51.02 6.94 2 0.00 25.09 0 1 1 1 1 9 3 87.6 27.5 72.2 14.9 1075 51.16 6.93 2 87.6 27.5 74.7 15.3 1146 47.93 7.38 2 6.20 20.36 1 2 1 1 0 10 3 87.3 33.3 34.4 31.1 1078 51.02 6.94 2 87.6 27.5 74.7 15.3 1146 47.93 7.38 2 5.93 20.36 1 1 1 1 1 11 2 87.7 21.7 70.6 20.4 1439 34.62 9.27 1 87.7 21.7 70.6 20.4 1439 34.62 9.27 1 0.00 0.00 2 2 2 0 0 12 2 87.5 27.5 72.2 14.9 1075 51.16 6.93 2 87.7 21.7 70.6 20.4 1439 34.62 9.27 1 25.30 0.00 2 1 2 1 0 13 2 87.3 33.3 34.4 31.1 1078 51.02 6.94 2 87.7 21.7 70.6 20.4 1439 34.62 9.27 1 25.09 0.00 2 1 1 1 1 14 5 4 86.8 27.5 34.6 25.8 894.7 59.35 5.76 2 86.8 27.5 34.5 25.8 891.8 59.48 5.74 2 −0.33 20.73 1 2 1 1 1 15 3 87 21.7 71.6 14.9 1067 51.52 6.87 2 87.1 21.7 73.5 15.3 1125 48.89 7.25 2 5.16 0.00 2 2 2 1 0 16 3 86.8 27.5 34.6 25.8 894.7 59.35 5.76 2 87.1 21.7 73.5 15.3 1125 48.89 7.25 2 20.47 0.00 2 1 1 2 1 17 6 4 86.3 21.7 35 20.3 712.2 67.64 4.59 2 86.5 21.7 76 9.7 738 66.47 4.75 2 3.50 30.38 2 2 2 1 1 18 3 86.6 15.8 71 14.9 1060 51.84 6.83 1 86.6 15.8 71 14.9 1060 51.84 6.83 1 0.00 0.00 3 2 2 2 0 19 3 86.3 21.7 35 20.3 712.2 67.64 4.59 2 86.6 15.8 71 14.9 1060 51.84 6.83 1 32.81 0.00 3 1 2 2 1 20 7 4 85.5 15.8 72.9 9.5 690.8 68.61 4.45 2 85.9 15.8 74.9 9.7 726.1 67.01 4.68 2 4.86 0.00 3 2 2 2 1 Figure A4. (I-V) and (P-V) Characteristic curves of the PV 2 × 4 system under different numbers of shaded modules as follow: ( a ) One shaded module, ( b ) Two shaded modules, ( c ) Three shaded modules, ( d ) Four shaded modules, ( e ) Five shaded modules, ( f ) Six shaded modules, and ( g ) Seven shaded modules. Figure A4. (I-V) and (P-V) Characteristic curves of the PV 2 × 4 system under different numbers of shaded modules as follow: ( a ) One shaded module, ( b ) Two shaded modules, ( c ) Three shaded modules, ( d ) Four shaded modules, ( e ) Five shaded modules, ( f ) Six shaded modules, and ( g ) Seven shaded modules. Table A5. System 2 × 5 case studies and the resulted data. Table A5. System 2 × 5 case studies and the resulted data. Case Number. Number of Shaded Modules Partial Shading Pattern Series-Parallel Total-Cross-Tied K T % K RT % V OC I SC V GMPP I GMPP P GMPP PL % Efficiency % Number of Local MPPs V OC I SC V GMPP I GMPP P GMPP PL % Efficiency % Number of Local MPPs 0 0 0 89.4 41.6 70.2 39.2 2751 0.00 14.18 1 89.4 41.6 70.2 39.2 2751 0.00 14.18 1 0.00 0.00 0 0 0 0 0 0 1 1 1 89.4 41.6 70.5 33.7 2376 13.63 12.24 2 89 41.6 71.7 34.5 2475 10.03 12.76 2 4.00 0.00 0 1 0 0 0 0 2 2 2 88.6 41.6 71 28.2 2002 27.23 10.32 2 88.7 41.6 73.2 29 2124 22.79 10.95 2 5.74 10.38 0 1 1 0 0 0 3 1 88.6 41.6 71 28.2 2002 27.23 10.32 2 88.7 35.8 70.3 33.7 2370 13.85 12.21 1 15.53 0.00 1 1 1 0 0 0 4 1 88.7 35.8 70.3 33.7 2370 13.85 12.21 1 88.7 35.8 70.3 33.7 2370 13.85 12.21 1 0.00 0.00 1 2 0 0 0 0 5 3 3 88.3 41.6 71.8 22.7 1630 40.75 8.40 2 88.3 41.6 74.6 23.4 1745 36.57 8.99 2 6.59 16.31 0 1 1 1 0 0 6 2 88.4 35.8 70.7 28.2 1995 27.48 10.28 2 88.4 35.8 72.1 28.9 2085 24.21 10.75 2 4.32 0.00 1 2 1 0 0 0 7 2 88.3 41.6 71.8 22.7 1630 40.75 8.40 2 88.4 35.8 72.1 28.9 2085 24.21 10.75 2 21.82 0.00 1 1 1 1 0 0 8 4 4 87.8 41.6 34.9 39.1 1366 50.35 7.04 2 87.9 41.6 75.9 17.8 1348 51.00 6.95 2 −1.34 32.26 0 1 1 1 1 0 9 3 87.9 35.8 71.4 22.7 1622 41.04 8.36 2 88 35.8 73.8 23.4 1725 37.30 8.89 2 5.97 13.32 1 2 1 1 0 0 10 3 87.8 41.6 34.9 39.1 1366 50.35 7.04 2 87.8 41.6 34.9 39.1 1366 50.35 7.04 2 0.00 31.36 1 1 1 1 1 0 11 2 88 30 70.5 28.2 1990 27.66 10.26 1 88 30 70.5 28.2 1990 27.66 10.26 1 0.00 0.00 2 2 2 0 0 0 12 2 87.9 35.8 71.4 22.7 1622 41.04 8.36 2 88 30 70.5 28.2 1990 27.66 10.26 1 18.49 0.00 2 1 2 1 0 0 13 2 87.8 41.6 34.9 39.1 1366 50.35 7.04 2 88 30 70.5 28.2 1990 27.66 10.26 1 31.36 0.00 2 1 1 1 1 0 14 5 5 87.3 41.6 34.3 39.2 1348 51.00 6.95 1 87.3 41.6 34.3 39.2 1348 51.00 6.95 1 0.00 20.43 0 1 1 1 1 1 15 4 87.4 35.8 72.8 17.2 1255 54.38 6.47 2 87.6 35.8 75.3 17.8 1337 51.40 6.89 2 6.13 21.07 1 2 1 1 1 0 16 4 87.3 41.6 34.3 39.2 1348 51.00 6.95 1 87.6 35.8 75.3 17.8 1337 51.40 6.89 2 −0.82 21.07 1 1 1 1 1 1 17 3 87.6 30 71.1 22.7 1616 41.26 8.33 2 87.7 30 72.6 23.3 1694 38.42 8.73 2 4.60 0.00 2 2 2 1 0 0 18 3 87.4 35.8 72.8 17.2 1255 54.38 6.47 2 87.7 30 72.6 23.3 1694 38.42 8.73 2 25.91 0.00 2 1 1 2 1 0 19 3 87.3 41.6 34.3 39.2 1348 51.00 6.95 1 87.7 30 72.6 23.3 1694 38.42 8.73 2 20.43 0.00 2 1 1 1 1 1 20 6 5 86.9 35.8 34.6 33.7 1164 57.69 6.00 2 87 35.8 34.5 33.7 1161 57.80 5.98 2 −0.26 27.84 1 2 1 1 1 1 21 4 87.1 30 72.2 17.3 1245 54.74 6.42 2 87.2 30 74.5 17.8 1323 51.91 6.82 2 5.90 17.78 2 2 2 1 1 0 22 4 86.9 35.8 34.6 33.7 1164 57.69 6.00 2 87.2 30 74.5 17.8 1323 51.91 6.82 2 12.02 17.78 2 1 1 1 2 1 23 3 87.3 24.1 70.7 22.8 1609 41.51 8.29 1 87.3 24.1 70.7 22.8 1609 41.51 8.29 1 0.00 0.00 3 2 2 2 0 0 24 3 87.1 30 72.2 17.3 1245 54.74 6.42 2 87.3 24.1 70.7 22.8 1609 41.51 8.29 1 22.62 0.00 3 1 2 2 1 0 25 3 86.9 35.8 34.6 33.7 1164 57.69 6.00 2 87.3 24.1 70.7 22.8 1609 41.51 8.29 1 27.66 0.00 3 1 1 2 1 1 26 7 5 86.5 30 34.8 28.2 981.3 64.33 5.06 2 86.6 30 34.6 28.2 975 64.56 5.02 2 −0.65 25.00 2 2 2 1 1 1 27 4 86.7 24.1 71.6 17.3 1237 55.03 6.37 2 86.8 24.1 73.4 17.7 1300 52.74 6.70 2 4.85 0.00 3 2 2 2 1 0 28 4 86.5 30 34.8 28.2 981.3 64.33 5.06 2 86.8 24.1 73.4 17.7 1300 52.74 6.70 2 24.52 0.00 3 1 1 2 2 1 29 8 5 86.1 24.1 73.6 11.9 872.6 68.28 4.50 2 86.2 24.1 75.6 12.1 917.5 66.65 4.73 2 4.89 25.41 3 2 2 2 1 1 30 4 86.4 18.3 71.2 17.3 1230 55.29 6.34 1 86.4 18.3 71.2 17.3 1230 55.29 6.34 1 0.00 0.00 4 2 2 2 2 0 31 4 86.1 24.1 73.6 11.9 872.6 68.28 4.50 2 86.4 18.3 71.2 17.3 1230 55.29 6.34 1 29.06 0.00 4 2 2 2 1 1 32 9 5 85.7 18.3 72.7 11.8 860.9 68.71 4.44 2 85.8 18.3 74.5 12.1 903.2 67.17 4.65 2 4.68 0.00 4 2 2 2 2 1 Figure A5. (I-V) and (P-V) characteristic curves of the PV 2 × 5 system under different numbers of shaded modules as follow: ( a ) One shaded module, ( b ) Two shaded modules, ( c ) Three shaded modules, ( d ) Four shaded modules, ( e ) Five shaded modules, ( f ) Six shaded modules, ( g ) Seven shaded modules, ( h ) Eight shaded modules, and ( i ) Nine shaded modules. Figure A5. (I-V) and (P-V) characteristic curves of the PV 2 × 5 system under different numbers of shaded modules as follow: ( a ) One shaded module, ( b ) Two shaded modules, ( c ) Three shaded modules, ( d ) Four shaded modules, ( e ) Five shaded modules, ( f ) Six shaded modules, ( g ) Seven shaded modules, ( h ) Eight shaded modules, and ( i ) Nine shaded modules. References Bollipo, R.B.; Mikkili, S.; Bonthagorla, P.K. Critical review on PV MPPT techniques: Classical, intelligent and optimization. IET Renew. Power Gener. 2020 , 14 , 1433–1452. [ Google Scholar ] [ CrossRef ] Subudhi, B.; Pradhan, R. A comparative study on maximum power point tracking techniques for photovoltaic power systems. IEEE Trans. Sustain. Energy 2013 , 4 , 89–98. [ Google Scholar ] [ CrossRef ] Jiang, S.; Wan, C.; Chen, C.; Cao, E.; Song, Y. Distributed photovoltaic generation in the electricity market: Status, mode and strategy. CSEE J. Power Energy Syst. 2018 , 4 , 263–272. [ Google Scholar ] [ CrossRef ] Wood, J. Renewable energy could power the world by 2050. Here’s what that future might look like. World Econ. Eorum 2020 . Available online: https://www.weforum.org/agenda/2020/02/renewable-energy-future-carbon-emissions/ (accessed on 3 January 2022). Reindl, K.; Palm, J. Installing PV: Barriers and enablers experienced by non-residential property owners. Renew. Sustain. Energy Rev. 2021 , 141 , 110829. [ Google Scholar ] [ CrossRef ] Kılıç, U.; Kekezoğlu, B. A review of solar photovoltaic incentives and Policy: Selected countries and Turkey. Ain Shams Eng. J. 2022 , 13 , 101669. [ Google Scholar ] [ CrossRef ] Almasri, R.A.; Alardhi, A.A.; Dilshad, S. Investigating the Impact of Integration the Saudi Code of Energy Conservation with the Solar PV Systems in Residential Buildings. Sustainability 2021 , 13 , 3384. [ Google Scholar ] [ CrossRef ] Mokhtara, C.; Negrou, B.; Settou, N.; Bouferrouk, A.; Yao, Y. Optimal design of grid-connected rooftop PV systems: An overview and a new approach with application to educational buildings in arid climates. Sustain. Energy Technol. Assess. 2021 , 47 , 101468. [ Google Scholar ] [ CrossRef ] Yousri, D.; Babu, T.S.; Mirjalili, S.; Rajasekar, N.; Elaziz, M.A. A Novel Objective Function with Artificial Ecosystem-Based Optimization for Relieving the Mismatching Power Loss of Large-Scale Photovoltaic Array. Energy Convers. Manag. 2020 , 225 , 113385. [ Google Scholar ] [ CrossRef ] Shimizu, T.; Hirakata, M.; Kamezawa, T.; Watanabe, H. Generation control circuit for photovoltaic modules. IEEE Trans. Power Electron. 2001 , 16 , 293–300. [ Google Scholar ] [ CrossRef ][ Green Version ] Ali, A.; Almutairi, K.; Padmanaban, S.; Tirth, V.; Algarni, S. Investigation of MPPT techniques under uniform and non-uniform solar irradiation condition—A retrospection. IEEE Access 2020 , 8 , 127368–127392. [ Google Scholar ] [ CrossRef ] Sahu, H.S.; Nayak, S.K.; Mishra, S. Maximizing the Power Generation of a Partially Shaded PV Array. IEEE J. Emerg. Sel. Top. Power Electron. 2016 , 4 , 626–637. [ Google Scholar ] [ CrossRef ] Mohamed, A.M.A.; El-Sayed, A.; Mohamed, Y.S.; Ramadan, H.A. Enhancement of photovoltaic system performance based on different array topologies under partial shading conditions. J. Adv. Eng. Trends 2021 , 40 , 49–62. [ Google Scholar ] [ CrossRef ][ Green Version ] Raj, A.; Gupta, M. Numerical Simulation and Comparative Assessment of Improved Cuckoo Search and PSO based MPPT System for Solar Photovoltaic System Under Partial Shading Condition. Turk. J. Comput. Math. Educ. 2021 , 12 , 3842–3855. Available online: https://turcomat.org/index.php/turkbilmat/article/view/7755 (accessed on 3 January 2022). Abri, W.A.; Abri, R.A.; Yousef, H.; Al-Hinai, A. A Simple Method for Detecting Partial Shading in PV Systems. Energies 2021 , 14 , 4938. [ Google Scholar ] [ CrossRef ] Chalh, A.; Hammoumi, A.E.; Motahhir, S.; Ghzizal, A.E.; Derouich, A.; Masud, M.; AlZain, M.A. Investigation of Partial Shading Scenarios on a Photovoltaic Array’s Characteristics. Electronics 2022 , 11 , 96. [ Google Scholar ] [ CrossRef ] Seritan, G.-C.; Enache, B.-A.; Adochiei, F.-C.; Argatu, F.C.; Christodoulou, C.; Vita, V.; Toma, A.R.; Gandescu, C.H.; Hathazi, F.-L. Performance Evaluation of Photovoltaic Panels Containing Cells with Different Bus Bars Configurations in Partial Shading Conditions. In Revue Roumaine des Sciences Techniques—Electrotechnique et Energetique ; Romanian Academy, Publishing House of the Romanian Academy: Bucharest, Romania, 2020; Volume 65, pp. 67–70. ISSN 0035-4066. Available online: http://elth.pub.ro/~sepius/REVUE/upload/77618212_GSeritan_RRST_1-2_2020_pp_67-70.pdf (accessed on 3 January 2022). Sarniak, M.T. Modeling the Functioning of the Half-Cells Photovoltaic Module under Partial Shading in the Matlab Package. Appl. Sci. 2020 , 10 , 2575. [ Google Scholar ] [ CrossRef ][ Green Version ] Hanifi, H.; Schneider, J.; Bagdahn, J. Reduced Shading Effect on Half-Cell Modules—Measurement and Simulation. In Proceedings of the 31st European Photovoltaic Solar Energy Conference and Exhibition, Hamburg, Germany, 14–18 September 2015; pp. 2529–2533, ISBN 3-936338-39-6. [ Google Scholar ] [ CrossRef ] Nazer, M.N.R.; Noorwali, A.; Tajuddin, M.F.N.; Khan, M.Z.; Tazally, M.A.I.A.; Ahmed, J.; Ghazali, N.H.; Chakraborty, C.; Kumar, N.M. Scenario-Based Investigation on the Effect of Partial Shading Condition Patterns for Different Static Solar Photovoltaic Array Configurations. IEEE Access 2021 , 9 , 116050–116072. [ Google Scholar ] [ CrossRef ] Madhu, G.M.; Vyjayanthi, C.; Modi, C.N. Investigation on Effect of Irradiance Change in Maximum Power Extraction From PV Array Interconnection Schemes During Partial Shading Conditions. IEEE Access 2021 , 9 , 96995–97009. [ Google Scholar ] [ CrossRef ] Bonthagorla, P.K.; Mikkili, S. Performance investigation of hybrid and conventional PV array configurations for grid-connected/standalone PV systems. CSEE J. Power Energy Syst. 2020 , 1–16. [ Google Scholar ] [ CrossRef ] Moballegh, S.; Jiang, J. Modeling, prediction, and experimental validations of power peaks of PV arrays under partial shading conditions. IEEE Trans. Sustain. Energy 2014 , 5 , 293–300. [ Google Scholar ] [ CrossRef ] Elyaqouti, M.; Izbaim, D.; Bouhouch, L. Study of the Energy Performance of Different PV Arrays Configurations Under Partial Shading. E3S Web Conf. 2021 , 229 , 01044. [ Google Scholar ] [ CrossRef ] Muhammad, A.; Babu, T.S.; Ramachandaramurthy, V.K.; Yousri, D.; Ekanayake, J.B. Static and dynamic reconfiguration approaches for mitigation of partial shading influence in photovoltaic arrays. Sustain. Energy Technol. Assess. 2020 , 40 , 100738. [ Google Scholar ] [ CrossRef ] Mishra, N.; Yadav, A.S.; Pachauri, R.; Chauhan, Y.K.; Yadav, V.K. Performance enhancement of PV system using proposed array topologies under various shadow patterns. Sol. Energy 2017 , 157 , 641–656. [ Google Scholar ] [ CrossRef ] Malathy, S.; Ramaprabha, R. Reconfiguration strategies to extract maximum power from photovoltaic array under partially shaded conditions. Renew. Sustain. Energy Rev. 2018 , 81 , 2922–2934. [ Google Scholar ] [ CrossRef ] Bonthagorla, P.K.; Mikkili, S. A novel fixed PV array configuration for harvesting maximum power from shaded modules by reducing the number of cross-ties. IEEE J. Emerg. Sel. Top. Power Electron. 2021 , 9 , 2109–2121. [ Google Scholar ] [ CrossRef ] Krishna, G.S.; Moger, T. Reconfiguration strategies for reducing partial shading effects in photovoltaic arrays: State of the art. Sol. Energy 2019 , 182 , 429–452. [ Google Scholar ] [ CrossRef ] Pachauri, R.K.; Mahela, O.P.; Sharma, A.; Bai, J.; Chauhan, Y.K.; Khan, B.; Alhelou, H.H. Impact of partial shading on various PV array configurations and different modeling approaches: A comprehensive review. IEEE Access 2020 , 8 , 181375–181403. [ Google Scholar ] [ CrossRef ] Venkateswari, R.; Rajasekar, N. Power enhancement of PV system via physical array reconfiguration based Lo Shu technique. Energy Convers. Manag. 2020 , 215 , 112885. [ Google Scholar ] [ CrossRef ] Anjum, S.; Mukherjee, V.; Mehta, G. Hyper SuDoKu-Based Solar Photovoltaic Array Reconfiguration for Maximum Power Enhancement Under Partial Shading Conditions. J. Energy Resour. Technol. 2022 , 144 , 031302. [ Google Scholar ] [ CrossRef ] Yang, B.; Shao, R.; Zhang, M.; Ye, H.; Liu, B.; Bao, T.; Wang, J.; Shu, H.; Ren, Y.; Ye, H. Socio-inspired democratic political algorithm for optimal PV array reconfiguration to mitigate partial shading. Sustain. Energy Technol. Assess. 2021 , 48 , 101627. [ Google Scholar ] [ CrossRef ] Yousri, D.; Babu, T.S.; Beshr, E.; Eteiba, M.B.; Allam, D. A robust strategy based on marine predators’ algorithm for large scale photovoltaic array reconfiguration to mitigate the partial shading effect on the performance of PV system. IEEE Access 2020 , 8 , 112407–112426. [ Google Scholar ] [ CrossRef ] Zsiborács, H.; Zentkó, L.; Pintér, G.; Vincze, A.; Baranyai, N.H. Assessing shading losses of photovoltaic power plants based on string data. Energy Rep. 2021 , 7 , 3400–3409. [ Google Scholar ] [ CrossRef ] Karmakar, B.K.; Karmakar, G. A Current Supported PV Array Reconfiguration Technique to Mitigate Partial Shading. IEEE Trans. Sustain. Energy 2021 , 12 , 1449–1460. [ Google Scholar ] [ CrossRef ] Srinivasan, A.; Devakirubakaran, S.; Sundaram, B.M.; Balachandran, P.K.; Cherukuri, S.K.; Winston, D.P.; Babu, T.S.; Alhelou, H.H. L-Shape Propagated Array Configuration with Dynamic Reconfiguration Algorithm for Enhancing Energy Conversion Rate of Partial Shaded Photovoltaic Systems. IEEE Access 2021 , 9 , 97661–97674. [ Google Scholar ] [ CrossRef ] Pachauri, R.K.; Kansal, I.; Babu, T.S.; Alhelou, H.H. Power Losses Reduction of Solar PV Systems Under Partial Shading Conditions Using Re-Allocation of PV Module-Fixed Electrical Connections. IEEE Access 2021 , 9 , 94789–94812. [ Google Scholar ] [ CrossRef ] MANUALZZ the Universal Manuals Library, STP275_270_24Vd1. Available online: https://manualzz.com/doc/10607158/stp275_270_24vd1 (accessed on 3 January 2022). Figure 1. Single diode model PV equivalent circuit. Figure 1. Single diode model PV equivalent circuit. Figure 2. Default MATLAB Simulink model. Figure 3. I-V and P-V curves at different radiation levels ( a ) Simulation results ( b ) Datasheet curves. Figure 3. I-V and P-V curves at different radiation levels ( a ) Simulation results ( b ) Datasheet curves. Figure 4. Examples to explain the simplifying method. Figure 4. Examples to explain the simplifying method. Figure 5. Diagram explaining the research methodology. Figure 5. Diagram explaining the research methodology. Figure 6. Bar chart of the output power for all 2 × 2 system cases. Figure 6. Bar chart of the output power for all 2 × 2 system cases. Figure 7. Bar chart of the output power for all 3 × 3 system cases. Figure 7. Bar chart of the output power for all 3 × 3 system cases. Figure 8. Bar chart of the output power for all 2 × 3 system cases. Figure 9. Bar chart of the output power for all 2 × 4 system cases. Figure 9. Bar chart of the output power for all 2 × 4 system cases. Figure 10. Bar chart of the output power for all 2 × 5 system cases. Figure 10. Bar chart of the output power for all 2 × 5 system cases. Table 1. Electrical characteristics of Suntech Power STD275-24-Vd PV module. Table 1. Electrical characteristics of Suntech Power STD275-24-Vd PV module. Parameter Value Maximum power (W) 275.184 Cells per module Ns 72 Open circuit voltage (V) 44.7 Short circuit current (A) 8.26 Voltage at maximum power point (V) 35.1 Current at maximum power point (A) 7.84 Voltage temperature coefficient (%/°C) −0.313 Current temperature coefficient (%/°C) 0.053995 Diode saturation current I 0 at STC (A) 4.8633 × 10 − 11 Diode ideality factor 0.93444 Shunt resistance (Ω) 830.73 Series resistance (Ω) 0.57826 Module efficiency at STC 14.2% Dimension 1.956 m × 0.992 m Table 2. Number of possible shading patterns before and after applying the simplifying method. Table 2. Number of possible shading patterns before and after applying the simplifying method. System Number of PS Patterns Can Be Simplified to a Repeated Distinguish Patterns Number of 2 × 2 4C1 = 4 1 4C2 = 6 3 4C3 = 4 1 Total = (14) Total = (5) 2 × 3 6C1 = 6 1 6C2 = 15 3 6C3 = 20 3 6C4 = 15 3 6C5 = 6 1 Total = (62) Total = (11) 2 × 4 8C1 = 8 1 8C2 = 28 3 8C3 = 56 3 8C4 = 70 6 8C5 = 56 3 8C6 = 28 3 8C7 = 8 1 Total = (254) Total = (20) 3 × 3 9C1 = 9 1 9C2 = 36 3 9C3 = 84 6 9C4 = 126 6 9C5 = 126 6 9C6 = 84 6 9C7 = 36 3 9C8 = 9 1 Total = (510) Total = (32) 2 × 5 10C1 = 10 1 10C2 = 45 3 10C3 = 120 3 10C4 = 210 6 10C5 = 252 6 10C6 = 210 6 10C7 = 120 3 10C8 = 45 3 10C9 = 10 1 Total = (1022) Total = (32) Five systems Total = 1862 Total = 100 Table 3. All possible numbers of improved cases according to the configuration. Table 3. All possible numbers of improved cases according to the configuration. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
https://www.mdpi.com/2071-1050/14/6/3681/htm
Doing Business in the 21st Century with the New Generation of Chinese Managers: A Study of Generational Shifts in Work Values in China | Request PDF Request PDF | Doing Business in the 21st Century with the New Generation of Chinese Managers: A Study of Generational Shifts in Work Values in China | Our goal is to develop a profile of Chinese managers, and in particular a profile of the New Generation of Chinese managers. The purpose for... | Find, read and cite all the research you need on ResearchGate Doing Business in the 21st Century with the New Generation of Chinese Managers: A Study of Generational Shifts in Work Values in China February 1999 Journal of International Business Studies 30(2):415-427 DOI: 10.1057/palgrave.jibs.8490077 Authors: Sally Stewart Abstract Our goal is to develop a profile of Chinese managers, and in particular a profile of the New Generation of Chinese managers. The purpose for developing this profile is primarily to provide relevant information for non-Chinese business people, especially Westerners, who plan to engage in business in China. This profile is based on measures of individual values (Individualism, Collectivism and Confucianism) relevant to China and business. Our findings suggest that the New Generation manager is more individualistic and more likely to act independently, while taking risks in the pursuit of profits. However, these New managers are, likewise, not forsaking their Confucian values. Thus, they may be viewed as crossverging their Eastern and Western influences, while on the road of modernization.© 1999 JIBS. Journal of International Business Studies (1999) 30, 415–427 2.3+ billion citations ... In the openness to change dimension, this study found that work meaningfulness has a role in bridging the relationship between openness to change toward work engagement. This finding contradicts a study by Ralston et al. (1999) that stated how individuals who value openness to new things and enjoy challenges tend to be incapable of focusing on what must be done. This is because individuals who value openness to change will consistently attempt to change and enjoy new challenges, hence they will try to seek better work opportunities in other places and seek better opportunities at what they think they are good at, which makes them to sustain or focus less on their jobs. ... ... Pada dimensi openness to change, studi ini menemukan bahwa work meaningfulness memiliki peran sebagai jembatan dalam hubungan openness to change terhadap work engagement. Temuan ini berkontradiksi dengan hasil studi oleh Ralston et al. (1999) yang menyatakan bahwa individu dengan nilai hidup terbuka pada hal baru dan menyukai tantangan cenderung tidak dapat berfokus pada apa yang dilakukan. Hal ini dikarenakan individu dengan nilai hidup terbuka pada perubahan selalu berusaha untuk berubah dan menyukai tantangan baru, sehingga mereka selalu berusaha untuk mengejar kesempatan kerja yang lebih baik di tempat lain dan mencari kesempatan yang mereka nilai lebih baik, yang menyebabkan mereka tidak bertahan lama dan berfokus pada pekerjaannya. ... Schwartz’s Values, Perceived Organizational Support (POS), and Work Engagement: The Mediating Role of Work Meaningfulness [Schwartz’s Values, Perceived Organizational Support (POS), dan Work Engagement: Peran Mediasi dari Work Meaningfulness] Conditions of the situation after the COVID-19 pandemic have an impact on the phenomenon of employee work engagement. Employees who are accustomed to working from home are asked to adjust to the new work design such as hybrid working. By having values and perceived organizational support (POS), employees who can find work meaningfulness will have higher work engagement in any work design after the COVID-19 pandemic. This study aims to examine the role of work meaningfulness as a mediator in the relationship between perceived organizational support (POS) and values toward work engagement. The data collection was carried out online and involved 220 Indonesian employees who worked in various fields. Study participants were recruited by purposive sampling method. Instruments of this study consist of the Survey of Perceived Organizational Support (SPOS), Portrait Values Questionnaire (PVQ), The Work and Meaning Inventory (WAMI), and Utrecht Work Engagement Scale (UWES). The data analysis in this study utilized the PROCESS mediation analysis. The results showed that work meaningfulness significantly had a mediating effect on perceived organizational support (POS) toward work engagement (β = .743; p < .001). Woek meaningfulness also had a mediating effect on values toward work engagement (β = .581; p < .001). Especially for values, work meaningfulness had a significant mediating effect on self-transcendence (β = .129; p < .01), openness to change (β = .120; p < .05), and conservation (β = .220; p < .01), but has no mediation effect on self-enhancement towards work engagement (β = .108; p > .05). This result confirms that having meaningfulness experience during working would increase the role of situational factors (perceived organizational support [POS]) and individual factor (values) toward work engagement. Kondisi pasca pandemi COVID-19 berdampak pada fenomena work engagement karyawan di tempat kerja. Karyawan yang terbiasa bekerja dari rumah diminta untuk menyesuaikan diri dengan desain kerja baru yang berupa hybrid working. Dengan memiliki values dan perceived organizational support (POS), karyawan yang dapat menemukan work meaningfulness akan memiliki work engagement yang lebih tinggi pada kondisi desain kerja apapun pasca pandemi COVID-19. Studi ini bertujuan menguji peran work meaningfulness sebagai mediator dalam hubungan antara perceived organizational support (POS) dan values terhadap work engagement. Pengumpulan data studi dilakukan secara daring dengan melibatkan 220 karyawan dari berbagai bidang. Partisipan studi direkrut dengan metode purposive sampling. Pengumpulan data menggunakan Survey of Perceived Organizational Support (SPOS), Portrait Values Questionnaire (PVQ), The Work and Meaningful Inventory (WAMI), dan Utrecht Work Engagement Scale (UWES). Analisis data menggunakan uji mediasi PROCESS. Hasil studi menunjukkan bahwa work meaningfulness secara signifikan memiliki efek mediasi pada perceived organizational support (POS) terhadap work engagement (β = 0,743; p < 0,001). Work meaningfulness juga mampu memediasi hubungan antara values dan work engagement (β = 0,581; p < 0,001). Khusus untuk variable values, work meaningfulness memiliki efek mediasi pada dimensi self-trancendence (β = 0,129; p < 0,01), openness to change (β = 0,120; p < 0,05), dan conservation (β = 0,220; p < 0,01) terhadap work engagement, namun pada dimensi self-enhancement, work meaningfulness tidak memiliki efek mediasi dalam hubungan antara self-enhancement terhadap work engagement (β = 0,108; p > 0,05). Hasil tersebut mengkonfirmasi bahwa memiliki pengalaman meaningful selama bekerja dapat meningkatkan peran faktor situasional (perceived organizational support [POS]) dan faktor individual (values) terhadap work engagement. ... Specifically for the Chinese context, the Chinese Cultural Connection (1987) study led by Michael Bond highlighted the importance of cultural values, and sparked off a number of peripheral studies about the uniqueness of the Chinese context. These are reviewed next for their relevance to a modern China, as particularly argued by Ralston et al. (1999) , China's rapid economic development since the 1970s has (already) resulted in significant generational shifts in work values (notwithstanding the impact of Industry 4.0). Thus, commonly associated Confucius values (see also Chau, 2013) have different meanings between the latter and present generations, which make it even more necessary to revisit the topic today. ... ... In a similar vein, Ralston et al. (1999) concluded that the rapid economic development in China since her opening-up policy could have the greatest influence in work values among different generations: more individualistic and less Confucian value ideologies were exposed to the new generation of Chinese managers compared with older ones. The combination of power distance and Chinese traditionality has been found to impact on organizational support and work outcomes, although power distance presented a stronger moderating effect than Chinese traditionalism (Farh et al., 2007). ... Insights on measuring China’s new national culture from leaders of the Fourth Industrial Revolution Ruiqi Zhang Liyan Tang Understanding China’s national culture is increasingly important for enabling greater international collaborative activities as China takes her central stage in the global arena. However, the country’s rapid modernization, such as through leading innovations in Industry 4.0 (specifically the ‘Made in China 2025’ policy), may have provoked a cultural turn that is difficult to capture with existing cultural measurement tools. This study conducted interviews with leaders of Chinese establishments that have updated their operations to the Industry 4.0 specification to understand their impact on general perception and workplace culture. Based on these insights, this article argues that existing models for measuring national culture are not necessarily being old that makes them unsuitable for application to a ‘new’ China but that Chinese establishments operating Industry 4.0 are a unique case for which generalized models can no longer be universally applicable. Instead, augmented/alternative cultural dimensions are suggested as new theoretical constructs for this unique context. ... In addition, individuals differ in their willingness to take responsibility for their harmful acts (Berscheid & Walster, 1967), especially due to different moral values rooted in culture. In Chinese society, Confucianism greatly shapes people's moral values despite the founding of the new China creating social change (Ralston, Egri, Stewart, Terpstra, & Kaicheng, 1999) . Confucian values have three elements, with ren emphasizing benevolence to or compassion for others (Wright & Twitchett, 1962), yi representing the principle of moral rightness (Cheng, 1972), and li specifying many concrete norms for social relationships (Wright & Twitchett, 1962). ... ... Moreover, when those around firm leaders also hold Confucian values, these individuals are likely to sensitize or even pressure firm leaders to accept responsibility for the harm. The impact of Confucian values varies across China due to its geographical vastness and the existence of many ethnic groups with subcultures (Ralston et al., 1999) . Thus, in areas with a stronger Confucian influence, leaders of privatized SOEs are more likely to recognize and feel responsible for the distress experienced by laid-off SOE workers and their families as a result of privatization and thus make restitution later through corporate philanthropy. ... Guilt and Corporate Philanthropy: The Case of the Privatization in China Firms’ harm-inflicting decisions/actions can make firm leaders feel guilt toward those who are harmed, which then motivates them to make restitution through corporate philanthropy. Our primary setting for investigating this proposition is the privatization of Chinese firms. We argue that massive layoffs resulting from privatization triggered guilt among firm leaders to drive corporate philanthropy. The analysis of a national survey of Chinese private firms shows that on average privatized firms made approximately 26% more charitable contributions than firms founded as private. This was particularly the case when (a) privatization resulted in layoffs (vs. no layoffs), (b) the firms’ provinces experienced greater unemployment at the time of privatization, (c) the firms’ leaders were directly involved in privatization, (d) the influence of Confucianism was stronger in their provinces, and (e) firm leaders had stronger ties with laid-off workers. An interview-based field study of 25 firm leaders involved in privatization provides qualitative evidence of the influence of guilt on privatized firms’ philanthropy. Finally, a vignette experiment conducted on EMBA students shows the mediation of guilt between privatization and firms’ philanthropic intention. These findings establish guilt as a potent emotional driver of corporate philanthropy, helping redirect the attention of corporate philanthropy research toward nonfinancial drivers. ... To address the research questions, a qualitative content analysis approach was used on a dataset obtained from interviews with managers from various backgrounds. Qualitative content analysis aims to interpret textual data through systematic classification process, with special consideration to their context, in order to identify the core concepts within the data (Mayring, 2010; Zhang and Wildemuth, 2016). It was chosen as method of inquiry because it is consistent with our research goal: during the data analysis, our goal was to identify the main concepts from the interviewees' narratives which relate to our research questions and provide a comparison between the concepts of The Analects, the concepts of international management literature on Confucian management and our empirical results. ... ... With all these considered, Confucianism is not the only ancient ideology impacting Chinese leadership ethics: Daoism, Mohism and Legalism also have had an influence (Cheung and Chan, 2005) -and there are many other cultural backdrops behind Chinese management. Therefore, and even though their impact is less emphasized and claimed to be less independent (Ralston et al., 1999) , the focus on Confucianism can also be considered as a limitation of this paper. ... Does Confucius have a say in management today Empirical evidence from Asia and Europe With the growing number of Sino-European business transactions, the cooperation of Chinese and European managers is becoming an increasingly important topic. In the theoretical foundation, we review the main concepts of Confucianism and apply them for modern management. The result is a conceptual framework which is tested in the empirical part, based on the results of more than 30 interviews. The data gained from Chinese managers was compared with that of a control group consisting of managers of European and Asian origin. The methodology and the findings of this research enabled us to discover more subtle differences between the concepts of Confucianism, Chinese, and Western management practices. View Show abstract ... We specifically focus on job demands as the push factors that affect Chinese migrant workers' decision to leave their urban job (i.e. the health-impairment process) and entrepreneurial resources as the pull factors that increase Chinese migrant workers' intention to seek self-employment as a career choice in their hometown (i.e. the motivational process) (Xanthopoulou et al. 2007). Further, given the significant economic, political, and social changes in transitional China and the effect of these changes on the work-value orientation of different generations of workers (Dou, Wang, and Zhou 2006;Egri and Ralston 2004; Ralston et al. 1999) , we attempt to discover whether there is any discrepancy in the antecedents of entrepreneurial intention between the 'new' and 'old' generations of migrant workers in China. ... ... Significant economic, political, and social changes in transitional China in the past decades have had significant effects on the work values of different generations of Chinese people (Dou, Wang, and Zhou 2006;Egri and Ralston 2004; Ralston et al. 1999) . The older and younger generations of migrant workers have had very different experiences in their growth environments, work participation, value orientation, and entrepreneurial spirit. ... Should I stay or should I go? Job demands' push and entrepreneurial resources' pull in Chinese migrant workers' return-home entrepreneurial intention ... Individualism is defined as a self-orientation that puts more emphasis on autonomy and control (Ralston, Egri, Stewart, Terpstra, & Kaicheng, 1999) , whereas collectivism is defined as group-orientation that attaches more importance to group interests and compliance (Ho & Chiu, 1994). Triandis (1995) stated that individualists are mainly driven by their own needs, preferences and rights, giving priority to themselves rather than to group. ... ... German people have a characteristic of individualism through autonomy and independence (Kühlmann & Rabl, 2009). While Chinese people are often portrayed as collectivist (Hsu, 1981;Hui & Triandis, 1986;Liu et al., 2007) and are depicted by the Confucian rules of face-saving (Boisot & Child, 1996;Liu et al., 2007; Ralston et al., 1999; Ralston, Kai-Cheng, Wang, Terpstra, & Wei, 1996;Redding, 1990) and forbearance (Hwang, 1997). Collectivist Chinese tend to accept one's fate, maintain harmony in a group, and give priority to group needs, interests and compliance rather than to themselves (Liu et al., 2007). ... Stress Management at the Workplace: A Comparative Study between Chinese and German Companies Thesis Sep 2020 Although extensive scholarly and practical attention has been paid to workplace stress in cross-cultural settings over the past decades, the comparative studies on workplace stress management between Chinese and German companies remain elusive. To fill this research gap, a comparative study on stress management at the workplace between Chinese and German companies has been conducted in two culturally different countries: China and Germany. To obtain a relatively comprehensive and accurate comparison of stress management at the workplace between Chinese and German companies, four new scales, namely Sources of Work Stress Scale, Coping with Stress Scale, Health and Well-being Scale, and Job Satisfaction Scale, have been developed and validated by several empirical studies with German and Chinese samples. The softwares SPSS 22, Smart PLS 3 and Amos 22 were used to test the factor structure, reliability, validity and the cross-cultural equivalence for each scale. The aim of these important steps is to lay a solid foundation for the current comparative study and ensure the validity of the research results. After the reliability, validity and cross-cultural equivalence were all established by several pre-surveys with Chinese and German samples, the formal questionnaire surveys with four scales were conducted in Chinese and German companies. Participants could finish either the paper-and-pencil version or the online version of questionnaires. In China, participants were randomly chosen from a variety of industries in different cities. Correspondingly, German participants were randomly selected from various industries in different cities in Germany. The independent-samples t test and effect size statistics were conducted to identify whether there are some significant differences between Chinese and German employees’ sources of work stress, coping with stress at work, and the consequences of work stress, such as health and well-being, and job satisfaction. Results of hypotheses testing regarding Chinese and German employees’ sources of work stress indicate that all the hypotheses were supported except one hypothesis. Specifically speaking, compared with their German counterparts, Chinese employees reported significantly more stress caused by workload, competition and comparison, role uncertainty, lack of control, pay and career prospects, lack of competency, relationships at work, and boredom at work. However, Chinese employees did not report significantly more stress caused by work-life balance compared with German employees. Results of hypotheses testing regarding Chinese and German employees’ coping with stress indicate that Chinese employees use positive thinking and self-blame as ways to deal with stress more often compared with their German counterparts. German employees use physical exercises, leisure and relaxation, and problem-solving coping as ways to deal with stress more often than their Chinese counterparts. Results of hypotheses testing show that German employees use religious coping as a way to deal with stress not significantly more often than Chinese employees. However, German employees use acceptance as a way to deal with stress more often rather than less often compared with their Chinese counterparts. Results of hypotheses testing regarding Chinese and German employees’ job satisfaction indicate that German employees reported significantly higher level of job satisfaction than their Chinese counterparts. Results of hypotheses testing regarding Chinese and German employees’ physical health and psychological well-being find that there is no significant difference between Chinese employees and German employees in physical health and there is also no significant difference between Chinese employees and German employees in psychological well-being. The correlation analyses were also conducted in both samples to observe the relationship between health and well-being and job satisfaction as well as the relationship between job satisfaction and turnover intention. Results of hypotheses testing find that the problems of physical health and the problems of psychological well-being are both negatively related to the level of job satisfaction in German samples. In Chinese samples, the problems of physical health are not significantly related to job satisfaction, only the problems of psychological well-being are negatively related to the level of job satisfaction. Results of hypotheses testing indicate that the job satisfaction is negatively related to turnover intention in both samples. Employees who report higher levels of job satisfaction will report lower intention to quit. ... States (Centers and Bugantal, 1966) and Japan (Worthley et al., 2009) found that women in the workplace placed a higher value on relationships with others than men did. Similarly, Chinese women were reported to tend to value collectivism more highly than men did (Ralston et al., 1999) . Empirical studies found perceived coworker support (Sloan, 2017) or satisfaction with co-workers (Boles et al., 2007) were more strongly related to OC for women than for men. ... ... Broadly, intrinsic rewards affected male OC more, while social rewards affected female OC more. These results support our hypotheses derived from prior studies (Gilligan, 1982;Gneezy et al., 2003;Hitotsuyanagi-Hansel et al., 2016;Keller et al., 2015;Law et al., 2009; Ralston et al., 1999; Sebastian Reiche, 2007;Tannen, 1994). To our knowledge, this study is the first to explain the difference in the OC-rewards relationship between male and female employees in companies with different national cultures. ... Gender differences in organizational commitment and rewards within Japanese manufacturing companies in China Abstract Purpose – The purpose of this paper is to investigate gender differences in organizational commitment (OC) and the relationship between OC and rewards among employees who work for Japanese manufacturing companies within China. Design/methodology/approach – This study utilized hierarchical regression analysis to examine survey data obtained from 27,854 employees who worked for 64 Japanese manufacturing companies within China. Findings – The results reveal that autonomy and role clarity had a stronger influence, and co-worker support had a weaker influence, on OC for male employees than for female employees. These differences may be because more male employees than female employees prefer working with higher autonomy and well-defined roles than with co-worker support. After all, male employees, who place a great emphasis on independence, competition, decision-making and challenges, rely on intrinsic rewards more than social rewards. Research limitations/implications – This study used data collected from Japanese manufacturing companies to understand the differences between OC and rewards in local male and female Chinese employees. We recommend that future research uses other national affiliates to clarify the characteristics of male and female Chinese workers more objectively and to test the validity of this research. Practical implications – The results of this study support revising human resource management practices within multinational enterprises to enable female and male host-country workers to contribute to their companies on a long-term basis by taking into account the differences between the cultures of the home and host countries. Originality/value – Although previous research has elucidated the OC–rewards relationship in particular countries, it has not met the requirements of foreign managers from different corporate cultures who face differences in the OC–rewards relationship between their male and female employees. In this sense, this research is the first attempt to tackle this theme and contribute to the literature. Keywords Exploratory factor analysis, Gender, Japanese manufacturing companies, China, Organizational commitment, Rewards Paper type Research paper ... Chinese society, Confucian culture greatly shapes moral values despite social changes after the founding of the new China (Ralston, Egri, Stewart, Terpstra, & Kaicheng, 1999) . Confucian values have three elements, with ren emphasizing benevolence to or compassion for others (Wright & Twitchett, 1962), yi representing the principle of moral rightness (Cheng, 1972), and li specifying many concrete norms for social relationships (Wright & Twitchett, 1962 (Ralston et al., 1999). ... ... Chinese society, Confucian culture greatly shapes moral values despite social changes after the founding of the new China (Ralston, Egri, Stewart, Terpstra, & Kaicheng, 1999). Confucian values have three elements, with ren emphasizing benevolence to or compassion for others (Wright & Twitchett, 1962), yi representing the principle of moral rightness (Cheng, 1972), and li specifying many concrete norms for social relationships (Wright & Twitchett, 1962 (Ralston et al., 1999) . Thus, in areas with stronger influence of Confucianism, leaders of privatized SOEs are more likely to recognize and feel responsible for the distress experienced by laid-off SOE workers and their families as a result of privatization and thus make restitution later through corporate philanthropy. ... Guilt and Corporate Philanthropy: The Case of the Privatization in China Firms' harm-inflicting decisions/actions can make firm leaders feel guilt toward those who are harmed, which then motivates them to make restitution through corporate philanthropy. Our primary setting for investigating this proposition is the privatization of Chinese firms. We argue that massive layoffs resulting from privatization triggered guilt among firm leaders to drive corporate philanthropy. The analysis of a national survey of Chinese private firms shows that on average privatized firms made approximately 26% more charitable contributions than firms founded as private. This is particularly the case when (1) privatization resulted in layoffs (vs. no layoffs), (2) their provinces experienced greater unemployment at the time of privatization, (3) their leaders were directly involved in privatization, (4) the influence of Confucianism was stronger in their provinces, and (5) firm leaders had stronger ties with laid-off workers. An interview-based field study of 25 firm leaders involved in privatization provides qualitative evidence for the influence of guilt on privatized firms' philanthropy. Finally, a vignette experiment conducted on EMBA students shows the mediation of guilt between privatization and firms' philanthropy intention. These findings establish guilt as a potent emotional driver of corporate philanthropy, helping redirect the attention of corporate philanthropy research to non-financial drivers. ABSTRACT Firms' harm-inflicting decisions/actions can make firm leaders feel guilt toward those who are harmed, which then motivates them to make restitution through corporate philanthropy. Our primary setting for investigating this proposition is the privatization of Chinese firms. We argue that massive layoffs resulting from privatization triggered guilt among firm leaders to drive corporate philanthropy. The analysis of a national survey of Chinese private firms shows that on average privatized firms made approximately 26% more charitable contributions than firms founded as private. This is particularly the case when (1) privatization resulted in layoffs (vs. no layoffs), (2) their provinces experienced greater unemployment at the time of privatization, (3) their leaders were directly involved in privatization, (4) the influence of Confucianism was stronger in their provinces, and (5) firm leaders had stronger ties with laid-off workers. An interview-based field study of 25 firm leaders involved in privatization provides qualitative evidence for the influence of guilt on privatized firms' philanthropy. Finally, a vignette experiment conducted on EMBA students shows the mediation of guilt between privatization and firms' philanthropy intention. These findings establish guilt as a potent emotional driver of corporate philanthropy, helping redirect the attention of corporate philanthropy research to non-financial drivers. ... Chinese society, Confucian culture greatly shapes moral values despite social changes after the founding of the new China (Ralston, Egri, Stewart, Terpstra, & Kaicheng, 1999) . Confucian values have three elements, with ren emphasizing benevolence to or compassion for others (Wright & Twitchett, 1962), yi representing the principle of moral rightness (Cheng, 1972), and li specifying many concrete norms for social relationships (Wright & Twitchett, 1962 (Ralston et al., 1999). ... ... Chinese society, Confucian culture greatly shapes moral values despite social changes after the founding of the new China (Ralston, Egri, Stewart, Terpstra, & Kaicheng, 1999). Confucian values have three elements, with ren emphasizing benevolence to or compassion for others (Wright & Twitchett, 1962), yi representing the principle of moral rightness (Cheng, 1972), and li specifying many concrete norms for social relationships (Wright & Twitchett, 1962 (Ralston et al., 1999) . Thus, in areas with stronger influence of Confucianism, leaders of privatized SOEs are more likely to recognize and feel responsible for the distress experienced by laid-off SOE workers and their families as a result of privatization and thus make restitution later through corporate philanthropy. ... Guilt and Corporate Philanthropy: The Case of the Privatization in China Qi Li Heli Wang Junkang Ji Zhi Huang Firms' harm-inflicting decisions/actions can make firm leaders feel guilt toward those who are harmed, which then motivates them to make restitution through corporate philanthropy. Our primary setting for investigating this proposition is the privatization of Chinese firms. We argue that massive layoffs resulting from privatization triggered guilt among firm leaders to drive corporate philanthropy. The analysis of a national survey of Chinese private firms shows that on average privatized firms made approximately 26% more charitable contributions than firms founded as private. This is particularly the case when (1) privatization resulted in layoffs (vs. no layoffs), (2) their provinces experienced greater unemployment at the time of privatization, (3) their leaders were directly involved in privatization, (4) the influence of Confucianism was stronger in their provinces, and (5) firm leaders had stronger ties with laid-off workers. An interview-based field study of 25 firm leaders involved in privatization provides qualitative evidence for the influence of guilt on privatized firms' philanthropy. Finally, a vignette experiment conducted on EMBA students shows the mediation of guilt between privatization and firms' philanthropy intention. These findings establish guilt as a potent emotional driver of corporate philanthropy, helping redirect the attention of corporate philanthropy research to non-financial drivers. ABSTRACT Firms' harm-inflicting decisions/actions can make firm leaders feel guilt toward those who are harmed, which then motivates them to make restitution through corporate philanthropy. Our primary setting for investigating this proposition is the privatization of Chinese firms. We argue that massive layoffs resulting from privatization triggered guilt among firm leaders to drive corporate philanthropy. The analysis of a national survey of Chinese private firms shows that on average privatized firms made approximately 26% more charitable contributions than firms founded as private. This is particularly the case when (1) privatization resulted in layoffs (vs. no layoffs), (2) their provinces experienced greater unemployment at the time of privatization, (3) their leaders were directly involved in privatization, (4) the influence of Confucianism was stronger in their provinces, and (5) firm leaders had stronger ties with laid-off workers. An interview-based field study of 25 firm leaders involved in privatization provides qualitative evidence for the influence of guilt on privatized firms' philanthropy. Finally, a vignette experiment conducted on EMBA students shows the mediation of guilt between privatization and firms' philanthropy intention. These findings establish guilt as a potent emotional driver of corporate philanthropy, helping redirect the attention of corporate philanthropy research to non-financial drivers. ... Dissanaike et al., 2020;Frattaroli, 2020). In addition, individualistic, self-serving Chinese managers are willing to take more risks to pursue profits than managers from previous generations or other countries (Ralston et al., 1999) . Aktas et al. (2016) also note that a manager's personal characteristics may result in suboptimal M&A target selection and that acquirers' CARs are negatively correlated with their incumbent CEOs' self-centeredness. ... Do antitrust laws erode shareholder returns? Evidence from the Chinese market Sang Jun Cho Chune Young Chung Daniel Sungyeon Kim Using data on 4784 completed mergers and acquisitions in China announced between 2002 and 2016, we find that the adoption of the Chinese Anti-Monopoly Law substantially reduces the shareholder returns for horizontal acquisitions. Based on our findings on reduced post-merger sales and returns, we argue that a loss of market power drives this negative relationship. We also find that the acquiring firms’ cost efficiency does not significantly change as a result of the combination, suggesting that the decline in shareholders’ wealth after horizontal mergers is not because of reduced cost efficiency. Furthermore, we conduct a series of robustness checks to examine how adopting antitrust law decreases the wealth of producing firms’ shareholders. Overall, our results indicate that the government must implement stricter guidelines for antitrust policies to protect consumer welfare. ... Prominent examples are early internet entrepreneurs like Jack Ma or Robin Li 1 , whose companies have since strongly influenced the whole country and have become entrepreneurial role models for people throughout China. That period saw a paradigmatic shift towards Western entrepreneurial values such as independence,individualism, and risk-taking on Chinese businesspeople (Ralston et al., 1999) . This shift of values favoured the development of China's entrepreneurial spirit.We suggest updatingDai et al.'s (2019) historical account and argue for adding a fourth type or generation, generation Z, to that classification system. ... Entrepreneurship in China: Autoethnographic Insights into a Pulsating Entrepreneurial Society Chapter Full-text available Jan 2022 Maximilian Scheu Andreas Kuckertz This paper provides a unique perspective on the Chinese entrepreneurial landscape via insights that result from a combination of evidence drawn from the academic literature and the lead author's experience from living for over two years in China. That experience underpins an autoethnographic account of entrepreneurship in China. That account is accompanied by reflections on China's entrepreneurship-backed rise, the idea of mass entrepreneurship, and characteristics of China's environment that affect entrepreneurship. The paper thus offers readers a first impression of the reality of entrepreneurship in China. It also provides real-world entrepreneurial insights into China from a foreign perspective. Those general impressions could equip readers to identify promising research paths and understand differences to the Western system. ... First, our sample only includes university students. It has been shown that values and mindsets differ across generational cohorts that have totally different childhood experience (Ralston et al., 1999; Hung et al., 2007;Wang et al., 2022). In the future, scholars should replicate this research in other populations, and, if possible, make a cross-generational comparison to enhance generalizability. ... Exploring the Antecedents of Money Attitudes in China: Evidence From University Students Article Full-text available Jun 2022 Yuqian Li Fengfei Hu With rapid economic growth and institutional reform, the pursuit of money and material possessions has become the most prevalent value in contemporary China. This study focuses on the cultural root of money attitudes among the young adults. Specifically, 332 Chinese university students participated in a survey to report on their need for power, need for achievement, belief in guanxi, and love of money. Confirmatory factor analysis and regression analysis were applied to test the proposed hypotheses. The results show positive influences of need for power and need for achievement on individuals’ love of money. Moreover, belief in guanxi mediates the relationship between need for power and love of money. The application of indigenous cultural concepts in analyzing social behavior in Eastern cultures is emphasized. Limitations and directions for future research are also discussed. ... The lack thereof is associated with less satisfaction and a worse work environment. Research on selfrealization, work values, workplace commitment, work satisfaction, and performance have attracted ample research in recent decades [88], especially due to the relation between these key variables and engagement and work motivation [89] [90] [91]. ... Public Service Motivation and Determining Factors to Attract and Retain Health Professionals in the Public Sector: A Systematic Review Article Full-text available Alexandre Fernandes Gonçalo Santinha Teresa Forte (1) Background: The motivational determinants of health professionals to choose and remain in the public sector have been increasingly addressed, including the customized approach of Public Service Motivation (PSM). However, to date, no systematic research overview has been performed in this domain, leaving the body of literature unstructured. This article fills this gap by assessing the motivational factors of choice for the public sector in the health field, and the conceptual and methodological trends of this research stream. (2) Methods: This study follows the PRISMA protocol to ascertain patterns in past research and inform researchers, practitioners, and policymakers. Eighty-nine documents published between 1998 and 2021 were retained after selecting them according to their theme and outlined goals. (3) Results: Common motivational determinants are remuneration, available resources, work conditions, and frequency of contact and interaction with patients. The PSM construct and scale are often employed as main frameworks, but there is also a concern in assessing motivation drawing on psychological constructs that reflect the challenging line of work and environment that is health care, such as presenteeism, stress, and perception of hindrances. (4) Conclusions: By focusing on health professionals’ motivation, this study contributes to a timely systematization in challenging times for health institutions and their human resources ... They also argue that generational cohorts explain differences better than age and they have become popular in industry reporting (KPMG 2017;Lu 2020;O'Reilly 2014). There is a lack of a unified and recognised definition and of China's generational cohorts (Hung et al. 2007; Ralston et al. 1999) Categorising generations by decade is common in China for both academics and practitioners (Liao and Zhang 2007;Pan 2017;Yang 2018). With respect to this reality and in line with research habits, this research adopts this segmentation method and focuses on five generational groups: post-60s (born between 1960 and 1969), post-70s (born between 1970 and 1979), post-80s (born 1980 and 1989), post-90s (born between 1990 and 1999) and post-00s (born between 2000 and 2009). ... Generational homogeneity and heterogeneity in city image perception: an explorative study of Guangzhou Article Full-text available Dec 2021 Dian Wang Bowen Zhang Yingying Wu Xinwen Zhang This study examines perceptions of Guangzhou and looks for generational differences in projected image and information channel preferences. Based on a content analysis of 47 official city image advertisements, 16 themes are extracted and tested as traits of Guangzhou’s city image. Targeting all of China, an online questionnaire is undertaken, returning 1601 valid responses covering five generational groups: post-60s, post-70s, post-80s, post-90s, and post-00s. Free factor analysis and Kendall correlation analysis are used. The results suggest that there are no significant differences among the generational groups for information channels or perceptions of Guangzhou, since the dimensions of image perception are similar. However, an emphasis on different traits is identified, suggesting different preferences among generational groups which requires the attention of the city image communication authorities. The purpose of this study is to examine audience perceptions of Guangzhou and to look for generational differences in projected image and information channel preferences. Based on a content analysis of 47 official city promotional videos, 16 themes are extracted and tested as traits of Guangzhou’s city image. Targeting all of China, an online questionnaire is undertaken, returning 1601 valid responses covering five generational groups: post-60s, post-70s, post-80s, post-90s, and post-00s. Free factor analysis and Kendall correlation analysis are used. The results suggest that there are no significant differences among the generational groups for information channels or perceptions of Guangzhou, since the dimensions of image perception are similar. However, an emphasis on different traits is identified, suggesting different preferences among generational groups which require the attention of the city image communication authorities. The similarities in perceptions of the dimensions of city image of the generational groups and the emphases on different traits are similar to existing research. However, a clear and theoretically based generational segmentation is required for future research. Consistency between the projected and perceived images of Guangzhou in all information channels suggest the need of continuous use of integrated marketing communication strategy. View ... A divergence theory believes that national (traditional) culture shapes the value systems (Lincoln et al., 1978;Kelley and Worthley, 1981), whereas the convergence theory proposes that the business environment is the driving force that mainly affects the values (England and Lee, 1974;Yip, 1992). Over the controversy, Ralston et al. (1993) proposed the cross-vergence theory as an alternative and perfected the theory in the subsequent studies (Ralston et al., 1997 (Ralston et al., , 1999a (Ralston et al., ,b, 2006a. A cross-vergence theory maintains that neither national culture nor economic ideology (the proxy of the business environment) can independently shape the contemporary values of a society. ... Values Evolution in Transitional China: An Institutional Perspective Nov 2021 Gong Sun Jian Li The values are greatly affected by the social and economic environment of a country. Thus, social transformation can lead to the values evolution. China has been experiencing a huge social, political, and economic transition in the past four decades. The previous studies that explore the value changes in China mainly compare the values across the regions or generation cohorts. This research investigates the issue from an institutional perspective. Specifically, we propose that the diversification of ownership types-the essence of the economic and institutional reform since 1978 may result in value change. By surveying 327 participants from the state-owned enterprises (SOEs) and 220 respondents from the privately owned enterprises (POEs), the comparisons between SOEs and POEs on four value dimensions-individualism, power distance, risk aversion, and money orientation-were performed. The results basically support cross-vergence theory in the values evolution. The implications and limitations are presented as well. ... Individual values are shaped by the institutions that structure a society; thus, by considering those institutions, we can ascertain the relative priorities that shape their managers' individual values. East Asia presents an interesting context for this analysis because of the socio-cultural similarities embedded in philosophical and spiritual traditions, as well as its diverging paths of economic development (Ralston, Egri, Stewart, Terpstra, & Yu, 1999) . Societies develop at different rates due to the interaction of exogenous influences-political, technological, and historical-and it would be naïve to assume that all managers in East Asia wholly subscribe to the same set of value priorities that drive their behaviors. ... Toward understanding Convergence and Divergence: Inter-ocular testing of traditional philosophies, economic orientation, and religiosity/spirituality J BUS RES Doris Viengkham Chris Baumann Hume F. Winzar This study brings together three institutional pillars that represent values in four East Asian societies-China, Japan, Korea, and Vietnam-traditional philosophies, economic orientation, and religiosity/spirituality-where previous literature examined these values domains separately and independently. In the process, we challenge the more traditional approaches to measuring values, and testing for differences and similarities among cultural groups. Personal values, by definition, are important influences on behaviour, but some values are more important than others. The appropriate measure for relative influence is an ipsative measure rather than a normative measure, such as a Likert scale. Contrary to conclusions drawn from null-hypothesis significance tests, we show that the four societies have similar perceptions of Capitalism and Modernization, and have small differences on most other dimensions. We show that measures of effect size and "inter-ocular testing" (looking at the data) produce more nuanced interpretations of divergence and convergence in the Confucian Orbit. ... A review by Schmitt et al. (1994) found a series of differences affecting management and business such as face saving, time perspective and differences in individualism/collectivism (Hofstede, 1980;Hofstede et al., 2010). Cultural differences have also been found to affect managerial decision making (Ralston et al., 1999; Casas Klett and Arnulf, 2020). ... Limits of a Second Language: Native and Second Languages in Management Team Communication Cultural differences in speech acts are common challenges in management involving Chinese and Western managers. Comparing four groups – Native-speaking Chinese, English-speaking Chinese, Chinese-speaking Westerners, and non-Chinese- speaking Westerners, we assessed the effects of language and ethnicity on the ability to predict communication obstacles in a management team scenario. Bilingual subjects were less likely to be influenced by ethnic biases. Still, bilinguals were not more likely to adjust their metacognitions about communication toward those of the native speakers. The study creates a link between management, cognition and linguistics, as well as having consequences for the study of metacognition in cross-cultural management. ... The basis of these assumptions is a binary between Western individualism, which emphasises 'I' consciousness, and East Asian collectivism, which emphasises 'we' consciousness (Brewer and Chen 2007). Recent studies in this academic tradition have found a trend towards individualisation in various Asian societies (Chiou 2001;Lu and Yang 2006;Omi 2012; Ralston et al. 1999 ). This encourages researchers to take a dynamic rather than a static perspective to analyse East Asian societies, including Taiwan. ... ‘Be true to yourself’: Transnational mobility, identity, and the construction of a mobile self by Taiwanese young adults Article Full-text available Adopting Salazar's 'imaginaries of mobility,' this paper investigates how transnational mobility becomes imaginable, desirable or even experientially imperative for mobile Taiwanese young adults in the context of globalisation. It analyses the ways by which they interpret their mobilities as a pursuit of self-identity while negotiating the tensions between collectivism and individualism of Taiwanese society. Based on personal profiles and self-narratives of mobility appearing on a Taiwanese media website devoted to the topic of transnational mobility, I demonstrate how writers present a 'mobile self' characterised by being geographically mobile, socially transgressive and culturally cosmopolitan. This self is depicted in sharp contrast with the immobile at home and narrated as an integral part of achieving identity through three kinds of self-transformation: becoming true to oneself , becoming independent, and becoming a dreamer. While these narratives resonate Western discourses of mobility, they are interpreted from the lens of individualism-collectivism opposition in East Asia and of generational conflicts in Taiwan. Specifically, transnational mobility, regardless forms, is framed as a generational revolt against a collectivist society that represses individuality. The results show how imaginaries of mobility are recontextualised, producing meaning and practice based on local references. ARTICLE HISTORY ... Culture is considered to be dynamic and constantly evolving in societies (Fang, 2012;Hofstede, 1991;Rokeach, 1973;Yan, 2010). In this regard, crossvergence theory (e.g., Ralston, Egri, Stewart, Terpstra, & Yu, 1999; Ralston, Gustafson, Cheung, & Terpstra, 1993;Ralston, Holt, Terpstra, & Yu, 1997) postulates that cultural values are subject to the influence of globalisation and to those of a unique national culture and social traditions. On one hand, cultures are becoming similar and displaying convergence among one another; on the other hand, national or local cultures continue to preserve features that render them distinct from other cultures. ... Developing and validating a Chinese cultural value scale in tourism TOURISM MANAGE Songshan Huang Chinese cultural values are important in understanding Chinese tourists’ behaviour. However, the literature is void of a relevant scale measuring Chinese cultural values in tourism. This research aims to develop and validate a Chinese cultural values scale in tourism (abbreviated as CCV-T). Following a rigorous scale development procedure and applying multi-stage studies, the research identified a 5-factor measurement scale of CCV-T, composed of 17 items with sufficient reliability and validity. The five Chinese cultural value factors are Leisure and Life Enjoyment (LLE), Filial Piety and Relationship (FPR), Self-fulfilment, Righteousness, and Humanity. The CCV-T scale provides a simplified and holistic structure measuring tourism-related Chinese cultural values. This research provides a solid base to further understand the relationships between Chinese cultural values and tourist behaviour. ... Evidence in the literature suggests that Chinese society remains deeply attached to the Confucian tradition in hierarchical and filial piety status, in spite of the introduction of Communism (Su and Littlefield, 2001). Empirical research (Ralston et al., 1999) also shows that business and organizational structures observe Confucian ethical values and adopt a Confucian-type hierarchical structure. ... The impact of organizational position level and cultural flow direction on the relationship between cultural intelligence and expatriate cross-border adaptation Article Ying Zhang Yuran Li Mark Frost Edwin T.C. Cheng Purpose This paper aims to examine the critical role played by cultural flow in fostering successful expatriate cross-border transitions. Design/methodology/approach The authors develop and test a model on the interplay among cultural intelligence, organizational position level, cultural flow direction and expatriate adaptation, using a data set of 387 expatriate on cross-border transitions along the Belt & Road area. Findings The authors find that both organizational position level and cultural flow moderate the relationship between cultural intelligence and expatriate adaptation, whereby the relationship is contingent on the interaction of organizational position status and assignment directions between high power distance and low power distance host environments. Originality/value Previous research has shown that higher levels of cultural intelligence are positively related to better expatriate adaptation. However, there is a lack of research on the effect of position difference and cultural flow on such relationship. Our study is among the first to examine how the interaction between cultural flow and organizational position level influences the cultural intelligence (CI) and cultural adjustment relationship in cross-cultural transitions. ... This sequence of low-level constructs seems like a more meaningful representation of the underlying dynamics than assessing Organizational Learning Capability as an overarching construct. This may happen because Chinese respondents are prone to think in particular, pragmatic terms and wary of abstract theoretical concepts (Ralston et al., 1999; Norenzayan et al., 2010) and frequently embrace paradoxes that would create contradiction and cognitive dissonance in Westerners (Li and Tang, 2013;Li, 2012). ... Developing a measurement scale for organizational learning capabilities in China Wanwen Dai Phoenia Iao Haojin Dai Jan Ketil Arnulf The purpose of this study was to develop a measurement instrument for organizational learning capability in a Chinese management context. Previous research has indicated a need for measurement instruments with proven ecological validity in China, because the learning capability of organizations is influenced by the organization’s external environment. We followed a consequent inductive procedure from item sampling through exploratory factor analysis (EFA) to confirmatory factor analysis (CFA) and nomological validation. The initial part sampled relevant descriptors from a diverse sample of 159 employees from heterogeneous backgrounds in China. After sorting by an expert panel, EFA of data from a sample of 161 executive students yielded a three-dimensional construct comprising Knowledge Acquisition, Knowledge Sharing, and Knowledge Utilization. These three constructs were again tested in CFA using a sample of 357 employees from five companies. Our findings across the three samples resulted in a three-dimensional measurement scale that we call the Organizational Learning Capability Questionnaire (OLCQ). The OLCQ displayed high internal consistency, reliability and nomological validity. This focus of this study has only been to establish a measurement instrument that allows indigenous research on organizational learning in China. The approach was statistically driven grounded approach, not a theoretical assumption of learning mechanisms special to the Chinese culture. Further research is needed to estimate how this approach yields results that are different from other cultures, or the extent to which our findings can be explained by features of the Chinese culture or business environment. This study offers a practical measurement instrument to assess practical and scientific problems of organizational learning i China. We provide a measurement instrument for organizational learning capability with proven ecological validity and with promising consequences for research and practice in China. The instrument is empirically grounded in the practices and behaviors of Chinese managers, avoiding biases that stem from previously identified shortcomings in cross-cultural management research. To our knowledge, it is the first of its kind and a contribution to a call for indigenous management theories with contextual validity. ... Unlike Western traditions and narratives, Chinese philosophy is rarely taught through long texts (although these exist) or sacred books, but is expressed as aphorisms that often live on as proverbs that most people know (Mou, 2009;Feng, 2015). These powerful traditions form a most important background to understand the emerging theories of Chinese management Ma and Tsui, 2015), as Chinese have a tendency to leap from philosophy to pragmatic action, bypassing theory (Ralston et al., 1999) . Chinese classics have been shown to be important strategic guidelines for Chinese business leaders (Chen and Lee, 2008). ... Are Chinese Teams Like Western Teams? Indigenous Management Theory to Leapfrog Essentialist Team Myths Our study analyzes a gap in research on Chinese and Western management teams, based on a broad literature review. We claim that prevalent theoretical perspectives in the management team literature might be biased toward a Western-centric view of team dynamics. This obscures alternative ways of understanding top teams encompassing Chinese cultural traditions. We outline how an essentialist team conceptualization leads to a paradox consisting of three mutually contradicting myths. Myth 1 implies that Western groups of managers comply with theoretically “ideal” team processes and characteristics. Myth 2 derives from research literature on Chinese teams claiming that team features are assumed absent or weak in China due to cultural particularities. Paradoxically, the same research tradition constructs another third myth by reporting that Chinese teams successfully comply with the Western ideal team model. The three coexisting myths point to a theoretical confounding of contextual mediators in team processes. We discuss how indigenous Chinese leadership theory and Chinese systems of philosophy give Chinese teams access to distinct and effective team processes to reach high-performance outcomes. This paper aims to open the rich possibilities of Chinese management and team practices to the cross-cultural context, and on return to novel understanding of Western teams beyond traditional essentialist theory anchors. ... Cross-cultural research of China reflects adherence to tradition and nationalism amidst the continually growing influence of Western ideas about business and management. While there are vast and multiple cultural values at play within the expanse of this Republic, the execution of typical autocratic praxis is, in large part, mutually incompatible with an effective leadership model predicated on the reach and governance of the Chinese Communist Party and communal ideologies (Chen, 1995;Fu et al., 2013, p. 886; Ralston et al., 1999) . Jackson, Louw, and Zhao (2013) examined the growing international and cross-cultural relationship between China and Africa within the last five years. ... A Review of Autocratic, Paternalistic, and Charismatic Leadership in Three Collectivist Cultures The conception of culture serves as a primary issue within both organization and leadership research. Examination of organizational leadership and culture provides researchers with comprehensive tools to better understand effective leadership within an increasingly globalized organizational context. Amidst the broad spectrum of leadership theory are the subsequent conceptions of three leadership theories: (a) autocratic leadership, (b) paternalistic leadership, (c) charismatic leadership. A deeper understanding of organizational leadership and its varied application and effectiveness requires fastidious consideration of the social, cultural and in some cases religious contexts in which leadership exists. The three selected theories are placed against the cultural contextual framework of Confucian Asia (China), Sub-Saharan Africa, and Latin America (Mexico) as representatives of many cultural dimensions identified within the GLOBE study. Therefore, the primary objective of this investigation is to review the development of specific leadership theories and cross-cultural values informed by their application or prevalence within three selected collectivist regions. Ultimately, the research findings support the contentions of some scholars, that while the nexus of organizational leadership theories should be cross-culturally static, the reality of shifting ideals relative to interface with a diverse global marketplace, presents differing behaviors across cultures and in some cases within regional cultural clusters. ... Work values reveal an individual's evaluative tendency toward work and reflect his/her attitudes toward all job-related rewards, level of participation and engagement, and career ambition [23,24]. Studies on work values and organizational issues such as workplace commitment, overall job satisfaction, and employee job performance have attracted extensive attention in the past decades [24][25][26][27][28][29] [30] , mainly because these work-related values can drive employees to involve themselves in their work [31] and further facilitate employee job performance [24]. ... Nurse Practitioners’ Work Values and Their Conflict Management Approaches in a Stressful Workplace: A Taiwan Study Globalization has created an urgent need to understand management practices in different cultures. This study examines Confucianism-based work values of nurse practitioners in Taiwan and explores their impact on conflict management approaches in order to help health practitioners maintain sustainable work relationships and improve organizational effectiveness in an increasingly stressful workplace. Based on the data from 259 nurse practitioners in Taiwan, this study shows that nurse practitioners in Taiwan consider holistic rewards, self-fulfillment and personal growth, challenge and responsibility, autonomy, and meaningfulness as important work values. Hierarchical regression results further indicate that nurse practitioners with strong group-centered needs, such as needs for holistic rewards, preferred collaborative methods to manage conflicts in the workplace, and individuals with strong self-centered needs, such as needs for personal growth and self-fulfillment and needs for autonomy, preferred competitive methods to manage conflicts. Interestingly, this study also finds that self-centered needs such as needs for self-fulfillment and personal growth, and needs for challenge and responsibility are also related to collaborative approaches. Managerial implications are then discussed for conflict management training for nurse practitioners under stressful work conditions. ... Hofstede's culture dimensions contend that values will differ by culture (Chow, Shields, & Wu, 1999). Work values have been assessed across different countries with examples including Canada (Kuron et al., 2015;Lyons, Higgins, & Duxbury, 2010), China (Ralston, Egri, Stewart, Terpstra, & Kaicheng, 1999) , New Zealand (Cennamo & Gardner, 2008), and the U.S. . In a rare multi-national study (U.S, Australian, Singapore, Germany, China), Cogin (2012) reveals both similarities and differences across cultures. ... Understanding the work values of Gen Z business students Nov 2019 Michael J. Maloni Mark S. Hiatt Stacy Campbell The next generation (i.e., post-Millennials/Gen Z) now represents a majority of our business students. Yet, there is limited empirical evidence of the career expectations of this emerging generation, thereby impeding our ability to effectively engage students both in the classroom and in the career development process. To overcome this gap, we surveyed business students at seven different U.S. universities to assess their career work expectations. The results show broad similarities between Gen Z and the prior Gen Y generation yet also highlight some meaningful, significant variations. Supporting and extending existing literature, the results depict a typical business student who focuses on a stable career by developing strong skillsets that allow them to advance quickly in the workplace. A follow up survey of business faculty and career service personnel reveals that both groups are relatively out of touch with such student expectations. Specific recommendations are subsequently provided to enable business faculty to enrich student interest in their courses as well as help academic programs and career services enhance the fit of these students with majors and careers. View ... Chinese managers are leaving their collectivistic values behind in favour of more individualistic ideals (Ralston, Egri, Stewart, Terpstra, & Kaicheng, 1999) . A more recent analysis confirms such modernisation theory that values change as countries prosper, noting "average increases in individualism and indulgence" (Beugelsdijk, Maseland, & van Hoorn, 2015, p. 237). ... Authentic leadership: An empirical assessment of the ephemeral Thesis Full-text available This thesis quantitatively examines how individual cultural differences impact on authentic leadership efficacy and isolates its key mediating mechanisms. Four major advances are presented. The first is a formula for calculating respondents’ Western Values Scores from existing indices – a logical advance along traditional lines of cultural research. The second is the development of a new Holistic Cognition Scale (HCS) that captures cultural differences in cognitive schemata. The third and fourth advances are the moderation and mediation assessments of authentic leadership efficacy. The results indicate that the final 14-item HCS is a valid and reliable measure of respondents’ analytic and holistic thought. Contrary to expectations, I find no significant moderation effects from individual cultural differences and authentic leadership proves remarkably robust to cultural forces. Lastly, I identify followers’ personal identification, affect-based trust, and work engagement as the three main mediating mechanisms through which authentic leadership positively influences desirable organisational outcomes. A Critical Discourse Analysis of News Reports on UN Climate Change Conferences from Chinese and US Mainstream Newspapers Thesis Full-text available Yuqing Zhao Since the time of the Industrial Revolution, human activities have been the main cause for various environmental issues. Under the circumstances, climate change, which puts the mere survival of human beings at risk, has become one of the biggest global concerns. With such a great urgency, UN climate change conferences, which provide forums for countries around the world to negotiate on the issue of climate change, have increasingly come into the spotlight of news media. In an attempt to figure out reporting focuses of both Chinese and US newspaper reports on those conferences, the research, under the guidance of critical discourse analysis (CDA), analyzed 792 newspaper reports on UN climate change conferences from 2015 to 2019, namely, on COP21, COP22, COP23, COP24 and COP25 with the combination of quantitative and qualitative methods. The quantitative method involves the corpus analysis, and the qualitative method entails Fairclough’s three stages of discourse analysis. The research also aims at uncovering hidden ideologies reflected in those reporting focuses, and factors affecting the formation of those ideologies. In the stage of description, the results show that both Chinese and US newspapers have a particular focus on their own countries and highest leaders, with emphases on different specific aspects. In Chinese newspaper articles, China’s national image, action and contribution in fighting against climate change, and cooperative interactions with other countries are specific areas of focus. In US newspapers, individualism in terms of government officials, the division between the central and local governments, and less cooperative international relationships are the main focuses. As for interactions between the highest leaders of the two countries, cooperation is the main focus for President Xi and President Obama. In terms of President Trump, however, his dropping out of the Paris Agreement is the reporting emphasis, which indicates his deviation from the cooperative path set by the Obama administration. In the stage of interpretation, in terms of news sources, it is found that journalists from both countries value the objectivity and reliability of reporting, applying reliable sources from people with influence. With regard to reporting modes, the application of direct discourse increases the authenticity and reliability of news reporting, and indirect discourse allows more room for journalists’ interpretation, affecting the truthfulness of reporting to some extent. Based on the two stages above, in the stage of explanation, the differences in reports indicate the two countries’ different political, economic, and cultural conditions. China is an emerging large country under the influence of Confucianism, which values collectivism and rules. Therefore, China tends to have consistence in climate change policies, and always shows cooperative attitudes to the global fight against climate change. In contrast, the US is an established great power that appreciates individualism and freedom because of the influence from Christianity. Hence, the US is inclined to emphasize the importance of individual roles, and tends to be inconsistent with its climate change policies because of the two-party system. The research provides an example of applying CDA to the field of climate change conferences, and gives an insight into the different ideologies that are reflected in Chinese and US newspapers. By knowing the reporting focuses and ideologies in US newspaper reports, Chinese media can better adjust and improve their reports so that Chinese stories can be more easily accepted among international readers. Beyond Positive and Negative eWOM: The Role of Trust Propensity and Individuation in Shaping Consumers’ Perception of Brand Image Article Oct 2021 Int J Hospit Tourism Admin Pengji Wang This study aims to identify the impact of psychological mechanisms, such as trust propensity and individuation, on response to eWOM by differentiating between volume of positive/negative eWOM and net eWOM valence (e.g., when positive eWOM volume exceeds negative eWOM volume and vice versa). Analysis based on 428 survey responses from Australia and China shows that positive eWOM positively influences brand image, particularly for individuals with a high trust propensity. Surprisingly, negative eWOM does not affect brand image, but negative net valence is influential, particularly for consumers with a high trust propensity and those scoring high on individuation. An empirical investigation of regional differences in consumption behaviors in an emerging economy Stephanie Geiger-Oneto Hieu Nguyen Widely regarded as one of the most dynamic economies in Southeast Asia, Vietnam has increasingly attracted scholarly interest from diverse business disciplines. However, previous marketing research on Vietnam largely treats the country as a homogenous society. We draw on the literature in sociology, geography, history and predict that significant regional differences exist in consumers' consumption behaviors between the North and South of Vietnam, bearing important implications for international marketers. Using secondary survey data collected by an international market research firm, we show that consumers in Hanoi (HN) and Ho Chi Minh City (HCMC) differ greatly in how they perceive the impact of an economic crisis, how they change their consumption behaviors as a result, and whether they will cut back on spending on themselves, their families, and children. Our results also demonstrate that HN and HCMC consumers differ in their attitude toward luxury product consumption, attitude toward advertising, and marketing versus non‐marketing controlled sources of information. Our research provides important implications for both managers and researchers interested in this fast‐growing economy. A cross-institutional exploratory investigation of COVID-19 spread: formal vs. informal institutions Oct 2022 Imane El Ouadghiri Jonathan Peillex We investigate the effect of culture on COVID-19 spread using a sample of 67 countries over the first 10 months of the pandemic. We find that individualistic countries have higher number of COVID-19 cases, an effect that is independent from formal institutions. A two-ways interaction effects, however, between formal institutions and individualism, shows that effective political institutions, sound governance, and better economic conditions reduce the effect on individualism on CVODI-19 spread. Our findings provide evidence that are useful not only for explaining differences in COVID-19 spread between countries but can also enable policymakers and organizations to understand what generally determines individuals’ compliance with formal rules and regulations. View Identity-Consistent Self-Image Maintenance Following Leader Abuse: Integrating Self-Presentation and Self-Concept Orientation Perspectives J MANAGE Lei Huang Ted A. Paterson Siting Wang Although coping with an abusive boss can be psychologically demanding, those who suffer from leader abuse often stay in these unpleasant relationships, actively managing the way they are viewed in the eyes of their abusive leader (source of the abuse) and coworkers (observers of the abuse). Accordingly, the abusive supervision literature has relied almost exclusively on an emotional appraisal perspective to study the self-image implications following leader abuse. The present study seeks to add to this emerging line of scholarly conversations by presenting a novel theoretical alternative. Specifically, we integrate self-presentation and self-concept orientation perspectives to portray individuals’ identity-driven self-image maintenance following leader abuse. We argue that only those with a stronger relational self-concept are likely to be motivated to preserve their identity-consistent self-image and present themselves in positive and socially desirable ways towards both their coworkers and leader following leader abuse. Using survey data collected from working professionals in China across two field studies, we found support for our hypotheses that when employees with a stronger relational self-concept experienced abusive supervision, they were motivated to help their coworkers as a result of their relational reputation maintenance concerns and use ingratiation tactics towards their leader due to their image preservation motives. We also offered insights about both theoretical and practical implications of our research and discussed study limitations and directions for future research. Chapitre 15. La contextualisation de la recherche : une démarche processuelle Chapter Sep 2020 Doha Sahraoui Bentaleb Chafik Bentaleb When and why narcissism leads to taking charge? The roles of coworker narcissism and employee comparative identity Xin Liu Jih-Yu Mao Xiaoming Zheng Peter D. Harms When and why do narcissists take charge in the workplace? Integrating the narcissism literature and self‐identity theory, we argue that coworker narcissism is a key contingency that triggers narcissistic employees' comparative identity, which subsequently facilitates their taking charge behaviours. The results of two studies (Study 1: a two‐wave survey study of 351 frontline employees and 67 team leaders; Study 2: a scenario‐based experimental study of 190 workers) provide evidence that coworker narcissism moderates the relationship between employee narcissism and employee comparative identity, such that the relationship is strengthened when coworker narcissism is high rather than low. Employee comparative identity is positively related to employee taking charge behaviour. Furthermore, coworker narcissism moderates the indirect effect of employee narcissism on employee taking charge behaviour through employee comparative identity, such that the indirect effect is strengthened when coworker narcissism is high rather than low. These results contribute to the growing literature on the interpersonal dynamics of narcissists in the workplace and the impacts of narcissism on proactive behaviours. Generations in Family Business: A Multi-field Review and Future Research Agenda Article Jan 2022 FAM BUS REV Vittoria Magrelli Paola Rovelli Carlotta Benedetti Alfredo De Massis The concept of generations has become increasingly important in the social science fields to explain diverse phenomena affecting organizations. This is especially true in the family business field where generations are considered a constitutive element. Nevertheless, there is still a limited understanding of generations and the implications of their involvement in family business. We review prior studies on generations by considering different social science fields, which we analyze according to a novel theoretical framework. Building on this framework, and placing particular emphasis on family firms, we identify important knowledge gaps that serve as a springboard for future research. CEO experience and corporate financing decisions: Evidence from a natural experiment in China Article Oct 2021 CHINA ECON REV Ying Hao Yuxiu Huang Xuegang Cui Qiang Liu Using the unique setting in China's economic transition and market reform, we investigate whether CEOs' experience regarding an economic boom affect corporate financing decisions. Economic booming, as a result of China's reform and open policy since 1978, affects individual risk preferences and decision behavior for those who grew up during the reform process. We find that Reform-and-Opening CEOs, who experience the reform and open-up era early in life, implement more aggressive capital structure policies and maintain higher leverage compared to Planned Economy CEOs. Furthermore, we determine that Reform-and-Opening CEOs tend to conduct debt issuance more frequently to cover financing needs as they can better deal with the liquidity risk of debt financing and confront the pressures arising from frequent monitoring by the debt markets. Using the stagewise regression, we find a cumulative effect of early growth experience. We also use the common trend test and placebo tests to deal with the concern that Reform-and-Opening CEOs pursue significantly more aggressive financial policies relevant to the systematic differences. Additional tests rule out the possibility that our results are driven by industry competition, state ownership, and educational ideology. Chinese Traditional Cultural and Cross-Cultural Management Article Full-text available Confucian culture is an ancient culture that has been circulating in China for thousands of years. It represents the value of most Chinese people and plays an important role in Chinese history. From state governance to family management, Confucian culture has influenced all aspects of Chinese people, and, of course, has a great influence on the management of Chinese enterprise managers. However, cultural differences and conflicts when managing multinational teams are inevitable. Therefore, in this article, we will discuss Confucian culture and how to integrate it into modern enterprise management to solve the adverse consequences of cultural differences and conflicts, and discuss the drawbacks of Confucianism to modern enterprise management. Human Resource Management in Asia Chapter Jan 2021 Fang Cooke Vivien Supangco This chapter reviews key characteristics and developments of human resource management (HRM) in Asian countries against the backdrop of their rich historical features and the rapidly changing landscape on many fronts. It takes stock of what has been researched in the HRM field and the theoretical perspectives underpinning it. There is a growing trend for positivist HRM studies of hypothesized organizational conditions and individual behaviors, at the expense of in-depth qualitative studies of the motivations, actions, and interactions of social groups, and outcomes in specific organizational settings. It is clear that Asian countries are advancing at a rapid pace in their economic development, powered by growing technological competences. However, each nation-state is confronted with a different set of HRM challenges, ranging from skills shortage to workforce aging, informalization of employment, changing expectations, behavior of the workforce, and so forth. We argue that the understanding of people management in workplaces must take into account a range of institutional, cultural, organizational, and individual factors. We also argue that HRM research needs to be engaged with real and live issues that are confronting employing organizations and individuals, with the aim of adding social value and extending our intellectual horizon. Two-way in-/congruence in three components of paternalistic leadership and subordinate justice: the mediating role of perceptions of renqing Article Feb 2021 Han Ren Zhengqiang Zhong Charles Weizheng Chen Chris Brewster This paper examines the effects of two-way congruences and incongruences between three components of paternalistic leadership, namely, benevolence, morality, and authoritarianism, on overall subordinate justice perceptions. We hypothesize that these dyad in-/congruences would differentially predict subordinate overall justice perceptions, with perceptions of renqing as a mediator. With data collected from two-wave surveys in the People’s Republic of China, the results indicate that dyad congruences and incongruences between benevolence, morality, and authoritarianism have significant impacts on subordinate perceptions of renqing and, ultimately, their overall justice perception. Our findings underscore that to fully understand the influencing processes of paternalistic leadership on subordinate outcomes, it is important to take into account the context and the different combinations of its three dimensions. How Ethics and Benevolence in Leadership Inspires Creativity: The Mediating Role of LMX and Motivation, Complemented by Culture with Greater Power Distance. Article Jan 2020 Mohsin Adnan Ansari Danish Ahmed Siddiqui Tournament incentives, age diversity and firm performance Article Jan 2021 J Empir Finance Oleksandr Talavera Shuxing Yin Mao Zhang This study introduces a new dimension, age diversity of non-CEO executives, which moderates the relationship between promotion-based tournament incentives, measured as the pay gap between the CEO and non-CEO executives, and firm performance. For a sample of Chinese listed firms from 2005 to 2015, we find that the tournament incentives for non-CEO executives relate positively to firm performance. This relationship is weaker when non-CEO executives are from different age cohorts, whereas the tournament effect is enhanced when non-CEO executives are from the same age cohort. The negative moderation effect of age diversity is more pronounced in state firms and in the Northern China Plain cultural region. The negative moderation effect disappears in firms with CEOs who have overseas experience. We reason that the peer pressure among the similar-aged non-CEO executives enhances the tournament competition and that age hierarchy reduces incentives for younger executives to compete. Our findings have important implications for firms not only in China, but also in countries and regions where seniority is highly valued when setting executive compensation and optimizing organizational structure. View Show abstract Conclusions, Implications, and Future Research Chapter Jan 2017 Chunyan Zhu A Cross-Cultural Study of Relationship Proneness and Its Implications for Relationship Marketing Chapter Jan 2013 Riyad Eid Jack Wei Faye Mcintyre Salil Taplade This paper examines relationship proneness of consumers in a cross-cultural setting; specifically, the relationship proneness between Chinese and U.S. consumers of Generation Y (born from 1976 to 1995) and its effects on relational satisfaction and relationship commitment. Based on previous research (e.g., De Wulf, Odekerken- Schröder, & Iacobucci, 2001) and cultural theories (e.g., Hofstede, 1980, 2001), nine hypotheses were developed involving the effects of relationship building tactics (i.e., direct mail, preferential treatment, communication, and tangible rewards) on relationship proneness, relational satisfaction and store loyalty. This quantitative study used a survey among two samples of consumers in China and the U.S. The final sample size was comprised of 349 student consumers. The findings of the research provide managerial implications for international retailers. Relationship proneness is a meaningful personal characteristic that can be used to describe or predict consumer behavior across cultures. A relationship marketing strategy that works for one culture may also work well in another culture. It is possible and appropriate, at least with generation Y consumers, to employ standardized approaches in relationship marketing across cultures. Literature Review and Research Hypotheses Chapter Jan 2017 Chunyan Zhu Zooming in on the Effect of National Culture on Knowledge Sharing Behavior Chapter Jan 2011 This research project investigates what are the national cultural factors that influence employees’ cross-cultural knowledge sharing in online environments and in what way. The chapter draws on findings from 41 in-depth interviewees conducted with 20 Chinese and 21 American employees who worked for a large multinational corporation. The rich interview data identified three national cultural differences that impacted Chinese and American participants s’ knowledge sharing through an online system, namely, language, differences grounded in collectivism/individualism, and different levels of uncertainty avoidance. English created a barrier for Chinese users to post their ideas but it didn’t seem to stop them from consuming knowledge. Differences grounded in collectivist/individualist values were mainly reflected in these two cultural groups’ different logic regarding the relationship between different working contexts and the need to share. Chinese participants also showed a higher level of uncertainty avoidance than American participants. Together these cultural differences could explain why Chinese shared knowledge less frequently than their American peers. Despite these reported cultural differences, findings from this research suggest that the actual cultural differences were smaller than what literature implies. Possible explanations for fewer cultural differences are explored. Practical implications for knowledge management practitioners are also offered. Guilty and Corporate Philanthropy: The Case of the Epic Privatization in China Long Term Orientation in China: Generational Differences and Cultural Measurement Standards Douglas Chun Zhen Zhang China has undergone significant societal changes in recent decades, however, questions remain as to how these changes have influenced the values of different generations in the country. Using concepts used to measure LTO from both Hofstede’s revised VSM08 questionnaire and Bearden et al.’s (2006) modified scale, we conducted a survey with 1154 people in China. We found participants born in or before 1981 have higher long-term orientation compared to individuals born after 1981. Perhaps more importantly, we found that when measured by these concepts, our overall sample scored lower on the STO/LTO scale than Hofstede’s LTO scale indicate. Our findings have large implications on the instruction educators and consultants are providing their students in regards to ethnic cultures. We suggest that business practitioners should be aware of these cultural value changes when formulating strategic plans, as these attitudinal and behavioral changes have the potential to greatly impact their business interactions, and that instructors should be aware of the plasticity of living cultures." Perspective taking and voice solicitation: a moderated mediation model Fangzhou Liu Employee voice can be beneficial and critical for organizational success. However, evidence shows that power and position create a ‘leaders’ bubble’ that is hard to penetrate unless leaders proactively solicit voice from employees. Drawing on the situated focus theory of power and supervisor‐subordinate goal‐congruence literature, we hypothesize that followers’ perspective taking affects leaders’ voice solicitation through supervisor‐subordinate goal congruence. Furthermore, we propose that the perception of organizational politics weakens this indirect relationship, whereas information sharing strengthens it. Survey data collected from 213 Chinese employees provide support for a positive indirect relationship that existed between perspective taking and voice solicitation through supervisor‐subordinate goal congruence, and this indirect relationship was stronger when the employees’ perception of organizational politics was low. Historical and Conceptual Context of Chinese International Students’ Citizenship This chapter explores the literature that relates to students studying abroad and the current research on Chinese students in New Zealand, more specifically providing a background for understanding the experiences of participants in this study. Second, the chapter provides a conceptual understanding of citizen and citizenship. The term ‘citizen’ is not independent of history. To understand the concept of citizenship, traditional notions are reviewed in a historical context. The historical development of the concept of ‘citizen’ is traced by considering differing philosophical perspectives on citizenship. A deep acting perspective generation Y hotel employees’ workplace deviance Yanping Yu Purpose This study aims to develop a measurement scale to assess generation Y China hotel employees’ workplace deviance and then investigate the effect of generation Y employees’ deep acting on workplace deviance by focusing on the mediating effect of emotional exhaustion and the moderating effect of organizational identification. Design/methodology/approach The study first adopts a mixed-methods approach to develop the scale of generation Y hotel employees’ workplace deviance, then multiple data is collected targeting 580 hotel employees by a three-stage survey. Structural equation modeling (SEM) and a hierarchical regression analysis were used to test the hypotheses. Findings Workplace deviance of generation Y hotel employees in China was divided into two dimensions, aggression and neglect. Deep acting was found to be negatively related to workplace deviance, and emotional exhaustion had a mediating effect on the relationship between deep acting and workplace deviance. Organizational identification strengthened the effect of deep acting on neglect and the effect of deep acting on emotional exhaustion, whereas it did not moderate the relationship between deep acting and aggression. Originality/value First, this study provides a more powerful explanatory perspective on the conservation of resources theory to explore future research by especially targeting generation Y employees. Second, this study develops the elements of workplace deviance structure of generation Y hotel employees, especially in the Chinese cultural context. Third, it explores the inherent mechanism of how and why deep acting impacts workplace deviance. Reverse Angle Chapter Paul Ross The most consequential relationship that a foreign employee working in a Chinese company is likely to have is with a direct supervisor. With an eye towards ensuring that the relationship between employee and supervisor is a positive one, this chapter endeavors to present the supervisor’s view of the world and give the foreign employee an appreciation for the supervisor’s motivations, concerns, and expectations. It also addresses the basic and very practical issue of how the foreign employee should approach the Chinese boss and take first critical steps on the road to building a relationship that is satisfactory and mutually beneficial. Does Latin America Exist? (And Is There a Confucian Culture?): A Global Analysis of Cross-Cultural Differences Does Latin America exist? Latin American studies centers (like African, or Middle Eastern or West European studies centers) are based on the assumption that Latin America (and Africa, the Middle East, etc.) are more than arbitary geographic expressions: they define coherent cultural regions, having people with distinctive values and worldviews that make them think differently and behave differently from people of other cultures. The most powerful challenge to this view currently comes from the rational choice school, whose practitioners occasionally mention the importance of cultural differences but whose models almost always ignore them, implicitly assuming that in a given situation all people will make the same “rational” choices regardless of cultural perspectives. But if major differences exist between the worldviews and motivations of people in different cultural zones, a rational choice model that applies to the United States may not accurately describe the behavior of people in other cultures. The existence of meaningful cultural areas has been challenged on other grounds as well. Modernization theory focuses on the differences between “traditional” and “modern” societies, each of which are characterized by distinctive economic, political, social, and cultural institutions. This perspective tends to attribute any differences between Latin American and highly industrialized societies to differences in their levels of economic development: with economic development, these differences will tend to disappear. Differences between various “traditional” cultures tend to be ignored. The usefulness of “Latin America” as a meaningful cultural boundary could also be disputed on various other grounds. The dimension of individualism-collectivism, as identified by Hofstede (1980), was studied using items developed both theoretically and emically in nine diverse cultures. The dimension was found to be analysable into four stable etic factors: Individualism had two aspects (Separation from Ingroups and Self-Reliance with Hedonism) and collectivism had two aspects (Family Integrity and Interdependence with Sociability). These four factors are orthogonal to each other. The location of nine cultures on these four factors was used to compute a “collectivism” score which correlated r = + · 73 with Hofstede's (1980) collectivism scores for the nine cultures. This approach enables the measurement of individualism-collectivism in each culture as well as across cultures, and shows that different methods for measuring individualism-collectivism converge. Universals in the Content and Structure of Values: Theoretical Advances and Empirical Tests in 20 Countries Publisher Summary This chapter addresses the universals in the content and structure of values, concentrating on the theoretical advances and empirical tests in 20 countries, and its four basic issues: substantive contents of human values; identification of comprehensive set of values; extent to which the meaning of particular values was equivalent for different groups of people; and how the relations among different values was structured. Substantial progress has been made toward resolving each of these issues. Ten motivationally distinct value types that were likely to be recognized within and across cultures and used to form value priorities were identified. Set of value types that was relatively comprehensive, encompassing virtually all the types of values to which individuals attribute at least moderate importance as criteria of evaluation was demonstrated. The evidence from 20 countries was assembled, showing that the meaning of the value types and most of the single values that constitute them was reasonably equivalent across most groups. Two basic dimensions that organize value systems into an integrated motivational structure with consistent value conflicts and compatibilities were discovered. By identifying universal aspects of value content and structure, the chapter has laid the foundations for investigating culture-specific aspects in the future. Fostering Corporate Entrepreneurship: Cross-Cultural Comparisons of the Importance of Individualism Versus Collectivism
https://www.researchgate.net/publication/5222864_Doing_Business_in_the_21st_Century_with_the_New_Generation_of_Chinese_Managers_A_Study_of_Generational_Shifts_in_Work_Values_in_China
Addiction doc says: It’s not the drugs. It’s the ACEs…adverse childhood experiences. – ACEs Too High He says: Addiction shouldn’t be called “addiction”. It should be called “ritualized compulsive comfort-seeking”. He says: Ritualized compulsive comfort-seeking (what traditionalists call addiction) is a normal response to the adversity experienced in childhood, just like bleeding is a normal response to being stabbed. He says: The solution to changing the illegal or unhealthy ritualized compulsive comfort-seeking behavior… He says: Addiction shouldn’t be called “addiction”. It should be called “ritualized compulsive comfort-seeking”. He says: Ritualized compulsive comfort-seeking (what traditionalists call addiction) is a normal response to the adversity experienced in childhood, just like bleeding is a normal response to being stabbed. He says: The solution to changing the illegal or unhealthy ritualized compulsive comfort-seeking behavior of opioid addiction is to address a person’s adverse childhood experiences (ACEs) individually and in group therapy; treat people with respect; provide medication assistance in the form of buprenorphine, an opioid used to treat opioid addiction; and help them find a ritualized compulsive comfort-seeking behavior that won’t kill them or put them in jail. This “he” isn’t some hippy-dippy new age dreamer. He is Dr. Daniel Sumrok, director of the Center for Addiction Sciences at the University of Tennessee Health Science Center’s College of Medicine. The center is the first to receive the Center of Excellence designation from the Addiction Medicine Foundation , a national organization that accredits physician training in addiction medicine. Sumrok is also one of the first 106 physicians in the U.S. to become board-certified in addiction medicine by the American Board of Medical Specialties . Sumrok, a family physician and former U.S. Army Green Beret who’s served the rural area around McKenzie, TN, for the last 28 years, combines the latest science of addiction and applies it to his patients, most of whom are addicted to opioids — but also to alcohol, food, sex, gambling, etc. He sees them in the center’s two outpatient clinics: his clinic, which the Center for Addiction Science has taken over as its rural clinic, and another that opened recently in downtown Memphis. Since he first sat down in the early 1980s to write a research paper (“ Public Health Legacy of the Vietnam War: Post-Traumatic Stress Disorder and Implications for Appalachians ”) to describe the symptoms of the newly named post-traumatic stress disorder in Vietnam veterans – “problems with the law, having trouble sleeping, anxiety, divorce, sleep troubles, substance use disorders, depression, anxiety, cognitive and chronic pain issues” — Sumrok has pieced together the ingredients for a revolutionary approach to addiction. It’s an approach that’s advocated by many of the leading thinkers in addiction and trauma, including Drs. Gabor Maté , Lance Dodes and Bessel van der Kolk . Surprisingly, it’s a fairly simple formula: Treat people with respect instead of blaming or shaming them. Listen intently to what they have to say. Integrate the healing traditions of the culture in which they live. Use prescription drugs, if necessary. And integrate adverse childhood experiences science: ACEs. “My patients seem to respond really well to this,” he says. ACEs understanding changes practice Learning about ACEs more than two years ago was a big turning point for his understanding of addictions, explains Sumrok. “I was working in an eating disorders clinic and someone told me ‘90 percent of these folks have sexual trauma’. I remember thinking: That can’t be right. But that was exactly right. Since I’ve learned about ACEs, I talk about it every day.” He also practices it every day, by integrating ACEs assessments for all patients in his clinics. He currently has about 200 patients who are addicted, most to opioids (heroin and prescription pain relievers, including oxycodone, hydrocodone, codeine, morphine, and fentanyl). “I’ve seen about 1,200 patients who are addicted,” he says. “Of those, more than 1,100 have an ACE score of 3 or more.” Sumrok knows that score says a lot about their health and ability to cope: ACEs comes from the CDC-Kaiser Permanente Adverse Childhood Experiences Study (ACE Study), groundbreaking research that looked at how 10 types of childhood trauma affect long-term health. They include: physical, emotional and sexual abuse; physical and emotional neglect; living with a family member who’s addicted to alcohol or other substances, or who’s depressed or has other mental illnesses; experiencing parental divorce or separation; having a family member who’s incarcerated, and witnessing a mother being abused. Subsequent ACE surveys include racism, witnessing violence outside the home, bullying, losing a parent to deportation, living in an unsafe neighborhood, and involvement with the foster care system. Other types of childhood adversity can also include being homeless, living in a war zone, being an immigrant, moving many times, witnessing a sibling being abused, witnessing a father or other caregiver or extended family member being abused, involvement with the criminal justice system, attending a school that enforces a zero-tolerance discipline policy, etc. The ACE Study is one of five parts of ACEs science, which also includes how toxic stress from ACEs damage children’s developing brains; how toxic stress from ACEs affects health; and how it can affect our genes and be passed from one generation to another (epigenetics); and resilience research, which shows the brain is plastic and the body wants to heal. Resilience research focuses on what happens when individuals, organizations and systems integrate trauma-informed and resilience-building practices, for example in education and in the family court system . The ACE Study found that the higher someone’s ACE score – the more types of childhood adversity a person experienced – the higher their risk of chronic disease, mental illness, violence, being a victim of violence and a bunch of other consequences. The study found that most people (64%) have at least one ACE; 12% of the population has an ACE score of 4. Having an ACE score of 4 nearly doubles the risk of heart disease and cancer. It increases the likelihood of becoming an alcoholic by 700 percent and the risk of attempted suicide by 1200 percent. (For more information, go to ACEs Science 101 . To calculate your ACE and resilience scores, go to: Got Your ACE Score? ) High ACE scores also relate to addiction: Compared with people who have zero ACEs, people with ACE scores are two to four times more likely to use alcohol or other drugs and to start using drugs at an earlier age. People with an ACE score of 5 or higher are seven to 10 times more likely to use illegal drugs, to report addiction and to inject illegal drugs. The ACE Study also found that it didn’t matter what the types of ACEs were . An ACE score of 4 that includes divorce, physical abuse, an incarcerated family member and a depressed family member has the same statistical health consequences as an ACE score of 4 that includes living with an alcoholic, verbal abuse, emotional neglect and physical neglect. Subsequent research on the link between childhood adversity and addiction corroborates the findings from the ACE Study, including studies that have found that people who’ve experienced childhood trauma have more chronic pain and use more prescription drugs; people who experienced five or more traumatic events are three times more likely to misuse prescription pain medications. Dr. Dan Sumrok with group therapy members at McKenzie, TN, clinic (Photo: Yalonda James, The Commercial Appeal) “ACEs just doesn’t predict substance abuse disorders,” says Sumrok. “All of our major chronic diseases link to substance abuse, so this is too big to ignore.” Whether you’re talking about obesity, addiction to cigarettes, alcohol or opioids, the cause is the same, he says: “It’s the trauma of childhood that causes neurobiological changes.” And the symptoms he saw 40 years ago in soldiers returning from Vietnam are the same in the people he sees today who are addicted to opioids or other substances or behaviors that help them cope with the anxiety, depression, hopelessness, fear, anger, and/or frustration that continues to be generated from the trauma they experienced as children. Learning about ACEs helped him understand that the original definition of PTSD, which many people still cling to, is not accurate. In the 1980s, PTSD was defined as a result of trauma that was outside the realm of normal experience. “That was just wrong,” says Sumrok. “Divorce, living with depressed or addicted family members are very common events for kids. My efforts are around helping people to see the connections, and that their experiences are predictable and normal. And the longer the experiences last, the bigger the effect.” He also says, “Drop the ‘D’, because PTSD is not a disorder.” It’s what he learned from van der Kolk, who wrote The Body Keeps the Score . “Bessel says we’ve named this thing wrong. Post-traumatic stress is a brain adaptation. It’s not an imagined fear. If one of your feet was bitten off by a lion, you’re going to be on guard for lions,” explains Sumrok. “Hypervigilance is not an imagined fear, if you’ve had one foot bitten off by a lion. It’s a real fear, and you’re going to be on the lookout for that lion. I tell my patients that they’ve had real trauma that’s not imagined. They’re not crazy.” Patients who learn about their ACEs understand that they can heal This is what happens when a person sees Sumrok for the first time: They fill out the 10-question ACE survey ( Got Your ACE Score? ) in the waiting room. “Then when I see them, I go through each question and ask them again,” says Sumrok, who also does a normal physical exam. “Frequently, there’s a difference between the two. For example, this morning, I saw a woman and she reported an ACE score of 1 on the survey. Then, when I asked her the questions, she reported nine out of 10.” That’s just how I grew up, she told Sumrok. She didn’t think being beaten, humiliated or seeing her mother smoking crack every day was harmful or unusual, especially since most kids she knew were experiencing the same thing. Sumrok normalizes their addiction, which he explains is the coping behavior they adopted because they weren’t provided with a healthy alternative when they were young. He explains the science of adverse childhood experiences to them, and how their addictions are a normal – and a predictable – result of their childhood trauma. He explains what happens in the brain when they experience toxic stress, how their amygdala is their emotional fuse box. How the thinking part of their brain didn’t develop the way it should have. How it goes offline at the first sign of danger, even if they’re not connecting the trigger with the experience. Drugs like Zoloft don’t really help much, he tells them. Zoloft and other anti-depressants don’t remove the memory triggered by the odor of after shave that was worn by your uncle who sexually abused you when you were eight, or the memory triggered by a voice that sounds just like your mother who used to beat you with a belt, or by a face of a man who looks like your father who used to scream at you about how worthless you were…the examples are infinite. That’s why van der Kolk says, “’The body keeps the score’,” Sumrok says. “After I explain all this to them, many of them stare at me and say: ‘You mean I’m not crazy?’” says Sumrok. “I tell them, ‘No, you’re not crazy’.” Sometimes he yells out the door to his nurse: ‘Patsy! Where’s my not-crazy stamp? I need to stamp this person’s chart.” For people who are addicted to opioids, he prescribes buprenorphine (one of the brand names: Suboxone), which helps them to withdraw from opioids and to keep their job, or return to work. For most people, the drug is less addictive than other opioids. Sometimes if people are young, healthy and haven’t been addicted long, they can withdraw from opioids without buprenorphine. “There’s no buzz associated with buprenorphine,” says Sumrok. “They can concentrate and think. Once they’re free of the continuous distraction of the acquisition and use of substances, they become pretty valuable employees.” For people who are addicted to alcohol, he prescribes naltrexone (one of the brand names: Revia), because alcoholics have a high risk of death if they aren’t provided medication. And in this current national attention on opioids, Sumrok is careful to point out that although 33,000 people died from opioid overdose in 2015 , 88,000 people die annually from alcohol-related causes , and 480,000 from cigarette smoking . The complicating factor — and why policies don’t work when they chase the eradication of one drug, only to focus on eradicating the next popular drug of choice for “ritualized compulsive comfort-seeking” — is that many people use opioids and alcohol and cigarettes. And if they receive no help to get at why they’re using legal or illegal substances, they will move on to another, more easily accessible drug when the current drug they’re using becomes more difficult to find. All patients sign a contract agreeing that they won’t drink alcohol or take other drugs. “We don’t mess around with that,” says Sumrok. “We can’t deal with them being deceptive, because if they drink or do other drugs, it can kill them. If their drug screens aren’t consistent, we ask them to find another doctor.” Just about everybody stays, he says. They also participate in group therapy. For physicians who prescribe buprenorphine, it’s now required, but Sumrok had seen the research about the effectiveness of group therapy, and had started 12-step groups for his patients about 10 years ago. Talking with others who have the same experiences helps each person normalize their own experiences. Sumrok and the others in the group help each other find “ritualized compulsive comfort-seeking behaviors” that won’t kill them or put them in jail, such as coaching their kid’s soccer team or volunteering at a food bank. (Sumrok often quotes Forest Gump: “Helping helps the helper.”). He also encourages them to integrate other rituals into their lives, such as walking 30 minutes a day or other exercise, joining a 12-step group or finding a path to encourage a spiritual awakening. “Six months into this,” says Sumrok, “they start saying things like, ‘My wife and I are back together’, they’re hanging out with their kids. It’s pretty cool to see how people get their lives back. My favorite word is ‘normal’. When they tell me they feel normal, I know they’re doing okay.” So, how long does it take before they’re cured? “How long should you take insulin if you have diabetes?” responds Sumrok, making the point that this is a chronic disease, that people should be in treatment for as long as it is necessary, and that some may relapse. His goal is for them to not have to use buprenorphine, but he knows that because of the number and duration of their ACEs, and the paucity of resilience factors provided to them when they were children, many will need continual support. He helps them learn how to integrate that support into their lives. “When a diabetes patient comes in with a blood sugar level of 300, we don’t say: ‘Give me back that insulin.’ We intensify the treatment to get them back in balance,” explains Sumrok. “Only in addictions do we shame people. We tell them they can’t be part of this recovery anymore. We create a teeny hoop that’s called abstinence, and not too many people can jump through that hoop. If every time we saw a diabetic, we told them that their kidneys were going to fail, they would be blind and we would amputate their extremities, there wouldn’t be many diabetics who got help. I have patients who drop out, and then return a couple of months later, and say, ‘Doc, Christmas came, I saw some of my buddies, and I started using again.’ I tell them, ‘Come on in. Let’s work with you.’ And I remind myself that I’m not saving souls, I’m saving their asses. It’s about getting them so they can function at work, at home, at play. It’s not about making them perfect human beings. “It has been abundantly clear to me and reinforced over a 40-year career,” continues Sumrok, “that patients desire, and respond better to, sensitive and informed care. From the Navajo Nation to Appalachia to Memphis and from the mountains of Honduras to the jungles of Amazonia, people regard respect as the sine qua non of quality care.” Stories AND data drive solutions Although Sumrok thinks his approach benefits his patients, he knows he needs data to prove it. When he saw a recent study that said 43% of people on buprenorphine were using other opioids, he did his own analysis of a sample of his patients, and found that only 8% were using other opioids. After tracking down those who were, most had good reasons, such as a man whose arm and shoulder were in a new cast after surgery repairing an injury, and he was taking a narcotic. Only one did not, and when shown his drug test, he said, “You know what? I slipped.” He talked about it in group, says Sumrok, and everyone in his group hovered around him to make sure he’d continue the program. Dr. Karen Derefinko Because Sumrok has kept fastidious records of the patients who have done their ACE scores, Dr. Karen Derefinko, a clinical psychologist and assistant professor in the Department of Preventive Medicine at the University of Tennessee Health Science Center, is starting a research project to examine all 1,200 records in Sumrok’s clinic in McKenzie to look at the relationship between people’s ACE scores and their adherence to treatment and their relapses. “We think that people with high ACE scores are likely to have more relapses,” she says. “And that may be because people with higher scores have fewer resources and more difficulty associated with adhering to their treatment plans.” She and her research assistant will de-identify the records, so that all information is anonymous, and then collect the data. Once that data is analyzed — probably within two months — Derefinko and her assistant will conduct focus groups of some of Sumrok’s patients. She’s already been sitting in some of the groups. “Dan encourages this participatory nature of his groups,” she says. “People are very willing to talk. After the group sessions, they’re often not done talking about why they came to Sumrok and why other programs didn’t work for them.” Through the records and the focus groups, Derefinko hopes to identify barriers to care, which include basics such as how people can find good care easily (most of Sumrok’s patients find out about him through word of mouth), being wary of the treatment because it isn’t explained to them, or — what Sumrok hears a lot — being judged or talked down to instead of given understanding and respect. “In Shelby County, people complain about barriers to care, which many people think is because of economics,” she says. “But it may not be just economics that is keeping people from accessing treatment; it may be more about being judged, and not knowing what the treatment looks like.” Being treated with respect builds trust, trust builds health One of Sumrok’s patients – I’ll call him John, which is not his real name – has been driving 140 miles from Southeast Missouri to see Sumrok for the last five years. He began using drugs off and on during his 20s. When he was in his 30s, he injured his back, was sent to a worker’s comp physician, who prescribed stronger doses of pain killers until his back stopped hurting. “I was taking pain pills like candy,” says the 46-year-old, who is married and has a son. “All of a sudden, the pills are gone, and you’re very sick, and I start looking for them everywhere – on the street, taking them from family members without asking – just to keep me from getting sick. I thought I had to have them to function. If I didn’t have six or seven pain pills, I wasn’t going to be able to get out of bed. If I didn’t get them, I’d be sick, puking….I’d do about anything to have those pills.” After he spent his and his wife’s life savings, and the money they’d put away to buy a home, and his retirement fund from a previous job; after he saw friends die from overdosing; and after he realized that he was risking losing his wife and son, he told his wife he needed help, and they found Sumrok. “It’s been a miracle, for sure,” says John. As the Suboxone took effect, “after two or three weeks, I began to feel normal again.” About two years ago, Sumrok asked him to fill out the ACE survey. “It really did make a difference,” says John. He had never connected experiences in his childhood with using drugs as an adult. “When I was just a baby,” recalls John, “my grandpa took me from my mother, and told my parents: ‘When you guys are stable, I’ll let you have him back.’ Up until I was 10 or 11, I called them ‘Mom’ and ‘Dad’.’” His older sisters were sent to live with his other set of grandparents. He didn’t live with his parents again until he was 15 years old. His sisters were adults and out on their own by then. Until he did the ACE survey and talked with Sumrok about his childhood, it didn’t dawn on him that losing his mother, father and his sisters at a young age could have affected him in ways he didn’t realize. “I knew I was loved by my grandfather and grandmother, but being a young kid and seeing other kids going out with their parents was frustrating,” he says. “I lived with old people who never left the house, while my parents were out running around. I maybe thought my mom and dad didn’t care about me enough to change. I might have always felt like I wasn’t important enough to my mom and dad for them to change the way they were living and acting.” But now he has a better understanding of what it was like to be a 19-year-old in the late 1960s and involved in the drug and party scene then, as his parents were. He understands them better, and why they weren’t able to care for him. He and his family members have “had our discussions,” says John. “My family life is a whole lot better. I didn’t have relationships with my parents or sisters. We only live seven miles apart, and I barely saw them twice a year, if that. But now I have my wife back. I’ve got my son back. And I see my parents and sisters all the time. We’re a tight-knit family.” He’s also able to hold a job, and is a reliable employee. John sees Sumrok once a month now. He participates in group therapy, where they can safely talk about their ACE scores without having to get into specifics. He checks in with Sumrok, who renews his prescription. “I like group therapy with Dr. Sumrok,” says John. “He talks to us with respect. We feel very comfortable with him. Dr. Sumrok never lies. I trust him fully. And he trusts me. It took five or six months to build that trust. The more I met with him, the more I realized that he was really concerned about me. He wants to help people. Let him train more doctors in the procedures he uses. You can’t treat people like they’re nobodies.” A 29-year-old patient, who chose to be called “Mr. Big” since I’m not using his real name, has been seeing Sumrok for the last six months. He had been in a methadone treatment program, and found Sumrok after he couldn’t pay for treatment any longer. Sumrok was the only physician who would take his insurance. Mr. Big filled out the ACE survey in the waiting room, but reported his score as a two. Then Sumrok went through the survey with him, and Mr. Big’s score climbed to an 8. “It does help me understand my addiction better,” says Mr. Big, who is a single father of two children, five and six years old. “For one, my trauma in my childhood was very dramatic. I thought everyone’s parents did what they were doing. I could see why I related to narcotics and stuff. It was the only place I had to turn. I started taking opiates when I was 11 or 12 years old. I was playing football, and broke my ankle. They gave me painkillers that made me feel like Superman. I couldn’t get enough, because I wasn’t feeling like Superman without it.” The Suboxone helps him feel “normal — probably the way everybody else feels,” says Mr. Big. “Nothing I took ever gave me that feeling before. I’m a better person, father, and a better brother” to his sister, whom he convinced to also get help from Sumrok. The first time he went for help, to a methadone clinic, he didn’t like it for two reasons: Methadone made him nod off or feel high, and the people at the clinic treated him as if he was a number, or just there for the drugs. “That’s just unprofessional, in my opinion,” he says. “Sumrok actually sits down and talks to you like a human being.” Mr. Big wants to work with Sumrok to develop a “game plan so that I can live without my medicine,” he says. He just wants to live a normal life. What does a normal life mean? “It means that I’m home overnight with my children,” he says. “I don’t have to rob, lie, steal, or cheat to find drugs. I can fit in with society and not be high off my mind. I can wake up every day and do stuff. My children — they know Daddy’s not in bed sick any more. It’s wonderful. I’m wore out. I never knew that first grade and kindergarten had homework that was so complicated.” With addictions and deaths on upswing, how to increase addiction docs? Prescription and illicit opioids are the “main driver of drug overdose deaths,” according to the CDC, with 33,091 deaths in 2015 . That’s four times more than 1999. And between 2014 and 2015, Tennessee saw a 13.8 percent increase in opioid deaths. More than 1,000 people died from opioid overdoses in 2014, and tens of thousands of people lead desperate lives, most of them unknowingly fueled by their childhood experiences. Only 10% of these are getting the help they need, says Sumrok. Dan Sumrok is just one doctor, in one part of the country. How can what he does be scaled up to thousands of physicians who can treat addiction — all types of addiction — successfully in all parts of the U.S.? By doing what Dr. David Stern, Robert Kaplan executive dean and vice-chancellor for clinical affairs for the University of Tennessee’s College of Medicine and the University of Tennessee Health Sciences Center, did: launch the Center for Addiction Science . “This really starts with Dr. Altha Stewart, who’s the director of the Center for Health in Justice-Involved Youth ,” says Stern. “She’s the one who showed me that kids with high ACE scores end up in trouble. When I developed the Center for Addiction Science, it had to be like a cancer center, it had to be multi-disciplinary. In the old days, we thought people who had addictions were weak in the moral department. You really needed someone to straighten you out, because your mother didn’t do a good enough job.” Dr. David Stern But that approach doesn’t work. Neither does criminalizing addictions. Stigma drives problems underground, says Stern, instead of driving them to a solution. The center is taking an integrated approach to using research and education to help people in all possible ways, from physiology to genetics to counseling. Stern believes that every physician should know about ACEs science, which is one of the reasons he chose Sumrok to lead the center, along with his willingness to be creative and seek solutions across disciplines. “Two of the most prevalent things in acute care are depression and addiction,” says Stern. “I think it’s important to be able to understand what ACEs mean to patients, what addiction is all about, how to recognize it, how to treat it.” He’s in the process of finding an associate dean for medical education, and is looking for someone who will integrate ACEs and other social determinants of health into the school’s curriculum. “I think a medical school should provide for the community it serves,” says Stern. “This medical school should be the medical school for Memphis. We should develop solutions that are scalable.” Dr. Altha Stewart, associate professor of psychiatry in the University of Tennessee College of Medicine, learned about ACEs in 2009 when a group in Shelby County began educating people about ACEs science. They brought Dr. Vincent Felitti, co-founder of the ACE Study, and Robin Karr Morse, who wrote Ghosts from the Nursery: Tracing the Roots of Violence , which was published in 2007, to give a presentation. (Karr-Morse later wrote Scared Sick: The Role of Childhood Trauma in Adult Disease with Meredith S. Wiley; it was published in 2012.) Dr. Altha Stewart “It’s become a core part of what I do now in my professional work,” says Stewart, who was recently named president-elect of the American Psychiatric Association . She’s working with the Shelby County community and the local criminal justice system to integrate trauma-informed and resilience-building practices to find ways to help youth who enter the justice system — all of whom have likely experienced ACEs — instead of shaming, blaming or punishing them. The things that have happened to kids — as well as to many people who come into the health care system — are out of their control, says Stewart. “When you’re a child, you don’t control the people who abuse and assault you, who create hostile environments, who don’t provide you with clean clothes,” she says. “If a child can’t control their environment, because of these things they grow up thinking they’re bad, different, horrible people. This new approach (integrating trauma-informed and resilient-building practices based on ACEs science) helps them feel like they’re not drowning anymore. When they can pop their head out of the water and get a breath, and see outstretched hands, a life preserver, a life boat, that changes their entire perspective.” When Sumrok began integrating ACEs into addiction treatment, that was innovative, says Stewart. “If you don’t ask these questions, people tend not to tell you,” she says. Sumrok’s approach is part of a shift in patient engagement and involvement. “The trend in health care is that patients are partners in their treatment.” This new knowledge about why and how humans behave the way they do also speaks to how “we have trained the medical profession,” says Stewart. The traditional approach is that physicians “know everything. The people whom we treat know nothing. We tell them what to do, and if they don’t get better or do what we say, it’s their own fault. “That’s simply not true,” she emphasizes. “Some of us have come to understand that there’s more expertise in the community and our patients than we’ve understood. That takes a bit of humility on the part of a physician, and an understanding that we are partners in helping a person heal.” Sumrok’s experience with the young fellows at the Center for Addiction Science is giving him some real hope that the medical profession can change. When he’s explained to them how important it is to ask patients about ACEs and other aspects of their lives — such as food availability, safe housing, transportation, jobs (in the medical profession vernacular: social determinants of health) — “they say ‘isn’t that just taking a patient history?’” He and others at the University of Tennessee Health Sciences Center have an opportunity to educate young physicians outside the state, too. Derefinko is also director of the newly created National Center for Research of the Addiction Medicine Foundation. The foundation oversees the 130 addiction medicine fellowships at 46 medical schools across the country. “We want metrics to understand the impact they’re having” when they go out in the world, says Derefinko: where they go, whom they’re treating, how they’re practicing, whether they’re integrating ACEs science. In addition, the foundation will be developing some accreditation guidelines so that all fellows receive the latest and best education in addiction medicine. One of those elements, says Sumrok, has to be empathy, which physicians can practice by listening, acknowledging and understanding how the experiences in a person’s childhood and adulthood have shaped their lives and health. “Can you teach empathy?” he asks. “Can people learn to be empathetic providers? I think you can. I think so.” _______________________ If you’re interested in becoming more involved in the PACEs science community, join our companion social network, PACEs Connection. Just go to PACEsConnection.com and click “Join”. PACEsConnection.com is the leading advocate for information about the science of positive and adverse childhood experiences (PACEs) and the rapidly expanding, global PACEs science movement. Share this: Email Print Facebook LinkedIn Twitter Reddit Tumblr Pinterest Like this: Like Loading...
https://acestoohigh.com/2017/05/02/addiction-doc-says-stop-chasing-the-drug-focus-on-aces-people-can-recover/?like_comment=57530&_wpnonce=4ce16ed19b
Rates of lymphocytic thyroiditis and ultrasound features of citologically-interrogated thyroid nodules based on the area of residence in a Sicily province | Request PDF Request PDF | Rates of lymphocytic thyroiditis and ultrasound features of citologically-interrogated thyroid nodules based on the area of residence in a Sicily province | PurposeTo verify the prevalence of autoimmune thyroiditis (AIT) and the ultrasound characteristics (composition and volume) of thyroid nodules... | Find, read and cite all the research you need on ResearchGate Rates of lymphocytic thyroiditis and ultrasound features of citologically-interrogated thyroid nodules based on the area of residence in a Sicily province Endocrine 72(Suppl 5) DOI: 10.1007/s12020-020-02521-z Authors: Università degli Studi di Messina Giovanni Capodicasa Show all 10 authors Hide Abstract and Figures PurposeTo verify the prevalence of autoimmune thyroiditis (AIT) and the ultrasound characteristics (composition and volume) of thyroid nodules with respect to the area of residence in the province of Messina, some areas having environmental issues.Methods Fine-needle aspiration-interrogated nodules (n = 902) of 809 patients were evaluated upon stratification into 8 areas of residence.ResultsOverall, women were younger than men (55.3 ± 14.0 vs. 58.6 ± 12.6 years, P = 0.0083). Patients residing in three areas (one hosting two garbage dumps, one hosting a petrochemical complex and a thermoelectrical power plant, and one hosting several ceramic factories [CFA]) were younger than those residing in the city of Messina (MEA) (52.9 ± 13.4 vs. 57.7 ± 13.6 years, P < 0.0001). Also, patients residing in those three areas had a greater rate of AIT, diagnosed either ultrasonographically/serologically (22.2% of patients) or cytologically (26.3% of nodules), compared with MEA (11.7% of patients, P = 0.0007 or 20.2% of nodules, P = 0.0815). Rates of AIT ranged 12.5–28.6% in the remaining four areas. Overall, nodules in women were smaller than in men (3.6 ± 5.7 vs. 6.1 ± 9.4 ml, P = 0.0006). Compared with the other seven areas, patients living in CFA had the largest nodules (6.8 ± 6.8 ml, P = 0.0040–0.0291), with the nodule volume being inversely correlated to patient’s age (r = −0.4955, P = 0.0431).Conclusion Rates of AIT and associated ultrasound features of thyroid nodules vary in different areas of our province. Further studies correlating these rates and features with exposure to specific toxicants are warranted. Province of Messina (Sicily, Italy) and its subdivision into eight areas (see text). The province is 68 km long on the Ionian seaside and 150 km long on the Tyrrhenian seaside. Abbreviations in alphabetical orde: CFA the area that hosts the major ceramic factory center of the northern Sicily, which includes five towns, EIA the seven Eolian Islands, including their four municipalities; GDA the garbage dump area, including the six towns that host two garbage dumps, ICA the Ionian coast area, which includes the 18 eastern costal towns overlooking the Ionian Sea, MEA the city of Messina and the four easternmost towns overlooking the Tyrrhenian Sea, MOA the 47 towns located on two mountain ranges (the Nebrodi and the Peloritani mountains), mun municipality, nod nodules, PCTPA the area that hosts a petrochemical complex and a thermoelectrical power plant, which includes 13 towns, pts patients, TCA the Tyrrhenian coast area, which includes the ten costal towns overlooking the Tyrrhenian Sea other than those of MEA, GDA, PCTPA, and CFA. For a list of all municipalities of the province of Messina see Supplementary Table 1 … Age at observation and F:M ratio (white bars = men; black bars = women; striped bars = men and women) based on area of residence. The polluted areas (GDA, PCTPA and CFA) were considered either alone or taken as a whole. Statistically significant differences are indicated by asterisks (*0.001 < P < 0.01; **0.001 < P < 0.0001; ***P < 0.0001), and borderline significant differences (0.05 < P < 0.10) are indicated by the caret (^). For abbreviations see Fig. 1 legend … Volume of thyroid nodules according to gender (white bars = men; black bars = women; striped bars = men and women) and area of residence. The polluted areas (GDA, PCTPA, and CFA) were considered either alone or taken as a whole. Statistically significant differences are indicated by asterisks (*0.001 < P < 0.01; **0.001 < P < 0.0001; ***P < 0.0001), and borderline significant differences (0.05 < P < 0.10) are indicated by the caret (^). For abbreviations see Fig. 1 legend … Frequency of serologically and/or ultrasonographically diagnosed autoimmune thyroiditis according to gender (white bars = men; black bars = women; striped bars = men and women) and area of residence. Autoimmune thyroiditis was diagnosed based on serum thyroid autoantibodies positivity (i.e., thyroid peroxidase antibodies and/or thyroglobulin antibodies) and/or the ultrasonographic appearance of the thyroid parenchyma (hypoechoic and inhomogeneous). The polluted areas (GDA, PCTPA, and CFA) were considered either alone or taken as a whole. Statistically significant differences are indicated by asterisks (*0.001 < P < 0.01; **0.001 < P < 0.0001; ***P < 0.0001), and borderline significant differences (0.05 < P < 0.10) are indicated by the caret (^). For abbreviations see Fig. 1 legend. Overall, AIT was significantly more frequent in females compared with males (110/637 [17.3%] vs. 16/172 [9.3%], OR = 2.035, 95% CI = 1.169–3.542, P = 0.0106) … Frequency of cytologically diagnosed autoimmune thyroiditis according to gender (white bars = men; black bars = women; striped bars = men and women) and area of residence. Note that cystic nodules were disregarded. Autoimmune thyroiditis was diagnosed based on the presence of lymphocytes either infiltrating thyroid follicles or in the background along with signs of inflammation and moderate amount of colloid. The polluted areas (GDA, PCTPA, and CFA) were considered either alone or taken as a whole. Statistically significant differences are indicated by asterisks (*0.001 < P < 0.01; **0.001 < P < 0.0001; ***P < 0.0001), and borderline significant differences (0.05 < P < 0.10) are indicated by the caret (^). For abbreviations see Fig. 1 legend … Figures - available from: Endocrine Endocrine (2021) 72:744 – 757 https://doi.org/10.1007/s12020-020-02521-z ORIGINAL ARTICLE Rates of lymphocytic thyroiditis and ultrasound features of citologically-interrogated thyroid nodules based on the area of residence in a Sicily province Roberto Vita 1 ● Flavia Di Bari 1 ● Giovanni Capodicasa 1 ● Sarah Perelli 1 ● Anna Maria Bonanno 2 ● Antonio Ieni 2 ● Mariacarla Moleti 1 ● Francesco Vermiglio 1,3 ● Giovanni Tuccari 2 ● Salvatore Benvenga 1,4,5 Received: 2 July 2020 / Accepted: 3 October 2020 / Published online: 15 October 2020 © Springer Science + Business Media, LLC, part of Springer Nature 2020 Abstract Purpose To verify the prevalence of autoimmune thyroiditis (AIT) and the ultrasound characte ristics (composition and volume) of thyroid nodules with respect to the area of residence in the province of Messina, some areas having environ- mental issues. Methods Fine-needle aspiration-interrogated nodules ( n = 902) of 809 pati ents were evaluated upon strati fi cation into 8 areas of residence. Results Overall, women were younger than men (55.3 ± 14.0 vs. 58.6 ± 12.6 years, P = 0 .0083). Patients residing in three areas (one hosting two garbage dumps, one hosting a petrochemical complex and a thermoel ectrical power plant, and one hosting several ceramic factories [CFA]) were younger than those residing in the city of Messina (MEA) (52.9 ± 13.4 vs. 57.7 ± 13.6 years, P < 0.0001). Also, patients residing in those three areas had a greater rate of AIT, diagnosed either ultrasonographically/serologically (22.2% of patients) or cytologically (26.3% of nodules), compared with MEA (11.7% of patients, P = 0.0007 or 20.2% of nodules, P = 0.0815). Rates of AIT ranged 12.5 – 28.6% in the remaining four areas. Overall, nodules in wom en were smaller than in men (3.6 ± 5.7 vs. 6.1 ± 9.4 ml, P = 0.0006). Compared with the other seven areas, patients living in CFA had the largest nodules (6.8 ± 6.8 ml, P = 0.0040 – 0.0291), with the nodule volume being inversely correlated to patient ’ s age ( r = − 0.4955, P = 0.0431). Conclusion Rates of AIT and associated ultrasound features of thyroid nodule s vary in different areas of our province. Further studies correlating these rates and features wi th exposure to speci fi c toxicants are warranted. Keywords Thyroid nodules ● Chronic lymphocytic thyroiditis ● Autoimmune thyroiditis ● Fine-n eedle aspiration ● Environment ● Pollution Abbreviations AIT autoimmune thyroiditis CAIT cytology-based autoimmune thyroiditis CFA ceramic factory area CO carbon monoxide EIA Eolian Islands FNA fi ne-needle aspiration FT3 free triiodothyronine FT4 free thyroxine GDA garbage dump area * Roberto Vita [email protected] 1 Department of Clinical and Experimental Medicine, University of Messina, Viale Gazzi, 98125 Messina, Italy 2 Department of Human Pathology of Adult and Evolutive Age Gaetano Barresi - Section of Pathological Anatomy, University of Messina, Viale Gazzi, 98125 Messina, Italy 3 Interdepartmental Program on New Models of Multidisciplinary Management in Endocrinology, University Hospital, A.O.U. Policlinico G. Martino, Viale Gazzi, 98125 Messina, Italy 4 Master Program on Childhood, Adolescent and Women ’ s Endocrine Health, University of Messina, Viale Gazzi, 98125 Messina, Italy 5 Interdepartmental Program of Molecular & Clinical Endocrinology and Women ’ s Endocrine Health, University Hospital, A.O.U. Policlinico G. Martino, Viale Gazzi, 98125 Messina, Italy Supplementary information The online version of this article ( https:// doi.org/10.1007/s12020-020-02521-z ) contains supplementary Trace Element Status and Hypothyroidism: A Systematic Review and Meta-analysis Sep 2020 BIOL TRACE ELEM RES Sepide Talebi Ehsan Ghaedi Erfan Sadeghi Gholamreza Askari The relationship between thyroid hormones metabolism and trace element levels has biological plausibility; however, previous reports that compared trace element levels in patients with hypothyroidism and healthy individuals yielded conflicting results. Therefore, the aim of this meta-analysis was to investigate the association between selected trace elements (i.e., selenium (Se), zinc (Zn), iron (Fe), manganese (Mn), copper (Cu), lead (Pb)), and magnesium (Mg) concentrations in patients with hypothyroidism and healthy controls. Electronic databases, including PubMed, Scopus, Embase, and Science Direct, were searched systematically until September 2019. Thirty-two observational studies were included in the final analyses. Hedges’ g tests were used to estimate effect sizes, as trace element concentrations were reported using different measurement units across the studies. Selenium (Hedges’ g = − 0.52; 95% CI = [− 1.05, − 0.002]; P = 0.049) and Zn (Hedges’ g = − 0.86; 95% CI = [− 1.66, − 0.06]; P = 0.035) concentrations were significantly lower, whereas Pb concentrations were significantly higher (Hedges’ g = 0.34; 95% CI = [0.10, 0.59]; P = 0.006) in patients with hypothyroidism compared with healthy controls. There were no differences in the concentrations of Fe, Cu, Mn, and Mg between the groups. Patients with hypothyroidism exhibited lower Se and Zn and increased Pb concentrations compared with healthy controls. High-quality studies with larger sample sizes are required to explicate the link between trace element status and hypothyroidism. View Show abstract Increased risk for hypothyroidism associated with carbon monoxide poisoning: a nationwide population-based cohort study Nov 2019 Chien-Cheng Huang Chung-Han Ho Yi-Chen Chen How-Ran Guo Carbon monoxide poisoning (COP) may cause injuries to the central nervous and endocrine systems, which might increase the risk of developing hypothyroidism. We wanted to evaluate the association between COP and the risk of developing hypothyroidism because epidemiological data on this potential association are limited. We conducted a nationwide population-based cohort study using the Nationwide Poisoning Database and identified 24,328 COP subjects diagnosed between 1999 and 2012. By matching the index date and age, we selected 72,984 non-COP subjects for comparison. Subjects with thyroid diseases and malignancy before 1999 were excluded. We followed up the two groups of subjects until 2013 and compared the risk of developing hypothyroidism. COP subjects had a significantly higher risk for hypothyroidism than non-COP subjects (adjusted hazard ratio [AHR]: 3.8; 95% confidence interval [CI]: 3.2–4.7) after adjusting for age, sex, underlying comorbidities, and monthly income, and the AHR was particular higher in subjects with diabetes mellitus, hyperlipidemia, and mental disorder. The increased risk was highest in the first month after COP (AHR: 41.0; 95% CI: 5.4–310.6), and the impact remained significant even after 4 years. In conclusion, COP was associated with an increased risk for hypothyroidism. Further studies regarding the underlying mechanisms are warranted. Association of Exposure to Ambient Air Pollution With Thyroid Function During Pregnancy Oct 2019 Akhgar Ghassabian Livia Pierotti Mikel Basterrechea Mònica Guxens Importance Air pollutants interact with estrogen nuclear receptors, but their effect on thyroid signaling is less clear. Thyroid function is of particular importance for pregnant women because of the thyroid’s role in fetal brain development. Objective To determine the short-term association of exposure to air pollution in the first trimester with thyroid function throughout pregnancy. Design, Setting, and Participants In this cohort study, 9931 pregnant women from 4 European cohorts (the Amsterdam Born Children and Their Development Study, the Generation R Study, Infancia y Medio Ambiente, and Rhea) and 1 US cohort (Project Viva) with data on air pollution exposure and thyroid function during pregnancy were included. The recruitment period for the Amsterdam Born Children and Their Development Study was January 2003 to March 2004; for Generation R, April 2002 to January 2006; for Infancia y Medio Ambiente, November 2003 to January 2008; for Rhea, February 2007 to February 2008; and for Project Viva, April 1999 to November 2002. Statistical analyses were conducted from January 2018 to April 2019. Main Outcomes and Measures Residential air pollution concentrations (ie, nitrogen oxide and particulate matter [PM]) during the first trimester of pregnancy were estimated using land-use regression and satellite-derived aerosol optical depth models. Free thyroxine, thyrotropin, and thyroid peroxidase antibody levels were measured across gestation. Hypothyroxinemia was defined as free thyroxine below the fifth percentile of the cohort distribution with normal thyrotropin levels, following the American Thyroid Association guidelines. Results Among 9931 participants, the mean (SD) age was 31.2 (4.8) years, 4853 (48.9%) had more than secondary educational levels, 5616 (56.6%) were nulliparous, 404 (4.2%) had hypothyroxinemia, and 506 (6.7%) tested positive for thyroid peroxidase antibodies. Concentrations of nitrogen dioxide and PM with an aerodynamic diameter of 2.5 μm or less (PM2.5) were lower and had less variation in women in the US cohort than those in European cohorts. No associations of nitrogen oxide with thyroid function were found. Higher exposures to PM2.5 were associated with higher odds of hypothyroxinemia in pregnant women (odds ratio per 5-μg/m3 change, 1.21; 95% CI, 1.00-1.47). Although exposure to PM with an aerodynamic diameter of 10 μm or less was not significantly associated with hypothyroxinemia, the coefficient was similar to that for the association of PM2.5 with hypothyroxinemia (odds ratio per 10-μg/m3 change, 1.18; 95% CI, 0.93-1.48). Absorbances of PM2.5 and PM with aerodynamic diameter from 2.5 to 10 μg and were not associated with hypothyroxinemia. There was substantial heterogeneity among cohorts with respect to thyroid peroxidase antibodies (P for heterogeneity, <.001), showing associations of nitrogen oxide and PM with thyroid autoimmunity only in the women in the Generation R Study. Conclusions and Relevance The findings of this study suggest that first-trimester exposures to PM2.5 were associated with mild thyroid dysfunction throughout pregnancy. The association of PM2.5 exposure with thyroid function during pregnancy is of global health importance because air pollution exposure is widespread and hypothyroxinemia may adversely influence the brain development of offspring. Stable consumption of swordfish favors, whereas stable consumption of oily fish protects from, development of postpartum thyroiditis Jul 2019 ENDOCRINE Salvatore Benvenga Roberto Vita Flavia Di Bari Maria Le Donne Purpose In 236 pregnant women, we showed that selective or predominant consumption of swordfish (group A) was associated with high rates of positivity for serum thyroid autoantibodies (TPOAb and TgAb) throughout day 4 postpartum. In contrast, selective or predominant consumption of oily fish (group B) was associated with TPOAb and TgAb negativity. Rates were intermediate in group C (scanty consumption of swordfish) and group D (consumption of fish other than swordfish and oily fish). Gestational TPOAb positivity is a risk factor for postpartum thyroiditis (PPT), which evolves into permanent hypothyroidism (PH) in about 50% of cases. Purpose of this study was to verify that the different rates of thyroid autoantibodies in the four groups translated into different PPT rates. Methods We expanded our previous cohort (n = 412) and duration of follow-up (month 12 postpartum), and measured frequency of PPT and PH. Results At first timester of gestation, we confirmed the different Ab positivity rates in group A vs. group B (TPOAb = 21.7% vs. 4.7%, P < 0.0001; TgAb = 14.1% vs. 2.4%, P < 0.05). Overall, PPT prevalence was 63/412 (15.3%), but 22/92 in group A (23.9%), 4/85 in group B (4.7%; P < 0.0001 vs. group A), 17/108 (15.7%) in group C, and 16/117 (13.7%) in group D. Approximately half of the PPT women had PH, regardless of fish group. Conclusions In conclusion, stable consumption of oily fish (which is enriched in polyunsaturated omega-3 fatty acids) protects from PPT, while stable consumption of swordfish (which is enriched in pollutants) favors PPT. Thus, a dietary prophylaxis of PPT is possible. The increasing prevalence of chronic lymphocytic thyroiditis in papillary microcarcinoma Dec 2018 REV ENDOCR METAB DIS Roberto Vita Antonio Ieni Prof. Dr. Giovanni Tuccari Salvatore Benvenga Although the incidence of some malignancy has decreased over the recent years, this is not the case of papillary thyroid microcarcinoma (PTMC), whose incidence has increased worldwide. Most PTMC are found incidentally after histological examination of specimens from surgery for benign thyroid disease. Hashimoto’s thyroiditis, whose incidence has also increased, coexists in about one in three PTMC patients. Three different mechanisms have been proposed to clarify the association between chronic lymphocytic thyroiditis and PTMC, namely tumor development/growth by: (i) TSH stimulation, (ii) expression of certain proto-oncogenes, (iii) chemokines and other molecules produced by the lymphocytic infiltrate. Whether Hashimoto’s thyroiditis protects against lymph node metastasis is debated. Overall, autommune thyroiditis seems to contribute to the favorable prognosis of PTMC. Major limitations of the studies so far performed include: (i) retrospective design, (ii) limited statistical power, (iii) high risk of selection bias, (iv) and predominant Asian ethnicity of patients. Full genetic profiling of both diseases and identification of environmental factors capable to trigger them, as well as well-powered prospective studies on different ethnical groups, may help understand their causal association and why their frequencies are continuing raising. View Show abstract
https://www.researchgate.net/publication/346242140_Rates_of_lymphocytic_thyroiditis_and_ultrasound_features_of_citologically-interrogated_thyroid_nodules_based_on_the_area_of_residence_in_a_Sicily_province
Network Working Group Henk Smit INTERNET DRAFT Tony Li Procket Networks August 2003 IS-IS extensions for Traffic Engineering <draft-ietf-isis-traffic-05.txt> Status This document is an Internet-Draft and is subject to all provisions of Section 10 of RFC2026. Internet-Drafts are working documents of the Internet Engineering Task Force (IETF), its areas, and its working groups. Note that other groups may also distribute working documents as Internet- Drafts. Internet-Drafts are draft documents valid for a maximum of six months and may be updated, replaced, or obsoleted by other documents at any time. It is inappropriate to use Internet-Drafts as reference material or to cite them other than as "work in progress." The list of current Internet-Drafts can be accessed at http://www.ietf.org/ietf/1id-abstracts.txt The list of Internet-Draft Shadow Directories can be accessed at http://www.ietf.org/shadow.html. Abstract This document describes extensions to the IS-IS protocol to support Traffic Engineering. This document extends the IS-IS protocol by specifying new information that an Intermediate System [router] can place in Link State Protocol Data Units. This information describes additional details of the state of the network that are useful for traffic engineering computations. Expiration Date February 2004 [Page 1] INTERNET DRAFT August 2003 1.0 Introduction The IS-IS protocol is specified in ISO 10589 [1], with extensions for supporting IPv4 specified in RFC 1195 [3]. Each Intermediate System (IS) [router] advertises one or more IS-IS Link State Protocol Data Units (LSPs) with routing information. Each LSP is composed of a fixed header and a number of tuples, each consisting of a Type, a Length, and a Value. Such tuples are commonly known as TLVs, and are a good way of encoding information in a flexible and extensible format. The changes in this document include the design of new TLVs to replace the existing IS Neighbor TLV, IP Reachability TLV and add additional information. Mechanisms and procedures to migrate to the new TLVs are not discussed in this document. The primary goal of these extensions is to add more information about the characteristics of a particular link to an IS-IS's LSP. The characteristics described in this document are needed for Traffic Engineering [4] (TE). Secondary goals include increasing the dynamic range of the IS-IS metric and improving the encoding of IP prefixes. The router id is useful for traffic engineering purposes because it describes a single address that can always be used to reference a particular router. 2.0 Introducing Sub-TLVs This document introduces a new way to encode routing information in IS-IS. The new object is called a sub-TLV. Sub-TLVs are similar to regular TLVs. They use the same concepts as regular TLVs. The difference is that TLVs exist inside IS-IS packets, while sub-TLVs exist inside TLVs. TLVs are used to add extra information to IS-IS packets. Sub-TLVs are used to add extra information to particular TLVs. Each sub-TLV consists of three fields. A one-octet Type field, a one-octet Length field, and zero or more octets of Value. The Type field indicates the type of items in the Value field. The Length field indicates the length of the Value field in octets. Each sub- TLV can potentially hold multiple items. The number of items in a sub-TLV can be computed from the length of the whole sub-TLV, when the length of each item is known. Unknown sub-TLVs are to be ignored and skipped on receipt. The Sub-TLV type space is managed by the IETF IS-IS WG (http://www.ietf.org/html.charters/isis-charter.html). New type values are allocated following review on the IETF IS-IS mailing list. This will normally require publication of additional documentation describing how the new type is used. In the event that the IS-IS Expiration Date February 2004 [Page 2] INTERNET DRAFT August 2003 working group has disbanded the review shall be performed by a Designated Expert assigned by the responsible Area Director. 3.0 The extended IS reachability TLV The extended IS reachability TLV is TLV type 22. The existing IS reachability (TLV type 2, defined in ISO 10589 [1]) contains information about a series of IS neighbors. For each neighbor, there is a structure that contains the default metric, the delay, the monetary cost, the reliability, and the 7-octet ID of the adjacent neighbor. Of this information, the default metric is commonly used. The default metric is currently one octet, with one bit used to indicate that the metric is present and one bit used to indicate whether the metric is internal or external. The remaining 6 bits are used to store the actual metric, resulting a possible metric range of 0-63. This limitation is one of the restrictions that we would like to lift. The remaining three metrics (delay, monetary cost, and reliability) are not commonly implemented and reflect unused overhead in the TLV. The neighbor is identified by its system Id (typically 6-octets), plus one octet to indicate the pseudonode number if the neighbor is on a LAN interface. Thus, the existing TLV consumes 11 octets per neighbor, with 4 octets for metric and 7 octets for neighbor identification. To indicate multiple adjacencies, this structure is repeated within the IS reachability TLV. Because the TLV is limited to 255 octets of content, a single TLV can describe up to 23 neighbors. The IS reachability TLV can be repeated within the LSP fragments to describe further neighbors. The proposed extended IS reachability TLV contains a new data structure, consisting of: 7 octets of system Id and pseudonode number 3 octets of default metric 1 octet of length of sub-TLVs 0-244 octets of sub-TLVs, where each sub-TLV consists of a sequence of 1 octet of sub-type 1 octet of length of the value field of the sub-TLV 0-242 octets of value Thus, if no sub-TLVs are used, the new encoding requires 11 octets and can contain up to 23 neighbors. Please note that while the encoding allows for 255 octets of sub-TLVs, the maximum value cannot fit in the overall IS reachability TLV. The practical maximum is 255 Expiration Date February 2004 [Page 3] INTERNET DRAFT August 2003 octets minus the 11 octets described above, or 244 octets. Further, there is no defined mechanism for extending the sub-TLV space for a particular neighbor. Thus, wasting sub-TLV space is discouraged. The metric octets are encoded as a 24-bit unsigned integer. Note that the metric field in the new extended IP reachability TLV is encoded as a 32-bit unsigned integer. These different sizes were chosen so that it is very unlikely that the cost of an intra-area route has to be chopped off to fit in the metric field of an inter-area route. To preclude overflow within a SPF implementation, all metrics greater than or equal to MAX_PATH_METRIC SHALL be considered to have a metric of MAX_PATH_METRIC. It is easiest to select MAX_PATH_METRIC such that MAX_PATH_METRIC plus a single link metric does not overflow the number of bits for internal metric calculation. We assume that this is 32 bits. Thus, MAX_PATH_METRIC is 4,261,412,864 (0xFE000000, 2^32 - 2^25). If a link is advertised with the maximum link metric (2^24 - 1), this link MUST NOT be considered during the normal SPF computation. This will allow advertisement of a link for other purposes than building the normal Shortest Path Tree. An example is a link that is available for traffic engineering, but not for hop-by-hop routing. Certain sub-TLVs are proposed here: Sub-TLV type Length (octets) Name 3 4 Administrative group (color) 6 4 IPv4 interface address 8 4 IPv4 neighbor address 9 4 Maximum link bandwidth 10 4 Reservable link bandwidth 11 32 Unreserved bandwidth 18 3 TE Default metric 250-254 Reserved for cisco specific extensions 255 Reserved for future expansion Each of these sub-TLVs is described below. Unless stated otherwise, multiple occurrences of the information are supported by multiple inclusions of the sub-TLV. 3.1 Sub-TLV 3: Administrative group (color, resource class) The administrative group sub-TLV contains a 4-octet bit mask assigned by the network administrator. Each set bit corresponds to one administrative group assigned to the interface. Expiration Date February 2004 [Page 4] INTERNET DRAFT August 2003 By convention the least significant bit is referred to as 'group 0', and the most significant bit is referred to as 'group 31'. This sub-TLV is OPTIONAL. This sub-TLV SHOULD appear at most once in each extended IS reachability TLV. 3.2 Sub-TLV 6: IPv4 interface address This sub-TLV contains a 4-octet IPv4 address for the interface described by the (main) TLV. This sub-TLV can occur multiple times. Implementations MUST NOT inject a /32 prefix for the interface address into their routing or forwarding table, because this can lead to forwarding loops when interacting with systems that do not support this sub-TLV. If a router implements the basic TLV extensions in this document, it MAY add or omit this sub-TLV to the description of an adjacency. If a router implements traffic engineering, it MUST include this sub- TLV. 3.3 Sub-TLV 8: IPv4 neighbor address This sub-TLV contains a single IPv4 address for a neighboring router on this link. This sub-TLV can occur multiple times. Implementations MUST NOT inject a /32 prefix for the neighbor address into their routing or forwarding table, because this can lead to forwarding loops when interacting with systems that do not support this sub-TLV. If a router implements the basic TLV extensions in this document, it MAY add or omit this sub-TLV to the description of an adjacency. If a router implements traffic engineering, it MUST include this sub-TLV on point-to-point adjacencies. 3.4 Sub-TLV 9: Maximum link bandwidth This sub-TLV contains the maximum bandwidth that can be used on this link in this direction (from the system originating the LSP to its neighbors). This is useful for traffic engineering. The maximum link bandwidth is encoded in 32 bits in IEEE floating point format. The units are bytes (not bits!) per second. Expiration Date February 2004 [Page 5] INTERNET DRAFT August 2003 This sub-TLV is optional. This sub-TLV SHOULD appear at most once in each extended IS reachability TLV. 3.5 Sub-TLV 10: Maximum reservable link bandwidth This sub-TLV contains the maximum amount of bandwidth that can be reserved in this direction on this link. Note that for oversubscription purposes, this can be greater than the bandwidth of the link. The maximum reservable link bandwidth is encoded in 32 bits in IEEE floating point format. The units are bytes (not bits!) per second. This sub-TLV is optional. This sub-TLV SHOULD appear at most once in each extended IS reachability TLV. 3.6 Sub-TLV 11: Unreserved bandwidth This sub-TLV contains the amount of bandwidth reservable in this direction on this link. Note that for oversubscription purposes, this can be greater than the bandwidth of the link. Because of the need for priority and preemption, each head end needs to know the amount of reserved bandwidth at each priority level. Thus, this sub-TLV contains eight 32 bit IEEE floating point numbers. The units are bytes (not bits!) per second. The values correspond to the bandwidth that can be reserved with a setup priority 0 through 7, arranged in increasing order with priority 0 occurring at the start of the sub-TLV, and priority 7 at the end of the sub-TLV. For stability reasons, rapid changes in the values in this sub-TLV SHOULD NOT cause rapid generation of LSPs. This sub-TLV is optional. This sub-TLV SHOULD appear at most once in each extended IS reachability TLV. 3.7 Sub-TLV 18: Traffic Engineering Default metric This sub-TLV contains a 24-bit unsigned integer. This metric is administratively assigned and can be used to present a differently weighted topology to traffic engineering SPF calculations. To preclude overflow within a SPF implementation, all metrics greater than or equal to MAX_PATH_METRIC SHALL be considered to have a metric of MAX_PATH_METRIC. It is easiest to select MAX_PATH_METRIC such Expiration Date February 2004 [Page 6] INTERNET DRAFT August 2003 that MAX_PATH_METRIC plus a single link metric does not overflow the number of bits for internal metric calculation. We assume that this is 32 bits. Thus, MAX_PATH_METRIC is 4,261,412,864 (0xFE000000, 2^32 - 2^25). This sub-TLV is optional. This sub-TLV SHOULD appear at most once in each extended IS reachability TLV. If a link is advertised without this sub-TLV, traffic engineering SPF calculations MUST use the normal default metric of this link, which is advertised in the fixed part of the extended IS reachability TLV. 4.0 The extended IP reachability TLV The extended IP reachability TLV is TLV type 135. The existing IP reachability TLVs (TLV type 128 and TLV type 130, defined in RFC 1195 [3]) carry IP prefixes in a format that is analogous to the IS neighbor TLV from ISO 10589 [1]. They carry four metrics, of which only the default metric is commonly used. Of this, the default metric has a possible range of 0-63. This limitation is one of the restrictions that we would like to lift. In addition, route redistribution (a.k.a. route leaking) has a key problem that was not fully addressed by the existing IP reachability TLVs. RFC 1195 [3] allows a router to advertise prefixes upwards in the level hierarchy. Unfortunately there were no mechanisms defined to advertise prefixes downwards in the level hierarchy. To address these two issues, the proposed extended IP reachability TLV provides for a 32 bit metric and adds one bit to indicate that a prefix has been redistributed 'down' in the hierarchy. The proposed extended IP reachability TLV contains a new data structure, consisting of: 4 octets of metric information 1 octet of control information, consisting of 1 bit of up/down information 1 bit indicating the presence of sub-TLVs 6 bits of prefix length 0-4 octet of IPv4 prefix 0-250 optional octets of sub-TVLs, if present consisting of 1 octet of length of sub-TLVs 0-249 octets of sub-TLVs, where each sub-TLV consists of a sequence of 1 octet of sub-type 1 octet of length of the value field of the sub-TLV Expiration Date February 2004 [Page 7] INTERNET DRAFT August 2003 0-247 octets of value This data structure can be replicated within the TLV, not to exceed the maximum length of the TLV. The 6 bits of prefix length can have the values 0-32 and indicate the number of significant bits in the prefix. The prefix is encoded in the minimal number of octets for the given number of significant bits. This implies: Significant bits Octets 0 0 1-8 1 9-16 2 17-24 3 25-32 4 The remaining bits of prefix are transmitted as zero and ignored upon receipt. If a prefix is advertised with a metric larger then MAX_PATH_METRIC (0xFE000000, see paragraph 3.0), this prefix MUST NOT be considered during the normal SPF computation. This allows advertisement of a prefix for other purposes than building the normal IP routing table. 4.1 The up/down bit Without any additional mechanisms, if routers were allowed to redistribute IP prefixes freely in both directions between level 1 and level 2, those routers can not determine looping of routing information. A problem occurs when a router learns a prefix via level 2 routing and advertises that prefix down into a level 1 area, where another router might pick up the route and advertise the prefix back up into the level 2 backbone. If the original source withdraws the prefix, those two routers might end up having a routing loop between them, where part of the looped path is via level 1 routing and the other part of the looped path is via level 2 routing. The solution that RFC 1195 [3] poses is to allow only advertising prefixes upward in the level hierarchy, and to disallow the advertising of prefixes downward in the hierarchy. To prevent this looping of prefixes between levels, a new bit of information is defined in the new extended IP reachability TLV. This bit is called the up/down bit. The up/down bit SHALL be set to 0 when a prefix is first injected into IS-IS. If a prefix is advertised from a higher level to a lower level (e.g. level two to level one), the bit SHALL be set to 1, to indicate that the prefix Expiration Date February 2004 [Page 8] INTERNET DRAFT August 2003 has traveled down the hierarchy. Prefixes that have the up/down bit set to 1 may only be advertised down the hierarchy, i.e. to lower levels. These semantics apply even if IS-IS is extended in the future to have additional levels. By insuring that prefixes follow only the IS-IS hierarchy, we have insured that the information does not loop, thereby insuring that there are no persistent forwarding loops. If a prefix is advertised from an area to another area at the same level, then the up/down bit SHALL be set to 1. This situation can arise when a router implements multiple virtual routers at the same level, but in different areas. The semantics of the up/down bit in the new extended IP reachability TLV are identical to the semantics of the up/down bit defined in RFC 2966 [2]. 4.2 Expandability of the extended IP reachability TLV with sub-TLVs The extended IP reachability TLV can hold sub-TLVs that apply to a particular prefix. This allows for easy future extensions. If there are no sub-TLVs associated with a prefix, the bit indicating the presence of sub-TLVs SHALL be set to 0. If this bit is set to 1, the first octet after the prefix will be interpreted as the length of all sub-TLVs associated with this IPv4 prefix. Please note that while the encoding allows for 255 octets of sub-TLVs, the maximum value cannot fit in the overall extended IP reachability TLV. The practical maximum is 255 octets minus the 5-9 octets described above, or 250 octets. This document does not define any sub-TLVs yet for the extended IP reachability TLV. 5.0 The Traffic Engineering router ID TLV The Traffic Engineering router ID TLV is TLV type 134. The router ID TLV contains the 4-octet router ID of the router originating the LSP. This is useful in several regards: For traffic engineering, it guarantees that we have a single stable address that can always be referenced in a path that will be reachable from multiple hops away, regardless of the state of the node's interfaces. Expiration Date February 2004 [Page 9] INTERNET DRAFT August 2003 If OSPF is also active in the domain, traffic engineering can compute the mapping between the OSPF and IS-IS topologies. If a router does not implement traffic engineering it MAY add or omit the Traffic Engineering router ID TLV. If a router implements traffic engineering, it MUST include this TLV in its LSP. This TLV SHOULD not be included more than once in a LSP. If a router advertises the Traffic Engineering router ID TLV in its LSP, and if it advertises prefixes via the Border Gateway Protocol (BGP) with the BGP next hop attribute set to the BGP router ID, in that case the Traffic Engineering router ID SHOULD be the same as the BGP router ID. Implementations MUST NOT inject a /32 prefix for the router ID into their forwarding table, because this can lead to forwarding loops when interacting with systems that do not support this TLV. 6. IANA Considerations 6.1 TLV codepoint allocations This document defines the following new ISIS TLV types that need to be reflected in the ISIS TLV code-point registry: Type Description IIH LSP SNP ---- ----------------------------------- --- --- --- 22 The extended IS reachability TLV n y n 134 The Traffic Engineering router ID TLV n y n 135 The extended IP reachability TLV n y n 6.2 New registries IANA is requested to create the following new registries. 6.2.1 Sub-TLVs for TLV 22 This registry contains codepoints for Sub-TLVs of TLV 22. The range of values is 0-255. Allocations within the registry require documentation of the use of the allocated value and approval by the Designated Expert assigned by the IESG (see [5]). Taking into consideration allocations specified in this document, the Expiration Date February 2004 [Page 10] INTERNET DRAFT August 2003 registry should be initialized as follows: Type Description ---- ----------------------------------- 0-2 unassigned 3 Administrative group (color) 4-5 unassiged 6 IPv4 interface address 7 unassigned 8 IPv4 neighbor address 9 Maximum link bandwidth 10 Reservable link bandwidth 11 Unreserved bandwidth 12-17 unassigned 18 TE Default metric 19-254 unassigned 255 Reserved for future expansion <IANA-note> To be removed by the RFC editor at the time of publication At the time of registry creation, please perform the following allocations in this registry: Type Description ---- ----------------------------------- 250 Reserved for Cisco-proprietary extensions 251 Reserved for Cisco-proprietary extensions </IANA-note> 6.2.2 Sub-TLVs for TLV 135 This registry contains codepoints for Sub-TLVs of TLV 135. The range of values is 0-255. Allocations within the registry require documentation of the use of the allocated value and approval by the Designated Expert assigned by the IESG (see [5]). No codepoints are defined in this document. Normative References [1] ISO, "Intermediate System to Intermediate System Intra-Domain Routeing Exchange Protocol for use in Conjunction with the Protocol for Providing the Connectionless-mode Network Service (ISO 8473)", International Standard 10589:2002, Second Edition Expiration Date February 2004 [Page 11] INTERNET DRAFT August 2003 [2] RFC 2966, "Domain-wide Prefix Distribution with Two-Level IS-IS", T. Li, T. Przygienda, H. Smit, October 2000. Informative References [3] RFC 1195, "Use of OSI IS-IS for routing in TCP/IP and dual environments", R.W. Callon, December 1990 [4] RFC 2702, "Requirements for Traffic Engineering Over MPLS," D. Awduche, J. Malcolm, J. Agogbua, M. O'Dell, and J. McManus, September 1999 [5] RFC 2434, "Guidelines for Writing an IANA Considerations Section in RFCs", Narten, T., and H. Alvestrand, BCP 26, October 1998 Security Considerations This document raises no new security issues for IS-IS. Acknowledgments The authors would like to thank Yakov Rekhter and Dave Katz for their comments on this work. Authors' Addresses Tony Li Procket Networks, Inc. 1100 Cadillac Court Milpitas, CA 95035 Email: [email protected] Voice: +1 408 6357900 Fax: +1 408 6356166 Henk Smit Email: [email protected] Expiration Date February 2004 [Page 12]
https://www.ietf.org/proceedings/58/I-D/draft-ietf-isis-traffic-05.txt
PART II PART II.  OFFENSES RELATED TO OBSCENITY §712-1210  Definitions of terms in this part.In this part, unless a different meaning is required: "Age verification records of sexually exploited individuals" means individually identifiable records pertaining to every sexually exploited individual provided to patrons or customers of a public establishment or in a private club or event. Such records shall include: (1)  Each sexually exploited individual's name and date of birth, as ascertained by an examination of the individual's valid driver's license, official state identification card, or passport; (2)  A certified copy of each sexually exploited individual's driver's license, official state identification card, or passport; and (3)  Any name ever used by each sexually exploited individual including but not limited to maiden name, aliases, nicknames, stage names, or professional names. "Age verification records of sexual performers" means individually identifiable records pertaining to every sexual performer portrayed in a visual depiction of sexual conduct, which include: (1)  Each performer's name and date of birth, as ascertained by the producer's personal examination of a performer's valid driver's license, official state identification card, or passport; (2)  A certified copy of each performer's valid driver's license, official state identification card, or passport; and (3)  Any name ever used by each performer including, but not limited to, maiden name, alias, nickname, stage name, or professional name. "Community standards" means the standards of the State. "Disseminate" means to manufacture, issue, publish, sell, lend, distribute, transmit, exhibit, or present material or to offer or agree to do the same. "Erotic or nude massager" means a nude person providing massage services with or without a license. "Exotic or nude dancer" means a person performing, dancing, or entertaining in the nude, and includes patrons participating in a contest or receiving instruction in nude dancing. "Intent to profit" means the intent to obtain monetary gain. "Material" means any printed matter, visual representation, or sound recording, and includes but is not limited to books, magazines, motion picture films, pamphlets, newspapers, pictures, photographs, drawings, sculptures, and tape or wire recordings. "Minor" means any person less than sixteen years old. "Nude" means unclothed or in attire, including but not limited to sheer or see-through attire, so as to expose to view any portion of the pubic hair, anus, cleft of the buttocks, genitals or any portion of the female breast below the top of the areola. "Performance" means any play, motion picture film, dance, or other exhibition performed before an audience. "Pornographic."  Any material or performance is "pornographic" if all of the following coalesce: (a)   The average person, applying contemporary community standards would find that, taken as a whole, it appeals to the prurient interest. (b)   It depicts or describes sexual conduct in a patently offensive way. (c)   Taken as a whole, it lacks serious literary, artistic, political, or scientific merit. "Pornographic for minors."  Any material or performance is "pornographic for minors" if: (1)  It is primarily devoted to explicit and detailed narrative accounts of sexual excitement, sexual conduct, or sadomasochistic abuse; and: (2)  It contains any photograph, drawing, or similar visual representation of any person of the age of puberty or older revealing such person with less than a fully opaque covering of his or her genitals and pubic area, or depicting such person in a state of sexual excitement or engaged in acts of sexual conduct or sadomasochistic abuse; and: "Produces" means to manufacture or publish any pornographic performance, book, magazine, periodical, film, videotape, computer image, or other similar matter and includes the duplication, reproduction, or reissuing of any such matter, but does not include mere distribution or any other activity that does not involve hiring, contracting for, managing, or otherwise arranging for the participation of the performers depicted. "Sadomasochistic abuse" means flagellation or torture by or upon a person as an act of sexual stimulation or gratification. "Sexual conduct" means acts of masturbation, homosexuality, lesbianism, bestiality, sexual intercourse or physical contact with a person's clothed or unclothed genitals, pubic area, buttocks, or the breast or breasts of a female for the purpose of sexual stimulation, gratification, or perversion. "Sexual excitement" means the condition of the human male or female genitals when in a state of sexual stimulation or arousal. "Sexually exploited individuals" means erotic or nude massagers and exotic or nude dancers. "Sexual performer" includes any person portrayed in a pornographic visual depiction engaging in, or assisting another person to engage in, sexual conduct. [L 1972, c 9, pt of §1; am L 1981, c 106, §1; am L 2002, c 240, §4; am L 2005 c 10, §1] COMMENTARY ON §712-1210 Act 106, Session Laws 1981, added the definition of "community standards," to mean a statewide standard.  It also amended the definitions of "pornographic" and "pornographic to minors."  The conference committee stated in its report (Senate Conference Committee Report No. 14 and House Conference Committee Report No. 12) that the amendments were merely to conform the definitions to the holdings of the United States Supreme Court in Miller v. California, 413 U.S. 15 (1973) and the Hawaii Supreme Court in State v. Manzo, 58 Haw. 440 (1978). Act 240, Session Laws 2002, amended this section by adding definitions to comport with sexual exploitation of a minor offenses created by the Act. Act 10, Session Laws 2005, amended this section by repealing the superfluous definition of "sexual conduct" added by Act 240, Session Laws 2002.  This section already provided a sufficient definition of "sexual conduct".  House Standing Committee Report No. 1281. Law Journals and Reviews State v. Kam:  The Constitutional Status of Obscenity in Hawaii.  11 UH L. Rev. 253. Case Notes Grand jury was presented with sufficient information to determine the existence of probable cause that material distributed to minor by defendant was pornographic for minors under paragraph (7)(a).  82 H. 474, 923 P.2d 891. Based on the plain language and legislative history of §707-700 and construing the definition of "sexual contact" with reference to other definitions relating to sexual relations in §707-700 and this section, contact with the interior of the mouth constitutes "touching of intimate parts" under the definition of "sexual contact" in §707-700.  108 H. 279, 118 P.3d 1222. Pornographic. Construed; provision not unconstitutional for overbreadth or void for vagueness.  58 H. 440, 573 P.2d 945. Material held to be "utterly without redeeming social value."  63 H. 418, 629 P.2d 1130. Cited:  413 U.S. 15, 93 S.Ct. 2607. Previous Vol14_Ch0701-0853 Next
https://www.capitol.hawaii.gov/hrsarchive/hrs2008/Vol14_Ch0701-0853/HRS0712/HRS_0712-1210.htm
ABSTRACTS - technology.matthey.com of current literature on the platinum metals and their alloys Share this page: Twitter Facebook LinkedIn Reddit Digg MIX PROPERTIES Theoretical Investigation of Isomer Stability in Platinum–Palladium Nanoalloy Clusters L. D. Lloyd, R. L. Johnston, S. Salhi and N. T. wilson , J. Mater. Chem. , 2004, 14 , (11), 1691–1704 doi:10.1039/b313811a http://dx.doi.org/10.1039/b313811a The interatomic interactions of Pt–Pd nanoalloy clusters (1) were modelled by the Gupta many-body potential. For 18–20 atom clusters, a general algorithm was used to establish the lowest energy structures for each size and for all possible compositions. In the lowest energy isotopes (homotops), the Pd atoms are mainly at the surface, with the Pt atoms preferentially occupying interior sites. Dendrimer-Templated Ag–Pd Bimetallic Nanoparticles Y.-M. Chung and H.-K. Rhee , J. Colloid Interface Sci. , 2004, 271 , (1), 131–135 doi:10.1016/j.jcis.2003.12.006 http://dx.doi.org/10.1016/j.jcis.2003.12.006 Ultrafine amine-terminated fourth-generation starburst poly(amidoamine) dendrimer-templated Ag–Pd bimetallic nanoparticles (1) were prepared from silver(I)-bis(oxalato)palladate(II) (2). The use of (2), in which two metal ions exist in one complex, prevented Ag halide formation. The particle size distributions of (1) were all in the narrow range of 2–5 nm, but were dependent upon the Ag/Pd ratio. CHEMICAL COMPOUNDS The Construction of P–O/P–N Ligands on Platinum and Palladium P. Bergamini, V. Bertolasi and F. Milani , Eur. J. Inorg. Chem. , 2004, (6), 1277–1284 doi:10.1002/ejic.200300642 http://dx.doi.org/10.1002/ejic.200300642 Pt II and Pd II diphenyldiphosphinites were prepared by adding diols to a solution containing cis -[MCl 2 (PPh 2 Cl 2 ] (M = Pt or Pd) preformed in situ from cis -[MCl 2 (1,5-COD)] and PPh 2 Cl. As for the P–O bond, the P–N bond can be formed via nucleophilic attack of an amine group on coordinated PPh 2 Cl in the presence of base to give aminophosphine-phosphinite and N , N ′-bis(antipyryl-4-methyl)piperazine complexes of Pt II and Pd II . C–H and N–H Activation by Pt(0) in N- and O-Heteroaromatic Compounds J. T. Chantson and S. Lotz , J. Organomet. Chem. , 2004, 689 , (7), 1315–1324 doi:10.1016/j.jorganchem.2004.01.030 http://dx.doi.org/10.1016/j.jorganchem.2004.01.030 [Pt(PEt 3 ) 4 ] reacts with azoles to give Pt(II) hydride complexes, trans -[PtH(1-azolyl)(PEt 3 ) 2 ] (azolyl = indolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl), by oxidative insertion of the Pt centre into the N–H bonds of the respective azoles. Pyrrole was much less reactive. The trans -[PtH(R)(PEt 3 ) 2 ] complexes (R = 2-furyl, 2-benzoxazolyl, 2-benzothiazolyl) were prepared via C–H bond activation. ELECTROCHEMISTRY The Electrochemical Formation and Properties of Bilayers Composed of Polypyrrole and C 60 Pd Films M. Wysocka, K. Winkler and A. L. Balch , J. Mater. Chem. , 2004, 14 , (6), 1036–1042 doi:10.1039/b312538f http://dx.doi.org/10.1039/b312538f Bilayers of polypyrrole and C 60 Pd were prepared by sequential electropolymerisation of the parent monomers and investigated by cyclic voltammetry. For the electrode/polypyrrole/C 60 Pd bilayer, the high permeability of the C 60 Pd film for the supporting electrolyte ions allowed the oxidation of the polypyrrole inner layer. For the electrode/C 60 Pd/polypyrrole bilayer, the outer polypyrrole layer inhibited the reduction of the inner C 60 Pd layer. PHOTOCONVERSION Effects of Chlorine Gas Exposure on the Optical Properties of Rhodium Phthalocyanine Films L. Gaffo, O. D. D. Couto, R. Giro, M. J. S. P. Brasil, D. S. GalvãO, F. Cerdeira, O. N. de Oliveira and K. Wohnrath , Solid State Commun. , 2004, 131 , (1), 53–56 doi:10.1016/j.ssc.2004.04.011 http://dx.doi.org/10.1016/j.ssc.2004.04.011 Rh phthalocyanine films (1) were deposited on glass by the Langmuir-Blodgett technique. On exposure to Cl 2 (1) changed from blue to transparent. Incorporation of Cl 2 caused quenching of the characteristic triplet centred around the Q-absorption band at 662 nm. Leaving prior Cl 2 exposed (1) in air for several hours resulted in a slow partial recovery of the optical spectra. A Synthesis and Luminescence Study of Ir(ppz) 3 for Organic Light-Emitting Devices E. J. Nam, J. H. Kim, B.-O. Kim, S. M. Kim, N. G. Park, Y. S. Kim, Y. K. Kim and Y. Ha , Bull. Chem. Soc. Jpn. , 2004, 77 , (4), 751–755 doi:10.1246/bcsj.77.751 http://dx.doi.org/10.1246/bcsj.77.751 OLEDs were fabricated with doped films of tris(1-phenyl-κ C 1 -pyrazolato-κ N 2 )iridium (1) in several hosts. The electroluminescence peak occurred at 450 nm. The luminance of the OLEDs was pure blue, but luminous efficiencies were low since the LUMO of (1) was higher than those of the hosts. Photobleaching and Single Molecule Detection of a Phosphorescent Organometallic Iridium(III) Complex M. Vacha, Y. Koide, M. Kotani and H. Sato , J. Luminesc. , 2004, 107 , (1–4), 51–56 doi:10.1016/j.jlumin.2003.12.015 http://dx.doi.org/10.1016/j.jlumin.2003.12.015 The photostability of bulk samples of Ir(ppy) 3 (1) (ppy = 2-phenylpyridine) in polymer films was examined by measuring the photobleaching kinetics under intense laser irradiation. On a single molecule level, (1) was characterised by phosphorescence time traces, distribution of phosphorescence intensity levels and by polarisation modulated excitation. Synthesis and Characterization of Naphthyridine and Acridinedione Ligands Coordinated Ruthenium(II) Complexes and Their Applications in Dye-Sensitized Solar Cells S. Anandan, J. Madhavan, P. Maruthamuthu, V. Raghukumar and V. T. Ramakrishnan , Sol. Energy Mater. Sol. Cells , 2004, 81 , (4), 419–428 doi:10.1016/j.solmat.2003.11.026 http://dx.doi.org/10.1016/j.solmat.2003.11.026 The title complexes were synthesised and characterised, and then used in dye-sensitised solar cells. From the I – V curves, the short-circuit photocurrent ( I SC ) and the open-circuit photovolatage ( V OC ) were measured. A maximum current conversion efficiency of ∼ 7.7% was achieved by the 5-amino-4-phenyl-2-(4-methylphenyl)-7-(pyrrolidin-1-yl)-1,6-naphthyridine-8-carbonitrile coordinated Ru(II) complex. ELECTRODEPOSITION AND SURFACE COATINGS Mesoporous Microspheres Composed of PtRu Alloy J. Jiang and A. Kucernak , Chem. Mater. , 2004, 16 , (7), 1362–1367 doi:10.1021/cm035237j http://dx.doi.org/10.1021/cm035237j Electrochemical co-reduction of H 2 PtCl 6 and RuCl 3 dissolved in the aqueous domains of the liquid crystalline phase of an oligoethylene oxide surfactant (C 16 EO 8 ) gave the title microspheres (1) (0.5–1 µm). The ordered mesoporous internal structure of (1) involves periodic pores of ∼ 2.4 nm in diameter separated by walls of ∼ 2.4 nm thick. (1) have high specific surface area. Synthesis of PtN x Films by Reactive Laser Ablation G. Soto , Mater. Lett. , 2004, 58 , (16), 2178–2180 doi:10.1016/j.matlet.2004.01.019 http://dx.doi.org/10.1016/j.matlet.2004.01.019 Thin films of Pt (1) with ∼ 14 at.% N were prepared by reactive laser ablation in molecular N 2 ambient. AES, XPS and electron energy loss spectroscopy were used to characterise (1). The existence of chemisorbed N was supported by the N 1s binding energy of 398.4 eV. The +0.2 eV shift of the Pt 4f peak position indicated charge transfer from Pt to N. The Pt formed an incipient nitride phase with composition near to Pt 6 N. APPARATUS AND TECHNIQUE Calorimetric Hydrocarbon Sensor for Automotive Exhaust Applications M.-C. Wu and A. L. Micheli , Sens. Actuators B: Chem. , 2004, 100 , (3), 291–297 doi:10.1016/j.snb.2003.11.010 http://dx.doi.org/10.1016/j.snb.2003.11.010 The title sensor (1) is a thermoelectric device supported on a planar Al 2 O 3 substrate. A non-selective Pt catalyst was used in (1) to detect hydrocarbons with high selectivity. For CO detection (1) uses a CO oxidation catalyst of Pb-modified Pt, which exhibits excellent CO selectivity at 200–400°C. (1) gave a linear output of 0–2.75 mV over 0–1000 ppm of propylene (at 350°C). Engine dynamometer evaluation showed that the response of (1) paralleled the change in concentration of the CO and hydrocarbons when the engine air:fuel ratio was varied. Chemiresistor Coatings from Pt- and Au-Nanoparticle/Nonanedithiol Films: Sensitivity to Gases and Solvent Vapors Y. Joseph, B. Guse, A. Yasuda and T. Vossmeyer , Sens. Actuators B: Chem. , 2004, 98 , (2–3), 188–195 doi:10.1016/j.snb.2003.10.006 http://dx.doi.org/10.1016/j.snb.2003.10.006 Layer-by-layer self-assembly using 1,9-nonanedi-thiol and dodecylamine-stabilised nanoparticles of Pt or Au gave films (1) of thickness, 66 ± 2 and 31 ± 1 nm, respectively. The sensitivity of (1) was investigated by dosing them with NH 3 , CO and vapours of H 2 O and toluene (300 ppb–5000 ppm). (1) have a high signal:noise ratio. A detection limit for NH 3 < 100 ppb was achieved. NH 3 and CO bind to vacant sites on the metal nanoparticle cores. HETEROGENEOUS CATALYSIS Palladium(II) Chloride Catalyzed Selective Acetylation of Alcohols with Vinyl Acetate J. W. J. Bosco and A. K. Saikia , Chem. Commun. , 2004, (9), 1116–1117 doi:10.1039/b401218f http://dx.doi.org/10.1039/b401218f PdCl 2 with CuCl 2 can be used for the catalytic acetylation of primary and secondary alcohols with vinyl acetate. The reaction is carried out in dry toluene at room temperature. The catalyst system can be recovered by filtration. The acetaldehyde byproduct can be removed by evaporation along with the toluene solvent. This mild reaction proceeds more rapidly with primary alcohols. Assembled Catalyst of Palladium and Non-Cross-Linked Amphiphilic Polymer Ligand for the Efficient Heterogeneous Heck Reaction Y. M. A. Yamada, K. Takeda, H. Takahashi and S. Ikegami , Tetrahedron , 2004, 60 , (18), 4097–4105 doi:10.1016/j.tet.2004.02.068 http://dx.doi.org/10.1016/j.tet.2004.02.068 An insoluble catalyst (1) was prepared from self-assembly of (NH 4 ) 2 PdCl 4 and a non-cross-linked amphiphilic phosphine polymer. (1) in only 5.0 × 10 −5 mol equiv. concentration was effective for the heterogeneous Heck reaction of aryl iodides with acrylates, styrenes and acrylic acid. (1) could be recycled five times. (1) showed good stability in toluene and H 2 O and so efficiently catalysed the Heck reaction in these media. (1) can be used for the synthesis of resveratrol, a cyclooxygenase-II inhibitor. Effect of Activated Carbon and Its Surface Property on the Activity of Ru/AC Catalyst W. Han, B. Zhao, C. Huo and H. Liu , Chin. J. Catal. , 2004, 25 , (3), 194–198 Activated C was pretreated by washing with HNO 3 and then calcined before the preparation of Ru/activated C catalysts (1) for NH 3 synthesis. The HNO 3 treatment increased the catalytic activity from 17.4 to 18.4%, due to the reduction of S and ash. Gas phase oxidation of the C caused the Ru to be more dispersed in (1) by changing the texture and surface groups of the support. Overall, the Ru dispersion and catalytic activity were improved from 43 to 62% and 17.4 to 19%, respectively. HOMOGENEOUS CATALYSIS The First Platinum-Catalyzed Hydroamination of Ethylene J.-J. brunet, M. Cadena, N. C. Chu, O. Diallo, K. Jacob and E. Mothes , Organometallics , 2004, 23 , (6), 1264–1268 doi:10.1021/om030605e http://dx.doi.org/10.1021/om030605e The hydroamination of ethylene with aniline, using PtBr 2 as a catalyst precursor in n -Bu 4 PBr under 25 bar of ethylene pressure, gave N -ethylaniline with 80 turnovers after 10 h at 150°C. 2-Methylquinoline was simultaneously produced in ∼ 10 cycles. Additions of P(OMe) 3 (2 equiv./PtBr 2 ) or of a proton source (3 equiv./PtBr 2 ) were beneficial. A TON of 145 after 10 h at 150°C was achieved with a biphasic system ( n -Bu 4 PBr/decane) in the presence of C 6 H 5 NH 3 + (3 equiv./PtBr 2 ). The lower the basicity of the arylamine, the higher the TON. Important Consequences for Gas Chromatographic Analysis of the Sonogashira Cross-Coupling Reaction E. H. Niemelä, A. F. Lee and I. J. S. Fairlamb , Tetrahedron Lett. , 2004, 45 , (18), 3593–3595 doi:10.1016/j.tetlet.2004.03.060 http://dx.doi.org/10.1016/j.tetlet.2004.03.060 Typical quenching procedures for GC analysis of the Sonogashira reaction for 4-bromo-6-methyl-2-pyrone with phenylacetylene (catalysed by (Ph 3 P) 2 PdCl 2 ) cannot be used. Turnover continues to occur in sample vials even after quenching by commonly used SiO 2 adsorption and product elution with CH 2 Cl 2 . Trace amounts of Pd are carried through the SiO 2 plug. Addition of 1,2-bis(diphenylphosphino)ethane to the sample inhibited any further reaction. Role of Base in Palladium-Catalyzed Arylation of Carbanions A. V. Mitin, A. N. Kashin and I. P. Beletskaya , J. Organomet. Chem. , 2004, 689 , (6), 1085–1090 doi:10.1016/j.jorganchem.2003.12.039 http://dx.doi.org/10.1016/j.jorganchem.2003.12.039 The arylation of carbanions, derived from various sulfones, cyanoacetic ester and malononitrile, with aryl bromides using Pd 2 dba 3 /3L, L = PPh 3 , P t Bu 3 , as well as the reaction of the carbanions with 1 equiv. of 4-CF 3 C 6 H 4 Pd(PPh 3 ) 2 Br were carried out. A base stronger than the initial carbanion was required. The reaction mechanism includes the acceleration of the reductive elimination due to the deprotonation of the intermediate ArPdL 2 CHXY. New Chiral Bis(oxazoline) Rh(I)-, Ir(I)- and Ru(II)-Complexes for Asymmetric Transfer Hydrogenations of Ketones n. debono, m. besson, c. pinel and l. djakovitch , Tetrahedron Lett. , 2004, 45 , (10), 2235–2238 doi:10.1016/j.tetlet.2003.12.163 http://dx.doi.org/10.1016/j.tetlet.2003.12.163 The transfer hydrogenation of acetophenone in 2-propanol was used to examine the title complexes. The Ru(II)-based catalyst exhibited good activity with 50% conversion and high enantioselectivity (89%), whereas the Rh(I)- and Ir(I)-complexes gave low conversions (∼ 20%) and poor enantioselectivities (16–20%). A free hydroxyl group on the ligand was a prerequisite for high enantioselectivity. The stronger the base present, the higher the conversion. FUEL CELLS Effect of Preparation Conditions of Pt/C Catalysts on Oxygen Electrode Performance in Proton Exchange Membrane Fuel Cells J. H. Tian, F. B. Wang, Z. H. Q. Shan, R. J. Wang and J. W. Zhang , J. Appl. Electrochem. , 2004, 34 , (5), 461–467 doi:10.1023/B:JACH.0000021860.94340.02 http://dx.doi.org/10.1023/B:JACH.0000021860.94340.02 Pt/C catalysts with 3.2 nm Pt crystallites were prepared by the impregnation-reduction method, varying conditions such as the reaction temperature, the concentration of H 2 PtCl 6 and different reducing agents. Heat treatment in N 2 of the C black support improved Pt dispersion and increased the relative content of Pt (111) orientation. This benefited the acceleration of the oxygen reduction reaction in the PEMFC. Preparation and Performance of Pt–Co/C Catalyst for PEMFC Y. Zhang, X. Li, X. Wu, M. Xu and L. Deng , Precious Met. (Chin.) , 2004, 25 , (1), 19–23 Pt–Co/C electrocatalysts (1) were prepared by the liquid deposition and high temperature alloying method. The Pt and Pt–Co have f.c.c. structure, with small particle size and high dispersity. The Co addition shortened the length of the Pt–Pt bond. (1) showed better performance than Pt/C in PEMFCs. The Co addition exhibited high catalytic activity. ELECTRICAL AND ELECTRONIC ENGINEERING Microstructure and Magnetic Properties of Bamboo-Like CoPt/Pt Multilayered Nanowire Arrays y.-k. su, d.-h. qin, h.-l. zhang, h. li and h.-l. li , Chem. Phys. Lett. , 2004, 388 , (4–6), 406–410 doi:10.1016/j.cplett.2004.03.041 http://dx.doi.org/10.1016/j.cplett.2004.03.041 Double-pulse electrodeposition into the pores of a porous anodic Al oxide template gave highly ordered CoPt/Pt multilayered nanowire arrays (1). The nanowires had a bamboo-like structure. The section lengths could be adjusted by varying the pulse width and pulse intensity. (1) exhibited in-plane anisotropy. High coercivity (H c = 1.8 kOe) and squareness (Mr/Ms) ∼ 0.35 were obtained in (1) when the field was applied perpendicular to the wire axis of (1). This is attributed to the disordered f.c.c. CoPt formation. Effects of Post-Annealing on the Dielectric Properties of Au/BaTiO 3 /Pt Thin Film Capacitors E. J. H. Lee, F. M. Pontes, E. R. Leite, E. Longo, R. Magnani, P. S. Pizani and J. A. Varela , Mater: Lett. , 2004, 58 , (11), 1715–1721 doi:10.1016/j.matlet.2003.10.047 http://dx.doi.org/10.1016/j.matlet.2003.10.047 BaTiO 3 thin films (1) were prepared by the polymeric precursor method and deposited onto Pt/Ti/SiO 2 /Si. The BaTiO 3 perovskite phase formation was investigated. (1) were post-annealed in O 2 and N 2 at 300°C for 2 h. Post-annealing in O 2 increased the dielectric relaxation phenomenon, whereas in N 2 a slight dielectric relaxation was produced. Read more of this issue Find an article ArticleSearch FIND About Editorial Policy The Editorial Board The Team Information For Librarians Open Access Policy Platinum Metals Review Journal Archive 2021 - 2030 2011 - 2020 2001 - 2010 1991 - 2000 1981 - 1990 1957 - 1980 Resources Questions & Answers Social Media Further Reading Glossary Careers at Johnson Matthey Help Alerts Email Alerts Twitter RSS Feed Terms and conditions Privacy Policy Cookies Special Issues Keep Updated Enter your email address to receive our quarterly alerts Please enter valid Email Address I accept the Terms and conditions Please accept the Terms and Conditions SIGNUP
https://technology.matthey.com/article/48/3/140-142/10.1016/10.1039/10.1246/10.1016/10.1021/om030605e
We depend on saliva to give us a sense of sweetness | The Splendid Table Anthropologist and evolutionary biologist Nathaniel Dominy has studied saliva from around the globe. We depend on saliva to give us a sense of sweetness Listen: We depend on saliva to give us a sense of sweetness Photo: Dorling Kindersley RF Photo: Dorling Kindersley RF Saliva helps us swallow food, protects our teeth and even gives us a sense of sweetness as it converts starch to glucose. Anthropologist and evolutionary biologistNathaniel Dominy, associate professor in the Department of Anthropology at Dartmouth College, has studied saliva from around the globe. He researches how humans acquire, process and assimilate food -- and how those behaviors affect the evolution of anatomical form and function. Lynne Rossetto Kasper: Why do our mouths water? Nathaniel Dominy: We produce saliva -- we produce quite a lot of it for four major reasons. It's also protective because it neutralizes very acidic foods. Acid has the effect of etching away your teeth. Saliva reduces the acidity of very acidic things like fruit. For example, lemon has a pH of about 2, so it's very acidic. Saliva also can act like an early alarm system. Your saliva is full of these proline-rich proteins, which appear to have no function other than to bind to tannins. Tannins give us that sense of astringency. If you've ever eaten an unripe banana for example, you feel that gritty sensation on your teeth, your teeth feel a little bit roughened. That's because all those tannins are binding to the proteins. You’re sacrificing all these proteins in your saliva to give you that roughened feeling in your mouth. This is thought to be an alarm system to let you know that what you’re eating isn't exactly the most nutritious thing because those tannins are something you generally want to avoid. The fourth thing the saliva does is it actually allows you to digest foods initially in the mouth. You tend to think of your stomach and your small intestine as being the digestive powerhouses of the body. But actually you do a significant amount of digestion in the mouth before food ever reaches your stomach. The major digestive enzyme in saliva is called amylase. Amylase is special because it hydrolyzes -- it dissolves starch grains in your foods. Most of the food that we eat is really starchy: potatoes, rice, bread, etc. Starch has become a central aspect of all modern human diets today, and we really depend on our saliva to help initiate digestion in the mouth and also give us a sense of sweetness. The reason why these things actually taste somewhat good is because in the mouth, the saliva is converting the starch grains directly into glucose, which is something that we perceive as relatively sweet. LRK: The human brain needs a very large amount of glucose. ND: Our brain is very costly to maintain, energetically. We spend about 20-25 percent of our energy feeding our brain. Our brain demands more energy than almost any other tissue in the body. We need sugary foods to feed the brain. But of course today we probably indulge too much. LRK: Different peoples across the planet eat different diets. Does their saliva test differently? ND: In fact, yes. We've done research looking at populations around the planet that have different traditional levels of starch intake. Americans and other North Americans tend to eat a lot of starch, so our diet is relatively starch-rich because of all the agricultural products that we eat. There are other populations around the planet, for example, certain Arctic populations that are living closer to the North Pole, who tend to have very little starch in their diet. There are hunter-gatherers who live in tropical Africa -- they tend to have very little starch in their diet as well. What we've shown is that the number of genes that allow you to produce this amylase enzyme in the saliva, they tend to vary globally and they vary as a function of the amount of starch in the diet. For example, people in North America tend to have a lot of copies of this particular gene. They produce a lot more amylase in saliva than populations that don't really need copies because they're eating much less starch.
https://www.splendidtable.org/story/2013/09/26/we-depend-on-saliva-to-give-us-a-sense-of-sweetness
(PDF) Advanced Access PDF | Evidence review work group (2011). Advanced Access. Rapid review. | Find, read and cite all the research you need on ResearchGate Research PDF Available Advanced Access January 2011 DOI: 10.13140/RG.2.2.23397.45283 Abstract Evidence review work group (2011). Advanced Access. Rapid review. Discover the world's research 25+ million members 160+ million publication pages V AIL-P ACT Mini-Review [May 2011] Evidence Review W ork Group Advanced Access For this mini-review , we searched the PubMed database from 1999-2011 for “advanced access” or “open access,” “primary health care” or “primary care” or “ambulatory care.” W e also did a Google search for similar terms to identify relevant res ources. What is advanced access? Advanced or open access is the reorganization of clinic practices to improve patients’ access to care. The objective is to allow patients to see a physician or other primary care practitioner at a time and date that is convenient for them. The advanced access model is often considered to be another scheduling system; however, it is better to be considered a comprehensive approach to reengineering patient care delivery. Since its introduction more than 12 years ago, advanced access has been the subject of much research. Advanced access conver ges to the following principles in determining successful implementation: 1. Understand supply/capacity and demand . Supply is the number of hours and appointments available in a clinical practice. Demand is the patients’ requests for appointments. Calculating demand allows appropriate matching of supply of services. 2. Reduce backlog . Backlog is the number of patients waiting to see a physician. Reducing backlog initially requires an upfront commitment of time from providers to work extra hours to clear the backlog before advanced access scheduling can begin. In addition, long term strategies can help sustain low backlog. Examples of these strategies include extending visit intervals, fully utilizing other care team members to shift clinical care and most clerical work away from providers, optimizing continuity , maximizing activities for one visit so as to reduce future work and reviewing schedules for duplicate visits. 3. Simplify appointment types and times . This implies equal access for any problem, whether it is urgent, routine or preventative. 4. Develop contingency plans to sustain the system . The clinical practice needs to plan for vacations, seasonal increases in demand (e.g. influenza season, back-to- school physicals), and unexpected staff illness. 5. Reduce demand for unnecessary visits . This is done by emphasizing continuity of care, managing of primary care panel size, extending visit intervals, and providing other sources of access to care such as group visits, phone visits and e- visits. 6. Optimize effective supply. Multiple steps are required to achieve this principle. Delegate physicians’ functions that can be performed by someone else and training allows. In addition, standardize best practices. Advanced access makes intuitive sense, which is why it is frequently considered in the context of patient-centered medical homes. Successful implementation of advanced access has the following theoretical benefits:  Better patient access to services – all levels (primary, secondary and tertiary).  Maximum utilization of staff – practitioners work at their full scope of practice thereby reducing practice overlaps and inefficiencies.  Better clinical outcomes – illnesses/diseases are diagnosed earlier, thus improving the chances of cure and/or treatment.  More patients able to access health care services – a more efficient clinical practice will be able to accommodate new patients.  Provider satisfaction improves.. Appropriate clinical practice size is determined so that demand and supply are balanced. As a result, providers do not redirect patients to the emergency departments or put them on long waiting lists.  Better utilization of financial resources – unnecessary and duplicate visits are eliminated and providers are engaged in appropriate service provision. What is the evidence that advanced access works? The evidence of the impact of advanced access has not been entirely positive. Early studies documenting the implementation of advanced access showed promising results such as reduced wait times and better patient satisfaction. But a recent review of 124 studies from 1998 to 2008 by Mehrotra et al. 1 showed the majority of studies had major methodological limitations. Among the studies that assessed outcomes beyond access to show rate. Mehrota et al. did an evaluation of six practices in the Boston area and showed that after implementation of advanced access, scheduling improved in some practices but none could achieve same-day access. Patient and staff satisfaction and patient no-show rate were unchanged. The author commented that there were multiple barriers contributing to the lack of demonstrative success after implementation. These barriers included extended provider leaves causing unexpected fluctuations of appointment supply; the inability to assess appointment demand accurately, which was caused by not knowing each physician’s panel size, which in turn not allow accurate calculation of demand. T antau 2 highlighted other pitfalls that prevented sus tainable implementation. These included the failure of not rigorously monitoring and matching daily and weekly demand and supply for each provider; practices revert to carving out strategies to reserve future supply rather than address backlog that will reemerge when demand and supply are not balanced; poor continuity of care, which drive up demand for visits; backlog reduction that relies solely on working harder and does not use other “smart strategies” to fundamentally change the way demand is managed; and after achieving improved delays, not continuing to aim for zero days’ delay . Recent qualitative research with patients has indicated that same-day appointments and the flexibility of accessing the appointment system at any time aren’t necessarily as important as anticipated. 3 Among patients with chronic conditions, predictable and regular appointment times that could be planned in advance may be more preferable, especially when patients may not remember to call for their next routine appointment when the time approaches. In contrast, patients with non-chronic or urgent medical needs value sooner appointments (such as for a cold or viral infection) and are not as worried about seeing their own provider. In fact, in one study , after the implementation of advanced access scheduling, the number of chronic disease follow-up appointments decreased but non-chronic disease care visits increased. 3 It was hypothesized that patients previously combined their routine visits with consultations for non-chronic/urgent problems. With advanced access in place, there could be a “decoupling” of the two types of visits. What these recent studies show is that patient’ s preference may influence how advanced access scheduling might be modified to accommodate their different needs. A survey of 13,000 patients in the United Kingdom after the implementation of advanced access showed that the top priority for patients was to be seen on their day of choice rather than to be seen quickly . However, different patient groups had dif ferent priorities--- younger patients preferred to be seen on a specific day, while patients with ongoing medical problems preferred the ability to book appointments well in advance. 4 It is important to note that better and quicker access to appointments is not equivalent to improved access to care. Improved access is also about care that is coordinated, a strong care relationship between provider and patient, and care that is longitudinally continuous with a given care team/provider. Practices solely focused on advanced access to improve the availability of same-day appointments, could miss the broader picture of improving access to care. 5 For example, Phan et al. 6 and Salisbury et al. 7 found that after the implementation of advanced access, continuity of care (as measured patients seeing the same doctor in a given period of time) either remained the same or declined. Thus, for successful implementation of advanced access practices should consider how the primary care practice functions and the way care is delivered, patients’ preferences, and barriers to sustainability . Resources for advanced access implementation Many resources are available that could inform advance access planning and implementation. Below are a few to consider: 1. Alberta Access Improvement Measure website has a comprehensive list of brief articles covering all aspects of advance access implementation. The website includes a series of over 50 short articles covering a range of topics such as : a. Examining Demand, Supply and Activity b. Tips for balancing demand and supply c. Strategies for reducing no-s hows d. Provider capacity limits e. Advanced access and contingency plans f. Plans for patients of the absent provider g. Five levels of mapping flow h. Key measures of advanced access i. Panel and caseload equity j. Scripting at the front desk http://www .alber taaim.ca/resourcespage.html 2. Mark Murray produced a short but helpful document on how to determine the panel size for doctors. http://www .aafp.o rg/fpm/2007/0400/p44.html 3. TransforMED, which is s a subsidiary of the American Academy of Family Physicians, is a firm that helps practices implement patient centered medical homes. Its resource website provides information on advanced access and other general access to care resource materials. http://www .transformed. com/resources/Access.cfm References 1. Mehrotra A, Keehl-Markowitz L, A yanian JZ. Implementing open-access scheduling of visits in primary care practices: a cautionary tale. Ann Intern Med. Jun 17 2008;148(12):915-922. 2. T antau C. Accessing patie nt-centered care using the advanced access model. J Ambul Care Manage. Jan-Mar 2009;32(1):32-43. 3. Gladstone J, Howard M. Effect of advanced access scheduling on chronic health care in a Canadian practice. Can Fam Physician. Jan 2011;57(1):e21-25.' 4. Salisbury C, Goodall S, Montgomery AA, et al. Does Advanced Access improve access to primary health care? Questionnaire survey of patients. Br J Gen Pract. Aug 2007;57(541):615-621. 5. Pope C, Banks J, Salisbury C, Lattimer V . Improving access to primary care: eight case studies of introducing Advanced Access in England. J Health Serv Res Policy. Jan 2008;13(1):33-39. 6. Phan K, Brown SR. Decreased continuity in a residency clinic: a consequence of open access scheduling. Fam Med. Jan 2009;41(1):46-50. 7. Salisbury C, Montgomery AA, Simons L, et al. Impact of Advanced Access on access, workload, and continuity: controlled before-and-after and simulated- patient study. Br J Gen Pract. Aug 2007;57(541):608-614. Summary of articles cited in this write-up Author/Y e . <       7$ D A#@4@ '0 <$
https://www.researchgate.net/publication/331314772_Advanced_Access
Applied Sciences | Free Full-Text | A Linked Data Application for Harmonizing Heterogeneous Biomedical Information In the biomedical field, there is an ever-increasing number of large, fragmented, and isolated data sources stored in databases and ontologies that use heterogeneous formats and poorly integrated schemes. Researchers and healthcare professionals find it extremely difficult to master this huge amount of data and extract relevant information. In this work, we propose a linked data approach, based on multilayer networks and semantic Web standards, capable of integrating and harmonizing several biomedical datasets with different schemas and semi-structured data through a multi-model database providing polyglot persistence. The domain chosen concerns the analysis and aggregation of available data on neuroendocrine neoplasms (NENs), a relatively rare type of neoplasm. Integrated information includes twelve public datasets available in heterogeneous schemas and formats including RDF, CSV, TSV, SQL, OWL, and OBO. The proposed integrated model consists of six interconnected layers representing, respectively, information on the disease, the related phenotypic alterations, the affected genes, the related biological processes, molecular functions, the involved human tissues, and drugs and compounds that show documented interactions with them. The defined scheme extends an existing three-layer model covering a subset of the mentioned aspects. A client& ndash;server application was also developed to browse and search for information on the integrated model. The main challenges of this work concern the complexity of the biomedical domain, the syntactic and semantic heterogeneity of the datasets, and the organization of the integrated model. Unlike related works, multilayer networks have been adopted to organize the model in a manageable and stratified structure, without the need to change the original datasets but by transforming their data & ldquo;on the fly& rdquo; to respond to user requests. A Linked Data Application for Harmonizing Heterogeneous Biomedical Information by Nicola Capuano 1,* , Pasquale Foggia 2 , Luca Greco 2 and Pierluigi Ritrovato 2 School of Engineering, University of Basilicata, 85100 Potenza, Italy Department of Information and Electrical Engineering and Applied Mathematics, University of Salerno, 84084 Fisciano, Italy Appl. Sci. 2022 , 12 (18), 9317; https://doi.org/10.3390/app12189317 Received: 8 August 2022 / Revised: 9 September 2022 / Accepted: 14 September 2022 / Published: 16 September 2022 Abstract : In the biomedical field, there is an ever-increasing number of large, fragmented, and isolated data sources stored in databases and ontologies that use heterogeneous formats and poorly integrated schemes. Researchers and healthcare professionals find it extremely difficult to master this huge amount of data and extract relevant information. In this work, we propose a linked data approach, based on multilayer networks and semantic Web standards, capable of integrating and harmonizing several biomedical datasets with different schemas and semi-structured data through a multi-model database providing polyglot persistence. The domain chosen concerns the analysis and aggregation of available data on neuroendocrine neoplasms (NENs), a relatively rare type of neoplasm. Integrated information includes twelve public datasets available in heterogeneous schemas and formats including RDF, CSV, TSV, SQL, OWL, and OBO. The proposed integrated model consists of six interconnected layers representing, respectively, information on the disease, the related phenotypic alterations, the affected genes, the related biological processes, molecular functions, the involved human tissues, and drugs and compounds that show documented interactions with them. The defined scheme extends an existing three-layer model covering a subset of the mentioned aspects. A client–server application was also developed to browse and search for information on the integrated model. The main challenges of this work concern the complexity of the biomedical domain, the syntactic and semantic heterogeneity of the datasets, and the organization of the integrated model. Unlike related works, multilayer networks have been adopted to organize the model in a manageable and stratified structure, without the need to change the original datasets but by transforming their data “on the fly” to respond to user requests. Keywords: linked data ; biomedical ontologies ; multilayer network analysis ; neuroendocrine neoplasms ; semantic information integration ; multi-model database 1. Introduction The massive and continuous growth of biomedical data of a heterogeneous nature requires ever greater efforts aimed at their integration. Indeed, the proliferation of non-integrated and non-interoperable data greatly hinders their interpretation and prevents computer-assisted reasoning. Data integration and reproducibility are essential to biomedical studies; it becomes extremely important to observe the FAIR guiding principles where research works are recommended to be findable, accessible, interoperable, and reusable [ 1 ]. Generally, a key requirement for allowing data to be FAIR is the use of open approaches and standardized representation formalisms such as ontologies. Indeed, ontologies have proved crucial in supporting omics data integration [ 2 ]. However, since hundreds of biomedical ontologies have been designed and are currently available, a new problem has arisen, i.e., how to integrate different ontological schemes and make them interoperable [ 3 ]. To this end, in addition to syntactic issues related to the variety of models and formats, semantic problems arising from context-related different interpretations need to be encountered [ 4 ]. To get the most out of these data, different approaches are required for querying multiple ontologies and databases to provide researchers with biomedical information organized as interconnected entities in a semantic fashion [ 5 ]. The research described in this paper attempts to contribute toward this end within a specific domain, through an ontology-based linked data application. An approach to data aggregation and analysis in the field of rare neuroendocrine neoplasms (NENs) is proposed. In previous research by the same authors [ 6 ] a novel linked data application was described for the same domain, integrating several existing biomedical ontologies including the National Cancer Institute Thesaurus , the Mondo Disease Ontology , the MedGen database, the Disease Ontology , the Orphanet Rare Disease Ontology , the DisGeNet database, and the Gene Ontology . Such data sources provided the relevant information to build a single knowledge model about NENs that is accessible via a client–server application. In this work, an extension of the previous model through the integration of additional data sources is proposed. The knowledge model relies on the multilayer network formalism to semantically link heterogeneous data sources while grouping them into several “layers”, each corresponding to a specific “aspect” of the domain [ 7 ]. The original model consisted of three interconnected layers representing: information about diseases, affected genes, biological processes, and molecular functions of such genes and related gene products. In addition to the information included in the original model, the extended version integrates information from new sources including the Human Phenotype Ontology , the HPO-ORDO Ontological Module , the Human Protein Atlas , the Drug–Gene Interaction Database as well as the ChEMBL database . Starting from the previous model, three additional layers have been designed and integrated to consider further aspects. The first additional layer provides details about disease-related phenotypes such as morphology, development, biochemical, physiological, and other features. It has been shown that a deep understanding of rare diseases together with the identification of prognostic and therapeutic implications can be accelerated by analyzing and correlating phenotypic and genomic data. The second additional layer provides an association between genes responsible for diseases and human tissue. This allows us to find commonalities between organs and illustrate the role of genes related to NENs. The third additional layer provides details about drugs with documented interactions with genes affected by NENs. The complexity in the extraction of relevant information about these tumors is motivated by the great heterogeneity in their biological features that can also determine heterogeneous responses to therapeutic agents. They often present subpopulations of cells with different angiogenic, invasive, and metastatic properties. According to [ 8 ], biomedical ontologies pose several integration challenges due to both the complexity of the domain and the characteristics of the ontologies themselves which include thousands of classes. Furthermore, biomedical ontologies present profound organizational differences to the point of often being difficult to reconcile due to syntactic and semantic heterogeneity. Although properly integrated, such ontologies are often difficult for researchers to use due to the lack of user-friendly interfaces. The developed model is aimed to meet these challenges by improving the way information is stored, enhancing interoperability while simplifying the work of scientists studying these rare diseases. Moreover, a user-friendly interface can guide healthcare professionals and researchers through the process of searching for relationships between pathologies (and their related genes) also highlighting the effectiveness of adopted drugs. The adopted multilayer network formalism is useful for organizing the model into a manageable and layered structure. In accordance with [ 4 ], a workflow-based approach has been adopted to integrate data from external sources “on the fly” on a frequently updated local copy, based on user requests, therefore without the need to modify the original datasets and without the risk of using obsolete data. The paper is organized as follows: in Section 2 some background information on NENs is provided and the related work on biomedical data integration is summarized; in Section 3 the starting point of this research is described, including the previous integration model as well the additional biomedical data sources; in Section 4 the structure of the new model and the related integration issues are presented; in Section 5 the extension of the developed application for browsing and querying the updated model is described. The last section summarizes the conclusions and outlines the ongoing work. 2. Background and Related Work The research work described in this paper aims at supporting biologists, researchers, and specialists in the collection, organization, and analysis of existing biomedical data on neuroendocrine neoplasms (NENs) through the definition and development of a linked data application. During the last four decades, these neoplasms have shown a 6.4-times increasing age-adjusted annual incidence [ 9 ]. NENs have been observed in almost every tissue, either in the pure endocrine organs, the nerve structures, or in the diffuse neuroendocrine system. The World Health Organization has defined two groups of NENs to enable consistent management of diseases regardless of their anatomical location [ 10 ]: neuroendocrine carcinomas (NECs) and neuroendocrine tumors (NETs). Although NETs appear as well-differentiated neoplasms and can be categorized into three levels—G1, G2, and G3 (low, intermediate, and high grade)—NECs are poorly differentiated neoplasms with only high grade (i.e., G3). Cell grade and differentiation often depend on different factors such as mitotic count and Ki-67 cell labeling index [ 11 ]. Moreover, NECs can be also classified into small- or large-cell-type NECs. The integration of information about NENs is still quite difficult since variations depending on anatomical sites often lead to definitions different from the accepted and established ones. Heterogeneous data sources with different schemes and formats make the information retrieval and analysis process quite difficult to perform and often require the clinician to have advanced programming skills. Some projects have been proposed to integrate and harmonize biological data sources. For example, in the Gene Expression Data Warehouse (GEDAW) project a data warehouse has been proposed to manage relevant information on liver gene expression data and related biomedical resources [ 12 ]. It provides the integration of gene information from several data sources, including GenBank and BioMeKe . Bio2RDF also has the purpose of transforming heterogeneous biomedical information into linked data using semantic Web technologies [ 13 ]. It currently consists of 11 billion triples and 35 connected datasets. Bio2RDF is part of the Life Sciences Linked Open Data (LSLOD), in the context of the Linked Open Data initiative [ 14 ]. The Knowledge Base of Biomedicine (KaBOB) integrates 18 biomedical data sources using 14 ontologies from the Open Biomedical Ontologies (OBO) initiative [ 15 ]. Such a model integrates data sources by producing a single biomedical entity for each set of data source-specific equivalent identifiers. Similarly, the Genomic and Proteomic Knowledge Base (GPKB) links several biomedical data sources such as Entrez Gene , UniProt , IntAct , Expasy Enzyme , GO , GOA , BioCyc , Kegg , Reactome, and OMIM [ 16 ]. It provides a set of maintenance procedures to update the knowledge base depending on the evolutions of its sources and their consistency. The Software for Flexible Integration of Annotation (SoFIA) aims at integrating omics information from several sources [ 17 ]. It relies on a minimal workflow that, given a starting goal indicated by the researchers, allows one to complete the task and return a relevant subset of information. More recently, the R package Onassis has been introduced to easily associate samples from large-scale biomedical repositories to ontology-based annotations [ 18 ]. Onassis leverages NLP techniques, biomedical ontologies, and the R statistical framework to identify, relate, and analyze datasets from public repositories. In the domain of cancer research, SysCancer has the aim to provide an integrated system that combines different stages of cancer studies [ 19 ]. The data warehouse can allow a multidimensional analysis of collected and integrated data meant for public access. In [ 20 ] the authors developed a cancer staging ontology based on the guidelines of the American Joint Commission on Cancer . The initial knowledge graph has been augmented by integrating additional open-source information about treatment and monitoring options depending on the inferred stage. A network-based data integration framework for the semantic integration of clinical and omic data on breast cancer and neuroblastoma is presented in [ 21 ]. Here, a NoSQL database is used to combine heterogeneous raw data records and external knowledge sources. A cervical cancer ontology has been developed by [ 22 ] where the authors define 880 standardized concepts, 1182 common terms, 16 relations, and 6 attributes which are organized into 6 levels and 11 classes. The first example of a linked data application, aimed at integrating and harmonizing existing information on NENs was reported in [ 6 ]. It connects data from several sources, providing a single access point to a detailed network of information, organized on three interconnected layers. The ontology developed in this latest paper and the related software prototype constitutes the starting point of the present study. As anticipated in the introductory section, this work extends the existing ontological model by designing and integrating three additional layers, which refer to further aspects of the domain. On the other hand, the new model exhibits the innovations already proposed in the previous version compared to the existing literature, i.e., the use of multilayer networks to organize the model in a manageable structure, the use of a workflow-based approach to integrating external data “on the fly”, and the use of a user-friendly interface based on a multi-modal database with polyglot persistence. 3. Initial Model and New Information Sources As anticipated in the previous section, the starting point of this work is the linked data application for NENs described in [ 6 ]. The next sub-section summarizes the content and the structure of the previous knowledge model whereas Section 3.2 provides a brief overview of the new biomedical information sources that, in the present study, have been integrated on top of the former model. 3.1. The Initial Integration Model The former model already integrates several existing biomedical ontologies and databases that describe diseases, genes, gene products, biological processes, molecular functions, and the gene–disease and disease–disease associations. The entire list of the integrated data sources is reported in Table 1 . A single knowledge model has been built by extracting and linking relevant information for research on NENs. Our model relies on the formalism of multilayer networks to address the heterogeneity of interconnected information; this allows us to represent complexity by generalizing a graph structure where the nodes and edges are distributed on different layers, each representing an “aspect” of the domain [ 23 ]. We define a multilayer network as a triple M = ( V , E , L ) where the sets V and E represent, respectively, the nodes and edges of the network, whereas L = { L 1 , … , L d } is the set of network layers [ 24 ]. In turn, each L i ∈ L is a subgraph L i = ( V i , E i ) composed by the nodes V i and the edges E i such that V = ∪ i = 1 d V i and E = ∪ i = 1 d E i . In Figure 1 a sketch of the former model is depicted. The three interconnected layers represent information on diseases, affected genes, and their functions. We define specific concepts as shared nodes that realize bridges between layers. Layer 1 collects information about NENs as available in NCIT, ORDO, and DO ontologies. The disease class (and its subclasses) acts as a bridge from layer 1 to layer 2 to highlight the variations in the human genome (available in the DisGeNet database) that lead to the NENs described at the first level as well as disease–disease associations based on their molecular causes. Then, the gene class (and its subclasses) acts as a bridge from layer 2 to layer 3 to highlight additional information on genes and gene products responsible for the onset of NENs (available in the Gene Ontology ). This also includes genes’ molecular functions (i.e., the elementary activities of a gene product at the molecular level, such as binding or catalysis) and biological processes (i.e., the operations or sets of events relevant to the operation of living units: cells, tissues, organs, and organisms). We implement interlayer relations with the equivalent-class OWL statement. In the same way, newly defined ontologies are linked with the original ontological sources. We developed a client–server application to access, browse, and query the defined model. 3.2. The Additional Biomedical Information Sources The list of additional data sources integrated with the updated knowledge model is reported in Table 2 which also includes a reference to the official website. The Human Phenotype Ontology (HPO) provides a standardized vocabulary of phenotypic abnormalities found in human diseases. It currently includes over 13,000 terms and more than 156,000 annotations describing phenotypic anomalies divided into five sub-ontologies that classify anomalies, link them to diseases, describe the mode of inheritance, the modifiers of clinical symptoms, the clinical course, and the frequency of specific clinical features. The ontological scheme is developed by the Monarch Initiative , using medical literature to improve biomedical research on rare diseases [ 25 ]. The HPO-ORDO Ontological Module (HOOM) is an ontology that integrates ORDO information on rare diseases with HPO information on phenotypic anomalies. HOOM qualifies the annotations between clinical entities and phenotypic anomalies according to the frequency and integrates the notion of diagnostic criterion. HOOM is intended for researchers and pharmaceutical companies wishing to co-analyze associations of rare and common disease phenotypes. Being designed to integrate the information of two different models, it does not contain instances but only classes and relationships. The Human Protein Atlas (HPA) maps human proteins in cells, tissues, and organs using the integration of several omic technologies, including antibody-based imaging, mass spectrometry-based proteomics, transcriptomics, and systems biology [ 26 ]. It has contributed to thousands of publications in the field of human biology and disease and is recognized by the intergovernmental organization ELIXIR as a central European resource for the life science community. HPA consists of ten parts, each focusing on a particular aspect of the genome-wide analysis of human proteins. In particular, the HPA Tissue Section has been used in this work. This section describes the expression profiles in human tissues of genes at both the mRNA and protein levels. The protein expression data of 44 normal human tissue types is derived from antibody-based protein profiling using immunohistochemistry. Protein data covers 15,323 genes (i.e., 76% of protein-coding genes) for which antibodies are available. The mRNA expression data is derived from deep RNA sequencing (RNA-seq) from 256 different types of normal tissue. The Drug–Gene Interaction Database (DGIdb) is a Web resource that provides information on drug–gene interactions and druggable genes from publications, databases, and other Web sources [ 27 ]. Data on drugs, genes, and interactions are normalized and merged into conceptual groups. In the current version (4.0), DGIdb includes 100,273 interaction statements and 33,577 druggable gene category claims. In total, it includes 10,606 druggable genes and 54,591 drug–gene interactions, covering 41,102 genes and 14,449 drugs. DGIdb is accessible via a Web-based search interface, an application programming interface (API), and is downloadable as a collection of TSV archives. The ChEMBL database is a large open-access drug discovery database managed by the European Molecular Biology Laboratory (EMBL). It is handled manually and has the purpose of capturing data and knowledge across the pharmaceutical research and development process. Information on molecules and their biological activity is extracted from full-text articles in several journals and supplemented with data on approved drugs and clinical development candidates, such as the mechanism of action and therapeutic indications [ 28 ]. It includes information on more than 2 million compounds and 14,000 drugs from more than 84,000 publications and about 200 datasets. It is accessible via a Web-based interface and can be downloaded as an SQL database or a collection of RDF files. 4. The Integration and Harmonization Process To integrate the biomedical data sources described in Section 3.2 , three additional layers were designed and harmonized with the initial model. Figure 2 shows the updated model which now consists of six interconnected layers. The additional layers (opaque in the figure) contain information on the phenotypic anomalies connected to the NENs (layer 1b), the involved human tissues (layer 4), and the pharmacological interactions with the connected genes (layer 5). As in the original model, we don’t include explicit interlayer connections since they can be inferred from the projections of the same node in different layers. Furthermore, each pair of adjacent layers shares at least one node. The new layer describing phenotypic anomalies, being closely related to diseases, is placed directly between layers 1 (diseases) and 2 (genes). In this way, the disease class (and its subclasses) allows a transition from layer 1 to layer 1b (to discover phenotypic anomalies related to diseases) and to layer 2 (to discover disease–gene connections). In turn, the gene class (and its subclasses) allows a transition from layer 2 to layer 3 (to discover gene functions), to layer 4 (to discover human tissues where gene products are expressed), and to layer 5 (to find drugs that have documented interactions with genes). In the next subsections, we describe in more detail the composition of each additional layer. 4.1. Layer 1b: Phenotypic Anomalies As introduced in Section 2 , NENs are rare diseases that include heterogeneous neoplasms such as high-grade NETs in the lung, mixed medullary and follicular cell carcinomas, intrathyroidal NENs with paraganglioma features, NENs of the breast, NETs in the kidney, NETs of the bladder, etc. [ 10 ]. Although a rare disease occurs in less than 1 in 2000 individuals, due to the high number of such diseases (about 8000 according to Orphanet), it is estimated that around 4% of the European population has a rare disease diagnosis [ 29 ]. According to [ 30 ], about 80% of rare diseases are of genetic origin. However, due to a lack of clinical and scientific knowledge, the molecular cause is unknown for about 40% of them. The second level of the proposed model already includes information on known genetic variants linked to NENs. However, despite the increasing number of identified genetic variants, their functional impact and, consequently, the connection with rare diseases is still largely unknown. Furthermore, even for diseases for which one or more causative genes have been identified, these often do not explain the totality of cases. This lack of knowledge often prevents patients from receiving adequate and timely care. It is estimated that specific therapies are available for less than 10% of rare diseases, including NENs. For this reason, having available detailed phenotypic data combined with ever-increasing amounts of genomic data is of enormous importance to accelerate the identification of clinically actionable prognostic or therapeutic implications and to improve the understanding of rare diseases [ 31 ]. Moreover, phenotype-based genomic analysis has also been shown to improve the diagnostic rate in patients with rare diseases [ 32 ]. Phenotypes are the observable traits of an organism. In medical contexts, however, the word phenotype is more often used to refer to some deviation from normal morphology, physiology, or behavior. A disease is commonly characterized by one or more phenotypic features which can affect all or only a subset of individuals with the disease as well as a time course over which the phenotypic features may have onset and evolve. The HPO ontology (see Section 3.2 ) describes a deep hierarchy of phenotypic abnormalities whereas the HOOM ontology (see Section 3.2 ) associates the phenotypic anomalies described in HPO with the clinical entities included in the ORDO ontology of rare diseases. By harmonizing the information included in HPO and HOOM with the classes and properties of the first three layers of the initial knowledge model, we were able to construct layer 1b, aimed at describing known associations between NENs and phenotypic anomalies. Figure 3 represents the main classes and relations of our model. Gray classes and bold relationships are introduced by the integration scheme of layer 1b except for the dotted classes which are projected from the previous and subsequent layers. The main classes of this layer are phenotypic anomaly , equivalent to the phenotypic abnormality class from HPO (i.e., the ancestor class of all described phenotypic anomalies), and the disease–phenotype association class, a subclass of the association class from HOOM (describing known associations between phenotypes and clinical entities). Only associations related to diseases classified as NENs in the first layer have been considered. Furthermore, a set of properties, inherited from HOOM and described in Table 3 , are linked to each association, to qualify it with information about the frequency and the diagnostic criteria, and the provenance (e.g., scientific articles or expert opinions). It should be noted that indirect connections between genes, gene variants, and phenotypic anomalies can be inferred from the model based on information from layer 2 that associates genes and gene variants with diseases. 4.2. Layer 4: Human Tissues This layer enhances the model with information, inherent to NENs, on the human tissues associated with the genes that cause these diseases. This information is retrieved from the Human Tissues section of the HPA (see Section 3.2 ) which defines the distribution of gene products in the main tissues and organs of the human body. The collection and analysis of information relating to normal tissues are important and allow us to compare a pathological state with normality. On the other hand, inter-individual variations in the norm (e.g., age-related) can present a challenge in distinguishing a physiological condition from a pathological one. The Human Tissues section of the HPA describes the level of expression of gene products in 44 different non-diseased tissues. These gene products and related genes play an important role in organ physiology and provide the basis for organ-specific research. By correlating genes and tissues it is possible to highlight genes that are simultaneously present in groups of tissues, compared to all other human tissues. Such information helps to find similar characteristics between different organs and allows us to elucidate the function of the genes associated with NENs. Table 4 shows the main fields of the HPA Normal Tissue Data Archive . It is a tabular TSV file where each row represents the association between a gene and a human tissue. We filtered this extensive dataset to consider only the associations with a medium or high level of protein expression ( level field), only for the subset of genes already included in layer 2 of the integrated model (therefore related to NENs). Then the value of the reliability field was considered. This value indicates the level of reliability of the analyzed protein expression pattern based on knowledge-based evaluation of available RNA-seq data, protein/gene characterization data, and immunohistochemical data from one or several antibodies designed toward non-overlapping sequences of the same gene. In our case, only the associations that are considered as enhanced , supported , or approved were retained whereas uncertain associations were discarded. To harmonize the filtered information with the multi-layered knowledge model, an ontological representation of gene–tissue association is created as represented in Figure 4 where gray classes and bold relationships are introduced by the scheme of this layer except for the dotted classes which are projected from the previous layers. In particular, the classes Tissues and Cell-Types were introduced whose instances are taken from the HPA-controlled vocabularies. A Gene–Tissue Association class was also introduced whose instances are dynamically generated from the filtered version of the HPA Normal Tissue Data Archive. Each instance maps a gene with a tissue and a cell type by also specifying the related level ( medium or high , which are instances of the Level class) and reliability ( enhanced , supported , or approved which are instances of the Reliability class). Even in this case, indirect connections between diseases and tissues can be inferred from the model based on information from the previous layers that associate genes and diseases. 4.3. Layer 5: Drug Interactions NENs are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. As their response to therapeutic agents is equally heterogeneous, their treatment still represents an important clinical problem [ 33 ]. Understanding drugs’ effects on NENs has been importantly investigated in the last years also using in vitro studies that have been essential to clarifying drug mechanism of action. Some innovative therapeutic options are also based on the study of the molecular pathways involved in the development and growth of NENs. In this context, the research has recently focused on the so-called druggable genome that is, genes and gene products known or expected to interact with bioavailable compounds. In addition to the presence of a protein structure that can be powerfully bound by small molecules, good potential targets are proteins for which modulation of biological function could provide therapeutic benefits for the patient. Targeted therapy has proven to be a successful strategy in oncology, with the introduction of new therapeutic agents, including monoclonal antibodies and small molecule kinase inhibitors [ 34 ]. Following this trend, whereas the previous levels of the model offer researchers the ability to find mutated or altered genes implicated in NENs, the last level is designed to provide them with information on compounds and drugs that show documented interactions with these genes. The main external information sources integrated into this level are ChEMBL and DGIdb (see Section 3.2 ) describing, respectively, drugs and drug–gene interactions. Table 5 shows the main fields of the DGIdb Interactions Archive . It is a tabular TSV file where each row represents a documented interaction between a drug and a gene. We filtered this information (made of more than 85,000 associations) to consider only interactions with genes already included in the model. The standardized HGNC (Human Genome Organization Gene Nomenclature Committee) gene name was used to associate the correct Gene class from layer 2. Instead, the drug-concept-id field was used to link the right instance of the Substance class from the ChEMBL ontology. To harmonize the filtered information with the multi-layered knowledge model, an ontological representation of drug–gene interaction is created as represented in Figure 5 where gray classes and bold relationships are introduced by the scheme of this layer except for the dotted classes which are projected from the previous layers. In particular, the new class Drug maps, through the equivalent-class relation, the external general Substance class from ChEMBL . The class Gene–Drug Interaction maps a row of the DGIdb Interactions Archive and connects the Gene class with the Drug class with the interaction-has-gene and the interaction-has-drug object properties, respectively. Additional information, connected to the Gene–Drug Interaction class through the interaction-has-type property, is the Interaction Type that explains the way a dug or compound interacts with a gene according to a controlled vocabulary defined by DGIdb as reported in Table 6 . Each term is represented within the model as an individual of the Interaction Type class. The meaning of each term is explained in the same table. Additional information like the interaction score (see Table 5 ) and a link to the ChEMBL Web page describing in detail each substance is included in the model through data properties. 5. Developed Prototype and Validation Results A client–server application was developed as an extension of the one already presented in [ 6 ] to retrieve the relevant information from our integrated model. We selected Virtuoso Universal Server as the middleware to store the original biomedical ontologies and databases; such an open-source solution allows us to manage different data formats with several access protocols. We store the original datasets to the server, scheduling periodical updates starting from the original endpoints (not straightly used for performance issues). Our multilayer integration model is also hosted on the same server. We developed a lightweight Java desktop application to allow quick and easy user interaction. A visual interface is provided to specify input queries, which are in turn translated as SPARQL sequences and forwarded via HTTP to the server. Obtained results are shown graphically to the user. For RDF and SPARQL management, our client application relies on the Jena Framework. We also use OWL API for the client-side manipulation of OWL ontologies. Figure 6 summarizes our system architecture highlighting the main modules. Notice that the dashed dataset comes from the previous version. Figure 7 shows the “phenotypes” section of the client application. Once the user has selected a subset of NETs and/or NECs from the “diseases” area—see (Capuano, Foggia, Greco, and Ritrovato, 2022)—this section allows him to obtain the phenotypic anomalies associated with the selected diseases. The user can decide whether to carry out the analysis only on the previously selected diseases or not. The information obtained in this phase is extracted from layer 1b (see Section 4.1 ) starting from the rare diseases present in the ORDO ontology, and then extrapolating the associations with the anomalies in ORDO-HOOM and finally the information relating to the anomalies in HPO. The user can click on the name of the anomaly and on the frequency value to get more information. Figure 8 shows the “tissue” section of the client application. Information about the human tissues in which a neoplasm can occur is extracted from layer 4 (see Section 4.2 ) starting from the Normal Tissue Data Archive of HPA. Once the user has selected a subset of genes involved in NETs and/or NECs under investigation (including gene–disease, variation–disease, and disease–disease associations, cytogenetics anomalies, molecular anomalies, etc.)—through the “genetic information” tab described in (Capuano, Foggia, Greco, and Ritrovato, 2022)—he can obtain here the list of human tissues in which each gene has a medium or high level of expression. Displayed data on each tissue is associated with a link to the online version of HPA where the user can find additional information (see Figure 9 ). Figure 10 shows the “drugs” section of the client application where the user can obtain information on compounds and drugs that show documented interactions with the genes selected in one of the preceding steps and, as consequence, can potentially impact the associated diseases. The information obtained in this phase is extracted from layer 5 (see Section 4.3 ) starting the integration of gene information included in GO with information on drugs included in ChEMBL and drug–gene interactions included in DGIdb. Displayed data on each drug is associated with a link to the online version of ChEMBL where the user can find additional information (see Figure 11 ). A test installation of the server was conducted on a Linux machine with a 2.3 GHz quad-core Intel Core i7 processor and 16 Gb of RAM. With this hardware configuration, most of the queries are answered in a fraction of a second, and only the most complex ones (that combine information from semantic and non-semantic sources) require longer: in rare cases more than 2 s. These results are in line with recent RDF store benchmarks [ 35 ] which rank Virtuoso Universal Server as one of the fastest triple stores for both instant and analytical queries. Our system validation was performed with the contribution of a domain expert that helped verify the consistency and correctness of the ontological knowledge as well as the quality of the alignment between the information sources. We adopted an iterative approach where the expert was asked to use the system and provide feedback; this allowed us to improve the level of alignment [ 36 ]. In the specific case, two validation iterations led to satisfactory results. 6. Conclusions and Further Work In this paper, we have described the extension of previous research work aimed at designing and implementing a domain-specific linked data application for integrating relevant biomedical information on NENs. Additional biomedical aspects covered by the updated model include the phenotypic anomalies linked to these diseases, the involved human tissues, and the documented pharmacological interactions of existing drugs and compounds. Through the alignment and the integration of existing semantic and non-semantic biomedical sources, we were able to compose a knowledge base as a multilayer network managed through a multi-model database providing polyglot persistence. The model can be easily navigated and queried using a client application that provides a user-friendly graphical interface. Several directions of extension of the proposed system can be envisaged. On the one hand, there is the possibility of integrating additional information sources within existing layers (integrating aspects already considered) as well as on additional layers (considering further aspects). On the other hand, it would be possible to apply the model to a connected biomedical domain, for example considering a different subset of rare diseases. The experimentation of the proposed system with researchers and professionals involved in the treatment of this type of neoplasms is also foreseen to collect feedback for system improvement as well as to assess the risks and critical success factors associated with the introduction of this kind of technology in real medical contexts [ 37 ]. Beyond the specific domain, the paper introduces and analyzes a way to integrate heterogeneous data sources, capable of being adapted to other contexts. Linked data makes the possible aggregation of information quite unlimited. Each information level can be enriched with further details so that the system becomes increasingly useful for user support. On the other hand, the multi-layer organization would help to deal with the variety of information in a more organized and governable way. Another promising research direction is the application of existing metrics, such as those defined in [ 38 ], to measure the quality of the integrated knowledge model in terms of relationship richness , attribute richness , inheritance richness , etc. Indeed, evaluating such metrics on the integrated model, which includes ontological and non-ontological information, could be an interesting but challenging task that would require revising the definition of such metrics to support hybrid models. Moreover, approaches to automatic ontology alignment could be investigated and incorporated into the proposed system as integrated schemas. Author Contributions Conceptualization, P.R. and P.F.; methodology, N.C. and L.G.; software, N.C. and L.G.; validation, P.R. and P.F.; formal analysis, N.C. and L.G.; writing-original draft preparation, N.C. and L.G.; writing-review and editing, N.C. and P.R.; supervision, P.F.; funding acquisition, P.R. All authors have read and agreed to the published version of the manuscript. Funding This work is partially supported by the RarePlatNet project on diagnostic and therapeutic innovations for neuroendocrine and endocrine tumors and glioblastoma through an integrated technological platform of clinical, genomic, ICT, pharmacological, and pharmaceutical skills , funded by the Campania region, Italy under the grant on POR CAMPANIA FESR 2014/2020, axis 1, objective 1.2. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. References Wilkinson, M.; Dumontier, M.; Aalbersberg, I.; Appleton, G.; Axton, M.; Baak, A.; Blomberg, N.; Boiten, J.; de Santos, L.B.; Bourne, P.E.; et al. The FAIR guiding principles for scientific data management and stewardship. Sci. Data 2016 , 3 , 160018. [ Google Scholar ] [ CrossRef ] [ PubMed ] Hancock, J. Editorial: Biological ontologies and semantic biology. Front. Genet. 2014 , 5 , 18. [ Google Scholar ] [ CrossRef ] [ PubMed ] Wang, Z.; He, Y. Precision omics data integration and analysis with interoperable ontologies and their application for COVID-19 research. Brief Funct. Genom. 2021 , 20 , 235–248. [ Google Scholar ] [ CrossRef ] [ PubMed ] Messaoudi, C.; Fissoune, R.; Hassan, B. A Survey of Semantic Integration Approaches in Bioinformatics. Int. J. Comput. Inf. Eng. 2016 , 10 , 2058–2063. [ Google Scholar ] Kamdar, M. Mining the Web of Life Sciences Linked Open Data for Mechanism-Based Pharmacovigilance. In Proceedings of the WWW’18: Companion Proceedings of the The Web Conference; ACM: New York, NY, USA, 2018; pp. 861–865. [ Google Scholar ] Capuano, N.; Foggia, P.; Greco, L.; Ritrovato, P. A semantic framework supporting multilayer networks analysis for rare diseases. Int. J. Semant. Web Inf. Syst. 2022 , in press. [ Google Scholar ] [ CrossRef ] Hammoud, Z.; Kramer, F. Multilayer networks: Aspects, implementations, and application in biomedicine. Big Data Anal. 2020 , 5 , 2. [ Google Scholar ] [ CrossRef ] Faria, D.; Pesquita, C.; Mott, I.; Martins, C.; Couto, F.; Cruz, I. Tackling the challenges of matching biomedical ontologies. J. Biomed. Semant. 2018 , 9 , 1–19. [ Google Scholar ] [ CrossRef ] Effraimidis, G.; Knigge, U.; Rossing, M.; Oturai, P.; Rasmussen, A.; Feldt-Rasmussen, U. Multiple endocrine neoplasia type 1 (MEN-1) and neuroendocrine neoplasms (NENs). Semin. Cancer Biol. 2021 , 79 , 141–162. [ Google Scholar ] [ CrossRef ] Rindi, G.; Klimstra, D.; Abedi-Ardekani, B.; Asa, S.; Bosman, F.; Brambilla, E.; Scarpa, A.; Scoazec, J.; Travis, W.D.; Tallini, G.; et al. A common classification framework for neuroendocrine neoplasms: An International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod. Pathol. 2018 , 31 , 1770–1786. [ Google Scholar ] [ CrossRef ] Nagtegaal, I.; Odze, R.; Klimstra, D.; Paradis, V.; Rugge, R.; Schirmacher, P.; Washington, K.M.; Carneiro, F.; Cree, I.; The WHO Classification of Tumours Editorial Board. The 2019 WHO classification of tumours of the digestive system. Histopathology 2019 , 76 , 182–188. [ Google Scholar ] [ CrossRef ] Guérin, E.; Marquet, G.; Burgun, A.; Loréal, O.; Berti-Equille, L.; Leser, U.; Moussouni, F. Integrating and Warehousing Liver Gene Expression Data and Related Biomedical Resources in GEDAW. In Proceedings of the 2nd International Workshop on Data Integration in the Life Sciences, San Diego, CA, USA, 20–22 July 2005; pp. 158–174. [ Google Scholar ] Belleau, F.; Nolin, M.; Tourigny, N.; Rigault, P.; Morissette, J. Bio2RDF: Towards a mashup to build bioinformatics knowledge systems. J. Biomed. Inform. 2008 , 706–716. [ Google Scholar ] [ CrossRef ] [ PubMed ] Bizer, C.; Heath, T.; Berners-Lee, T. Linked Data—The Story So Far. Int. J. Semant. Web Inf. Syst. 2009 , 5 , 1–22. [ Google Scholar ] [ CrossRef ] Livingston, K.; Bada, M.; Baumgartner, W.; Hunter, L. KaBOB: Ontology-based semantic integration of biomedical databases. BMC Bioinform. 2015 , 16 , 126. [ Google Scholar ] [ CrossRef ] [ PubMed ] Masseroli, M.; Canakoglu, A.; Ceri, S. Integration and querying of genomic and proteomic semantic annotations for biomedical knowledge extraction. IEEE/ACM Trans. Comput. Biol. Bioinform. 2016 , 13 , 209–219. [ Google Scholar ] [ CrossRef ] Childs, L.; Mamlouk, S.; Brandt, J.; Sers, C.; Leser, U. SoFIA: A data integration framework for annotating high-throughput datasets. Bioinformatics 2016 , 37 , 2590–2597. [ Google Scholar ] [ CrossRef ] Galeota, E.; Kishore, K.; Pelizzola, M. Ontology-driven integrative analysis of omics data through Onassis. Sci. Rep. 2020 , 10 , 703. [ Google Scholar ] [ CrossRef ] Bensz, W.; Borys, D.; Fujarewicz, K.; Herok, K.; Jaksik, R.; Krasucki, M.; Kurczyk, A.; Matusik, K.; Mrozek, D.; Ochab, M.; et al. Integrated system supporting research on environment related cancers. In Recent Developments in Intelligent Information and Database Systems ; Springer: Berlin/Heidelberg, Germany, 2016; pp. 339–409. [ Google Scholar ] Seneviratne, O.; Rashid, S.; Chari, S.; McCusker, J.; Bennett, K.; Hendler, J.; McGuinness, D. Knowledge Integration for Disease Characterization: A Breast Cancer Example. In Proceedings of the 17th International Semantic Web Conference, Monterey, CA, USA, 8–12 October 2018; pp. 223–238. [ Google Scholar ] Zhang, H.; Guo, Y.; Prosperi, M.; Bian, J. An ontology-based documentation of data discovery and integration process in cancer outcomes research. BMC Med Inform. Decis. Mak. 2020 , 20 , 292. [ Google Scholar ] [ CrossRef ] Hong, N.; Chang, F.; Ou, Z.; Wang, Y.; Yang, Y.; Guo, Q.; Ma, J.; Zhao, D. Construction of the cervical cancer common terminology for promoting semantic interoperability and utilization of Chinese clinical data. BMC Med Inform. Decis. Mak. 2021 , 21 , 309. [ Google Scholar ] [ CrossRef ] Kivelä, M.; Arenas, A.; Barthelemy, M.; Gleeson, J.; Moreno, Y.; Porter, M. Multilayer networks. J. Complex Netw. 2014 , 2 , 203–271. [ Google Scholar ] [ CrossRef ] Boccaletti, S.; Bianconi, G.; Criado, R.; Del Genio, C.; Gómez-Gardeñes, J.; Romance, M.; Sendiña-Nadal, J.; Wang, Z.; Zanin, M. The structure and dynamics of multilayer networks. Phys. Rep. 2014 , 544 , 1–122. [ Google Scholar ] [ CrossRef ] Robinson, P.; Köhler, S.; Bauer, S.; Seelow, D.; Horn, D.; Mundlos, S. The Human Phenotype Ontology: A Tool for Annotating and Analyzing Human Hereditary Disease. Am. J. Hum. Genet. 2008 , 83 , 610–615. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Thul, P.; Lindskog, C. The human protein atlas: A spatial map of the human proteome. Tools Protein Sci. 2018 , 27 , 233–244. [ Google Scholar ] [ CrossRef ] [ PubMed ] Freshour, S.; Kiwala, S.; Cotto, K.; Coffman, A.; McMichael, J.; Song, J.; Griffith, M.; Griffith, O.L.; Wagner, A.H.; Wagner, A.; et al. Integration of the Drug–Gene Interaction Database (DGIdb 4.0) with open crowdsource efforts. Nucleic Acids Res. 2021 , 49 , D1144–D1151. [ Google Scholar ] [ CrossRef ] [ PubMed ] Mendez, D.; Gaulton, A.; Bento, A.; Chambers, J.; De Veij, M.; Félix, E.; Magariños, M.P.; Mosquera, J.F.; Mutowo, P.; Nowotka, M.; et al. ChEMBL: Towards direct deposition of bioassay data. Nucleic Acids Res. 2019 , 45 , D930–D940. [ Google Scholar ] [ CrossRef ] [ PubMed ] Maiella, S.; Olry, A.; Hanauer, M.; Lanneau, V.; Lourghi, H.; Donadille, B.; Rodwel, C.; Köhler, S.; Seelow, D.; Jupp, S.; et al. Harmonising phenomics information for a better interoperability in the rare disease field. Eur. J. Med Genet. 2018 , 61 , 706–714. [ Google Scholar ] [ CrossRef ] Aitken, M.; Kleinrock, M.; Munoz, E.; Porwal, U. Orphan Drugs in the United States, Rare Disease Innovation and Cost Trends through 2019 ; IQVIA Institute for Human Data Science: Parsippany, NJ, USA, 2020. [ Google Scholar ] Boycott, K.; Rath, A.; Chong, J.; Hartley, T.; Alkuraya, F.; Baynam, G.; Brookes, A.J.; Brudno, M.; Carracedo, A.; den Dunnen, J.T.; et al. International cooperation to enable the diagnosis of all rare genetic diseases. Am. J. Hum. Genet. 2017 , 100 , 695–705. [ Google Scholar ] [ CrossRef ] Wright, C.; Fitzgerald, T.; Jones, W.; Clayton, S.; McRae, J.; van Kogelenberg, M.; King, D.A.; Ambridge, K.; Barrett, D.M. Genetic diagnosis of developmental disorders in the DDD study: A scalable analysis of genome-wide research data. Lancet 2015 , 385 , 1305–1314. [ Google Scholar ] [ CrossRef ] Fidler, I.; Ellis, L. Chemotherapeutic drugs—More really is not better. Nat. Med. 2000 , 6 , 500–502. [ Google Scholar ] [ CrossRef ] Dupont, C.; Riegel, K.; Pompaiah, M.; Juhl, H.; Rajalingam, K. Druggable genome and precision medicine in cancer: Current challenges. FEBS J. 2021 , 288 , 6142–6158. [ Google Scholar ] [ CrossRef ] Atemezing, G.; Amardeilh, F. Benchmarking commercial RDF stores with publications office dataset. In Proceedings of the European Semantic Web Conference; Springer: Cham, Switzerland, 2018; pp. 379–394. [ Google Scholar ] Dragisic, Z.; Ivanova, V.; Lambrix, P.; Faria, D.; Jiménez-Ruiz, E.; Pesquita, C. User validation in ontology alignment. In Proceedings of the International Semantic Web Conference; Springer: Cham, Switzerland, 2016; pp. 200–217. [ Google Scholar ] Vicedo, P.; Gil-Gómez, H.; Oltra-Badenes, R.; Guerola-Navarro, V. A bibliometric overview of how critical success factors influence on enterprise resource planning implementations. J. Intell. Fuzzy Syst. 2020 , 38 , 5475–5487. [ Google Scholar ] [ CrossRef ] Tartir, S.; Arpinar, I. Ontology evaluation and ranking using OntoQA. In Proceedings of the International Conference on Semantic Computing (ICSC 2007), Irvine, CA, USA, 17–19 September 2007; pp. 185–192. [ Google Scholar ] Figure 1. Visual representation of the initial integration model. Figure 1. Visual representation of the initial integration model. Figure 2. Visual representation of the updated integration model. Figure 2. Visual representation of the updated integration model. Figure 3. Relevant classes and relations of the additional layer 1b. Figure 3. Relevant classes and relations of the additional layer 1b. Figure 4. Relevant classes and relations of the additional layer 4. Figure 4. Relevant classes and relations of the additional layer 4. Figure 5. Relevant classes and relations of the additional layer 5. Figure 5. Relevant classes and relations of the additional layer 5. Figure 6. Client–server architecture of the developed prototype. Figure 6. Client–server architecture of the developed prototype. Figure 7. The “Phenotypes” section of the client application. Figure 7. The “Phenotypes” section of the client application. Figure 8. The “Tissues” section of the client application. Figure 8. The “Tissues” section of the client application. Figure 9. Additional online information from HPA linked to the “tissues” section. Figure 9. Additional online information from HPA linked to the “tissues” section. Figure 10. The “Drugs” section of the client application. Figure 10. The “Drugs” section of the client application. Figure 11. Additional online information from ChEMBL linked to the “drugs” section. Figure 11. Additional online information from ChEMBL linked to the “drugs” section. Table 1. List of the biomedical information sources integrated with the former model. Table 1. List of the biomedical information sources integrated with the former model. Information Source Format Website National Cancer Institute Thesaurus (NCIT) OWL, OBO ncithesaurus.nci.nih.gov Orphanet Rare Disease Ontology (ORDO) OWL www.ebi.ac.uk/ols/ontologies/ordo Disease Ontology (DO) OWL, OBO disease-ontology.org Mondo Disease Ontology (MONDO) OWL, OBO mondo.monarchinitiative.org Gene Ontology (GO) OWL, OBO, CSV geneontology.org MedGen database CSV www.ncbi.nlm.nih.gov/medgen DisGeNet database RDF, CSV www.disgenet.org Table 2. List of additional biomedical information sources. Table 2. List of additional biomedical information sources. Information Source Format Website Human Phenotype Ontology (HPO) OWL, OBO hpo.jax.org HPO-ORDO Ontological Module (HOOM) OWL bioportal.bioontology.org/ontologies/HOOM Human Protein Atlas (HPA) TSV www.proteinatlas.org Drug–Gene Interaction Database (DGIdb) TSV www.dgidb.org ChEMBL Database RDF, SQL www.ebi.ac.uk/chembl Table 3. The HOOM sub-classes qualifying a disease–phenotype association. Table 3. The HOOM sub-classes qualifying a disease–phenotype association. Class Sub classes Description Frequency Association Obligate The phenotypic abnormality is always present, and the diagnosis cannot be confirmed if it is absent Very Frequent The phenotypic abnormality is present in 80% to 99% of cases Frequent The phenotypic abnormality is present in 30% to 79% of cases Rare The phenotypic abnormality is present in 5% to 29% of cases Very Rare The phenotypic abnormality is present in 1% to 4% of cases Diagnostic Criteria Criterion The phenotypic anomaly is used consensually to establish the clinical diagnosis Exclusion The phenotypic anomaly allows to exclude the diagnosis Pathognomonic The phenotypic anomaly is sufficient to undoubtedly establish the diagnosis Provenance … Each subclass represents a set of scientific articles or expert advice qualifying the association Table 4. The main fields of the HPA Normal Tissue Data Archive . Table 4. The main fields of the HPA Normal Tissue Data Archive . Table 5. The main fields of the DGIdb Interactions Archive . Table 5. The main fields of the DGIdb Interactions Archive . Field Description Example gene-name Gene identifier ( HGNC taxonomy) ITGB5 entrez-id Gene identifier ( NCBI Entrez taxonomy) 3693 drug-name Name of the interacting drug CILENGITIDE drug-concept-id Drug identifier ( ChEMBL taxonomy) CHEMBL429876 interaction-types Types of gene–drug interaction (controlled vocabulary, see Table 6 ) inhibitor interaction-score The strength of the interaction calculated by multiplying the number of sources that report the interaction with its specificity (if the gene or the drug interacts with many other drugs or genes, the interaction specificity is low, otherwise it is high) 9.55 Table 6. Types of drug–gene interactions supported by layer 5. Table 6. Types of drug–gene interactions supported by layer 5. Interaction Type Description activator A drug activates a biological response from a target, although the mechanism by which it does so may not be understood agonist A drug binds to a target receptor and activates the receptor to produce a biological response allosteric modulator Drugs exert their effects on their protein targets via a different binding site than the natural (orthosteric) ligand site antagonist A drug blocks or dampens agonist-mediated responses rather than provoking a biological response itself upon binding to a target receptor antibody An antibody drug specifically binds the target molecule antisense oligonucleotide A complementary RNA drug binds to an mRNA target to inhibit translation by physically obstructing the mRNA translation machinery inducer The drug increases the activity of its target enzyme inhibitor The drug binds to a target and decreases its expression or activity inhibitory allosteric modulator The drug will inhibit activity of its target enzyme inverse agonist A drug binds to the same target as an agonist but induces a pharmacological response opposite to that of the agonist modulator The drug regulates or changes the activity of its target, but it may not involve any direct binding to the target negative modulator The drug negatively regulates the amount or activity of its target, but it may not involve any direct binding to the target partial agonist A drug will elicit a reduced amplitude functional response at its target receptor, as compared to the response elicited by a full agonist positive modulator The drug increases activity of the target enzyme suppressor The drug directly or indirectly affects its target, suppressing a physiological process vaccine The drugs stimulate or restore an immune response to their target Chicago/Turabian Style Capuano, Nicola, Pasquale Foggia, Luca Greco, and Pierluigi Ritrovato. 2022. "A Linked Data Application for Harmonizing Heterogeneous Biomedical Information" Applied Sciences12, no. 18: 9317. https://doi.org/10.3390/app12189317 Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here . Export citation file: BibTeX | EndNote | RIS MDPI and ACS Style Capuano, N.; Foggia, P.; Greco, L.; Ritrovato, P. A Linked Data Application for Harmonizing Heterogeneous Biomedical Information. Appl. Sci. 2022, 12, 9317. https://doi.org/10.3390/app12189317 AMA Style Capuano N, Foggia P, Greco L, Ritrovato P. A Linked Data Application for Harmonizing Heterogeneous Biomedical Information. Applied Sciences. 2022; 12(18):9317. https://doi.org/10.3390/app12189317 Chicago/Turabian Style Capuano, Nicola, Pasquale Foggia, Luca Greco, and Pierluigi Ritrovato. 2022. "A Linked Data Application for Harmonizing Heterogeneous Biomedical Information" Applied Sciences12, no. 18: 9317. https://doi.org/10.3390/app12189317
https://www.mdpi.com/2076-3417/12/18/9317
The Oxford Oratory A sanctuary in the midst of the city The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman. Heart of Jesus, all-holy! Fountain of all blessings, I adore thee, I love thee, and with a lively sorrow for my sins, I offer thee this poor heart of mine. Make me humble, patient, pure, and wholly obedient to thy will. Good Jesus, grant that I may live in thee and for thee. Protect me in the midst of danger; comfort me in my afflictions; give me health of body, assistance in my temporal needs, thy blessing on all that I do, and the grace of a holy death. Amen. #oxfordoratory A photo from Sunday’s Solemn Mass for Corpus Christi. #oxfordoratory June Music Sunday 4 JuneSolemn Mass 11:00The Most Holy TrinityKyrie MundyMissa Euge bone TyeLibera nos SheppardHonor, virtus et potestas Tallis Sunday 11 JuneSolemn Mass 11:00Corpus ChristiMissa Pange lingua JosquinLauda Sion PalestrinaOculi omnium Byrd Friday 16 JuneSolemn Mass 18:00The Most Sacred Heart of JesusMissa Dormendo un giorno GuerreroImproperium PalestrinaSancte Deus Tallis Sunday 18 JuneSolemn Mass 11:0011th Sunday of the YearMissa Brevis in F Op.117 RheinbergerBenedicam Dominum VictoriaSalve Regina Poulenc Wednesday 21 JuneSolemn Mass 18:00St Aloysius GonzagaMissa O quam gloriosum VictoriaJustitiae Domini A ScarlattiO bone Jesu Anchieta Sunday 25 JuneSolemn Mass 11:0012th Sunday of the YearMissa Repleatur os meum PalestrinaPerfice gressus meos LassusHomo quidam fecit coenam magnam Mouton Thursday 29 JuneSolemn Mass 18:00St Peter and St PaulMissa Petre ego pro te rogavi LoboPetre ego pro te rogavi GuerreroJanitor caeli Ortiz The Sacred Heart Love is a funny thing. Materialists will tell us that it is purely the result of a series of electro-chemical responses in the brain, and yet others will tell us that it is the result of fate, the conspiracy of the alignment of the planets or the times we find ourselves in. The heart has long been understood as the centre of a person, a place of knowledge as much as will. It makes us do unreasonable things like acts of unwarranted kindness and altruism and by the edge of its blade we can be hurt in ways that we just can’t speak about. And yet none of these express what love is in itself — only God does that. On Friday we venerate the Heart of our Lord as the symbol of his human love in which God’s divine love is revealed to us. In most of the prayers to or the meditations on the Sacred Heart, even those very ancient prayers, the woundedness of our Lord’s heart comes to the fore. That heart pierced with a lance and bruised with outrages and blasphemies is a stark and realistic image of the extent to which Christ loves us. Christ, who is the image of the unseen God, the Icon of the Father, shows us precisely what God’s love for us looks like. And it looks like a heart pierced and bruised on account of our sins, yet burning with ardent love for you and for me. This divine love is not for softies. The time when we celebrate this feast is very fitting. We have come to the end of the Church’s celebration of the mysteries of our redemption: the Passion, the Cross, the Resurrection, the Ascension, Pentecost, the Feast of the Blessed Trinity and Corpus Christi. But today we commemorate the divine-human love which motivated them all. In adoring the Sacred Heart, we adore the totality of Christ’s saving work — it represents the way in which God holds nothing back from us. And in order to share his divine life with us, he reaches down into the very depths of our life, even — and especially — where it is painful, difficult to speak of, hidden. By taking it all and joining it to himself, he scoops us up, he enables us to become like him. By sharing our life, and by sharing our pains, he heals us, he sanctifies us, and he strengthens us. It is also true that his heart welcomes us precisely so that we might become like it. The whole thrust of our Christian life is that we might be conformed to our Saviour, that we might resemble him, and in this sense, in the life of faith, we should ask ourselves continually whether our heart resembles his. His Sacred Heart is both the example and the cause of our becoming like him. His love is attractive. The more we consider the love with which Jesus acted, and spoke and gave of himself for us, the more we can begin, by his grace, to imitate him — it is truly the school of Christian perfection. And we begin in that school by prayer. When St John Henry Newman, our Cardinal, chose his motto, he looked to St Francis de Sales’ Treatise on the Love of God. The phrase he chose and paraphrased, Cor ad Cor loquiturrepresents for us the central mystery of the prayer that can begin to transform us. St Francis de Sales wrote: Truly the chief exercise in mystical theology is to speak to God and to hear God speak in the bottom of the heart; and because this discourse passes in most secret aspirations and inspirations, we term it a silent conversing. Eyes speak to eyes, and heart to heart, and none understand what passes save those who speak. We may be no great shakes at the spiritual life, or prayer, or we may feel that excelling in virtue is beyond us, but if we can in the simplest of ways open our poor heart to his Sacred Heart, and speak to him as to a friend, if we can entrust our lives to him and ask him devoutly and sincerely to shape us after the model of his Heart, then our Christian life will be all the more graced. The Corpus Christi procession concluded with Benediction at the University Chaplaincy. #oxfordoratory The procession finished at the University’s Catholic Chaplaincy. #oxfordoratory The numbers caught the attention of the local media: https://www.oxfordmail.co.uk/news/23582016.oxfords-catholic-congregations-take-part-corpus-christi-procession/ #oxfordoratory Children scattered flower petals before the Blessed Sacrament all the way. #oxfordoratory Our route now passes through the city in a straight line, taking us directly through the busiest shopping areas. #oxfordoratory The canopy was carried by members of the University of Oxford wearing their academic dress. #oxfordoratory Fr Robert Ombres OP preached a sermon. #oxfordoratory We paused at Blackfriars. #oxfordoratory We were joined by local clergy and religious orders as we processed through the streets to the Dominican Priory at Blackfriars. #oxfordoratory The processions sets off… #oxfordoratory We had record numbers for the procession this year. There wasn’t space in church for everyone at the beginning! There were more people outside too. #oxfordoratory The beginning of our Corpus Christi procession last Sunday.#oxfordoratory The Oratory Prayer Book is now shipping internationally! We’ve made it even easier to buy the Oratory Prayer Book from anywhere in the world. And we’ve made it easier to order multiple copies too — in the UK and worldwide. Order your copy here:https://tinyurl.com/opb-buy If you have one, we’d love to hear what you think about it. Let us know in the comments, or tag a photo of your prayer book in the wild with #oratoryprayerbook Thanks to @acatholicinoxford for the photo. #oxfordoratory Worship What does it actually mean to worship God? In the New Testament, the word we most often translate as ‘worship’ doesn’t mean to reverence another in some abstract sense. It always involves some kind of bodily action. When we think about the magi visiting the Holy Family, we sometimes convey this motion by describing them — after they fall to their knees — as ‘doing homage’. But it’s actually that same word here we might translate elsewhere as ‘worship’. It’s just that we recognise the need to describe the bodily sign of their submission and adoration of the new born King with something that sounds a bit more physical. The word we usually translate as ‘worship’ ( proskuneo) comes literally from a root meaning ‘to make yourself like a dog before the other person’. It originally meant prostrating yourself on the floor to show your humble submission before another. By the time of the New Testament, people wouldn’t necessarily have had the root of this word in mind whenever they used it,* but the word still carries with it the idea of doing something with your body to express your worship. The feast of Corpus Christi is all about this kind of bodily worship. It’s tied to the fact that we are not pure spirits, but that we are human beings, body and soul. To worship God is not just a spiritual act. The right worship of God does not consist in simply having the right kinds of thoughts towards him. But the worship of God involves the humble submission of our entire human being, body and soul, before the God who is greater than all of us. And ever since the Incarnation, we do this not just before an abstract spirit. Because, from the moment of the Incarnation, God really does have a human body, that we can worship, that we fall down on our knees before, like the magi and the Canaanite woman, and so many others in the Gospel who kneel down and worship Christ. When we worship God, we kneel before God who is present in the flesh, under the appearances of bread and wine, in our churches all over the world. Corpus Christi is a joyful celebration of Christ’s presence among us, and it gives us an opportunity to think about how we respond to that gift. All this talk of kneeling and worship might not sound so joyful, but one of the great paradoxes of Christianity is that we find our greatest freedom in the humble service of God. Our greatest joy really should be found in finding ways to express this loving worship. So at least once a year, it is no bad thing to think about how we express with our own bodies that worship of God’s body, and what ways we can find to worship him even more perfectly. This Sunday, we will carry Christ’s Body through the streets of our city. We have a chance to demonstrate to the world our love, our joyful service, our worship of him, through our presence. The procession leaves our church at 2:30pm. Make sure you are there. But we should also think about the more ordinary things, like making sure we show that worship whenever we are in his presence. We should show through our behaviour in church that we believe him to be there: by genuflecting before him in the tabernacle of the church, and by keeping the church quiet and prayerful. We show our worship above all by kneeling down before him — like all those people in the Gospel — for the moment of Holy Communion. And we allow the priest to place the Host on our tongues, so that we don’t handle unnecessarily what is holy and precious, and no particles of Our Lord’s Body are ever dropped or lost through carelessness. We continue that worship in our prayers of thanksgiving after Communion and once the Mass has ended. We certainly never leave church during Communion. And we might think of ways of extending the time we spend with Christ present in the Blessed Sacrament: by attending Mass during the week sometimes, or visiting him during the times each week when his Body is exposed solemnly on the altar for Adoration, or even just by visiting an empty church, where he is waiting for us to show him our worship. Our Lord is hidden there, waiting for us to come and visit him, and make our request to him. See how good he is! He is there in the Sacrament of his love, sighing and interceding incessantly with his Father for sinners. To what outrages does he not expose himself, that he may remain in the midst of us! He is there to console us; and therefore we ought often to visit him. How pleasing to him is the short quarter of an hour that we steal from our occupations, from something of no use, to come and pray to him, to visit him, to console him for all the outrages he receives! When he sees pure souls coming eagerly to him, he smiles upon them. They come with that simplicity which pleases him so much, to ask his pardon for all sinners, for the outrages of so many ungrateful men. What happiness do we not feel in the presence of God, when we find ourselves alone at his feet before the holy tabernacles! ‘Come, my soul, redouble thy fervour; thou art alone adoring thy God. His eyes rest upon thee alone.’ — St John Mary Vianney * One exception is that I do think Christ had this root meaning in mind when he spoke to the Canaanite woman in Matthew 15:21–28. He wasn’t randomly insulting her by comparing her to a dog, but drawing attention to the fact that she was making herself like a dog before him — i.e. worshipping him — because she recognised him to be God. In other words, he was acknowledging her worship as proof of her faith and humility. On Saturday, Fr Rupert led Men’s Oratory on a walking pilgrimage to Islip, birthplace of St Edward the Confessor. #oxfordoratory Congratulations to Elizabeth who was received into the Church yesterday evening on the Feast of the Visitation. #oxfordoratory
https://www.oxfordoratory.org.uk/tour/blog/post/9981-9981/blog/post/10006-10006/getting-here.php
JCM | Free Full-Text | Combining HAIC and Sorafenib as a Salvage Treatment for Patients with Treatment-Failed or Advanced Hepatocellular Carcinoma: A Single-Center Experience Background: Hepatic arterial infusion chemotherapy (HAIC) has been proven to be an effective treatment for advanced HCC. In this study, we present our single-center experience of implementing combined sorafenib and HAIC treatment for these patients and compare the treatment benefit with that of sorafenib alone. Methods: This was a retrospective single-center study. Our study included 71 patients who started taking sorafenib between 2019 and 2020 at Changhua Christian Hospital in order to treat advanced HCC or as a salvage treatment after the failure of a previous treatment for HCC. Of these patients, 40 received combined HAIC and sorafenib treatment. The efficacy of sorafenib alone or in combination with HAIC was measured in regard to overall survival and progression-free survival. Multivariate regression analysis was performed to identify factors associated with overall survival and progression-free survival. Results: HAIC combined with sorafenib treatment and sorafenib alone resulted in different outcomes. The combination treatment resulted in a better image response and objective response rate. Moreover, among the patients aged under 65 years old and male patients, the combination therapy resulted in a better progression-free survival than sorafenib alone. A tumor size ≥ 3 cm, AFP > 400, and ascites were associated with a poor progression-free survival among young patients. However, the overall survival of these two groups showed no significant difference. Conclusions: Combined HAIC and sorafenib treatment showed a treatment effect equivalent to that of sorafenib alone as a salvage treatment modality used to treat patients with advanced HCC or with experience of a previously failed treatment. Combining HAIC and Sorafenib as a Salvage Treatment for Patients with Treatment-Failed or Advanced Hepatocellular Carcinoma: A Single-Center Experience by Chia-Bang Chen 1,* , Chun-Min Chen 2 , Ruo-Han Tzeng 3 , Chen-Te Chou 1 , Pei-Yuan Su 4 , You-Chuen Hsu 4 and Cheng-Da Yang 4 1 Department of Medical Imaging, Changhua Christian Hospital, Changhua 500, Taiwan 2 Big Data Center, Changhua Christian Hospital, Changhua 500, Taiwan 3 Department of Hematology, Changhua Christian Hospital, Changhua 500, Taiwan 4 Division of Gastroenterology & Hepatology, Changhua Christian Hospital, Changhua 500, Taiwan * Author to whom correspondence should be addressed. J. Clin. Med. 2023 , 12 (5), 1887; https://doi.org/10.3390/jcm12051887 Received: 11 January 2023 / Revised: 15 February 2023 / Accepted: 24 February 2023 / Published: 27 February 2023 (This article belongs to the Special Issue Gastrointestinal Malignancies: Screening, Diagnosis, and Treatment: Part II ) Background: Hepatic arterial infusion chemotherapy (HAIC) has been proven to be an effective treatment for advanced HCC. In this study, we present our single-center experience of implementing combined sorafenib and HAIC treatment for these patients and compare the treatment benefit with that of sorafenib alone. Methods: This was a retrospective single-center study. Our study included 71 patients who started taking sorafenib between 2019 and 2020 at Changhua Christian Hospital in order to treat advanced HCC or as a salvage treatment after the failure of a previous treatment for HCC. Of these patients, 40 received combined HAIC and sorafenib treatment. The efficacy of sorafenib alone or in combination with HAIC was measured in regard to overall survival and progression-free survival. Multivariate regression analysis was performed to identify factors associated with overall survival and progression-free survival. Results: HAIC combined with sorafenib treatment and sorafenib alone resulted in different outcomes. The combination treatment resulted in a better image response and objective response rate. Moreover, among the patients aged under 65 years old and male patients, the combination therapy resulted in a better progression-free survival than sorafenib alone. A tumor size ≥ 3 cm, AFP > 400, and ascites were associated with a poor progression-free survival among young patients. However, the overall survival of these two groups showed no significant difference. Conclusions: Combined HAIC and sorafenib treatment showed a treatment effect equivalent to that of sorafenib alone as a salvage treatment modality used to treat patients with advanced HCC or with experience of a previously failed treatment. Keywords: hepatocellular carcinoma ; hepatic arterial infusion chemotherapy ; sorafenib 1. Introduction The poor prognosis of hepatocellular carcinoma (HCC) is a global health concern [ 1 ]. A total of 840,000 new cases of liver cancer and 780,000 related deaths were reported in 2018 [ 2 ], and it was estimated that more than 1 million people are affected by HCC annually by 2025 [ 3 ]. As screening for HCC has become more prevalent in recent years, HCC can be diagnosed in its early stage more frequently, and patients with early HCC can be treated with curative methods such as surgical resection, liver transplantation, or radiofrequency ablation (RFA). Trans-arterial chemoembolization (TACE) or Yttrium-90 radioembolization is the proper treatment for patients who cannot undergo these curative procedures due to their advanced tumor stage, poor liver function, or inadequate liver reserve [ 4 , 5 ]. Alternatively, if the tumor has invaded the major vascular system or if previous treatment has failed, only limited treatment modalities are available, including systemic chemotherapy, targeted therapy, or hepatic arterial infusion chemotherapy (HAIC) [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. According to several guidelines from Japan, Europe, and the United States, the first-line treatment for patients with advanced or treatment-failed HCC is sorafenib [ 11 ]. In addition to sorafenib, HAIC can also be applied. Through the direct delivery of chemotherapy agents into the hepatic tumor-feeding vessels, an increased local chemotherapy drug concentration and reduced systemic toxicity can be achieved [ 12 ], and several studies have shown HAIC to be effective in improving the treatment response and survival. Traditionally, HAIC has been carried out through the implantation of a chemoport. A modification of HAIC was presented by Tsai [ 13 ], who used an angiographic catheter inserted into the left subclavian artery to deliver the chemotherapy drug without a chemoport. The HAIC procedure implemented at our hospital was further modified based on catheter insertion through the left brachial arterial approach, together with the use of sorafenib during the outpatient department follow-up. Previous clinical trials have shown that the addition of HAIC to sorafenib is equally effective as compared to sorafenib therapy alone in terms of overall survival (OS) [ 14 ]. In this study, we compared the OS and progression-free survival (PFS) of patients with advanced or treatment-failed HCC receiving either a combination of HAIC and sorafenib or sorafenib alone and attempted to identify the possible prognostic factors. 2. Methods 2.1. Study Design and Patient Selection All patients included in the study were affected by advanced or treatment-failed HCC and received sorafenib and/or HAIC treatment between January 2019 and May 2020 at the Changhua Christian Hospital. The inclusion criteria for HAIC were as follows: (1) patients with advanced HCC who were ineligible for surgical resection, RFA, or TACE; (2) patients who had experienced previous treatment for HCC with progressive disease; (3) patients with an adequate liver reserve and serum bilirubin levels < 2 mg/dL; (4) patients without extra-hepatic metastases; (5) patients with ECOG 0 or 1; and (6) patients aged > 20 years old. The exclusion criteria included (1) patients with decompensated hepatic failure and serum total bilirubin levels > 2 mg/dL; (2) patients with extra-hepatic metastases; and (3) patients with an active inflammatory or infections process and a serum white blood cell count > 10,000/μL. In total, 75 patients with advanced HCC were enrolled, including 44 patients in the combination group and 31 patients taking sorafenib alone. However, four patients in the combination group were lost to follow-up after the first course of HAIC, and these four patients were excluded. Finally, 71 patients were enrolled in this study, including 40 patients in the combination group and 31 patients receiving sorafenib alone. Data were retrospective collected and analyzed, including age, sex, previous treatments, and laboratory test results including albumin, bilirubin, the Child–Pugh score (CPS), the albumin-bilirubin (ALBI) grade, and alpha-fetoprotein (AFP) before and after procedures. The characteristics of the tumors, including the size, T-stage, vascularity, Barcelona clinic liver cancer (BCLC) stage (0: very early stage; A: early stage; B: intermediate stage; C: Advanced stage; D: any kind of tumor burden), and portal vein tumor thrombus classification according to the liver cancer study group of Japan (PVTT), were recorded after reviewing the CT or MRI and angiography images. The clinical course and 1-year survival rates of all the patients were retrospectively analyzed. 2.2. Treatment Protocol Regarding the HAIC procedure, after the patient was hospitalized and transferred to the angiosuite, sonography of the left subclavian or brachial artery was performed to assess the patency of these vessels. For the 40 patients included in the combination group, the left subclavian arterial was accessed for the 9 starting patients, and the left brachial artery was accessed for the following 31 patients. After puncturing the target artery under sonographic guidance using a micro-puncture set (Cook Medical LLC, Birmingham, UK), a 0.035 inch guidewire and a 4 Fr. Mariner Cobra 1 catheter (Angiodynamics, Latham, NY, USA) were inserted. Angiography of the celiac trunk and the superior mesenteric artery was performed. Embolization of the gastroduodenal artery was routinely performed using metallic coils. In cases of any vascular branch arising from the proper hepatic artery so as to supply the stomach or duodenum, embolization was also performed on these vessels, and if necessary, a microcatheter (1,98Fr. Parkway Soft, Asahi, Japan) was used. However, if these vessels could not be accessed, the catheter tip was located at least 2 cm distal to these vascular branches so as to avoid gastroduodenal injury caused by chemotherapy. Intra-arterial chemotherapy lasted for 5 days, and the regimen included the following: Cisplatin (10 mg/m 2 ) and mitomycin-C (2 mg/m 2 ) dissolved in 50 mL of isotonic sodium chloride solution, infused for 20–30 min each and continued for 5 days; 100 mg/m 2 of 5-fluorouracil (5-FU) dissolved in 250 mL of isotonic sodium chloride solution, administered for 24 h using an infusion pump for 5 days; Leucovorin (15 mg/m 2 ) every day. After completion of the 5 days of chemotherapy, 10 mL of lipiodol (Guerbet, Paris, France) was delivered through the catheter for tumoral embolization, followed by the removal of the catheter and manual compressions of the puncture site for hemostasis for 20 min. The patient was discharged after 6 h of observation in the ward. The next course of HAIC was initiated after 4 to 6 weeks, according to the patient’s condition and will. Sorafenib was administered 7 days after discharge and discontinued 7 days before the next HAIC course. A dose reduction or discontinuation of sorafenib was performed according to the clinician’s decision. Computed tomography (CT) or magnetic resonance imaging (MRI) evaluation was performed after one or two cycles of HAIC or every 3–6 months. 2.3. Response and Definitions The response was defined according to the mRECIST criteria as follows: (1) complete response (CR), indicating the disappearance of any intratumoral arterial enhancement in all the target lesions; (2) partial response (PR), marked by a decrease of at least 30% in the sum of the diameters of the target lesions; (3) progressive disease (PD), marked by an increase of at least 20% in the sum of the diameters of the viable target lesions; and (4) stable disease (SD) or any case that did not qualify for either PR or PD [ 15 ]. If CR was achieved, if PD was observed in the following image evaluation, or if the HAIC treatment was not favored by the patients, no further HAIC was arranged, and only sorafenib was prescribed at follow-up in the outpatient department. If SD or PR was achieved, another course of HAIC was arranged and performed for further treatment. 2.4. Follow-Up and Data Collection Based on a standardized outcome protocol, we conducted a retrospective chart review. The demographics, treatment procedures, and outcomes of patients were collected. All causes of mortality were considered in this study. The primary outcome includes overall survival (OS), which was the primary endpoint and was defined as therapy time from the assignment of therapy to death. From the assignment of treatment to the development of disease progression or death from any cause, progression-free survival (PFS) was calculated. A regular outpatient evaluation was conducted after patients were discharged. A chart review and three-monthly evaluations were conducted in the first year after treatment. 2.5. Statistical Analysis Statistical analysis was performed using the Statistical Package for the Social Sciences software version 22 (IBM Corporation, Armonk, NY, USA). A chi-square test was performed to demonstrate differences in the baseline characteristics. For continuous variables, the Mann–Whitney U test was used to compare the groups. The 12-month survival rate was estimated using the Kaplan–Meier method with right censoring at the 12-month mark, and the survival outcomes of the groups were compared by the log-rank test. Cox proportional hazards models were used to calculate the OS and PFS. Multivariate Cox regression analysis was performed to determine the prognostic factors for the survival outcomes and to calculate the hazards ratios (HR). The tumor response to treatment was evaluated using the chi-square test. Multivariate analyses of factors that influenced survival were conducted using the Cox proportional hazards model. Statistical significance was defined as a two-sided p -value < 0.05. 3. Results 3.1. Patient Characteristics The basic characteristics of the enrolled patients are summarized in Table 1 . A total of 71 patients were enrolled in our study. These 71 patients had a median age of 66 years (ranging from 42 to 85). Male predominance was observed in both groups. More than 65% of the patients in the combination group had tumors of T-stages 3–4; however, 65% of the sorafenib group had T-stages 1–2. There were also significant differences in the BCLC stages and VP scores of these two groups. The patients in the HAIC group had more advanced HCC than the other group. There were no significant differences in age, prior HCC treatment (TACE/surgery), ascites, the Child–Pugh score, preoperative AFP, albumin, bilirubin, the ALBI score, or the tumor size. 3.2. Responses of the Combination and Sorafenib Groups The responses of the combination and sorafenib groups are detailed in Table 2 . The median PFS tended to be longer in the combination group than the sorafenib group (6 vs. 4 months), but the difference was not statistically significant ( p = 0.106). The median OS (12 months) was similar in both groups. In the combination group, 14 (35%), 15 (38%), 6 (15%), and 5 (13%) patients exhibited CR, PR, SD, and PD. However, in the sorafenib group, a relatively poor response was noted, with 4 (13%), 6 (19%), 5 (16%), and 16 (52%) patients exhibiting CR, PR, SD, and PD. The objective response rate was significantly higher in the combination group than in the sorafenib group (73% vs. 32%, p = 0.001). Considering a reduction in AFP as an indicator of response to treatment, 40% of patients in the combination group showed reductions in AFP, but a reduction in AFP only occurred in 13% of patients in the sorafenib group. Among the patients who had AFP > 20 ng/mL before treatment, more than half in the combination group showed AFP reduction, but this only occurred in a quarter of those in the sorafenib group, indicating a better treatment response in the combination group. 3.3. Hazard Rate over One Year Approximately 93% of progressions and 84–93% of deaths occurred within 9 months after treatment in both groups. The maximum risk of death and progression increased at 6 months, while the risk decreased at 9 months. Compared to the sorafenib group, the combination group had a lower mortality rate (6%) and disease progression rate at 3 months (24%) as well as a lower disease progression rate at 9 months (17%) ( Figure 1 ). 3.4. Survival Outcomes During the first year after treatment, 18 patients in the combination group and 14 patients in the sorafenib group died, while 29 patients in the combination group and 28 patients in the sorafenib group had progressive disease. Kaplan–Meier curves showed that the entire population who received combination treatment had better OS and PFS than the sorafenib group, but no significant statistical difference could be found ( p = 0.779 in OS and p = 0.075 in PFS) ( Figure 2 ). Stratified analysis was performed according to age ( Figure 3 ) and gender ( Figure 4 ). Compared to the sorafenib group, the combination treatment was associated with better PFS among those patients less than 65 years in age ( p = 0.023 in Figure 3 C) and also among the male patients ( p = 0.045 in Figure 4 D). In patients aged < 65, the median PFS was 7.0 months in the combination group, which was better than the 4.0 months observed in the sorafenib group. Moreover, among the male patients, a longer median PFS was observed in the combination group (6 vs. 3 months) compared to the sorafenib group. 3.5. Multivariate Analysis of Tumoral Progression A subgroup prognostic analysis of all the clinical variables was performed using the Cox proportional hazards model. The results of the multivariate analysis are listed in Table 3 (Model A–B). In Model A, for all patients aged under 65 years, combination treatment (HR = 0.08, 95% CI: 0.02–0.35; p = 0.001), preoperative AFP > 400 ng/mL (HR = 5.21, 95% CI: 1.13–23.99; p = 0.034), and a tumor size ≥ 3 cm (HR = 6.81, 95% CI: 1.35–34.25; p = 0.020) were prognostic predictors of PFS. In Model B, the survival analysis showed that combination treatment (HR = 0.29, 95% CI: 0.11–0.71; p = 0.007), an age ≥ 65 (HR = 2.71, 95% CI: 1.33–5.51; p = 0.006), and ascites (HR = 4.31, 95% CI: 1.43–13.01; p = 0.009) were significant predictors of PFS among male patients. In conclusion, the adjuvant treatment group showed a significant negative relationship with tumor progression in the subgroups analysis. 4. Discussion In this study, we retrospectively evaluated the treatment benefits of combined HAIC-sorafenib and sorafenib alone for patients with advanced HCC or for whom previous treatments failed. Several studies have investigated the effects of sorafenib in combination with other treatments including HAIC [ 6 , 7 , 10 , 14 ], TACE [ 8 ], chemotherapy [ 9 ], and other molecular targeting agents [ 16 ]. In Taiwan, sorafenib therapy is the most common treatment modality for these patients due to the fact that its payment is fully covered by national health insurance. Our study revealed the combination treatment results in a better response in the image follow-up and a better objective response rate. The OS and PFS appeared to be better in patients receiving the combination treatment, but there was no significant statistical difference between the two groups. In the multivariate analysis, we observed that male patients who were under 65 years old with tumor sizes < 3 cm and a lower preoperative AFP level (<400 ng/mL) who were treated with combination therapy but were without ascites had a significantly better PFS. There have been several studies discussing the treatment effects of HIAC or HAIC combined with sorafenib for HCC patients [ 5 , 6 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 16 , 17 ]. Most showed promising treatment effects of HIAC, with a median OS ranging from 10.1 to 17.1 months compared to sorafenib alone and with a median OS ranging from 6.5 to 10.7 months. Moreover, in patients affected by macroscopic vascular invasion of HCC, HAIC could provide a much better OS than sorafenib alone [ 10 , 17 ]. In our study, patients in the combination group had a more advanced tumor status and more tumors with macrovascular invasion, and combining HAIC with sorafenib as a salvage treatment could provide an OS of approximately 12 months, which is compatible with the results in the literature. Recent studies have identified AFP as an important independent risk predictor associated with the pathological grade, progression, and survival risk [ 18 ]. Our results showed that patients with AFP > 400 ng/mL had a poorer prognosis than those with AFP < 20 or between 20 and 400 ng/mL. In addition to the serum AFP level, the tumor size is also an indicator of prognosis. A previous study showed that a tumor size ≥ 5 cm was associated with early recurrence and poor overall survival in patients with solitary HCC [ 19 ]. Our study showed that hazard ratios for a poor PFS sharply increased in patients with tumor sizes larger than 3 cm. For patients with larger tumors, aggressive treatment and close follow-up for the identification of early recurrence and possible metastases should be considered. A gender disparity affecting the prognosis after treatment was noted in our study. It was previously demonstrated that male patients are affected HCC more frequently than females [ 20 , 21 ], which was also noted in our study. Moreover, after curative hepatectomy, a higher early recurrence rate was observed in males compared to females [ 21 ], and a longer survival was observed in females with HCC than in males [ 22 ]. However, our results showed that male patients had a better PFS after receiving combined HAIC and sorafenib treatment, which is not consistent with results in the literature. More studies and larger study populations are required to identify the potential influence of gender on HCC. Patients with ascites are at risk of developing complications and have high mortality. Of the 71 patients in our study, ascites developed in 7 during follow-up. In the multivariant analysis, ascites was considered as a prognostic factor with a hazard ratio of approximately 4.31, indicating a poor prognosis. Our study had some limitations. Firstly, the sample size was small since our investigation was a single-center study. Secondly, this study was carried out retrospectively, and selection bias could not be avoided. Additional research is therefore needed, including a validation study with a larger sample size or even a multi-center prospective study. 5. Conclusions In conclusion, our study revealed that as a salvage treatment modality for patients with advanced HCC or those who underwent a previously failed treatment, combined HAIC and sorafenib treatment, showed equivalent treatment effects to sorafenib alone. Our findings support the prognostic impacts of the baseline tumor size, AFP, and ascites as important factors to consider in trial design. The current analyses also suggest that young male patients aged < 65 years old may benefit more from this combination treatment. Author Contributions Conceptualization, C.-B.C.; Methodology, C.-B.C.; Software, C.-M.C.; Formal analysis, C.-M.C.; Resources, R.-H.T., C.-T.C., P.-Y.S., Y.-C.H. and C.-D.Y.; Data curation, C.-B.C., R.-H.T., C.-T.C., P.-Y.S., Y.-C.H. and C.-D.Y.; Writing—original draft, C.-B.C.; Writing—review & editing, C.-M.C. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Institutional Review Board Statement The study protocol was approved by the Institutional Review Board of Changhua Christian Hospital (IRB number: 210620) and conformed with the principles of the Declaration of Helsinki. Informed Consent Statement The requirement to obtain informed consent from patients was waived due to the retrospective nature of the study. Data Availability Statement Data supporting the findings of this study are available from Changhua Christian Hospital. Restrictions apply to the availability of these data, which were used under license in this study. The data are, however, available from the authors upon request and with permission from Changhua Christian Hospital. Conflicts of Interest The authors declare that they have no conflict of interest. References Akinyemiju, T.; Abera, S.; Ahmed, M.; Alam, N.; Alemayohu, M.A.; Allen, C.; Al-Raddadi, R.; Alvis-Guzman, N.; Amoako, Y.; Artaman, A.; et al. The Burden of Primary Liver Cancer and Underlying Etiologies from 1990 to 2015 at the Global, Regional, and National Level: Results from the Global Burden of Disease Study 2015. JAMA Oncol. 2017 , 3 , 1683–1691. [ Google Scholar ] [ PubMed ] Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018 , 68 , 394–424. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Philips, C.A.; Rajesh, S.; Nair, D.C.; Ahamed, R.; Abduljaleel, J.K.; Augustine, P. Hepatocellular Carcinoma in 2021: An Exhaustive Update. Cureus 2021 , 13 , e19274. [ Google Scholar ] [ CrossRef ] [ PubMed ] Yi, Y.; Tongguo, S. Yttrium-90 transarterial radioembolization versus conventional transarterial chemoembolization for patients with hepatocellular carcinoma: A systematic review and meta-analysis. Cancer Biol. Med. 2018 , 15 , 299–310. [ Google Scholar ] [ CrossRef ] Samant, H.; Amiri, H.S.; Zibari, G.B. Addressing the worldwide hepatocellular carcinoma: Epidemiology, prevention and management. J. Gastrointest. Oncol. 2021 , 12 (Suppl. 2), S361–S373. [ Google Scholar ] [ CrossRef ] Ikuta, S.; Aihara, T.; Yamanaka, N. Efficacy of sequential sorafenib plus hepatic arterial infusion chemotherapy in patients with Barcelona Clinic Liver Cancer stage B and C hepatocellular carcinoma: A retrospective single-institution study. Contemp. Oncol. Pozn. 2018 , 22 , 165–171. [ Google Scholar ] [ CrossRef ] Zhuang, B.-W.; Li, W.; Xie, X.-H.; Hu, H.-T.; Lu, M.-D.; Xie, X.-Y. Sorafenib versus hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: A systematic review and meta-analysis. Jpn. J. Clin. Oncol. 2019 , 49 , 845–855. [ Google Scholar ] [ CrossRef ] Kimura, Y.; Kaneko, R.; Yano, Y.; Kamada, K.; Ikehara, T.; Nagai, H.; Sato, Y.; Igarashi, Y. The Prognosis of Hepatocellular Carcinoma Treated with Sorafenib in Combination with TACE. Asian Pac. J. Cancer Prev. 2020 , 21 , 1797–1805. [ Google Scholar ] [ CrossRef ] Abou-Alfa, G.K.; Shi, Q.; Knox, J.J.; Kaubisch, A.; Niedzwiecki, D.; Posey, J.; Tan, B.R., Jr.; Kavan, P.; Goel, R.; Lammers, P.E.; et al. Assessment of Treatment with Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients with Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial. JAMA Oncol. 2019 , 5 , 1582–1588. [ Google Scholar ] [ CrossRef ] Zheng, K.; Zhu, X.; Fu, S.; Cao, G.; Li, W.-Q.; Xu, L.; Chen, H.; Wu, D.; Yang, R.; Wang, K.; et al. Sorafenib Plus Hepatic Arterial Infusion Chemotherapy versus Sorafenib for Hepatocellular Carcinoma with Major Portal Vein Tumor Thrombosis: A Randomized Trial. Radiology 2022 , 303 , 455–464. [ Google Scholar ] [ CrossRef ] Saeki, I.; Yamasaki, T.; Maeda, M.; Hisanaga, T.; Iwamoto, T.; Fujisawa, K.; Matsumoto, T.; Hidaka, I.; Marumoto, Y.; Ishikawa, T.; et al. Treatment strategies for advanced hepatocellular carcinoma: Sorafenib vs hepatic arterial infusion chemotherapy. World J. Hepatol. 2018 , 10 , 571–584. [ Google Scholar ] [ CrossRef ] [ PubMed ] Song, M.J. Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma. World J. Gastroenterol. 2015 , 21 , 3843–3849. [ Google Scholar ] [ CrossRef ] [ PubMed ] Tsai, W.-L.; Lai, K.-H.; Liang, H.-L.; Hsu, P.-I.; Chan, H.-H.; Chen, W.-C.; Yu, H.-C.; Tsay, F.-W.; Wang, H.-M.; Tsai, H.-C.; et al. Hepatic Arterial Infusion Chemotherapy for Patients with Huge Unresectable Hepatocellular Carcinoma. PLoS ONE 2014 , 9 , e92784. [ Google Scholar ] [ CrossRef ] Kudo, M.; Ueshima, K.; Yokosuka, O.; Ogasawara, S.; Obi, S.; Izumi, N.; Aikata, H.; Nagano, H.; Hatano, E.; Sasaki, Y.; et al. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): A randomised, open label, phase 3 trial. Lancet Gastroenterol. Hepatol. 2018 , 3 , 424–432. [ Google Scholar ] [ CrossRef ] [ PubMed ] Lencioni, R.; Llovet, J.M. Modified RECIST (mRECIST) Assessment for Hepatocellular Carcinoma. Semin. Liver Dis. 2010 , 30 , 52–60. [ Google Scholar ] [ CrossRef ][ Green Version ] Niu, M.; Yi, M.; Li, N.; Wu, K.; Wu, K. Advances of Targeted Therapy for Hepatocellular Carcinoma. Front. Oncol. 2021 , 11. [ Google Scholar ] [ CrossRef ] Kodama, K.; Kawaoka, T.; Aikata, H.; Uchikawa, S.; Inagaki, Y.; Hatooka, M.; Morio, K.; Nakahara, T.; Murakami, E.; Tsuge, M.; et al. Comparison of clinical outcome of hepatic arterial infusion chemotherapy and sorafenib for advanced hepatocellular carcinoma according to macrovascular invasion and transcatheter arterial chemoembolization refractory status. J. Gastroenterol. Hepatol. 2018 , 33 , 1780–1786. [ Google Scholar ] [ CrossRef ] Lee, W.-C. Value of alpha-fetoprotein in hepatocellular carcinoma. Transl. Gastroenterol. Hepatol. 2021 , 6 , 52. [ Google Scholar ] [ CrossRef ] Liang, B.-Y.; Gu, J.; Xiong, M.; Zhang, E.-L.; Zhang, Z.-Y.; Chen, X.-P.; Huang, Z.-Y. Tumor size may influence the prognosis of solitary hepatocellular carcinoma patients with cirrhosis and without macrovascular invasion after hepatectomy. Sci. Rep. 2021 , 11 , 16343. [ Google Scholar ] [ CrossRef ] Greten, T.F. Gender disparity in HCC: Is it the fat and not the sex? J. Exp. Med. 2019 , 216 , 1014–1015. [ Google Scholar ] [ CrossRef ] Liang, T.; He, Y.; Mo, S.; Chen, Z.; Liao, X.; Zhou, X.; Yang, C.; Zhao, S.; Han, C.; Zhu, G.; et al. Gender disparity in hepatocellular carcinoma recurrence after curative hepatectomy. Ann. Hepatol. 2022 , 27 , 100695. [ Google Scholar ] [ CrossRef ] [ PubMed ] Liao, C.-Y.; Lee, C.-Y.; Wei, C.-Y.; Chao, Y.; Huang, Y.-H.; Hou, M.-C.; Su, Y.-H.; Wu, J.-C.; Su, C.-W. Differential prognoses among male and female patients with hepatocellular carcinoma. J. Chin. Med. Assoc. 2022 , 85 , 554–565. [ Google Scholar ] [ CrossRef ] [ PubMed ] Figure 1. Percentages of death ( A ) and progression ( B ) by treatment strategy at 3 M, 6 M, 9 M, and 12 M (M, months). Figure 1. Percentages of death ( A ) and progression ( B ) by treatment strategy at 3 M, 6 M, 9 M, and 12 M (M, months). Figure 2. Kaplan–Meier survival analysis according to different treatments (HAIC-sorafenib versus sorafenib alone) for patients with HCC: ( A ) OS and ( B ) PFS. Blue, sorafenib with HAIC; red, sorafenib alone. HAIC, hepatic arterial infusion chemotherapy. Although the survival curves show a better OS and PFS in the combination group than in the sorafenib group, the log-rank test indicates no significant statistical difference between the survival curves. Figure 3. Kaplan–Meier survival analysis according to different treatments (HAIC-sorafenib versus sorafenib alone) for patients of different age groups: ( A , B ) OS and ( C , D ) PFS. Among those younger than 65 years, the survival curves show a better OS and PFS in the combination group ( A , C ), and the log-rank test indicates a significant difference in PFS ( p = 0.023 in ( C )). Among those aged 65 and older, the log-rank test shows no significant differences between the survival curves ( B , D ). Figure 3. Kaplan–Meier survival analysis according to different treatments (HAIC-sorafenib versus sorafenib alone) for patients of different age groups: ( A , B ) OS and ( C , D ) PFS. Among those younger than 65 years, the survival curves show a better OS and PFS in the combination group ( A , C ), and the log-rank test indicates a significant difference in PFS ( p = 0.023 in ( C )). Among those aged 65 and older, the log-rank test shows no significant differences between the survival curves ( B , D ). Figure 4. Kaplan–Meier survival analysis according to different treatments (HAIC-sorafenib versus sorafenib alone) for patients of different genders: ( A , B ) OS and ( C , D ) PFS. The log-rank test indicates no significant differences between the survival curves for females ( A , C ). For male patients, the survival curve shows a better OS and PFS ( B , D ), and a significant difference was noted in PFS ( p = 0.045 in ( D )) according to the log-rank test. Figure 4. Kaplan–Meier survival analysis according to different treatments (HAIC-sorafenib versus sorafenib alone) for patients of different genders: ( A , B ) OS and ( C , D ) PFS. The log-rank test indicates no significant differences between the survival curves for females ( A , C ). For male patients, the survival curve shows a better OS and PFS ( B , D ), and a significant difference was noted in PFS ( p = 0.045 in ( D )) according to the log-rank test. Table 1. Patient characteristics. Table 1. Patient characteristics. HAIC-Sorafenib ( n = 40) Sorafenib ( n = 31) n % n % p -Value Age Aged < 65 21 53% 11 35% 0.153 Aged ≥ 65 19 48% 20 65% Gender Female 6 15% 11 35% 0.045 Male 34 85% 20 65% Prior treatment Without 6 15% 4 13% 0.801 With 34 85% 27 87% T-stage 1 0 0% 7 23% 0.002 2 14 35% 13 42% 3–4 26 65% 11 35% Ascites Absence 34 85% 30 97% 0.099 Presence 6 15% 1 3% Child Pugh Score A5 26 65% 20 65% 0.631 A6 9 23% 8 26% B7 3 8% 3 10% B8 2 5% 0 0% BCLC Stage A (early stage) 0 0% 7 23% <0.001 B (intermediate stage) 23 58% 13 42% C (advanced stage) 17 42% 11 35% PVTT stage 0 23 58% 26 84% 0.044 1–2 6 15% 1 3 3 5 12% 1 3 4 6 15% 3 10 Preoperative AFP <20 (ng/mL) 12 30% 15 48% 0.136 20–400 (ng/mL) 12 30% 10 32% >400 (ng/mL) 16 40% 6 19% Albumin ≤3.5 g/dL 11 28% 13 42% 0.202 >3.5 g/dL 29 73% 18 58% Bilirubin ≥1 mg/dL 13 33% 8 26% 0.540 <1 mg/dL 27 68% 23 74% ALBI score Mean ± SD −2.41 ± 0.4 −2.36 ± 0.46 0.643 Grade 1 (<−2.6) 13 32% 9 29% Grade 2 (−1.39 to −2.6) 27 68% 22 71% Grade 3 (>−1.39) 0 0% 0 0% Tumor size <3 cm 12 30% 14 45% 0.188 ≥3 cm 28 70% 17 55% HAIC courses Mean ± SD 2.03 ± 1.1 1 14 35% 2 18 45% 3 3 7% 4 3 7% 5 2 6% Abbreviation: HAIC, hepatic arterial infusion chemotherapy. BCLC stage, Barcelona clinic liver cancer stage. PVTT, portal vein tumor thrombus. AFP, alpha-fetoprotein. ALBI score, albumin-bilirubin grade score. SD, standard deviation. Footnotes: BCLC stages A, B, and C (Stage A: Early stage. Tumors of any size or up to three tumors less than 3 cm, with well-preserved liver function. Stage B: Intermediate Stage. Tumors in the liver with well-preserved liver function. Stage C: Advanced stage, including invasion of the hepatic blood vessels or extrahepatic spread). Table 2. Efficacy of and Response Rates for Sorafenib and HAIC-Sorafenib Therapy. Table 2. Efficacy of and Response Rates for Sorafenib and HAIC-Sorafenib Therapy. HAIC-Sorafenib ( n = 40) Sorafenib ( n = 31) n % n % p -Value Overall survival, months Median (range) 12.0 (2–12) 12.0 (2–12) 0.594 Time to progression, months Median (range) 6.0 (1–12) 4.0 (1–12) 0.106 Level of response, No. (%) Complete response 14 35% 4 13% 0.002 Partial response 15 38% 6 19% Stable response 6 15% 5 16% Progressive 5 13% 16 52% Response rate 29 73% 10 32% 0.001 AFP response AFP < 20 11 28% 15 48% 0.033 Non-AFP reduction group 13 33% 12 39% AFP reduction group 16 40% 4 13% Abbreviation: AFP, alpha-fetoprotein. Table 3. Cox regression analyses of DFS in patients aged under 65 (A) and in males (B). Table 3. Cox regression analyses of DFS in patients aged under 65 (A) and in males (B). Factors Associated with Tumor Progression Model A Model B HR 95% CI p -Value HR 95% CI p -Value Sex Female 1.42 (0.26–7.77) 0.684 Age age ≥ 65 2.71 (1.33–5.51) 0.006 Treatment strategy HAIC-sorafenib 0.08 (0.02–0.35) 0.001 0.29 (0.11–0.71) 0.007 Albumin alb ≤ 3.5 g/dL 1.23 (0.32–4.74) 0.760 0.99 (0.45–2.17) 0.977 Bilirubin >1 mg/dL 0.70 (0.19–2.53) 0.586 0.98 (0.45–2.12) 0.962 Preoperative T-stage Stage 1/2 1.67 (0.38–7.29) 0.497 1.70 (0.72–4.05) 0.227 Preoperative AFP AFP 20–400 (ng/mL) 1.53 (0.29–8.19) 0.617 0.150 Preoperative AFP AFP >400 (ng/mL) 5.21 (1.13–23.99) 0.034 1.47 (0.49–4.39) 0.490 Tumor size ≥3 cm 6.81 (1.35–34.25) 0.020 2.75 (0.94–8.05) 0.065 Ascites With 3.87 (0.31–48.00) 0.292 4.31 (1.43–13.01) 0.009 Prior treatment With 0.67 (0.09–4.87) 0.692 8.05 (0.75–86.17) 0.085 Child–Pugh Score Score B7/8 0.26 (0.02–4.20) 0.345 0.78 (0.09–6.68) 0.820 Abbreviations: HR, hazard ratio; CI, confidence interval; AFP, alpha-fetoprotein; HAIC, hepatic arterial infusion chemotherapy.
https://www.mdpi.com/2077-0383/12/5/1887/xml
Implementation of Technology-based Patient Engagement Strategies within Practice-based Research Networks | American Board of Family Medicine Implementation of Technology-based Patient Engagement Strategies within Practice-based Research Networks Beth Careyva , Kyle Shaak , Geoffrey Mills , Melanie Johnson , Samantha Goodrich , Brian Stello and Lorraine S. Wallace The Journal of the American Board of Family Medicine September 2016, 29 (5) 581-591; DOI: https://doi.org/10.3122/jabfm.2016.05.160044 Beth Careyva the Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA (BC, KS, MJ, BS); the Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia (GM); the Department of Community Health, Lehigh Valley Health Network, Allentown (SG); and the Department of Family Medicine, Ohio State University, Columbus, OH (LSW). Kyle Shaak the Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA (BC, KS, MJ, BS); the Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia (GM); the Department of Community Health, Lehigh Valley Health Network, Allentown (SG); and the Department of Family Medicine, Ohio State University, Columbus, OH (LSW). Geoffrey Mills the Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA (BC, KS, MJ, BS); the Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia (GM); the Department of Community Health, Lehigh Valley Health Network, Allentown (SG); and the Department of Family Medicine, Ohio State University, Columbus, OH (LSW). Melanie Johnson the Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA (BC, KS, MJ, BS); the Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia (GM); the Department of Community Health, Lehigh Valley Health Network, Allentown (SG); and the Department of Family Medicine, Ohio State University, Columbus, OH (LSW). Samantha Goodrich the Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA (BC, KS, MJ, BS); the Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia (GM); the Department of Community Health, Lehigh Valley Health Network, Allentown (SG); and the Department of Family Medicine, Ohio State University, Columbus, OH (LSW). Brian Stello the Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA (BC, KS, MJ, BS); the Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia (GM); the Department of Community Health, Lehigh Valley Health Network, Allentown (SG); and the Department of Family Medicine, Ohio State University, Columbus, OH (LSW). Lorraine S. Wallace the Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA (BC, KS, MJ, BS); the Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia (GM); the Department of Community Health, Lehigh Valley Health Network, Allentown (SG); and the Department of Family Medicine, Ohio State University, Columbus, OH (LSW). Article Figures & Data References PDF Abstract Background:Technology-based patient engagement strategies (such as patient portals) are increasingly available, yet little is known about current use and barriers within practice-based research networks (PBRNs). PBRN directors have unique opportunities to inform the implementation of patient-facing technology and to translate these findings into practice. Methods:PBRN directors were queried regarding technology-based patient engagement strategies as part of the 2015 CAFM Educational Research Alliance (CERA) survey of PBRN directors. A total of 102 PBRN directors were identified via the Agency for Healthcare Research and Quality's registry; 54 of 96 eligible PBRN directors completed the survey, for a response rate of 56%. Results:Use of technology-based patient engagement strategies within PBRNs was limited, with less than half of respondents reporting experience with the most frequently named tools (risk assessments/decision aids). Information technology (IT) support was the top barrier, followed by low rates of portal enrollment. For engaging participant practices, workload and practice leadership were cited as most important, with fewer respondents noting concerns about patient privacy. Discussion:Given limited use of patient-facing technologies, PBRNs have an opportunity to clarify the optimal use of these strategies. Providing IT support and addressing clinician concerns regarding workload may facilitate the inclusion of innovative technologies in PBRNs. Decision Support Techniques Electronic Health Records Health Services Research Patient Participation Practice-based Research Privacy Registries Risk Assessment Surveys & Questionnaires United States Agency for Healthcare Research and Quality Workload Practice-based research network (PBRN) directors are uniquely poised to answer questions regarding the pragmatic implementation of evolving patient engagement technologies within PBRNs. Given the increasing availability of technology to communicate with patients, it was anticipated that PBRN directors may have valuable experience to share in using patient engagement technologies within practice-based research. PBRNs offer a rich research laboratory across multiple settings, ownership models, and organizational models, and even more diverse populations within ambulatory primary care practices. 1Primary care researchers within PBRNs have unique opportunities to inform the implementation of patient-facing technology, thereby translating research findings into practice. 2 , 3 Patient engagement strategies encompass information exchange and shared decision making to promote patient activation and self-management. 4Using technology—including videoconferencing, web-based tools, texting, and patient portals—for patient engagement may be instrumental in facilitating patient-centered care and improving both health-related outcomes and workflow. 5 ⇓ ⇓ – 8Technology-based patient engagement strategies include activities such as the transmission of clinical questions, biometric data, patient surveys (eg, decision aids and patient-reported outcomes), and risk calculators. Real-world examples include the use of videoconferencing to facilitate patient visits in rural areas, the use of portals to collect patient-reported outcomes, and Internet-connected scales to communicate daily body weight. With the combination of an aging population and a primary care workforce shortage, there is a greater-than-ever need to explore innovative technology strategies that empower patients to be active participants in their health and health care. 9 , 10Primary care research is needed to inform the optimal use of these technologies to meet the tenets of the triple aim of better care, better quality, and lower cost. 11 , 12However, little is known about current research efforts related to the use of technology to engage patients and, more important, which barriers need to be overcome to optimize the use of such innovations. Technology has the potential to improve systems of care and health outcomes; therefore, further research is needed to inform the optimal implementation and evaluation of outcomes moving forward. 8 , 13 , 14 Clinician acceptance has been shown to be a major factor in the uptake of new technologies in practice. 15In a prior survey of clinicians, while most felt positive about technology use for patient engagement, concerns about workload and patient safety also surfaced. 16While the issue of clinician attitudes toward technology use has been examined previously, to our knowledge, no studies have queried technology use and acceptance among those leading PBRNs. To address this gap in the literature, the purpose of this study was to assess the current use of and perceived barriers to patient engagement technologies within practice-based research among a sample of PRBN directors throughout the United States and Canada. Methods Data for this study were collected via the Council of Academic Family Medicine Educational Research Alliance's (CERA) 2015 survey of PBRN directors. CERA is a joint initiative of all 4 major US academic family medicine organizations (Society of Teachers of Family Medicine, North American Primary Care Research Group, Association of Departments of Family Medicine, and Association of Family Medicine Residency Directors). Detailed information about CERA has been published elsewhere. 17All procedures used in this study were approved by the American Academy of Family Physicians Institutional Review Board. Data Collection Procedures Between September and October 2015, PRBN directors (n = 102) identified within the Agency for Healthcare Research and Quality's PBRN registry received an electronic invitation to complete a 10-minute survey. The survey was introduced as part of an electronic message that included a personalized greeting, a letter signed by each CERA organization president, and a link to the survey. Nonrespondents were sent 3 follow-up E-mails encouraging participation. Five E-mail invitations were returned (“bounced back”) and 1 individual indicated that the PBRN was no longer active; therefore, the useable sample included a total of 96 PBRN directors. Overall, 54 PBRN directors completed the survey, yielding a 56% overall response rate. A collaborative team of researchers developed original content to design the 10-question survey. The survey included a collection of close-ended items addressing (1) demographic characteristics related to the scope and functioning of each director's PBRN, (2) current use of technology-based patient engagement strategies, (3) perceived barriers to the use of patient engagement technologies, and 4) factors affecting participant practice recruitment. Sample items included: “What proportion of practices within your PBRN have access to patient portals that could be used for research purposes,?” “In your opinion, which of the following are the 3 most important factors in determining which technology-based strategy to incorporate into your practice-based research?” and “How likely are each of the following characteristics to affect physician participation in studies using technology-based patient engagement strategies?” The questions pertaining to technology-based patient engagement strategies are included in the Appendix. Survey items aimed to evaluate the impact of PBRN scope (local, state, regional, national) on the use of technology-based patient engagement strategies within PBRNs, the role of patient portals in the overall use of technology-based patient engagement strategies, and the influence of familiarity with Health Insurance Portability and Accountability Act (HIPAA) regulations for technology use. Hypotheses being tested included the following: (1) regional/national PBRNs are more likely to be using technology-based patient engagement strategies than local/state PBRNs, and (2) PBRNs with increased access to patient portals in member practices are more likely to be engaged in studies involved patient engagement technologies. Data Analysis Descriptive statistics (frequencies, percentages) were used to depict characteristics of PBRNs in terms of current practices, barriers and facilitators, and attitudes toward the use of technology-based patient engagement strategies. For survey items that included count data, χ 2tests were used to compare PBRNs in terms of current practices, barriers and facilitators, and attitudes toward the use of technology-based patient engagement strategies. All data analyses were conducted using the SPSS version 22.0 (SPSS, Inc./IBM, Chicago, IL). Response rates varied per survey question, as represented in the tables. Results Overall PBRN characteristics are presented inTable 1. Survey respondents included representation from local (n = 11), state (n = 18), regional (n = 16), and national (n = 9) PBRNs. Almost half (46%) of PBRN directors were leading PBRNs that had been in existence a decade or longer. Table 1. Practice-Based Research Network Characteristics The proportion of studies within each PBRN using technology-based patient engagement strategies is listed inTable 2. Of the 49 PBRN directors who responded to this question, 39 (80%) indicated using technology-based patient engagement strategies in fewer than 25% of their studies in the past 5 years. When comparing the percentage of studies using technology-based patient engagement strategies in the past 5 years, no significant differences were observed based on the scope of the PBRN (local/state vs regional/national; χ 2= 3.91; P> .05). Table 2. Percentage of Studies Including Technology-Based Patient Engagement Strategies among Practice-Based Research Networks Technology-based patient engagement strategies used in the past 5 years by PBRNs are outlined inTable 3. Risk assessments or decision aids administered by web-based tools (n = 20), waiting room kiosks/computers (n = 13), or smartphone/personal tablet applications (n = 13) were most commonly used, whereas videoconferencing for patient visits (n = 4) and texting to transmit clinical information (n = 4) were used least frequently. Table 3. Practice-Based Research Network Use of Technology-Based Patient Engagement Strategies in the Past 5 Years In terms of importance in determining which type of technology-based patient engagement strategy to incorporate into research studies, PBRN directors most frequently identified ease of use for practices (n = 33), ease of use for patients (n = 30), and ease of use for clinicians (n = 23). Factors least likely to affect the type of technology selected included cost (n = 16) and patient population (n = 5). Directors' rankings of the top barriers to incorporating technology into research studies are reported inTable 4. Low rates of portal enrollment was selected as a top barrier, though only 47% PBRNs (n = 22) had access to patient portals in >50% of their practices. PBRN directors reported access to patient portals (Table 5). Among PBRN directors reporting technology-based patient engagement strategies in 0%, 1% to 50%, and >50% of studies, those who reported access to portals in ≥50% of the practices were not significantly more likely to have engaged in studies involving technology-based patient engagement strategies than PBRNs with access to portals in <50% of practices (χ 2= 1.92; P> .05). Table 4. Barriers to Incorporating Technology-Based Patient Engagement Strategies into Practice Table 5. Practices with Patient Portals in Each Practice-Based Research Network In terms of familiarity with HIPAA regulations pertaining to the transfer of electronic information, PBRN directors described practices being most familiar with E-mail, followed by patient portals, texting, and videoconferencing (Figure 1). There were no significant differences between familiarity with HIPAA regulations (not at all familiar/slightly familiar/somewhat familiar vs moderately familiar/extremely familiar) and use of E-mail (χ 2= 0.12; P> .05), portal use (χ 2= 0.037; P> .05), texting (χ 2= 1.14; P> .05), or videoconferencing (χ 2= 1.42; P> .05). Figure 1. Familiarity with Health Insurance Portability and Accountability Act regulations for the transmission of electronic data. Of the 39 PBRN directors who reported the use of technology-based patient engagement strategies, 35 responded to the survey question regarding the ease of recruitment for studies using these strategies. Of these, 54% reported ease of recruitment as good (n = 15) or very good (n = 4). A total of 34% of responding directors (n = 12) reported ease of recruitment as fair and 11% (n = 4) reported it as poor. PBRN directors' perceptions of factors that may affect physician participation in studies are shown inFigure 2. Overall, workload was the most concerning factor identified, followed closely by practice leadership. Practice models identified as most likely to participate in PBRN studies were individual practitioner or group practice (n = 14), hospital-owned and university-affiliated (n = 11), federally qualified health center (n = 7), hospital-owned community-based practice (n = 2), and federal/national government health care agency (n = 2). Figure 2. Factors that may affect physician participation in studies including technology-based patient engagement strategies. Discussion This study aimed to evaluate the current use of, barriers to, and clinician acceptance of patient engagement technologies within studies conducted in PBRNs. Based on the increasing availability of new technologies, it was anticipated that PBRN directors would have experience with studies encompassing many different technology-based modalities for patient engagement. Instead, some of the most common technology-based tools (risk assessments or decision aids transmitted by web-based tools, kiosks, smartphones/tablets, or portals) were used by less than half of the PBRNs in the past 5 years. Decision aids have been found to improve knowledge and decrease decisional conflict when administered through different modalities and settings, which may explain their routine use within practice-based research. 18Further study is needed to clarify the optimal use of technology-based tools (such as videoconferencing, texting, and portals) to transmit other types of clinical data, including the contexts in which they may be most beneficial. 19 ⇓ – 21 It was expected that regional and national PBRNs would be more likely to have experience with technology-based patient engagement strategies because of increased access to technology within diverse practice sites, but no significant differences were noted based on scope of PBRN (local/state vs regional/national). This may be related to variability in the number of practices and resources within each PBRN, irrespective of geographic coverage, as well as increased probability of a greater number of technology platforms for regional and national PBRNs. The overall limited use of patient engagement technologies in practice-based research identified in this survey is consistent with a recent evaluation of patient engagement technologies in the inpatient setting, in which a systematic review highlighted limited use and gaps in the literature surrounding optimal implementation. 22 In terms of factors influencing the inclusion of technology in practice-based research studies, PBRN directors reported ease of use (for patients, practices, and clinicians, in descending order) as the most frequently cited factor in determining which technology-based patient engagement strategy to use in research. User-friendly technology has been found to be critical to successful implementation in the practice setting. 23Cost and the availability of tools in multiple languages were cited less frequently as factors in choosing which type of technology to implement. While a prior study noted cost as a barrier, 24this may be less relevant to practice-based researchers who are seeking to optimize the use of existing technologies in practices rather than purchasing new systems. Linked to electronic medical records, patient portals are an example of existing technology available in an ever increasing number of practices for research purposes. However, most directors in this sample reported access to portals in less than half of practices within their PBRN. Given the potential for portals to be used to transmit decision aids, risk assessments, and clinical information, and to maximize the study sample and standardize data collection methods, it was expected that PBRNs with portal access in a greater number of practices may use technology-based patient engagement strategies more frequently than PBRNs with a patient portal in fewer practices. The lack of significant differences noted between PBRNs with varying degrees of access to patient portals and studies involving technology may be the result of both low rates of enrollment and a limited understanding of optimal implementation of patient portals for both clinical and research purposes. Further efforts to facilitate patient enrollment and to evaluate who might benefit most from patient engagement via patient portals may facilitate their use within practice-based research. In addition to establishing current use of technology-based patient engagement strategies within PBRNs, directors were queried about barriers to technology implementation. Information technology (IT) support was the most frequently cited barrier to incorporating technology in practice settings. It is unclear whether the IT barrier is limited availability, lack of IT personnel trained in implementation science, institutional regulations, or something else. Further study is needed to clarify the type of IT support needed to optimize the implementation of technology for patient engagement. Similar to other studies, practice champions were also found to be particularly critical to successful implementation. 25Technology-based tools in multiple languages were cited as a barrier less frequently than anticipated based on a prior study, though this is undoubtedly dependent on the patient populations of each PBRN. 26Access to smartphones was 1 of the least commonly cited barriers, which corresponds to a recent study indicating that 55% of primary care patients use smartphones, and 70% of those patients with smartphones use them for health-related purposes. 27 An additional potential barrier to studies involving technology-based patient engagement strategies is clinician acceptance. Clinician acceptance is critical to the successful recruitment of practices and has been found to facilitate study implementation. 28We aimed to determine factors that were most critical for physician participation in studies involving technology for patient engagement. All but 1 PBRN director cited workload as a major factor in physician participation, whereas patient safety and patient privacy were cited less frequently than in prior studies. 16 , 29This may be in part the result of evolving experience and institutional policies regarding the management of patient privacy and patient safety within patient-facing technology-based interventions. Further study is needed to clarify whether workload is a greater concern for studies involving patient engagement technologies than for other types of practice-based research. In light of expected concerns with patient privacy, PBRN directors reported practice familiarity with HIPAA regulations for transmission of clinical data. The directors reported variable practice familiarity with HIPAA regulations; practices were most familiar with regulations regarding E-mail and least familiar with those regarding videoconferencing. To be HIPAA compliant, E-mail, texting, portals, and other forms of patient-facing technology need to include safeguards for the transmission of protected health information, potentially including encryption and patient logins. 30 , 31There is more debate about adequate safeguards for videoconferencing, which is reflected in the PBRN directors' perceptions of decreased familiarity with HIPAA regulations for videoconferencing within practices. While it was thought that PBRNs reporting increased familiarity with HIPAA regulations may be more likely to use various technology-based tools to transmit clinical information, no significant differences were noted with respect to HIPAA familiarity and the reported percentage of studies using technology for patient engagement. This may be linked to other findings within this study indicating that patient privacy was not a major factor affecting physician participation. In addition, a more recent study confirmed the feasibility of protecting patient privacy while harnessing mobile technology to enhance patient and family engagement 32; however, questions still remain regarding adequate protection of patient privacy within other modalities such as videoconferencing. 33 Limitations The findings generated from this study should be considered within the context of several limitations. First, generalizability of the study findings is limited by the response rate (56%) of PBRN directors polled. Second, as with all studies that rely on self-report, response bias remains a possibility. Third, the cross-sectional nature of the study limits causality. Last, reporting is second-hand; individual PBRN-member clinics and clinicians may have different perceptions of technology strategies than the PBRN director, particularly with regard to knowledge of HIPAA regulations. Conclusion Decision aids and risk assessments were the most commonly used types of technology-based patient engagement strategies within the PBRNs. Even in practices with access to portals and other technologies, few PBRNs are engaging in studies of technology implementation or related outcomes. IT support was the top-ranked barrier to incorporating technology into practice, though practice champions were also cited as being critical to successful implementation. For participant practices, workload and practice leadership were cited as major factors in physician participation in studies involving technology-based patient engagement strategies—more so than concerns about patient safety and patient privacy. Optimizing IT support and addressing workload concerns may facilitate increased use of technology-based patient engagement strategies within practice-based research. Acknowledgments The authors thank Jacqueline Grove for assistance with editing and manuscript preparation. Appendix Questions Regarding Technology-Based Patient Engagement Strategies Below are some examples of technology-based patient engagement strategies. Has your PBRN conducted studies that relied on any of the following technology-based patient engagement strategies in the past 5 years? (Please select all that apply.) Patient visits with primary care physicians remotely by audio/video Electronic transmission of vital signs or clinical data (eg, blood pressure, weight, blood glucose) Waiting room kiosk computers/tablets for risk assessments or decision aids Web-based risk assessments or decision aids Smartphones/personal tablet applications for risk assessments or decision aids Electronic medical record portal-based risk assessments or decision aids Texting to patients (eg, reminders, educational materials) Texting from patients (eg, transmission of vital signs or clinical data) E-mail What proportion of studies within your PBRN have relied on technology-based patient engagement strategies in the past 5 years? 0% 1% to 25% 26% to 50% 51% to 75% 76% to 99% 100% What proportion of practices within your PBRN have access to patient portals that could be incorporated for research purposes? 0% 1% to 25% 26% to 50% 51% to 75% 76% to 99% 100% In your opinion, which of the following are the 3 most important factors in determining which technology-based patient engagement strategy to incorporate into your practice-based research? Clinical utility Ease of use for patients Ease of use for clinicians Ease of implementation for practices Availability of a particular technology Cost Patient population How familiar are your practices with HIPAA regulations surrounding the transmission of electronic data pertaining to: Patient portals E-mail Texting Videoconferencing Responses to question 5 were rated on a Likert scale (1 to 5): not at all familiar, slightly familiar, somewhat familiar, moderately familiar, extremely familiar. In your experience as a PBRN director, what are the 3 most critical barriers to successfully incorporating technology-based patient engagement strategies into clinical practice? Lack of patient portals within electronic medical records Low rates of portal enrollment among patients Access to smartphones Cost of health care technology Staff comfort with use of technology Patient willingness to use technology Tools that interface with electronic medical records Availability of tools in multiple languages IT support Lack of practice champions In your experience as a PBRN director, what are the 3 most critical facilitators to successfully incorporating technology-based patient engagement strategies into clinical practice? Patient portals within electronic medical records Portal enrollment Access to smartphones Cost of health care technology Staff comfort with use of technology Patient willingness to use technology Tools that interface with electronic medical records Availability of tools in multiple languages IT support Practice champions Across all studies incorporating technology-based patient engagement strategies in your PBRN, please describe the overall ease of recruitment of participant practices for the studies. Poor Fair Good Very good Excellent How likely are the following to affect physician participation in studies using technology-based patient engagement strategies? Comfort with technology Training Practice leadership Concerns about workload or time Concerns about patient safety Concerns about patient privacy Sustainability of interventions Responses to question 9 were rated on a Likert scale (1 to 5): extremely unlikely, unlikely, neutral, likely, extremely likely. In your opinion, what practice ownership model is most likely to participate in studies using technology-based patient engagement strategies? Individual practitioner or group practice Hospital-owned, university-affiliated practice Hospital-owned, community-based practice Federally qualified health center Federal or national government health care agency Not sure Notes This article was externally peer reviewed. Funding:none. Conflict of interest:none declared. Received for publication January 28, 2016. Revision received April 18, 2016. Accepted for publication April 22, 2016. References 1. ↵ Agency for Healthcare Research and Quality . Primary care practice-based research networks . Available from: http://www.ahrq.gov/research/findings/factsheets/primary/pbrn/index.html . Updated October 2013 . Accessed May 11, 2015 . Google Scholar 2. ↵ Heintzman J , Gold R , Krist A , Crosson J , Likumahuwa S , DeVoe JE . Practice-based research networks (PBRNs) are promising laboratories for conducting dissemination and implementation research . J Am Board Fam Med 2014 ; 27 : 759 – 62 . 3. ↵ Krist AH , Green LA , Phillips RL , et al . Health information technology needs help from primary care researchers . J Am Board Fam Med 2015 ; 28 : 306 – 10 . 4. ↵ James J . Health policy brief: Patient engagement . Available from: http://www.healthaffairs.org/healthpolicybriefs/brief.php?brief_id=86 . Updated February 14, 2013 . Accessed May 15, 2015 . Google Scholar 5. ↵ Mosen DM , Schmittdiel J , Hibbard J , Sobel D , Remmers C , Bellows J . Is patient activation associated with outcomes of care for adults with chronic conditions? J Ambul Care Manage 2007 ; 30 : 21 – 9 . 6. ↵ Riva G , Baños RM , Botella C , Wiederhold BK , Gaggioli A . Positive technology: using interactive technologies to promote positive functioning . Cyberpsychol Behav Soc Netw 2012 ; 15 : 69 – 77 . OpenUrl CrossRef PubMed Google Scholar 7. ↵ Finkelstein J , Knight A , Marinopoulos S , et al . Enabling patient-centered care through health information technology . AHRQ publication no. 12-E005-EF. Available from: http/www.effectivehealhcare.ahrq.gov/reports/final.cfm . Rockville, MD : Agency for Healthcare Research and Quality ; 2012 . Google Scholar 8. ↵ Ricciardi L , Mostashari F , Murphy J , Daniel JG , Siminerio EP . A national action plan to support consumer engagement via e-health . Health Aff (Millwood) 2013 ; 32 : 376 – 84 . 9. ↵ Kvedar J , Coye M , Everett W . Connected health: a review of technologies and strategies to improve patient care with telemedicine and telehealth . Health Aff (Millwood) 2014 ; 33 : 194 – 9 . 10. ↵ Petterson SM , Liaw WR , Phillips RL Jr . , Rabin DL , Meyers DS , Bazemore AW . Projecting US primary care physician workforce needs: 2010–25 . Ann Fam Med 2012 ; 10 : 503 – 9 . 11. ↵ Berwick DM , Nolan TW , Whittington J . The triple aim: care, health, and cost . Health Aff (Millwood) 2008 ; 27 : 759 – 69 . 12. ↵ Phillips RL Jr . , Bazemore AW , DeVoe JE , et al . A family medicine health technology strategy for achieving the triple aim for US health care . Fam Med 2015 ; 47 : 628 – 35 . 13. ↵ Blumenthal D , Tavenner M . The “meaningful use” regulation for electronic health records . N Engl J Med 2010 ; 363 : 501 – 4 . OpenUrl CrossRef PubMed Google Scholar 14. ↵ Ahern DK , Woods SS , Lightowler MC , Finley SW , Houston TK . Promise of and potential for patient-facing technologies to enable meaningful use . Am J Prev Med 2011 ; 40 : S162 – 72 . 15. ↵ Ward R , Stevens C , Bretnall P , Briddon J . The attitudes of health care staff to information technology: a comprehensive review of the research literature . Health Info Libr J 2008 ; 25 : 81 – 97 . 16. ↵ Davidson E , Simpson CR , Demiris G , Sheikh A , McKinstry B . Integrating telehealth care-generated data with the family practice electronic medical record: qualitative exploration of the views of primary care staff . Interact J Med Res 2013 ; 2 : e29 . 17. ↵ Mainous AG , Seehusen D , Shokar N . CAFM Educational Research Alliance (CERA) 2011 residency director survey: background, methods, and respondent characteristics . Fam Med 2012 ; 44 : 691 – 3 . 18. ↵ Stacey D , Légaré F , Col NF , et al . Decision aids for people facing health treatment or screening decisions . Cochrane Database Syst Rev 2014 ; 1 : CD001431 . 19. ↵ Irizarry T , DeVito Dabbs A , Curran CR . Patient portals and patient engagement: a state of the science review . J Med Internet Res 2015 ; 17 : e148 . 20. ↵ Goldzweig CL , Orshansky G , Paige NM , et al . Electronic patient portals: evidence on health outcomes, satisfaction, efficiency, and attitudes: a systematic review . Ann Intern Med 2013 ; 159 : 677 – 87 . 21. ↵ Fanning J , Mullen SP , McAuley E . Increasing physical activity with mobile devices: a meta-analysis . J Med Internet Res 2012 ; 14 : e161 . 22. ↵ Prey JE , Woollen J , Wilcox L , et al . Patient engagement in the inpatient setting: a systematic review . J Am Med Inform Assoc 2014 ; 21 : 742 – 50 . 23. ↵ Vuononvirta T , Timonen M , Keinänen-Kiukaaniemi S , et al . The compatibility of telehealth with health-care delivery . J Telemed Telecare 2011 ; 17 : 190 – 4 . 24. ↵ Walker J , Whetton S . The diffusion of innovation: factors influencing the uptake of telehealth . J Telemed Telecare 2002 ; 8 : 73 – 5 . 25. ↵ Shaw EK , Howard J , West DR , et al . The roles of the champion in primary care change efforts: from the State Networks of Colorado Ambulatory Practices and Partners (SNOCAP) . J Am Board Fam Med 2012 ; 25 : 676 – 85 . 26. ↵ Dawson J , Doll H , Fitzpatrick R , Jenkinson C , Carr AJ 27. ↵ Bauer AM , Rue T , Keppel GA , Cole AM , Baldwin LM , Katon W . Use of mobile health (mHealth) tools by primary care patients in the WWAMI Region Practice and Research Network (WPRN) . J Am Board Fam Med 2014 ; 27 : 780 – 8 . 28. ↵ Wade VA , Hiller JE . Clinician acceptance is the key factor for sustainable telehealth services . Qual Health Res 2014 ; 24 : 682 – 94 . 29. ↵ Beasley JW , Wetterneck TB , Temte J , et al . Information chaos in primary care: implications for physician performance and patient safety . J Am Board Fam Med 2011 ; 24 : 745 – 51 . 30. ↵ US Department of Health and Human Services . Does the HIPAA Privacy Rule permit health care providers to use e-mail to discuss health issues and treatment with their patients? Available from: http://www.hhs.gov/hipaa/for-professionals/faq/570/does-hipaa-permit-health-care-providers-to-use-email-to-discuss-health-issues-with-patients/index.html . Updated December 15, 2008 . Accessed December 23, 2015 . Google Scholar 31. ↵ Office of the National Coordinator for Health Information Technology . Guide to privacy and security of health information . Chapter 4: Understanding electronic health records, the HIPAA security rule, and cybersecurity. Available from: https://www.healthit.gov/sites/default/files/pdf/privacy/privacy-and-security-guide-chapter-4.pdf . Accessed January 23, 2016 . Google Scholar 32. ↵ Gordon CR , Li A , et al . Digital mobile technology facilitates HIPAA-sensitive perioperative messaging, improves physician-patient communication, and streamlines patient care . Patient Saf Surg 2015 ; 9 : 21 . 33. ↵ Armfield NR , Gray LC , Smith AC . Clinical use of Skype: a review of the evidence base . J Telemed Telecare 2012 ; 18 : 125 – 7 .
https://www.jabfm.org/content/29/5/581.full
Publications - Global Disability Innovation Hub The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good. Type Conference Paper Themes Assistive & Accessible Technology Culture and Participation The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya Giulia Barbareschi,Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, Joyce Olenja We present the findings of a case study of mobile technology use by People with Visual Impairment (VIPs) in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted. CHI '20: Proceedings of the 2020 CHI Conference; 2020 Abstract The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya Living in an informal settlement with a visual impairment can be very challenging resulting in social exclusion. Mobile phones have been shown to be hugely beneficial to people with sight loss in formal and high-income settings. However, little is known about whether these results hold true for people with visual impairment (VIPs) in informal settlements. We present the findings of a case study of mobile technology use by VIPs in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted. Cite The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya Giulia Barbareschi, Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, and Joyce Olenja. 2020. The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya. In Proceedings of the 2020 CHI Conference on Human Factors in Computing Systems (CHI '20). Association for Computing Machinery, New York, NY, USA, 1–15.https://doi.org/10.1145/331383... The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya Type Conference Paper Disability design and innovation in computing research in low resource settings Dafne Zuleima Morgado-Ramirez,Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney,Catherine Holloway 80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes. ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020 Abstract Disability design and innovation in computing research in low resource settings 80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes. In short, researchers rarely examine what was challenging in the process of collaboration. We present reflections from the field across four studies. Our contributions are: (1) an overview of past work in computing with a focus on disability in low resource settings and (2) learnings and recommendations from four collaborative projects in Uganda, Jordan and Kenya over the last two years, that are relevant for future HCI studies in low resource settings with communities with disabilities. We do this through a lens of Disability Interaction and ICT4D. Disability design and innovation in computing research in low resource settings Dafne Zuleima Morgado-Ramirez, Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney, and Catherine Holloway. 2020. Disability design and innovation in computing research in low resource settings. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 11, 1–7.https://doi.org/10.1145/337362... Disability design and innovation in computing research in low resource settings Type Workshop Themes Assistive & Accessible Technology Research Group Disability Interactions Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution Sahan Bulathwela, María Pérez-Ortiz,Catherine Holloway, John Shawe-Taylor This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies. Workshop on Machine Learning for the Developing World (ML4D) at the Conference on Neural Information Processing Systems 2021; 2021 Abstract Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution Artificial Intelligence (AI) in Education has been said to have the potential for building more personalised curricula, as well as democratising education worldwide and creating a Renaissance of new ways of teaching and learning. Millions of students are already starting to benefit from the use of these technologies, but millions more around the world are not. If this trend continues, the first delivery of AI in Education could be greater educational inequality, along with a global misallocation of educational resources motivated by the current technological determinism narrative. In this paper, we focus on speculating and posing questions around the future of AI in Education, with the aim of starting the pressing conversation that would set the right foundations for the new generation of education that is permeated by technology. This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies. Finally, we ask what would it take for this educational revolution to provide egalitarian and empowering access to education, beyond any political, cultural, language, geographical and learning ability barriers. Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution Type Workshop Themes Assistive & Accessible Technology Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts Tabish Ahmed, Sahan Bulathwela The informational needs of people are highly contextual and can depend on many different factors such as their current knowledge state, interests and goals [1, 2, 3]. However, an effective information retrieval companion should minimise the human effort required in i) expressing a human information need and ii) navigating a lengthy result set. Using topical representations of the user history (e.g. [4]) can immensely help formulating zero shot queries and refining short user queries that enable proactive information retrieval (IR). While the world has digital textual information in abundance, it can often be noisy (e.g. extracted through Automatic Speech Recognition (ASR), PDF text extraction etc.), leading to state-of-the-art neural models being highly sensitive to the noise producing sub-optimal results [5]. This demands denoising steps to refine both query and document representation. In this paper, we argue that Wikipedia, an openly available encyclopedia, can be a humanly intuitive knowledge base [6] that has the potential to provide the world view many noisy information Retrieval systems need. Published at the First Workshop on Proactive and Agent-Supported Information Retrieval at CIKM 2022; 2022 Abstract Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts Extracting useful information from the user history to clearly understand informational needs is a crucial feature of a proactive information retrieval system. Regarding understanding information and relevance, Wikipedia can provide the background knowledge that an intelligent system needs. This work explores how exploiting the context of a query using Wikipedia concepts can improve proactive information retrieval on noisy text. We formulate two models that use entity linking to associate Wikipedia topics with the relevance model. Our experiments around a podcast segment retrieval task demonstrate that there is a clear signal of relevance in Wikipedia concepts while a ranking model can improve precision by incorporating them. We also find Wikifying the background context of a query can help disambiguate the meaning of the query, further helping proactive information retrieval. Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts Type Book Research Group Disability Interactions Disability Interactions Creating Inclusive Innovations Catherine Holloway,Giulia Barbareschi Abstract Disability Interactions Creating Inclusive Innovations Disability interactions (DIX) is a new approach to combining cross-disciplinary methods and theories from Human Computer Interaction (HCI), disability studies, assistive technology, and social development to co-create new technologies, experiences, and ways of working with disabled people. DIX focuses on the interactions people have with their technologies and the interactions which result because of technology use. A central theme of the approach is to tackle complex issues where disability problems are part of a system that does not have a simple solution. Therefore, DIX pushes researchers and practitioners to take a challenge-based approach, which enables both applied and basic research to happen alongside one another. DIX complements other frameworks and approaches that have been developed within HCI research and beyond. Traditional accessibility approaches are likely to focus on specific aspects of technology design and use without considering how features of large-scale assistive technology systems might influence the experiences of people with disabilities. DIX aims to embrace complexity from the start, to better translate the work of accessibility and assistive technology research into the real world. DIX also has a stronger focus on user-centered and participatory approaches across the whole value chain of technology, ensuring we design with the full system of technology in mind (from conceptualization and development to large-scale distribution and access). DIX also helps to acknowledge that solutions and approaches are often non-binary and that technologies and interactions that deliver value to disabled people in one situation can become a hindrance in a different context. Therefore, it offers a more nuanced guide to designing within the disability space, which expands the more traditional problem-solving approaches to designing for accessibility. This book explores why such a novel approach is needed and gives case studies of applications highlighting how different areas of focus—from education to health to work to global development—can benefit from applying a DIX perspective. We conclude with some lessons learned and a look ahead to the next 60 years of DIX. Disability Interactions Creating Inclusive Innovations Type Conference Paper Themes Assistive & Accessible Technology Value beyond function: analyzing the perception of wheelchair innovations in Kenya Barbareschi, G; Daymond, S; Honeywill, J; Singh, A; Noble, D; Mbugua, N; Harris, I;Austin, V;Holloway, C The World Health Organization (WHO) defines Assistive Technology (AT) as “an umbrella term covering the systems and services related to the delivery of assistive products and services” [6]. This definition highlights how AT encompasses not only the physical and digital products used by millions of persons with disabilities (PWDs) worldwide, but also the systems and services that accompany the provision of these devices [78]. ASSETS '20: The 22nd International ACM SIGACCESS Conference on Computers and Accessibility.; 2020 Abstract Value beyond function: analyzing the perception of wheelchair innovations in Kenya Innovations in the field of assistive technology are usually evaluated based on practical considerations related to their ability to perform certain functions. However, social and emotional aspects play a huge role in how people with disabilities interact with assistive products and services. Over a five months period, we tested an innovative wheelchair service provision model that leverages 3D printing and Computer Aided Design to provide bespoke wheelchairs in Kenya. The study involved eight expert wheelchair users and five healthcare professionals who routinely provide wheelchair services in their community. Results from the study show that both users and providers attributed great value to both the novel service delivery model and the wheelchairs produced as part of the study. The reasons for their appreciation went far beyond the practical considerations and were rooted in the fact that the service delivery model and the wheelchairs promoted core values of agency, empowerment and self-expression. Value beyond function: analyzing the perception of wheelchair innovations in Kenya Type Conference Paper Themes Assistive & Accessible Technology Culture and Participation Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh Nusrat Jahan,Giulia Barbareschi, Clara Aranda Jan, Charles Musungu Mutuku, Naemur Rahman,Victoria Austin,Catherine Holloway Worldwide it is estimated that there are over a billion people who live with some form of disability[1]. Approximately 80% of people with disabilities live in low-and-middle income countries (LMICs). The combination of an inaccessible environment compounded by socio-economic factors such as poverty and stigma, makes it more likely for people with disabilities to be marginalised and excluded from society[1]. Assistive Technologies (ATs) are known to bridge the accessibility gaps and allow for greater social inclusion. However, there is a lack of adequate access to ATs in LMICs, combined with often poorly designed services, which only magnifies these challenges, thus limiting the opportunities for persons with disabilities to live an independent life[2]. Despite the importance of AT, access to AT globally is inadequate with only 10 percent of those in need having access to the ATs that they need[2]. 2020 IEEE Global Humanitarian Technology Conference Abstract Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh Globally, mobile technology plays a significant role connecting and supporting people with disabilities. However, there has been limited research focused on understanding the impact of mobile technology in the lives of persons with disabilities in low or middle- income countries. This paper presents the findings of a participatory photovoice study looking at the role that mobile phones play in the daily lives of 16 persons with disabilities in Kenya and Bangladesh. Participants used a combination of pictures and voice recordings to capture their own stories and illustrate the impact that mobile phone use has on their lives. Through thematic analysis, we categorized the benefits of mobile phones captured by participants as 1) Improved social connection; 2) Increased independence and 3) Access to opportunities. While mobile phones are ubiquitously used for communication, for persons with disabilities they become essential assistive technologies that bridge barriers to opportunities which are not accessible otherwise. Our paper adds evidence to the need for mobile phones for persons with disabilities to enable communication and connectivity in support of development. Cite Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh N. Jahan et al., "Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh," 2020 IEEE Global Humanitarian Technology Conference (GHTC), Seattle, WA, USA, 2020, pp. 1-8, doi: 10.1109/GHTC46280.2020.9342934. Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh Type Conference Paper Themes Assistive & Accessible Technology Research Group Local Productions A Preliminary Study to Understand How Mainstream Accessibility and Digital Assistive Technologies Reaches People in Lower- and Middle-Income Countries Tigmanshu Bhatnagar, George Torrens, Ben Oldfrey, Priya MorjariaFelipe Ramos Barajas, Katherine PerryandCatherine Holloway Access to information on digital platforms not only facilitates education, employment, entertainment, social interaction but also facilitates critical governmental services, ecommerce, healthcare services and entrepreneurship [1]. Article 9 of United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) enforces its signatories to commit to provide full accessibility to every citizen of the nation [2]. This has helped to spearhead accessibility directives such as the European Accessibility Act [3] that aims to improve the functioning of markets for accessible products and services. Such directives contribute to ensure that mainstream digital technologies (smartphones, computers etc.) are accessible for everyone and without being socially remarkable, they are able to assist in daily living. Additionally, there is evidence that improving access in mainstream technologies improves product experience and usability for everyone [4]. However, mainstream access has not been fully realized, leading to inferior opportunities for people with disabilities, a disparity which is more prominent in lower and middle-income countries [5]. RESNA Annual Conference; 2021 A Preliminary Study to Understand How Mainstream Accessibility and Digital Assistive Technologies Reaches People in Lower- and Middle-Income Countries Type Toolkit Innovate Now Toolkit As an entrepreneur, learning how to solve problems by creating and experimenting with different strategies is a core pillar of the entrepreneurial mindset you need to succeed. However, there’s rarely a single correct way to solve problems as an entrepreneur, so you need to learn how to create and compare different solutions. The open entrepreneurship toolkit is a set of learning materials that can help you and your team do just that. Covering the domains of user, product, market and business development, the set of cards have been designed to be used by two or more group members to actively experiment with different solutions. Innovate Now Type PhD Themes Assistive & Accessible Technology Research Group Disability Interactions Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design Troy Bodkin Doctoral Thesis. This work is one of four multidisciplinary research studies conducted by members of this research cluster, focusing on the area of Computer Aided Design (CAD) for improving the interface with Additive Manufacture (AM) to solve some of the challenges presented with improving prosthetic socket design, with an aim to improve and streamline the process to enable the involvement of clinicians and patients in the design process. Loughborough University Abstract Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design For many years, the biggest issue that causes discomfort and hygiene issues for patients with lower limb amputations have been the interface between body and prosthetic, the socket. Often made of an inflexible, solid polymer that does not allow the residual limb to breathe or perspire and with no consideration for the changes in size and shape of the human body caused by changes in temperature or environment, inflammation, irritation and discomfort often cause reduced usage or outright rejection of the prosthetic by the patient in their day to day lives. To address these issues and move towards a future of improved quality of life for patients who suffer amputations, Loughborough University formed the Next Generation Prosthetics research cluster. This work is one of four multidisciplinary research studies conducted by members of this research cluster, focusing on the area of Computer Aided Design (CAD) for improving the interface with Additive Manufacture (AM) to solve some of the challenges presented with improving prosthetic socket design, with an aim to improve and streamline the process to enable the involvement of clinicians and patients in the design process. The research presented in this thesis is based on three primary studies. The first study involved the conception of a CAD criteria, deciding what features are needed to represent the various properties the future socket outlined by the research cluster needs. These criteria were then used for testing three CAD systems, one each from the Parametric, Non Uniform Rational Basis Spline (NURBS) and Polygon archetypes respectively. The result of these tests led to the creation of a hybrid control workflow, used as the basis for finding improvements. The second study explored emerging CAD solutions, various new systems or plug-ins that had opportunities to improve the control model. These solutions were tested individually in areas where they could improve the workflow, and the successful solutions were added to the hybrid workflow to improve and reduce the workflow further. The final study involved taking the knowledge gained from the literature and the first two studies in order to theorise how an ideal CAD system for producing future prosthetic sockets would work, with considerations for user interface issues as well as background CAD applications. The third study was then used to inform the final deliverable of this research, a software design specification that defines how the system would work. This specification was written as a challenge to the CAD community, hoping to inform and aid future advancements in CAD software. As a final stage of research validation, a number of members of the CAD community were contacted and interviewed about their feelings of the work produced and their feedback was taken in order to inform future research in this area. Cite Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design Bodkin, Troy L. (2017): Specifying a hybrid, multiple material CAD system for next-generation prosthetic design. Loughborough University. Thesis.https://hdl.handle.net/2134/25...; Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design Type PhD Themes Assistive & Accessible Technology Research Group Disability Interactions YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers Giulia Barbareschi Doctoral Thesis. This thesis makes two contributions to facilitate wheelchair users’ engagement in the participatory design process for ATs, while being mindful of the burden of participation. The first contribution is a framework that provides a modular structure guiding the participatory design process from initial problem identification and analysis to facilitating collaborations between wheelchair users and designers. The framework identifies four factors determining the need and adoption process for ATs: (i) People focuses on the target population, (ii) Person includes personal characteristics, (iii) Activity refers to the challenges associated with the task, and (iv) Context encompasses the effect of the environment in which the activity takes place. The second contribution constitutes a rich picture of personal and external elements influencing real world wheelchair transfers that emerged from four studies carried out to investigate the effect of the framework factors on the design process for ATs. UCL (University College London) Abstract YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers Transferring independently to and from their wheelchair is an essential routine task for many wheelchair users but it can be physically demanding and can lead to falls and upper limb injuries that reduce the person’s independence. New assistive technologies (ATs) that facilitate the performance of wheelchair transfers have the potential to allow wheelchair users to gain further independence. To ensure that users’ needs are addressed by ATs, the active involvement of wheelchair users in the process of design and development is critical. However, participation can be burdensome for many wheelchair users as design processes where users are directly involved often require prolonged engagement. This thesis makes two contributions to facilitate wheelchair users’ engagement in the participatory design process for ATs, while being mindful of the burden of participation. The first contribution is a framework that provides a modular structure guiding the participatory design process from initial problem identification and analysis to facilitating collaborations between wheelchair users and designers. The framework identifies four factors determining the need and adoption process for ATs: (i) People focuses on the target population, (ii) Person includes personal characteristics, (iii) Activity refers to the challenges associated with the task, and (iv) Context encompasses the effect of the environment in which the activity takes place. The second contribution constitutes a rich picture of personal and external elements influencing real world wheelchair transfers that emerged from four studies carried out to investigate the effect of the framework factors on the design process for ATs. A related outcome based on these contributions is a framing document to share knowledge between wheelchair users and designers to provide focus and promote an equal collaboration among participants. Cite YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers Barbareschi, Giulia. “YouTransfer, YouDesign : a Participatory Approach to Design Assistive Technology for Wheelchair Transfers / Giulia Barbareschi.” Thesis (Ph.D.)--University College London, 2018., 2018. Print. YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers Type PhD Themes Assistive & Accessible Technology Research Group Disability Interactions Understanding wrist splint user needs and personalisation through codesign Charlotte Pyatt A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy at Loughborough University. Loughborough University Abstract Understanding wrist splint user needs and personalisation through codesign Wrist splints are a common treatment for rheumatoid arthritis, however their effectiveness is compromised by patients not wearing splints as often as prescribed. Previous research has identified a number of reasons for non-compliance, but typically lacks insights that could lead to improved splint design. This thesis investigates the motivators for patients to wear and not wear their wrist splints and, the impact of personalisation of splint appearance on patient wear. The work is based on the premise that digital design and manufacturing processes, such as Computer-Aided Design (CAD) and 3D Printing, can produce bespoke splints on demand. The research begins with a literature review across the core areas of: splinting, additive manufacture, product appearance and personalisation. This literature review identifies gaps in knowledge from which research questions are established for the work. The research employs a qualitative, generative design research approach and, follows a codesign framework employing telling, making and enacting tools. The thesis is made up of three studies. The first study is a sensitisation study and uses design probes to prepare the participants for the research and begin exploring the problem space. The second is a comprehensive study into participants splint wear behaviour and uses context mapping and scenario picture card tools to investigate the motivators for participants to wear and not wear wrist splints, along with positive and negative outcomes or wearing/not wearing splints. The final study uses a personalisation toolkit to elicit patient needs for a future wrist splint design and investigate self-reported expectations regarding compliance of patients who used the toolkit. The research finds that patient compliance is affected by practical and aesthetic limitations of current splints. It identifies 4 motivating factors to wear a splint and 10 motivating factors to not wear a splint. Additionally, it identifies 6 positive outcomes of wearing splints, 6 negative outcomes of wearing splints, 3 positive outcomes of not wearing splints and 3 negative outcomes of not wearing splints. Requirements for an improved splint design are established and form the basis of the design for a prototype personalisation toolkit. Testing of this toolkit reveals that patients are keen to own more than one splint and personalise splints to match the scenario in which it is to be worn. Patients reported that they expected to be more compliant with a personalised splint when compared to their current splint. Cite Understanding wrist splint user needs and personalisation through codesign Pyatt, Charlotte (2018): Understanding wrist splint user needs and personalisation through codesign. Loughborough University. Thesis.https://doi.org/10.26174/thesi...; Understanding wrist splint user needs and personalisation through codesign Type PhD Themes Assistive & Accessible Technology Shared Control for Wheelchair Interfaces Dr Chinemelu Ejiamatu Muoma Ezeh Doctoral Thesis. Independent mobility is fundamental to the quality of life of people with impairment. Most people with severe mobility impairments, whether congenital, e.g., from cerebral palsy, or acquired, e.g., from spinal cord injury, are prescribed a wheelchair. A small yet significant number of people are unable to use a typical powered wheelchair controlled with a joystick. Instead, some of these people require alternative interfaces such as a head- array or Sip/Puff switch to drive their powered wheelchairs. However, these alternative interfaces do not work for everyone and often cause frustration, fatigue and collisions. This thesis develops a novel technique to help improve the usability of some of these alternative interfaces, in particular, the head-array and Sip/Puff switch. UCL (University College London) Abstract Shared Control for Wheelchair Interfaces Independent mobility is fundamental to the quality of life of people with impairment. Most people with severe mobility impairments, whether congenital, e.g., from cerebral palsy, or acquired, e.g., from spinal cord injury, are prescribed a wheelchair. A small yet significant number of people are unable to use a typical powered wheelchair controlled with a joystick. Instead, some of these people require alternative interfaces such as a head- array or Sip/Puff switch to drive their powered wheelchairs. However, these alternative interfaces do not work for everyone and often cause frustration, fatigue and collisions. This thesis develops a novel technique to help improve the usability of some of these alternative interfaces, in particular, the head-array and Sip/Puff switch. Control is shared between a powered wheelchair user, using an alternative interface and a pow- ered wheelchair fitted with sensors. This shared control then produces a resulting motion that is close to what the user desires to do but a motion that is also safe. A path planning algorithm on the wheelchair is implemented using techniques in mo- bile robotics. Afterwards, the output of the path planning algorithm and the user’s com- mand are both modelled as random variables. These random variables are then blended in a joint probability distribution where the final velocity to the wheelchair is the one that maximises the joint probability distribution. The performance of the probabilistic approach to blending the user’s inputs with the output of a path planner, is benchmarked against the most common form of shared control called linear blending. The benchmarking consists of several experiments with end users both in a simulated world and in the real-world. The thesis concludes that probabilistic shared control provides safer motion compared with the traditional shared control for difficult tasks and hard-to-use interfaces. Shared Control for Wheelchair Interfaces Ezeh, Chinemelu Ejiamatu Muoma. Shared Control for Wheelchair Interfaces. UCL (University College London), 2018. Print. Type PhD Themes Assistive & Accessible Technology Research Group Disability Interactions Materials For Facial Prostheses In Resource Limited Countries Sophia Esther Liiba Tetteh A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University Loughborough University Materials For Facial Prostheses In Resource Limited Countries Facial prostheses are artificial devices that replace a missing body part in the facial and neck regions of the body. Defects or deformities in these regions can lead to functional deficiencies; social and psychological effects in addition to cosmetic defects. Restoration or rehabilitation in resource limited countries is usually provided by charities and organisations volunteering assistance overseas, with some training of local staff in the fabrication of these prostheses. Furthermore, these countries typically lack technical knowhow and trained personnel. In industrialised nations maxillofacial prosthetics has developed into a sophisticated medical speciality requiring highly skilled staff and expensive facilities. In resource limited countries surgical procedures may be an option for rehabilitation of these deformities/defects however, they tend to be unavailable or unaffordable and donated prostheses are not suitable. Hence, this research explores, from first principles, the appropriate and affordable local provision of maxillofacial prostheses in resource constrained regions. The investigation provides knowledge on identifying requirements for resource limited areas, resulting in the creation of a guideline constituting priorities, requirements and specifications. It further explores the viability of potentially cheaper, locally available candidate materials via weathering and antimicrobial methods in ascertaining material longevity. Materials For Facial Prostheses In Resource Limited Countries Tetteh, Sophia (2019): Materials for facial prostheses in resource-limited countries. Loughborough University. Thesis.https://doi.org/10.26174/thesi...; Type PhD Themes Assistive & Accessible Technology Research Group Disability Interactions Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers Rhys James Williams Thesis: Firstly, the research provides a methodological contribution showing how to conduct mixed-methods research to obtain rich insights into complex prosthesis phenomena. Secondly, the research highlights the need to appreciate psychological and contextual factors when researching prosthesis wearer thermal comfort. The research contributions are also converted into an implication for prosthesis design. The concept of 'regaining control' to psychologically mitigate thermal discomfort could be incorporated into technologies by using 'on-demand' thermal discomfort relief, rather than 'always-on' solutions, as have been created in the past. UCL, ProQuest Dissertations Publishing Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers Amongst lower-limb prosthesis wearers, thermal discomfort is a common problem with an estimated prevalence of more than 50%. Overheating does not just create discomfort to the user, but it has been linked to excessive sweating, skin damage caused by a moist environment and friction. Due to impermeable prosthetic components and a warm moist environment, minor skin damage can result in skin infections that can lead to prosthesis cessation, increased social anxiety, isolation and depression. Despite the seriousness of thermal discomfort, few studies explore the issue, with research predominantly constrained to controlled laboratory scenarios, with only one out of laboratory study. In this thesis, studies investigate how thermal discomfort arises and what are the consequences of thermal discomfort for lower-limb prosthesis wearers. Research studies are designed around the principles of presenting lived experiences of the phenomenon and conducting research in the context of participants' real-life activities. A design exploration chapter investigates modifying liner materials and design to create a passive solution to thermal discomfort. However, this approach was found to be ineffective and unfeasible. Study 1 presents a qualitative study which investigates the user experience of a prosthesis, thermal discomfort and related consequences. Study 2 explores limb temperature of male amputees inside and outside the laboratory, with the latter also collecting perceived thermal comfort (PTC) data. Finally, Study 3 investigates thermal discomfort in the real-world and tracks limb temperature, ambient conditions, activities, and experience sampling of PTC. While there were no apparent relationships presented in sensor data, qualitative data revealed that in situations where prosthesis wearers perceived a lack of control, thermal discomfort seemed to be worse. When combined, the studies create two knowledge contributions. Firstly, the research provides a methodological contribution showing how to conduct mixed-methods research to obtain rich insights into complex prosthesis phenomena. Secondly, the research highlights the need to appreciate psychological and contextual factors when researching prosthesis wearer thermal comfort. The research contributions are also converted into an implication for prosthesis design. The concept of 'regaining control' to psychologically mitigate thermal discomfort could be incorporated into technologies by using 'on-demand' thermal discomfort relief, rather than 'always-on' solutions, as have been created in the past. Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers Williams, Rhys James. “Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers.” ProQuest Dissertations Publishing, 2020. Print. Type PhD Themes Assistive & Accessible Technology Research Group Disability Interactions Design rules for additively-manufactured wrist splints Sarah Kelly A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University. Loughborough University Design rules for additively-manufactured wrist splints Additive Manufacturing (AM) often known by the term three-dimensional printing (3DP) has been acknowledged as a potential manufacturing revolution. AM has many advantages over conventional manufacturing techniques; AM techniques manufacture through the addition of material - rather than traditional machining or moulding methods. AM negates the need for tooling, enabling cost-effective low-volume production in high-wage economies and the design & production of geometries that cannot be made by other means. In addition, the removal of tooling and the potential to grow components and products layer-by-layer means that we can produce more from less in terms of more efficient use of raw materials and energy or by making multifunctional components and products. The proposed Centre for Doctoral Training (CDT) in Additive Manufacturing and 3D Printing has the vision of training the next generation of leaders, scientists and engineers in this diverse and multi-disciplinary field. As AM is so new current training programmes are not aligned with the potential for manufacturing and generally concentrate on the teaching of Rapid Prototyping principles, and whilst this can be useful background knowledge, the skills and requirements of using this concept for manufacturing are very different. This CDT will be training cohorts of students in all of the basic aspects of AM, from design and materials through to processes and the implementation of these systems for manufacturing high value goods and services. The CDT will also offer specialist training on aspects at the forefront of AM research, for example metallic, medical and multi-functional AM considerations. This means that the cohorts graduating from the CDT will have the background knowledge to proliferate throughout industry and the specialist knowledge to become leaders in their fields, broadening out the reach and appeal of AM as a manufacturing technology and embedding this disruptive technology in company thinking. In order to give the cohorts the best view of AM, these students will be taken on study tours in Europe and the USA, the two main research powerhouses of AM, to learn from their international colleagues and see businesses that use AM on a daily basis. One of the aims of the CDT in AM is to educate and attract students from complementary basic science, whether this be chemistry, physics or biology. This is because AM is a fast moving area. The benefits of having a CDT in AM and coupling with students who have a more fundamental science base are essential to ensure innovation & timeliness to maintain the UK's leading position. AM is a disruptive technology to a number of industrial sectors, yet the CDTs industrial supporters, who represent a breadth of industrial end-users, welcome this disruption as the potential business benefits are significant. Growing on this industry foresight, the CDT will work in key markets with our supporters to ensure that AM is positioned to provide a real and lasting contribution & impact to UK manufacturing and provide economic stability and growth. This contribution will provide societal benefits to UK citizens through the generation of wealth and employment from high value manufacturing activities in the UK. Design rules for additively-manufactured wrist splints Kelly, Sarah (2020): Design rules for additively-manufactured wrist splints. Loughborough University. Thesis.https://doi.org/10.26174/thesi...; Type PhD Themes Assistive & Accessible Technology Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece Anna Vlachaki The literature shows that research into the aesthetic aspects of prostheses is limited. Although there are suggestions that prostheses with high levels of emotionally-driven design may improve users’ well-being, they are based only on theoretical findings. Therefore, in this thesis the effects of emotionally-driven prostheses on users’ lives and society’s attitudes were explored, with respect to culture and more specifically, the theories of individualism/ collectivism. In order to investigate the effects of culture, the research was conducted in two countries with different cultures; the UK (individualistic) and Greece (collectivistic). The thesis began with a literature review across three core areas: user, product and environment, and revealed the importance of investigating an additional area; that of prosthetists. The research employed a qualitative approach and consisted of four studies. Loughborough University Abstract Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece The literature shows that research into the aesthetic aspects of prostheses is limited. Although there are suggestions that prostheses with high levels of emotionally-driven design may improve users’ well-being, they are based only on theoretical findings. Therefore, in this thesis, the effects of emotionally-driven prostheses on users’ lives and society’s attitudes were explored, with respect to culture and more specifically, the theories of individualism/ collectivism. In order to investigate the effects of culture, the research was conducted in two countries with different cultures; the UK (individualistic) and Greece (collectivistic). The thesis began with a literature review across three core areas: user, product and environment, and revealed the importance of investigating an additional area; that of prosthetists. The research employed a qualitative approach and consisted of four studies. Study I was an online questionnaire to explore users’ preferences towards prostheses, with respect to their culture. Study II consisted of semi-structured interviews and informational probes to comprehend the role of prostheses on users’ lives, with respect to prosthetic appearance. In Study III, the aim was to investigate prosthetists’ attitudes towards the needs of prosthetic users by conducting semi-structured interviews. Finally, Study IV was an online questionnaire to explore non-users’ attitudes towards the design of prostheses. The research showed that the use of prostheses for the completion of users’ body was not an adequate factor to improve their well-being, and a shift on users’ desires towards emotionally-driven prostheses has occurred. From the variables that were tested, sex, age, cause and area of limb-loss may affect people’s attitudes towards the design of prostheses. Furthermore, the results showed that prostheses with high emotionally-driven design evoked emotions, in both users and non-users, with higher levels of pleasantness and arousal than the emotions that were elicited by the prostheses of lower emotionally-driven designs and thus, they may trigger a greater behavioural reaction. This suggested that emotionally-driven prostheses may eliminate users’ stigmatisation by increasing their self-confidence and altering society’s attitudes. However, attention needs to be paid in collectivistic countries, as emotionally-driven prostheses may enhance users’ stigmatisation. Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece Vlachaki, Anna (2020): Emotionally-driven prostheses: exploring the effects on users’ lives and societies’ attitudes in the UK and Greece. Loughborough University. Thesis.https://doi.org/10.26174/thesi...; Type Workshop Themes Assistive & Accessible Technology Culture and Participation Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions Maryam Bandukda, Aneesha Singh,Catherine Holloway,Nadia Berthouze, Emeline Brulé, Ana Tajadura-Jiménez, Oussama Metatla, Ana Javornik, and Anja Thieme The emerging possibilities of multisensory interactions provide an exciting space for disability and open up opportunities to explore new experiences for perceiving one's own body, it's interactions with the environment and also to explore the environment itself. In addition, dynamic aspects of living with disability, life transitions, including ageing, psychological distress, long-term conditions such as chronic pain and new conditions such as long-COVID further affect people's abilities. Interactions with this diversity of embodiments can be enriched, empowered and augmented through using multisensory and cross-sensory modalities to create more inclusive technologies and experiences. To explore this, in this workshop we will explore three related sub-domains: immersive multi-sensory experiences, embodied experiences, and disability interactions and design. CHI EA '21: Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems Abstract Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions The emerging possibilities of multisensory interactions provide an exciting space for disability and open up opportunities to explore new experiences for perceiving one's own body, it's interactions with the environment and also to explore the environment itself. In addition, dynamic aspects of living with disability, life transitions, including ageing, psychological distress, long-term conditions such as chronic pain and new conditions such as long-COVID further affect people's abilities. Interactions with this diversity of embodiments can be enriched, empowered and augmented through using multisensory and cross-sensory modalities to create more inclusive technologies and experiences. To explore this, in this workshop we will explore three related sub-domains: immersive multi-sensory experiences, embodied experiences, and disability interactions and design. The aim is to better understand how we can re-think the senses in technology design for disability interactions and the dynamic self, constructed through continuously changing sensing capabilities either because of changing ability or because of the empowering technology. This workshop will: (i) bring together HCI researchers from different areas, (ii) discuss tools, frameworks and methods, and (iii) form a multidisciplinary community to build synergies for further collaboration. Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions Maryam Bandukda, Aneesha Singh, Catherine Holloway, Nadia Berthouze, Emeline Brulé, Ana Tajadura-Jiménez, Oussama Metatla, Ana Javornik, and Anja Thieme. 2021. Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions. Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems. Association for Computing Machinery, New York, NY, USA, Article 118, 1–5. DOI:https://doi.org/10.1145/341176... Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions Type Conference Paper Themes Assistive & Accessible Technology Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People Maryam Bandukda,Catherine Holloway, Aneesha Singh,Giulia Barbareschi, Nadia Berthouze We conducted semi-structured interviews with 20 BPS people and 8 Mobility and Orientation Trainers (MOT). The interviews were thematically analysed and organised into four overarching themes discussing factors influencing the self-efficacy belief of BPS people: Tools and Strategies for O&M training, Technology Use in O&M Training, Changing Personal and Social Circumstances, and Social Influences. We further highlight opportunities for combinations of multimodal technologies to increase access to and effectiveness of O&M training. ASSETS '21: Proceedings of the 23rd International ACM SIGACCESS Conference on Computers and Accessibility Abstract Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People Orientation and mobility (O&M) training provides essential skills and techniques for safe and independent mobility for blind and partially sighted (BPS) people. The demand for O&M training is increasing as the number of people living with vision impairment increases. Despite the growing portfolio of HCI research on assistive technologies (AT), few studies have examined the experiences of BPS people during O&M training, including the use of technology to aid O&M training. To address this gap, we conducted semi-structured interviews with 20 BPS people and 8 Mobility and Orientation Trainers (MOT). The interviews were thematically analysed and organised into four overarching themes discussing factors influencing the self-efficacy belief of BPS people: Tools and Strategies for O&M training, Technology Use in O&M Training, Changing Personal and Social Circumstances, and Social Influences. We further highlight opportunities for combinations of multimodal technologies to increase access to and effectiveness of O&M training. Type Conference Paper Themes Assistive & Accessible Technology What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT Giulia Barbareschi, Norah Shitawa Kopi,Ben Oldfrey,Catherine Holloway In this paper, we examine how young Kenyans without disabilities view people with disabilities and AT users. Findings show that while the portrayal of disability is often shaped by negative emotion, participants felt that many of the barriers affecting people with disabilities were created by society. Perceptions of AT differed –devices were not only seen as a mark of disability but also as a sign of access to resources. Therefore, what we see is an emergent picture where social barriers can be reinforced by poverty, and where poverty reinforces social barriers faced by people with disabilities. We conclude that access to appropriate technology alongside societal interventions tackling incorrect beliefs about disability can help to overcome the stigma faced by people with disabilities. ASSETS '21: Proceedings of the 23rd International ACM SIGACCESS Conference on Computers and Accessibility Abstract What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT Most research which investigates stigma towards with people with disabilities and the use of Assistive Technology (AT) are based in the Global North and focus on the experiences of people with disabilities and the consequences that stigma has on choices surrounding AT. However, stigma is a societal construct rooted in the attitude and beliefs that people without disabilities hold on disability and AT. Furthermore, the portrayal of people with disabilities and AT is dependent on the social context. In this paper, we examine how young Kenyans without disabilities view people with disabilities and AT users. Findings show that while the portrayal of disability is often shaped by negative emotion, participants felt that many of the barriers affecting people with disabilities were created by society. Perceptions of AT differed –devices were not only seen as a mark of disability but also as a sign of access to resources. Therefore, what we see is an emergent picture where social barriers can be reinforced by poverty, and where poverty reinforces social barriers faced by people with disabilities. We conclude that access to appropriate technology alongside societal interventions tackling incorrect beliefs about disability can help to overcome the stigma faced by people with disabilities. Cite What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT Giulia Barbareschi, Norah Shitawa Kopi, Ben Oldfrey, and Catherine Holloway. 2021. What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT. In The 23rd International ACM SIGACCESS Conference on Computers and Accessibility( ASSETS '21). Association for Computing Machinery, New York, NY, USA, Article 18, 1–13. DOI:https://doi.org/10.1145/3441852.3471226 What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT Type Workshop Themes Assistive & Accessible Technology Research Group Disability Interactions Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI. Giulia Barbareschi,Dafne Zuleima Morgado-Ramirez,Catherine Holloway, Swami Manohar Swaminathan, Aditya Vashistha, and Edward Cutrell. Approximately 15% of the world's population has a disability and 80% live in low resource-settings, often in situations of severe social isolation. Technology is often inaccessible or inappropriately designed, hence unable to fully respond to the needs of people with disabilities living in low resource settings. Also lack of awareness of technology contributes to limited access. This workshop will be a call to arms for researchers in HCI to engage with people with disabilities in low resourced settings to understand their needs and design technology that is both accessible and culturally appropriate. Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems. Abstract Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI. Approximately 15% of the world's population has a disability and 80% live in low resource-settings, often in situations of severe social isolation. Technology is often inaccessible or inappropriately designed, hence unable to fully respond to the needs of people with disabilities living in low resource settings. Also lack of awareness of technology contributes to limited access. This workshop will be a call to arms for researchers in HCI to engage with people with disabilities in low resourced settings to understand their needs and design technology that is both accessible and culturally appropriate. We will achieve this through sharing of research experiences, and exploration of challenges encountered when planning HCI4D studies featuring participants with disabilities. Thanks to the contributions of all attendees, we will build a roadmap to support researchers aiming to leverage post-colonial and participatory approaches for the development of accessible and empowering technology with truly global ambitions. Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI. Giulia Barbareschi, Dafne Zuleima Morgado-Ramirez, Catherine Holloway, Swami Manohar Swaminathan, Aditya Vashistha, and Edward Cutrell. 2021. Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI. Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems. Association for Computing Machinery, New York, NY, USA, Article 124, 1–5. DOI:https://doi.org/10.1145/3411763.3441340 Type Conference Paper Themes Assistive & Accessible Technology Inclusive Educational Technology Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution Tigmanshu Bhatnagar, Nicolai Marquardt, Mark Miodownik,Catherine Holloway Shape changing materials create a unique opportunity to design reconfigurable tactile display actuators. In this paper, we present a method that transforms a single thin monolithic sheet of Nitinol into a passive reconfigurable tactile pixel array at Braille resolution. We have designed a 27x27 tactile pixel array in which each pixel can be selectively actuated with an external source of heat. The pixels rise 0.4mm vertically with a peak blocked force of 0.28kg and have an average blocked force of 0.23kg at room temperature. After cooling, the pixels can be mechanically reconfigured back to their flat state for repeatable actuation. We demonstrate this actuator’s interactive capabilities through a novel erasable tactile drawing interface. IEEE World Haptics Conference; 2021 Abstract Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution Shape changing materials create a unique opportunity to design reconfigurable tactile display actuators. In this paper, we present a method that transforms a single thin monolithic sheet of Nitinol into a passive reconfigurable tactile pixel array at Braille resolution. We have designed a 27x27 tactile pixel array in which each pixel can be selectively actuated with an external source of heat. The pixels rise 0.4mm vertically with a peak blocked force of 0.28kg and have an average blocked force of 0.23kg at room temperature. After cooling, the pixels can be mechanically reconfigured back to their flat state for repeatable actuation. We demonstrate this actuator’s interactive capabilities through a novel erasable tactile drawing interface. Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution T. Bhatnagar, N. Marquardt, M. Miodownik and C. Holloway, "Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution," 2021 IEEE World Haptics Conference (WHC), 2021, pp. 409-414, doi: 10.1109/WHC49131.2021.9517239.
https://www.disabilityinnovation.com/publications?page=4&type=phd+book+conference-paper+toolkit+workshop
Sustainability | Free Full-Text | Getting Involved with Vaccination. Swiss Student Teachers’ Reactions to a Public Vaccination Debate Vaccination is an explicit topic of the United Nations’ 2030 Agenda for Sustainable Development. The present article explores a new way of involving student teachers into the vaccination debate. To this aim, 273 students at a Swiss university for teacher education were invited to read a debate between a vaccination proponent and a vaccination opponent that had been published in a free local newspaper. Then, they were asked to judge five of the main arguments of each discussant and to take a (hypothetical) general decision in favor or against vaccination. This decision, the judgements, and students’ comments were investigated with a mixed method approach in order to better understand the students’ needs and to refine the new approach. It was found that the students eagerly took part in the intervention, but that they were very ambivalent concerning the arguments. They could be classified into three groups. Two groups, called the acceptors and the rejectors, supported the proponent and the opponent, respectively, and decided accordingly in favor or against vaccination. However, there remained a considerably large group that was called the hesitators. They were particularly ambivalent towards both types of argumentation, but, as structural equation modelling revealed, they eventually were more influenced by the arguments in favor than by those against vaccination. In their comments, these students wanted to know more about the prevented diseases, and they often referred to their personal experience but not to the experts’ arguments. It was concluded that this group would benefit most from the new type of intervention. A shared-decision approach, as is today prominently discussed in medicine, could improve its impact, and ways should be found to more seriously and consistently include empathetic understanding in pedagogical settings—for example, by adapting the three-step model from medicine or the reflective equilibrium approach from applied ethics. Department of Science; University of Teacher Education Lucerne, Pfistergasse 20, CH-6000 Lucerne 7, Switzerland Sustainability 2019 , 11 (23), 6644; https://doi.org/10.3390/su11236644 Received: 6 October 2019 / Revised: 17 November 2019 / Accepted: 20 November 2019 / Published: 24 November 2019 (This article belongs to the Special Issue Teaching Sustainable Development Goals in Science Education ) Abstract Keywords: vaccination vaccination hesitancy decision making teacher education education 1. Introduction Vaccines are a suggested topic of the education for sustainable development goals, as they are included in the educational part of the 2030 Agenda for Sustainable Development, which was adopted by all United Nations member states in 2015. Schools could be important places for improving vaccination acceptancy in society. Dubé et al. point out that “ensuring education and knowledge about vaccines in younger individuals (children, adolescents, young adults), possibly through school-based programs, may provide a good opportunity to encourage future vaccine acceptance by parents and adults and minimize the potential for development of hesitancy” [ 1 ]. These authors indicate that more research is needed to evaluate such a strategy. The present research has been conducted in the context of a Swiss teacher education university. In this institution, one week per year is reserved for health issues in schools. In this special week (called “Impulswoche,” a week for new impulses), all future teachers for primary and lower secondary levels learn about a variety of health issues in school, such as the management of chronic diseases in school, first-aid issues, common health problems in daily school life, and issues of prevention and health promotion in school. The basic idea of this study was to test an intervention about vaccination during this special week. To achieve this, a vaccination debate published in a free local newspaper was presented to the students. Choosing a population of future teachers met Dubé et al.’s request for more strategy evaluation in two ways. First, many of these student teachers will indeed be parents themselves in a few years. Second, once on the job, they will teach children and adolescents about health issues. Therefore, it is important to understand how they react to vaccination information in the media. This may allow teacher training to be tailored to their needs. 2. Theoretical Background Today, according to many public health experts, vaccination hesitancy is increasing among parents [ 3 ]. A number of surveys over the past two decades have concluded that, although parents generally consider immunization to be important, a majority of them reported vaccine concerns [ 4 ]. There is a broad range of factors contributing to these concerns. For example, parents are uncomfortable about mandatory vaccination, they feel unable to control potential adverse reactions, they prefer “natural” risks to “manmade” risks, and they have little to no experience of diseases prevented by vaccines, such as polio, measles, and diphtheria [ 4 ]. However, contrary to some experts’ explanations, parents’ decision against vaccination is not simply thoughtless, irrational, or the result of a lack of knowledge about vaccines. Detailed studies have shown that vaccine-refusing parents are well-informed individuals with considerable interest in health-related issues and who actively seek information [ 5 ]. Many other communication tools that help healthcare providers to discuss vaccination with vaccine-hesitant parents have been published, but they have seldom been evaluated [ 1 ]. In fact, there is still a significant lack of solid empirical information on effective strategies to address vaccine hesitancy [ 4 ]. In light of this, the SAGE Working Group on Vaccine Hesitancy emphasizes the importance of understanding the specific concerns of the various groups of vaccine-hesitant individuals [ 1 ]. In particular, studies are needed that test the effectiveness of delivering information to parents through different media in order to better inform public health awareness initiatives [ 3 ]. Many motives for non-compliance have to do with deliberate avoidance. Extensive research literature has suggested that reasons for opposing vaccination in general include concerns about vaccine safety and efficacy, as well as a distrust of the conventional medical establishment and government as health information sources [ 6 , 7 ]. People also avoid vaccination against diseases that they perceive as not serious or eradicated in their areas. A good example is the case of Human Papilloma Virus (HPV) vaccination. Here, individuals often express concerns about HPV vaccine being too new to have accumulated sufficient long-term safety data. Parents are also concerned about the perceived connection between HPV vaccination and early sexual activity [ 8 ]. As a result, many parents of children and adolescents are reluctant to vaccinate their children. For example, in the US, according to the Center for Disease Control, only 43% of adolescents are up-to-date on their HPV vaccination [ 9 ]. In Switzerland, the estimated HPV immunization rate is 57%, following the vaccination campaign of 2008/09, which is still unsatisfactorily low [ 10 ]. Public health brochures and websites typically discuss vaccination via factual statements about its safety, effectiveness, and benefits, and they provide practical vaccination information (e.g., places to get vaccination). Usually, these documents do not introduce biological concepts that may be essential to addressing safety information needs and dismantling misunderstandings around vaccination. In a qualitative study, Zeyer and Sidler investigated the impact of reading a standard HPV vaccination information flyer on the participants’ attitudes towards HPV vaccination. They found that reading the flyer had no impact on the students’ interest in receiving the vaccine, with pre-test misconceptions not affected by the flyer [ 11 ]. This raises questions about the sufficiency of factual information for belief changes and asks for different approaches to vaccination education. Another place where individuals may encounter information about vaccinations is the school system [ 12 ]. However, the science education systems of most countries do not include the coverage of microbiology and immunology that would constitute conceptual basis for understanding vaccination [ 13 ]. Studies have suggested that European and US students at all grade levels have a limited understanding of viruses, contagion, vaccination, and vaccine-preventable diseases. For example, in a study with a sample of 11-year-olds in the UK, Byrne and Grace found that while most participants knew that microorganisms could cause diseases, their understanding of vaccination-induced prevention was very limited [ 14 ]. Many thought that vaccines attacked and killed pathogens, thus essentially viewing vaccines as medicine. While these students were young, other studies suggest that misinformation about microorganisms, infection and vaccination persist into later school years [ 15 ]. Focusing on knowledge about influenza, Romine, Barrow, and Folk discovered that Midwestern US high school students (grades 9–12) hold a number of misconceptions about vaccine and vaccination, including the belief that a vaccine acts as medicine [ 16 ]. In this context, it is be essential to know the attitude of teachers towards vaccination and the role of education in this context. Unfortunately, these questions seem to have been widely neglected in research thus far, e.g., [ 12 ]. In a small qualitative study, Zeyer and Di Rocco investigated problems with HPV vaccination in a Swiss lower secondary school. Interviews with students, teachers and parents revealed, that—besides the well-known reluctance of parents, particularly mothers—about half of the interviewed teachers questioned this vaccination and, generally, their role in the vaccination issue. The authors concluded that involving student teachers with vaccination issues would be an important and rewarding task in the education for sustainability [ 17 ]. 3. Research Context, Research Question and Hypothesis This study made use of an article in a free local paper, distributed to more than a million Swiss households. This free paper, provided by a Swiss supermarket chain, is very popular in Switzerland, and it is read and shared within families, particularly among parents and grandparents. Besides containing advertisements and marketing information, it also includes highly appreciated articles about issues of daily life and health. The article used in this study included a debate on vaccines between the pro and the contra vaccination community in Switzerland [ 18 ]. The pro vaccination exponent was a professor for pediatric infectious diseases at Basel University Hospital. The contra vaccination exponent was a Swiss general practitioner, well known in Switzerland for his pointed rejection of vaccines and for attracting a great number of vaccination rejecters around him. In the article, both exponents presented their viewpoints by answering an interviewer’s questions, and they also were given the opportunity to directly contest their opponent’s statements. The article included a biographical sketch of each person but refrains from making an editorial comment. The approach taken in this study was to give the article to the student teachers and to let them read it. Then, the students had to judge five core statements of each expert and to answer the question of how they would decide if they were parents and had to vaccinate their child. The research question with this procedure was: (RQ1) How and to what extent do the judgements relate to each student’s vaccination decision? It was hypothesized that the pro and the contra arguments would have an approximately equal but inverse influence, i.e., that agreement with the pro vaccination argumentation would entail a positive vaccination decision and vice versa. Structural equation modelling provided an appropriate method for testing this hypothesis. At the end of this procedure, the students had the opportunity to make comments about their vaccination decision. The research question in this context was the following: (RQ2) Can students’ comments be qualitatively classified into groups of different attitudes, and how do these groups relate to the students’ vaccination decision? 4. Method 4.1. Questionnaire Five core statements of both standpoints were identified by carefully reading the article and discussing it with students of another group in another university. Each statement had to be judged on a scale between −3 (full dissent) and +3 (full consent). In this way, a questionnaire with 10 items was created, with 5 items representing the construct pro vaccination and 5 questions representing the construct contra vaccination. In a pre-test with 35 students, a classical factor analysis was done. Both constructs showed a high face validity and a good statistical reliability [ 19 ]. The items of the questionnaire are displayed in Table 1 and Table 2 below. The questionnaire included an additional item (No. 11). In this item, students were asked to imagine that they were parents and how they would “generally” decide about their child’s vaccinations: “In general, would you rather accept or reject vaccination for your child?” The students had to choose between “rather accept” (1) and “rather reject” (0). Table 1. Items of the “pro vaccination” construct, showing means and standard deviation (SD). Table 2. Items of the “contra vaccination” construct, showing means and standard deviation (SD). 4.2. Sample and Procedure Data were collected during two “special weeks” of two consecutive years at a Swiss university of teacher education (see introduction). The definitive sample comprised 272 student teachers (see descriptive measures below). Permission for participation and ethical approval was given by the authority of the Lucerne University of Teacher Education (Prorektorat Forschung Pädagogische Hochschule Luzern), which, in Switzerland, is the institutional board responsible for approving minimal-risk research, conducted with adult participants in an established educational setting. Before data collection, all students were informed about their right not to participate. All participants were adults over 18 years of age. No personally identifiable information was collected in the survey. There was no key connecting the answers to students. The students read the vaccination debate in the article. The questionnaire was distributed. At the end of the session, the volunteers were invited to contribute their completed questionnaire for the present study. A proctor, not connected to the course, collected contributed materials. Students not willing to contribute their materials retained them. According to the Swiss Coordination Office for Research on Human beings (Kofam), this research project did not come under the scope of application of the Human Research Act, because the health-related data were collected anonymously [ 20 ]. 4.3. Statistical Analysis A classical statistical analysis was done by means of IBM SPSS (Version 25) [ 21 ]. For structural equation modelling (SEM), IBM SPSS AMOS 21.0 and the maximum-likelihood estimation approach were used [ 22 ]. 4.4. The Structural Model Structural equation modelling (SEM) is a statistical method that takes a confirmatory approach to a structural theory underlying some phenomenon. Hypothesized causal relations between involved factors are modelled by structural graphs and statistically tested in a simultaneous analysis of the entire system of variables. Its particular strength is the testing of theoretical constructs which are represented by latent variables [ 23 ]. The modeling estimates impact factors of causal influences and calculates covariances between variables. Because this study was particularly interested in the impact of experts’ arguments (condensed in two latent variables) on students’ decision making, SEM, a widely used method in social sciences, was considered to be appropriate [ 24 ]. The tested structural model reflected the research hypothesis. Thus, the two endogenous variables, representing the pro vaccination construct (5 items) and the contra vaccination construct (5 items) were designed to model a symmetric causal impact on the variable vaccination decision (exogenous discrete variable). In other words, it was expected that the impact of the variable contra vaccination on the variable vaccination decision would be negative and the impact of pro vaccination on vaccination decision would be positive. Furthermore, SEM assumes as a standard—that the two variables pro vaccination and contra vaccination covary. The covariance was expected to be negative because the model represents a controversy between two experts of opposing opinion (see Figure 1 ). Figure 1. Basic structure of the structural model. A two-step process was established to test the model [ 23 ]. As a first step, the pro vaccination and contra variation measurement models were tested through a confirmatory factor analysis. The five items of each of these variables were then combined, not in a Likert scale, but rather with weighted factors that the program calculated. This allowed for a better fit of the full model. In a second step, the two measurement models and the decision variable were combined into the full model for the vaccination decision. 5. Results Generally, it can be stated that the intervention was implemented without problems. The students were interested and focused. Though their participation in the study was explicitly declared as voluntary, the majority of the students filled in the questionnaire and completed the survey with a short comment. 5.1. Descriptive Measures The data were collected from a total of 273 students. Data were excluded if a student had not answered every question or if answers could not definitively be identified. After this raw data cleaning, the sample included 255 students (18 omitted cases, 6.59%), 170 females (66.6%) and 85 males (33.3%). The mean age was M age = 23.2 years (SD = 3.26). 5.1.1. Statistics of the Pro and Contra Vaccination Statements and of the Vaccination Decision Table 1 and Table 2 display the pro vaccination and the contra vaccination statements, their means, and their standard deviations. The Cronbach’s alpha for the five pro vaccination statements was 0.797, and it was 0.682 for the five contra vaccination statements, i.e., both scales were of acceptable internal reliability. The mean of the pro vaccination statements was 0.92 (SD 1.16), i.e., these statements were, on average, judged as slightly positive by the students. The mean of the contra vaccination statements was 0.22 (SD 1.06), i.e., the average judgment of these items was almost neutral. The average student mean for the pro vaccination arguments was 0.0922 (SD 1.16), i.e., the students, on average, agreed slightly with the pro vaccination arguments. The average student mean for the contra vaccination arguments was smaller (0.023, SD 1.06), but the students, on average, also slightly agreed with the contra vaccination arguments. All in all, the students were, on average, almost neutral towards both groups of arguments, with a small advantage for the pro argumentation. Two hundred and eight students answered that they would, in principle, vaccinate their child (76.6%). Forty-six students answered that they would decide against vaccination of their child (16.8%). Eighteen students (6.6%) did not answer this question. 5.1.2. Qualitative Content Analysis of Students’ Open Answers The qualitative content analysis of the open question yielded four different student groups of different sizes. In the following, each of these groups is shortly described. The rejectors group (15 students, 5.6%) reproduced arguments provided by the contra vaccination expert. Examples include: To me, it is important that a child would go through the real disease. That makes them more immune than vaccination would do (stud8#38). I believe that one should vaccinate as little as possible. The body does it itself. It gets then stronger (stud8#59). There are no studies that investigate which other diseases can be triggered by vaccination (immunodeficiency, allergies, children’s diseases, etc.) (stud8#116). In their open answer, the acceptors group reproduced arguments provided by the pro vaccination expert. This group contained of 68 students (26.7% of the sample). Examples of argumentation include: Complications of the original disease are too dangerous. Children should be protected (stud 8#14). Additional security. Vaccination complications are smaller, less probable (stud8#33) I’d never expose my child to the risk of long-term effects, if I can prevent these (stud8#79). We call the third group the evaluators. This group included 49 students (19.2%) and conveyed that they would not want to decide “in principle” but their decision would be dependent on the (perceived) severity of the illness. Many of them referred to concrete diseases that they perceived as severe and others they perceived as harmless and did not see a need to vaccinate against them. Here are some examples: I’d vaccinate against measles by all means. For all other diseases I’d apply only the minimum (stud10#93). I’d vaccinate against hepatitis, etc. Against the measles, [I’d vaccinate] only when the child is getting older (stud10#58). Vaccination against children’s diseases only in adulthood, if the child has not already gone through it. Yes for vaccination against polio (stud10#008). Finally, the last group referred to personal experience for motivating their decisions (Label “experiencers,” 35 students, 13.7%). Examples are: I’ve been vaccinated myself—and I never experienced complications (stud10#60). I’ve never got into the issue deeply, but I’ve been vaccinated myself and it did no harm to me (stud8#149). I’ve never been vaccinated and it did no harm to me (stud9#131). 92 (36.1%) students did not provide a statement that could be coded (Label “not coded”), either because they didn’t write an answer or because the answer was not readable. Table 3 and Table 4 bring the four essential groups into relation to the statistical results. Table 3 provides the numbers and the percentage of pro vaccination and contra vaccination decisions for each group. The percentage was calculated “within group.” That is, within the group of rejectors (15 students), fourteen students, i.e., 93.3% of them, answered that, in general, they would not vaccinate their child. One student, i.e., 6.7%, answered that, in general, they would vaccinate their child. Table 3. Numbers and the percentage of pro vaccination and contra vaccination decisions for each group. Table 4. Mean averages for pro vaccination and contra vaccination arguments per group (z-values). Table 4 displays how every group, on average, judged the core statements of the pro vaccination and the contra vaccination expert. In this table, we used the z-value, which shows how much each group, on average, deviated from the mean, as indicated in standard deviations. For example, if the z-value is −1, this shows, that the judgement of the respective group was one standard deviation more negative than the average judgement of all students. The same holds for the third column, which shows the z-values of the contra vaccination statements for each group. Table 3 Table 4 Table 5 , finally, compares the distribution of the four groups in the general sample with the situation among those student teachers who had chosen science as one of their educational subjects. There were, in percentage terms, less acceptors within the science students (13.6%) than within the non-science students (26.8%), and less rejectors (2.3% vs. 6.1%). Among science students were more evaluators (27.3%) than among non-science students (16.2%). As to the experiencers, their percentage was approximately the same for both subgroups (13.6% vs. 12.7%). Table 5. Group percentages. Comparison between non-science students and science students. 5.2. The Structural Model Structural modelling can add more insights to these findings, because it combines calculated impacts between different variables in one model. The full structural model for vaccination decisions is displayed in Figure 2 . This figure includes all standardized regression weights. Figure 2. Structural model for vaccination decisions. As a first step, the fit of the model was investigated. The model was well-fitting and produced highly significant results. In technical terms, this means: All factor loadings of the measurement model were statistically highly significant ( p < 0.001), except the factor loading of contra vaccination on vaccination decision. The corresponding signs concurred with the hypotheses. The standardized estimates confirmed the formal validity of the individual items [ 23 ]. Descriptively, the model worked well, which was first indicated by a highly acceptable goodness-of-fit index (GFI) of 0.95 (>0.9 for good fit; for fit measures, see [ 25 ] p. 551ff). Second, the baseline comparison, the comparative fit index (CFI), was excellent (CFI = 0.989 (>0.9)). From an inferential point of view, the model was compatible with the data (CMIN/DF = 1.496, p = 0.023,). Finally, RMSEA = 0.048 (<0.05) and PCLOSE = 0.517 (>0.5) also indicated a good fit. As a next step, the relations between the variables were evaluated. It was found that, in accordance with the hypothesis, the explanatory power of the variable pro vaccination was very high. Indeed, its standardized regression weight on the variable vaccination decision was very high and highly significant (.874, p < 0.001). This means that the variable pro vaccination explained more than half of the variance of the variable vaccination decision (64%). However, in contrast to the hypothesis, there was only a low and not significant impact of the variable contra vaccination on the variable vaccination decision (−0.101, p = 0.06), i.e., this variable had no statistical impact on the decision. Furthermore, and also different from the hypothesis, the covariance between the two variables pro vaccination and contra vaccination was positive (0.53, p < 0.001). This suggests that most people who agreed with the pro vaccination also did with the contra vaccination and vice versa. In addition, during the confirmatory process, two error correlations were added in order to improve the model fit. Both may have a straight forward interpretations. The negative covariance between the errors of items 7 and item 8 takes into account that these two statements are directly opposed, while the positive covariance between item 2 and item 4 reflects that these two statements are related in content. 6. Discussion This study aimed to model the vaccination decision of student teachers after reading a debate between a person who supports vaccination and one who opposes it. The tested structural model reflects the hypothesis that agreeing with the arguments of the pro vaccination proponent would have a direct positive impact on the (hypothetical) decision of student teachers to vaccinate their own child. Conversely, it was assumed that the belief in arguments of the contra vaccination proponent would have a negative impact on that decision. The model strongly confirmed the first part of the hypothesis. The pro vaccination variable explains 48% of the variation of the variable vaccination decision. The second part of the hypothesis, however, was not confirmed. In fact, there was no effect at all of the contra vaccination variable on the decision. This result was unexpected. Since the contra vaccination expert strongly argued against vaccination, one could assume that agreement with his arguments would entail rejection of vaccination. The situation found its explanation in the descriptive statistical results. They produced four different groups. We called them the acceptors, the rejectors, the evaluators and the experiencers. The acceptors, the group that strongly believed in the pro vaccination argumentation, generally decided pro vaccination. The rejectors, the group that decisively reproduced the contra vaccination argumentation, consistently decided against vaccination. However, there were two considerable groups of students, the evaluators and the experiencers, who tended to be pro vaccination but were deeply unsure. The evaluators, in particular, tended strongly towards the contra argumentation but indicated that, in general, they would decide to vaccinate their child. The experiencers tended towards the pro argumentation, but they did not clearly disapprove of the contra argumentation. They also, in general, would decide to vaccinate their child. The structural equation model mirrored this insecurity of many students in a highly positive covariance between the pro vaccination and the contra vaccination variables. It confirms that many students who believed in the pro vaccination argumentation also accepted the contra vaccination argumentation and vice versa. The two groups together, the evaluators and the experiencers, seem to represent those people who often are called the hesitators (see Introduction). In our sample, this group was rather large (77 of 160 coded students), and it explained the unexpected finding of the lack of impact of contra vaccination on vaccination decision. Many of the hesitators were positive, or at least non-negative towards the argumentation of the vaccination opponent. However, when it comes to a general decision for or against vaccination, they seemed to make a positive decision towards vaccination. We conclude from this constellation that the hesitators represent a high potential target group for pro vaccination persuasion work. Actually, they are, in principle, pro vaccination. However, the impact of both the pro vaccination and the contra vaccination arguments on their general vaccination decision was small. Obviously, since they accepted both types of argumentation, their decision remained vastly unimpressed by the debate between the two experts. Other factors seemed to be important in their decision-making process. The decision of evaluators depended on the type of vaccinations and on the diseases they aim to prevent. Their remarks in the survey showed that they want to know more about these contexts—and not about the general vaccination process—in order to be able to make an informed decision. The second group of hesitators, the experiencers, based their decision on their personal experience with vaccinations in the past. If these experiences with concrete vaccinations were problematic, they decided against vaccination. In the other case (which is more frequent), positive vaccination experiences entailed a positive general decision. Again, both experts’ argumentations did not seem to decisively impact the decision making process. An interesting group, finally, were the future science teachers. The percentage of acceptors among them was only half as large as in the non-science teacher group. Almost none of them belonged to the rejectors. If they were hesitators, they tended to belong to the evaluators, i.e., they wanted to know more about the diseases prevented by the different types of vaccinations. Only a small minority of them decided based on personal experiences. 7. Limitations There were some limitations with this study. One limitation was the sample, as it was a census of two consecutive school years in a university of teacher education. However, because these students come from every part of Central Switzerland, they very much represent the teacher population there, with students from rural and urban areas, as well as students from different socio-economic backgrounds. In addition, the majority of females in the sample reflects the fact that more women than men become teachers for primary and secondary one levels. This statistical weakness was also tolerated because in daily life, it is mainly mothers who decide the vaccination status of their children. Another limitation was that the structural model represented a very basic decision between “acceptors” and “rejecters.” The students were forced to decide between these two alternatives, which reflect only the two extremal points of vaccination hesitancy. This simplification was a consequence of the approach of using an article that only presented arguments of acceptors and rejecters. 8. Conclusions All in all, it can be stated that the presented intervention at the university of teacher education was able to involve students and to successfully spark reflection and discussion. However, the results show that there is space for more. Obviously, the four groups that were identified have different needs and may benefit from different approaches. The acceptors, the group that identifies with the pro vaccination argumentation in the text, seemed to be fine with this intervention and did not need further information. Conversely, the rejectors apparently followed the contra vaccination argumentation and did not ask for more information. Both groups seemed to have made up their minds and may be difficult to persuade to move away from their standpoints. This is not the case for the two other groups, the evaluators and the experiencers, which together formed the group of hesitaters in this population. Tending basically towards vaccination acceptance, they nevertheless were insecure about the pro and contra argumentation’s value, and they eventually relied upon other points of view than those presented by both experts. The first group, the evaluators, asked for more concrete information about the prevented diseases. The experiencers ultimately based their decision on personal experience. These results suggest that the chosen strategies of both experts, be they pro or contra vaccination, are fairly inappropriate for promoting vaccination. Both appeal to one group of students that is already convinced of their arguments, and, thus, each of them fails to have an impact on the fluid group of the hesitators that is still ready to change position. Indeed, our findings suggest that hesitators need a different approach that may be captured best by the shared decision-making model, which is probably today’s most popular model in patient-centered medicine [ 26 ]. Shared decision-making has been defined as an approach where clinicians and patients share the best available evidence when faced with the task of making decisions. However, patients are also supported to consider personal options and to achieve informed preferences [ 27 ]. This description has also been condensed to the formula of getting both evidence and preferences into health care [ 28 ] (p. 407). Actually, this is more than a nice label, as Elwyn et al.’s (2017) article in the influential British Medical Journal pointed out: “Instead of assuming that decisions should be guided by scientific consensus about effectiveness, shared decision making proposes that informed preferences—by which is meant what matters to patients and families—should play a major role in decision making processes. Shared decision making is more than being attentive to patients’ needs or concerns—it represents an important shift in the roles of both patients and clinicians.” [ 29 ] (p. 1). Interestingly, in our newspaper article, the two experts (who both are physicians), addressed the evidence side of shared decision making. Surely, from the point of view of school medicine, the evidence of the pro vaccination expert was much better than that of the contra vaccination expert. Nevertheless, the latter also referred to evidence in the sense of experience and observed cases. The hesitators in the student teachers’ collective, however, were found to be concerned with preference questions and asked for the opportunity to find out more about them. An adequate approach could be inspired by the three-step model of shared decision making [ 29 ], which has been developed to help physicians and patients to find their way between evidence and preference. It starts with choice talk, wherein the importance of respecting individual preferences is underlined and the role of uncertainty in medicine is explained. In a second step, the options talk, options are listed and potential harms and benefits are clarified. The process ends with step 3, the decision talk, wherein preferences are elicited, and, eventually, a decision is made or else deferred. In this three-step model, the choice between scientific evidence and alternative evidence should be supported. Students obviously feel disconcerted and unsure vis-a-vis two completely disparate epistemic claims. The finding that science teacher students opted three times more for scientific evidence than other evidence suggests that science education could have a role here. In the field of public understanding and public engagement of science, two strategies for dealing with such conflicts are well known and hotly debated [ 30 ]. The first strategy, called “learning orientation,” typically focuses on learning and understanding scientific content that, at least in principle, can be understood by the non-expert public. This approach fits with the direct positive impact of the pro vaccination argumentation on the vaccination decision. The second strategy, called “communications orientation,” focuses on improving attitudes about science and trust in scientists. This approach seems to be particularly suitable for dealing with the indirect negative attitudinal effect of the contra vaccination argumentation. The two orientations differ in a fundamental way and normally are conceived as controversial in the field of public understanding of science [ 31 ]. Interestingly, the presented model suggests that both orientations seem to be indispensable for a successful campaign to increase vaccination acceptance, as they complement each other. The learning orientation obviously is present in research on vaccination hesitancy [ 1 ]. Indeed, the learning and understanding of vaccination content is one of the factors that has been demonstrated to be efficient [ 2 ]. The learning orientation has been investigated in a number of disciplinary communities, including educational psychology, learning sciences, and science education. However, the communications orientation, aimed at attitudes and perceptions about science (so-called “nature of science attitudes”), seems to be a fairly new perspective for vaccination hesitancy. Nevertheless, it also has a long research tradition in communication sciences, social psychology, and, to some degree, in sociology and science and technology studies [ 30 ]. This research has been carried out in the context of teacher education in Switzerland. Qualitative research in Swiss schools has already been able to document how teachers’ negative nature of science attitudes can have a negative impact on the HPV vaccination decision [ 12 , 17 , 32 ]. Thus, a communications-oriented teacher education could have a considerable impact on this goal of the education for sustainable development. 33 Science 34 35 Funding The authors received no specific funding for this work. Conflicts of Interest The authors declare no conflict of interest. References Dubé, E.; Gagnon, D.; MacDonald, N.E.; Eskola, J.; Liang, X.; Chaudhuri, M. Strategies intended to address vaccine hesitancy: Review of published reviews. Vaccine 2015 , 33 , 4191–4203. [ Google Scholar ] [ CrossRef ] Jarrett, C.; Wilson, R.; O’Leary, M.; Eckersberger, E.; Larson, H.J.; Eskola, J. Strategies for addressing vaccine hesitancy: A systematic review. Vaccine 2015 , 33 , 4180–4190. [ Google Scholar ] [ CrossRef ] [ PubMed ] Sadaf, A.; Richards, J.L.; Glanz, J.; Salmon, D.A.; Omer, S.B. A systematic review of interventions for reducing parental vaccine refusal and vaccine hesitancy. Vaccine 2013 , 31 , 4293–4304. [ Google Scholar ] [ CrossRef ] [ PubMed ] Salmon, D.A.; Dudley, M.Z.; Glanz, J.M.; Omer, S.B. Vaccine hesitancy: Causes, consequences, and a call to action. Am. J. Prev. Med. 2015 , 49 , 391–398. [ Google Scholar ] [ CrossRef ] [ PubMed ] Dubé, E.; Vivion, M.; Sauvageau, C.; Gagneur, A.; Gagnon, R.; Guay, M. “Nature does things well, why should we interfere?” Vaccine hesitancy among mothers. Qual. Health Res. 2016 , 26 , 411–425. [ Google Scholar ] [ CrossRef ] [ PubMed ] Salmon, D.A.; Moulton, L.H.; Omer, S.B.; DeHart, M.P.; Stokley, S.; Halsey, N.A. Factors associated with refusal of childhood vaccines among parents of school-aged children: A case-control study. Arch. Pediatr. Adolesc. Med. 2005 , 159 , 470–476. [ Google Scholar ] [ CrossRef ] Thorpe, E.L.; Zimmerman, R.K.; Steinhart, J.D.; Lewis, K.N.; Michaels, M.G. Homeschooling parents’ practices and beliefs about childhood immunizations. Vaccine 2012 , 30 , 1149–1153. [ Google Scholar ] [ CrossRef ] Holman, D.M.; Benard, V.; Roland, K.B.; Watson, M.; Liddon, N.; Stokley, S. Barriers to human papillomavirus vaccination among US adolescents: A systematic review of the literature. JAMA Pediatr. 2014 , 168 , 76–82. [ Google Scholar ] [ CrossRef ] Center for Disease Control. HPV Vaccination Coverage Data. 2017. Available online: https://www.cdc.gov/hpv/hcp/vacc-coverage.html (accessed on 15 June 2017). Gesundheitsdirektion Zürich. Das HPV-Impfprogramm im Kanton Zürich. 2012. Available online: http://www.gd.zh.ch/internet/gesundheitsdirektion/de/themen/bevoelkerung/gesund_bleiben/schutz_vor_uebertragbarenkrankheiten.html (accessed on 12 July 2017). Zeyer, A.; Sidler, T. Wie wirken sich Informationen zur HPV-Impfung auf den Impfentscheid junger Frauen aus? Prävention Und Gesundheitsförderung 2015 , 10 , 153–158. [ Google Scholar ] [ CrossRef ] Zeyer, A.; Keselman, A.; Levin, D. For the Mutual Benefit: Health Information Provision in a Science Classroom. In Meeting Health Information Needs Outside of Healthcare ; Arnott Smith, C., Keselman, A., Eds.; Chandos Publishing: Oxford, UK, 2015. [ Google Scholar ] Kilstadius, M.; Gericke, N. Defining contagion literacy: A Delphi study. Int. J. Sci. Educ. 2017 , 39 , 2261–2282. [ Google Scholar ] [ CrossRef ] Byrne, J.; Grace, M. Using a concept mapping tool with a photograph association technique (CoMPAT) to elicit children’s ideas about microbial activity. Int. J. Sci. Educ. 2010 , 32 , 479–500. [ Google Scholar ] [ CrossRef ] Byrne, J. Models of Micro-Organisms: Children’s knowledge and understanding of micro-organisms from 7 to 14 years old. Int. J. Sci. Educ. 2011 , 33 , 1927–1961. [ Google Scholar ] [ CrossRef ] Romine, W.L.; Barrow, L.H.; Folk, W.R. Exploring secondary students’ knowledge and misconceptions about influenza: Development, validation, and implementation of a multiple-choice influenza knowledge scale. Int. J. Sci. Educ. 2013 , 35 , 1874–1901. [ Google Scholar ] [ CrossRef ] Di Rocco, S.; Zeyer, A. Wie entscheiden sich Schülerinnen für oder gegen eine HPV-Impfung. Prävention Und Gesundheitsförderung 2013 , 8 , 29–35. [ Google Scholar ] [ CrossRef ] Nidegger, E. Impfen: Ja oder nein? Coop. Zeitung 2007 , 8. Available online: https://wemf.ch/de/downloads/audit-statistcs/auflagebeglaubigung/wemf-auflagebulletin-2019.pdf#page=30 (accessed on 23 November 2019). Zeyer, A.; Knierim, B. Die Einstellung von zukünftigen Lehrpersonen zum Impfen vor und nach einer Informationsveranstaltung. Prävention und Gesundheitsförderung 2009 , 4 , 235–239. [ Google Scholar ] [ CrossRef ] Koordinationsstelle Forschung am Menschen. 2019. Available online: https://www.kofam.ch/en/home/ (accessed on 15 November 2019). IBM Corp. IBM SPSS Statistics for Windows , version 25.0; IBM Corp: Armonk, NY, USA, 2017. [ Google Scholar ] Arbuckle, J.L. AMOS User’s Guide , version 3.6; Smallwaters: Chicago, IL, USA, 1997. [ Google Scholar ] Byrne, B. Structural Equation Modeling with AMOS ; University of Ottawa: Ottawa, ON, Canada, 2010. [ Google Scholar ] Bollen, K.A. Latent variables in psychology and the social sciences. Annu. Rev. Psychol. 2002 , 53 , 605–634. [ Google Scholar ] [ CrossRef ] Jöreskog, K.G. Testing structural equation models. In Testing Structural Equation Models ; Bollen, K.A., Long, J.S., Eds.; Sage: Newbury Park, CA, USA, 1993; pp. 142–149. [ Google Scholar ] Elwyn, G.; Laitner, S.; Coulter, A.; Walker, E.; Watson, P.; Thomson, R. Implementing shared decision making in the NHS. BMJ 2010 , 341 , c5146. [ Google Scholar ] [ CrossRef ] Elwyn, G.; Frosch, D.; Thomson, R.; Joseph-Williams, N.; Lloyd, A.; Kinnersley, P.; Barry, M. Shared decision making: A model for clinical practice. J. Gen. Intern. Med. 2012 , 27 , 1361–1367. [ Google Scholar ] [ CrossRef ] Barratt, A. Patient Education and Counseling Evidence Based Medicine and Shared Decision Making: The challenge of getting both evidence and preferences into health care. Patient Educ. Couns. 2008 , 73 , 407–412. [ Google Scholar ] [ CrossRef ] Elwyn, G.; Durand, M.A.; Song, J.; Aarts, J.; Barr, P.J.; Berger, Z.; Van Der Weijden, T. A three-talk model for shared decision making: Multistage consultation process. BMJ 2017 , 359 , 1–7. [ Google Scholar ] [ CrossRef ] [ PubMed ] Bromme, R.; Goldman, S.R. The public’s bounded understanding of science. Educ. Psychol. 2015 , 49 , 59–69. [ Google Scholar ] [ CrossRef ] Sturgis, P.; Allum, N. Science in society: Re-evaluating the deficit model of public attitudes. Public Underst. Sci. 2004 , 13 , 55–74. [ Google Scholar ] [ CrossRef ] Zeyer, A. The Doctor’s Office as an Educational Institution Critical Health Literacy—What can doctors contribute. Dtsch Medizinische Wochenschrift 2015 , 140 , 206–208. [ Google Scholar ] Zeyer, A.; Dillon, J. Science|Environment|Health—Towards a reconceptualization of three critical and inter-linked areas of education. Int. J. Sci. Educ. 2014 , 36 . [ Google Scholar ] [ CrossRef ] Hofman, J.M.; Sharma, A.; Watts, D.J. Prediction and Explanation in social systems. Science 2017 , 488 , 486–488. [ Google Scholar ] [ CrossRef ] [ PubMed ] Zeyer, A.; Dillon, J. The role of empathy for learning in complex Science|Environment|Health contexts. Int. J. Sci. Educ. 2019 , 41 , 297–315. [ Google Scholar ] [ CrossRef ][ Green Version ] Figure 1. Basic structure of the structural model. Figure 2. Structural model for vaccination decisions. Table 1. Items of the “pro vaccination” construct, showing means and standard deviation (SD). Number Item Mean SD Item p1 After two doses of the vaccine, the body’s immunity is equal to that after the illness. 0.39 1.767 Item p2 By vaccination, the illness, and thus severe complications and long-term consequences, are prevented. 1.28 1.447 Item p3 Vaccination does not trigger epilepsy. This has been shown in many studies. 0.36 1.524 Item p4 Complications of vaccination can be severe, and therefore vaccination is needed. 1.27 1.524 Item p5 Vaccination complications are much less probable than those of the illness itself. 1.26 1.505 Table 2. Items of the “contra vaccination” construct, showing means and standard deviation (SD). Number Item Mean SD Item c1 Having the illness results in a better immunity than being vaccinated. 1.31 1.574 Item c2 Having the illness strengthens children’s immunity and fosters their development. 0.56 1.685 Item c3 In practice, you often experience that vaccination triggers epilepsy. −1.22 1.338 Item c4 If you strengthen your body, for example by homeopathy, then it can withstand the germs and you do not need vaccination. −0.32 1.762 Item c5 There are no studies demonstrating the safety of vaccination. 0.69 1.657 Table 3. Numbers and the percentage of pro vaccination and contra vaccination decisions for each group. Group Label Contra Vaccination Pro Vaccination Total Rejectors Number 14 1 15 % within group 93.3% 6.7% 100.0% Acceptors Number 2 66 68 % within group 2.9% 97.1% 100.0% Evaluators Number 13 29 42 % within group 31.0% 69.0% 100.0% Experiencers Number 5 30 35 % within group 14.3% 85.7% 100.0% Not coded Number 12 83 92 % within group 12.2% 87.8% 100.0% Total Number 46 209 255 % within group 18.0% 82.0% 100.0% Table 4. Mean averages for pro vaccination and contra vaccination arguments per group (z-values). Group Pro Vaccination Contra Vaccination Not coded Mean Average (z-value) 0.082 −0.022 Rejectors Mean Average (z-value) −1.48 1.40 Acceptors Mean Average (z-value) 0.60 −0.55 Evaluators Mean Average (z-value) −0.63 0.47 Experiencers Mean Average (z-value) 0.21 −0.18 Table 5. Group percentages. Comparison between non-science students and science students. Group Non-Science Students Science Students Not coded Number 75 17 % within subject 35.1% 43.2% Rejectors Number 14 1 % within subject 6.1% 2.3% Acceptors Number 61 6 % within subject 26.8% 13.6% Evaluators Number 37 12 % within subject 16.2% 27.3% Experiencers Number 29 6 % within subject 12.7% 13.6% MDPI and ACS Style Zeyer, A. Getting Involved with Vaccination. Swiss Student Teachers’ Reactions to a Public Vaccination Debate. Sustainability 2019, 11, 6644. https://doi.org/10.3390/su11236644 AMA Style Zeyer A. Getting Involved with Vaccination. Swiss Student Teachers’ Reactions to a Public Vaccination Debate. Sustainability. 2019; 11(23):6644. https://doi.org/10.3390/su11236644 Chicago/Turabian Style Zeyer, Albert. 2019. "Getting Involved with Vaccination. Swiss Student Teachers’ Reactions to a Public Vaccination Debate" Sustainability11, no. 23: 6644. https://doi.org/10.3390/su11236644 Zeyer, Albert. 2019. "Getting Involved with Vaccination. Swiss Student Teachers’ Reactions to a Public Vaccination Debate" Sustainability11, no. 23: 6644. https://doi.org/10.3390/su11236644
https://www.mdpi.com/2071-1050/11/23/6644/html#B27-sustainability-11-06644
(PDF) Profiles of fatty acids and the main lipid peroxidation products of human atherogenic low density lipoproteins PDF | Cardiovascular diseases (CVD), a worldwide leading cause of mortality and morbidity, are generated mainly by atherosclerosis. The serum fatty... | Find, read and cite all the research you need on ResearchGate Article PDF Available Profiles of fatty acids and the main lipid peroxidation products of human atherogenic low density lipoproteins January 2016 Revista de Chimie -Bucharest- Original Edition-67(1) Authors: <here is a image 3d030fdbba7fd3cf-1c2ee0c43508aeb6> Mariana Deleanu Nicolae Simionescu Institute of Cellular Biology and Pathology <here is a image f2779f7226f7d77e-4079804dc0de5159> Gabriela M Sanda Nicolae Simionescu Institute of Cellular Biology and Pathology <here is a image 1a932a77dc103715-66a7398ce7b36ae5> Camelia Sorina Stancu Nicolae Simionescu Institute of Cellular Biology and Pathology <here is a image 0f718d5abb60cf42-22b69b10ad958941> Mona Elena Popa University of Agricultural Sciences and Veterinary Medicine of Bucharest Abstract and Figures Cardiovascular diseases (CVD), a worldwide leading cause of mortality and morbidity, are generated mainly by atherosclerosis. The serum fatty acids (FA) and some of their peroxidation products, such as 4-hydroxy-trans-2-nonenal (4-HNE) and malondyaldehyde (MDA), are known risk factors for CVD. Our aim was to determine in atherogenically-modified low-density lipoproteins (LDL), either oxidized or glycated, the FA composition, quantify the levels of 4-HNE, MDA and of cholesterol’s main oxidation product, 7-kethocholesterol (7-KC). Profiles of FA, conjugated dienes , 4-HNE, MDA and 7-KC were determined in native LDL (nLDL) isolated from blood donors from the Hematology Center, Bucharest, copper-oxidized LDL (oxLDL) and non-enzymatically glycated LDL (gLDL). The FA composition was determined by Gas Chromatography with a flame ionization detector and the conjugated dienes by absorbtion in UV at 234 nm. Free 4-HNE and 7-KC levels were determined by Gas-Chromatography-Triple Quadrupol Mass Spectrometry in Electron Ionization mode and total MDA by reversed-phase Ultra High Performance Lichid Chromatography. Results showed that the polyunsaturated fatty acids (PUFAs) were totally reduced in oxLDL (except linoleic acid) and decreased in gLDL, while the monounsaturated fatty acids remained almost unchanged in both oxLDL and gLDL. Lipid peroxidation products increased as follows: conjugated dienes were significantly increased both in gLDL (29%, p<0.05) and oxLDL (1.5 fold higher, p<0.01) compared to nLDL; free 4-HNE level in oxLDL (2.75±1.01 nmoles/mg protein) was ~100 times the level in nLDL (0.02±0.01 nmoles/mg protein), while gLDL (0.05±0.02 nmoles/mg protein) had only twice the nLDL level; MDA levels in oxLDL were statistically increased (1.05±0.44 nmoles/mg protein) compared to nLDL (0.05± 0.02 nmoles/mg protein) and to gLDL (0.19±0.05 nmoles/mg protein); 7-KC level was significantly increased in oxLDL (674.39± 207.70 nmoles/mg protein) and gLDL (1.21± 0.32 nmoles/mg protein) compared to nLDL (0.13± 0.04 nmoles/mg protein). Our data demonstrate that the alteration of the FA composition of modified LDL has two negative consequences: (i) the reduction of PUFA levels, most importantly the essential w-3 and w-6 fatty acids, and (ii) the increase of the main peroxidation products of FA and cholesterol such as conjugated dienes, free 4-HNE, MDA and 7-KC, transforming LDL into atherogenic lipoproteins. Keywords: Fatty acids, 4-HNE, oxidized LDL, glycated LDL, GC/MS/MS <here is a image bfb0957792fa22b0-633996f21a117d16> 7-Ketocholesterol (7-KC) in native low density lipoproteins (nLDL), oxidized low density lipoproteins (oxLDL) and glycated low density lipoproteins (gLDL). The data are expressed as mean ± SD; n=3 samples for each histogram, **p<0.01 oxLDL versus nLDL, ##p<0.01 gLDL versus nLDL, && p<0.01 oxLDL versus gLDL. … 8 Profiles of Fatty Acids and the Main Lipid Peroxidation Products of Human Atherogenic Low Density Lipoproteins MARIANA DELEANU 1,2 , GABRIELA M. SANDA 1 , CAMELIA S. STANCU 1 , MONA E. POPA 2 , ANCA V. SIMA 1 * 1 “Nicolae Simionescu” Institute for Cellular Biology and Pathology of the Romanian Academy, 8 B.P. Hasdeu Str, 050568, Bucharest, Romania 2 University of Agronomical Sciences and Veterinary Medicine Bucharest, Faculty of Biotechnology, 59 Marasti Blvd., 011464, Bucharest, Romania Cardiovascular diseases (CVD), a worldwide leading cause of mortality and morbidity, are generated mainly by atherosclerosis. The serum fatty acids (FA) and some of their peroxidation products, such as 4-hydroxy- trans-2-nonenal (4-HNE) and malondyaldehyde (MDA), areknown risk factors for CVD. Our aim was to determine in atherogenically-modified low-density lipoproteins (LDL), either oxidized or glycated, the FA composition, quantify the levels of 4-HNE, MDA and of cholesterol’s main oxidation product, 7-kethocholesterol (7-KC). Profiles of FA, conjugated dienes , 4-HNE, MDA and 7-KC were determined in native LDL (nLDL) isolated from blood donors from the Hematology Center, Bucharest, copper-oxidized LDL (oxLDL) and non-enzymatically glycated LDL (gLDL). The FA composition was determined by Gas Chromatography with a flame ionization detector and the conjugated dienes by absorbtion in UV at 234 nm. Free 4-HNE and 7-KC levels were determined by Gas-Chromatography- Triple Quadrupol Mass Spectrometry in Electron Ionization mode and total MDA by reversed-phase Ultra High Performance Lichid Chromatography. Results showed that the polyunsaturated fatty acids (PUFAs) were totally reduced in oxLDL (except linoleic acid) and decreased in gLDL, while the monounsaturated fatty acids remained almost unchanged in both oxLDL and gLDL. Lipid peroxidation products increased as follows: conjugated dienes were significantly increased both in gLDL (29%, p<0.05) and oxLDL (1.5 fold higher, p<0.01) compared to nLDL; free 4-HNE level in oxLDL (2.75±1.01 nmoles/mg protein) was ~100 times the level in nLDL (0.02±0.01 nmoles/mg protein), while gLDL (0.05 ±0.02 nmoles/mg protein) had only twice the nLDL level; MDA levels in oxLDL were statistically increased (1.05±0.44 nmoles/mg protein) compared to nLDL (0.05± 0.02 nmoles/ mg protein) and to gLDL (0.19±0.05 nmoles/mg protein); 7-KC level was significantly increased in oxLDL (674.39± 207.70 nmoles/mg protein) and gLDL (1.21± 0.32 nmoles/mg protein) compared to nLDL (0.13± 0.04 nmoles/mg protein). Our data demonstrate that the alteration of the FA composition of modified LDL has two negative consequences: (i) the reduction of PUFA levels, most importantly the essential ω -3 and ω -6 fatty acids, and (ii) the increase of the main peroxidation products of FA and cholesterol such as conjugated dienes, free 4-HNE, MDA and 7-KC, transforming LDL into atherogenic lipoproteins. Keywords: F atty acids, 4-HNE, oxidized LDL, glycated LDL, GC/MS/MS * email: [email protected]; Tel.: +40(0)21.319.4518 Cardiovascular diseases (CVD) caused by athero- sclerosis and their associated adverse complications are major causes of morbidity and mortality in western societies [1]. The non-enzymatic glycation of plasma proteins, such as in diabetes, can increase their atherogenic potential. During the last years a considerable amount of research was focused on the susceptibility of low-density lipoproteins (LDL) to oxidation. Modified LDL that cause cellular lipid loading were proven to be atherogenic and involved in the development of CVD [2]. Glycation of LDL is significantly increased in diabetic patients even in the case of good glycemic control [3]. LDL, either oxidized and/or glycated, are present in the plasma and in the affected vasculature of obese, diabetic and CVD patients [4]. Fatty acids (FA) profiling of biological samples (plasma) has a great importance for the understanding of the relation between dietary lipids and the development of diabetes and CVD [5]. Conventional methods for the profiling of FA consist of several steps : lipids extraction with organic solvents, hydrolysis, methylation/derivatization, and finally, analysis and quantification by gas chromatography (GC). Linoleic acid and arachidonic acid are the major polyunsaturated fatty acids (PUF As) in LDL, the former being present mostly in the cholesteryl esters (CE) core of the lipoproteins. The FA composition varies between various sources of LDL (different subjects) and depends on the diet [2]. During the formation of hydroperoxides from unsaturated FA, conjugated dienes are typically produced, due to the rearrangement of the double bonds. The resulting conjugated dienes exhibit a characteristic absorption at 234 nm. An increase in UV absorption theoretically reflects the formation of primary oxidation products in lipids [6, 7]. The oxidation of PUFAs generates highly reactive α , β- unsaturated hydroxyalkenals, such as 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal (4-HHE) and 4-hydroxy- dodecadienal (4-HDDE) [6]. Oxidation of ω -6 PUFAs (linoleic and arachidonic acids) leads to the formation of 4-HNE [8], whereas oxidation of ω -3 PUFAs (docosa- hexaenoic acid, eicosapentaenoic acid and linolenic acid) generates 4-HHE [9]. 4-HNE can react with histidine (His), cysteine (Cys) or lysine (Lys) residues of proteins, leading to the formation of stable Michael adducts with a hemiacetal structure [10], modifying the proteins’ epitopes that intereact with specific receptors. The hydroxy-alkenals levels have been measured with high performance liquid chromatography (HPLC) using the UV absorption detector. REV.CHIM.(Bucharest) ♦ 67 ♦ No.1 ♦ 2016 http://www.revistadechimie.ro9 However, this method’s sensitivity is limited. Another method far more sensitive for the determination of 4-HNE and 4-HHE is the GC coupled to a mass spectrometer (MS) [6]. MDA is one of the most abundant aldehydes, resulting from the peroxidation of arachidonic, eicosapentaenoic and docosahexaenoic acids [11]. MDA reacts with the Lys residues of proteins to form Schiff bases [8] and plays a major role in the LDL oxidative modifications [12-13]. The oxidative hypothesis of atherosclerosis proposed by Steinberg postulates that 4-HNE- and MDA-modified LDL are taken up by macrophages in the artery wall, which become foam cells and form fatty streaks, an early step of the atherogenic process [14]. MDA can be measured in biological fluids as well as in isolated cells by the thiobarbituric acid (TBA) reaction and the resulting absorbance at 532 nm or fluorescence can be determined by HPLC [6]. Cholesterol may be oxidized by enzymatic or non- enzymatic pathways [15]. Cholesterol oxidation products have received increasing attention as diagnostic markers of oxidative stress, intermediates in cholesterol transport and messengers for cell signaling or intermediates in bile acid biosynthesis [15]. 7-Ketocholesterol (7-KC), a major cholesterol oxidation product (oxysterols), is found in high concentrations in atherosclerotic plaques and contributes to its development [16]. Experimental part Materials and methods 4-HNE was purchased from Cayman Chemicals, 1,1,3,3- tetramethoxypropan (malonaldehyde bis(dimethyl acetal) 99% (TMP), 5-cholesten-3 β -ol-7-one (7-ketocholesterol), 5 α -cholestane, hexane, sodium hydroxide, methanol (HPLC grade), perchloric acid 70%, hydrochloric acid 37% were purchased from Sigma-Aldrich. FAME MIX 37 and hexamethyldisilazane:trimethylchlorosilane:pyridine 3:1:9 (Sylon HTP) were purchased from Supelco. O -(2,3,4,5,6- Pentafluorobenzyl)hydroxylamine PFBHA HCl), N,O-bis (tri- methylsilyl)trifluoroacetamide (BSTFA) + 1% tri- methylchlorosilane (TMCS) and 2,4-dinitrophenyl- hydrazine (DNPH) 50%, were purchased from Fluka. Acetonitrile (HPLC grade), methanol (HPLC grade) and toluene were purchased from Merck and acetic acid (HPLC grade) was purchased from Panreac Quimica Spain. LDL isolation, in vitro oxidation and glycation LDL was isolated from human plasma of healthy donors from the Blood Hematology Center, Bucharest by density gradient ultracentrifugation in Optima LE-80 and XP-80 ultracentrifuges (Beckman Coulter International SA, Nyon, Switzerland). Oxidized LDL (oxLDL) was prepared by incubation for 24 h with 10 µ M CuSO 4 as previously described [17]. Non-enzymatically irreversibly glycated LDL (gLDL) was prepared by incubation of LDL with 0.2 M D(+) glucose for 4 weeks at 37 °C , in the presence of antioxidants (1 mg/mL EDTA and l M BHT) under sterile conditions and extensively dialyzed before use [18]. Deter mination of P rotein Protein concentration of LDL was measured by an adapted Lowry method as modified for lipoproteins employing bovine serum albumin as a standard [19]. A nalysis of fatty acids distribution by GC-FID Lipids were extracted by a modified Bligh and Dyer method [20] from LDL samples. The fatty acids methyl esters (FAMEs) were obtained by mild methanolysis with 8% HCl methanolic solution, according to the procedure suggested by Ichihara and Fukubayashi [21]. GC-FID analyses were performed on an Agilent Technologies gas chromatograph GC 7890A coupled with FID detector. A fused-silica capillary column DB-225 ms (60 m× 0.25 mm i.d., 0.25 µ m film thickness) from Agilent J&W was used for separation FAMEs. Aliquots (each 1 µ L) were injected in the split mode (1:100) with an auto injector. Helium was used as the carrier gas, at a flow rate of 1 mL/ min. The initial temperature of 120 °C was maintained for 1 min and then increased to 220 °C at 4 °C /min. The temperature of the injector was 260 °Cand the FID detector was set at 280 °C . Identification of fatty acids methyl esters was made with a standard mixture of 37 esters of fatty acids (FAME MIX 37) from SUPELCO. Determination of conjugated dienes The formation of conjugated dienes was detected in UV at λ =234 nm in native and modified LDL [6, 7]. Determination of free 4-HNE by GC/MS/MS According to the procedure suggested by van Kuijk and Rauli [22, 23], LDL sample was incubated for 30 min with 0.05 M PFBHA HCl in water with continuous stirring. The pentafluorbenzyl-oxime (PFBO)-derivatives were extracted with hexane and evaporated under nitrogen. The sample was derivatised with 50 µ L of N,O -bis (trimethylsilyl) trifluoroacetamide (BSTFA) + 1% trimethylchlorosilane (TMCS) at 80 °C for 1 h and were transformed in PFBO-TMS of 4-HNE derivatives ( 2 , scheme 2). GC/MS/MS analyses were performed on an Agilent Technologies 7000A GC/MS Triple Quad directly interfaced with a gas chromatograph GC 7890A. A fused-silica capillary column HP-5 ms (30 m× 0.25 mm i.d., 0.25 µ m film thickness) from Agilent J&W was used for separation of 4-HNE derivatives. Aliquots (each 2 µ L ) were injected in the split less mode with an auto injector. Helium was used as the carrier gas, at a flow rate of 1 mL/min. The initial temperature of 85°C was maintained for 1 min and then increased to 145°C at 20°C/min (3min), and to 300°C at 8°C/min (10 min). The temperature of the injector was 260°C and the transfer line was set at 280°C. Mass spectrometry detection was performed in Electron Ionization mode (EI) with a 70 eV electron energy, at 230°C source temperature and 150°C MS1 and MS2 temperature. The optimization of the collision energy voltage and the selection of precursor ions to generate product ions will be presented in the section Results and discussions. The calibration curve was constructed with known amounts of standard 4-HNE solution. The highest level of target analyte was 2 nmoles/mL. Six calibration solutions were prepared by 1:2:2:2:2:2 dilution ratios. The standard solutions were derivatized in the same mode as samples. Determination of total MDA by UHPLC For the alkaline hydrolysis of protein bound MDA, a volum of 6 M NaOH was added to the LDL sample and incubated in a 60°C water bath for 45 min [24]. After protein precipitation with 35% perchloric acid and centrifugation, 250 µ L supernatant were derivatizated with 25 µ L DNPH solution 5 mM in 2 M HCl and incubated for 10 min at room temperature. The samples were filtered through a 0.22 µ m filter. Aliquots of 3 µ L were injected in an Ultra High Performance Liquid Chromatography (UHPLC) system (Agilent Technologies 1290 Infinity) equipped with binary solvent delivery pump (with four channels), auto sampler, thermostatic column compartment, a Diode Array Detector and Agilent ChemStation software for data acquisition and processing. http://www.revistadechimie.ro REV.CHIM.(Bucharest) ♦ 67 ♦ No.1 ♦ 2016 10 The chromatographic separation was performed on a ZORBAX Eclipse Plus C18 column narrow bore RR (150 mm x 2.1 mm, 3.5 µ m) with the mobile phase consisting of a 0.2% aqueous acetic acid and acetonitrile (62:38) v/v at a flow rate 0.25 mL/min. The detector wavelength was set at 310 nm and the column was maintained at 25°C. MDA standards were prepared from 1 mM stock solution of TMP. The calibration curve was constructed in the range 0.625-10 nmol/mL TMP. 250 µ L of standards were mixed with 25 µ L DNPH in the same condition as the samples. Determination of 7-ketocholesterol by GC/MS/MS The sample preparation method was an adapted method after Matysik [25]. Briefly, to LDL sample/standard were added 2000 ng of 5 α -cholestane internal standard (IS) and freshly prepared 1 M potassium hydroxide in ethanol to cleave the ester bonds for 60 min at 25 °C under magnetic agitation. Afterwards, the reaction solution was adjusted to p H 7 and s terols were extracted with hexane. The solvent was evaporated to dryness under nitrogen and the residue was dissolved in 100 µ L of the reagent Sylon HTP for derivatization, 1 h at 60 °C . The derivatized samples were transferred to GC vials for direct injections. For separation of the trimethysilyl ether derivatives of 7- ketocholesterol (TMS derivatives of 7-KC) ( 1 , scheme 1) was used the same technology and the same column as for determination of 4-HNE. Aliquots (each 2 µ L) were injected in the splitless mode with an auto injector. Helium was used as the carrier gas, at a flow rate of 1.2 mL/min. The initial temperature of 180 °C was maintained for 1 min and then increased to 250 at 20 °C /min, and to 295°C at 5 °C /min and to 300 °C at 1 °C min (10 min). The temperature of the injector was 275°C and the transfer line was set at 280 °C . Mass spectrometry detection was performed in EI mode with a 70 eV electron energy, at 230°C source temperature and 150 °C MS1 and MS2 temperature. The collision energy voltage was optimized to fragment the precursor ion m/z 472.5 by collision-induced dissociation (CID) to generate the product ions selected as quantification and qualifier ions in the multiple reactions monitoring (MRM) method for analyte. The quantification ion was m/z 455.4 and qualifier ion m/z 382.6. Precursor ion of 5 α -cholestane (IS) was m/z 357.4. The quantification ion was m/z 189.2 and qualifier ion m/z 203.1. The calibration curve was constructed in the range 50- 5000 ng/mL in the same mode as samples. Results and discussions It is well known that the high saturated fat intake generates high serum lipids levels and the development of atherosclerosis. The analysis of serum and tissue FA distribution was included in population studies on CVD and their risk factors [26]. It has been determined the content of linoleic acid (C18:2) (34.22±1.57, expressed as %( w/w) and arachidonic acid (C20:4) (6.97±0.54), known as the most abundant ω -6 PUFAs present in nLDL, and ω -3 PUFAs, such eicosapentaenoic acid, EPA (C20:5) and docosa- pentaenoic, DHA (C22:6), which occur only in minor amounts (fig. 1). The FA distribution in oxLDL (expressed as %w/w) was altered after LDL oxidation with copper ions as compared to the FA distribution in nLDL. The percent of saturated FA in oxLDL increased compared to nLDL: the palmitic acid (C16:0) (50.06±2.45 versus 23.99±0.69, p< 0.001) and the stearic acid (C18:0) (31.60±2.39 versus 13.39±0.46, p< 0.01). The abundance of monounsaturated FA, such as the palmitoleic acid (C16:1) (1.47±0.52 versus 1.51±0.59), oleic acid (C18:1) (13.05±0.06 versus 12.66±1.79) and (C18:1 cis vaccenic) (1.41±0.17 versus 1.51±0.59) remained statistically unchanged. The linoleic acid was statistically decreased in oxLDL (1.94±0.56 versus 34.22±1.57 , p< 0.001) compared to nLDL, while the ω -6 dihomogammalinolenic acid (C20:3) (1.72±0.04, p< 0.001) and arachidonic acid (C20:4) (6.97±0.54, p< 0.001) were completely oxidized in oxLDL ( fig. 1 ). The ω -3 FA, EPA (1.16±0.23, p <0.001) and DHA (1.71±0.54, p <0.001) were totally reduced, being transformed in peroxidation products ( fig. 1 ). In gLDL compared to nLDL, the decrease of linoleic acid (27.03±2.31 versus 34.22±1.57, p< 0.05), of dihomo- gammalinolenic acid (0.97±0.29 versus 1.55±0.29, p <0.05) and arachidonic acid (3.98±1.03 versus 6.97± 0.54, p< 0.05), was statistically significant. There is a tendency for ω -3 FA abundance to decrease, as they were reduced in half in gLDL compared to nLDL, EPA (0.58 ±0.50 versus 1.16±0.23 and DHA (0.58±0.83 versus 1.71±0.54) (fig. 1). In oxLDL compared to gLDL, the linoleic acid (1.94±0.56 versus 27.03±2.31, p< 0.01) was significantly decreased. Conjugated dienes, detected in UV at λ =234 nm, were significantly increased in both gLDL and oxLDL with 29%, p <0.05 and ~ 1.5 fold higher, p <0.01, respectively, compared to nLDL (fig. 2). Conjugated dienes detection by UV is easy, but the method is neither very specific, nor very sensitive. Like other aldehydes, 4-HNE was derivatized into pentafluorobenzyl oxime directly in the LDL sample as previously described [22, 23]. Their derivatives were extracted with hexane, and the hydroxyl group was converted into trimethysilyl ether with N,O - bis(trimethylsilyl)-trifluoroacetamide, and the penta- Scheme 1. Chemical structure of TMS derivatives of 7-ketocholesterol (1) Fig. 1. Composition of fatty acids (FA) in oxidized low density lipoproteins (oxLDL) and glycated low density lipoproteins (gLDL) compared to native low density lipoproteins (nLDL). The data are expressed as mean ± SD; n=3 samples for each histogram,** p <0.01 oxLDL versus nLDL , ∗∗∗ p <0.001 oxLDL versus nLDL, # p <0.05 gLDL versus nLDL, ## p <0.01 gLDL versus nLDL, ### p <0.001 gLDL versus nLDL, && p <0.01 oxLDL versus gLDL, &&& p <0.01 oxLDL versus gLDL. REV.CHIM.(Bucharest) ♦ 67 ♦ No.1 ♦ 2016 http://www.revistadechimie.ro11 (0.19±0.05 versus 0.05±0.02 nmoles/mg protein, p< 0.001) ( fig. 5 ). The mean MDA level was ~3 fold lower in oxLDL (1.05±0.44 nmoles/mg protein) than 4-HNE (2.75±1.01 nmoles/mg protein, while in gLDL, the MDA level (0.19±0.05 nmoles/mg protein) was ~ 4-fold higher than 4-HNE level (0.05±0.02 nmoles/mg protein). These differences of MDA levels versus 4-HNE in gLDL could be explained by the fact that our GC/MS/MS method for quantification 4-HNE has a high degree of specificity while the determination of MDA by HPLC with DNPH Fig. 2. Conjugated dienes in native low density lipoproteins (nLDL), oxidized low density lipoproteins (oxLDL) and glycated low density lipoproteins (gLDL). The data are expressed as mean ± SD; n=6 samples for each histogram, ** p <0.01 oxLDL versus nLDL, # p <0.05 gLDL versus nLDL, & p <0.05 oxLDL versus gLDL. Scheme 2. Chemical structure of PFBO-TMS derivatives of 4-HNE ( 2 ) fluorbenzyl oxime trimethysilyl ether derivatives (PFBO- TMS) of 4-HNE ( 2 , scheme 2) were analyzed by negative ion chemical ionization (NICI) GC-MS [22, 23]. A GC/MS/MS Triple Quad in EI mode method for quantification of 4-HNE has been developed . First was performed scan a quadrupole 1 (Q1) to produce a MS pattern in EI mode for PFBO -TMS derivatives of 4-HNE from standard solutions. The characteristic fragment ions ( fig. 3 ) corresponded well with those given in the literature [27]. Two precursor ions ( m/z 242 and m/z 352) were chosen for product scans and the most abundant product ions were chosen to define specific multiple reaction monitoring (MRM). The collision energy voltage was optimized in the range 1-10 eV to fragment the most abundant precursor ion m/z 352 by collision-induced dissociation (CID) to generate the product ions selected as quantification and qualifier ions in the multiple reaction monitoring (MRM) method for analyte. The optimum collision energy voltage was 10 eV and the dwell time was fixed at 150 ms for MRM transition. The quantification ion was m/z 155.9 and the qualifier ion, m/z 180.9 ( fig. 4 ). The 4-HNE levels were significantly increased in oxLDL compared to both nLDL and gLDL (2.75±1.01 versus 0.02±0.01 nmoles/mg protein, p< 0.001, and 0.05±0.02 nmoles/mg protein, p< 0.05, respectively) ( fig. 4). The mean MDA level in oxLDL was significantly increased compared to nLDL (1.05±0.44 v ersus 0.05±0.02 nmoles/mg protein, p< 0.001) and to gLDL (0.19±0.05 nmoles/mg protein, p< 0.001). The increase of MDA in gLDL compared to nLDL was statistically significant Fig. 3. Mass spectra of Q1 scan after positive electron ionization (EI) of the PFBO-TMS-derivatives of 4-HNE standards. Fig. 4. MRM chromatograms of quantifier, qualifier and peak spectrum of PFBO-TMS derivatives of 4-HNE standards. Fig. 5. Free 4-HNE and total MDA in native low density lipoproteins (nLDL), oxidized low density lipoproteins (oxLDL) and glycated low density lipoproteins (gLDL). The data are expressed as mean ± SD; n=6 samples for each histogram, *** p <0.001 oxLDL versus nLDL, # p <0.05 gLDL versus nLDL, ### p <0.001 gLDL versus nLDL, &&& p <0.001 oxLDL versus gLDL. http://www.revistadechimie.ro REV.CHIM.(Bucharest) ♦ 67 ♦ No.1 ♦ 2016 12 Fig. 6. 7-Ketocholesterol (7-KC) in native low density lipoproteins (nLDL), oxidized low density lipoproteins (oxLDL) and glycated low density lipoproteins (gLDL). The data are expressed as mean ± SD; n=3 samples for each histogram, ** p <0.01 oxLDL versus nLDL, ## p <0.01 gLDL versus nLDL, && p <0.01 oxLDL versus gLDL. derivatization is specific for all carbonyl groups and gLDL have a high number of carbonyl groups. Next to 27-hydroxycholesterol, 7-ketocholesterol is the next most abundant oxysterol in advanced human atherosclerotic lesion [29]. During the in vitro oxidation of LDL, a substantial loss of free and esterified cholesterol occurs as both these molecules are oxidized [15]. The mean 7-KC level was significantly increased in oxLDL compared to both nLDL and gLDL (674.39±207.70 versus 0.13± 0.04 nmoles/mg protein, p< 0.01, 1.21±0.32 nmoles/mg protein, p< 0.01, respectively) ( fig. 6). The mean 7-KC level was ~ 550-fold higher in oxLDL (674.39±207.70 nmoles/mg protein) than in gLDL (1.21±0.32 nmoles/mg protein). Conclusions The experimental results demonstrate that the glycation and mostly the oxidation of LDL have negative consequences on the particles biochemical composition involving the following processes: (i) the reduction of PUFAs levels, most importantly the essential ω -3 and ω -6 fatty acids and (ii) the increase of the main peroxidation products of FA and cholesterol, such as conjugated dienes, free 4-HNE, MDA and 7-KC, which taken together transform LDL into atherogenic lipoproteins. Acknowledgments: This work was supported by the UEFISCDI project PN-II-PT-PCCA-2011-3.1-0184 and by the Romanian Academy. Dr. Gabriela M. Sanda acknowledges the support of the strategic grant „POSDRU/159/1.5/S/133391-financed by the European Social Found within the Sectorial Operational Program Human Resources Development 2007 – 2013". References 1. MCINTYRE, M.T., HAZEN, L.S., Circ.Res., 107 , 2010, p. 1167 . 2. NIKI, E., Biochim. Biophys. Acta, 1840, 2014, p. 809. 3. LYONS, J.T., Am. J. Cardiol. 71 , 1993, p. 26. 4. VIRELLA, G., THORPE, R.S., ALDERSON L.N., STEPHAN, M.E., ATCHLEY, D., WAGNER, F., VIRELLA-LOPEZ, F.M., DCCT/EDIC RESEARCH GROUP, J. Lipid Res. 44 , 2003, p. 487. 5. SIMOPOULOS, A.P., Am. J. Clin. Nutr. 54, 1991, p. 438. 6. GUICHARDANT, M., LAGARDE, M., Eur. J. Lipid Sci. Technol., 111 , 2009, p. 75. 7. ESTERBAUER, H., STRIEGL, G., PUHL, H., ROTHENEDER, M. Free Rad. Res. 6 , 1989, nr. 1, p. 67 8. ESTERBAUER, H., Am. J. Clin. Nutr. 57 , 1993, p. 779S, discussion p. 785S. 9. VAN KUIJK, F.T., HOLTE, L.L., DRATZ, E.A., Biochim. Biophys. Acta. 1043, 1990, p. 116. 10. SCHAUR, R.J., Mol. Aspects Med., 24 , 2003, p. 149. 11. ESTERBAUER, H., SCHAUR, R.J., ZOLLNER, H., Free Radic. Biol. Med. 11, 1991, p. 81. 12. PALINSKI, W., ROSENFELD, E.M., YLA-HERTUALA, S., GURTNER, C.G., SOCHER, S.S., BUTLER, W.S., PARTHASARATHY, S., CAREW, E.T., STEINBERG, D., WITZUM, L.J., Proc. Natl. Acad. Sci. USA, 86 , 1989, p. 1372. 13. STEINBERG, D., J. Biol. Chem. 272 , 1997, p. 20963. 14. NEGRE-SALVAYRE, A., COATREUX, C., INGUENEAU, C., SALVAYRE, R., Br. J. Pharmacol . 153 , 2008, p. 6. 15.YOSHIDA, Y., UMENO, A., SHICHIRI, M., J. Clin. Biochem. Nutr., 52 , 2013, p. 9 16. BROWN, J.A., JESSUP, W., Atherosclerosis, 142 , 1999, p. 1. 17. SIMA, A.V., BOTEZ, G.M., STANCU, C.S., MANEA, A., RAICU, M., SIMONESCU, M., J. Cell Mol. Med., 14 , 2010, p. 2790. 18. TOMA, L., STANCU, C.S., BOTEZ, G.M., SIMA, A.V., SIMIONESCU,M., Biochem. Biophys. Res. Commun., 390 , 2009, p. 877. 19. MARKWELL, M.A., HAAS, L.L., BIEBER, L.L., TOLBERT, N.E., Anal. Biochem., 87 , 1978, p. 206. 20. BLIGH, E.G., DYER, W.J., Can. J. Biochem. Physiol., 37 , 1959, p. 911. 21. ICHIHARA, K., FUKUBAYASHI, Y., J. Lipid Res., 51 , 2010, p. 635. 22. VAN KUIJK, F.J., SIAKOTOS, A.N., FONG, L.G., THOMAS, D.W., Anal. Biochem., 224 , 1995, p. 420. 23. RAULI, S., PUPPO, M.D., MAGNI, F., KIENLE, M.G., J.,Biochem., 123 , 1998, p. 918. 24. TÜKÖZKAN, N., ERDAMAR, H., SEVEN, I., Firat Tip Dergisi, 11 , 2006, p. 88. 25. MATYSIK, S., SCHMITZ, G., Biochimie, 95 , 2013, p. 489. 26. SEPPANEN-LAAKSO, T., LAAKSO, I., HILTUNEN, R., Anal. Chim. Acta, 465 , 2002, p. 39. 27. BERDYSHEV, E.V., Biochim. Biophys. Acta, 1811 , 2011, p. 680. 28. STOCKER, R., KEANEY, J.F., JR., Physiol. Rev. 84 , 2004, p. 1381 Manuscript received: 4.05.2015 ... Modified LDL were then centrifuged at 10,000xg for 10 min and the precipitated fraction composed of 100% agLDL was added to cell cultures [26,27]. In vitro oxLDL was prepared by incubating nLDL with 10 μM CuSO 4 for 24 h at 37˚C in the absence of antioxidant protection, and characterized as described [25, 28] . The lipid peroxides levels in LDL were measured as thiobarbituric acid reactive substances (TBARS) by Ultra High Pressure Liquid Chromatography (UHPLC) method [29] and expressed as malondialdehyde (MDA) pmoles/mg LDL protein. ... ... Free cholesterol (FC) and total cholesterol (TC) content of nLDL, agLDL and oxLDL, and of the macrophages exposed to nLDL, agLDL or oxLDL were analyzed by gas chromatographymass spectrometry (GC-MS), as previously reported [28] . ... Aggregated LDL turn human macrophages into foam cells and induce mitochondrial dysfunction without triggering oxidative or endoplasmic reticulum stress Uptake of modified lipoproteins by macrophages turns them into foam cells, the hallmark of the atherosclerotic plaque. The initiation and progression of atherosclerosis have been associated with mitochondrial dysfunction. It is known that aggregated low-density lipoproteins (agLDL) induce massive cholesterol accumulation in macrophages in contrast with native LDL (nLDL) and oxidized LDL (oxLDL). In the present study we aimed to assess the effect of agLDL on the mitochondria and ER function in macrophage-derived foam cells, in an attempt to estimate the potential of these cells, known constituents of early fatty streaks, to generate atheroma in the absence of oxidative stress. Results show that agLDL induce excessive accumulation of free (FC) and esterified cholesterol in THP-1 macrophages and determine mitochondrial dysfunction expressed as decreased mitochondrial membrane potential and diminished intracellular ATP levels, without generating mitochondrial reactive oxygen species (ROS) production. AgLDL did not stimulate intracellular ROS (superoxide anion or hydrogen peroxide) production, and did not trigger endoplasmic reticulum stress (ERS) or apoptosis. In contrast to agLDL, oxLDL did not modify FC levels, but stimulated the accumulation of 7-ketocholesterol in the cells, generating oxidative stress which is associated with an increased mitochondrial dysfunction, ERS and apoptosis. Taken together, our results reveal that agLDL induce foam cells formation and mild mitochondrial dysfunction in human macrophages without triggering oxidative or ERS. These data could partially explain the early formation of fatty streaks in the intima of human arteries by interaction of monocyte-derived macrophages with non-oxidatively aggregated LDL generating foam cells, which cannot evolve into atherosclerotic plaques in the absence of the oxidative stress. ... Similarly to the results observed in the current experiment Bessa et al. [32] using sunflower oil in a study carried out with lambs, observed an increase in CLA t10,c12 in response to soybean oil supplementation to high-concentrate diets. Although C18:1 trans-11 seems to play a more important role than the trans-10 isomer in modulating plasma lipid and lipoprotein metabolism, C18:2 c9,t11 and CLA t10,c12 have potential beneficial effects for human health [36] . ... ... In the present study, the n-6/n-3 ratio was more beneficial in intramuscular fat of lambs compared of subcutaneous fat. It can be considered a beneficial property for human nutrition [36] . However, this value is higher for control and SO samples than the recommendation of nutritionists [27]. ... Research Regarding Fatty Acid Profile and Health Lipid Indices in the Lambs Meat of Employing Feed Supplemented with Different Vegetable Oils Enhancing healthy fatty acids (FA) in lamb tissues is a important research issue in meat science. The present study examined the effects of feeding-protected lipid supplements rich in linoleic acid or linolenic acid on the lipid composition of muscle and adipose tissues of lambs. Thirty, 10-week-old Tsigai breed ram lambs were assigned to one of three experimental diets (forage/concentrate ratio 40:60): no oil Ca soap (CControl), with 4% sunflower oil Ca soap (SO-high in 18:2n-6), with 4% camelina oil Ca soap (CO-high in 18:3n-3). The diet high in a-linolenic acid (CO diet) produced the highest levels of n-3 FAs: 18:3n-3 (ALA), 20:5n-3 (EPA) and 22:6n-3 (DHA) intramuscular fat. In addition, the animals fed with the diet CO have intramuscular fat the lowest n-6/n-3 ratio, atherogenic (AI) and thrombogenic index (TI). In the intramuscular fat of the animals fed with the diet high in linoleic acid (SO diet), conjugated linoleic acid (CLA) isomers and trans 18:1 reached their highest concentrations. The results of this study indicated that linoleic acid was more effective in enhancing contents of CLA in muscle and adipose tissue than linolenic acid, which contributes to the enrichment of n-3 FA lamb meat. Feeding camelina oil Ca soap has been shown to be the most effective dietary management to improve health lipid indices (n-6/n-3 ratio, AI, TI) in lambs' meat. ... Native LDL (nLDL) were isolated from human plasma of healthy donors from the Blood Transfusion Center, Bucharest, by density gradient ultracentrifugation in Optima LE-80 or XP-80 ultracentrifuges (Beckman Coulter International SA, Nyon, Switzerland). Copper-oxidized LDL (oxLDL) was prepared and characterized as previously described [Sima et al., 2010; Deleanu et al., 2016] . ... ... Free cholesterol (FC), total cholesterol (TC), and 7-ketocholesterol (7-KC) content of oxLDL and of macrophages exposed to oxLDL for 24 h was analyzed by gas chromatography-mass spectrometry (GS-MS) on an Agilent Technologies 7000 A GC/MS Triple Quad direct interfaced with a gas chromatograph GC 7890A, as previously reported [Ahmida et al., 2006; Deleanu et al., 2016] . ... Oxidized LDL-Exposed Human Macrophages Display Increased MMP-9 Expression and Secretion Mediated by Endoplasmic Reticulum Stress
https://www.researchgate.net/publication/292315360_Profiles_of_fatty_acids_and_the_main_lipid_peroxidation_products_of_human_atherogenic_low_density_lipoproteins
The molecular chaperone Hsp90 is required for high osmotic stress response in Saccharomyces cerevisiae | Request PDF Request PDF | The molecular chaperone Hsp90 is required for high osmotic stress response in Saccharomyces cerevisiae | Exposure of Saccharomyces cerevisiae to high osmotic stress evokes a number of adaptive changes that are necessary for its survival. These... | Find, read and cite all the research you need on ResearchGate The molecular chaperone Hsp90 is required for high osmotic stress response in Saccharomyces cerevisiae April 2006 FEMS Yeast Research6(2):195-204 DOI: 10.1111/j.1567-1364.2006.00026.x Authors: Xiao-Xian Yang Xiao-Xian Yang Kick C T Maurer Michiel Molanus Michiel Molanus <here is a image 882e5b1d7e5b963a-9c1975d2b22f65ec> Willem H Mager Vrije Universiteit Amsterdam Abstract Exposure of Saccharomyces cerevisiae to high osmotic stress evokes a number of adaptive changes that are necessary for its survival. These adaptive responses are mediated via multiple mitogen-activated protein kinase pathways, of which the high-osmolarity glycerol (HOG) pathway has been studied most extensively. Yeast strains that bear the hsp82T22I or hsp82G81S mutant alleles are osmosensitive. Interestingly, the osmosensitive phenotype is not due to inappropriate functioning of the HOG pathway, as Hog1p phosphorylation and downstream responses including glycerol accumulation are not affected. Rather, the hsp82 mutants display features that are characteristic for cell-wall mutants, i.e. resistance to Zymolyase and sensitivity to Calcofluor White. The osmosensitivity of the hsp82T22I or hsp82G81S strains is suppressed by over-expression of the Hsp90 co-chaperone Cdc37p but not by other co-chaperones. Hsp90 is shown to be required for proper adaptation to high osmolarity via a novel signal transduction pathway that operates parallel to the HOG pathway and requires Cdc37p. <here is a image 175d1bd4b7439d95-754927124da715c1> ... For example, the induction of osmostress specific genes is regulated by the activation of the high osmolarity glycerol (HOG) pathway MAPK, Hog1, Saito and Posas 2012), whereas, the increased expression of environmental stress responsive genes involved in metabolic pathways is regulated by the activation of glycogen synthase kinase 3 (GSK3) (Hirata et al. 2003;Stankiewicz and Mayer 2012). Hsp90 has been found to be directly involved in the activation or maturation of both of these kinases and the transcription factor, Hsf1 is involved in promoting the induction of heat shock proteins (Yang et al. 2006; Stankiewicz and Mayer 2012). Therefore, in the following chapters we investigate the effects of Hsp90 mutations on yeast short-term adaptation to conditions directly associated with increased expression of Hsp90 including, thermal stress (37°C), oxidative stress (H 2 0 2 or diamide), ethanol stress and nitrogen depletion (Gasch et al. 2000) or conditions associated with Hsp90 client binding-maturation function in stress response pathways such as, the HOG pathway induced by hyperosmotic stress (NaCl or sorbitol) (Gasch et al. 2000;Yang et al. 2006). ... ... Hsp90 has been found to be directly involved in the activation or maturation of both of these kinases and the transcription factor, Hsf1 is involved in promoting the induction of heat shock proteins (Yang et al. 2006;Stankiewicz and Mayer 2012). Therefore, in the following chapters we investigate the effects of Hsp90 mutations on yeast short-term adaptation to conditions directly associated with increased expression of Hsp90 including, thermal stress (37°C), oxidative stress (H 2 0 2 or diamide), ethanol stress and nitrogen depletion (Gasch et al. 2000) or conditions associated with Hsp90 client binding-maturation function in stress response pathways such as, the HOG pathway induced by hyperosmotic stress (NaCl or sorbitol) (Gasch et al. 2000; Yang et al. 2006 ). ... ... Hsp90 levels were monitored by western blotting. Specifically, Hsp90 is required to buffer proteotoxic and deleterious fitness effects that arise during short-term environmental stress and can disrupt protein and cellular function, ultimately affecting organismal fitness and survival (Gasch et al. 2000; Yang et al. 2006; Richter et al. 2010 Middle-C terminal domain and regulation of ATPase-Chaperone activity (Nathan and Lindquist 1995;Nathan et al. 1997;Meyer et al. 2003;Hawle et al. 2006;Hagn et al. 2011). As a result, mutations within this region could impact diverse aspects of Hsp90 such as, relative affinity and priority of different clients involved in different stress response pathways, which may provide an adaptive benefit to specific environments. ... Investigating Evolutionary Innovation in Yeast Heat Shock Protein 90 Article Full-text available Jul 2020 Pamela A. Cote-Hammarlof The Heat Shock Protein 90 (Hsp90) is an essential and highly conserved chaperone that facilitates the maturation of a wide array of client proteins, including many kinases. These clients in turn regulate a wide array of cellular processes, such as signal transduction, and transcriptional reprogramming. As a result, the activity of Hsp90 has the potential to influence physiology, which in turn may influence the ability to adapt to new environments. Previous studies using a deep mutational scanning approach, (EMPIRIC) identified multiple substitutions within a 9 amino acid substrate-binding loop of yeast Hsp90 that provides a growth advantage for yeast under elevated salinity conditions and costs of adaptation under alternate environments. These results demonstrate that genetic alterations to a small region of Hsp90 can contribute to evolutionary change and promote adaptation to specific environments. However, because Hsp90 is a large, highly dynamic and multi-functional protein the adaptive potential and evolutionary constraints of Hsp90 across diverse environments requires further investigation. In this dissertation I used a modified version of EMPIRIC to examine the impact of environmental stress on the adaptive potential, costs and evolutionary constraints for a 118 amino acid functional region of the middle domain of yeast Hsp90 under endogenous expression levels and the entire Hsp90 protein sequence under low expression levels. Endogenous Hsp90 expression levels were used to observe how environment may affect Hsp90 mutant fitness effects in nature, while low expression levels were used as a sensitive readout of Hsp90 function and fitness. In general, I found that mutations within the middle domain of Hsp90 have similar fitness effects across many environments, whereas, under low Hsp90 expression I found that the fitness effects of Hsp90 mutants differed between environments. Under individual conditions multiple variants provided a growth advantage, however these variants exhibited growth defects in other environments, indicating costs of adaptation. When comparing experimental results to 261 extant eukaryotic sequences I find that natural variants of Hsp90 support growth in all environments. I identified protein regions that are enriched in beneficial, deleterious and costly mutations that coincides with residues involved in co-chaperone-client-binding interactions, stabilization of Hsp90 client-binding interfaces, stabilization of Hsp90 interdomains and ATPase chaperone activity. In summary, this thesis uncovers the adaptive potential, costs of adaptation and evolutionary constraints of Hsp90 mutations across several environments. These results complement and extend known structural and functional information, highlighting potential adaptive mechanisms. Furthermore, this work elucidates the impact environment can have on shaping Hsp90 evolution and suggests that fluctuating environments may have played a role in the long-term evolution of Hsp90. ... It has ∼70 % of its kinome destabilised, revealing that S14 phosphorylation of Cdc37 is important for protecting nascent kinase chains against degradation and maintaining appropriate in vivo levels of protein kinases (Mandal et al. 2007). We and others have shown that this Ser14 phosphorylation is essential for the functionality of several stress-responsive, mitogen-activated protein kinase (MAPK) pathways in yeast, the cdc37(S14A) mutation causing loss of Cdc37 interaction with key signalling components of these pathways, notably the kinases Ste11, Kss1, Hog1 and Slt2 (Abbas-Terki et al. 2000;Hawle et al. 2007; Yang et al. 2006) . Here, we describe our discovery, through yeast two-hybrid (Y2H) screening, of a Cdc37 client kinase whose stable association with Cdc37 and in vivo expression level appears not to depend upon this Ser14 phosphorylation of Cdc37. ... ... Except for the two-hybrid screen (see below), yeast cells were routinely grown at 24°C in either yeast peptone dextrose (YPD) or synthetic yeast nitrogen base (YNB) medium supplemented with the required amino acids. Analysis of the rescue of osmosensitivity by Cdc37 constructs was as previously described (Yang et al. 2006; Vaughan et al. 2008). ... ... Amongst the Cdc37 proteins of distantly related species, it is only the 20-30 amino acids at the extreme N-terminus of Cdc37 that are highly conserved in sequence (MacLean and Picard 2003), indicating that this N-terminal region is important for the functionality of Cdc37. Consistent with this, we have noted that, while Cdc37 overexpression will normally rescue the osmosensitive growth of the hsp90-G81S mutant (Yang et al. 2006) , overexpressions of N-terminally green fluorescent protein (GFP)-or glutathione transferase (GST)tagged forms of Cdc37 cannot provide any rescue of this mutant in the presence of 2 M sorbitol ( Fig. 1a). Contrasting with this are the experiences of placing sequences at the Cterminus of Cdc37. ... Cdc37 engages in stable, S14A mutation-reinforced association with the most atypical member of the yeast kinome, Cdk-activating kinase (Cak1) Article Full-text available Jan 2014 CELL STRESS CHAPERON <here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Patricija Van Oosten Mohammed A Alkuriji <here is a image ce1d5550b9b9c9cc-237b52e706a03cf2> Stefan Millson <here is a image 186ed615fcbadcba-a39f27a298c27efc> Peter Piper In most eukaryotes, Cdc37 is an essential chaperone, transiently associating with newly synthesised protein kinases in order to promote their stabilisation and activation. To determine whether the yeast Cdc37 participates in any stable protein interactions in vivo, genomic two-hybrid screens were conducted using baits that are functional as they preserve the integrity of the conserved N-terminal region of Cdc37, namely a Cdc37-Gal4 DNA binding domain (BD) fusion in both its wild type and its S14 nonphosphorylatable (Cdc37(S14A)) mutant forms. While this failed to identify the protein kinases previously identified as Cdc37 interactors in pull-down experiments, it did reveal Cdc37 engaging in a stable association with the most atypical member of the yeast kinome, cyclin-dependent kinase (Cdk1)-activating kinase (Cak1). Phosphorylation of the conserved S14 of Cdc37 is normally crucial for the interaction with, and stabilisation of, those protein kinase targets of Cdc37, Cak1 is unusual in that the lack of this Cdc37 S14 phosphorylation both reinforces Cak1:Cdc37 interaction and does not compromise Cak1 expression in vivo. Thus, this is the first Cdc37 client kinase found to be excluded from S14 phosphorylation-dependent interaction. The unusual stability of this Cak1:Cdc37 association may partly reflect unique structural features of the fungal Cak1. ... Since Hsp90 is a chaperone involved in the response to thermal stress as well as in the regulation of osmotic stress (Yang et al., 2006; Boucher et al., 2014), we tested which factors can explain variation in codon fitness effects. For that we performed model selection using the leaps package (Lumley, 2017). ... ... Overall differences between synonymous mutations are higher than two random draws of the posterior. On average, the effects of synonymous mutations are larger in the 36N environment (Table S4, Fig. S10), where Hsp90 is expected to be more important for organism survival (Yang et al., 2006; Boucher et al., 2014;Mishra et al., 2016). ... The fitness landscape of the codon space across environments Fitness landscapes map the relationship between genotypes and fitness. However, most fitness landscape studies ignore the genetic architecture imposed by the codon table and thereby neglect the potential role of synonymous mutations. To quantify the fitness effects of synonymous mutations and their potential impact on adaptation on a fitness landscape, we use a new software based on Bayesian Monte Carlo Markov Chain methods and reestimate selection coefficients of all possible codon mutations across 9 amino-acid positions in Saccharomyces cerevisiae Hsp90 across 6 environments. We quantify the distribution of fitness effects of synonymous mutations and show that it is dominated by many mutations of small or no effect and few mutations of larger effect. We then compare the shape of the codon fitness landscape across amino-acid positions and environments, and quantify how the consideration of synonymous fitness effects changes the evolutionary dynamics on these fitness landscapes. Together these results highlight a possible role of synonymous mutations in adaptation and indicate the potential mis-inference when they are neglected in fitness landscape studies. ... Since Hsp90 is a chaperone involved in the response to thermal stress as well as in the regulation of osmotic stress (Boucher et al. 2014; Yang et al. 2006) , we tested which factors can explain variation in codon fitness effects. For that we performed model selection using the leaps package (Lumley 2017). ... ... Overall differences between synonymous mutations are higher than two random draws of the posterior. On average, the effects of synonymous mutations are larger in the 36N environment (Table S4, Fig. S10), where Hsp90 is expected to be more important for organism survival (Boucher et al. 2014;Mishra et al. 2016; Yang et al. 2006) . ... The fitness landscape of the codon space across environments HEREDITY <here is a image d2578e0e6e04eed8-f0d241f643793e08> Inês Fragata Sebastian Matuszewski Mark A. Schmitz Claudia Bank Fitness landscapes map the relationship between genotypes and fitness. However, most fitness landscape studies ignore the genetic architecture imposed by the codon table and thereby neglect the potential role of synonymous mutations. To quantify the fitness effects of synonymous mutations and their potential impact on adaptation on a fitness landscape, we use a new software based on Bayesian Monte Carlo Markov Chain methods and re-estimate selection coefficients of all possible codon mutations across 9 amino acid positions in Saccharomyces cerevisiae Hsp90 across 6 environments. We quantify the distribution of fitness effects of synonymous mutations and show that it is dominated by many mutations of small or no effect and few mutations of larger effect. We then compare the shape of the codon fitness landscape across amino acid positions and environments, and quantify how the consideration of synonymous fitness effects changes the evolutionary dynamics on these fitness landscapes. Together these results highlight a possible role of synonymous mutations in adaptation and indicate the potential mis-inference when they are neglected in fitness landscape studies. ... Hsp82p, which belongs to Hsp90 protein family in S. cerevisiae, is highly conserved among eukaryotes. Experimental evidences showed that the molecular chaperone Hsp82p is required for high osmotic stress response in S. cerevisiae and its mutation results in osmosensitive phenotype [58] . Human Hsp90, Hsp90p, is involved in the activation of an important set of cell regulatory proteins, including many whose disregulation drives cancer. ... ... For example, Hsp82p and Hsc82p are two hub proteins in the signaling regulatory pathway. Hsp82p and Hsc82p, which are redundant in function and nearly identical with each other, are essential for osmotic and heat shock stresses [58, 67]. They are also required for the activation of many key cellular regulatory and signaling proteins like kinases and transcription factors [68]. ... Integrated cellular network of transcription regulations and protein-protein interactions BMC SYST BIOL <here is a image 99fd8ba21bab5b20-39ebbcfbcefce7ab> Yu-Chao Wang <here is a image e188fbf4effaea1f-82f854abf543493c> B. S. Chen With the accumulation of increasing omics data, a key goal of systems biology is to construct networks at different cellular levels to investigate cellular machinery of the cell. However, there is currently no satisfactory method to construct an integrated cellular network that combines the gene regulatory network and the signaling regulatory pathway. In this study, we integrated different kinds of omics data and developed a systematic method to construct the integrated cellular network based on coupling dynamic models and statistical assessments. The proposed method was applied to S. cerevisiae stress responses, elucidating the stress response mechanism of the yeast. From the resulting integrated cellular network under hyperosmotic stress, the highly connected hubs which are functionally relevant to the stress response were identified. Beyond hyperosmotic stress, the integrated network under heat shock and oxidative stress were also constructed and the crosstalks of these networks were analyzed, specifying the significance of some transcription factors to serve as the decision-making devices at the center of the bow-tie structure and the crucial role for rapid adaptation scheme to respond to stress. In addition, the predictive power of the proposed method was also demonstrated. We successfully construct the integrated cellular network which is validated by literature evidences. The integration of transcription regulations and protein-protein interactions gives more insight into the actual biological network and is more predictive than those without integration. The method is shown to be powerful and flexible and can be used under different conditions and for different species. The coupling dynamic models of the whole integrated cellular network are very useful for theoretical analyses and for further experiments in the fields of network biology and synthetic biology. ... In addition, pkc1 mutant yeast are sensitive to the cell-wall dye CW (Schmitz et al. 2001), which binds and perturbs the architectural integrity of this structure. Since the introduction of additional copies of MID2 and PKC1 affect the growth of ydj1D and hsp82 yeast, it is possible that these mutant strains also have cell-wall defects, as hinted at by previous studies (Lussier et al. 1997; Yang et al. 2006) . ... ... First, it was observed that strains containing mutations in KAR2, which encodes an ER Hsp70, have decreased amounts of b1,6-glucan in the cell wall when ER-resident glucanases are disabled (Simons et al. 1998). Second, some but not all hsp82 mutant alleles exhibit sensitivity to growth on medium containing high sorbitol, which was interpreted as a connection between Hsp90 function and the HOG signaling pathway even though other hsp82 mutants were sensitive to CW (Yang et al. 2006 ). On the basis of the growing importance of chaperones in nearly every aspect of cell function and maintenance, we anticipate that additional connections between chaperone function and cell-wall architecture will be uncovered. ... The Hsp40 Molecular Chaperone Ydj1p, Along With the Protein Kinase C Pathway, Affects Cell-Wall Integrity in the Yeast Saccharomyces cerevisiae Molecular chaperones, such as Hsp40, regulate cellular processes by aiding in the folding, localization, and activation of multi-protein machines. To identify new targets of chaperone action, we performed a multi-copy suppressor screen for genes that improved the slow-growth defect of yeast lacking the YDJ1 chromosomal locus and expressing a defective Hsp40 chimera. Among the genes identified were MID2, which regulates cell-wall integrity, and PKC1, which encodes protein kinase C and is linked to cell-wall biogenesis. We found that ydj1delta yeast exhibit phenotypes consistent with cell-wall defects and that these phenotypes were improved by Mid2p or Pkc1p overexpression or by overexpression of activated downstream components in the PKC pathway. Yeast containing a thermosensitive allele in the gene encoding Hsp90 also exhibited cell-wall defects, and Mid2p or Pkc1p overexpression improved the growth of these cells at elevated temperatures. To determine the physiological basis for suppression of the ydj1delta growth defect, wild-type and ydj1delta yeast were examined by electron microscopy and we found that Mid2p overexpression thickened the mutant's cell wall. Together, these data provide the first direct link between cytoplasmic chaperone function and cell-wall integrity and suggest that chaperones orchestrate the complex biogenesis of this structure. ... Hsp70, the highly conserved 70kDa family of heat shock proteins aids in the re-folding of misfolded proteins (Verghese et al., 2012;Lotz et al., 2019). Hsp90 proteins specialise in the assembly of macromolecular structures and maturation of proteins such as transcription factors and kinases (Yang et al., 2006) . Hsp104 recognises misfolded aggregates of proteins, effectively separating these aggregates and facilitating the correct folding (Verghese et al., 2012). ... Heterogeneity in brewing yeast populations During brewing fermentations, yeast cells are subjected to a range of stress factors including ethanol, osmotic and oxidative stress. These have an impact on population health, affecting fermentation consistency, efficiency, and quality of the product. Typically, the tolerance of a yeast culture to stress is assessed via analysis of the entire population generating mean data, assuming each cell has broadly equivalent characteristics. This can mask detail at the cellular level which can only be obtained by analysing individual cells. In this study, a range of yeast strains significant to the brewing industry were investigated for tolerance to a variety of environmental challenges. This was performed using a novel high throughput assay for investigating ‘population heterogeneity’, based on cell cytotoxicity. This revealed that some cells within a population were more tolerant to stresses than others. Furthermore, the dynamics of the stress response differed between strains in both the maximum tolerance and degree of heterogeneity. To identify potential sources of variation within populations, key cell organelles were analysed for variation in structural integrity. Yeast cells were also separated according to replicative age, by sorting based on bud scar material, this allowed for the physiological differences between daughter and aged cells to be investigated. Based on this analysis, we provide evidence to suggest that population variation is an innate inheritable characteristic. Subsequently, cell metabolites upregulated under stressed conditions were identified using metabolomics, this data was used this to conduct targeted single cell gene expression analysis, using a highly heterogenous and a less heterogeneous strain. From this, we were able to conclude that genes upregulated in response to stress were heterogenous in nature, matching the phenotypic data observed previously. We also demonstrate that the cause of phenotypic heterogeneity was likely a result of an accumulation of many heterogeneous gene expression events. Clusters were identified in specific groups of cells, implying the presence of population organisation, likely to be a ‘division of labour’ survival strategy. This data has implications for our understanding of strain specific fermentation limits and the techniques developed here may facilitate screening and prediction of the suitability of yeast strains for specific fermentation types. ... Present research revealed that heat shock protein-82 (HSP82) locus is present on chromosome number 13 and shows up-regulation under the organic and inorganic chemical stresses. These important proteins may involve in mediating adaptive responses to high osmolarity in S. cerevisiae, or for functionality of the targets of osmoadaptive signaling (Yang et al., 2006) . ... In-silico identification and characterization of organic and inorganic chemical stress responding genes in yeast (Saccharomyces cerevisiae) <here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Muhammad ZEESHAN Younas <here is a image 741cab5351473008-a5139027d4c474d7> Muhammad Younas Khan Barozai <here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Farrukh Bashir <here is a image b4dd391572c85a15-d5bfa03b61c95fb2> Muzaffar Khan ... These compounds protect cells against toxic metabolites such as ethanol and acetaldehyde (Li et al., 2017). Other proteins reported, such as Hsp82p and Hsc82p, from the HSP90 cytoplasmic chaperones family, work in conjunction with trehalose (Tps1p) to withstand this stress (Li et al., 2017; Yang et al., 2006) . First, trehalose prevents proteins denaturation, then chaperones difficult their aggregation (Li et al., 2017). ... Effect of endogenous CO2 overpressure on the yeast “stressome” during the “prise de mousse” of sparkling wine <here is a image f9cfd2af1902bd38-1fccf03e7ee3033c> Juan Antonio Porras Agüera <here is a image 8fef26f6fdc20958-f34d819db494919e> Juan J. Román-Camacho <here is a image 00e93749f653db02-e180e45c8f619309> Jaime Moreno-García <here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Teresa García-Martínez Sparkling wines elaboration by the "Champenoise" method involves a second fermentation of a base wine in hermetically sealed bottles and a subsequent aging period. The whole process is known as "prise de mousse". The endogenous CO2 pressure produced during the second fermentation by the yeast Saccharomyces cerevisiae could modify the sub-proteome involved in the response to different stresses, or "stressome", and cell viability thus affecting the wine organoleptic properties. This study focuses on the stressome evolution along the prise de mousse under CO2 overpressure conditions in an industrial S. cerevisiae strain. The results reveal an important effect of endogenous CO2 overpressure on the stress sub-proteome, cell viability and metabolites such as glycerol, reducing sugars and ethanol. Whereas the content of glycerol biosynthesis-related proteins increased in sealed bottle, those involved in the response to toxic metabolites like ROS, ethanol, acetaldehyde and acetic acid, decreased in content. Proteomic profile obtained in this study may be used to select suitable wine yeast strains for sparkling wine elaboration and improve their stress tolerance. ... In the early fermentation stages, the greatest environmental constraint is osmotic stress, which generates a water flow from inside to outside the cytoplasmic membrane. Later, the yeast cell adapts itself through multi-level specific response mechanisms ( Hohmann, 2002;Tapia, Young, Fox, Bertozzi, & Koshlanda, 2015; Yang et al., 2006; Zuzuarregui, Monteoliva, Gil, & Del Olmo, 2006). However, the main response of yeast cells to high-osmolarity is the production of glycerol, the best osmotic balance stabilizer ( Hohmann, 2002). ... Enhanced arginine biosynthesis and lower proteolytic profile as indicators of Saccharomyces cerevisiae stress in stationary phase during fermentation of high sugar grape must: A proteomic evidence FOOD RES INT <here is a image 9bd65ccf78c2c5a3-e20d1e42b4f5f260> Olta Noti <here is a image 47d4605874dd7ab6-7208c296029d3458> Enrico Vaudano <here is a image df6f7570efea9029-6a1cc13e54ac4987> Maria Gabriella Giuffrida <here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Enrica Pessione A strain of Saccharomyces (S) cerevisiae (ISE19), which displayed an initial good adaptation to a high sugar medium with increased acetate and glycerol production but weak overall growth/fermentation performances, was selected during the alcoholic fermentation of Cortese grape must. To obtain insights into the metabolic changes that occur in the must during growth in particular conditions (high ethanol, high residual sugars and low nitrogen availability) leading to a sluggish fermentation or even fermentation arrest, comparative in-gel proteomic analyses were performed on cells grown in media containing 200 g/L and 260 g/L of glucose, respectively, while the YAN (Yeast Assimilable Nitrogen) concentration was maintained as it was. Two post-translationally different arginine synthases (pIs 5.6 and 5.8) were found in higher abundances in the high glucose-grown cells, together with an increased abundance of a glycosyltransferase involved in cell-wall mannans synthesis, and of two regulatory proteins (K7_Bmh1p and K7_Bmh2p) that control membrane transport. In parallel, a proteinase K-like proteolytic enzyme and three other protein fragments (Indolepyruvate decarboxylase 1, Fba1p and Eno1p) were present in lower abundances in the high glucose condition, where oxidative stress and cell cycle involved enzymes were also found to be less abundant. The overall results suggest that in stationary phase stress conditions, leading to stuck fermentation, S. cerevisiae ISE19 decreases cell replication, oxidative stress responses and proteolytic activity, while induces other metabolic modifications that are mainly based on cell-wall renewal, regulation of the solute transport across the cell membrane and de novo arginine synthesis. ... The mutants exhibit defects in cell-wall synthesis during osmotic stress. This phenotype is probably not caused by an impaired HOG pathway, as HOG1 phosphorylation and glycerol accumulation still function in the mutant strains, but by another pathway, designated as the filamentous growth pathway, which regulates osmoadaptation parallel to the HOG pathway [38, 39] . Imai and Yahara [40] have shown that a decrease of HSP90 expression level to below 30% of normal is accompanied by hypersensitivity of S. cerevisae cells to salt stress. ... The conserved protective function of heat shock protein expression during osmotic stress Cells respond to an increased extracellular tonicity initially with a net uptake of inorganic electrolytes to restore ionic balance with the environment and to counteract cell shrinkage. However, high intracellular concentrations of inorganic ions may lead to enhanced accumulation of misfolded or aggregated proteins. To prevent excess protein denaturation, cells induce various osmoprotective mechanisms. One of the most conserved mechanisms is the expression of protein-stabilizing heat shock proteins (HSPs). Elevated cellular levels of HSPs (or their homologues) have been found in numerous organisms during osmotic stress, such as the enterobacterium Escherichia coli, the yeast strain Saccharomyces cerevisiae, the plant Arabidopsis thaliana (Thale cress), the nematode Caenorhabditis elegans, the fish Sparus sarba (silver sea bream) as well as in mammals like mice or rats, illustrating the important osmoprotective function of HSPs in the whole alive nature. The present article provides an overview of HSP function during osmotic stress in various pro-and eukaryotic organisms. The main focus lies on the role of HSPs in mammalian cells and especially in cells of the mammalian kidney, where cells are routinely exposed to high osmolarities in the renal medulla. The abundance of these HSPs in the kidney often correlates with the corticomedullary osmotic gradient, with low amounts in the isoosmotic cortex and highest amounts in the inner medulla, contributing to the remarkable abillity of these cells to deal with the high osmolarities observed in these tissues. ... Based on the observation that substrate binding mutants of ERdj3 were unable to rescue hlj1∆ydj1-151 phenotypes ( Figure 28 and 29), and that hlj1∆ yeast do not exhibit slow growth and cell wall phenotypes (data not shown) but ydj1∆ do 126,355 , I surmise that cell wall function and robust growth at elevated temperature are linked to the ability of Ydj1 to bind to specific substrates. Formally, the cell wall phenotypes may also arise from the ability of Ydj1 to partner with Hsp82, the cytosolic Hsp90 which plays a role in high osmotic stress response in yeast 355,370, 371 and functions in conjunction with Ydj1 in the folding and maturation of certain client proteins 368,372,373 . The cell wall phenotype may additionally arise from altered association with Sse1, the cytosolic Hsp110 370 , which has previously been shown to genetically interact with 261 , it appears that for many cellular processes, the JDP-stimulated high affinity binding of partner Hsp70s to substrates is sufficient. ... Genetic and biochemical analyses of Hsp70-Hsp40 interactions in Saccharomyces cerevisiae provide insights into specificity and mechanisms of regulation <here is a image 132d0d7ab8eba599-1d09475bc1436aee> Shruthi Vembar Heat shock proteins of 70kDa (Hsp70s) and their J domain-containing Hsp40 cofactors are conserved chaperone pairs that facilitate diverse cellular processes. One essential Hsp70 in the endoplasmic reticulum (ER) lumen, BiP (Kar2p in yeast), participates in polypeptide translocation into the ER, protein folding, and ER-associated degradation (ERAD). Like other Hsp70s, BiP contains an N-terminal ATPase domain, followed by a substrate binding domain and a C-terminal lid domain. To better define how substrate affinity and Hsp40 interaction affect BiP function, I constructed and characterized a mutation, R217A, in the putative J domain-interacting surface of yeast BiP. The mutation compromises ATPase stimulation by Sec63p, an Hsp40 required for translocation, but stimulation by Jem1p, an Hsp40 required for ERAD, is robust. In accordance with these data, yeast expressing R217A BiP exhibit translocation defects, but no ERAD defects, and a genetic interaction study using this mutant yielded data consistent with defects in translocation. In contrast, mutations in the substrate binding domain that either disrupt an ionic contact with the lid or remove this domain are deficient for peptide-stimulated ATPase activity. Expression of these mutants in yeast results in varying translocation and ERAD defects. Taken together, these data indicate that BiP can distinguish between its ER-resident cochaperones, and that optimal substrate binding is a key determinant of BiP function.Next, I tested the hypothesis that the functional specificity of Hsp70s is regulated by cognate Hsp40s. If this is true, one might expect divergent Hsp70-Hsp40 pairs to be unable to function in vivo. However, I discovered that a mammalian ER-lumenal Hsp40, ERdj3, when directed to the yeast cytosol, was able to rescue the temperature-sensitive growth phenotype of yeast containing mutant alleles in two cytosolic Hsp40s, HLJ1 and YDJ1. Moreover, ERdj3 activated the ATPase activity of Ssa1p, the yeast cytosolic Hsp70 that partners with Hlj1p and Ydj1p. Intriguingly, ERdj3 mutants that were compromised for substrate binding were unable to rescue the hlj1ydj1 growth defect, even though they stimulated Ssa1p ATPase activity. These data suggest that the substrate binding properties of certain Hsp40s—not simply the formation of unique Hsp70-Hsp40 pairs—is critical to specify in vivo function. ... Both KCl and sorbitol activate the MAPK-regulated stress response pathway, which has been shown to mediate resistance to azoles in yeast (reviewed in [21]). Inhibition of the heat shock protein Hsp90, a molecular chaperone and downstream target of the MAPK pathway has been shown to enhance sensitivity to fluconazole in both S. cerevisiae and C. albicans [21,49, 50] . KCl and sorbitol may thus influence sensitivity to azoles via activation of the MAPK-regulated stress response pathway. ... Suppression of Sensitivity to Drugs and Antibiotics by High External Cation Concentrations in Fission Yeast Potassium ion homeostasis plays an important role in regulating membrane potential and therefore resistance to cations, antibiotics and chemotherapeutic agents in Schizosaccharomyces pombe and other yeasts. However, the precise relationship between drug resistance in S. pombe and external potassium concentrations (particularly in its natural habitats) remains unclear. S. pombe can tolerate a wide range of external potassium concentrations which in turn affect plasma membrane polarization. We thus hypothesized that high external potassium concentrations suppress the sensitivity of this yeast to various drugs. We have investigated the effect of external KCl concentrations on the sensitivity of S. pombe cells to a wide range of antibiotics, antimicrobial agents and chemotherapeutic drugs. We employed survival assays, immunoblotting and microscopy for these studies. We demonstrate that KCl, and to a lesser extent NaCl and RbCl can suppress the sensitivity of S. pombe to a wide range of antibiotics. Ammonium chloride and potassium hydrogen sulphate also suppressed drug sensitivity. This effect appears to depend in part on changes to membrane polarization and membrane transport proteins. Interestingly, we have found little relationship between the suppressive effect of KCl on sensitivity and the structure, polarity or solubility of the various compounds investigated. High concentrations of external potassium and other cations suppress sensitivity to a wide range of drugs in S. pombe. Potassium-rich environments may thus provide S. pombe a competitive advantage in nature. Modulating potassium ion homeostasis may sensitize pathogenic fungi to antifungal agents. ... Interestingly, Znf1 was recently reported in a high-throughput ChIP-chip and gene knockout study of transcription factors and it appears to co-operate in the network of regulators that mediate stress tolerance (Yang et al., 2010). Despite it remains unknown whether regulation of some osmotic stress genes (Fig. 8) is directly governed by Znf1 or indirectly via other regulatory proteins of stress responsive pathways (Rep et al., 1999a; Yang et al., 2006) . It is clear that Znf1 is another regulator that mediates transcriptional activation in response to osmotic stress and provides a connection to the HOG pathway. ... Zinc cluster protein Znf1, a novel transcription factor of non-fermentative metabolism in Saccharomyces cerevisiae Pitchya Tangsombatvichit <here is a image 9dcd8ee1ea295240-f22dedb0d03502e8> Marta Semkiv Andriy A. Sibirny <here is a image c60f3cda8e309d0f-0ea9c2e1bb482f08> Nitnipa Soontorngun The ability to rapidly respond to nutrient changes is a fundamental requirement for cell survival. Here, we show that the zinc cluster regulator Znf1 responds to altered nutrient signals following glucose starvation through the direct control of genes involved in non-fermentative metabolism, including those belonged to the central pathways of gluconeogenesis (PCK1, FBP1 and MDH2), glyoxylate shunt (MLS1 and ICL1) and the tricarboxylic acid cycle (ACO1), which is demonstrated by Znf1-binding enrichment at these promoters during the glucose-ethanol shift. Additionally, reduced Pck1 and Fbp1 enzymatic activities correlate well with the data obtained from gene transcription analysis. Cells deleted for ZNF1 also display defective mitochondrial morphology with unclear structures of the inner membrane cristae when grown in ethanol, in agreement with the substantial reduction in the ATP content, suggesting for roles of Znf1 in maintaining mitochondrial morphology and function. Furthermore, Znf1 also plays a role in tolerance to pH and osmotic stress, especially during the oxidative metabolism. Taken together, our results clearly suggest that Znf1 is a critical transcriptional regulator for stress adaptation during non-fermentative growth with some partial overlapping targets with previously reported regulators in Saccharomyces cerevisiae. © FEMS 2015. All rights reserved. For permissions, please e-mail: [email protected]. ... Present research revealed that heat shock protein-82 (HSP82) locus is present on chromosome number 13 and shows up-regulation under the organic and inorganic chemical stresses. These important proteins may involve in mediating adaptive responses to high osmolarity in S. cerevisiae, or for functionality of the targets of osmoadaptive signaling (Yang et al., 2006) . ... In-silico identification and characterization of organic and inorganic chemical stress responding genes in yeast (Saccharomyces cerevisiae) <here is a image 741cab5351473008-a5139027d4c474d7> Muhammad Younas Khan Barozai <here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Farrukh Bashir <here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Shafia Muzaffar <here is a image b4dd391572c85a15-d5bfa03b61c95fb2> Muzaffar Khan ... Hsp82 is upregulated up to 20 times under heat stress [12]. The expression of Heat Shock Protein 90 is upregulated under diverse stressful situations as oxidative stress [13], osmotic stress [14] , elevated acetic acid concentrations [15] or especially at elevated temperatures [12]. Under these conditions, many proteins are prone to aggregation and subsequent degradation if there is no rescue system. ... NMR Methyl Chemical Shift Assignments of the Hsp90 Chaperone <here is a image a0b100e972729157-469dd62a71374054> Maximilian Brackmann Protein folding and maintenance of the cellular function of proteins are central tasks of chaperones. Although some chaperones such as Heat Shock Protein 90 (Hsp90) are essential in eukaryotes and in some prokaryotes, their exact mechanism remains not well understood. For a better understanding of the mode of function of Hsp90 a better insight into the dynamics of the structure and the binding of client proteins and cochaperones is necessary. NMR-spectroscopy provides a high potential to address these questions as it is suited to discover binding sites. In this work, NMR spectra of methyl groups of two out of three individual domains were partially assigned, which serves as a base for binding studies and further analysis. ... Three additional treatments consisted of the addition of 0.5 M sodium chloride (NaCl) at each temperature (hereafter referred to as the 25S, 30S, and 36S treatments). Elevated NaCl does not induce increased Hsp90 levels (Gasch et al. 2000;Causton et al. 2001;Berry and Gasch 2008), although its basal activity is required for activation of the high-osmolarity glycerol pathway that provides for efficient growth in elevated salinity environments (Hohmann 2002; Yang et al. 2006 Yang et al. , 2007Hawle et al. 2007). Based on these observations and the absolute growth rates of wild-type yeast in the six environments (Table 1), we state the following (cf. ... A Bayesian MCMC Approach To Assess the Complete Distribution of Fitness Effects of New Mutations: Uncovering the Potential for Adaptive Walks in Challenging Environments. The role of adaptation in the evolutionary process has been contentious for decades. At the heart of the century-old debate between neutralists and selectionists lies the distribution of fitness effects (DFE) - that is, the selective effect of all mutations. Attempts to describe the DFE have been varied, occupying theoreticians and experimentalists alike. New high-throughput techniques stand to make important contributions to empirical efforts to characterize the DFE, but the usefulness of such approaches depends on the availability of robust statistical methods for their interpretation. We here present and discuss a Bayesian MCMC approach to estimate fitness from deep sequencing data, and use it to assess the DFE for the same 560 point mutations in a coding region of Hsp90 in Saccharomyces cerevisiae across six different environmental conditions. Using these estimates, we compare the differences in the DFEs resulting from mutations covering 1, 2 and 3 nucleotide steps from the wild type - showing that multiple-step mutations harbor more potential for adaptation in challenging environments, but also tend to be more deleterious in the standard environment. All observations are discussed in the light of expectations arising from Fisher's geometric model. ... DnaJ-domain proteins are molecular chaperones that aid protein folding, prevent aggregation and repair damaged proteins following cellular stress [62]. They are members of the heat shock protein (Hsp) family, which have been shown to play important roles in the response to numerous stress conditions including osmotic stress and also can act as cochaperones by stimulating the activity of other chaperones such as DnaK [63][64] [65] . TM2 domain proteins are composed of a pair of alpha helices connected by a short linker. The function of this domain is unknown; however it occurs in a wide range of protein contexts. ... Functional Environmental Screening of a Metagenomic Library Identifies stlA; A Unique Salt Tolerance Locus from the Human Gut Microbiome Functional environmental screening of metagenomic libraries is a powerful means to identify and assign function to novel genes and their encoded proteins without any prior sequence knowledge. In the current study we describe the identification and subsequent analysis of a salt-tolerant clone from a human gut metagenomic library. Following transposon mutagenesis we identified an unknown gene (stlA, for "salt tolerance locus A") with no current known homologues in the databases. Subsequent cloning and expression in Escherichia coli MKH13 revealed that stlA confers a salt tolerance phenotype in its surrogate host. Furthermore, a detailed in silico analysis was also conducted to gain additional information on the properties of the encoded StlA protein. The stlA gene is rare when searched against human metagenome datasets such as MetaHit and the Human Microbiome Project and represents a novel and unique salt tolerance determinant which appears to be found exclusively in the human gut environment. ... For example, elevated salinity (0.7 or 1 M sodium chloride ) does not cause a statistically significant change in Hsp90 mRNA levels in yeast over either short or long time periods (Gasch et al. 2000; Causton et al. 2001; Berry and Gasch 2008). Although Hsp90 is not upregulated in response to elevated salinity, its basal function is required for robust growth under hyperosmotic conditions ( Yang et al. 2006 ). Indeed Hsp90 and its co-chaperone Cdc37 are both required for activation of the high osmolarity glycerol pathway (Hawle et al. 2007; Yang et al. 2007) that yeast require for growth under conditions of elevated salinity (Hohmann 2002). ... Shifting Fitness Landscapes In Response To Altered Environments The role of adaptation in molecular evolution has been contentious for decades. Here, we shed light on the adaptive potential in Saccharomyces cerevisiae by presenting systematic fitness measurements for all possible point mutations in a region of Hsp90 under four environmental conditions. Under elevated salinity, we observe numerous beneficial mutations with growth advantages up to 7% relative to the wild type. All of these beneficial mutations were observed to be associated with high costs of adaptation. We thus demonstrate that an essential protein can harbor adaptive potential upon an environmental challenge, and report a remarkable fit of the data to a version of Fisher's geometric model that focuses on the fitness trade-offs between mutations in different environments. ... Importantly, the different mutant forms of Hsp82p that have been studied have different genetic interactions with the cochaperone proteins. Genetic interactions have been identified between some of these Hsp82p mutants and certain co-chaperones but these interactions have not been extensively characterized [32,35, 36] . Of the Hsp82p mutants identified that confer ts phenotypes to yeast, only Hsp82p G170D is thought to be thermolabile [34] and biochemical studies have confirmed that several of these Hsp82p mutants do not lose activity at elevated temperatures [22,37]. ... The Co-Chaperone Hch1 Regulates Hsp90 Function Differently than Its Homologue Aha1 and Confers Sensitivity to Yeast to the Hsp90 Inhibitor NVP-AUY922 <here is a image d69e900cecafd1e6-9ee6e9d9d19300a4> Heather Armstrong <here is a image d2e49bcbad02e7b9-a197aa403a86d8a7> Annemarie Wolmarans Rebecca Mercier <here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Paul LaPointe Hsp90 is a dimeric ATPase responsible for the activation or maturation of a specific set of substrate proteins termed 'clients'. This molecular chaperone acts in the context of a structurally dynamic and highly regulated cycle involving ATP, co-chaperone proteins and clients. Co-chaperone proteins regulate conformational transitions that may be impaired in mutant forms of Hsp90. We report here that the in vivo impairment of commonly studied Hsp90 variants harbouring the G313S or A587T mutation are exacerbated by the co-chaperone Hch1p. Deletion of HCH1, but not AHA1, mitigates the temperature sensitive phenotype and high sensitivity to Hsp90 inhibitor drugs observed in Saccharomyces cerevisiae that express either of these two Hsp90 variants. Moreover, the deletion of HCH1 results in high resistance to Hsp90 inhibitors in yeast that express wildtype Hsp90. Conversely, the overexpression of Hch1p greatly increases sensitivity to Hsp90 inhibition in yeast expressing wildtype Hsp90. We conclude that despite the similarity between these two co-chaperones, Hch1p and Aha1p regulate Hsp90 function in distinct ways and likely independent of their roles as ATPase stimulators. We further conclude that Hch1p plays a critical role in regulating Hsp90 inhibitor drug sensitivity in yeast. ... The client proteins, Hsp90, Hsp70 and the regulatory proteins assemble into a large multichaperone machine to regulate the client protein function and turnover [14,19]. In Saccharomyces cerevisiae, Hsp90 is found to be required for the high osmotic stress response and regulates a novel signaling pathway via the co-chaperone Cdc37p parallel to the HOG pathway [20, 21]. Considering that Hsp70-and Hsp90-like proteins were upregulated in Dunaliella under halophilic conditions [11] and the importance of Hsp90 in the stress response of eukaryotic cells, it is possible that Dunaliella Hsp90 (DsHsp90) is involved in the halotolerance of Dunaliella. ... DsHsp90 Is Involved in the Early Response of Dunaliella salina to Environmental Stress Heat shock protein 90 (Hsp90) is a molecular chaperone highly conserved across the species from prokaryotes to eukaryotes. Hsp90 is essential for cell viability under all growth conditions and is proposed to act as a hub of the signaling network and protein homeostasis of the eukaryotic cells. By interacting with various client proteins, Hsp90 is involved in diverse physiological processes such as signal transduction, cell mobility, heat shock response and osmotic stress response. In this research, we cloned the dshsp90 gene encoding a polypeptide composed of 696 amino acids from the halotolerant unicellular green algae Dunaliella salina. Sequence alignment indicated that DsHsp90 belonged to the cytosolic Hsp90A family. Further biophysical and biochemical studies of the recombinant protein revealed that DsHsp90 possessed ATPase activity and existed as a dimer with similar percentages of secondary structures to those well-studied Hsp90As. Analysis of the nucleotide sequence of the cloned genomic DNA fragment indicated that dshsp90 contained 21 exons interrupted by 20 introns, which is much more complicated than the other plant hsp90 genes. The promoter region of dshsp90 contained putative cis-acting stress responsive elements and binding sites of transcriptional factors that respond to heat shock and salt stress. Further experimental research confirmed that dshsp90 was upregulated quickly by heat and salt shock in the D. salina cells. These findings suggested that dshsp90 might serve as a component of the early response system of the D. salina cells against environmental stresses. ... This has three probable causes.First, Melamed et al. (2008)used high osmotic stress (1 M NaCl). High or severe hyperosmotic stress is known to activate other signal transduction chains beside the HOG pathway, and functions outside of the HOG pathway are required for survival under such conditions ( Yang et al., 2006 ). Second, activation of stress responses is slower and less distinct under high osmostress than under moderate hyperosmotic shock as in our work (Van Wuytswinkel et al., 2000). ... ADP Ribosylation Factors 1 and 4 and Group VIA Phospholipase A2 Regulate Morphology and Intraorganellar Traffic in the Endoplasmic Reticulum–Golgi Intermediate Compartment Organelle morphology of the endomembrane system is critical for optimal organelle function. ADP ribosylation factors (Arfs), a family of small GTPases, are required for maintaining the structure of the Golgi and endosomes. What determines the discontinuous nature of the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) as tubulovesicular clusters is unknown. In search of morphological determinants for the ERGIC, we found that a double knockdown of Arf1+Arf4 induced dynamic ERGIC tubules that connect ERGIC clusters, indicating that the tubules mediated lateral intraERGIC traffic. Tubule formation was inhibited by an antagonist of group VI calcium-independent phospholipase A₂ (PLA2G6) and by silencing the A isoform of PLA2G6 (PLA2G6-A). Arf1+Arf4 depletion altered the expression of PLA2G6-A splice variants and relocalized PLA2G6-A from the cytosol to ERGIC clusters and tubules, suggesting that the enzyme became locally active. We show that changes in Arf1 can modulate the activity of PLA2G6-A. We propose that a concerted action of Arf1, Arf4, and PLA2G6-A controls the architecture of the ERGIC in a way that is predicted to impact the rate and possibly the destination of cargos. Our findings have identified key components in the molecular mechanism underlying the regulation of tubules in the ERGIC and uncover tubular carriers as tightly controlled machinery. ... This situation poses the question of the specificity of Sho1 sensor in signaling different stimuli, with the additional complication that elements of the SVG cascade are in common with the pheromone cascade (Schwartz & Madhani, 2004; Seet & Pawson, 2004). In parallel to the Sln1 and Sho1 branches, the osmotic response seems to have additional signaling pathways, which may lead or not lead to Hog1 phosphorylation (Van Wuytswinkel et al., 2000; Yang et al., 2006 ). Besides the regular top-down signaling, also lateral inputs to or from other pathways might play a role in response to certain stimuli. ... ... In mammalian cells, Hsp90 is an important component of the transcriptional arm of the unfolded protein response (UPR) and plays important roles in the cellular response to cytoplasmic stresses (Marcu et al. 2002). Hsp90 could protect mammal cells from 3-hydroxykynurenine (3HK)induced oxidative stress by reducing reactive oxygen species (ROS) levels (Lee et al. 2005), and be required for yeast cells to adapt to high osmotic stress (Yang et al. 2006) . ... (66)
https://www.researchgate.net/publication/7290480_The_molecular_chaperone_Hsp90_is_required_for_high_osmotic_stress_response_in_Saccharomyces_cerevisiae
Shadrach's Ex Battery and Rescued chickens thread. | Page 1479 | BackYard Chickens - Learn How to Raise Chickens Oh my, this sounds like a great Tom Waits song. Or a Charles Bukowski poem. Goes with Henry's nicotine stained feathers ... Tom Waits is one of my... Shadrach's Ex Battery and Rescued chickens thread. TropicalChickies said: BDutch said: Oh boy my chickens were nervous this morning. The chicken door didn’t open up automatically. 6 adults and 9 chicks is toooooo much in such a small coop ( 2,5 m2 floor space + 2 laying nests + 2 small platforms/roost areas. After work I tried to fix the problem. My Chicken Guard finally broke down, Thought the batteries were empty last evening. The door closed only half and the red light for trouble was on. Changed the batteries. Closed the pop door. But the door didn’t open again this morning. Did another calibration. But the system didn’t work again. After the calibration the door wont open as it sais in the manual. While I worked on the chicken guard I let the chicks out on the grass. 5 of them managed to escape. The rabbit fences are easy peasy to jump over now. View attachment 3539027 MDH: “A giant chicken in the coop” in the coop trying to fix the chicken guard. View attachment 3539028 The results of no mow may is too nice to mow now it’s June. The chicks in the background (photo taken yesterday). Warm with a bit of morning rain. Had domestic stuff to do today and only managed two hours at the allotments. What's more I was busy and then chatting to one of my favourite plot holders and forgot to take pictures until the chickens were heading for home. I've got a friend coming to stay for a couple of days and my spare bed is out on loan. It's coming back tomorrow but at an unspecified time in the afternoon. Hopefully it will be early and my friend and I can go and talk chicken at the allotments with time to spare. The bed is particulary important because I'm the one going to be sleeping on it. My friend is disabled so he gets my bed. He's a chicken keeper with two tribes. Stuff is still growing. The recent rain has made a difference. I'll just leave this here... fuzzi said: I'll just leave this here... View attachment 3539632 Adorable! Are they Sussex? @Shadrach i hope you enjoy visiting with your friend! Iluveggers said: Adorable! Are they Sussex? @Shadrach i hope you enjoy visiting with your friend! Speckled Sussex, bantams. Rahab is on the left, Martha is on the right. Shadrach said: How long have you had the chicken guard for? I bought it 7.5 years ago. Have been reading a bit more. Vaguely remembering something about a reset. I found some more info on the internet why it’s possibly not opening again. Seems that the older chickens guard from before 2017 work a bit different . I’ll try if I can make it work once more today (unscrewing, checking cord, reset) and keep you updated. fuzzi said: Speckled Sussex, bantams. Rahab is on the left, Martha is on the right. I love the colouring. Thats one of the reasons why I bought bantam Red Speckled Sussex hatching eggs. This is what the bantam Sussex look like when they are young. The person I bough the eggs from suspects that the first photo is of a cockerel wit a perfect comb. The second a pullet. Shadrach said: The term coop almost always needs some clarification. I've always built what I describe as coops. The recycled plastic construction I now have is a coop. Some other people have constructions that could be described as aviaries. Some people have buildings that may be better described as sheds, or outhouses. When I write about coops I have a quite specific construction in mind. Royalchick for example has what I would describe as an aviary. You have an outhouse. It's a definition problem. Perhaps the easiest resolution to the inaccuracies of language when it comes to coops is to take the chicken bit out of the description and consider what it is one has left. Interesting perspective. You're right that we are probably comparing things that shouldn't be. On the other hand one of the first very good advice almost always given on BYC to people who ask about coops, is to take into account their climate and local setting before deciding what will be the right coop for them. The problem I have with being an idealist is everything falls short, including myself. There is no acceptable way of turning back, Pol Pot had a try and despite what some may consider his initial good intentions, he's remembered by history as a bad thing. TropicalChickies said: Hi @ManueB , thanks for the mention... I just want to say I don't mean to come off as all 'woke" and "virtuous" over here on my off grid mud house. There's nothing worse than sanctimonious holier-than-thou posturing on the internet. Our lifestyle isn't perfect. We have a jeep, for example. Living out here without a vehicle would be more difficult than I can handle right now. I use the internet. In many ways, I have to in order to keep the farm going by having visitors and programs to supplement our income. But I also use it recreationally, and thank goodness I'm limited by the sometimes poor satellite connection. And after living like this, in relatively splendid isolation for seven years, I'm not sure I even could go back to urban or "normal" life, not without some serious psychological problems... But, yes, the way my partner and I live is very different. I'm not optimistic that we can really change the destructive trajectory humans are on, but perhaps we can leave a roadmap for future generations to say, "ah now, these people were on to something..." I don't think people in rich countries will necessarily be completely sheltered from climate crisis. But they can certainly act like they are "in their bubble" for a longer time. Just the other day I saw a photo of a suburban house renovation underway in California USA with an eerie orange sky in the background from an approaching wildfire. I mean, who does this? Comfortably middle class people who don't think this crisis will touch them. For people in Southeast Asia and Central America, however, it has already begun in earnest. Over a billion people have already been displaced by rising ocean levels, heat, and drought. Mexico has its own border crisis as people from Nicaragua, Honduras and Guatemala flee their scorched farmlands. Cities in SE Asia now have new ghettos of refugees whose homes are underwater. These stories don't often make the news, but they are happening. Plus, to be honest, I have reasons for living like I do, and not all of them are altruistic. I like animals, trees, and books more than people. enjoy the satisfaction of building structures with dirt, pulling food put of the ground. Hand washing clothes, not so much. But it's part of the package. And I don't overestimate how much individual actions like mine can really impact the situation. The nefarious actors, the big banks, the multilateral institutions, the mega corporations, the one percent -- they are a much bigger problem than your plastic freezer bags or my Jeep. We need a real uprising, a revolution, and the people willing to go to the front lines. I apologize if I sounded ironic or judgemental, english isn't my language and I guess what I write doesn't sound exactly like what I think. I sincerely admire what both of you are doing in your different ways, and I believe if more of us acted in accordance to our beliefs like you both do, things could get better. I'm just feeling totally despaired and angry and also guilty as to why our specie has such a tendency to do everything to destroy the world we live in. And I don't want to look at the splinter in my neighbor's eye, ignoring the log in mine . BDutch said: Oh boy my chickens were nervous this morning. The chicken door didn’t open up automatically. 6 adults and 9 chicks is toooooo much in such a small coop ( 2,5 m2 floor space + 2 laying nests + 2 small platforms/roost areas. After work I tried to fix the problem. My Chicken Guard finally broke down, Thought the batteries were empty last evening. The door closed only half and the red light for trouble was on. Changed the batteries. Closed the pop door. But the door didn’t open again this morning. Did another calibration. But the system didn’t work again. After the calibration the door wont open as it sais in the manual. While I worked on the chicken guard I let the chicks out on the grass. 5 of them managed to escape. The rabbit fences are easy peasy to jump over now. View attachment 3539027 MDH: “A giant chicken in the coop” in the coop trying to fix the chicken guard. View attachment 3539028 The results of no mow may is too nice to mow now it’s June. The chicks in the background (photo taken yesterday). What a day, sounds like you all had quite the adventure ! I'm sure the chicks enjoyed it if not the adults. Warm with a bit of morning rain. Had domestic stuff to do today and only managed two hours at the allotments. What's more I was busy and then chatting to one of my favourite plot holders and forgot to take pictures until the chickens were heading for home. I've got a friend coming to stay for a couple of days and my spare bed is out on loan. It's coming back tomorrow but at an unspecified time in the afternoon. Hopefully it will be early and my friend and I can go and talk chicken at the allotments with time to spare. The bed is particulary important because I'm the one going to be sleeping on it. My friend is disabled so he gets my bed. He's a chicken keeper with two tribes. View attachment 3539420 View attachment 3539419 View attachment 3539421 View attachment 3539417 View attachment 3539414 Stuff is still growing. The recent rain has made a difference. View attachment 3539415 Well, let's hope the bed makes it on time, by whatever means of transportation it intends to reach your place . Nice that you have some visit of a chicken keeper friend. Maybe you'll tell us more about it. Am I seeing an attempt at growing a few tomatoes ? Preening mamma tax Mr Grumpy. Shadrach said: … I've got a friend coming to stay for a couple of days and my spare bed is out on loan. It's coming back tomorrow but at an unspecified time in the afternoon. Hopefully it will be early and my friend and I can go and talk chicken at the allotments with time to spare. The bed is particulary important because I'm the one going to be sleeping on it. My friend is disabled so he gets my bed. He's a chicken keeper with two tribes. View attachment 3539420 View attachment 3539419 View attachment 3539421 View attachment 3539417 View attachment 3539414 Stuff is still growing. The recent rain has made a difference. View attachment 3539415 Enjoy this day with your friend. Maybe he can make some nice pictures of you holding Henri and your other tribe members. After reading about boiling water for tea: I have an electric water kettle that lasts for at least 10 years now. Because it has a flat bottom , it can cook one cup of water. It’s 1,7 liter, switches of automatically. Brand Tefal (imported stuff and labeled as if it is Dutch). I bought it in a housewares shop. Also use it to boil water for (pre)cooking because we have many solar panels and its better (cheaper) to use that energy, than it is to use fossil gas. Furthermore about A-mazon: I never buy from A.mazon because the company is too big, the owner spills his money on fossil fuels to go halfway to the moon and labourers are underpaid. My husband did buy something from Bezos once because it was so cheap compared to other sellers - but it had no warranty and it broke down within 2 years. … fourth reason. It sells cheap crap.
https://www.backyardchickens.com/threads/shadrachs-ex-battery-and-rescued-chickens-thread.1502267/page-1479
Portrait of Dr. P.J.H. Cuypers (1827-1921) [Thérèse Schwartze] | Sartle - Rogue Art History Painting by Thérèse Schwartze Artworks Portrait of Dr. P.J.H. Cuypers Thérèse Schwartze Rijksmuseum Museumstraat 1Amsterdam,Netherlands Arty Fact The Rijksmuseumgives a 33-year window for the creation of this work: 1885-1918, perhaps getting all the whiskers in his beard took a long time. Mr. Cuypers was the architect of the Rijksmuseum, where this work is now housed. The sitter's nephew and protegé, Eduard Cuypers, was commissioned by Schwartze to build a studio. More about Portrait of Dr. P.J.H. Cuypers Type Painting Year 1885 View all Medium Canvas, Oil paint Genre Portraiture View all Catalog Number SK-A-4948 Collection Rijksmuseum View all Credit Line Gift of Cuypers-archief View all Considering the prominence of Thérèse Schwartze, the wealthiest artist in turn-of-the-century Amsterdam, and the fame of her sitter, who has both a street and a museum named for him, it's quite odd that there is so little published literature about the Portrait of Pierre J.H. Cuypers . The owners of the work, the sprawling, Gothic Rijksmuseum inAmsterdam, situate their collection in buildings designed by Cuypers. They received the work as a donation from the Cuypers archives in 1919. Art historians consider the precise dating of works to be thebread and butterof the profession, like speech-giving to a mayor or carrying plastic bags to a dog walker. And yet the Rijksmuseum offers a window which covers most of Schwartze's professional career, up until her final year of life, for the dating of this painting: 1885-1918. In fact, the research of Cora Hollema, the reigning dean of Schwartze studies, gives only seven works as "autograph," or painted in the artist's own hand without assistance, prior to 1885. The artist commissioned the sitter's nephew and protegé, Eduard Cuypers, to build her new studio when she moved out of her late dad's workshop in the attic of the Schwartze home. Born in Roermond in 1827 to Joannes Hubertus Cuypers and Maria Joanna Bex, Pierre J.H. Cuypers was one of the most famous architects in Dutch history, building dozens of churches and other important landmarks. If you want to sound sufficiently Dutch, you'd pronounce his name somewhat like "kye-purzsh," with that distinctive buzzing "zzh" sound unique to the Dutch "s." The Netherlands was still recovering from its colonization by the Spanish Habsburg empire, which had ended just over a century before the architect's birth. The state religion of the Spanish Netherlands was Roman Catholicism, and the vibe in the Netherlands was tense between Catholics and Protestants. Maybe almost as tense as the vibe betweenRepublicans and Democratsin the 2016 U.S. Presidential election. For instance, just before the Habsburgs took over, the family of the artist John de Critzhad fled the Netherlands for Protestant England, where de Critz became a spy for the Protestant cause. Cuypers made no apologies for his Catholic background, which made him many adversaries who shared the "Protestant and liberal view." For them, Cuypers' Gothic, Romanesque architecture threatened to bring the Netherlands  "back to the dark Middle Ages and the infinitehedonismof Rome." Bas Kromhout uses the Dutch term vleespottento describe the Protestant view of the sexual attitudes of the Romans in this sentence, which literally means "fleshpots." For the Dutch Roman Catholics, however, Kromhout writes, "Cuypers was almost a saint, whose buildings radiated the self-confidence of cultural revival." Sources Sources Hollema, Cora. "Thérèse Schwartze, 19th Century Amsterdam Painter." YouTube video, Dec. 20, 2015, 37:02, https://youtu.be/61lqsJ2MzEA . Hollema, Cora, and Pieternel Kouwenhoven. Thérèse Schwartze (1851-1918). Een vorstelijk portrettiste. Zutphen: Walberg, 1998. Jensen, Lotte Eilskov, Joseph Theodoor Leerssen, and Marita Mathijsen. Free Access to the Past: Romanticism, Cultural Heritage and the Nation. Leiden: Brill, 2010. Kromhout, Bas. "Pierre Cuypers." Historische Nieuwsblad, https://www.historischnieuwsblad.nl/pierre-cuypers/ . "Rijksmuseum Amsterdam." Werkgroep Pierre Cuypers, Roermond, https://www.cuypersroermond.nl/rijksmuseum.html . "Wie was Pierre Cuypers?" Cuypershuis, https://www.cuypershuisroermond.nl/nl/ontdek/cuypers-en-het-cuypershuis… .
https://www.sartle.com/artwork/portrait-of-dr.-p.j.h.-cuypers-1827-1921-therese-schwartze
EC:1.2.1.4 - FACTA Search Gene/Protein Disease Symptom Drug Enzyme Compound Pivot Concepts: Target Concepts: Query: EC:1.2.1.4 ( aldehyde dehydrogenase ) Recently, the principles of density gradient cell separation have been transferred to the marrow fractionation, and the Ficoll technique by using a COBE 2991 blood cell processor has been developed and widely employed as well. This method is particularly useful in view of a chemical antineoplastic purging intended for autologous marrow transplantation. Forty marrows, which derived from patients suffering with leukemia and lymphoma, were fractionated with Ficoll on a COBE machine and in vitro purged with Mafosfamide at a dose of 50 micrograms/ml/1 x 10e7 MN cells. The density gradient separation enables to reduce the initial volume to 10%, the contaminating RBC to less than 1%, the total nucleated cells to 25% (greater than 80% of MNC) sparing about 80% of the CFU-GM. After purging, the surviving hemopoietic progenitor cells were 2.5%. The clinical effects of the fractionated purged cells were studied in 11 autotransplanted patients and compared with 14 transplants performed with untreated buffy-coat marrow derived cells. Ficoll cells produced less adverse effects at the time of reinfusion, while, as expected, the time of hematopoietic recovery was delayed in these patients (mafosfamide treated cells). These results confirm the usefulness of the gradient density cell separation to reduce the side effects of the DMSO and to make reliable the Mafosfamide purging manoeuvre, preventing the interference of contaminating RBC aldehyde dehydrogenase . ... PMID:Density gradient separation of hematopoietic stem cells in autologous bone marrow transplantation. 167 10 Resistance to multiple chemotherapeutic agents is a common clinical problem in the treatment of cancer: such resistance may occur in primary therapy or be acquired during treatment. The most commonly used antineoplastic agents in the treatment of disseminated breast cancer are adriamycin, methotrexate and cyclophosphamide. Cell lines selected for resistance to adriamycin often develop cross-resistance to structurally dissimilar antineoplastic drugs with different mechanisms of cytotoxic action; this phenomenon has been called pleiotropic or multidrug resistance (MDR). In vitro models of MDR have shown that this type of resistance is accompanied by a decrease in cellular drug accumulation, mediated by the over-expression of a 170 kD plasma membrane glycoprotein referred to as P170. Glycoprotein P170 is an energy-dependent multidrug efflux pump, whose activity can be inhibited in vitro by a variety of agents including verapamil, quinidine and reserpine. P170 is over-expressed also in some human malignancies, and evidence exists about its role in examples of clinical resistance in vitro. Clinical trials using verapamil, a calcium channel blocker which selectively enhances drug cytotoxicity in MDR cell lines, have been prompted for leukemia and ovarian cancer. In addition other approaches are the subject of current preclinical investigations. Several observations as well the phenomenon of "atypical" MDR in cell lines which do not overexpress P170, suggest that also other factors are involved in multidrug resistance. Qualitative or quantitative changes in the activity of topoisomerases, protein kinase-related systems and glutathione S-transferase, may confer pleiotropic resistance. As the role of these genes and their regulation is clarified, they may also serve as useful targets for pharmacologic intervention in the treatment of drug-resistant human tumors. The mechanisms involved in resistance to methotrexate and cyclophosphamide are less studied, particularly in vivo samples. Methotrexate resistance is probably a complex multifactorial phenomenon; in some cases it is due to an increase in the expression of the drug target dihydrofolate reductase, often as a result of gene amplification, but in other cases a transport defect of the methotrexate or alterations of the activity of different enzymes have been reported. Cyclophosphamide (CP) resistance has been attributed to an increased activity of two different enzymes, glutathione S-transferase, also involved in MDR phenotype, and aldehyde dehydrogenase , which catalyzes inactivation of CP in non cytotoxic metabolites. This paper reviews the current state of our knowledge of chemo-resistance and the utility of available markers to identify potentially resistant tumors in vivo; the strategies that might be used to overcome this phenomenon are also described. ... PMID:Chemoresistance in breast tumors. 168 Jun 89 These investigations were performed to clarify the molecular basis for the enhanced expression of cytosolic aldehyde dehydrogenase (ALDH-1) enzymatic activity in the cyclophosphamide-resistant L1210/CPA murine leukemia cell line, as compared to the parental L1210/O strain. Western immunoblot analysis was performed using a 15-fold greater quantity of cytosolic protein from the L1210/O as compared to the L1210/CPA cell line. Nevertheless, ALDH-1 immunoreactive protein could be detected only in the L1210/CPA cells. Northern analyses, performed using total cellular and polyadenylated RNA, again demonstrated ALDH-1-specific transcripts only in the L1210/CPA cell line. This transcript was identical in size to the ALDH-1 message expressed by normal murine hepatocytes. On Southern analysis, no evidence of gene amplification, gene rearrangement, or significant mutations of length was detected. These studies suggest that the ALDH-1 protein produced by the L1210/CPA cell line is structurally normal. Moreover, overexpression of the gene does not appear to have arisen as a result of an incremental process, such as gene amplification. Rather, a qualitative abnormality in the regulation of this gene appears to exist in the L1210/CPA cells, which distinguishes them from L1210/O cells and from normal murine lymphocytes. ... PMID:Structure and expression of the cytosolic aldehyde dehydrogenase gene in cyclophosphamide-resistant murine leukemia L1210 cells. 174 71 Several mouse aldehyde dehydrogenases catalyze the detoxification of aldophosphamide, the pivotal metabolite of the prodrugs cyclophosphamide, mafosfamide, and other oxazaphosphorines. N-Isopropyl-p-formylbenzamide, a major metabolite of procarbazine, was found to be an excellent substrate (Km = 0.84 microM) for at least one of these enzymes, namely, mouse aldehyde dehydrogenase -2. The Km for mouse aldehyde dehydrogenase -2-catalyzed detoxification of aldophosphamide is 16 microM. Thus, competition between N-isopropyl-p-formylbenzamide and aldophosphamide for the catalytic site on the enzyme should strongly favor the former, and the rate at which aldophosphamide is detoxified should be markedly retarded. Mouse L1210/OAP and P388/CLA leukemia cells are relatively insensitive to the oxazaphosphorines because they contain large amounts of mouse aldehyde dehydrogenase -2. As predicted, N-isopropyl-p-formylbenzamide markedly potentiated the cytotoxic action of mafosfamide against these cells. Mouse L1210/0 and P388/0 lack the enzyme. Again as expected, N-isopropyl-p-formylbenzamide essentially did not potentiate the cytotoxic action of mafosfamide against these cells. Certain mouse and human hematopoietic progenitor cells also contain an aldehyde dehydrogenase that catalyzes the detoxification of aldophosphamide, but the specific identity of this enzyme remains to be established. N-Isopropyl-p-formylbenzamide potentiated the cytotoxic action of mafosfamide against these cells as well. Clinically, procarbazine and the oxazaphosphorines are used to treat certain neoplastic diseases. Frequently, they are used in combination. Our findings demonstrate the potential for both desirable and undesirable drug interactions when these agents are used concurrently. Similar drug interactions can be expected when other substrates for, or inhibitors of, the relevant aldehyde dehydrogenases, e.g., chloramphenicol, chloral hydrate, and methyltetrazolethiol-containing cephalosporins, are co-administered with the oxazaphosphorines. ... PMID:Potentiation of the cytotoxic action of mafosfamide by N-isopropyl-p-formylbenzamide, a metabolite of procarbazine. 186 38 4-amino-4-methyl-2-pentyne-1-al (AMPAL), a new irreversible inhibitor of aldehyde dehydrogenase ( ALDH ) has been assayed for its in vitro and in vivo antitumor activity. In vitro, AMPAL inhibits the proliferation and the ALDH activity of L1210 and RBL5 cell lines. In vivo, AMPAL significantly increases the mean survival time of mice i.p. grafted with leukemia (L1210, P815, MBL2, EL4, RBL5 cell lines) or carcinoma cells (Krebs cell line), without haematopoetic toxicity. No carcinostatic effect was observed against the P388 leukemia and the 3LL Lewis lung carcinoma. A possible relationship between the ALDH isoenzyme activity of the tumor and its sensitivity to AMPAL is discussed in the light of previous reports concerning the role of aldehydes in cell growth control. ... PMID:In vivo antitumor activity of 4-amino 4-methyl 2-pentyne 1-al, an inhibitor of aldehyde dehydrogenase. 251 73 A cyclophosphamide-resistant L1210 cell line has been shown to have unusually high aldehyde dehydrogenase activity. The sensitivity of this cell line to 4-methylcyclophosphamide and phosphoramide mustard in vivo and corresponding sensitivities in vitro indicate that 4-hydroxycyclophosphamide and/or aldophosphamide is the form in which cyclophosphamide reaches these tumor cells in mice and that intracellular aldehyde dehydrogenase activity is an important determinant of cyclophosphamide sensitivity in these leukemia cell lines. ... PMID:Role of aldehyde dehydrogenase in cyclophosphamide-resistant L1210 leukemia. 648 75 The development of drug resistance is an important factor contributing to failure of chemotherapy in cancer patients. Cyclophosphamide (CP) is a cytostatic drug widely used in the treatment of haematological malignancies and solid tumours. Because CP requires bioactivation to become cytotoxic, an in vivo approach was chosen to generate a subline of the Brown Norway rat acute myelocytic leukaemia (BNML/CPR) highly resistant to CP to serve as a model to investigate the molecular mechanism(s) of cyclophosphamide resistance. The role of the CP-detoxifying enzyme aldehyde dehydrogenase ( ALDH ) in the molecular mechanism of CP resistance in this subline of the BNML has been investigated. Compared to the parent BNML cell line, the BNML/CPR cell line displayed an approximately 6-fold higher level of ALDH enzyme activity. Pretreatment of leukaemic rats with the ALDH inhibitor disulfiram resulted in a restoration of CP sensitivity of animals carrying the BNML/CPR cells. Furthermore, in vitro incubation of BNML/CPR cells with disulfiram prior to incubation with the activated CP derivative mafosfamide resulted in an extra 2-3 log cell kill as indicated by the survival time of rats which were injected with disulfiram pretreated BNML/CPR cells compared to non-pretreated BNML/CPR cells. Data on the glutathione S-transferases (GSTs) isozyme profiles of cytoplasmic liver and spleen extracts of BNML- and BNML/CPR-carrying leukaemic rats indicated that the total GST enzyme amount was lower in BNML/CPR cells than in parent BNML cells. Furthermore, the BNML/CPR subline proved to be sensitive to phosphoramide mustard, both in vivo and in vitro. ... PMID:Aldehyde dehydrogenase involvement in a variant of the brown Norway rat acute myelocytic leukaemia (BNML) that acquired cyclophosphamide resistance in vivo. 785 14 The compound 4-(diethylamino)benzaldehyde (DEAB) is a potent inhibitor of cytosolic (class 1) aldehyde dehydrogenase ( ALDH ) in vitro and can overcome cyclophosphamide resistance in murine leukemia cells characterized by their high content of ALDH . In this study, we examined the in vivo effect of DEAB in mice on ethanol metabolism and on antipyrine clearance as a measure of the microsomal mixed function oxidase activity. DEAB administered in doses of 50 and 100 mg/kg increased the blood acetaldehyde concentration and decreased the plasma acetate concentration in mice treated with ethanol. A pharmacokinetic approach demonstrated that DEAB in doses of 50 and 100 mg/kg inhibited the fraction of ethanol converted to acetate by 32.5 and 67.5%, respectively. This inhibition was comparable with that produced by disulfiram. DEAB produced optimal inhibition of ALDH 10-15 min after administration. DEAB did not change the half-life or the total clearance of antipyrine. We conclude that DEAB is a potent inhibitor of ALDH in vivo and has no effect on the mixed function oxidase activity as determined by antipyrine clearance. ... PMID:Effect of 4-(diethylamino)benzaldehyde on ethanol metabolism in mice. 811 35 The bovine leukaemia inhibitory factor was isolated from a phage library and sequences for the gene, in addition to 1213 bp of 5' and 432 bp of 3' sequences, were obtained and compared with other mammalian leukaemia inhibitory factor genes. Comparisons indicated amino acid homologies ranging from 89.6% to 77.2% with the human and mouse homologues, respectively. Analysis of 500 bp of 5' regulatory regions indicated homologies ranging from 83.6% to 74.4% with the corresponding human and sheep sequences, respectively. Additionally, bovine leukaemia inhibitory factor-specific primers were prepared, and a panel of bovine x hamster somatic cell lines were analysed by the polymerase chain reaction (PCR). Data indicated 93% concordance of leukaemia inhibitory factor with aldehyde dehydrogenase 2 located on bovine chromosome 17, and concordance of 81% with myelin basic protein situated on bovine chromosome 24. Southern analysis of selected hybrids confirmed the PCR results, thus conclusively assigning the bovine leukaemia inhibitory factor gene to chromosome 17. Sequence analysis also revealed a microsatellite in intron 2 of the bovine leukaemia inhibitory factor. Analysis of this region by PCR in 22 unrelated Bos taurus and 19 unrelated Bos indicus cattle detected nine different alleles. Polymorphic information content values were 0.53 and 0.80 in B. taurus and B. indicus, respectively. Additionally, the same leukaemia inhibitory factor primers successfully detected allelic variants at this locus in Bos javanicus, Bos guarus and Bison bison but not in Odocoileus virginianus. ... PMID:Genetic characterization of the bovine leukaemia inhibitory factor (LIF) gene: isolation and sequencing, chromosome assignment and microsatellite analysis. 912 2 Previously, we have reported the successful expression of human aldehyde dehydrogenase class-1 (ALDH-1) in K562 leukemia cells using a retroviral vector and demonstrated low expression that resulted in up to three-fold increase in resistance to 4-hydroperoxycyclophosphamide (4-HC), an active derivative to cyclophosphamide. The purpose of this study was to investigate whether in vitro treatment with 4-HC will allow selection of K562 cells expressing higher levels of ALDH-1, and whether these selected cells are more resistant to 4-HC. Stably transfected or transduced K562 cells with retroviral pLXSN vector containing ALDH-1 cDNA (ALDH-1 cells) were treated repeatedly with 4-HC and then allowed to grow to confluence in liquid culture. Subsequently, the resistance to 4-HC of ALDH-1 cells treated once (ALDH-1+) or twice (ALDH-1++) with 4-HC was compared to ALDH-1 cells or wild-type K562 cells (WT cells). The results show significant increase in 4-HC resistance of ALDH-1+ (2- to 16-fold, p < 0.005) over ALDH-1 or WT cells. No difference was detected between ALDH-1+ and ALDH-1++. In addition, higher ALDH-1 mRNA and enzyme activity were found in ALDH-1+ compared to ALDH-1 cells. Southern analysis of DNA extracted from the different experimental groups demonstrated an eight-fold increase in ALDH-1 cDNA in ALDH-1+ versus the ALDH-1 cells. This was confirmed by sequential FISH analysis using biotin labeled pLXSN/ALDH-1 vector. Positive signals consistently localized to the centromeric region of chromosome 9 and the long arm of chromosome 17 were demonstrated only in the ALDH-1+ cells and represented a fusion product of multiple copies of the pLXSN/ALDH-1 vector. In summary, we have demonstrated that in vitro treatment with 4-HC results in the selection of K562 cells with multiple copies of ALDH-1 gene that are clustered in two main integration sites. These cells demonstrate significantly higher resistance to 4-HC when compared to previously untreated cells. Such successful in vitro selection could have significant implications for future cancer gene therapy protocols. ... PMID:In vitro selection for K562 cells with higher retrovirally mediated copy number of aldehyde dehydrogenase class-1 and higher resistance to 4-hydroperoxycyclophosphamide. 955 9
http://www.nactem.ac.uk/facta/cgi-bin/facta3.cgi?query=EC%3A1.2.1.4%7C111111%7C0%7C0%7C107119%7C0%7C10
The Dangers of Privatizing Tax Collection: Priceline.com, Inc. v. City of Anaheim | Tax Foundation Improving Lives Through Smart Tax Policy The Dangers of Privatizing Tax Collection: Priceline.com, Inc. v. City of Anaheim IntroductionThe city of Anaheim, California argues that they are owed hotel occupancytaxes from online travel booking services such as Priceline.com, Expedia.com, and Orbitz.com. The city’s hotel tax, which is charged to anyone who rents a room, is based on the retail price of the hotel room. The online companies facilitate transactions and receive from consumers a payment that is not included in calculating the hotel tax the consumer must pay. The city filed a lawsuit to challenge this practice. The litigation is not being managed by city lawyers but rather by outside private contingency fee lawyers. Contingency fee lawyers are not paid for their services unless they win the case, in which case they receive a percentage share of the winnings. If the contingency fee lawyers succeed in winning the case, the city may collect substantial revenue from the online companies, with a share going to the private lawyers. In a case pending before the California Court of Appeal, Priceline.com, Inc. v. City of Anaheim, the online travel companies argue that the private lawyers cannot impartially enforce the city’s tax laws because of their significant financial interest in the outcome of the case. Further, they argue that the city has failed to maintain sufficient control over the lawyers’ activities. The Tax Foundation’s amicus curiaebrief argues that Anaheim must even-handedly enforce its tax code, precluding the city’s use of contingency fee attorneys. The brief also urges the court to evaluate the sufficiency of the Anaheim’s oversight mechanisms, particularly in light of the recent failure and termination of the federal Internal Revenue Service’s private debt collection program. Private Debt Collectors at the Federal Level Went Overboard Despite IRS OversightIn an attempt to cut costs and increase revenue from back-taxes, the IRS contracted with private debt collection agencies to collect tax debts for the United States. These companies were paid by the United States on a contingency fee basis, based on the amount of tax debt that they collected. When the IRS deals directly with taxpayers, it has governmental discretion to negotiate settlements with taxpayers, including the power to suspend or cancel debts. Private collections cannot make such offers, so the IRS limited private debt collectors to “easy” cases that did not require any governmental discretion to resolve. Unfortunately, it has become clear that few if any cases do not require governmental discretion to resolve, so the private collectors were often assigned cases that they could not resolve. Much to the exasperation of taxpayers, people were pressured into sending their payments instead of being referred to the IRS where they could have received a more beneficial settlement. This practice was attributed to the private debt collectors’ financial interest in payments. The failure of the program occurred despite extensive oversight of the private debt collection agencies’ practices by the IRS. The IRS mobilized: (1) a taxpayer complaint process; (2) ongoing reviews of private collector actions; (3) rules regulating referrals back to the IRS in cases where taxpayers were found to be unable to pay; (4) a dispute appeals process; (5) comprehensive training materials; (6) active regulation of private collector training programs; (7) direct oversight by IRS employees meant to ensure that cases were handled properly; and (8) active procedural and legal review of the private collection processes. Nevertheless, these abuses occurred, and the program’s inefficiency led to its termination in early 2009. Lessons of the IRS’s Experience for AnaheimThe IRS’s experience with its private debt collection program revealed that despite even the most ardent attempts to ensure that private parties performing government functions act neutrally, it can still occur. The IRS employed an impressive array of oversight mechanisms, which still did not completely prevent the private debt collection agencies’ self interests from undermining the neutrality of the IRS’s tax debt collection. The Tax Foundation’s argues that the court should be critical of the Anaheim’s claim that its oversight has been completely effective. The IRS’s experience conveys the idea that to ensure absolute neutrality, governmental oversight would have to be nearly flawless and it is difficult to imagine such a system in light of the failure of the IRS’s efforts. The authors would like to acknowledge the assistance of Edward Teyssier for acting as pro bono local counsel for the Tax Foundation in the filing of this amicus curiae brief. Topics Center for Federal Tax Policy California Amicus Briefs Excise Taxes Hotel and Tourism Taxes Tax Law Tags State Tax and Spending Policy
https://taxfoundation.org/dangers-privatizing-tax-collection-pricelinecom-inc-v-city-anaheim/
Financial Services (Miscellaneous Amendments) Regulations 2022 - Motion to Approve: 15 Nov 2022: House of Lords debates - TheyWorkForYou & ndash; in the House of Lords at 7:02 pm 15 November 2022 Financial Services (Miscellaneous Amendments) Regulations 2022 - Motion to Approve – in the House of Lords at 7:02 pm on15 November 2022. Baroness Penn: Moved by Baroness Penn That the draft Regulations laid before the House on 17 October be approved. Baroness Penn The Parliamentary Secretary, HM Treasury My Lords, this statutory instrument comprises two sets of provisions relating to Gibraltarian firms operating in the UK market and to securitisation. The proposed legislation will remedy technical deficiencies identified in financial services legislation that was put in place to help manage our withdrawal from theEU. In relation to Gibraltar, this instrument will fix temporary market access arrangements put in place to ensure that Gibraltarian firms did not face a cliff-edge loss of market access into the UK when we left the EU. In particular, these amendments will complete the intended transfer of powers to the Treasury and theFinancial Conduct Authorityin three specific areas. This transfer will give the UK authorities powers in relation to Gibraltarian firms where operating in the UK market, consistent with their powers over domestic firms. It is worth remembering that financial services legislation was amended on withdrawal from the EU to adjust the treatment ofEEAfirms; in particular, to remove passporting rights, which were a function of the EU’s single market. At this time, because Gibraltarian firms had benefited from equivalent rights, separate provisions were necessary to preserve the existing arrangements supporting market access for financial services between the UK and Gibraltar. These arrangements were always intended to be temporary. Through theFinancial ServicesAct 2021, we are working to replace them with a new permanent regime designed specifically for Gibraltar that reflects our unique history and relationship. The temporary regime that the Government put in place for Gibraltarian firms unintentionally prevented the transfer of powers to the Treasury and the Financial Conduct Authority being completed in certain areas, leaving gaps in UK law. This SI will exclude provisions from this temporary regime to remove these gaps in the powers available to the Treasury and theFCA. This is equitable and proportionate, as it will enable the treatment of Gibraltarian firms to be brought in line with that of UK firms. Closing these gaps will provide for a more consistent legal and regulatory environment, as intended. This SI will have an impact on three regulations that affect Gibraltarian firms operating in our market. Under the Short Selling Regulation, the Treasury’s power to modify the reporting threshold relating to net short positions will extend to Gibraltarian firms trading shares on a UK trading venue. Under the Markets in Financial Instruments Regulation, the FCA will be able to apply technical standards relating to post-trade disclosure obligations to Gibraltarian investment firms in the UK. Similarly, under the Packaged Retail and Insurance-based Investment Products Regulation, the FCA will be able to apply technical standards to Gibraltar firms selling, advising on or manufacturing PRIIPs to retail investors in the UK. I turn now to the second area the SI covers, securitisation provisions. Securitisation is the packaging up of assets or loans and selling them on to investors. This allows lenders such as banks to transfer the risks of assets to other banks and investors to free up their balance sheets and allow for further lending to the real economy.The UKsupports the implementation of international standards to promote simple, transparent and standardised—orSTS—securitisations. STS securitisations are easier for investors to understand and assess the risks of. As a result, some STS investors will benefit from lower capital requirements. Generally, only firms established in the UK can designate their securitisations as STS. However, transitional arrangements were put in place to allow for certain EU STS securitisations issued prior to the end of 2022 to be recognised in the UK. These arrangements were extended to the end of 2024 by another set of EU exit regulations earlier this year. The instrument being debated today will simply extend the end date of two requirements for EU STS securitisations to the end of 2024, rather than 2022. This will ensure that UK investors do the appropriate due diligence checks when investing in EU STS securitisations, and that these securitisations remain exempt from clearing requirements, to prevent unnecessary administrative burden. The amendments thus maintain the current requirements as long as the transitional arrangements last. I beg to move. Lord Jones Labour My Lords, I thank theMinisterfor her lucid introduction. I refer to paragraph 7.26 of the Explanatory Memorandum. Will she tell us just how busy Gibraltar firms are? How many of them are there—that is, those that are “acting as sellers, advisers or manufacturers of PRIIPs to retail investors in the UK”? Gibraltar is a very small place. We might ask, with regard to the Explanatory Memorandum, what is going on in Gibraltar? There is a plethora of technical terms, a multitude of abbreviations in capital letters and specialist vocabulary, and it is all a blizzard of necessitous complexity, the House might agree. Of course, the Minister is a master of it all and, again, I thank her for her lucid introduction. Baroness Bowles of Berkhamsted Liberal Democrat My Lords, I thank theMinisterfor the introduction. It does not matter how many times I read these kinds of explanations about what is going on, I still find them totally incomprehensible and I doubt I am alone. I have two very short questions. First, does this mean that for a period there was a lacuna when neitherEUnor UK regulators held sway and Gibraltar was doing its own thing while having access to the UK as it always had done? If that was the case, did the Gibraltarian financial services authorities know? I cannot tell whether there was such a lacuna or not. Secondly, on the temporary permissions relating toSTS—I declare an interest as an erstwhile director of Prime Collateralised SecuritiesASBL, which looked over such things as STS to check them out—is this how it will be for ever? Will we extend this by another two years every two years? Does this happen until the UK regulators think they need a change and do something different? It seems to me that we did an awful lot of temporary permissions. I do not like to think that we will have to do them all over again every two years, because that will take an awful lot of parliamentary time. I would like to get a handle on whether this is the way of the future or whether there will be an end to these temporary permissions. Lord Tunnicliffe Shadow Spokesperson (Defence), Shadow Spokesperson (Treasury), Shadow Minister (Transport) My Lords, I thank theMinisterfor introducing this SI. It seems that she and I agree that it is really two SIs, covering Gibraltar and securitisation. To take Gibraltar first, as far as I can tell, the SI simply clarifies the application of UK regulation to Gibraltar. The Money Laundering and Terrorist Financing (High-Risk Countries) ( Amendment ) (No. 2) Regulations 2022 set out a new list of high-risk third countries in relation to which enhanced due diligence requirements apply under the principal money laundering regulations. Gibraltar has been added and Malta removed; the changes apply from 12 July 2022. Will this SI assist Gibraltar in getting off the high-risk list? If so, how will the UK regulatory authorities be involved? I am trying to understand this; how different will the regulation of financial services firms in Gibraltar be from, for example, the regulation of a financial services firm in Birmingham? The second part of this SI seems solely about extending the present transitional arrangements for a further two years. The clearest statement of this is in the de minimis assessment—I like the assessments, when I get round to reading them, because they tend to be written in easier language: “This SI is required to address this misalignment of dates in order to prevent looser due diligence requirements forEUSTSsecuritisations than UK ones. This SI will also prevent additional administrative burdens on firms which could arise from the absence of an exemption for EU STS securitisations from the clearing obligation. This instrument will help”— I would quibble with that word— “bridge this gap until a permanent framework for designating equivalent jurisdictions with regard to securitisation regimes is in effect and an assessment of the EU can be undertaken under it.” Am Iright in my precis? When and how will “a permanent framework for designating equivalent jurisdictions” be determined? Lord Teverson Liberal Democrat Lords Spokesperson (Energy and Climate Change), Chair, EU Environment Sub-Committee, Chair, EU Environment Sub-Committee My Lords, I apologise for speaking slightly out of order. As part of the European Union Committee, I took a great interest in the Gibraltarian situation. As theMinisterwill know, Gibraltar was not covered by the trade and co-operation agreement. At the moment, negotiations are still going on between the UK and theEUon Gibraltar’s status—I think we are on round nine. Can the Minister be clear on whether financial services are included in trying to reach a final agreement between the EU and the UK on Gibraltar and its relationship with the EU? If that is the case, will these SIs become redundant and be replaced by another regime completely? I would be interested to understand that from a strategic point of view. Baroness Penn The Parliamentary Secretary, HM Treasury 7:15, 15 November 2022 My Lords, I thank all noble Lords for their contributions to this debate. With this SI, the Government aim to remedy technical deficiencies identified in financial services legislation arising from the UK’s withdrawal from theEU. Nevertheless, a number of pertinent questions were asked. To give the noble Lord, Lord Jones, a better picture of Gibraltarian firms operating in the UK and their involvement in our financial services sector, data from theGovernment of Gibraltarhighlights that approximately 95% of Gibraltar’s financial services business is with the UK. From the other end of the telescope, around 29% of motor insurance policies in the UK—some 8.5 million—are provided by Gibraltar-based insurers. According to 2022 data from theFCA, over 100 Gibraltarian firms are operating in the UK, including insurance firms, banks, asset managers and e-money firms. The number of firms that might be affected by this SI is roughly 18, but in practice we think it will be fewer. Although there is large-scale involvement of Gibraltarian firms in UK financial services, the impact of this SI would be more limited. The noble Lord, Lord Tunnicliffe, asked whether this SI will assist Gibraltar in getting off the high-risk list from theFATF. This statutory instrument will not have a direct bearing on Gibraltar’s status in that respect.The UKis a supportive and strong member of the FATF and the Government are committed to making the UK a hostile place for illicit finance and economic crime. We are also committed to supporting Gibraltar to achieve full implementation of the FATF standards by addressing the weaknesses in its regime to tackle illicit finance. The noble Lord also asked how different the regulation of financial services firms in Gibraltar will be compared to the regulation of financial firms in the UK—for example, in Birmingham. As members of the EU, Gibraltar and the UK implemented the same EU rules on financial services, so we start from the same place. The current temporary regime maintains market access on that basis while we implement the new regime provided for in theFinancial ServicesAct 2021. That will require alignment with UK law and practice. In effect, firms in Gibraltar and the UK will be subject to the same rules under the new system. Lord Tunnicliffe Shadow Spokesperson (Defence), Shadow Spokesperson (Treasury), Shadow Minister (Transport) The same rules and the same regulators? (Citation: HL Deb, 15 November 2022, c843) Baroness Penn The Parliamentary Secretary, HM Treasury I will double-check that for the noble Lord. I believe so, but I would prefer to write and confirm it. In the noble Lord’s precis, he asked whether this simply extends the status quo for two years. Yes, that is the correct interpretation of this SI. The noble Baroness, Lady Bowles, asked whether we are in a process of extending it in another two years, and then another two years after that. TheFinancial Servicesand Markets Bill, which has just finished Committee in theother place, has introduced a permanent equivalence regime to allow the Treasury to recogniseSTS-equivalent securitisations issued by firms in other countries. The temporary recognition ofEUSTS will help bridge the gap until we can undertake assessments under this new regime in the Bill currently going through. We have a plan and the legislation is passing; we fully expect that the extension to 2024 would be the last such extension and that we would have a new regime up and running by that point. The noble Baroness asked about the regulation of these firms in the intervening period. I will write to her on that point to ensure that I do not get anything wrong, and I will also write to the noble Lord, Lord Teverson, on his question. To reassure the noble Baroness, looking at the data in terms of the specific regulations in this area, about five Gibraltar firms could fall within the scope of the 0.1% reporting threshold in the short selling regulation, theSSR. We are giving the regulators here the power to change that threshold to align with the EU. It is a small number. No Gibraltar PRIIPs manufacturers operate in the UK, so the power we have to change the provisions there currently would not bite. Five Gibraltar firms in the UK are using branch passports underMiFIR. I know that does not directly answer the noble Baroness’s question, so I will write to her. However, to give a sense of the scale of the gap—if there was any such gap—we believe it to have been small. (Citation: HL Deb, 15 November 2022, c844) Lord Tunnicliffe Shadow Spokesperson (Defence), Shadow Spokesperson (Treasury), Shadow Minister (Transport) Will theMinisterensure that all letters are copied to all participants? (Citation: HL Deb, 15 November 2022, c844) Baroness Penn The Parliamentary Secretary, HM Treasury I will ensure that all letters are copied to all participants in the debate andplaced in the Libraryof the House. Motion agreed. (Citation: HL Deb, 15 November 2022, c844)
https://www.theyworkforyou.com/lords/?id=2022-11-15d.840.1
Sending single transmission to multiple nodes? Sending single transmission to multiple nodes? Sending single transmission to multiple nodes? I'm currently creating an automated blind system. Right now I have a Wifi to RF gateway controlling the different blinds separately. One of my stretch goals is to add the ability to control a group of blinds at once. Instead of sending a value (0-180) to a single blind, I want to send it to a range or subset of them. Is this possible or will I have to manually trigger each one separately? That's easily possible: just send the packet to node address 255 and all nodes will receive. The problem with broadcasts is ACKs which would collide. The typical approach to deal with that weakness is to just send the data redundantly. So instead of one packet you send 3 and hope that at least one makes it to every destination. joe I agree with Joe and would add that the packet that you broadcast could contain flags related to each of your nodes so, instead of sending to a node, whose blinds you want to adjust, you set the corresponding flag in the packet.  Each receiving node can then check to see if the broadcast affects them. So that almost gets me where I need to be, the problem is that at this point I'm going to have 5 blinds connected but only three of them would function as a group. Are the only options all or one? blebson, I would add a "group" field to your packet.  That way, you could still send a broadcast to node 255.  Everyone would receive the message, but they would only respond if they were in the group ID. If you are going to have 5 blinds why not just use a byte or bit in the payload to correspond to each blind?  As others have said, broadcast to node 255 so they all receive the packet and then within the packet if I find 01000 000 in a byte and that 1 is my bit, then I change from open/close.  If I find a 0, I do nothing.  Or the 0s and 1s could be closed and open and I make my state whatever the flag calls for.  Just don't request an ack when your gateway broadcasts to node 255 so you don't have to handle collisions. EDIT: Or I could have said exactly what Tom suggested, oops!  Flags is the way to go here. Quote from: blebson on March 16, 2017, 11:26:57 AM So that almost gets me where I need to be, the problem is that at this point I'm going to have 5 blinds connected but only three of them would function as a group. Are the only options all or one? am/are saying: Code: [Select] struct PACKET { uint8_t flags, openness; } packetOut; # define BLINDS_1   0b00000001 # define BLINDS_2   0b00000010 # define BLINDS_3   0b00000100 # define BLINDS_4   0b00001000 # define BLINDS_5   0b00010000 # define LIVING_ROOM_GROUP  (BLINDS_1 | BLINDS_2 | BLINDS_3) # define DINING_ROOM_GROUP (BLINDS_4 | BLINDS_5) ... // open up the livingroom blinds packetOut.flags = LIVING_ROOM_GROUP; packetOut.openness = FULL_OPEN;    // whatever FULL Open value is... // do three sends like Joe suggested radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); ... // close the dining room blinds packetOut.flags = DINNG_ROOM_GROUP; packetOut.openness = FULL_CLOSE;    // whatever FULL Close value is... // do three sends like Joe suggested radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); ... And in each of the nodes: Code: [Select] # define MY_NODE_FLAG   BLINDS_3 if (radio.receiveDone()) { if (radio.DATALEN==sizeof(struct PACKET)  && radio.TARGET == RFM69_BROADCAST) { struct PACKET *myPacket = (struct PACKET *)radio.DATA; if (myPacket->flags & MY_NODE_FLAG) { openBlinds( myPacket->openness); } } } or some such... So I'm currently using the Low Power Listening fork of the RFM69 library. All of my blinds are battery powered so I wanted to ensure they can be sustained but a small solar panel in cloudy Seattle... This means that all of my transmissions will be the wake-up burst. Will this packet-based ID still work in this application? Quote from: blebson on March 16, 2017, 07:39:04 PM So I'm currently using the Low Power Listening fork of the RFM69 library. All of my blinds are battery powered so I wanted to ensure they can be sustained but a small solar panel in cloudy Seattle... This means that all of my transmissions will be the wake-up burst. Will this packet-based ID still work in this application? Yes, the content is still the same, regardless of transmission method. Tom Quote from: TomWS on March 16, 2017, 07:33:50 PM Here is an example of what I (and apparently ChemE and syrinxtech am/are saying: Code: [Select] struct PACKET { uint8_t flags, openness; } packetOut; # define BLINDS_1   0b00000001 # define BLINDS_2   0b00000010 # define BLINDS_3   0b00000100 # define BLINDS_4   0b00001000 # define BLINDS_5   0b00010000 # define LIVING_ROOM_GROUP  (BLINDS_1 | BLINDS_2 | BLINDS_3) # define DINING_ROOM_GROUP (BLINDS_4 | BLINDS_5) ... // open up the livingroom blinds packetOut.flags = LIVING_ROOM_GROUP; packetOut.openness = FULL_OPEN;    // whatever FULL Open value is... // do three sends like Joe suggested radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); ... // close the dining room blinds packetOut.flags = DINNG_ROOM_GROUP; packetOut.openness = FULL_CLOSE;    // whatever FULL Close value is... // do three sends like Joe suggested radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); radio.send(RFM69_BROADCAST, &packetOut, sizeof(packetOut); delay(40); ... And in each of the nodes: # define MY_NODE_FLAG   BLINDS_3 if (radio.receiveDone()) { if (radio.DATALEN==sizeof(struct PACKET)  && radio.TARGET == RFM69_BROADCAST) { struct PACKET *myPacket = (struct PACKET *)radio.DATA; if (myPacket->flags & MY_NODE_FLAG) { openBlinds( myPacket->openness); } } } or some such... TomWS, that's a sweet piece of code you provided.  I like your method better than my "group" idea.  Bit fiddling is a lost art in a lot of today's world...thanks for reminding us. TomWS, I ended up using your packet idea and it worked great. I am now working on the response from the Moteino back to the base station. I wanted to use the same 'Packet' technique but add different data types. There would be three types of data, a battery percentage (int), a battery voltage (float), and a solar charging status (char or String). Is there any way to use this struct to send all three data types at once? I currently have it defined as the following: Code: [Select] struct PACKET { uint8_t percent; float voltage; String charger; } packetOut; however the float and String value don't seem to be transmitting correctly, is this a limitation of the packet concept or am I doing something wrong? Quote from: blebson on May 10, 2017, 11:30:24 PM TomWS, I ended up using your packet idea and it worked great. I am now working on the response from the Moteino back to the base station. I wanted to use the same 'Packet' technique but add different data types. There would be three types of data, a battery percentage (int), a battery voltage (float), and a solar charging status (char or String). Is there any way to use this struct to send all three data types at once? I currently have it defined as the following: Code: [Select] struct PACKET { uint8_t percent; float voltage; String charger; } packetOut; however the float and String value don't seem to be transmitting correctly, is this a limitation of the packet concept or am I doing something wrong? A String 'type' is actually an instance of a class and has beaucoup stuff hidden behind the 'scenes'.  Use fixed length char array and you'll be fine.  Also, you can represent the battery voltage in uint16_t and get millivolt resolution and save two bytes (and a bunch of floating point code overhead). As long as both ends know the structure of the packet and its based on primitive types, sending structures is trivial. Tom PS: I'll wager that if you search this forum for 'readvcc' you'll find a number of examples on how to read the processor's VCC in exactly uint16_t resolution. So at this point I'm stuck trying to send the 4 digit int for the milivolt value of the battery. I've tried sending as uint16_t and uint8_t but get garbage values from the receiving arduino. my packet definition looks as follows; struct PACKET { uint8_t percent; uint16_t voltage; char charger; } packetOut; Where percent is a 2 digit int, voltage is a 4 digit int and charger is a single char. Quote from: blebson on May 11, 2017, 10:12:35 PM So at this point I'm stuck trying to send the 4 digit int for the milivolt value of the battery. I've tried sending as uint16_t and uint8_t but get garbage values from the receiving arduino. my packet definition looks as follows; Code: [Select] struct PACKET { uint8_t percent; uint16_t voltage; char charger; } packetOut; Where percent is a 2 digit int, voltage is a 4 digit int and charger is a single char. There's nothing wrong with the structure definition, there must be a problem with the way you're sending it and/or processing it on the receiving end.  If you post those code snippets, we'll take a look. Tom I can try to post the code tonight. I'm using low power listening mode on the moteino but I'm not sure if that matters. The base station is receiving the battery percentage correctly but then gets a garbage value for voltage and nothing for charger.
https://lowpowerlab.com/forum/rf-range-antennas-rfm69-library/sending-single-transmission-to-multiple-nodes/msg19673/
U.S. Census Bureau QuickFacts: Bergen County, New Jersey; United States; Hunterdon County, New Jersey; Somerset County, New Jersey; Monmouth County, New Jersey; New Jersey Frequently requested statistics for: Bergen County, New Jersey; United States; Hunterdon County, New Jersey; Somerset County, New Jersey; Monmouth County, New Jersey; New Jersey U.S. Census Bureau QuickFacts: Bergen County, New Jersey; United States; Hunterdon County, New Jersey; Somerset County, New Jersey; Monmouth County, New Jersey; New Jersey Please note that new Connecticut county level geographies are not availabe within the map. An official website of the United States government Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock A locked padlock ) or https:// means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites. What's New & FAQs QuickFacts Bergen County, New Jersey; United States; Hunterdon County, New Jersey; Somerset County, New Jersey; Monmouth County, New Jersey; New Jersey QuickFacts provides statistics for all states and counties, and for cities and towns with a population of 5,000 or more . -- Select a fact -- Population Estimates, July 1, 2022, (V2022) Population estimates base, April 1, 2020, (V2022) Population, percent change - April 1, 2020 (estimates base) to July 1, 2022, (V2022) Population, Census, April 1, 2020 Population, Census, April 1, 2010 Persons under 5 years, percent Persons under 18 years, percent Persons 65 years and over, percent Female persons, percent White alone, percent Black or African American alone, percent (a) American Indian and Alaska Native alone, percent (a) Asian alone, percent (a) Native Hawaiian and Other Pacific Islander alone, percent (a) Two or More Races, percent Hispanic or Latino, percent (b) White alone, not Hispanic or Latino, percent Veterans, 2017-2021 Foreign born persons, percent, 2017-2021 Housing units, July 1, 2022, (V2022) Owner-occupied housing unit rate, 2017-2021 Median value of owner-occupied housing units, 2017-2021 Median selected monthly owner costs -with a mortgage, 2017-2021 Median selected monthly owner costs -without a mortgage, 2017-2021 Median gross rent, 2017-2021 Building permits, 2022 Households, 2017-2021 Persons per household, 2017-2021 Living in same house 1 year ago, percent of persons age 1 year+, 2017-2021 Language other than English spoken at home, percent of persons age 5 years+, 2017-2021 Households with a computer, percent, 2017-2021 Households with a broadband Internet subscription, percent, 2017-2021 High school graduate or higher, percent of persons age 25 years+, 2017-2021 Bachelor's degree or higher, percent of persons age 25 years+, 2017-2021 With a disability, under age 65 years, percent, 2017-2021 Persons without health insurance, under age 65 years, percent In civilian labor force, total, percent of population age 16 years+, 2017-2021 In civilian labor force, female, percent of population age 16 years+, 2017-2021 Total accommodation and food services sales, 2017 ($1,000) (c) Total health care and social assistance receipts/revenue, 2017 ($1,000) (c) Total transportation and warehousing receipts/revenue, 2017 ($1,000) (c) Total retail sales, 2017 ($1,000) (c) Total retail sales per capita, 2017 (c) Mean travel time to work (minutes), workers age 16 years+, 2017-2021 Median household income (in 2021 dollars), 2017-2021 Per capita income in past 12 months (in 2021 dollars), 2017-2021 Persons in poverty, percent Total employer establishments, 2021 Total employment, 2021 Total annual payroll, 2021 ($1,000) Total employment, percent change, 2020-2021 Total nonemployer establishments, 2019 All employer firms, Reference year 2017 Men-owned employer firms, Reference year 2017 Women-owned employer firms, Reference year 2017 Minority-owned employer firms, Reference year 2017 Nonminority-owned employer firms, Reference year 2017 Veteran-owned employer firms, Reference year 2017 Nonveteran-owned employer firms, Reference year 2017 Population per square mile, 2020 Population per square mile, 2010 Land area in square miles, 2020 Land area in square miles, 2010 Clear   6 Table Map   Bergen County, New Jersey  United States  Hunterdon County, New Jersey  Somerset County, New Jersey  Monmouth County, New Jersey  New Jersey  More Print CSV Email Map TIGERweb Population Estimates, July 1, 2022, (V2022) - - - - - Populations below 5,000 are not in QuickFacts and therefore Not Selectable Selectable Not Selectable Value Notes   Estimates are not comparable to other geographic levels due to methodology differences that may exist between different data sources. Some estimates presented here come from sample data, and thus have sampling errors that may render some apparent differences between geographies statistically indistinguishable. ] Click the Quick Info  icon to the left of each row in TABLE view to learn about sampling error. In Vintage 2022, as a result of the formal request from the state, Connecticut transitioned from eight counties to nine planning regions. For more details, please see the Vintage 2022 release notes available here: Release Notes. The vintage year (e.g., V2022) refers to the final year of the series (2020 thru 2022). Different vintage years of estimates are not comparable. Users should exercise caution when comparing 2017-2021 ACS 5-year estimates to other ACS estimates. For more information, please visit the 2021 5-year ACS Comparison Guidance page. Fact Notes (a) Includes persons reporting only one race (c) Economic Census - Puerto Rico data are not comparable to U.S. Economic Census data (b) Hispanics may be of any race, so also are included in applicable race categories Value Flags - Either no or too few sample observations were available to compute an estimate, or a ratio of medians cannot be calculated because one or both of the median estimates falls in the lowest or upper interval of an open ended distribution. F Fewer than 25 firms D Suppressed to avoid disclosure of confidential information N Data for this geographic area cannot be displayed because the number of sample cases is too small. FN Footnote on this item in place of data X Not applicable S Suppressed; does not meet publication standards NA Not available Z Value greater than zero but less than half unit of measure shown QuickFacts data are derived from: Population Estimates, American Community Survey, Census of Population and Housing, Current Population Survey, Small Area Health Insurance Estimates, Small Area Income and Poverty Estimates, State and County Housing Unit Estimates, County Business Patterns, Nonemployer Statistics, Economic Census, Survey of Business Owners, Building Permits. Close Close Please Note! Close CONNECT WITH US Information Quality Data Linkage Infrastructure Data Protection and Privacy Policy Accessibility FOIA Inspector General No FEAR Act U.S. Department of Commerce USA.gov Measuring America's People, Places, and Economy  Is this page helpful? Yes No  Thank you for your feedback. Comments or suggestions?  Comments or suggestions? 255 characters maximum ⚠ 255 characters maximum reached NO THANKS SUBMIT
https://www.census.gov/quickfacts/fact/map/bergencountynewjersey,US,hunterdoncountynewjersey,somersetcountynewjersey,monmouthcountynewjersey,NJ/PST045222
Burden of bacterial bloodstream infection – A brief update on epidemiology and significance of multidrug-resistant pathogens | Request PDF Request PDF | Burden of bacterial bloodstream infection – A brief update on epidemiology and significance of multidrug-resistant pathogens | Background: Bloodstream infections comprise a wide variety of pathogens and clinical syndromes with considerable overlap with similar syndromes... | Find, read and cite all the research you need on ResearchGate November 2019 Clinical Microbiology and Infection 26(2) DOI: 10.1016/j.cmi.2019.10.031 Authors: Winfried V Kern University Medical Center Freiburg Siegbert Rieg Siegbert Rieg This person is not on ResearchGate, or hasn't claimed this research yet. Request full-text Download citation Copy link Link copied Request full-text Download citation Copy link Link copied To read the full-text of this research, you can request a copy directly from the authors. Citations (116) References (120) Abstract Background: Bloodstream infections comprise a wide variety of pathogens and clinical syndromes with considerable overlap with similar syndromes of non-bacteremic infections and quite diverse risk factors, therapeutic implications and outcomes. Yet, this heterogenous "entity" has the advantage to be pathogen-defined compared with the broad and even more heterogenous entity "sepsis", and thus has become helpful for clinicians and epidemiologists for research and surveillance purposes. The increasing availability of population-based and large multicenter well-defined cohort studies should allow to assess with much confidence and details its burden, the significance of antimicrobial resistance, and areas of uncertainty regarding the further epidemiologic evolution and optimized treatment regimens. Aim: To review key aspects of bloodstream infection epidemiology and burden and summarize recent news and questions concerning critical developments. Sources: Peer-reviewed articles based on the search terms 'bloodstream infection' and 'bacteremia' combined with the terms 'epidemiology' and 'burden'. The emphasis was on new information from studies in adult patients and on the added burden due to pathogen resistance to first- and second-line antimicrobial agents. Content: Topics covered include recent developments in the epidemiology of bloodstream infection due to key pathogens and published information about the relevance of resistance for patient outcomes. Implications: Despite the availability of population-based and an increasing number of large well-defined multicenter cohort studies, more surveillance and systematic data on BSI epidemiology at regional level and in resource-limited settings may be needed to better design new ways for prevention and define the need for and further develop optimized therapeutic strategies. Discover the world's research 25+ million members 160+ million publication pages 2.3+ billion citations Join for free No full-text available To read the full-text of this research, you can request a copy directly from the authors. Request full-text PDF Citations (116) References (120) ... A recent systematic review established that the most important predictors of mortality in patients with MRSA (Methicillin-Resistant Staphylococcus aureus) bloodstream infection are age, patient condition, timing and appropriateness of antimicrobial treatment, surgical intervention and disease severity as evaluated by the APACHE II score [5]. The incidence of BSI due to Escherichia coli is higher than that of Staphylococcus aureus bacteremia, but the mortality is lower: the in-hospital and 30-day case-fatality is approximately 10-15%; mortality is highly dependent on age, hospital acquisition and co-morbidity, initial presentation with septic shock/severe disease and resistance to fluoroquinolones and third-generation cephalosporin resistance [1] . Although less frequent than E. coli among bacteremia isolates, BSI due to extended-spectrum beta-lactamase (ESBL)-positive K. pneumoniae carries a worse prognosis, including more frequent intensive care unit admission and higher 30-day case-fatality or in-hospital mortality. ... ... Although less frequent than E. coli among bacteremia isolates, BSI due to extended-spectrum beta-lactamase (ESBL)-positive K. pneumoniae carries a worse prognosis, including more frequent intensive care unit admission and higher 30-day case-fatality or in-hospital mortality. Many European and North American studies show an association between ESBL-positive Enterobacterales and both excess length of stay and increased mortality rate [1, [6][7][8]. Klebsiella pneumoniae is also the most prominent among carbapenem-resistant Gram-negative bacteria causing BSI. The case-fatality of BSI due to carbapenem-resistant Klebsiella is higher than that due to carbapenem-susceptible K. pneumoniae, and the likelihood of initially inappropriate therapy and of suboptimal definitive therapy was significant and a major prognostic factor for poor outcomes before the availability of newer antibiotics. ... ... The case-fatality of BSI due to carbapenem-resistant Klebsiella is higher than that due to carbapenem-susceptible K. pneumoniae, and the likelihood of initially inappropriate therapy and of suboptimal definitive therapy was significant and a major prognostic factor for poor outcomes before the availability of newer antibiotics. A particularly high risk of fatal outcome after BSI due to carbapenem-resistant Gram-negative bacteria in general has been reported for immunocompromised patients [1] . ... Development and Validation of a Prognostic Model for Multi-Drug-Resistant Non-Hospital-Acquired Bloodstream Infection Article Full-text available May 2023 Emanuele Pivetta Silvia Corcione Paolo Peasso Giuseppe Montrucchio Bloodstream infections (BSI) are an increasing cause of admissions to hospitals. Non-hospital-acquired BSI are defined by blood cultures that are positive less than 48 hours after admission, but a relevant difference exists between community-acquired and healthcare-associated (HCA) BSI in terms of risk of multidrug resistance (MDR). We planned a retrospective study in three different cohorts in order to develop and to temporally and spatially validate an easy and rapid prognostic model for identifying MDR non-hospital-acquired (non-HA) BSI. The pathogens most involved in BSI are Staphylococcus spp. and Escherichia coli, responsible for about 75% of all MDR isolated. The model includes age, gender, long-term care facility admission, immunocompromise, any recent invasive procedures and central line placement, recent intravenous treatment and antibiotic treatment. It shows an acceptable performance, especially for intermediate probabilities of MDR infection, with a C-index of 70%. The model was proposed in a nomogram that could allow better targeting of antibiotic therapy for non-HA BSI admitted in hospital. However, it should be further validated to determine its applicability in other populations. View Show abstract ... In many studies, E. coli and S. aureus are numerically the most frequent, and with P. aeruginosa, constitute the most prevalent reported organisms causing mortality [16, 18] . P. aeruginosa, K. pneumoniae and staphylococci are typically associated with healthcare acquisition, while E. coli is more frequent among community-acquired cases [18]. ... ... In many studies, E. coli and S. aureus are numerically the most frequent, and with P. aeruginosa, constitute the most prevalent reported organisms causing mortality [16,18]. P. aeruginosa, K. pneumoniae and staphylococci are typically associated with healthcare acquisition, while E. coli is more frequent among community-acquired cases [18] . Our data are consistent with these observations. ... ... This observation that mortality was irrespective of methicillin resistance status perhaps advances a case towards novel interventions such as decolonisation strategies [24]. In general, AMR levels in this study were similarly high as those reported in the Mediterranean, including Italy and Israel [7, 18] . However, except for A. baumannii, none of the other pathogens presented an XDR phenotype. ... Burden of multidrug and extensively drug-resistant ESKAPEE pathogens in a secondary hospital care setting in Greece Article Full-text available Sep 2022 EPIDEMIOL INFECT Evangelos I Kritsotakis Dimitra Lagoutari Efstratios Michailellis Achilleas Gikas Bacterial antibiotic resistance (AMR) is a significant threat to public health, with the sentinel "ESKAPEE" pathogens, being of particular concern. A cohort study spanning 5.5 years (2016 to 2021) was conducted at a provincial general hospital in Crete, Greece, to describe the epidemiology of ESKAPEE-associated bacteraemia regarding levels of AMR and their impact on patient outcomes. In total, 239 bloodstream isolates were examined from 226 patients (0.7% of 32,996 admissions) with a median age of 75 years, 28% of whom had severe comorbidity, and 46% with prior stay in ICU. Multidrug resistance (MDR) was lowest for Pseudomonas aeruginosa (30%) and Escherichia coli (33%), and highest among Acinetobacter baumannii (97%); the latter included 8 (22%) with extensive drug-resistance (XDR), half of which were resistant to all antibiotics tested. MDR bacteraemia was more likely to be healthcare-associated than community-onset (RR 1.67, 95%CI 1.04-2.65). Inpatient mortality was 22%, 35% and 63% for non-MDR, MDR and XDR episodes, respectively (p=0.004). Competing risks survival analysis revealed increasing mortality linked to longer hospitalization with increasing AMR levels, as well as differential pathogen-specific effects. A.baumannii bacteraemia was the most fatal (14-day death hazard ratio 3.39, 95%CI 1.74-6.63). Differences in microbiology, AMR profile and associated mortality compared to national and international data emphasize the importance of similar investigations of local epidemiology. View Show abstract ... Staphylococcus aureus is a major human pathogen associated with a large range of infections [1]. It is one of the most common causes of bloodstream infections (BSI) worldwide, causing bacteremia with incidence ranging from 3 to 50 episodes per 100,000 person-years, with large geographical variations [2][3] [4] . Methicillin-resistant S. aureus (MRSA) is challenging in terms of therapeutic strategies, and the occurrence of bacteremia is associated with metastatic infections, recurrence, and high mortality rates (ranging from 15% to 40%). MRSA has a global prevalence ranging from less than 5% to over 80%, being a prominent burden in many countries [5,6]. ... ... MRSA was mostly considered a healthcare-related pathogen, although an increase in the number of community-acquired MRSA (CA-MRSA) infections is being observed in several regions. Current studies suggest that MRSA is a particularly important pathogen in developing countries [4, 7]. Several factors, such as pathogen virulence determinants, antimicrobial resistance, patients' characteristics, and clinical management, have been studied to understand a patient's prognosis upon MRSA bacteremia [1,8]. ... Epidemiology and risk factors for mortality among methicillin-resistant Staphylococcus aureus bacteremic patients in Southern Brazil Article Full-text available Apr 2023 PLOS ONE Cezar Vinícius Würdig Riche Renato Cassol Diego Rodrigues Falci Cícero Armídio Gomes Dias This study aimed to evaluate the epidemiology and 30-day mortality of adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. We retrospectively reviewed the demographic and clinical data of adult patients with S. aureus bloodstream infections (BSI), admitted to a tertiary public teaching medical center in Porto Alegre, Southern Brazil, from January 2014 to December 2019. A total of 928 patients with S. aureus BSI were identified in the study period (68.5 per 100,000 patient-years), and the proportion of MRSA isolates was 22% (19-27%). Thus, 199 patients were included in the analyses. The median age was 62 (IQR: 51-74) years, Charlson Comorbidity Index (CCI) median was 5 (IQR: 3-6), the Pitt bacteremia score (PBS) median was 1 (IQR: 1-4), and the most common site of infection was skin and soft tissue (26%). Most infections were hospital-acquired (54%), empirical anti-MRSA treatment was initiated in 34% of the cases, and in 44% vancomycin minimum inhibitory concentration was 1.5mg/L or above. Sixty-two (31.2%) patients died up to 30 days after the bacteremia episode. Patients with more comorbid conditions (higher CCI; aOR 1.222, p = 0.006) and a more severe presentation (higher PBS; aOR 1.726, p<0.001) were independently associated with mortality. Empiric antimicrobial therapy with an anti-MRSA regimen was associated with reduced mortality (aOR 0.319, p = 0.016). Our study identified significant risk factors for 30-day mortality in patients with MRSA BSI in a population with a high incidence of S. aureus bacteremia. Empiric treatment with an anti-MRSA drug was a protective factor. No significant variation in the incidence of S. aureus BSI was recorded throughout the period. View Show abstract ... Antimicrobial resistance develops from antibiotics misuse and micro-organisms evolving many different resistance mechanisms. [1, 3] BSI caused by resistant micro-organisms frequently fail to respond to treatment, thus leading to septicaemia, prolonged hospital admission, increased costs of treatment and worsening morbidity and mortality. [1,3] There is accumulated evidence that BSI and sepsis are important triggers for stroke and its reoccurrence. ... ... [1,3] BSI caused by resistant micro-organisms frequently fail to respond to treatment, thus leading to septicaemia, prolonged hospital admission, increased costs of treatment and worsening morbidity and mortality. [1, 3] There is accumulated evidence that BSI and sepsis are important triggers for stroke and its reoccurrence. Haemodynamic instability, atrial fibrillation, prolonged systemic inflammatory responses and coagulopathy have been the possible linkage between sepsis and stroke. ... Blood Stream Infection in Stroke Patients: Spectrum of Microbial Isolates and Antimicrobial Resistance Article Full-text available Mar 2023 FE Odiase PV Lofor Background: Bloodstream infection (BSI) is frequent in stroke, with poorer outcomes when microbial isolates are multi-drug resistant. There is a shortage of published data on BSI amongst stroke patients in Nigeria. Objective: To describe the microbial isolates and the antimicrobial resistance pattern among microbial isolates in BSI in stroke patients. Methods: This retrospective study of all hospitalized stroke patients with BSI at the University of Benin Teaching Hospital, Benin City, Nigeria covered July 2018 to June 2022. The demographics, stroke type, microbial isolates and antimicrobial resistance patterns were studied. Results: Blood culture studies were conducted among 834 stroke patients with infections; 410 (49.2%) had positive growth for microbial organisms. Amongst those with positive blood cultures, 53% (217/410) were females, while 56% had a haemorrhagic stroke. The mean age was 76.9±13.9 years, with about 80% of them aged ≥ 65. Infections of the respiratory tract (45%) and the urinary tract (33%) were the possible primary sources of BSI. The leading isolates included Enterococcus faecalis (18.5%), Klebsiella oxotyca (12.9%), Proteus mirabilis (12.9%), Staphylococcus aureus (11.5%), and Escherichia coli (11.2%). Approximately 88% of the isolates were multi-drug resistant, with 100% resistance to cefuroxime, ceftazidime, and co-trimoxazole, 83.3% to erythromycin and 75% resistance to ampicillin. The elderly patients were significantly more likely to acquire multi-drug resistant micro-organisms (p = 0.007). Conclusion: Stroke patients, especially the older ones, are susceptible to bloodstream infection from multi-drug-resistant micro-organisms, contributing to increased morbidity and mortality among stroke patients. View Show abstract ... Page 2 of 21 Khankhel et al. Ann Clin Microbiol Antimicrob (2022) 21:42 Background Bloodstream infections (BSIs), also referred to as bacteremia, are responsible for considerable disease burden worldwide with incidence estimated to be 189 per 100,000 persons in the United States (US) and to range between 168 and 220 persons per 100,000 across various Northern European nations [1] [2][3]. BSIs or positive blood cultures can be considered primary (i.e., the sole source of infection) or secondary to another source of infection, such as the respiratory tract. Both grampositive (e.g. ... ... Further, many of the pathogens causing bacteremia are multi-drug resistant (MDR), extensively-drug resistant (XDR), or pan drug-resistant (PDR). Delays in appropriate treatment of bacteremia are associated with increasing morbidity, mortality, and costs [1] [2][3]. To optimize management of the infection it is imperative to promptly identify the causative pathogen, susceptibility status, and physical source(s) of infection. ... Ceftolozane/tazobactam for the treatment of bacteremia: a systematic literature review (SLR) Article Full-text available Oct 2022 Z. S. Khankhel Ryan J Dillon M. Thosar Laura Puzniak Background Bloodstream infections (BSIs), or bacteremia, are responsible for considerable disease burden. Increasing rates of antibiotic resistance and delays in selection of appropriate treatment lead to increased morbidity, mortality, and costs. Due to limitations of current standard treatments, especially for bacteremia caused by resistant pathogens, a systematic literature review (SLR) was conducted to understand the utilization of ceftolozane/tazobactam (C/T) in bacteremia. Methods Electronic database searches of EMBASE®, MEDLINE®, CCTR and Northern Lights, as well as hand searches of conference proceedings from the last two annual meetings (i.e., 2018, 2019) of the European Congress of Clinical Microbiological and Infectious Diseases (ECCMID) and the Infectious Diseases Society of America’s annual meeting (IDWeek) were conducted. A total of 23 studies reporting on patients with bacteremia receiving C/T were included in the review. Results Most studies were observational (k = 20 studies), though few interventional studies were also identified (k = 3). Heterogeneity was ubiquitous with respect to source of bacteremia (i.e., primary or secondary), source of infection (for secondary bacteremia), pathogen type, antibiotic resistance, C/T dose, and outcome definitions. This heterogeneity, along with limited data, and small sample sizes (n = 1 to 31) made it difficult to draw any substantial conclusions, though overall results were favorable to C/T with respect to the outcomes of interest. Nineteen studies reported clinical cure or success (primary bacteremia: k = 6, reported range: 33.3% to 100%; secondary bacteremia: k = 8, 60% to 100%; mixed/unspecified bacteremia: k = 10, 50% to 91.7%). Eight studies reported microbiological cure or eradication rates (primary: k = 3, all reporting 100%; secondary: k = 4, 68% to 80%; mixed/unspecified: k = 5, 60% to 80%). Thirteen studies reported mortality (primary: k = 4, 0% to 14%; secondary: k = 7, 0% to 100%; or mixed/unspecified bacteremia: k = 7, 0% to 51.6%). One study each also reported composite clinical response, relapse, hospital re-admission, and hospital length of stay. Conclusions Although the available evidence and observed trends for C/T in bacteremia should be interpreted with caution, the direction of effect would support the utilization of C/T for these difficult to treat infections. Future research should supplement the existing evidence by considering the impact of key treatment effect modifiers without contributing to the observed heterogeneity. View Show abstract ... Page 2 of 10 Augusto et al. Antimicrobial Resistance & Infection Control (2022) 11:114 Background Staphylococcus aureus is one of the most common causes of bloodstream infections (BSI) worldwide [1, 2] . The presence of an indwelling device or a skin and soft tissue infection (SSTI) associated to hospital (HA) or community (CA) BSI are the most common sources of this pathogen [3]. ... ... Although daptomycin resistance among S. aureus remains rare worldwide (< 0.1%) [1], Silva et al. [46] also found isolates non-susceptible to daptomycin (4.7%) in a Brazilian study involving 128 clinical S. aureus isolates. We have already described BSI caused by non-susceptible daptomycin S. aureus isolates (MIC of 2 and 4 mg/L) among MRSA-VISA isolates in the hospital of the present study [2] . This data is of great concern because of its impact on the patient's outcome. ... Pandemic clone USA300 in a Brazilian hospital: detection of an emergent lineage among methicillin-resistant Staphylococcus aureus isolates from bloodstream infections Article Full-text available Sep 2022 Mariana Fernandes Augusto Débora Cristina da Silva Fernandes Tamara Lopes Rocha de Oliveira Kátia Regina Netto dos Santos Background Staphylococcus aureus is one of the leading causes of bloodstream infections (BSI) worldwide. In Brazil, the hospital-acquired methicillin-resistant S. aureus USA100/SCC mec II lineage replaced the previously well-established clones. However, the emergence of community-associated (CA) MRSA lineages among hospitalized patients is an increasing issue. Methods Consecutive S. aureus isolates recovered from BSI episodes of patients admitted between January 2016 and December 2018 in a Brazilian teaching hospital were tested for antimicrobial resistance, their genotypic features were characterized, and the clinical characteristics of the patients were evaluated. Results A total of 123 S. aureus isolates were recovered from 113 patients. All isolates were susceptible to linezolid, teicoplanin and vancomycin and 13.8% were not susceptible to daptomycin. Vancomycin MIC 50 and MIC 90 of 2 mg/L were found for both MRSA and MSSA isolates. The MRSA isolation rate was 30.1% (37/123), and 51.4% of them carried the SCC mec type II, followed by SCC mec IV (40.5%). Among the 37 MRSA isolates, the main lineages found were USA100/SCC mec II/ST5 and ST105 (53.7%) and USA800/ST5/SCC mec IV (18.9%). Surprisingly, six (16%) CA-MRSA isolates, belonging to USA300/ST8/SCC mec IVa that carried PVL genes and the ACME cassette type I, were detected. These six patients with USA300 BSI had severe comorbidities, including cancer, and most had a Charlson score ≥ 5; furthermore, they were in wards attended by the same health professionals. MRSA isolates were associated with hospital acquired infections ( p = 0.02) in more elderly patients ( p = 0.03) and those diagnosed with hematologic cancer ( p = 0.04). Among patients diagnosed with MRSA BSI, 19 (54.3%) died. Conclusions The pandemic MRSA USA300 was detected for the first time in the Brazilian teaching hospital under study, and its cross-transmission most probably occurred between patients with BSI. This lineage may already be circulating among other Brazilian hospitals, which highlights the importance of carrying out surveillance programs to fight multidrug resistant and hypervirulent isolates. View Show abstract ... E. coli is one of the most clinically important bacterial pathogens worldwide 74 . Its ubiquitous presence in the human intestinal tract 75 , capacity to cause diverse intestinal and extraintestinal infections and the emergence of MDR have made the control of E. coli infections a major public health priority 76 . ... Evolutionary and functional history of the Escherichia coli K1 capsule Article Full-text available Jun 2023 Sergio Arredondo-Alonso George Blundell Zuyi Fu Alex Mccarthy Escherichia coli is a leading cause of invasive bacterial infections in humans. Capsule polysaccharide has an important role in bacterial pathogenesis, and the K1 capsule has been firmly established as one of the most potent capsule types in E. coli through its association with severe infections. However, little is known about its distribution, evolution and functions across the E. coli phy-logeny, which is fundamental to elucidating its role in the expansion of successful lineages. Using systematic surveys of invasive E. coli isolates, we show that the K1-cps locus is present in a quarter of bloodstream infection isolates and has emerged in at least four different extraintestinal pathogenic E. coli (ExPEC) phylogroups independently in the last 500 years. Phenotypic assessment demonstrates that K1 capsule synthesis enhances E. coli survival in human serum independent of genetic background, and that therapeutic targeting of the K1 capsule re-sensitizes E. coli from distinct genetic backgrounds to human serum. Our study highlights that assessing the evolutionary and functional properties of bacterial virulence factors at population levels is important to better monitor and predict the emergence of virulent clones, and to also inform therapies and preventive medicine to effectively control bacterial infections whilst significantly lowering antibiotic usage. View Show abstract ... As antimicrobial resistance rates rise globally, extended-spectrum βlactamase-producing Enterobacterales (ESBL-E) have emerged as one of the most clinically threatening bacteria, causing community-onset infections [2][3][4]. BSIs due to ESBL-E are associated with increased mortality, hospital length of stay, and overall healthcare costs [5, 6]. This is particularly relevant as the incidence rate of infections due to ESBL-E has recently increased in the studied community [7,8]. ... Optimization of Empirical Antimicrobial Therapy in Enterobacterales Bloodstream Infection Using the Extended-Spectrum Beta-Lactamase Prediction Score Article Full-text available Jun 2023 Brian J. Haimerl Rodrigo Encinas Julie Ann Justo Majdi Al-Hasan Clinical tools for the prediction of antimicrobial resistance have been derived and validated without examination of their implementation in clinical practice. This study examined the impact of utilization of the extended-spectrum beta-lactamase (ESBL) prediction score on the time to initiation of appropriate antimicrobial therapy for bloodstream infection (BSI). The quasi-experimental cohort study included hospitalized adults with BSI due to ceftriaxone-resistant (CRO-R) Enterobacterales at three community hospitals in Columbia, South Carolina, USA before (January 2010 to December 2013) and after (January 2014 to December 2019) implementation of an antimicrobial stewardship intervention. In total, 45 and 101 patients with BSI due to CRO-R Enterobacterales were included before and after the intervention, respectively. Overall, the median age was 66 years, 85 (58%) were men, and 86 (59%) had a urinary source of infection. The mean time to appropriate antimicrobial therapy was 78 h before and 46 h after implementation of the antimicrobial stewardship intervention (p = 0.04). Application of the ESBL prediction score as part of an antimicrobial stewardship intervention was associated with a significant reduction in time to appropriate antimicrobial therapy in patients with BSI due to CRO-R Enterobacterales. Utilization of advanced rapid diagnostics may be necessary for a further reduction in time to appropriate antimicrobial therapy in this population. View Show abstract ... Enterobacterales are a family of Gram-negative rods, which include E. coli, the most prevalent cause of BSI worldwide [37] . Beta-lactamase production is the most prominent mechanism of resistance among Enterobacterales, while third-generation cephalosporins and carbapenems are the main targets of beta-lactamases producing multi-drug resistant (MDR) organisms [38]. ... The Hidden Cost of COVID-19: Focus on Antimicrobial Resistance in Bloodstream Infections Article Full-text available May 2023 Giulia Micheli Flavio Sangiorgi Francesca Catania Rita Murri Antibiotic resistance is one of the greatest growing public health threats and a worldwide priority. According to the WHO, drug-resistant diseases may cause 10 million deaths a year by 2050 and have a substantial impact on the global economy, driving up to 24 million people into poverty. The ongoing COVID-19 pandemic has exposed the fallacies and vulnerability of healthcare systems worldwide, displacing resources from existing programs and reducing funding for antimicrobial resistance (AMR) fighting efforts. Moreover, as already seen for other respiratory viruses, such as flu, COVID-19 is often associated with superinfections, prolonged hospital stays, and increased ICU admissions, further aggravating healthcare disruption. These events are accompanied by widespread antibiotic use, misuse, and inappropriate compliance with standard procedures with a potential long-term impact on AMR. Still, COVID-19-related measures such as increasing personal and environmental hygiene, social distancing, and decreasing hospital admissions could theoretically help the AMR cause. However, several reports have shown increased antimicrobial resistance during the COVID-19 pandemic. This narrative review focuses on this “twindemic”, assessing the current knowledge of antimicrobial resistance in the COVID-19 era with a focus on bloodstream infections and provides insights into the lessons learned in the COVID-19 field that could be applied to antimicrobial stewardship initiatives. View Show abstract ... di-and triacyl lipopeptides, lipoteichoic acids, macrophage-activating peptide-2 (MALP2) or intact Gram-positive bacteria are also capable to induce the tolerant cell state in monocytes via the TLR1/TLR2 or TLR2/TLR6 signaling pathways and epigenetic alterations (13)(14)(15)(16)(17)(18) with protective effects during sepsis in mouse models (15,19). S. aureus is a Gram-positive pathogen that can cause superficial skin infections, serious invasive infections such as septic arthritis, osteomyelitis or endocarditis and is one of the leading causes of life-threatening bloodstream infections, such as sepsis (20, 21). It is ranked second after Escherichia coli causing community-acquired and nosocomial bloodstream infections with 10 to 30 cases per 100.000 ... Staphylococcus aureus induces tolerance in human monocytes accompanied with expression changes of cell surface markers Article Full-text available Mar 2023 Mario Marco Müller Christian Baldauf Stella Hornischer Hortense Slevogt Exposure of human monocytes to lipopolysaccharide (LPS) or other pathogen-associated molecular pattern (PAMPs) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance (ET), associated with the pathogenesis of sepsis. In this study, we aimed to characterize the cellular state of human monocytes from healthy donors stimulated with Staphylococcus aureus in comparison to TLR2-specific ligands. We analyzed S. aureus induced gene expression changes after 2 and 24 hours by amplicon sequencing (RNA-AmpliSeq) and compared the pro-inflammatory response after 2 hours with the response in re-stimulation experiments. In parallel, glycoprotein expression changes in human monocytes after 24 hours of S. aureus stimulation were analyzed by proteomics and compared to stimulation experiments with TLR2 ligands Malp-2 and Pam3Cys and TLR4 ligand LPS. Finally, we analyzed peripheral blood monocytes of patients with S. aureus bloodstream infection for their ex vivo inflammatory responses towards S. aureus stimulation and their glycoprotein expression profiles. Our results demonstrate that monocytes from healthy donors stimulated with S. aureus and TLR ligands of Gram-positive bacteria entered the tolerant cell state after activation similar to LPS treatment. In particular reduced gene expression of pro-inflammatory cytokines (TNF, IL1β) and chemokines (CCL20, CCL3, CCL4, CXCL2, CXCL3 and CXCL8) could be demonstrated. Glycoprotein expression changes in monocytes tolerized by the different TLR agonists were highly similar while S. aureus -stimulated monocytes shared some of the PAMP-induced changes but also exhibited a distinct expression profile. 11 glycoproteins (CD44, CD274, DSC2, ICAM1, LAMP3, LILRB1, PTGS2, SLC1A3, CR1, FGL2, and HP) were similarly up- or downregulated in all four comparisons in the tolerant cell state. Monocytes from patients with S. aureus bacteremia revealed preserved pro-inflammatory responsiveness to S. aureus stimulation ex vivo, expressed increased CD44 mRNA but no other glycoprotein of the tolerance signature was differentially expressed. View Show abstract ... The incidence of bloodstream infections (BSI) is estimated to be between 113 and 204 per 100,000 persons per year [1] , corresponding to a burden of 1,200,000 episodes each year in Europe alone [2]. With mortality rates ranging from 10-40% [3,4], appropriate and expeditious antimicrobial therapy is of paramount importance [5]. ... EUCAST rapid antimicrobial susceptibility testing (RAST) compared to conventional susceptibility testing: implementation and potential added value in a tertiary hospital in Belgium Article Mar 2023 Gregory Strubbe Anne-Sophie Messiaen Stien Vandendriessche Jerina Boelens Objectives: EUCAST breakpoints for short incubation disk diffusion allow rapid antimicrobial susceptibility testing (RAST) directly from positive blood cultures. We evaluate the RAST methodology and assess its potential added value in a setting of low prevalence of multidrug-resistant (MDR) organisms. Methods: In our two-part study, we performed RAST on 127 clinical blood cultures at 6 and 8 h and determined categorical agreement with direct susceptibility testing. We also measure the impact of susceptibility results on antimicrobial therapy compared to empirical treatment. Results: Categorical agreement was 96.2% at 6 h (575/598 isolate-drug combinations) and 96.6% at 8 h (568/588 combinations). Major errors involved piperacillin/tazobactam in 16 of 31 cases. The second part of our study shows that AST reporting proved essential in correcting ineffective empirical therapy in 6.3% of the patients (8/126). Conclusion: EUCAST RAST is an inexpensive and reliable method of susceptibility testing, although care must be taken with reporting piperacillin/tazobactam. In support of RAST implementation, we show that AST remains of great importance in providing effective therapy, even in a setting of low MDR prevalence and elaborate antibiotic guidelines. View Show abstract ... 8,9 During infections, it causes a diverse range of infections such as pimples, boils, impetigo, folliculitis, cellulitis, carbuncles, abscesses, lifethreatening endocarditis, bacteremia, sepsis, pneumonia, meningitis, osteomyelitis, toxic shock syndrome, surgical site infection, and catheter-associated bloodstream infections. [10][11][12] [13] Most of these infections emerged due to evolving drug resistance commonly to methicillin. 12 The World Health Organization (WHO) report of 2019 suggested that antimicrobial resistance causes 700,000 deaths each year. ... Antimicrobial effect of pimozide by targeting ROS-mediated killing in Staphylococcus aureus Article Full-text available Mar 2023 BIOTECHNOL APPL BIOC Siddhartha Kumar Kumar Sandeep Rakesh Kumar Antresh Kumar In spite of the higher nosocomial and community-acquired infections acquired by Staphylococcus aureus, emerging drug resistance is a leading cause of increased mortality and morbidity associated with the overuse of antimicrobials. It is an emergent need to find out new molecules to combat such infections. In the present study, we analyzed the antibacterial effect of pimozide (PMZ) against Gram +ve and Gram -ve bacterial strains including methicillin-sensitive (MSSA) and methicillin resistance (MRSA) S. aureus. The growth of MSSA and MRSA was completely inhibited at concentrations of 12.5 μg/ml and 100 μg/ml, respectively which is referred to as 1x MIC. The cell viability was completely eliminated within 90 min of PMZ treatment (2x MIC) through ROS-mediated killing without affecting cell membrane permeability. It suppressed α-hemolysin biofilm formation of different S. aureus strains by almost 50% at 1x MIC concentration and was found to detach matured biofilm. PMZ treatment effectively eliminates S. aureus infection in C. elegans and improves its survival by 90% and found safe to use with no hemolytic effect on human and chicken blood tissues. Taken together, it is concluded that PMZ may turn out to be an effective antibacterial for treating bacterial infections including MSSA and MRSA. This article is protected by copyright. All rights reserved. View Show abstract ... Even in developed countries, 30-day death rates range from 3 to 47% when a definitive diagnosis of clinically significant bacteraemia caused by Staphylococcus aureus, Escherichia coli, Klebsiella spp., and Pseudomonas spp. is made [7, 8] . In most cases of bacteraemia, the bacteria are rapidly eliminated from the bloodstream; however, patients with sepsis have a poor prognosis due to systemic infection and damage to several organs. ... Clinical and Microbiological Features of Fulminant Haemolysis Caused by Clostridium perfringens Bacteraemia: Unknown Pathogenesis Article Full-text available Mar 2023 Ai Suzaki Satoshi Hayakawa Bacteraemia brought on by Clostridium perfringens has a very low incidence but is severe and fatal in fifty per cent of cases. C. perfringens is a commensal anaerobic bacterium found in the environment and in the intestinal tracts of animals; it is known to produce six major toxins: α-toxin, β-toxin, ε-toxin, and others. C. perfringens is classified into seven types, A, B, C, D, E, F and G, according to its ability to produce α-toxin, enterotoxin, and necrotising enterotoxin. The bacterial isolates from humans include types A and F, which cause gas gangrene, hepatobiliary infection, and sepsis; massive intravascular haemolysis (MIH) occurs in 7–15% of C. perfringens bacteraemia cases, resulting in a rapid progression to death. We treated six patients with MIH at a single centre in Japan; however, unfortunately, they all passed away. From a clinical perspective, MIH patients tended to be younger and were more frequently male; however, there was no difference in the toxin type or genes of the bacterial isolates. In MIH cases, the level of θ-toxin in the culture supernatant of clinical isolates was proportional to the production of inflammatory cytokines in the peripheral blood, suggesting the occurrence of an intense cytokine storm. Severe and systemic haemolysis is considered an evolutionary maladaptation as it leads to the host’s death before the bacterium obtains the benefit of iron utilisation from erythrocytes. The disease’s extraordinarily quick progression and dismal prognosis necessitate a straightforward and expedient diagnosis and treatment. However, a reliable standard of diagnosis and treatment has yet to be put forward due to the lack of sufficient case analysis. View Show abstract ... It is a systemic infectious disease that can develop into sepsis in severe cases, causing shock, disseminated intravascular coagulation and multiple organ failure. The BSI's incidence ranges from 113 to 204 per 100,000 population (1, 2) . With the widespread application of broad-spectrum antibiotics and hormones andthe development of invasive diagnosis and treatment techniques, the incidence of bloodstream infections has been increasing yearly (3,4). ... Comparison of metagenomic next-generation sequencing and blood culture in patients with suspected bloodstream infection Preprint Full-text available Feb 2023 Wen Shi Yuhua Zhou Yi Wen Tongtian Ni Background The application of metagenomic next-generation sequencing (mNGS) has gradually been carried out by clinical practitioner. However, few studies have compared it with blood cultures in patients suffering from suspected bloodstream infections. The purpose of this study was to compare the detection of pathogenic microorganisms by these two assays in patients with suspected bloodstream infection. Methods We retrospectively studied patients with fever, chills, antibiotic use for more than 3 days, suspected bloodstream infection, and admission to the emergency department of Ruijin Hospital from January 2020 to June 2022. All patients had blood drawn on the same day for blood mNGS and blood cultures. Clinical and laboratory parameters were collected on the day blood was drawn. The detection of pathogenic microorganisms by the two methods was compared. Risk factors and in-hospital mortality in patients with bloodstream infections were analysed separately for these two assays. Results In all 99 patients, the pathogenic microorganisms detection rate in blood mNGS was significantly higher than that in blood culture. Blood mNGS was consistent with blood culture in only 12.00% of all positive bacterial and fungal test results. The level of CRP is related to bacteraemia, fungaemia and viraemia detected by blood mNGS. No clear risk factors could be found in patients with a positive blood culture. In critically ill patients, both tests failed to improve patient outcomes. Conclusion In patients with suspected bloodstream infection, mNGS is not yet a complete replacement for blood cultures. The results of both tests could not improve in-hospital mortality. View Show abstract ... Staphylococcus aureus bacteraemia (SAB) is one of the most common bloodstream infections worldwide [1, 2]. In 2019, S. aureus was amongst the top three pathogens responsible for global deaths associated with antimicrobial resistance (AMR), with methicillin-resistant S. aureus (MRSA) causing more than 100,000 annual deaths [3]. ... Epidemiology and clinical presentation of community-acquired Staphylococcus aureus bacteraemia in children under 5 years of age admitted to the Manhiça District Hospital, Mozambique, 2001-2019 Article Full-text available Mar 2023 EUR J CLIN MICROBIOL Marcelino Garrine Llorenç Quintó Sofia Santos Costa Inácio Mandomando Staphylococcus aureus bacteraemia (SAB) is one of the most common bloodstream infections globally. Data on the burden and epidemiology of community-acquired SAB in low-income countries are scarce but needed to define preventive and management strategies. Blood samples were collected from children < 5 years of age with fever or severe disease admitted to the Manhiça District Hospital for bacterial isolation, including S. aureus. Between 2001 and 2019, 7.6% (3,197/41,891) of children had bacteraemia, of which 12.3% corresponded to SAB. The overall incidence of SAB was 56.1 episodes/100,000 children-years at risk (CYAR), being highest among neonates (589.8 episodes/100,000 CYAR). SAB declined significantly between 2001 and 2019 (322.1 to 12.5 episodes/100,000 CYAR). In-hospital mortality by SAB was 9.3% (31/332), and significantly associated with infections by multidrug-resistant (MDR) strains (14.7%, 11/75 vs. 6.9%, 14/204 among non-MDR, p = 0.043) and methicillin-resistant S. aureus (33.3%, 5/15 vs. 7.6%, 20/264 among methicillin-susceptible S. aureus, p = 0.006). Despite the declining rates of SAB, this disease remains an important cause of death among children admitted to MDH, possibly in relation to the resistance to the first line of empirical treatment in use in our setting, suggesting an urgent need to review current policy recommendations. View Show abstract ... An elevated risk of S. aureus bloodstream infection in patients undergoing general, orthopedic, or thoracic surgery, being treated in the intensive care unit, or undergoing hemodialysis or continuous peritoneal dialysis has been reported in many studies (1,5). S. aureus-induced bloodstream infections are characterized by high mortality rates despite appropriate treatment (20 to 50%, depending on infection severity), frequent recurrence (5 to 10%), and lasting impairments in .33% of survivors (6) . ... Oral Vaccination with Engineered Probiotic Limosilactobacillus reuteri Has Protective Effects against Localized and Systemic Staphylococcus aureus Infection Article Full-text available Feb 2023 Na Pan Yang Liu Haochi Zhang Xiao Wang Staphylococcus aureus is a Gram-positive bacterium responsible for most hospital-acquired (nosocomial) and community-acquired infections worldwide. The only therapeutic strategy against S. aureus-induced infections, to date, is antibiotic treatment. A protective vaccine is urgently needed in view of the emergence of antibiotic-resistant strains associated with high-mortality cases; however, no such vaccine is currently available. In our previous work, the feasibility of implementing a Lactobacillus delivery system for development of S. aureus oral vaccine was first discussed. Here, we describe systematic screening and evaluation of protective effects of engineered Lactobacillus against S. aureus infection in terms of different delivery vehicle strains and S. aureus antigens and in localized and systemic infection models. Limosilactobacillus reuteri WXD171 was selected as the delivery vehicle strain based on its tolerance of the gastrointestinal environment, adhesion ability, and antimicrobial activities in vitro and in vivo. We designed, constructed, and evaluated engineered L. reuteri strains expressing various S. aureus antigens. Among these, engineered L. reuteri WXD171-IsdB displayed effective protection against S. aureus-induced localized infection (pneumonia and skin infection) and, furthermore, a substantial survival benefit in systemic infection (sepsis). WXD171-IsdB induced mucosal responses in gut-associated lymphoid tissues, as evidenced by increased production of secretory IgA and interleukin 17A (IL-17A) and proliferation of lymphocytes derived from Peyer's patches. The probiotic L. reuteri-based oral vaccine appears to have strong potential as a prophylactic agent against S. aureus infections. Our findings regarding utilization of Lactobacillus delivery system in S. aureus vaccine development support the usefulness of this live vaccination strategy and its potential application in next-generation vaccine development. IMPORTANCE We systematically screened and evaluated protective effects of engineered Lactobacillus against S. aureus infection in terms of differing delivery vehicle strains and S. aureus antigens and in localized and systemic infection models. Engineered L. reuteri was developed and showed strong protective effects against both types of S. aureus-induced infection. Our findings regarding the utilization of a Lactobacillus delivery system in S. aureus vaccine development support the usefulness of this live vaccination strategy and its potential application in next-generation vaccine development. View Show abstract ... Finally, the present study only involved the rapid identification of pathogens and lacked important antimicrobial susceptibility markers. Exploring the ability of this PCR-QDFA method to detect drug resistance genes has become particularly important because of the worldwide increase in bacterial multidrug resistance (Kern & Rieg, 2020) . ... Clinical evaluation of polymerase chain reaction coupled with quantum dot fluorescence analysis in the identification of bacteria and yeasts in patients with suspected bloodstream infections Article Full-text available Feb 2023 Jie Li Wenjia Fan Xuehan Zou Huang Haijun Bloodstream infections are serious and complex infectious diseases that often require a rapid diagnosis. Polymerase chain reaction coupled with quantum dot fluorescence analysis (PCR-QDFA) is a novel diagnostic technique. This study aimed to evaluate the diagnostic performance of PCR-QDFA for pathogen detection in patients with suspected bloodstream infections (BSIs). It evaluates 29 kinds of common pathogens (24 bacteria and 5 yeasts) from blood culture bottles. The results of PCR-QDFA identification and traditional microbial laboratory identification were compared, and the latter was used as the 'gold standard' to analyse the diagnostic performance of the PCR-QDFA. In total, 517 blood culture bottles were included in this study. The PCR-QDFA identified microorganisms in 368/422 (87.2%) samples with monomicrobial growth. For the pathogens on the PCR-QDFA list, the assay showed a higher sensitivity of 97.4% (368/378). When polymicrobial growth was analysed, the PCR-QDFA successfully detected 19/25 (76%) microorganisms on the PCR-QDFA list. In addition, 82/82 negative blood culture bottles also showed no pathogens by PCR-QDFA with a specificity of 100%. In conclusion, the PCR-QDFA assay could identify a majority of the common pathogens encountered in clinical practice, showing excellent diagnostic performance for pathogen detection in patients with suspected BSIs. View Show abstract ... This finding is consistent with the previous reports from Saudi Arabia, in which the majority of K. pneumoniae were isolated from blood and respiratory specimens [12]. The present finding relies on the fact that K. pneumoniae is one of the main causative agents of bloodstream infection and respiratory tract infection, and it should be taken into consideration during the diagnosis of respiratory infection [24, 25] . ... Prevalence and Antibiogram Pattern of Klebsiella pneumoniae in a Tertiary Care Hospital in Makkah, Saudi Arabia: An 11-Year Experience Article Full-text available Jan 2023 Naif A. Jalal Abdulrahman M Al-Ghamdi Aiman M Momenah Hani Faidah View ... This finding is consistent with the previous reports from Saudi Arabia, in which the majority of K. pneumoniae were isolated from blood and respiratory specimens [12]. The present finding relies on the fact that K. pneumoniae is one of the main causative agents of bloodstream infection and respiratory tract infection, and it should be taken into consideration during the diagnosis of respiratory infection [24, 25] . ... Prevalence and Antibiogram Pattern of Klebsiella pneumoniae in a Tertiary Care Hospital in Makkah, Saudi Arabia: An 11-Year Experience Article Full-text available Jan 2023 Faez Bahuwayrith Infectious disease is one of the greatest causes of morbidity and mortality worldwide, and with the emergence of antimicrobial resistance, the situation is worsening. In order to prevent this crisis, antimicrobial resistance needs to be monitored carefully to control the spread of multidrug-resistant bacteria. Therefore, in this study, we aimed to determine the prevalence of infection caused by Klebsiella pneumoniae and investigate the antimicrobial profile pattern of K. pneumoniae in the last eleven years. This retrospective study was conducted in a tertiary hospital in Makkah, Saudi Arabia. Data were collected from January 2011 to December 2021. From 2011 to 2021, a total of 61027 bacterial isolates were collected from clinical samples, among which 14.7% (n = 9014) were K. pneumoniae. The antibiotic susceptibility pattern of K. pneumoniae revealed a significant increase in the resistance rate in most tested antibiotics during the study period. A marked jump in the resistance rate was seen in amoxicillin/clavulanate and piperacillin/tazobactam, from 33.6% and 13.6% in 2011 to 71.4% and 84.9% in 2021, respectively. Ceftazidime, cefotaxime, and cefepime resistance rates increased from 29.9%, 26.2%, and 53.9%, respectively, in 2011 to become 84.9%, 85.1%, and 85.8% in 2021. Moreover, a significant increase in the resistance rate was seen in both imipenem and amikacin, with an average resistance rate rise from 6.6% for imipenem and 11.9% for amikacin in 2011 to 59.9% and 62.2% in 2021, respectively. The present study showed that the prevalence and drug resistance of K. pneumoniae increased over the study period. Thus, preventing hospital-acquired infection and the reasonable use of antibiotics must be implemented to control and reduce antimicrobial resistance . View Show abstract ... 1,2 These infections have a high morbidity rate and often require revision surgeries which burden the healthcare system with increased costs. 1,3,4 With the increased prevalence of multidrug-resistant pathogens, [5] [6][7] common antibiotics are becoming less effective at inhibiting pathogen growth, necessitating the development of alternative antimicrobial treatments. 6,8 This need for alternative antimicrobial therapies is additionally heightened by the challenges of biofilms and persister cells. ... Silver Carboxylate as an Antibiotic-Independent Antimicrobial: A Review of Current Formulations, in vitro Efficacy, and Clinical Relevance Article Full-text available Dec 2022 Makena Mette Liam Connolly Neel Vishwanath Dioscaris R. Garcia The increasing prevalence of multi-drug resistant pathogens has led to a renewed focus on the use of silver as an antibiotic-independent antimicrobial. Unfortunately, the use of many silver formulations may be limited by an uncontrolled release of silver with the potential for significant cytotoxic effects. Silver carboxylate (AgCar) has emerged as an alternative formulation of silver with the potential to mitigate these concerns while still displaying significant bactericidal activity. This article reviews the efficacy of silver carboxylate formulations as a promising novel antibiotic-independent antimicrobial. This study was conducted through a search of five electronic databases (PubMed, Embase, MEDLINE, Cochrane Library, and Web of Science) for relevant studies up to September 2022. Searches were conducted for types of “silver carboxylate” formulations. Sources were compiled based on title and abstract and screened for inclusion based on relevance and study design. A review of the antimicrobial activity and cytotoxicity of silver carboxylate was compiled based on this search. Current body of data suggests that silver carboxylate shows promise as an emerging antibiotic-independent antimicrobial, with significant bactericidal effects while minimizing cytotoxicity. Silver carboxylate addresses several of the limitations of more primitive formulations, including controlled dosing and fewer negative effects on eukaryotic cell lines. These factors are concentration-dependent and largely rely on the vehicle system used to deliver it. Although several silver carboxylate-based formulations like titanium dioxide/ polydimethylsiloxane (TiO2/PDMS) matrix-eluting AgCar have shown promising results in vitro, and could potentially be utilized independently or in conjunction with current and future antimicrobial therapies, there is a need for further in vivo studies to validate their overall safety and efficacy profile. View Show abstract ... Blood culture is the laboratory gold standard for the diagnosis of blood stream infection; it guides antimicrobial treatment and monitoring of antimicrobial resistant patterns [1]. BSI has emerged as a public health concern with especially rising drug resistance, morbidity and mortality worldwide [2] . Low-and middle-income countries bear disproportionately the burden of BSI [3] [4] [5]. ... Transitioning to Automated Microbiologic Era: Blood Culture Isolates in Children and Adults in Federal Teaching Hospital in Gombe, North East Nigeria 2016-2020 Article Full-text available Jan 2022 Elon Warnow Isaac Iliya Jalo Mohammed M Manga Muhammad Saminu Charanci View ... While individuals of all ages are prone to infection, immune-compromised neonates, children and adults mostly succumb to sepsis. Though any opportunistic pathogen can trigger sepsis, among bacteria, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae (Kp), Acinetobacter baumannii (Acb), Pseudomonas aeruginosa and Enterobacter sp. are the prominent drivers [5][6][7] [8] [9]. In LMICs, the bulk of the neonatal blood culture-positive sepsis cases (45-55%) are triggered by two Gram-negative septicemia-and pneumonia-causing bacterial pathogens, Acb and Kp [10][11][12][13]. ... Genomic islands and their role in fitness traits of two key sepsis-causing bacterial pathogens Article Dec 2022 Brief Funct Genomics Mohd Ilyas Dyuti Purkait Krishnamohan Atmakuri To survive and establish a niche for themselves, bacteria constantly evolve. Toward that, they not only insert point mutations and promote illegitimate recombinations within their genomes but also insert pieces of ‘foreign’ deoxyribonucleic acid, which are commonly referred to as ‘genomic islands’ (GEIs). The GEIs come in several forms, structures and types, often providing a fitness advantage to the harboring bacterium. In pathogenic bacteria, some GEIs may enhance virulence, thus altering disease burden, morbidity and mortality. Hence, delineating (i) the GEIs framework, (ii) their encoded functions, (iii) the triggers that help them move, (iv) the mechanisms they exploit to move among bacteria and (v) identification of their natural reservoirs will aid in superior tackling of several bacterial diseases, including sepsis. Given the vast array of comparative genomics data, in this short review, we provide an overview of the GEIs, their types and the compositions therein, especially highlighting GEIs harbored by two important pathogens, viz. Acinetobacter baumannii and Klebsiella pneumoniae, which prominently trigger sepsis in low- and middle-income countries. Our efforts help shed some light on the challenges these pathogens pose when equipped with GEIs. We hope that this review will provoke intense research into understanding GEIs, the cues that drive their mobility across bacteria and the ways and means to prevent their transfer, especially across pathogenic bacteria. View Show abstract ... Staphylococcus aureus (SA) is a leading cause of bacteremia. High mortality rates from 20% to 50%, frequent recurrences from 5% to 10%, and lasting impairment in more than one-third of the survivors characterize S. aureus bloodstream infections (BSI) (Asgeirsson et al. 2018; Kern and Rieg 2020) . S. aureus infections are particularly problematic due to the frequent antibiotic resistance, among which methicillin resistance is the most clinically relevant (Turner et al. 2019). ... Rapid and Simple Approaches for Diagnosis of Staphylococcus aureus in Bloodstream Infections Article Full-text available Dec 2022 Pol J Microbiol Rui Duan Pei Wang Staphylococcus aureus is an important causative pathogen of bloodstream infections. An amplification assay such as real-time PCR is a sensitive, specific technique to detect S. aureus. However, it needs well-trained personnel, and costs are high. A literature review focusing on rapid and simple methods for diagnosing S. aureus was performed. The following methods were included: (a) Hybrisep in situ hybridization test, (b) T2Dx system, (c) BinaxNow Staphylococcus aureus and PBP2a, (d) Gram staining, (e) PNA FISH and QuickFISH, (f) Accelerate PhenoTM system, (g) MALDI-TOF MS, (h) BioFire FilmArray, (i) Xpert MRSA/SA. These rapid and simple methods can rapidly identify S. aureus in positive blood cultures or direct blood samples. Furthermore, BioFire FilmArray and Xpert MRSA/SA identify methicillin-resistant S. aureus (MRSA), and the Accelerate PhenoTM system can also provide antimicrobial susceptibility testing (AST) results. The rapidity and simplicity of results generated by these methods have the potential to improve patient outcomes and aid in the prevention of the emergence and transmission of MRSA. View Show abstract ... Here, we focused on the role of livestock keeping within households across Nairobi, Kenya, as a highrisk urban interface for the emergence and transmission of AMR bacteria between humans and animals. We use Escherichia coli, a common commensal and pathogenic bacterium [6] in vertebrates, to investigate the dispersal of AMR between human and animal hosts in 99 households across Nairobi using an epidemiologically structured analytical framework. ... Genomic epidemiology of Escherichia coli: antimicrobial resistance through a One Health lens in sympatric humans, livestock and peri-domestic wildlife in Nairobi, Kenya Article Full-text available Dec 2022 BMC MED Dishon Muloi James M. Hassell Bryan A. Wee M. E. J. Woolhouse Background Livestock systems have been proposed as a reservoir for antimicrobial-resistant (AMR) bacteria and AMR genetic determinants that may infect or colonise humans, yet quantitative evidence regarding their epidemiological role remains lacking. Here, we used a combination of genomics, epidemiology and ecology to investigate patterns of AMR gene carriage in Escherichia coli, regarded as a sentinel organism. Methods We conducted a structured epidemiological survey of 99 households across Nairobi, Kenya, and whole genome sequenced E. coli isolates from 311 human, 606 livestock and 399 wildlife faecal samples. We used statistical models to investigate the prevalence of AMR carriage and characterise AMR gene diversity and structure of AMR genes in different host populations across the city. We also investigated household-level risk factors for the exchange of AMR genes between sympatric humans and livestock. Results We detected 56 unique acquired genes along with 13 point mutations present in variable proportions in human and animal isolates, known to confer resistance to nine antibiotic classes. We find that AMR gene community composition is not associated with host species, but AMR genes were frequently co-located, potentially enabling the acquisition and dispersal of multi-drug resistance in a single step. We find that whilst keeping livestock had no influence on human AMR gene carriage, the potential for AMR transmission across human-livestock interfaces is greatest when manure is poorly disposed of and in larger households. Conclusions Findings of widespread carriage of AMR bacteria in human and animal populations, including in long-distance wildlife species, in community settings highlight the value of evidence-based surveillance to address antimicrobial resistance on a global scale. Our genomic analysis provided an in-depth understanding of AMR determinants at the interfaces of One Health sectors that will inform AMR prevention and control. View Show abstract ... Populationbased studies estimated that there were 575,000-677,000 episodes of BSI and 79,000-94,000 deaths per year in North America, more than 1,200,000 episodes of BSI and 157,000 deaths per year in Europe [1,2]. A good progress has been achieved in the diagnosis and treatment of BSIs, but the mortality associated with some pathogens such as methicillin-resistant Staphylococcus aureus, vancomycinresistant enterococci, carbapenem-resistant Enterobacteriaceae is still high [3] . ... Development of a risk prediction model for bloodstream infection in patients with fever of unknown origin Article Full-text available Dec 2022 J TRANSL MED Teng Xu Shi Wu Jingwen Li Haihui Huang Background Bloodstream infection (BSI) is a significant cause of mortality among patients with fever of unknown origin (FUO). Inappropriate empiric antimicrobial therapy increases difficulty in BSI diagnosis and treatment. Knowing the risk of BSI at early stage may help improve clinical outcomes and reduce antibiotic overuse. Methods We constructed a multivariate prediction model based on clinical features and serum inflammatory markers using a cohort of FUO patients over a 5-year period by Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression. Results Among 712 FUO patients, BSI was confirmed in 55 patients. Five independent predictors available within 24 h after admission for BSI were identified: presence of diabetes mellitus, chills, C-reactive protein level of 50–100 mg/L, procalcitonin > 0.3 ng/mL, neutrophil percentage > 75%. A predictive score incorporating these 5 variables has adequate concordance with an area under the curve of 0.85. The model showed low positive predictive value (22.6%), but excellent negative predictive value (97.4%) for predicting the risk of BSI. The risk of BSI reduced to 2.0% in FUO patients if score < 1.5. Conclusions A simple tool based on 5 variables is useful for timely ruling out the individuals at low risk of BSI in FUO population. View Show abstract ... Multidrug-resistant ExPEC strains have been implicated in several recent infections, especially UTI and BSI worldwide (Antimicrobial Resistance Collaborators, 2022; Kern and Rieg, 2020) . The continuing global rise of multidrug-resistant ExPEC clones is not only found in clinical settings (Giufrè et al., 2012;Ranjan et al., 2017) but also in food animals (Johnson et al., 2012;Zou et al., 2021). ... Urinary tract infection and sepsis causing potential of multidrug-resistant Extraintestinal pathogenic E. coli isolated from plant-origin foods Article Dec 2022 INT J FOOD MICROBIOL Priyanka Priyanka Prem R. Meena Ph.D Dharma Raj Arvind Pratap Singh The dissemination of Extraintestinal pathogenic Escherichia coli (ExPEC) in food is a critical concern for human health and food safety. The present study is the first to systematically examine the diverse plant-origin foods such as cucumber, carrot, tomato, radish, chilli, fenugreek, coriander, peppermint, spring onion, cabbage, and spinach for the presence of ExPEC or specific putative ExPEC pathotypes with an in-depth assessment of their phylogenetics, virulence, and drug resistance. A total of 77 (15.9 %) ExPEC isolates were recovered from 1780 samples of the diverse plant-origin foods of distinct environments. Specific putative ExPEC pathotypes such as Uropathogenic E. coli (UPEC, 23.3 %) and Septicemia-associated E. coli (SEPEC, 24.6 %) were identified among ExPEC isolates. The Clermont revisited new phylotyping method revealed the varied distribution (1–27 %) of specific putative ExPEC pathotypes in the different phylogenetic lineages such as A, D/E, B1, and Clade 1, etc. All putative ExPEC pathotypes possess multiple genes (4.3–92.8 %) or phenotypes (3.3–100 %) associated with their virulence. In-vitro antimicrobial susceptibility testing of all putative ExPEC pathotypes demonstrated the presence of 100 % multidrug resistance with moderate to high (52–100 %) resistance to drugs used as last-resorts (chloramphenicol, colistin) or frontline (nitrofurantoin, sulfamethoxazole, ampicillin, gentamicin) in ExPEC-associated infections in humans. Overall, the present findings significantly contribute to our better understanding of the presence of ExPEC in the non-clinical niche, such as plant-origin foods with a possible consequence on human health and food safety. View Show abstract ... Due to the high mortality of BSIs and sepsis, early administration of empiric broadspectrum antimicrobials is normally the first step in the treatment of these infections, but in many occasions this it is not accurate for the actual bacterial pathogen causing BSI or sepsis, leading to therapeutic failure and death [1][2][3] 5] . Therefore, it is imperative to identify, in a timely manner, the infectious agent causing BSI or infection leading to sepsis (bacteria, fungi, or virus) as well as possible associated antimicrobial resistances [2,4], in order to administer tailored antimicrobial therapy. ... Quantification of bacterial DNA in blood using droplet digital PCR: a pilot study Preprint Full-text available Dec 2022 Ana P. Tedim Irene Merino Alicia Ortega Jesus F Bermejo-Martin Aim To use genus/species-specific genes droplet digital PCR (ddPCR) assays to detect/quantify bacterial DNA from Escherichia coli , Klebsiella pneumoniae , Staphylococcus aureus and Enterococcus spp in blood samples. Methods and Results Bacterial DNA from clinical strains (4<n<12) was extracted, quantified and diluted (10-0.0001ng/μL) and ddPCR assays were performed in triplicate. These ddPCR assays showed low replication variability, low detection limit (1–0.1pg/μL) and high genus/species specificity. ddPCR assays were also used to quantify bacterial DNA obtained from spiked blood (1×104-1CFU/mL) of each bacterial genus/species. Comparison between ddPCR assays and bacterial culture was performed by Pearson correlation. There was an almost perfect correlation (r≥0.997, p≤0.001) between the number of CFU/mL from bacterial culture and the number of gene copies/mL detected by ddPCR. The time from sample preparation to results was determined to be 3.5-4h. Conclusions The results demonstrated the quantification capacity and specificity of the ddPCR assays to detect/quantify four of the most important bloodstream infection (BSI) bacterial pathogens directly from blood. Significance and Impact This pilot study results reinforce the potential of ddPCR for the diagnosis and/or severity stratification of BSI. Applied to patients’ blood samples it can improve diagnosis and diminish sample-to-results time, improving patient care. View Show abstract ... Overall, the articles in this Research Topic highlight a spectrum of research encompassing the importance of pursuing work to explore new ways of treating multidrug resistant bacteria. Despite the availability of a range of antimicrobials, multidrug resistant (MDR) bacterial infections continue to have a significant impact, contributing to the burden on the public health sector of various countries (Cerceo et al., 2016;Jabbour et al., 2020;Jernigan et al., 2020;Karaman et al., 2020; Kern and Rieg, 2020; Jean et al., 2022). The discovery of antibiotics, starting with the introduction of penicillin in the 1940s, dramatically improved outcomes of bacterial infections, however increasing incidence of infections with multidrug resistant organisms has created an impending healthcare crisis associated with escalating patient morbidity, mortality and health care costs (Medina and Pieper, 2016;Campanini-Salinas et al., 2018;Escolà-Vergé et al., 2020). ... Editorial: Novel approaches to the treatment of multidrug-resistant bacteria, Volume II Article Full-text available Nov 2022 Priyia Pusparajah Vengadesh Letchumanan Bey Hing Goh Lyndy Mcgaw View ... At present, the incidence of bacteremia is already high worldwide, and the incidence, mortality and medical costs of bacteremia are still increasing (Kern and Rieg, 2020) . Blood culture is still the "gold standard" for the diagnosis of bacteremia (Adrie et al., 2017), but it always has a low positive rate and a long time. ... Microbiological characteristics and risk factors on prognosis associated with Acinetobacter baumannii bacteremia in general hospital: A single-center retrospective study Article Full-text available Nov 2022 Zhiyong Wei Shuai Zhou Ying Zhang Keliang Xie Objective Acinetobacter baumannii is one of the most important pathogenic bacteria causing nosocomial infections and has a high mortality rate. Assessment of the microbiological characteristics and risk factors on prognosis associated with A.baumannii is essential. In this study, we aimed to investigate the clinical characteristics and prognostic risk factors of patients with A.baumannii bacteremia. Patients and Methods This study retrospectively analyzed the antibiotic resistance of pathogens based on the clinical data of A.baumannii bacteremia patients presented in a tertiary teaching hospital from 2017 to 2022. Logistic regression and decision tree identified the prognostic risk factors for patients with baumannemia. Kaplan-Meier method was used for survival analysis between MDR and Non-MDR groups. The area under receiver-operating characteristic curve (ROC curve) was used to compare the predictive value of the APACHE II score and Sequential Organ Failure Assessment (SOFA) score. Results A total of 110 patients with positive A. Baumannii blood cultures were included. Most of the patients were from intensive care unit (ICU) wards. The drug sensitivity results showed that the resistance rate of A. baumannii to colistin was the lowest (1.1%), followed by tigecycline (3.6%). The survival time of MDR group was significantly shorter than that of Non-MDR group. Multivariate analysis showed that, APACHE II score and SOFA score were independent risk factors affecting the prognosis of 28 days of A.baumannii bacteremia. And both scores displayed excellent AUROCs (SOFA: 0.909, APACHE II: 0.895 in predicting 28-day mortality). The two scoring systems were highly correlated and predicted no significant difference ( r ² = 0.4410, P < 0.001). We found that SOFA > 7 and APACHE II > 21 are associated with significantly higher mortality rates. Conclusion A.baumannii bacteremia have the highest incidence in the ICU, with high drug resistance and mortality rates. The survival time of patients with MDR A. Baumannii bacteremia was significantly shortened. The SOFA score and APACHE II score can reflect the severity of A.baumannii bacteremia patients and evaluate the 28-day prognosis. In addition, for the convenience of calculation, the SOFA score may be more clinically useful than the APACHE II score in predicting the mortality rate of A.baumannii bacteremia. View Show abstract ... Bloodstream infection rates were estimated to reach two million episodes yearly in North America and Europe combined, with an estimated one-quarter of a million deaths [2]. Escherichia coli has the highest incidence, whereas Staphylococcus aureus and Pseudomonas aeruginosa cause higher mortality rates [3] . ... Development of a Multiplex Polymerase Chain Reaction-Based DNA Lateral Flow Assay as a Point-of-Care Diagnostic for Fast and Simultaneous Detection of MRSA and Vancomycin Resistance in Bacteremia Article Full-text available Nov 2022 Mona Kashef Omneya Mohamed Helmy To reduce high mortality and morbidity rates, timely and proper treatment of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection is required. A multiplex polymerase reaction (mPCR)-based DNA lateral flow assay (MBDLFA) was developed as a point-of-care diagnostic for simultaneous identification of S. aureus, methicillin resistance, and vancomycin resistance directly from blood or blood cultures. A mPCR was developed to detect nuc, mecA, and vanA/B; its sensitivity, specificity, and limit of detection (LOD) were determined. The developed reaction was further modified for use in MBDLFA and its sensitivity for detection of target genes from artificially inoculated blood samples was checked. The optimized mPCR successfully detected nuc, mecA, and vanA/B from genomic DNA of bacterial colonies with LODs of 107, 107, and 105 CFU/mL, respectively. The reaction was sensitive and specific. The optimized mPCR was used in MBDLFA that detected nuc, mecA, and vanA/B with LODs of 107, 108, and 104 CFU/mL, respectively, directly from artificially inoculated blood. The developed MBDLFA can be used as a rapid, cheap point-of-care diagnostic for detecting S. aureus, MRSA, and vancomycin resistance directly from blood and blood cultures in ~2 h with the naked eye. This will reduce morbidity, mortality, and treatment cost in S. aureus bacteremia. View Show abstract ... Bloodstream infections (BSI) are the leading cause of morbidity and mortality worldwide and as a life-threatening condition require prompt diagnosis and treatment. In Europe and North America BSI incidence ranges between 113 and 204 per 100,000 people [1] [2] [3][4]. Furthermore, the incidence of BSI is rising, probably related to an aging population and an increasing prevalence of underlying conditions and invasive procedures [5]. Mortality estimates vary with country from 15.3% to 40.0% [6]. ... Sepsityper® Kit versus In-House Method in Rapid Identification of Bacteria from Positive Blood Cultures by MALDI-TOF Mass Spectrometry Article Full-text available Oct 2022 Gabrijela Perše Ivana Samošćanec Zrinka bošnjak Ivana Marekovic In order to further accelerate pathogen identification from positive blood cultures (BC), various sample preparation protocols to identify bacteria with MALDI-TOF MS directly from positive BCs have been developed. We evaluated an in-house method in comparison to the Sepsityper® Kit (Bruker Daltonics, Bremen, Germany) as well as the benefit of an on-plate formic acid extraction step following positive signal by the BACTECTM FX system. Confirmation of identification was achieved using subcultured growing biomass used for MALDI-TOF MS analysis. A total of 113 monomicrobial positive BCs were analyzed. The rates of Gram-positive bacteria correctly identified to the genus level using in-house method and Sepsityper® Kit were 63.3% (38/60) and 81.7% (49/60), respectively (p = 0.025). Identification rates at species level for Gram-positive bacteria with in-house method and Sepsityper® kit were 30.0% (18/60) and 66.7% (40/60), respectively (p < 0.001). Identification rates of Gram-negative bacteria were similar with the in-house method and Sepsityper® Kit. Additional on-plate formic acid extraction demonstrated significant improvement in the identification rate of Gram-positive bacteria at both genus and species level for both in-house (p = 0.001, p < 0.001) and Sepsityper® Kit methods (p = 0.007, p < 0.001). Our in-house method is a candidate for laboratory routines with Sepsityper® Kit as a back-up solution when identification of Gram-positive bacteria is unsuccessful. View Show abstract ... Staphylococcus aureus menyebabkan BSI dengan insiden tahunan sekitar 30-40 per 100.000 populasi dan tingkat fatalitas kasus terkait sebesar 20% (1, 2) . ... Antibacterial Effect Combination of Moringa Leaf Extract (Moringa oleifera Lam.) and Amoxicillin against Staphylococcus aureus and Escherichia coli in Vitro Article Full-text available Apr 2022 Setiadi Abdillah Pratama Tri Widyawati Muhammad Ichwan Dian Dwi Wahyuni Staphylococcus aureus and Escherichia coli often infect humans and risky cause antibiotics resistance including amoxicillin. This encourages us finding alternative active ingredients: Moringa oleifera leaf. This study evaluated antibacterial activity of combination of Moringa leaf extract (KDK) and amoxicillin (KA) against S. aureus and E. coli in vitro. The research methods with true experimental research with post-test control group design. KDK obtained by maceration. Four concentrations of KDK test materials (20, 30, 40, 50%) and 1 concentration of KA (3 mg/mL). Disc diffusion test method taken and the parameter measured: the diameter of the disc inhibition zone. Data analyzed by One-way ANOVA and further Tukey’s test. KDK+KA against S. aureus (20.77±1.79 – 21.33±1.74 mm)>KDK (11.45±0.21 – 12.45±0.28 mm) or KA (14.50±0.42 mm). KDK+KA against E. coli (15.53±0.71 – 17.87±0.42 mm)>KDK (9.00±0.28 – 10.30±0.42 mm) or KA (13.45±0.35 mm). A significant (p<0.05) was obtained between the combination group (KDK+KA) versus a group (KDK or KA). The combination of Moringa leaf ethanol extract and amoxicillin synergistically effected as antibacterial against S. aureus and E. coli in vitro. View Show abstract ... aeruginosa), and coagulase-negative staphylococci [5]. Several studies have reported the highest incidence for E. coli especially as regards hospital-acquired infections, while S. aureus and P. aeruginosa are among the prominent causes of mortality [6] . Major dramatic changes have emerged with E. coli and K. pneumoniae epidemiology in BSIs owing to their resistance to third-generation cephalosporins, which is primarily due to the production of the extended-spectrum beta-lactamase (ESBL) enzymes. ... BioFire FilmArray BCID2 Versus VITEK-2 System in Determining Microbial Etiology and Antibiotic-Resistant Genes of Pathogens Recovered from Central Line-Associated Bloodstream Infections Article Full-text available Oct 2022 Heba M. El Sherif Mahitab Elsayed Mona El-Ansary Khaled M. Elsayed Central line-associated bloodstream infection (CLABSI) is among the most serious hospital acquired infections. Therefore, the rapid detection of the causative microorganism is of crucial importance to allow for the appropriate antimicrobial therapy. In the present study, we analyzed the clinical performance of the BioFire FilmArray Blood Culture Identification 2 (BCID2) panel in the identification of 33 microbial species and 10 antibiotic resistance genes in comparison to the VITEK-2 system. A total of 104 blood specimens were included. The FilmArray BCID2 results were concordant with the VITEK-2 system in 69/97 specimens (71.1%). Non-concordance was either due to the detection of more pathogens by the FilmArray BCID2 23/28 (82%) or microbial species were misidentified 5/28 (18%). Hence, in comparison to the VITEK-2 system, the FilmArray BCID2 panel showed an overall sensitivity of 75.8% (95% CI, 66–83%) and an overall specificity of 98% (95% CI, 97–98.8%) in detecting microbial species. For the resistance genes, the FilmArray BCID was able to detect the presence of blaCTX-M gene in 23 Gram-negative isolates, blaNDM and blaOXA-48- like genes in 14 and 13 isolates, respectively. The mecA and mecC genes were found in 23 Staphylococcus species, while mecA, mecC and MREJ genes were found in 4 Staphylococcus aureus isolates. The sensitivity and specificity for detecting resistance genes by the FilmArray BCID2 was 90% (95% CI, 81.4–95%) and 99.6% (95% CI, 99–100%), respectively. As concluded, the present study emphasizes the high sensitivity and specificity of the FilmArray BCID2 in the rapid and reliable detection of different bacteria and fungi from positive blood culture bottles, as well as the accurate detection of various antibiotic resistance markers. View Show abstract ... Bloodstream infection (BSI) is generally defined by the presence of viable bacterial or fungal microorganisms in the bloodstream confirmed by blood cultures, which include a wide variety of pathogens and clinical syndromes [1]. Although epidemiology of BSI from well-designed population-based surveillance is lacking, especially at a regional level and in resourcelimited settings [2] , the incidence of BSI is estimated to be similar to stroke or venous thrombosis (about 100-200 per 100,000 population) in the general population [3,4], of which nosocomial BSI accounts for about 30-50% [5,6]. This has become a heavy burden for healthcare, as the presence of BSI is often associated with both worse prognosis (including prolonged lengths of hospital stay and increased mortality risk) and increased cost, especially for critically ill patients [7][8][9]. ... Incidence, Clinical Features, and Association with Prognosis of Bloodstream Infection in Pediatric Patients After Percutaneous or Surgical Treatment for Ventricular Septal Defect or Atrial Septal Defect: A Retrospective Cohort Study Article Full-text available Oct 2022 Qinchang Chen Jinjin Yu Pingchuan Huang Shushui Wang Introduction Bloodstream infection (BSI) may occur after cardiac procedures, but this has rarely been investigated specifically in pediatric patients after percutaneous or surgical treatment for ventricular septal defect (VSD) or atrial septal defect (ASD) with recent data. The current study aimed to investigate the incidence, clinical features, and association with prognosis of BSI in this patient population. Methods Pediatric patients who received percutaneous or surgical procedure for VSD or ASD between 2010 and 2018 in a large children’s hospital in China were retrospectively enrolled via the Pediatric Intensive Care database, but only those who had blood culture records within 24 h after the procedure and who had no prior positive blood culture records were included. BSI after the procedure was identified by reviewing blood culture records, and baseline characteristics associated with BSI were explored by univariable logistic regression. In-hospital mortality and length of hospitalization were studied as prognostic outcomes and compared between patients with and without BSI. Results A total of 1340 pediatric patients were included. Among them, 46 (3.43%) patients had BSI within 24 h after the procedure, of which the majority (78.26%, 36/46) were caused by Gram-positive bacteria and 65.22% (30/46) had antibiotic-resistant organisms. Age [odds ratio (OR) 0.98 per 1-month increase, 95% confidence interval (CI) 0.97–1.00, P = 0.021] and antibiotic use within 72 h before the procedure (OR 1.81, 95% CI 1.00–3.26, P = 0.049) were statistically significantly associated with developing BSI. Compared with patients without BSI, there was no statistically significant difference in in-hospital mortality (0.00% versus 0.54%, P = 1.000), but patients with BSI had statistically significantly longer length of hospitalization (median 14.51 versus 12.94 days, P = 0.006), while the association was not statistically significant after adjustment for baseline characteristics by multivariable linear regression (β = 1.73, 95% CI −0.59 to 4.04, P = 0.144). Conclusion BSI is relatively uncommon in pediatric patients after procedures for VSD or ASD, but a younger age seems a risk factor. Developing BSI appears to be associated with increased length of hospitalization but not in-hospital mortality. View Show abstract ... BSI are caused by a broad spectrum of pathogens and the emergence and spread of multidrug resistant pathogens has complicated treatment of the disease. Therefore, understanding the epidemiology of the disease can be useful in informing effective public health interventions [2] . Surveillance to understand the epidemiology of BSI is important for local and global comparisons and for advising standardized empirical treatment regimens; however, there is heterogeneity in the global data due to geographic and demographic differences [3]. ... Bloodstream infections and antibiotic resistance patterns: a six-year surveillance study from southern Italy Article Full-text available Oct 2022 Francesco Foglia Maria Teresa Della Rocca Colombina Melardo Massimiliano Galdiero Bloodstream infections (BSI) are associated with high morbidity and mortality. This study aimed to describe the epidemiology of BSI and antimicrobial resistance patterns amongst its common bacterial causes. We conducted a retrospective record review of blood culture results of patients hospitalized with BSI at University Hospital 'L. Vanvitelli' from 2016 to 2021. For each patient records were obtained from the database using microbiological information. Gram-positive bacteria were the most predominant pathogens followed by Gram-negative bacteria. Among all isolates, bacterial pathogens most frequently identified included coagulase-negative Staphylococci (CoNS), Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and enterococci. We noted a general decrease in antimicrobial resistance amongst BSI pathogens in the latter years of the study. High levels of macrolide and aminoglycoside resistance amongst CoNS were reported. Carbapenem resistance amongst E. coli was barely reported, while resistance rates amongst K. pneumoniae declined considerably between 2018 and 2021. The prevalence of methicillin-resistant S. aureus decreased during the study period while that of methicillin-resistant CoNS remained relatively high throughout. The prevalence of extended spectrum ß-lactamase - producing E. coli increased considerably between 2016 and 2018 but showed a slight decrease thereafter. Conversely, there was a general decline in the resistant rates of extended spectrum ß-lactamase - producing K. pneumoniae between 2016 and 2018 with a similar trend being noted for carbapenem resistance in K. pneumoniae. Continuously monitoring the changes in the trends in BSI microbiological profiles, including pathogen profiles and the associated antibiotic resistance patterns, can help diagnostic approaches, treatment strategies and prevention programs. View Show abstract ... The estimated average annual incidence of BSI in multi-year population-based studies conducted in North America (USA and Canada) and Europe (Sweden, Norway, Denmark, England, Finland, Switzerland, and Spain) ranged between 91 and 220 per 100,000 population. 1, 2 Higher incidence rates were reported in recent years from Switzerland and Finland, reaching 240 and 309 cases/100,000, respectively. 3,4 The case fatality rate (CFR) of BSI varied greatly by the affected population (i. ... One-year mortality and years of potential life lost following bloodstream infection among adults: A nation-wide population based study Article Full-text available Dec 2022 Vered Schechner Liat Wulffhart Elizabeth Temkin Yehuda Carmeli Background Limited data exist on long-term consequences of bloodstream infections (BSIs). We aimed to examine incidence, 1-year mortality, and years of potential life lost (YPLL) following BSI. We estimated the relative contribution of hospital-onset BSI (HO-BSI) and antibiotic-resistant BSI to incidence, mortality and YPLL. Methods We used data from Israel's national BSI surveillance system (covering eight sentinel bacteria, comprising 70% of all BSIs) and the national death registry. Adults with BSI between January 2018 and December 2019 were included. The outcomes were all-cause 30-day and 1-year mortality, with no adjustment for co-morbidities. We calculated the age-standardized mortality rate and YPLL using the Global Burden of Disease reference population and life expectancy tables. Findings In total, 25,376 BSIs occurred over 2 years (mean adult population: 6,068,580). The annual incidence was 209·1 BSIs (95% CI 206·5–211·7) per 100,000 population. The case fatality rate was 25·6% (95% CI 25·0-26·2) at 30 days and 46·4% (95% CI 45·5-47·2) at 1 year. The hazard of death increased by 30% for each decade of age (HR=1·3 [95% CI 1·2-1·3]). The annual age-standardized mortality rate and YPLL per 100,000 were 50·8 (95% CI 49·7-51·9) and 1,012·6 (95% CI 986·9-1,038·3), respectively. HO-BSI (6,962 events) represented 27·4% (95% CI 26·9-28·0) of BSIs, 33·9% (95% CI 32·6-35·0) of deaths and 39·9% (95% CI 39·5-40·2) of YPLL. HO-BSI by drug-resistant bacteria (3,072 events) represented 12·1% (95% CI 11·7-12·5) of BSIs, 15·6% (95% CI 14·7-16·5) of deaths, and 18·4% (95% CI 18·1-18·7) of YPLL. Interpretation One-year mortality following BSI is high. The burden of BSI is similar to that of ischemic stroke. HO-BSI and drug-resistant BSI contribute disproportionately to BSI mortality and YPLL. Funding None. View Show abstract ... The majority of infections result in self-limiting gastroenteritis, but invasive bloodstream infections can also occur, with children, the elderly, and immunocompromised individuals at highest risk of developing life-threatening illness (GBD 2017(GBD , 2019. The medical treatment of severe Salmonella infections can also become complicated by the presence of antimicrobial resistance (AMR; ; resistant infections contribute to an increased risk of complications and death, as well as prolonged recovery times (Kern & Rieg, 2020; Tanwar et al., 2014). The widespread use of antimicrobials in agriculture and in humans is thought to drive the selection of resistance and virulence among pathogenic organisms such as Salmonella (Kumar et al., 2020;Bawn et al., 2020), and although wildlife species are increasingly being examined for their potential role in zoonotic diseases (Torres et al., 2020), their role in the epidemiology of Salmonella and AMR is not entirely clear. ... Using whole-genome sequencing and a One Health approach to understand the epidemiology of zoonotic pathogens and antimicrobial resistance at the human, wildlife, environmental, and livestock interface in southern Ontario Thesis Full-text available Jun 2021 Nadine A. Vogt View ... To our knowledge, this is the first study that evaluated the MicroScan Dried MICs on clinical isolates with typical LRS pathogens [57, 58] . Furthermore, we assessed robustness and ease of use. ... Validation of Three MicroScan® Antimicrobial Susceptibility Testing Plates Designed for Low-Resource Settings Article Full-text available Aug 2022 J.-B. Ronat Saoussen Oueslati Alessandra Natale Thierry Naas Easy and robust antimicrobial susceptibility testing (AST) methods are essential in clinical bacteriology laboratories (CBL) in low-resource settings (LRS). We evaluated the Beckman Coulter MicroScan lyophilized broth microdilution panel designed to support Médecins Sans Frontières (MSF) CBL activity in difficult settings, in particular with the Mini-Lab. We evaluated the custom-designed MSF MicroScan Gram-pos microplate (MICPOS1) for Staphylococcus and Enterococcus species, MSF MicroScan Gram-neg microplate (MICNEG1) for Gram-negative bacilli, and MSF MicroScan Fastidious microplate (MICFAST1) for Streptococci and Haemophilus species using 387 isolates from routine CBLs from LRS against the reference methods. Results showed that, for all selected antibiotics on the three panels, the proportion of the category agreement was above 90% and the proportion of major and very major errors was below 3%, as per ISO standards. The use of the Prompt inoculation system was found to increase the MIC and the major error rate for some antibiotics when testing Staphylococci. The readability of the manufacturer’s user manual was considered challenging for low-skilled staff. The inoculations and readings of the panels were estimated as easy to use. In conclusion, the three MSF MicroScan MIC panels performed well against clinical isolates from LRS and provided a convenient, robust, and standardized AST method for use in CBL in LRS. View Show abstract ... Intestinal E. coli pathotypes are strongly linked to diarrheal diseases as well as other clinical manifestations such as haemolytic uraemic syndrome and haemorrhagic colitis (Ameer et al., 2021). In some areas, the proportion of resistant E. coli isolates from bloodstream infections to routinely used antibiotics such as fluoroquinolones and third-generation cephalosporins (3GC) might be as high as 60% (Kern & Rieg, 2020) . Resistance to ciprofloxacin, trimethoprimsulphamethoxazole and fluoroquinolone has also been identified in E. coli urine isolates (Kaye et al., 2021). ... Antimicrobial betalains Article Full-text available Aug 2022 Vindya Nilakshi Wijesinghe Wee-Sim Choo Betalains are nitrogen‐containing plant pigments that can be red‐violet (betacyanins) or yellow‐orange (betaxanthins), currently employed as natural colorants in the food and cosmetic sectors. Betalains exhibit antimicrobial activity against a broad spectrum of microbes including multi‐drug resistant bacteria, as well as single‐species and dual‐species biofilm‐producing bacteria, which is highly significant given the current antimicrobial resistance issue reported by The World Health Organization. Research demonstrating antiviral activity against dengue virus, in silico studies including SARS‐CoV‐2, and anti‐fungal effects of betalains highlight the diversity of their antimicrobial properties. Though limited in vivo studies have been conducted, antimalarial and anti‐infective activities of betacyanin have been observed in living infection models. Cellular mechanisms of antimicrobial activity of betalains are yet unknown; however existing research has laid the framework for a potentially novel antimicrobial agent. This review covers an overview of betalains as antimicrobial agents and discussions to fully exploit their potential as therapeutic agents to treat infectious diseases. View Show abstract Genetic and immune determinants of E. coli liver abscess formation Preprint Full-text available Jun 2023 Karthik Hullahalli Katherine G Dailey Yuko Hasegawa Matthew K Waldor Systemic infections can yield distinct outcomes in different tissues. In mice, intravenous inoculation of E . coli leads to bacterial replication within liver abscesses while other organs such as the spleen largely clear the pathogen. Abscesses are macroscopic necrotic regions that comprise the vast majority of the bacterial burden in the animal, yet little is known about the processes underlying their formation. Here, we characterize E. coli liver abscesses and identify host determinants of abscess susceptibility. Spatial transcriptomics revealed that liver abscesses are associated with heterogenous immune cell clusters comprised of macrophages, neutrophils, dendritic cells, innate lymphoid cells, and T-cells that surround necrotic regions of the liver. Susceptibility to liver abscesses is heightened in the C57BL/6 lineage, particularly in C57BL/6N females. Backcross analyses demonstrated that abscess susceptibility is a polygenic trait inherited in a sex-dependent manner without direct linkage to sex chromosomes. As early as one day post infection, the magnitude of E. coli replication in the liver distinguishes abscess-susceptible and abscess-resistant strains of mice, suggesting that the immune pathways that regulate abscess formation are induced within hours. We characterized the early hepatic response with single-cell RNA sequencing and found that mice with reduced activation of early inflammatory responses, such as those lacking the LPS receptor TLR4, are resistant to abscess formation. Experiments with barcoded E. coli revealed that TLR4 mediates a tradeoff between abscess formation and bacterial clearance. Together, our findings define hallmarks of E. coli liver abscess formation and suggest that hyperactivation of the hepatic innate immune response drives liver abscess susceptibility. Importance Animal models of disseminating bacterial infections are critical for developing therapeutic interventions. Following systemic dissemination in mice, E. coli undergo dramatic replication within abscesses in the liver but not in other organs. Although liver abscesses are the largest reservoir of bacteria within the animal, the processes that lead to abscess formation are not known. Here, we characterize E. coli liver abscess formation and identify several determinants of abscess susceptibility, including sex, mouse genotype, and innate immune factors. By combining spatial and single-cell transcriptomics with genetic and phenotypic analyses, we delineate critical host pathways that underlie abscess formation. Our findings define several avenues for future studies to unravel how abscess susceptibility determinants interact to modulate clearance of systemic infections and govern tissue-specific bacterial replication. View Show abstract Comparison of pathogen detection consistency between metagenomic next-generation sequencing and blood culture in patients with suspected bloodstream infection Article Full-text available Jun 2023 Yuhua Zhou Wen Shi Yi Wen Tongtian Ni The application of metagenomic next-generation sequencing (mNGS) has gradually been carried out by clinical practitioner. However, few studies have compared it with blood cultures in patients suffering from suspected bloodstream infections. The purpose of this study was to compare the detection of pathogenic microorganisms by these two assays in patients with suspected bloodstream infection. We retrospectively studied patients with fever, chills, antibiotic use for more than 3 days, suspected bloodstream infection, and admission to the emergency department of Ruijin Hospital from January 2020 to June 2022. All patients had blood drawn on the same day for blood mNGS and blood cultures. Clinical and laboratory parameters were collected on the day blood was drawn. The detection of pathogenic microorganisms by the two methods was compared. Risk factors and in-hospital mortality in patients with bloodstream infections were analysed separately for these two assays. In all 99 patients, the pathogenic microorganisms detection rate in blood mNGS was significantly higher than that in blood culture. Blood mNGS was consistent with blood culture in only 12.00% of all positive bacterial and fungal test results. The level of CRP is related to bacteraemia, fungaemia and viraemia detected by blood mNGS. No clear risk factors could be found in patients with a positive blood culture. In critically ill patients, both tests failed to improve patient outcomes. In patients with suspected bloodstream infection, mNGS is not yet a complete replacement for blood cultures. View Show abstract Impact on clinical outcome of follow-up blood cultures and risk factors for persistent bacteraemia in patients with gram-negative bloodstream infections: a systematic review with meta-analysis Article Mar 2023 CLIN MICROBIOL INFEC Milo Gatti Cecilia Bonazzetti Beatrice Tazza Maddalena Giannella Background: The clinical usefulness of follow-up blood cultures (FUBCs) in Gram-negative bloodstream infections (GN-BSIs) represents a debated issue. Objective: To assess the impact on clinical outcome of FUBCs in patient with GN-BSI and to predict risk factors for persistent bacteremia. Data source: PubMed-MEDLINE, Scopus, and Cochrane Library Database were independently searched until 24 June 2022. Study eligibility criteria: Randomized controlled trials or prospective/retrospective observational studies including patients affected by GN-BSIs. Primary endpoints were in-hospital mortality rate, and persistent BSI defined as FUBC positive for the same pathogen isolated from index BCs. Participants: Hospitalized patients with documented GN-BSIs. Intervention: Performance of FUBCs (defined as subsequent BCs collected at least 24 hours after index BCs). Assessment of risk of bias: Quality of included studies was independently assessed according to ROB 2.0 and ROBINS-I tools. Methods: Of data synthesis: Meta-analysis was performed by pooling odds ratio (OR) retrieved from studies providing adjustment for confounders using random-effect model with inverse variance method. Risk factors for persistent BSIs were also assessed. Results: 3,747 articles were screened, and eleven observational studies (six assessing impact on outcome [N=4,631], and five investigating risk factors for persistent GN-BSI [N=2,566]), conducted between 2002-2020 were included. Execution of FUBCs were associated with significant lower risk of mortality (OR 0.58; 95%CI 0.49-0.70; I2=0.0%). Presence of end-stage renal disease (OR 2.99; 95%CI 1.77-5.05), central venous catheter (OR 3.30; 95%CI 1.82-5.95), infections due to ESBL-producing strains (OR 2.25; 95%CI 1.18-4.28), resistance to empirical treatment (OR 2.70; 95%CI 1.65-4.41), and unfavourable response at 48 hours (OR 2.99; 95%CI 1.44-6.24) emerged as independent risk factors for persistent bacteremia. Conclusions: The execution of FUBCs is associated with a significant lower risk of mortality in patients with GN-BSIs. Our analysis could be useful to stratify patients at high-risk for persistent bacteraemia to optimize the use of FUBCs. View Show abstract Risk of Bloodstream Infection in Patients with Systemic Lupus Erythematosus Exposed to Prolonged Medium-to-High-Dose Glucocorticoids Article Mar 2023 LUPUS Mi Hyeon Kim Se Rim Choi Jin Kyun Park Jun Won Park Objectives: This study aimed to investigate the incidence rate and risk factors of bloodstream infection (BSI) in patients with systemic lupus erythematosus (SLE) exposed to medium to high doses of glucocorticoids. Methods: This study included 1109 treatment episodes with prolonged (≥4 weeks) medium-to-high-dose glucocorticoids (≥15 mg/day prednisolone) in 612 patients with SLE for over 14 years. Clinical features regarding systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K), immunosuppressant use, and laboratory results were obtained from the electronic medical database. The primary outcome of this study was the 1-year incidence of BSI. The effect of clinical factors on the outcome was investigated using a generalized estimating equation. Results: During a total of 1078.64 person-years, 30 cases of BSI occurred, with an incidence rate of 2.78 (95% confidence interval (CI) 1.88-3.97) per 100 person-years. Mortality rate of the treatment episodes with BSI was 16.7%, which was significantly higher than that in the other episodes (incidence rate ratio (IRR) 19.59, 95% CI 7.33-52.44). When the incidence rate of BSI was stratified by baseline glucocorticoid dose and SLEDAI-2K score, a higher incidence rate of BSI occurred as disease activity or baseline glucocorticoid dose increased. In the multivariable analysis, SLEDAI-2K ≥20 (adjusted IRR (aIRR) 4.66, 95% CI 2.17-10.00), initial baseline prednisolone ≥ 60 mg/day (aIRR 2.42, 95% CI 1.11-5.32), and cumulative prednisolone dose ≥15 mg/day during the previous 6 months (aIRR 2.13, 95% CI 1.03-4.40) significantly increased the risk of BSI. Conclusion: In patients with SLE exposed to prolonged medium-to-high-dose glucocorticoids, the 1-year incidence rate of BSI was significantly higher than previously reported in the general patients with SLE. Severe disease activity, and high-dose glucocorticoid treatment previously or at baseline increased the risk of BSI. View Show abstract Oral stepdown in Gram-positive bloodstream infections: A step in the right direction Article Feb 2023 PHARMACOTHERAPY Kaylee Caniff Nicholas Rebold Michael Rybak Bloodstream infections (BSIs) due to Gram-positive organisms have traditionally been treated with prolonged courses of intravenous antimicrobials. However, this dogma is associated with substantial burden to the patient and health care system. Consequently, there is growing interest in the utilization of oral stepdown therapy, defined as the transition of intravenous therapy to an active oral agent, for this indication. This review highlights available literature examining oral stepdown in adult patients with BSI due to commonly encountered Gram-positive pathogens, including Staphylococcus aureus, Streptococcus spp., and Enterococcus spp. Support for oral stepdown in this setting is primarily derived from observational studies subject to selection bias. Nevertheless, this treatment strategy exhibits promising potential in carefully selected patients as it is consistently associated with reductions in hospital length of stay without jeopardizing clinical cure or survivability. Prospective, randomized trials are needed for validation of oral stepdown in Gram-positive BSI and to identify the optimal patient population and regimen. View Show abstract Concordance of the Filmarray Blood Culture Identification Panel 2 and Classical Microbiological Methods in a Bacteriemia Diagnostic Unit Article Jan 2022 Celia García Rivera Monica Parra Grande Esperanza Merino Juan Carlos Rodriguez Díaz View Uncorrected Preoperative Infection Causing the Death of a Patient with a Thoracic Aortic Aneurysm Article Full-text available Jan 2023 Xin-Qi He Hui-Qing Qiu Meng Wang Le Wang Background: A thoracic aortic aneurysm (TAA) is a known condition seen in cardiovascular practice. A TAA rupture and postoperative infection may result in death. Preoperative infections leading to death are extremely rare. Case study: A 62-year-old Chinese female was admitted to The First Hospital of Hebei Medical University with a two-day history of abdominal pain. She was diagnosed with a TAA rupture and underwent immediate surgery. The preoperative urine analysis indicated that the positive bacteria and white blood cell count suggested a urinary tract bacterial infection. The patient was administered the empiric antibiotics, cefazolin; however, her blood pressure continued to drop during the perioperative period and she died of uncorrectable acidosis 8 h after the operation. On the second day after death, both the blood and urine cultures were positive for Pseudomonas aeruginosa. Conclusion: Given that this patient with a TAA rupture died of uncorrected acidosis caused by preoperative infection, it is important to evoke the diagnosis in the context of TAA. Routine laboratory indicators are valuable factors for surgeons and physicians in assessing a patient's condition and improving their prognosis. View Show abstract Resolving colistin resistance and heteroresistance in Enterobacter species Article Full-text available Jan 2023 Swapnil Prakash Doijad Nicolas Gisch Renate Frantz Trinad Chakraborty Species within the Enterobacter cloacae complex (ECC) include globally important nosocomial pathogens. A three-year study of ECC in Germany identified Enterobacter xiangfangensis as the most common species (65.5%) detected, a result replicated by examining a global pool of 3246 isolates. Antibiotic resistance profiling revealed widespread resistance and heteroresistance to the antibiotic colistin and detected the mobile colistin resistance (mcr)−9 gene in 19.2% of all isolates. We show that resistance and heteroresistance properties depend on the chromosomal arnBCADTEF gene cassette whose products catalyze transfer of L-Ara4N to lipid A. Using comparative genomics, mutational analysis, and quantitative lipid A profiling we demonstrate that intrinsic lipid A modification levels are genospecies-dependent and governed by allelic variations in phoPQ and mgrB, that encode a two-component sensor-activator system and specific inhibitor peptide. By generating phoPQ chimeras and combining them with mgrB alleles, we show that interactions at the pH-sensing interface of the sensory histidine kinase phoQ dictate arnBCADTEF expression levels. To minimize therapeutic failures, we developed an assay that accurately detects colistin resistance levels for any ECC isolate. Taxonomical complexity has muddled the classification of clinically relevant Enterobacter species. Authors carry out a genome-based study on clinical isolates to investigate colistin resistance and heteroresistance in Enterobacter. View Show abstract Impact of 18F-FDG-PET/CT on the management of Staphylococcus aureus bacteraemia: a retrospective observational study Article Oct 2022 Paula Suanzes Rein Willekens Mireia Puig-Asensio Benito Almirante Objectives To assess the impact of ¹⁸F-FDG-PET/CT on the diagnosis and management of patients with Staphylococcus aureus bacteraemia (SAB). Methods Post hoc analysis of a prospective cohort of consecutive adult patients diagnosed with SAB (January 2013–December 2017). Patients who underwent ¹⁸F-FDG-PET/CT at the discretion of the attending physician were included. Endpoints were the identification of previously unknown infectious foci and changes in clinical management, defined as changes in the duration or class of antibiotic therapy, a surgical procedure on the source of infection or a change in the decision to remove or retain an implantable device. Results We included 39 patients (median age: 69 years, IQR:60–79). Fifteen (39%) patients did not have an infectious focus identified before ¹⁸F-FDG-PET/CT). Thirty new infectious foci were detected in 22/39 (56%) patients. In 11/15 (73%) patients without an identified focus at least one infectious focus was detected by ¹⁸F-FDG-PET/CT. In 22/26 (85%) patients with implantable devices, ¹⁸F-FDG-PET/CT confirmed or ruled out infection or detected local complications. Out of 13 device infections, 10 were detected by ¹⁸F-FDG-PET/CT (7/10 for the first time). In 19/39 (49%) patients ¹⁸F-FDG-PET/CT results led to changes in clinical management (15 changes in antibiotic therapy, 2 device removals, 2 surgical procedures, 1 avoidance of a surgical procedure). Conclusions ¹⁸F-FDG-PET/CT may be a useful asset in the management of selected SAB cases, allowing the identification of previously undetected infectious foci and optimization of therapy, particularly in patients with endovascular devices. Indication should be made on a case-by-case basis. View Show abstract Molecular Mechanisms Involved in Pseudomonas aeruginosa Bacteremia Chapter Oct 2022 ADV EXP MED BIOL Stéphane Pont Manon Janet-Maitre Eric Faudry Ina Attree Bloodstream infections (BSI) with Pseudomonas aeruginosa account for 8.5% of all BSIs, their mortality rate, at about 40%, is the highest among causative agents. For this reason and due to its intrinsic and acquired resistance to antibiotics, P. aeruginosa represents a threat to public health systems. From the primary site of infection, often the urinary and respiratory tracts, P. aeruginosa uses its arsenal of virulence factors to cross both epithelial and endothelial barriers, ultimately reaching the bloodstream. In this chapter, we review the main steps involved in invasion and migration of P. aeruginosa into blood vessels, and the molecular mechanisms governing bacterial survival in blood. We also review the lifestyle of P. aeruginosa "on" and "in" host cells. In the context of genomic and phenotypic diversity of laboratory strains and clinical isolates, we underline the need for more standardized and robust methods applied to host-pathogen interaction studies, using several representative strains from distinct phylogenetic groups before drawing general conclusions. Finally, our literature survey reveals a need for further studies to complete our comprehension of the complex interplay between P. aeruginosa and the immune system in the blood, specifically in relation to the complement system cascade(s) and the Membrane Attack Complex (MAC), which play crucial roles in counteracting P. aeruginosa BSI. View Show abstract Strategies on Reducing Blood Culture Contamination and Improving Differential Diagnostic Accuracy Among Cancer Patients Article Jan 2022 Jia Lu Enlv Hong Wenbin Gao Chun Huang View Show more Strong correlation between the rates of intrinsically antibiotic-resistant species and the rates of acquired resistance in Gram-negative species causing bacteraemia, EU/EEA, 2016 Article Full-text available Sep 2019 Vincent Jarlier Ole E Heuer Maja Subelj Liselotte Diaz Högberg EARS-Net participants. Strong correlation between the rates of intrinsically antibiotic-resistant species and the rates of acquired resistance in Gram-negative species causing bacteraemia, EU/EEA, 2016. Background: Antibiotic resistance, either intrinsic or acquired, is a major obstacle for treating bacterial infections. Aim: Our objective was to compare the country-specific species distribution of the four Gram-negative species Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter species and the proportions of selected acquired resistance traits within these species. Method: We used data reported for 2016 to the European Antimicrobial Resistance Surveillance Network (EARS-Net) by 30 countries in the European Union and European Economic Area. Results: The country-specific species distribution varied considerably. While E. coli accounted for 31.9% to 81.0% (median: 69.0%) of all reported isolates, the two most common intrinsically resistant species P. aeruginosa and Acinetobacterspp. combined (PSEACI) accounted for 5.5% to 39.2% of isolates (median: 10.1%). Similarly, large national differences were noted for the percentages of acquired non-susceptibility to third-generation cephalospor-ins, carbapenems and fluoroquinolones. There was a strong positive rank correlation between the country-specific percentages of PSEACI and the percentages of non-susceptibility to the above antibiotics in all four species (rho > 0.75 for 10 of the 11 pairs of variables tested). Conclusion: Countries with the highest proportion of P. aeruginosa and Acinetobacter spp. were also those where the rates of acquired non-susceptibility in all four studied species were highest. The differences are probably related to national differences in antibiotic consumption and infection prevention and control routines. 2 www.eurosurveillance.org View Show abstract Changing Characteristics of Staphylococcus aureus Bacteremia: Results From a 21-Year, Prospective, Longitudinal Study Article Full-text available Apr 2019 CLIN INFECT DIS Maria Souli Felicia Ruffin Seong-Ho Choi Vance G Fowler Background: We conducted a longitudinal study to evaluate changes in the clinical presentation and epidemiology of Staphylococcus aureus bacteremia (SAB) in an academic, US medical center. Methods: Consecutive patients with monomicrobial SAB were enrolled from January 1995 to December 2015. Each person's initial bloodstream S. aureus isolate was genotyped using spa typing. Clonal complexes (CCs) were assigned using Ridom StaphType software. Changes over time in both the patient and bacterial characteristics were estimated with linear regression. Associations between genotypes or clinical characteristics and complications were estimated using multivariable regression models. Results: Among the 2348 eligible participants, 54.2% had an implantable, foreign body of some type. This proportion increased significantly during the 21-year study period, by 0.96% annually (P = .002), as did comorbid conditions and acquisition outside of the hospital. Rates of any metastatic complication also significantly increased, by 0.94% annually (P = .019). Among the corresponding bloodstream S. aureus isolates, spa-CC012 (multi-locus sequence type [MLST] CC30), -CC004 (MLST CC45), -CC189 (MLST CC1), and -CC084 (MLST CC15) all significantly declined during the study period, while spa-CC008 (MLST CC8) significantly increased. Patients with SAB due to spa-CC008 were significantly more likely to develop metastatic complications in general, and abscesses, septic emboli, and persistent bacteremia in particular. After adjusting for demographic, racial, and clinical variables, the USA300 variant of spa-CC008 was independently associated with metastatic complications (odds ratio 1.42; 95% confidence interval 1.02-1.99). Conclusions: Systematic approaches for monitoring complications of SAB and genotyping the corresponding bloodstream isolates will help identify the emergence of hypervirulent clones and likely improve clinical management of this syndrome. View Show abstract Epidemiology and Outcome Determinants of Staphylococcus aureus Bacteremia Revisited: A Population-Based Study Article Full-text available Dec 2019 INFECTION John C. Lam Daniel Gregson Stephen Robinson Michael D. Parkins Purpose Staphylococcus aureus bacteremia (SAB) is associated with significant morbidity and mortality. We sought to re-define the burden, epidemiology and mortality-associated risk factors of SAB in a large Canadian health region. Methods Residents (> 18 years) experiencing SAB from 2012 to 2014 were assessed. Incidence rates were calculated using civic census results. Factors associated with 30-day mortality were determined through multivariate logistic regression. Incidence and risk factors for SAB were compared to 2000–2006 data. Results 780 residents experienced 840 episodes of SAB (MRSA; 20%). Incidence rates increased from 23.5 to 32.0 cases/100,000 from 2012 to 2014; [IRR 1.15 (95% CI 1.07–1.23); p < 0.001]. Compared to a decade ago, incidence of SAB has increased [IRR 1.28 (95% CI 1.21–1.36); p < 0.001] despite minimal change in nosocomial SAB. MRSA proportion did not change through the study (p = 0.3), but did increase relative to a decade ago (20.0% vs 11.0%, p < 0.001). Thirty-day mortality rates were 30.6% and 21.3% for MRSA and MSSA, respectively (p = 0.01), similar to rates from 2000 to 2006. Several clinical, demographic, and biochemical factors were independently associated with SAB mortality. Conclusions SAB is common within our population resulting in significant mortality. Incidence rates of SAB are increasing in our health region; however, 30-day mortality rates remain stable. View Show abstract Antimicrobial resistance trends in bloodstream infections at a large teaching hospital in China: A 20-year surveillance study (1998-2017) Article Full-text available May 2019 Lei Tian Zhen Zhang Ziyong Sun Background: Bacterial bloodstream infections (BSIs) cause high morbidity and mortality worldwide in humans, but the pathogenic spectrum varies from region to region. Long-term monitoring of the pathogenic spectrum and changes in bacterial antibiotic resistance is hugely important for effective clinical therapy and infection control. This study examined the data for BSIs in Tongji Hospital, one of the largest teaching hospitals in China, in an attempt to gain better understanding of bacterial antibiotic resistance in China, focusing on central China. Methods: Data from Tongji Hospital for a 20-year period (1998-2017) were used for a retrospective analysis to understand the pathogenic spectrum of BSIs and the changes occurring in antimicrobial resistance in central China. The disk diffusion and E test methods were used for antimicrobial susceptibility testing according to Clinical & Laboratory Standards Institute methodologies, and the data were analyzed by WHONET 5.6 software. Results: The isolated pathogens mainly came from hospitalized patients not treated in intensive care units (ICUs), and accounted for 81.5% of the total (9130/11200). The most common Gram-negative and Gram-positive bacterial BSI-causing pathogens were Escherichia coli and Staphylococcus aureus, respectively. The detection rate for methicillin-resistant S. aureus (MRSA) in the hospitalized non-ICU patients increased from 8.4% in 1998-2002 to 63% in 2013-2017, while the detection rate for carbapenem-resistant (CR) Klebsiella pneumoniae was below 5% in 1998-2012 but increased to 34.9% in 2013-2017. In contrast, worryingly, the detection rate for CR K. pneumoniae in ICU patients increased from 0% in 2013 to 75% in 2016. E. coli displayed the highest sensitivity rates to imipenem, meropenem and amikacin, all of which were > 90%, followed by cefoxitin at > 80%, and cefoperazone/sulbactam at > 70%. K. pneumoniae isolates were most sensitive to imipenem, meropenem and amikacin antibiotics, with sensitivity rates exceeding 60%. S. aureus isolates were most sensitive to vancomycin, teicoplanin and trimethoprim/sulfamethoxazole, with sensitivity rates exceeding 90%. Conclusions: BSIs caused by CR K. pneumoniae clearly posed a severe challenge to infection control and treatment of ICU and non-ICU patients in this retrospective study, while MRSA was an issue for non-ICU patients. View Show abstract Age-Dependent Increase in Incidence of Staphylococcus aureus Bacteremia, Denmark, 2008–2015 Article Full-text available May 2019 EMERG INFECT DIS Louise Thorlacius-Ussing Håkon Sandholdt Anders Rhod Larsen Thomas Benfield Staphylococcus aureus bacteremia (SAB) is a major cause of illness and death worldwide. We analyzed temporal trends of SAB incidence and death in Denmark during 2008-2015. SAB incidence increased 48%, from 20.76 to 30.37 per 100,000 person-years, during this period (p<0.001). The largest change in incidence was observed for persons >80 years of age: a 90% increase in the SAB rate (p<0.001). After adjusting for demographic changes, annual rates increased 4.0% (95% CI 3.0-5.0) for persons <80 years of age, 8.4% (95% CI 7.0-11.0) for persons 80-89 years of age, and 13.0% (95% CI 9.0-17.5) for persons >90 years of age. The 30-day case-fatality rate remained stable at 24%; crude population death rates increased by 53% during 2008-2015 (p<0.001). Specific causes and mechanisms for this rapid increase in SAB incidence among the elderly population remain to be clarified. View Show abstract The Microbiology of Bloodstream Infection: 20-Year Trends from the SENTRY Antimicrobial Surveillance Program Article Full-text available Apr 2019 Po-Ren Hsueh Rodrigo E Mendes Daniel Diekema Ronald Jones Bloodstream infection (BSI) organisms were consecutively collected from >200 medical centers in 45 nations between 1997 and 2016. Species identification and susceptibility testing followed Clinical and Laboratory Standards Institute broth microdilution methods at a central laboratory. Clinical data and isolates from 264,901 BSI episodes were collected. The most common pathogen overall was Staphylococcus aureus (20.7%), followed by Escherichia coli (20.5%), Klebsiella pneumoniae (7.7%), Pseudomonas aeruginosa (5.3%), and Enterococcus faecalis (5.2%). S. aureus was the most frequent pathogen overall in the 1997–2004 period, but E. coli was the most common after 2005. Pathogen frequency varied by geographic region, hospital-onset or community-onset status, and patient age. The prevalence of S. aureus resistant to oxacillin (MRSA) increased until 2005–08, then declined among hospital-onset and community-acquired BSI in all regions. The prevalence of vancomycin-resistant enterococci (VRE) was stable after 2012 (16.4% overall). Daptomycin resistance among S. aureus and enterococci (DRE) remained rare (<0.1%). In contrast, the prevalence of multidrug-resistant (MDR) Enterobacteriaceae increased from 6.2% in 1997–2000 to 15.8% in 2013–16. MDR rates were highest among non-fermentative Gram-negative bacilli (GNB), and colistin was the only agent with predictable activity against Acinetobacter baumannii-calcoaceticus complex (97% susceptible). In conclusion, S. aureus and E. coli were the predominant causes of BSI worldwide during this 20-year surveillance period. Important resistant phenotypes among Gram-positive pathogens (MRSA, VRE, or DRE) were stable or declining, whereas the prevalence of MDR-GNB increased continuously during the monitored period. MDR-GNB pose the greatest therapeutic challenge among common bacterial BSI pathogens. View Show abstract Shifting trends and age distribution of ESKAPEEc resistance in bloodstream infection, Southwest China, 2012–2017 Article Full-text available Mar 2019 Shuangshuang Yang Haofeng Xu Jide Sun Shan Sun Background ESKAPEEc contribute to a majority of bloodstream infections (BSIs) and their antibiogram have changed overtime, while data concerning about these alterations are lacking in China. Added that a paucity of studies referred to ESKAPEEc in pediatric BSIs, our study aimed to demonstrate the longitudinal alterations of ESKAPEEc distribution and antibiogram in adult and pediatric BSIs in Southwest China. Methods A multicenter retrospective surveillance study was launched from 2012 to 2017. Data of China Antimicrobial Resistance Surveillance System (CARSS) was analyzed by Whonet 5.6 and Graphpad Prism 6 Software. Chi-square test or Fisher’s exact test was used to examine and compare temporal changes. Results A total of 32,259 strains was isolated, with 17.4% from pediatric BSIs. ESKAPEEc contributed to 58.67% (18,924/32,259) of BSIs, with 65.3% of adult BSIs and 27.2% of pediatric BSIs. Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) were the two predominant species. Carbapenem resistance was prevalent in 0.76, 4.60, 9.47,13.66, 59.47% of E. coli, K. pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa (P. aeruginosa) and Acinetobacter baumannii (A. baumannii), respectively. The proportions of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREFM) were 28.91% and 2.20%, respectively. Between 2012-2014 and 2015–2017, E. coli and K. pneumonia showed significantly increased resistance rates to imipenem but decreased to ceftriaxone and ceftazidime, while A. baumannii exhibited reduced resistances to almost all the beta-lactams tested. The prevalence of antimicrobial resistance to most of agents against Gram-positive ESKAPEEc did not significantly varied during the same timeframe. In comparison with those from adult BSIs, K. pneumoniae from pediatric BSIs exhibited high resistance rates to all the beta-lactams tested, especially to carbapenems (12.79% vs 3.87%), while A. baumannii showed low resistance rates to all the agents. Conclusions Ongoing burden of ESKAPEEc in BSIs and increasing trend of imipenem resistance in E. coli and K. pneumoniae call for continued surveillance. Carbapenems are still active against Gram-negative ESKAPEEc, except for A. baumannii and vancomycin or linezolid is still effective against Gram-positive ESKAPEEc. Carbapenem-resistant K. pneumoniae in children and carbapenem-resistant A. baumannii in adults necessitate effective antimicrobial strategies in consideration of age stratification. View Show abstract A Cohort Study of the Impact of Carbapenem-Resistant Enterobacteriaceae Infections on Mortality of Patients Presenting with Sepsis Article Full-text available Apr 2019 Sabrina Sabino Silvia Soares Fabiano Ramos Maria Helena Rigatto The objective of this study is to evaluate the impact of carbapenemresistant Enterobacteriaceae (CRE) infection on sepsis 30-day mortality. A retrospective cohort of patients > 18 years old with sepsis and organ dysfunction or septic shock was conducted. Univariate analysis was done for variables potentially related to 30-day mortality, and the ones with P values of < 0.05 were included in a backward stepwise hierarchic Cox regression model. Variables that remained with P values of < 0.05 were retained in the model. A total of 1,190 sepsis episodes were analyzed. Gram-negative bacterial infections occurred in 391 (68.5%) of 571 patients with positive cultures, of which 69 (17.7%) were caused by a CRE organism. Patients with CRE infections had significantly higher 30-day mortality: 63.8% versus 33.4% (P < 0.01). CRE infection was also associated with a lower rate of appropriate empirical therapy (P < 0.01) and with the presence of septic shock (P < 0.01). In the hierarchic multivariate model, CRE remained significant when controlling for demographic variables, comorbidities, and infection site but lost significance when controlling for septic shock and appropriate empirical therapy. Older age (P < 0.01), HIV-positive status (P < 0.01), cirrhosis (P < 0.01), septic shock (P < 0.01), higher quick sepsisrelated organ failure assessment (quick-SOFA) (P < 0.01), and appropriate empirical therapy (P=0.01) remained in the final model. CRE infections were associated with higher crude mortality rates. A lower rate of appropriate empirical therapy and late diagnosis were more frequent in this group, and improvement of stewardship programs is needed. View Show abstract Moving beyond unsolicited consultation: additional impact of a structured intervention on mortality in Staphylococcus aureus bacteraemia Article Full-text available Apr 2019 María Teresa Pérez-Rodríguez Adrián Sousa Luis Eduardo López Cortés Jesús Rodríguez-Baño Background Some evidence-based bundles have tried to standardize the management of Staphylococcus aureus bacteraemia (SAB) to improve the outcome. The aim of our study was to analyse the additional impact on mortality of a structured intervention in patients with SAB. Methods Compliance with the bundle was evaluated in an ambispective cohort of patients with SAB, which included a retrospective cohort [including patients treated before and after the implementation of a bacteraemia programme (no-BP and BP, respectively)] and a prospective cohort (i-BP), in which an additional specific intervention for bundle application was implemented. Multivariate logistic regression was used to measure the influence of the independent variables including compliance with the bundle on 14 and 30 day crude mortality. Results A total of 271 adult patients with SAB were included. Mortality was significantly different among the three groups (no-BP, BP and i-BP): mortality at 14 days was 18% versus 7% versus 2%, respectively, P = 0.002; and mortality at 30 days was 20% versus 12% versus 5%, respectively, P = 0.011. The factors associated with 14 and 30 day mortality in multivariable analysis were heart failure (OR = 7.63 and OR = 2.27, respectively), MRSA infection (OR = 4.02 and OR = 4.37, respectively) and persistent bacteraemia (OR = 11.01 and OR = 7.83, respectively); protective factors were catheter-related bacteraemia (OR = 0.16 and OR = 0.19, respectively) and >75% bundle compliance (OR = 0.15 and OR = 0.199, respectively). Time required to perform the intervention and the follow-up was 50 min (IQR 40–55 min) per patient. Conclusions High-level compliance with a standardized bundle of intervention for management of SAB that requires little time was associated with lower mortality at 14 and 30 days. View Show abstract Increasing incidence of invasive nontyphoidal Salmonella infections in Queensland, Australia, 2007-2016 Article Full-text available Mar 2019 PLOS NEGLECT TROP D Andrea Parisi Russell J Stafford Martyn D Kirk John Crump Nontyphoidal Salmonella is a major contributor to the global burden of foodborne disease, with invasive infections contributing substantially to illnesses and deaths. We analyzed notifiable disease surveillance data for invasive nontyphoidal Salmonella disease (iNTS) in Queensland, Australia. We used Poisson regression to estimate incidence rate ratios by gender, age group, and geographical area over 2007-2016. There were 995 iNTS cases, with 945 (92%) confirmed by blood culture. Salmonella Virchow accounted for 254 (25%) of 1,001 unique iNTS isolates. Invasive NTS disease notification rates peaked among infants, during the summer months, and in outback Queensland where the notification rate (95% CI) was 17.3 (14.5-20.1) cases per 100,000 population. Overall, there was a 6,5% annual increase (p<0.001) in iNTS disease incidence. In conclusion, high iNTS rates among males, infants, and the elderly require investigation of household level risk factors for NTS infection. Controlling Salmonella Virchow infections is a public health priority. View Show abstract Prognostic Power of Pathogen Cell-Free DNA in Staphylococcus aureus Bacteremia Article Full-text available Mar 2019 Johnny Gutierrez Stacey A Maskarinec Alessander O Guimaraes Carrie M. Rosenberger Background Staphylococcus aureus is a leading global cause of bacteremia leading to invasive tissue infections with high morbidity and mortality despite appropriate antibiotic therapy. Clinicians lack sufficient tools to rapidly identify patients with a poor prognosis to guide diagnostic workup and treatment decisions. Host cell-free DNA provides valuable prognostic value across a spectrum of critical illnesses, including S. aureus bacteremia and sepsis. Metrics of high bacterial load are associated with disease severity in S. aureus bacteremia, and the objective of this study was to evaluate whether incorporating quantitation of cell-free bacterial DNA would provide additive prognostic value when combined with biomarkers of the inflammatory response. Methods S. aureus cell-free DNA was measured by quantitative PCR in baseline serum samples from an observational cohort of 111 patients with complicated S. aureus bacteremia and correlated with host inflammatory markers and clinical outcomes. Results High levels of S. aureus cell-free DNA at the time of positive index blood culture was prognostic for all-cause and attributable mortality, persistent bacteremia, and associated with infective endocarditis. However, it did not provide additive value to biomarkers of the host response to infection in multivariate analysis. Conclusions Measurements of bacterial load by PCR is a clinically feasible candidate biomarker for stratifying patients at higher risk for complications and poor outcomes. Its diagnostic and prognostic value for identifying foci of infection and influencing treatment remains to be evaluated in additional cohorts. View Show abstract Twenty-Year Trends in Antimicrobial Susceptibilities Among Staphylococcus aureus From the SENTRY Antimicrobial Surveillance Program Article Full-text available Mar 2019 Daniel Diekema Michael A. Pfaller Dee Shortridge Ronald Jones Background Staphylococcus aureus is among the most common human pathogens, with therapy complicated by the epidemic spread of methicillin-resistant Staphylococcus aureus (MRSA). Methods The SENTRY Antimicrobial Surveillance Program evaluated the in vitro activity of >20 antimicrobials against 191 460 clinical S. aureus isolates collected from 427 centers in 45 countries from 1997 to 2016. Each center contributed isolates and clinical data for consecutive episodes of bacteremia, pneumonia in hospitalized patients, urinary tract infection, and skin and skin structure infection. Results Overall, 191 460 S. aureus isolates were collected, of which 77 146 (40.3%) were MRSA, varying geographically from 26.8% MRSA in Europe to 47.0% in North America. The highest percentage of MRSA was in nosocomial isolates from patients aged >80 years. Overall, MRSA occurrences increased from 33.1% in 1997–2000 to a high of 44.2% in 2005–2008, then declined to 42.3% and 39.0% in 2009–2012 and 2013–2016, respectively. S. aureus bacteremia had a similar trend, with nosocomial and community-onset MRSA rates peaking in 2005–2008 and then declining. Vancomycin activity against S. aureus remained stable (minimum inhibitory concentration [MIC]90 of 1 mg/L and 100% susceptibility in 2016; no increase over time in isolates with a vancomycin MIC >1 mg/L). Several agents introduced during the surveillance period exhibited in vitro potency against MRSA. Conclusions In a large global surveillance program, the rise of MRSA as a proportion of all S. aureus peaked a decade ago and has declined since, consistent with some regional surveillance program reports. Vancomycin maintained high activity against S. aureus, and several newer agents exhibited excellent in vitro potencies. View Show abstract Epidemiology and Antimicrobial Susceptibility of Salmonella enterica Bloodstream Isolates Among Febrile Children in a Rural District in Northeastern Tanzania: A Cross-sectional Study Article Full-text available Mar 2019 Omari Abdul Msemo Joyce Mbwana Coline Mahende John P. A. Lusingu Background Salmonella enterica including Salmonella Typhi and nontyphoidal Salmonella (NTS) are the predominant cause of community-acquired bloodstream infections in sub-Saharan Africa (sSA). Multiple-drug resistance and emerging fluoroquinolone resistance are of concern. Data on the age distribution of typhoid fever in sSA are scarce but essential for typhoid conjugate vaccine policy. We sought to describe Salmonella bloodstream infections, antimicrobial resistance, and age distribution at a rural district hospital in northeastern Tanzania. Methods From 2008 to 2016, febrile children or children with a history of fever aged 1 month to 5 years admitted to Korogwe District Hospital were enrolled. Demographic, clinical data and blood cultures were collected. Organisms were identified by conventional microbiological methods, and antimicrobial susceptibility test was done by disc diffusion. Results Of 4176 participants receiving blood cultures, 383 (9.2 %) yielded pathogens. Of pathogens, 171 (44.6%) were Salmonella enterica of which 129 (75.4%) were Salmonella Typhi, and 42 (24.6%) were NTS. The median (interquartile range age of participants was 13.1 (6.3–28.0) months for those with Salmonella Typhi and 11.5 (8.5–23.4) months for NTS. Of 129 Salmonella Typhi, 89 (89.9%) were resistant to amoxicillin, 85 (81.0%) to chloramphenicol, and 93 (92.1%) to trimethoprim-sulfamethoxazole compared with 22 (62.9%), 15 (39.4%), and 27 (79.4%), respectively, for NTS. Multidrug resistance was present in 68 (81.0%) of Salmonella Typhi and 12 (41.4%) of NTS. Conclusion Salmonella Typhi was the leading cause of bloodstream infection among infants and young children <2 years of age admitted to Korogwe District Hospital. Multidrug resistance was common, highlighting a role for typhoid conjugate vaccine into routine infant vaccine schedules. View Show abstract Global Typhoid Fever Incidence: A Systematic Review and Meta-analysis Article Full-text available Mar 2019 CLIN INFECT DIS Christian S. Marchello Chuen Yen Hong John Crump Background: Contemporary incidence estimates of typhoid fever are needed to guide policy decisions and control measures and to improve future epidemiological studies. Methods: We systematically reviewed 3 databases (Ovid Medline, PubMed, and Scopus) without restriction on age, country, language, or time for studies reporting the incidence of blood culture-confirmed typhoid fever. Outbreak, travel-associated, and passive government surveillance reports were excluded. We performed a meta-analysis using a random-effects model to calculate estimates of pooled incidence, stratifying by studies that reported the incidence of typhoid fever and those that estimated incidence by using multipliers. Results: Thirty-three studies were included in the analysis. There were 26 study sites from 16 countries reporting typhoid cases from population-based incidence studies, and 17 sites in 9 countries used multipliers to account for underascertainment in sentinel surveillance data. We identified Africa and Asia as regions with studies showing high typhoid incidence while noting considerable variation of typhoid incidence in time and place, including in consecutive years at the same location. Overall, more recent studies reported lower typhoid incidence compared to years prior to 2000. We identified variation in the criteria for collecting a blood culture, and among multiplier studies we identified a lack of a standardization for the types of multipliers being used to estimate incidence. Conclusions: Typhoid fever incidence remains high at many sites. Additional and more accurate typhoid incidence studies are needed to support country decisions about typhoid conjugate vaccine adoption. Standardization of multiplier types applied in multiplier studies is recommended. View Show abstract Salmonella Typhi From Blood Cultures in the Democratic Republic of the Congo: A 10-Year Surveillance Article Full-text available Mar 2019 CLIN INFECT DIS Bieke Tack Marie-France Phoba Sandra Van Puyvelde Jan Jacobs Background: This study gives an overview of a decade (2007-2017) of hospital-based Salmonella Typhi bloodstream infection (BSI) surveillance in the Democratic Republic of the Congo (DRC), at 4 main sampling sites. Methods: Blood cultures were sampled in hospital-admitted patients with suspected BSI, according to standardized clinical indications. The results of the surveillance period 2015-2017 were compiled with those of previous surveillance periods (2007-2010 and 2011-2014). Whole genome sequencing of isolates with decreased ciprofloxacin susceptibility (DCS) was performed. Results: Salmonella Typhi was isolated in 1.4% (531/37 388) and 10.3% (531/5177) of suspected and culture-confirmed BSI episodes, respectively. Salmonella Typhi ranked first among the BSI pathogens in adults (n = 220), but was mostly (n = 301 [56.7%]) isolated from children, of which 72.1% (217/301) and 31.6% (95/301) were <10 years and <5 years old, respectively. Multidrug resistance (MDR), DCS, and combined MDR/DCS were found in 38.3% (n = 180), 24.5% (n = 115), and 11.9% (n = 56) of 470 first isolates, respectively. MDR and DCS rates had increased since 2007, but remained stable during 2015-2017 with no geographical clustering at the province level. Most (91/93 [97.8%]) DCS isolates sequenced belonged to Genotyphi genotype 2.5.1, and gyr S83 was the most frequent DCS mutation (76/93 [81.7%]). Infections occurred perennially, but increased during the rainy season. Conclusions: Salmonella Typhi was a frequent cause of BSI in adults and children in DRC, with high rates of antibiotic resistance. Sustainable surveillance and implementation of vaccination are compelling. View Show abstract Vital Signs : Trends in Staphylococcus aureus Infections in Veterans Affairs Medical Centers — United States, 2005–2017 Article Full-text available Mar 2019 Makoto Jones John A Jernigan Martin Evans Matthew Samore Introduction: By 2007, all Department of Veterans Affairs medical centers (VAMCs) had initiated a multifaceted methicillin-resistant Staphylococcus aureus (MRSA) prevention program. MRSA and methicillin-susceptible S. aureus (MSSA) infection rates among VAMC inpatients from 2005 to 2017 were assessed. Methods: Clinical microbiology data from any patient admitted to an acute-care VAMC in the United States from 2005 through 2017 and trends in hospital-acquired MRSA colonization were examined. Results: S. aureus infections decreased by 43% overall during the study period (p<0.001), driven primarily by decreases in MRSA, which decreased by 55% (p<0.001), whereas MSSA decreased by 12% (p = 0.003). Hospital-onset MRSA and MSSA infections decreased by 66% (p<0.001) and 19% (p = 0.02), respectively. Community-onset MRSA infections decreased by 41% (p<0.001), whereas MSSA infections showed no significant decline. Acquisition of MRSA colonization decreased 78% during 2008-2017 (17% annually, p<0.001). MRSA infection rates declined more sharply among patients who had negative admission surveillance MRSA screening tests (annual 9.7% decline) compared with those among patients with positive admission MRSA screening tests (4.2%) (p<0.05). Conclusions and implications for public health practice: Significant reductions in S. aureus infection following the VAMC intervention were led primarily by decreases in MRSA. Moreover, MRSA infection declines were much larger among patients not carrying MRSA at the time of admission than among those who were. Taken together, these results suggest that decreased MRSA transmission played a substantial role in reducing overall S. aureus infections at VAMCs. Recent calls to withdraw infection control interventions designed to prevent MRSA transmission might be premature and inadvisable, at least until more is known about effective control of bacterial pathogen transmission in health care settings. Effective S. aureus prevention strategies require a multifaceted approach that includes adherence to current CDC recommendations for preventing not only device- and procedure-associated infections, but also transmission of health care-prevalent strains. View Show abstract Vital Signs: Epidemiology and Recent Trends in Methicillin-Resistant and in Methicillin-Susceptible Staphylococcus aureus Bloodstream Infections — United States Article Full-text available Mar 2019 Athena Kourtis Kelly M Hatfield James Baggs Denise Cardo Introduction: Staphylococcus aureus is one of the most common pathogens in health care facilities and in the community, and can cause invasive infections, sepsis, and death. Despite progress in preventing methicillin-resistant S. aureus (MRSA) infections in health care settings, assessment of the problem in both health care and community settings is needed. Further, the epidemiology of methicillin-susceptible S. aureus (MSSA) infections is not well described at the national level. Methods: Data from the Emerging Infections Program (EIP) MRSA population surveillance (2005-2016) and from the Premier and Cerner Electronic Health Record databases (2012-2017) were analyzed to describe trends in incidence of hospital-onset and community-onset MRSA and MSSA bloodstream infections and to estimate the overall incidence of S. aureus bloodstream infections in the United States and associated in-hospital mortality. Results: In 2017, an estimated 119,247 S. aureus bloodstream infections with 19,832 associated deaths occurred. During 2005-2012 rates of hospital-onset MRSA bloodstream infection decreased by 17.1% annually, but the decline slowed during 2013-2016. Community-onset MRSA declined less markedly (6.9% annually during 2005-2016), mostly related to declines in health care-associated infections. Hospital-onset MSSA has not significantly changed (p = 0.11), and community-onset MSSA infections have slightly increased (3.9% per year, p<0.0001) from 2012 to 2017. Conclusions and implications for public health practice: Despite reductions in incidence of MRSA bloodstream infections since 2005, S. aureus infections account for significant morbidity and mortality in the United States. To reduce the incidence of these infections further, health care facilities should take steps to fully implement CDC recommendations for prevention of device- and procedure-associated infections and for interruption of transmission. New and novel prevention strategies are also needed. View Show abstract The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017 Article Full-text available Feb 2019 LANCET INFECT DIS Jeffrey D Stanaway Robert Charles Reiner Brigette F Blacker Simon Iain Hay Background: Efforts to quantify the global burden of enteric fever are valuable for understanding the health lost and the large-scale spatial distribution of the disease. We present the estimates of typhoid and paratyphoid fever burden from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, and the approach taken to produce them. Methods: For this systematic analysis we broke down the relative contributions of typhoid and paratyphoid fevers by country, year, and age, and analysed trends in incidence and mortality. We modelled the combined incidence of typhoid and paratyphoid fevers and split these total cases proportionally between typhoid and paratyphoid fevers using aetiological proportion models. We estimated deaths using vital registration data for countries with sufficiently high data completeness and using a natural history approach for other locations. We also estimated disability-adjusted life-years (DALYs) for typhoid and paratyphoid fevers. Findings: Globally, 14·3 million (95% uncertainty interval [UI] 12·5-16·3) cases of typhoid and paratyphoid fevers occurred in 2017, a 44·6% (42·2-47·0) decline from 25·9 million (22·0-29·9) in 1990. Age-standardised incidence rates declined by 54·9% (53·4-56·5), from 439·2 (376·7-507·7) per 100 000 person-years in 1990, to 197·8 (172·0-226·2) per 100 000 person-years in 2017. In 2017, Salmonella enterica serotype Typhi caused 76·3% (71·8-80·5) of cases of enteric fever. We estimated a global case fatality of 0·95% (0·54-1·53) in 2017, with higher case fatality estimates among children and older adults, and among those living in lower-income countries. We therefore estimated 135·9 thousand (76·9-218·9) deaths from typhoid and paratyphoid fever globally in 2017, a 41·0% (33·6-48·3) decline from 230·5 thousand (131·2-372·6) in 1990. Overall, typhoid and paratyphoid fevers were responsible for 9·8 million (5·6-15·8) DALYs in 2017, down 43·0% (35·5-50·6) from 17·2 million (9·9-27·8) DALYs in 1990. Interpretation: Despite notable progress, typhoid and paratyphoid fevers remain major causes of disability and death, with billions of people likely to be exposed to the pathogens. Although improvements in water and sanitation remain essential, increased vaccine use (including with typhoid conjugate vaccines that are effective in infants and young children and protective for longer periods) and improved data and surveillance to inform vaccine rollout are likely to drive the greatest improvements in the global burden of the disease. Funding: Bill & Melinda Gates Foundation. View Show abstract Risk Factors for Elizabethkingia Acquisition and Clinical Characteristics of Patients, South Korea Article Full-text available Jan 2019 EMERG INFECT DIS Min Hyuk Choi Myungsook Kim Sujin Jeong Kwang jo Lee Elizabethkingia infections are difficult to treat because of intrinsic antimicrobial resistance, and their incidence has recently increased. We conducted a propensity score-matched case-control study during January 2016-June 2017 in South Korea and retrospectively studied data from patients who were culture positive for Elizabethkingia species during January 2009-June 2017. Furthermore, we conducted epidemiologic studies of the hospital environment and mosquitoes. The incidence of Elizabethkingia increased significantly, by 432.1%, for 2016-2017 over incidence for 2009-2015. Mechanical ventilation was associated with the acquisition of Elizabethkingia species. Because Elizabethkingia infection has a high case-fatality rate and is difficult to eliminate, intensive prevention of contamination is needed. View Show abstract Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis Article Full-text available Nov 2018 LANCET INFECT DIS Alessandro Cassini Liselotte Diaz Högberg Diamantis Plachouras Susan Hopkins Background Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). Methods We estimated the incidence of infections with 16 antibiotic resistance–bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011–12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. Findings From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148–763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480–38 430) attributable deaths and 874 541 (768 837–989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. Interpretation Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases. View Show abstract Management and outcome of bloodstream infections: a prospective survey in 121 French hospitals (SPA-BACT survey) Article Full-text available Aug 2018 Olivier Robineau Jerome Robert C. Rabaud Serge Alfandari Background Bloodstream infections (BSIs) are severe infections that can be community or hospital acquired. Effects of time to appropriate treatment and impact of antimicrobial management team are discussed in terms of outcome of BSI. We sought to evaluate the impact of initial BSI management on short-term mortality. Patients and methods A prospective, multicenter survey was conducted in 121 French hospitals. Participants declaring BSI during a 1-month period were included consecutively. Data on patient comorbidities, illness severity, BSI management, and resistance profile of bacterial strains were collected. Predictors of 10-day mortality were identified by multivariate regression for overall BSI, health care-related and hospital-acquired BSI. Results We included 1,952 BSIs. More than a third of them were hospital acquired (39%). Multidrug resistance was identified in 10% of cases, mainly in health care-related BSI. Empirical therapy and targeted therapy were appropriate for 61% and 94% of cases, respectively. Increased 10-day mortality was associated with severe sepsis, septic shock, increasing age, and any focus other than the urinary tract. Decreased mortality was associated with receiving at least one active antibiotic within the first 48 hours. Intervention of antimicrobial management team during the acute phase of BSI was associated with a decreased mortality at day 10 in the overall population and in health care-related BSI. Conclusion Optimizing BSI management by increasing rapidity of appropriate treatment initiation may decrease short-term mortality, even in countries with low rate of multidrug-resistant organisms. Early intervention of antimicrobial management team is crucial in terms of mortality. View Show abstract Treatment options and clinical outcomes for carbapenem-resistant Enterobacteriaceae bloodstream infection in a Chinese university hospital Article Full-text available Aug 2018 Chen Li Yi Li Zhichang Zhao Bin Li Background: Carbapenem resistant Enterobacteriaceae (CRE) has become a serious public health problem. Limited information is available about the treatment options that physicians used to fight CRE infections and related clinical outcomes in China. The aim of the present study was to explore the treatment options and clinical outcomes of patients with CRE bloodstream infection (BSI) in a Chinese teaching hospital. Methods: A retrospective study was conducted during 2011 to 2015 in one Chinese teaching hospital. Demographic, microbiological and clinical characteristics of enrolled subjects were collected from medical records. Data were analyzed by Kaplan-Meier graphs, log-rank test, and Cox regression. Results: A total of 98 inpatients with CRE BSI were enrolled in this study. For empirical therapy, 26 patients (26.5%) received at least one active drug within 48h after the onset of bacteremia. For definitive treatment, 59.2% (49/82) patients received at least one active drug and 40.2% (33/82) patients received therapy with no active drug. The overall 30-day mortality was 53.1% (52/98). Adverse outcome appeared to be more likely among patients with previous carbapenem exposure, neutropenia, severity of septic and time to initiation of BSIs. There was no significant difference in the mortality between the two groups of patients with combination therapy versus monotherapy (p=0.105). Severity of sepsis and neutropenia were identified as independent predictors of mortality. Conclusions: Our study demonstrated a high mortality associated with CRE BSI and a high percentage of inappropriate empirical treatment for CRE BSI patients in a Chinese teaching hospital. Particular attention should be given to the patients with CRE BSI. View Show abstract Incidence and antimicrobial resistance trends in bloodstream infections caused by ESKAPE and Escherichia coli at a large teaching hospital in Rome, a 9-year analysis (2007–2015) Article Full-text available Sep 2018 EUR J CLIN MICROBIOL Giulia De Angelis Barbara Fiori Giulia Menchinelli Teresa Spanu The proportion of antimicrobial resistance (AMR) among the ESKAPE and Escherichia coli (ESKAPEEc) pathogens causing bloodstream infection (BSI) increased worldwide. We described longitudinal trends in ESKAPEEc BSI and AMR over 9 years (2007–2015) at a large teaching hospital in Italy. Of 9720 unique BSI episodes, 6002 (61.7%) were caused by ESKAPEEc pathogens. The majority of these episodes (4374; 72.9%) were hospital-onset infections. The most frequent pathogen was E. coli (32.8%), followed by Staphylococcus aureus (20.6%), Klebsiella pneumoniae (16.1%), and Pseudomonas aeruginosa (11.6%). There was a significant increase of hospital-onset K. pneumoniae (from 2.3 to 5.0 per 10,000 patient-days; P = 0.001) and community-onset E. coli (from 3.3 to 9. 1 per 10,000 emergency admissions; P = 0.04) BSIs. Among hospital-onset BSIs, increases of extended-spectrum β-lactamase (ESBL)-producing E. coli (from 25.4 to 35.2%, P = 0.006), carbapenemase-producing K. pneumoniae (from 4.2 to 51.6%, P < 0.001), and methicillin-resistant S. aureus (from 33.9 to 44.4%, P < 0.001) BSIs were observed between the 2007–2009 and 2010–2012 study periods. In contrast, a decrease of BSIs caused by P. aeruginosa resistant to ceftazidime (from 45.5 to 28.2%, P < 0.001), ciprofloxacin (from 46 to 36.3%, P = 0.05), and meropenem (from 55 to 39.9%, P = 0.03) was observed through all 9 years of the study period. Among community-onset BSIs, increases of BSIs caused by ESBL-producing E. coli (from 28.6 to 42.2%, P = 0.002) and carbapenemase-producing K. pneumoniae (from 0 to 17.6%) were observed between the 2007–2009 and 2010–2012 study periods. Our findings show increased rates of BSI and relative AMR for specific pathogen-health care setting combinations, and call for continued active surveillance and infection control policies. View Show abstract National Costs Associated with Methicillin-susceptible and Methicillin-resistant S. aureus Hospitalizations in the United States, 2010-2014 Article Full-text available May 2018 CLIN INFECT DIS Eili Y Klein Wendi Jiang Nestor Mojica Trish M Perl Background: Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have been associated with worse patient outcomes and higher costs of care than susceptible (MSSA) infections. However, the healthcare landscape has changed since prior studies found these differences, including widespread dissemination of community-associated strains of MRSA. Our objective was to provide updated estimates of the excess costs of resistant S. aureus infections. Methods: We conducted a retrospective analysis using data from the National Inpatient Sample from the Agency for Healthcare Research and Quality for the years 2010 to 2014. We calculated costs for hospitalizations including MRSA- and MSSA-related septicemia and pneumonia infections, as well as MRSA- and MSSA-related infections from conditions classified elsewhere and of an unspecified site ("other infections"). Differences in the costs of hospitalization were estimated using propensity score adjusted mortality outcomes for 2010 through 2014. Results: In 2014, estimated costs were highest for pneumonia and sepsis-related hospitalizations. Propensity score-adjusted costs were significantly higher for MSSA-related pneumonia ($40,725 vs $38,561; p=0.045) and other hospitalizations ($15,578 vs $14,792; p<0.001) than for MRSA-related hospitalizations. Similar patterns were observed from 2010 to 2013, though crude cost differences between MSSA- and MRSA-related pneumonia hospitalizations rose from 25.8% in 2010 to 31.0% in 2014. MRSA-related hospitalizations had a higher adjusted mortality rate than MSSA-related hospitalizations. Conclusions: Though MRSA infections had been previously associated with higher hospitalization costs, our results suggest that in recent years, costs associated with MSSA-related infections have converged with and may surpass costs of similar MRSA-related hospitalizations. View Show abstract Staphylococcus aureus Bacteremia Incidence and Methicillin Resistance in Rural Thailand, 2006–2014 Article Full-text available May 2018 Julia Rhodes Toni Whistler Ornuma Sangwichian Henry C. Baggett Staphylococcus aureus is a common cause of bloodstream infection and methicillin-resistant S. aureus (MRSA) is a growing threat worldwide. We evaluated the incidence rate of S. aureus bacteremia (SAB) and MRSA from population-based surveillance in all hospitals from two Thai provinces. Infections were classified as community-onset (CO) when blood cultures were obtained ≤ 2 days after hospital admission and as hospital-onset (HO) thereafter. The incidence rate of HO-SAB could only be calculated for 2009-2014 when hospitalization denominator data were available. Among 147,524 blood cultures, 919 SAB cases were identified. Community-onset S. aureus bacteremia incidence rate doubled from 4.4 (95% confidence interval [CI]: 3.3-5.8) in 2006 to 9.3 per 100,000 persons per year (95% CI: 7.6-11.2) in 2014. The highest CO-SAB incidence rate was among adults aged 50 years and older. Children less than 5 years old had the next highest incidence rate, with most cases occurring among neonates. During 2009-2014, there were 89 HO-SAB cases at a rate of 0.13 per 1,000 hospitalizations per year (95% CI: 0.10-0.16). Overall, MRSA prevalence among SAB cases was 10% (90/911) and constituted 7% (55/736) of CO-SAB and 20% (22/111) of HO-SAB without a clear temporal trend in incidence rate. In conclusion, CO-SAB incidence rate has increased, whereas MRSA incidence rate remained stable. The increasing CO-SAB incidence rate, especially the burden on older adults and neonates, underscores the importance of strong SAB surveillance to identify and respond to changes in bacteremia trends and antimicrobial resistance. View Show abstract Current and future burden of venous thrombosis: Not simply predictable Article Full-text available Apr 2018 Luuk Scheres Willem M. Lijfering Suzanne C. Cannegieter Essentials • The incidence of venous thrombosis has remained stable over the past decade. • Risk factors and diagnostic and prophylaxis strategies are determinants of the overall incidence. • Given current trends of the determinants, we are making progress in reducing the burden. • More progress can be made by implementing validated risk assessment models. Venous thrombosis is a major contributor to the global disease burden. In this review we aim to answer two important questions: (1) are we making progress in reducing this disease burden and (2) how can we further improve? To answer these questions, we first evaluated the disease burden, that is, the incidence of first venous thrombosis over the past decade(s) and discuss its most important determinants. We found that the incidence of first venous thrombosis remained relatively unchanged, despite an increase in risk factor prevalence and a rise in identification of subsegmental pulmonary emboli due to enhanced image quality and utilization. This is, however, balanced by improved thromboprophylaxis strategies, resulting in an overall unchanged venous thrombosis incidence. We can further improve by developing, validating, and implementing risk assessment strategies, allowing us to identify persons at high or low risk in whom thromboprophylaxis can be provided or withheld, respectively. View Show abstract Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study Article Full-text available Dec 2017 PLOS NEGLECT TROP D Calman Maclennan Chisomo L Msefula Esther N. Gondwe Stephen M Graham Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0-15 years) and 52/256 children (20%; 95%CI 15-25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71-82%), 123/240 (51%; 95%CI 45-58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36-49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8-35.1), dyspnea (OR 4.2; 95%CI 1.5-12.0) and HIV infection (OR 3.3; 95%CI 1.1-10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children. View Show abstract Elizabethkingia in Children: A Comprehensive Review of Symptomatic Cases Reported from 1944–2017 Article Full-text available Dec 2017 CLIN INFECT DIS Eric J. Dziuban Jessica L Franks Marvin So David D Blaney Elizabethkingia species often exhibit extensive antibiotic resistance and result in high morbidity and mortality, yet no systematic reviews exist that thoroughly characterize and quantify concerns for infected infants and children. We performed a review of literature and identified an initial 902 articles; 96 articles reporting 283 pediatric cases met our inclusion criteria and were subsequently reviewed. Case reports spanned 28 countries and ranged from 1944 to 2017. Neonatal meningitis remains the most common presentation of this organism in children, along with a range of other clinical manifestations. The majority of reported cases occurred as isolated cases, rather than within outbreaks. Mortality was high but has decreased in recent years, although neurologic sequelae among survivors remains concerning. Child outcomes can be improved through effective prevention measures and early identification and treatment of infected patients. View Show abstract Temporal trends and patterns in heart failure incidence: A population-based study of 4 million individuals Article Full-text available Nov 2017 Nathalie Conrad Andrew Judge Jenny Tran Kazem Rahimi Background: Large-scale and contemporary population-based studies of heart failure incidence are needed to inform resource planning and research prioritisation but current evidence is scarce. We aimed to assess temporal trends in incidence and prevalence of heart failure in a large general population cohort from the UK, between 2002 and 2014. Methods: For this population-based study, we used linked primary and secondary electronic health records of 4 million individuals from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex. Eligible patients were aged 16 years and older, had contributed data between Jan 1, 2002, and Dec 31, 2014, had an acceptable record according to CPRD quality control, were approved for CPRD and Hospital Episodes Statistics linkage, and were registered with their general practice for at least 12 months. For patients with incident heart failure, we extracted the most recent measurement of baseline characteristics (within 2 years of diagnosis) from electronic health records, as well as information about comorbidities, socioeconomic status, ethnicity, and region. We calculated standardised rates by applying direct age and sex standardisation to the 2013 European Standard Population, and we inferred crude rates by applying year-specific, age-specific, and sex-specific incidence to UK census mid-year population estimates. We assumed no heart failure for patients aged 15 years or younger and report total incidence and prevalence for all ages (>0 years). Findings: From 2002 to 2014, heart failure incidence (standardised by age and sex) decreased, similarly for men and women, by 7% (from 358 to 332 per 100 000 person-years; adjusted incidence ratio 0·93, 95% CI 0·91-0·94). However, the estimated absolute number of individuals with newly diagnosed heart failure in the UK increased by 12% (from 170 727 in 2002 to 190 798 in 2014), largely due to an increase in population size and age. The estimated absolute number of prevalent heart failure cases in the UK increased even more, by 23% (from 750 127 to 920 616). Over the study period, patient age and multi-morbidity at first presentation of heart failure increased (mean age 76·5 years [SD 12·0] to 77·0 years [12·9], adjusted difference 0·79 years, 95% CI 0·37-1·20; mean number of comorbidities 3·4 [SD 1·9] vs 5·4 [2·5]; adjusted difference 2·0, 95% CI 1·9-2·1). Socioeconomically deprived individuals were more likely to develop heart failure than were affluent individuals (incidence rate ratio 1·61, 95% CI 1·58-1·64), and did so earlier in life than those from the most affluent group (adjusted difference -3·51 years, 95% CI -3·77 to -3·25). From 2002 to 2014, the socioeconomic gradient in age at first presentation with heart failure widened. Socioeconomically deprived individuals also had more comorbidities, despite their younger age. Interpretation: Despite a moderate decline in standardised incidence of heart failure, the burden of heart failure in the UK is increasing, and is now similar to the four most common causes of cancer combined. The observed socioeconomic disparities in disease incidence and age at onset within the same nation point to a potentially preventable nature of heart failure that still needs to be tackled. Funding: British Heart Foundation and National Institute for Health Research. View Show abstract Methicillin-susceptible and Methicillin-resistant Staphylococcus aureus Bacteremia: Nationwide Estimates of 30-Day Readmission, In-hospital Mortality, Length of Stay, and Cost in the United States Article Nov 2019 CLIN INFECT DIS Kengo Inagaki Jose Lucar Chad Blackshear Charlotte V Hobbs Background: Information on outcomes of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) bacteremia, particularly readmission, is scarce and requires further research to inform optimal patient care. Methods: We performed a retrospective analysis using the 2014 Nationwide Readmissions Database, capturing 49.3% of US hospitalizations. We identified MSSA and MRSA bacteremia using International Classification of Diseases, Ninth Revision, Clinical Modification among patients aged ≥18 years. Thirty-day readmission, mortality, length of stay, and costs were assessed using Cox proportional hazards regression, logistic regression, Poisson regression, and generalized linear model with gamma distribution and log link, respectively. Results: Of 92 089 (standard error [SE], 1905) patients with S. aureus bacteremia, 48.5% (SE, 0.4%) had MRSA bacteremia. Thirty-day readmission rate was 22% (SE, 0.3) overall with no difference between MRSA and MSSA, but MRSA bacteremia had more readmission for bacteremia recurrence (hazard ratio, 1.17 [95% confidence interval {CI}, 1.02-1.34]), higher in-hospital mortality (odds ratio, 1.15 [95% CI, 1.07-1.23]), and longer hospitalization (incidence rate ratio, 1.09 [95% CI, 1.06-1.11]). Readmission with bacteremia recurrence was particularly more common among patients with endocarditis, immunocompromising comorbidities, and drug abuse. The cost of readmission was $12 425 (SE, $174) per case overall, and $19 186 (SE, $623) in those with bacteremia recurrence. Conclusions: Thirty-day readmission after S. aureus bacteremia is common and costly. MRSA bacteremia is associated with readmission for bacteremia recurrence, increased mortality, and longer hospitalization. Efforts should continue to optimize patient care, particularly for those with risk factors, to decrease readmission and associated morbidity and mortality in patients with S. aureus bacteremia. View Show abstract Bloodstream Infections Caused By Klebsiella Pneumoniae in Onco-Hematological Patients: Incidence and Clinical Impact of Carbapenem Resistance in a Multicentre Prospective Survey Article Dec 2015 Enrico MARIA Trecarichi Mario Tumbarello Roberta Di Blasi Livio Pagano INTRODUCTION. Resistance to carbapenems by Klebsiella pneumoniae (KP) isolates has become a significant problem in recent years in several countries, and has been recently highlighted as one of the major emerging causes of severe and fatal infections in patients suffering from hematological malignancies (HM). The aim of the present study was to identify risk factors for mortality in HM patients with concurrent bloodstream infections (BSIs) caused by KP. Particular attention was focused on defining the impact of carbapenem resistance by the bacterial isolates on mortality. METHODS. We conducted a prospective cohort study including all consecutive cases of BSIs caused by KP diagnosed in 13 Italian hematological units participating to HEMABIS registry-SEIFEM group. The outcome measured was death within 30 days of the first positive blood culture. Survivor and non-survivor subgroups were compared, and logistic regression analysis was conducted to identify independent predictors of mortality. RESULTS. A total of 278 episodes of KP BSI were included in the study between January 2010 and June 2014. One hundred-sixty-one (57.9%) KP isolates were carbapenem resistant (CRKP). The rate of carbapenem resistance among KP isolates significantly increased from 21.4% in 2010 to 75.9% in 2013 (P<0.001), and it was 61.1% during the first six months of 2014. The overall 30-day mortality rate was 36.3% (101/278); however, it was significantly higher for patients with CRKP BSI (84/161, 52.2%) than for those with BSI caused by carbapenem susceptible KP (CSKP) (17/117, 14.5%; P<0.001). Compared to patients with CSKP BSI, those with CRKP BSI more likely were older, had an indwelling peripherally inserted central catheters (PICCs), suffered from acute myeloid leukemia, had previous CRKP culture-positive surveillance swabs, and received antibiotic prophylaxis, in particular with fluoroquinolones. On the other hand, patients who had indwelling centrally inserted (both short- and long-term) venous catheters (CVCs) and those who suffered from non Hodgkin's lymphoma and/or underwent hematopoietic stem cell transplantation, had more likely a BSI episode caused by CSKP. In multivariate analysis, significant predictors of mortality were septic shock (OR 17.34, 95% CI 6.65-45.23; P<0.001), acute respiratory failure (OR 6.65, 95% CI 2.89-15.31; P<0.001), altered state of consciousness (OR 6.01, 95% CI 1.86-19.45; P=0.003), carbapenem resistance by KP isolate (OR 4.21, 95% CI 1.87-9.47; P=0.001), corticosteroid therapy (OR 2.35, 95% CI 1.09-5.07; P=0.02), and older age (OR 1.02, 95% CI 1.01-1.04; P=0.03). CONCLUSIONS. Carbapenem resistance has dramatically emerged during the last years as the most frequent and fatal cause of BSI among KP isolates in HM patients in Italy. Although further studies to better define epidemiology and clinical impact of these infections are needed, the efficacy of therapeutic treatment protocols for HM patients could be probably improved through the sound knowledge of the local distribution of KP isolates and their susceptibility patterns and judicious use of antibiotics and control measures to prevent the development and spread of CRKP. Disclosures No relevant conflicts of interest to declare. View Show abstract Survival following Staphylococcus aureus bloodstream infection; a prospective multinational cohort study assessing the impact of place of care Article Dec 2018 J INFECTION H Siefert Kate Nambiar Siegbert Rieg Achim J. Kaasch BACKGROUND: Staphylococcus aureus bloodstream infection (SAB) is a common, life-threatening infection with a high mortality. Survival can be improved by implementing quality of care bundles in hospitals. We previously observed marked differences in mortality between hospitals and now assessed whether mortality could serve as a valid and easy to implement quality of care outcome measure. METHODS: We conducted a prospective observational study between January 2013 and April 2015 on consecutive, adult patients with SAB from 11 tertiary care centers in Germany, South Korea, Spain, Taiwan, and the United Kingdom. Factors associated with mortality at 90 days were analyzed by Cox proportional hazards regression and flexible parametric models. RESULTS: 1851 patients with a median age of 66 years (64% male) were analyzed. Crude 90-day mortality differed significantly between hospitals (range 23–39%). Significant variation between centers was observed for methicillin-resistant S. aureus, community-acquisition, infective foci, as well as measures of comorbidities, and severity of disease. In multivariable analysis, factors independently associated with mortality at 90 days were age, nosocomial acquisition, unknown infective focus, pneumonia, Charlson comorbidity index, SOFA score, and study center. The risk of death varied over time differently for each infective focus. Crude mortality differed markedly from adjusted mortality. DISCUSSION: We observed significant differences in adjusted mortality between hospitals, suggesting differences in quality of care. However, mortality is strongly influenced by patient mix and thus, crude mortality is not a suitable quality indicator. View Show abstract Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae: Update on Molecular Epidemiology and Treatment Options Article Aug 2019 DRUGS Gisele Peirano Johann D D Pitout Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are a major global public health concern. Presently, Escherichia coli with CTX-Ms are the most common species associated with global ESBLs; CTX-M-15 is the most frequent CTX-M worldwide and is followed by CTX-M-14, which is often found in South-East Asia. Recent surveillance studies showed that CTX-M-27 is emerging in certain parts of the world especially in Japan and Europe. The population structure of ESBL-producing E. coli is dominated globally by an high-risk clone named ST131. Escherichia coli ST131 belongs to three clades (A, B, and C) and three different subclades (C1, C1-M27, and C2). Clade C1-M27 is associated with blaCTX-M-27, and C2 with blaCTX-M-15. Recent whole genome sequencing studies have shown that clade C has evolved from clade B in a stepwise fashion, resulting in one of the most influential global antimicrobial resistance clones that has emerged during the 2000’s. Other important E. coli clones that have been detected among ESBL producers include ST405, ST38, ST648, ST410, and ST1193. The INCREMENT project has shown that ertapenem is as effective as other carbapenems for treating serious infections due to ESBL-producing Enterobacteriaceae. The results of the MERINO open-label randomized controlled study has provided clear evidence that piperacillin-tazobactam should be avoided for targeted therapy of blood-stream infections due to ESBL-producing E. coli and K. pneumoniae, regardless of the patient population, source of infection, bacterial species, and susceptibility result of piperacillin-tazobactam. Research is still warranted to define the optimal therapy of less severe infections due to ESBL-producing Enterobactericeae. View Show abstract Antimicrobial resistance in South Korea: A report from the Korean global antimicrobial resistance surveillance system (Kor-GLASS) for 2017 Article Jul 2019 Changseung Liu Eun-Jeong Yoon Dokyun Kim Seok Hoon Jeong At the end of 2015, a global action plan on antimicrobial resistance (AMR) was proposed by the World Health Organization, and the Global AMR Surveillance System (GLASS) was subsequently initiated. The Centers for Disease Control and Prevention of South Korea established a customized AMR surveillance system for South Korea, called Kor-GLASS, in early 2016. A pilot phase of Kor-GLASS was operated from May to December 2016 with six sentinel hospitals, and phase I of Kor-GLASS started in January 2017 with eight sentinel hospitals. Previous surveillance data for overestimated AMR due to duplicate isolation of drug-resistant pathogens were corrected and error-free AMR data were compared with those from other countries. One-half (53.2%, 377/708) of Staphylococcus aureus blood strains exhibited resistance to cefoxitin, indicating methicillin-resistant S. aureus. Resistance to ampicillin in Enterococcus faecalis blood strains was rare (0.6%, 1/175), while the resistance rate to penicillin was 26.3% (46/175). Resistance to vancomycin (34.0%, 98/288) and teicoplanin (18.8%, 98/288) was frequently observed in Enterococcus faecium strains. The resistance rate of Escherichia coli strains to cefotaxime was 32.4% (574/1772), and that of Klebsiella pneumoniae strains was 26.1% (181/693). The resistance rates of Pseudomonas aeruginosa strains to imipenem and meropenem were 19.5% (29/149) and 18.1% (27/149), respectively. And 92.1% (187/203) of Acinetobacter baumannii strains were resistant to both imipenem and meropenem. The high incidence of bacteremia caused by major AMR pathogens among hospitalized patients especially in intensive care units emphasized the importance of hospital infection control and the need to improve the crowded hospitalization system in South Korea. The isolation rate of the Salmonella spp. is decreasing, reflecting the current socio-economic status of South Korea. The proportions of bacterial species in the blood strains were similar to those in other Asian countries with similar lifestyles. View Show abstract Global Extraintestinal Pathogenic Escherichia coli (ExPEC) Lineages Article Jun 2019 Amee R Manges Hyun Min Geum Alice Guo Johann D D Pitout Extraintestinal pathogenic Escherichia coli (ExPEC) strains are responsible for a majority of human extraintestinal infections globally, resulting in enormous direct medical and social costs. ExPEC strains are comprised of many lineages, but only a subset is responsible for the vast majority of infections. Few systematic surveillance systems exist for ExPEC. To address this gap, we systematically reviewed and meta-analyzed 217 studies (1995 to 2018) that performed multilocus sequence typing or whole-genome sequencing to genotype E. coli recovered from extraintestinal infections or the gut. Twenty major ExPEC sequence types (STs) accounted for 85% of E. coli isolates from the included studies. ST131 was the most common ST from 2000 onwards, covering all geographic regions. Antimicrobial resistance-based isolate study inclusion criteria likely led to an overestimation and underestimation of some lineages. European and North American studies showed similar distributions of ExPEC STs, but Asian and African studies diverged. Epidemiology and population dynamics of ExPEC are complex; summary proportion for some STs varied over time (e.g., ST95), while other STs were constant (e.g., ST10). Persistence, adaptation, and predominance in the intestinal reservoir may drive ExPEC success. Systematic, unbiased tracking of predominant ExPEC lineages will direct research toward better treatment and prevention strategies for extraintestinal infections. View Show abstract Epidemiology of Infectious and Noninfectious Catheter Complications in Patients Receiving Home Parenteral Nutrition: A Systematic Review and Meta‐Analysis Article Jun 2019 Ruth Reitzel Joel Rosenblatt Anne-Marie Chaftari Issam Raad Patients receiving parenteral nutrition (PN) as their primary source of nutrition are at high risk for both infectious and noninfectious catheter complications (catheter‐related infections, catheter occlusion, and venous thrombosis). The aim of this review was to synthesize and evaluate what is known about catheter complications and prevention strategies in the PN population. Three electronic databases (Medline, Embase, and CINAHL) were screened for studies published between January 2012 and February 2019 regarding infectious and noninfectious catheter complications in patients receiving PN. Rates of infectious and noninfectious catheter complications, prevalence of causative pathogens, potential risk factors, and prevention strategies via the use of antimicrobial lock therapy (ALT) were assessed. Fifty‐three catheter complication studies and 12 ALT studies were included. Studies were grouped by definition of complication: catheter‐related bloodstream infections (CRBSI) or central line–associated bloodstream infections (CLABSI). Random effects summary rates per 1000 catheter days were 0.85 CRBSI episodes (95% CI 0.27–2.64) and 1.65 CLABSI episodes (95% CI 1.09–2.48). Use of taurolidine or ethanol ALT was efficacious in reducing infectious catheter complications; however, several studies had concerns for adverse mechanical complications. Potential risk factors for catheter complications were highly varied and often contradictory between studies. The rates of catheter complications were higher among catheterized patients receiving PN compared with nationally reported rates of complications in all catheterized patients. Risk factors for catheter complications need to be better understood for targeted prophylactic use of ALT. Future studies are warranted; however, they should be conducted using more standardized definitions and criteria. View Show abstract Hypervirulent Klebsiella pneumoniae Article May 2019 Thomas A Russo Candace Marr Hypervirulent K. pneumoniae (hvKp) is an evolving pathotype that is more virulent than classical K. pneumoniae (cKp). hvKp usually infects individuals from the community, who are often healthy. Infections are more common in the Asian Pacific Rim but are occurring globally. hvKp infection frequently presents at multiple sites or subsequently metastatically spreads, often requiring source control. hvKp has an increased ability to cause central nervous system infection and endophthalmitis, which require rapid recognition and site-specific treatment. The genetic factors that confer hvKp’s hypervirulent phenotype are present on a large virulence plasmid and perhaps integrative conjugal elements. Increased capsule production and aerobactin production are established hvKp-specific virulence factors. Similar to cKp, hvKp strains are becoming increasingly resistant to antimicrobials via acquisition of mobile elements carrying resistance determinants, and new hvKp strains emerge when extensively drug-resistant cKp strains acquire hvKp-specific virulence determinants, resulting in nosocomial infection. Presently, clinical laboratories are unable to differentiate cKp from hvKp, but recently, several biomarkers and quantitative siderophore production have been shown to accurately predict hvKp strains, which could lead to the development of a diagnostic test for use by clinical laboratories for optimal patient care and for use in epidemiologic surveillance and research studies. View Show abstract Hospital epidemiologists' and infection preventionists' opinions regarding hospital-onset bacteremia and fungemia as a potential healthcare-associated infection metric Article May 2019 INFECT CONT HOSP EP Lilian Abbo Deverick Anderson Raymund B. Dantes Clare Rock Objective: To ascertain opinions regarding etiology and preventability of hospital-onset bacteremia and fungemia (HOB) and perspectives on HOB as a potential outcome measure reflecting quality of infection prevention and hospital care. Design: Cross-sectional survey. Participants: Hospital epidemiologists and infection preventionist members of the Society for Healthcare Epidemiology of America (SHEA) Research Network. Methods: A web-based, multiple-choice survey was administered via the SHEA Research Network to 133 hospitals. Results: A total of 89 surveys were completed (67% response rate). Overall, 60% of respondents defined HOB as a positive blood culture on or after hospital day 3. Central line-associated bloodstream infections and intra-abdominal infections were perceived as the most frequent etiologies. Moreover, 61% thought that most HOB events are preventable, and 54% viewed HOB as a measure reflecting a hospital's quality of care. Also, 29% of respondents' hospitals already collect HOB data for internal purposes. Given a choice to publicly report central-line-associated bloodstream infections (CLABSIs) and/or HOB, 57% favored reporting either HOB alone (22%) or in addition to CLABSI (35%) and 34% favored CLABSI alone. Conclusions: Among the majority of SHEA Research Network respondents, HOB is perceived as preventable, reflective of quality of care, and potentially acceptable as a publicly reported quality metric. Further studies on HOB are needed, including validation as a quality measure, assessment of risk adjustment, and formation of evidence-based bundles and toolkits to facilitate measurement and improvement of HOB rates. View Show abstract Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study Article Apr 2019 LANCET INFECT DIS Andrew Stewardson Kalisvar Marimuthu Sharmila Sengupta Stephan Harbarth View Staphylococcus capitis and NRCS-A clone: the story of an unrecognized pathogen in neonatal intensive care units Article Mar 2019 Frédéric Laurent Marine Butin Background: In neonatal intensive care units (NICUs), nosocomial late-onset sepsis (LOS), mostly due to coagulase negative staphylococci, constitute a major cause of death or impairment. Staphylococcus capitis, usually considered as a poorly virulent species, has been reported as a cause of LOS. Objectives: To review data regarding S. capitis neonatal LOS and the features of isolates involved. Sources: PubMed was searched up to August 2018 to retrieve studies on the topic; the keywords used were 'S. capitis', 'neonate', 'neonatal ICU', 'bloodstream infection' and 'late onset sepsis'. Content: Published data highlight the worldwide endemicity of a single S. capitis clone, named NRCS-A, specifically involved in LOS. NRCS-A harbours a multidrug resistance profile (including resistance to the usual first-line antibiotics used in NICUs). It is also able to adapt under vancomycin selective pressure that could confer an advantage for its implantation and dissemination in NICUs where this selective pressure is high. Moreover, a severe morbidity has been observed in NRCS-A-related LOS. The NICU environment, and especially incubators, constitute reservoirs of NRCS-A from which it could diffuse inside the setting. Finally, the virulome and resistome of S. capitis NRCS-A contain many genes potentially implicated in its specific epidemiology and pathophysiology, including the gene nsr that may be involved in its fitness and implantation in neonatal gut flora. Implications: S. capitis must be considered as a true pathogen in neonates. The decreased susceptibility to vancomycin may be involved in failure of vancomycin therapy. Further studies are needed to better manage its diffusion inside each NICU but also worldwide. View Show abstract Mortality associated with in-hospital bacteraemia caused by Staphylococcus aureus: a multistate analysis with follow-up beyond hospital discharge Article Jan 2010 Martin Wolkewitz Uwe Frank Gabby Philips on behalf of the BURDEN study group View Trends in Incidence of Methicillin-resistant Staphylococcus aureus Bloodstream Infections Differ by Strain Type and Healthcare Exposure, United States, 2005–2013 Article Feb 2019 CLIN INFECT DIS Isaac See Yi Mu Valerie Albrecht Alexander J Kallen Background: Previous reports suggested that U.S. methicillin-resistant Staphylococcus aureus (MRSA) strain epidemiology has changed since the rise of USA300 MRSA. We describe invasive MRSA trends by strain type. Methods: Data came from five CDC Emerging Infections Program sites conducting population-based surveillance and collecting isolates for invasive MRSA (i.e., from normally sterile body sites), 2005-2013. MRSA bloodstream infection (BSI) incidence/100,000 population was stratified by strain type and epidemiologic classification of healthcare exposures. Invasive USA100 vs USA300 case characteristics from 2013 were compared through logistic regression. Results: From 2005-2013, USA100 incidence decreased most notably for hospital-onset (6.1 vs 0.9 / 100,000 persons, P<0.0001) and healthcare-associated, community-onset (10.7 vs 4.9 / 100,000 persons, P<0.0001) BSIs. USA300 incidence for hospital-onset BSIs also decreased (1.5 vs 0.6 / 100,000 persons, P<0.0001). However, USA300 incidence did not significantly change for healthcare-associated, community-onset (3.9 vs 3.3 / 100,000 persons, P=0.05) or community-associated BSIs (2.5 vs 2.4 / 100,000 persons, P=0.19). Invasive MRSA was less likely to be USA300 in patients who were older (adjusted odds ratio [aOR] 0.97 per year, 95% confidence interval [CI] 0.96-0.98), previously hospitalized (aOR 0.36, 95% CI 0.24-0.54), or had central lines (aOR 0.44, 95% CI 0.27-0.74) and associated with USA300 in people who inject drugs (aOR 4.58, 95% CI 1.16-17.95). Conclusions: Most of the decline in MRSA BSIs was from decreases in USA100 BSI incidence. Prevention of USA300 MRSA BSIs in the community will be needed to further reduce burden from MRSA BSIs. View Show abstract Preventability of hospital onset bacteremia and fungemia: A pilot study of a potential healthcare-associated infection outcome measure Article Feb 2019 Raymund B. Dantes Clare Rock Aaron M Milstone Surbhi Leekha Hospital-onset bacteremia and fungemia (HOB), a potential measure of healthcare-associated infections, was evaluated in a pilot study among 60 patients across 3 hospitals. Two-thirds of all HOB events and half of nonskin commensal HOB events were judged as potentially preventable. Follow-up studies are needed to further develop this measure. View Show abstract Factors that impact on the burden of Escherichia coli bacteraemia: Multivariable regression analysis of 2011-2015 data from West London Article Nov 2018 J HOSP INFECT Oliver Blandy Kate Honeyford Myriam Gharbi Shiranee Sriskandan Background: The incidence of Escherichia coli bacteraemia in England is increasing amid concern regarding the roles of antimicrobial resistance and nosocomial acquisition on burden of disease. Aim: To determine the relative contributions of hospital-onset E. coli blood stream infection and specific E. coli antimicrobial resistance patterns to the burden and severity of E. coli bacteremia in West London. Methods: Patient and antimicrobial susceptibility data were collected for all cases of E. coli bacteraemia between 2011 and 2015. Multivariable logistic regression was used to determine the association between the category of infection (hospital or community-onset) and length of stay, intensive care unit admission, and 30-day all-cause mortality. Findings: E. coli bacteraemia incidence increased by 76% during the study period, predominantly due to community-onset cases. Resistance to quinolones, third-generation cephalosporins, and aminoglycosides also increased over the study period, occurring in both community- and hospital-onset cases. Hospital-onset and non-susceptibility to either quinolones or third-generation cephalosporins were significant risk factors for prolonged length of stay, as was older age. Rates of mortality were 7% and 12% at 7 and 30 days, respectively. Older age, a higher comorbidity score, and bacteraemia caused by strains resistant to three antibiotic classes were all significant risk factors for mortality at 30 days. Conclusion: Multidrug resistance, increased age, and comorbidities were the main drivers of adverse outcome. The rise in E. coli bacteraemia was predominantly driven by community-onset infections, and initiatives to prevent community-onset cases should be a major focus to reduce the quantitative burden of E. coli infection. View Show abstract Survival following bloodstream infection; a prospective multinational cohort study assessing the impact of place of care Article Sep 2018 J INFECTION Kate Nambiar Harald Seifert Siegbert Rieg Achim J. Kaasch Background: Staphylococcus aureus bloodstream infection (SAB) is a common, life-threatening infection with a high mortality. Survival can be improved by implementing quality of care bundles in hospitals. We previously observed marked differences in mortality between hospitals and now assessed whether mortality could serve as a valid and easy to implement quality of care outcome measure. Methods: We conducted a prospective observational study between January 2013 and April 2015 on consecutive, adult patients with SAB from 11 tertiary care centers in Germany, South Korea, Spain, Taiwan, and the United Kingdom. Factors associated with mortality at 90 days were analyzed by Cox proportional hazards regression and flexible parametric models. Results: 1,851 patients with a median age of 66 years (64% male) were analyzed. Crude 90-day mortality differed significantly between hospitals (range 23% to 39%). Significant variation between centers was observed for methicillin-resistant S. aureus, community-acquisition, infective foci, as well as measures of comorbidities, and severity of disease. In multivariable analysis, factors independently associated with mortality at 90 days were age, nosocomial acquisition, unknown infective focus, pneumonia, Charlson comorbidity index, SOFA score, and study center. The risk of death varied over time differently for each infective focus. Crude mortality differed markedly from adjusted mortality. Discussion: We observed significant differences in adjusted mortality between hospitals, suggesting differences in quality of care. However, mortality is strongly influenced by patient mix and thus, crude mortality is not a suitable quality indicator. View Show abstract A prognostic model of persistent bacteremia and mortality in complicated S. aureus bloodstream infection Article Aug 2018 CLIN INFECT DIS Alessander O Guimaraes Yi Cao Kyu Hong Carrie M. Rosenberger Background: Staphylococcus aureus is a leading cause of bacteremia, yet there remains a significant knowledge gap in the identification of relevant biomarkers that predict clinical outcomes. Heterogeneity in the host response to invasive S. aureus infection suggests that specific biomarker signatures could be utilized to differentiate patients prone to severe disease, thereby facilitating earlier implementation of more aggressive therapies. Methods: To further elucidate the inflammatory correlates of poor clinical outcomes in patients with S. aureus bacteremia, we evaluated the association between a panel of blood proteins at initial presentation of bacteremia and disease severity outcomes using two cohorts of patients with S. aureus bacteremia (n=32 and n=124). Results: We identified 13 candidate proteins that were correlated with mortality and persistent bacteremia. Prognostic modeling identified IL-8 and CCL2 as the strongest individual predictors of mortality, with the combination of these biomarkers classifying fatal outcome with 89% sensitivity and 77% specificity (p<0.0001). Baseline IL-17A levels were elevated in patients with persistent bacteremia (p<0.0001), endovascular (p=0.026) and metastatic tissue infections (p=0.012). Conclusions: These results demonstrate the potential utility of selected biomarkers to distinguish patients with the highest risk for treatment failure and bacteremia-related complications, providing a valuable tool for clinicians in the management of S. aureus bacteremia. Additionally, these biomarkers could identify patients with the greatest potential to benefit from novel therapies in clinical trials. View Show abstract Clinical and Molecular Correlates of Escherichia coli Bloodstream Infection from Two Geographically Diverse Centers in Rochester, Minnesota, and Singapore Article Aug 2018 Shehara M Mendis Shawn Vasoo Brian Johnston Ritu Banerjee Escherichia coli bacteremia is caused mainly by sequence type complex (STc) 131 and two clades within its fluoroquinolone resistance-associated H 30 subclone, H 30R1 and H 30Rx. We examined clinical and molecular correlates of E. coli bacteremia in two geographically distinct centers. We retrospectively studied 251 unique E. coli bloodstream isolates from 246 patients (48 from the Mayo Clinic, Rochester, Minnesota [MN], 198 from Tan Tock Seng Hospital, Singapore [SG]), from October 2013 through March 2014. Isolates underwent PCR for phylogroup, STc, blaCTX-M type, and virulence gene profiles, and medical records reviewed. Although STc131 accounted for 25-27% of all E. coli bacteremia isolates at each site, its extended-spectrum β-lactamase-associated H 30Rx clade was more prominent in SG than MN (15% versus 4%, P = 0.04). In SG only, patients with STc131 ( versus other E. coli ) were more likely to receive inactive initial antibiotics (odds ratio [OR] 2.8, P = 0.005); this was true specifically for patients with H 30Rx (OR 7.0, P = 0.005). H 30Rx comprised 16% of community-onset bacteremia episodes in SG, but none in MN. In SG, virulence scores were higher for H 30Rx, as compared to H 30R1, non- H 30 STc131, and non-STc131 isolates ( P < 0.02, all comparisons). At neither site did mortality differ by clonal status. The ESBL-associated H 30Rx clade was more prevalent and more often of community-onset in SG, where it predicted inactive empiric treatment. Clonal distribution varies geographically and has potentially important clinical implications. Rapid susceptibility testing and clonal diagnostics for H 30/ H 30Rx might facilitate earlier prescribing of active therapy. View Show abstract Comparison of Predictors and Mortality Between Bloodstream Infections Caused by ESBL-Producing Escherichia coli and ESBL-Producing Klebsiella pneumoniae Article Apr 2018 Oded Scheuerman Vered Schechner Yehuda Carmeli Jesús Rodríguez-Baño OBJECTIVE To compare the epidemiology, clinical characteristics, and mortality of patients with bloodstream infections (BSI) caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBL-EC) versus ESBL-producing Klebsiella pneumoniae (ESBL-KP) and to examine the differences in clinical characteristics and outcome between BSIs caused by isolates with CTX-M versus other ESBL genotypes METHODS As part of the INCREMENT project, 33 tertiary hospitals in 12 countries retrospectively collected data on adult patients diagnosed with ESBL-EC BSI or ESBL-KP BSI between 2004 and 2013. Risk factors for ESBL-EC versus ESBL-KP BSI and for 30-day mortality were examined by bivariate analysis followed by multivariable logistic regression. RESULTS The study included 909 patients: 687 with ESBL-EC BSI and 222 with ESBL-KP BSI. ESBL genotype by polymerase chain reaction amplification of 286 isolates was available. ESBL-KP BSI was associated with intensive care unit admission, cardiovascular and neurological comorbidities, length of stay to bacteremia >14 days from admission, and a nonurinary source. Overall, 30-day mortality was significantly higher in patients with ESBL-KP BSI than ESBL-EC BSI (33.7% vs 17.4%; odds ratio, 1.64; P =.016). CTX-M was the most prevalent ESBL subtype identified (218 of 286 polymerase chain reaction-tested isolates, 76%). No differences in clinical characteristics or in mortality between CTX-M and non–CTX-M ESBLs were detected. CONCLUSIONS Clinical characteristics and risk of mortality differ significantly between ESBL-EC and ESBL-KP BSI. Therefore, all ESBL-producing Enterobacteriaceae should not be considered a homogeneous group. No differences in outcomes between genotypes were detected. CLINICAL TRIALS IDENTIFIER ClinicalTrials.gov. Identifier: NCT01764490. Infect Control Hosp Epidemiol 2018;1–8 View Show abstract Epidemiology of carbapenem-resistant Enterobacteriaceae infections: report from China CRE Network Article Dec 2017 Yawei Zhang Qi Wang Yuyao Yin Hui Wang Carbapenem-resistant Enterobacteriaceae (CRE) infection is highly endemic in China, but estimates of infection burden are lacking. We established incidence of CRE infection from a multicenter study that covered 25 tertiary hospitals in 14 provinces. CRE cases defined as carbapenem non-susceptible C. freundii , E. coli , E. cloacae , or K. pneumoniae infections during January to December 2015 were collected and reviewed from medical records. Antimicrobial susceptibility testing and carbapenemase genes identification were performed. Among 664 CRE cases, most were caused by K. pneumoniae (73.9%), followed by E. coli (16.6%), and E. cloacae (7.1%). The overall CRE infection incidence per 10,000 discharges was 4.0, and differed significantly by region, with the highest in Jiangsu (14.97), and the lowest in Qinghai (0.34). 83.8% of patients had underlying co-morbidities; the median age was 62 years (range, 45–74) and 450 (67.8%) were male. Lower respiratory tract infections (65.4%) were most common, followed by urinary-tract infection (16.6%), intra-abdominal infection (7.7%), and bacteremia (7.7%). The overall hospital mortality rate was 33.5%. All isolates showed non-susceptibility to carbapenems and cephalosporins. Susceptibility rate of Polymyxin B was >90%. Tigecycline demonstrated higher susceptibility rate against E. coli , compared with K. pneumoniae (90.9% vs. 40.2%). Of 155 clinical isolates analyzed, 89% produced carbapenemases with a majority of isolates producing KPC (50%) and/or NDM (33.5%)-type beta-lactamases among K. pneumoniae and E. coli . Incidence of CRE infection in China was 4.0 per 10,000 discharges. The patient-based disease burden in tertiary hospitals in China is severe, suggesting an urgent need to enhance infection control. View Show abstract Trends in incidence and resistance patterns of Staphylococcus aureus bacteremia Article Nov 2017 Elina Jokinen Janne Laine Reetta Huttunen Jaana Syrjänen Background: Staphylococcus aureus bacteremia (SAB) causes a significant burden on the population. Several infection control measures have been implemented in Pirkanmaa county to combat a local epidemic with methicillin-resistant Staphylococcus aureus (MRSA). We aimed to study the epidemiology of SAB and antibiotic resistance of S. aureus and the possible influence of improved infection control. Methods: Register data from 2005 to 2015 were retrospectively analysed to study the antimicrobial susceptibility, the incidence and mortality in SAB in a population-based setting. Results: The incidence of SAB increased during the study period from 21.6 to 35.8/100,000 population. The number of both health care-associated (HA) and community-associated (CA) cases has increased. The incidence of MSSA bacteremia increased from 19.9 to 35.2/100,000 population in Pirkanmaa in parallel to other parts of Finland. The incidence of MRSA bacteremia was 10-fold (4.5/100,000 population) higher in 2011 than in other parts of the country, but sank to the national level (0.59/100,000 population) in 2015. The fatality rate decreased from 22% to 17%. The proportion of penicillin-susceptible Staphylococcus aureus (PSSA) increased from 23.9% in 2008 to 43.1% in 2015. Conclusion: The incidence of both HA and CA SAB has increased since 2005. Conversely, the proportion of MRSA and PRSA bacteremia has decreased. Promotion of infection control measures may have reduced the incidence of MRSA bacteremia but not the overall incidence of SAB. The rising proportion of PSSA enables the use of targeted, narrow spectrum antimicrobials. View Show abstract Show more Recommendations Discover more about: Epidemiology Article Population and transmission dynamics of cowpox in bank voles: Testing fundamental assumptions September 1998 · Ecology Letters Mike Begon Feore Kevin Bown Chantrey The idea that the rate of production of new infections, of directly transmitted microparasites, is a reflection of an interaction between the number of infectious hosts and the number of susceptible hosts in a population is central to our understanding of dynamical processes in epidemiology. Empirical support for the idea has been seriously lacking, especially for endemic infections in natural ... [Show full abstract] hosts, but is provided here for cowpox virus infection in bank voles (Clethrionomys glareolus), using alternative descriptions of transmission dynamics: true and pseudo mass action. The former appears, overall, to give a better description of the dynamics. Transmission rates differ in two natural populations, but both support previously untested theories on the allometric scaling of transmission rates. Read more Chapter Homopteran Transmission of Xylem-Inhabiting Bacteria January 1990 Alexander H Purcell The great majority of bacteria associated with plants are not pathogens, and pathogenicity is the exception, not the rule (53). Of the relatively few bacteria that are pathogens, most do not require mobile vectors such as insects (6, 34, 82). Of the bacterial phytopathogens that have insect vectors, a wide range of relationships have been documented (34). This chapter deals with Homopteran ... [Show full abstract] transmission of the relatively few (described so far) types of xylem-limited bacteria (XLB) that are transmitted by insects. Such bacteria are transmitted—not surprisingly—by xylem-feeding insects. The ecological and evolutionary implications of XLB transmission by insects will also be discussed, relevant to the epidemiology of XLB. Read more Article Studies on the Experimental Epidemiology of Respiratory Infections: I. An Apparatus for the Quantita... September 1950 · The Journal of Infectious Diseases W R LEIF A P KRUEGER Read more Article Bacterium-host protein-carbohydrate interactions and pathogenicity September 1999 · Biochemical Society Transactions Karl-Anders Karlsson Read more Looking for the full-text? You can request the full-text of this article directly from the authors on ResearchGate. Request full-text Already a member? Log in ResearchGate iOS App Get it from the App Store now. Install Keep up with your stats and more Access scientific knowledge from anywhere or Discover by subject area Recruit researchers Join for free Login Email Tip: Most researchers use their institutional email address as their ResearchGate login Password Forgot password? Keep me logged in Log in or Continue with Google Welcome back! Please log in. Email · Hint Tip: Most researchers use their institutional email address as their ResearchGate login Password Forgot password? Keep me logged in Log in or Continue with Google No account? Sign up Company About us News Careers Support Help Center Business solutions Advertising Recruiting
https://www.researchgate.net/publication/337142394_Burden_of_bacterial_bloodstream_infection_-_A_brief_update_on_epidemiology_and_significance_of_multidrug-resistant_pathogens
(PDF) Polarización de la estructura funcional de las capitales de provincia y autonomía en España. 1981‑2011 PDF | Some fundamental trends of the recent reorganization of economic activities in Spain are defined by the growing concentration in certain urban... | Find, read and cite all the research you need on ResearchGate Polarización de la estructura funcional de las capitales de provincia y autonomía en España. 1981‑2011 June 2014 Estudios Geográficos 75(276) DOI: 10.3989/estgeogr.201404 CC BY-NC 4.0 Abstract Some fundamental trends of the recent reorganization of economic activities in Spain are defined by the growing concentration in certain urban areas of certain economic activities, especially those related to the creation, management and use of innovation and knowledge, and selective decentralization of others. The main hypothesis of this work assumes that capital of autonomy is a factor that exerts some influence on the structure of economic activities in a city. In this paper we study the scope of this thesis referred to municipalities and provincial capitals of autonomy between 1981 and 2011. The study conducted helps verify the trend towards concentration of capital in certain activities of the knowledge economy. The good connectivity of cities or the proximity to large urban areas are attractive forces; the capital of autonomy has a limited influence on intermediate sized nuclei located in dynamic regional contexts.Parte de la reorganización reciente de las actividades económicas en España se define por la concentración en determinadas áreas urbanas de ciertas actividades económicas, especialmente las relacionadas con la creación, gestión y uso de la innovación y el conocimiento, y por la descentralización selectiva de otras. La hipótesis principal de este trabajo asume que la capitalidad de autonomía es un factor que ejerce influencia en la estructura de las actividades económicas de una ciudad. En este marco se estudia el alcance de estas tesis referidas a los municipios capitales de provincia y de autonomía entre 1981 y 2011. El estudio permite constatar la tendencia a la concentración en determinadas capitales de las actividades de la «economía del conocimiento» . La buena conectividad de las ciudades o la cercanía a grandes áreas urbanas son fuerzas de atracción de este tipo de actividades; la capitalidad de autonomía tiene una influencia limitada en núcleos de tamaño intermedio ubicados en contextos regionales dinámicos. [fr] La réorganisation récente des activités économiques en Espagne est définie d’un côté par la concentration de certaines d’entre elles, en particulier celles liées à la création, gestion et utilisation de l’innovation et de la connaissance dans des zones urbaines concrètes, et de l’autre, par la décentralisation sélective d’autres activités. L’hypothèse principale de cette recherche accepte que la «capitalité» d’une région autonome a des conséquences sur la structure des activités économiques de cette ville. Nous allons donc vérifier cette thèse référée aux municipalités capitales de province ou de région autonome dans la période 1981-2011. Cette analyse permettra de confirmer la tendance à la concentration des activités de l’économie de la connaissance dans certaines de ces capitales. Une connectivité performante ou la proximité de grands réseaux urbains constituent des pôles d’attraction pour ces activités; la «capitalité» d’une région autonome a une influence limitée dans le cas de villes moyennes situées dans un contexte régional dynamique. Content uploaded by Severino Escolano Utrilla Polarización de la estructura funcional de las capitales de provincia y de autonomía en España: 1981-2011 * Polarization of the functional structure of capital cities of provinces and autonomies in Spain: 1981-2011 Severino Escolano Utrilla ** 1. I NTRODUCCIÓN Entre las transformacio nes urbanas más import antes de las últimas décadas figuran las registrad as en las economí as de las ciudade s que se han plasmado, tanto en los modos de organiza ción de la producción , la distribución y el con- sumo, como en la produc tivida d, la composició n de los tipos de actividad eco- nómica y otros aspectos del «paisaje económico». El estudio de la re-es tructur ación de las econ omías ur banas c onstitu ye uno de los tema s centra - les d e la inve stigaci ón c ientífi ca so bre las ciudad es ( Moulaer t y Scott , 19 97, p . 4) Parte de los c ambios de las a ctivida des e conómi cas u rbanas puede n ser inte r- preta dos consider ando las ciudades de un espacio determi nado como un sis- tema d e luga res a lterna tivos, en compe tencia y cooper ación, para loc alizar activid ades económica s. En este marco, la composic ión del mix de actividades económi cas de l as ciuda des, qu e varía constan temente , obede ce a la in teracc ión complej a de múltip les f actor es y , por tanto , sin tetiza bien la p osición de una c iu- dad en la je rarqu ía urb ana y es un indica dor de l pote ncial económi co-soc ial, d el grado d e moder nizaci ón y ot ras pr opieda des de las ec onomías urban as. Estudios Geográficos V ol. LXXV , 276, pp. 139-175 Enero-junio 2014 ISSN: 0014-1496 eISSN: 1988-8546 doi: 10.3989/estgeogr.201404 * Este texto se enmarca en el proyecto de investigación «Las ciudades españolas en la etapa autonómica (1978-2008). Dinámicas, procesos y políticas». CSO 2009-11261-(Subpr ograma GEOG), del Ministerio de Ciencia e Innovación. ** Universidad de Zaragoza. Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 139 Por otro lado, desde hace dos décadas la innovación tecnológica y el cono- cimiento científico se han revelado como fuerzas emergentes y decisivas tanto para mejorar la competitividad de ciudades y territorios a todas las escalas como para impulsar la modernización de la sociedad en general. Alguna de las tendencias fundamentales de la reorganización reciente de las actividades económicas en España se definen por la creciente concentra- ción en determinadas áreas urbanas de ciertas actividades económicas, en es- pecial las relacionadas con la creación, gestión y uso de la innovación, el conocimiento y la información, y por la descentralización, también selectiva, de otras. En este trabajo se estudia el alcance de estas tesis referidas a los municipios capitales de provincia y de autonomía entre 1981 y 2011. En concreto se pre- tende responder a las tres preguntas siguientes: 1. ¿Cuál ha sido la variación de los perfiles de actividad económica de las capitales de provincia y de autonomía entre 1981 y 2011? 2. ¿Se pueden identificar tipos de trayectorias seguidas por las ciudades en la conformación de sus perfiles de actividad económica? 3. ¿Se aprecian patrones nítidos de cambio y de especialización asociados a la función de capitalidad autonómica? Los contenidos de este trabajo están organizados en tres partes, además de la introducción y las consideraciones finales. En la primera se presentan algu- nos procesos y factores que configuran la mezcla de actividades económicas urbanas y se fundamenta la delimitación espacial y temática así como el enfo- que de estudio adoptado. La siguiente se dedica a describir y justificar la me- todología utilizada y a caracterizar los datos. En la tercera se exponen y explican los resultados de los análisis. Finalmente se realizan algunas valora- ciones acerca del grado y modo de influencia de la capitalidad autonómica en la especialización funcional de las ciudades. 2. F ACTORES Y TENDENCIAS DE LA ESTRUCTURA FUNCIONAL Y ESP ACIAL DE LAS ACTIVIDADES ECONÓMICAS DE LAS CIUDADES La composición de los tipos de actividad económica de las ciudades en un momento dado es el resultado de un balance instantáneo entre varias catego- rías relativamente simples: la creación de nuevas empresas, la desaparición de otras y e l saldo d e traslados hacia y desde otras ciudades, a lo que cabría añadir los cambios de actividad. Sin embargo, los movimientos de estas variables es- SEVERINO ESCOLANO UTRILLA 140 Estudios Geográficos, V ol. LXXV , 276, pp. 139-175, enero-junio 2014 ISSN: 0014-1496, eISSN: 1988-8546, doi: 10.3989/estgeogr.201404 Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 140 tán sujetos a las complejas interacciones de diversas fuerzas que cristalizan en modelos espaciales espe cíficos de localización d e las actividades económ icas. La estructura y variación de los perfiles de actividad económica de las ciu- dades se explica por la actuación conjunta de factores que, tradicionalmente, se han considerado que conforman los procesos de localización de las activi- dades económicas: las ventajas competitivas de las economías de aglomera- ción y «desaglomeración», la accesibilidad a los mercados de factor es de producción, las configuraciones de la r edes urbanas a diversas escalas, la posi- ción y distancia física y funcional entre ciudades, el estado y dotación de in- fraestructuras y , en fin, las políticas económicas y de ordenación urbana y territorial, entre otras. Algunos enfoques de la teoría económica han destacado la importancia de la estructura económica en el desarrollo socioeconómico de los países, regio- nes y ciudades, es decir , asocian el potencial socioeconómico de un área o una ciudad al mayor o menor peso relativo que las diversas actividades tienen en la composición de la estructura económica de cada entidad. Diversos factores modifican constantemente la importancia absoluta y rela- tiva de los principios de localización espacial y , en consecuencia, las ventajas de localización de las ciudades. Ello hace que los patrones de localización in- crementen su complejidad debido a la combinación de gradientes de actividad asociados a la contigüidad con discontinuidades espaciales generadas por la alta conectividad digital y de los modernos sistemas de transportes y comuni- caciones. 2.1. La influencia de la integración socioeconómica y del conocimiento científico La localización de las actividades económicas en las ciudades está influida por múltiples procesos interrelacionados, entr e los que sobresalen la creciente internacionalización de la economía y la sociedad y la emergencia de nuevas fuerzas económicas y sociales relacionadas con las innovaciones tecnológicas y el conocimiento científico. Además, otras dimensiones urbanas, de natura- leza económica, demográfica, paisajística y espacial están afectadas también por la intervención de estos dos vectores. La inserción de las economías urbanas en mercados globales promueve la aparición de nuevas conexiones de todo tipo, de alcance planetario, continen- tal, nacional, regional y local, establecidas entre una multitud de agentes (paí- ses, bloques de países, organizaciones, empresas, personas), lo que facilita POLARIZACIÓN DE LA ESTRUCTURA FUNCIONAL DE LAS CAPITALES DE PROVINCIA 141 Estudios Geográficos, V ol. LXXV , 276, pp. 139-175, enero-junio 2014 ISSN: 0014-1496, eISSN: 1988-8546, doi: 10.3989/estgeogr.201404 Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 141 nuevas divisiones del trabajo y especializaciones económicas que operan en nuevos escenarios de competitividad y cooperación. La globalización significa también la aceleración de los procesos económicos, la integración de los siste- mas financieros, la reor ganización funcional y espacial de los procesos de pro- ducción facilitadas por las innovaciones tecnológicas y , en fin, la cr eciente importancia de actividades económicas relacionadas con la creatividad, el co- nocimiento y la tecnología (Drucker, 1969; Stehr, 1994; Jonhston, Taylor et al. , 2002; UNESCO, 2005). La integración de España en la Unión Europea (UE) constituye un hecho relevante que modifica las condiciones y ventajas de localización de activida- des económicas en buena parte de las grandes ciudades españolas. La amplia- ción del espacio económico, político y administrativo facilita la r eorgani - zación de las redes urbanas y con ello procesos de centralización y descentra- lización de actividades a escala de la UE. El proceso de restructuración político administrativa que supone la cons- trucción del «Estado de las Autonomías», iniciado en 1978, afecta específica- mente a las ciudades españolas. La transferencia de personas, medios y funciones desde el Estado central a las instituciones autonómicas para el ejer- cicio de sus competencias acarrea también un incremento de la actividad eco- nómica, principalmente en las capitales de autonomía. No obstante, y como se indicó en otro trabajo (Escolano, 2012) es difícil identificar y cuantificar los efectos económicos y de otro tipo producidos por la capitalidad autonómica más allá de la contabilización de los medios materiales y personales asociados a la misma, pues este hecho crea externalidades de diversa naturaleza y muy ramificadas por el tejido socioeconómico. En todo caso, se puede aceptar que la capitalidad de autonomía genera nuevas oportunidades para el desarrollo de actividades económicas. La creación y aplicación del conocimiento científico y de innovaciones tec- nológicas, configuran otro potente conjunto de fuerzas que influyen en la es- tructura funcional y espacial de las actividades económicas urbanas de múltiples modos: inciden, de forma indirecta, a través de movimientos de cambio que impulsan en otras muchas actividades y , de modo dir ecto, me- diante la formación de nuevos subsectores de actividad muy dinámicos. En efecto, se ha constatado la influencia significativa de estas actividades en el crecimiento económico y en la mejora de la competitividad a todas las escalas (Korres, 2009; V ar ga, 2009; Cooke, Asheim et al. , 2011), su considera- ble impacto en la or ganización social y del trabajo (Coats, 2005; Coats y Lekhi, 2008), así como la importancia de la política institucional en el naci- miento y consolidación de este tipo de actividades. También es destacable la SEVERINO ESCOLANO UTRILLA 142 Estudios Geográficos, V ol. LXXV , 276, pp. 139-175, enero-junio 2014 ISSN: 0014-1496, eISSN: 1988-8546, doi: 10.3989/estgeogr.201404 Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 142 desigual incidencia social (brecha digital: digital divide ) y espacial de las acti- vidades de la economía del conocimiento (Hepworth, 1986; EUROSTA T, 2011; Korres, T sobanoglou et al. , 2011). Por otra parte, las innovaciones tecnológicas y de organización de los siste- mas de producción, distribución y consumo han promovido el nacimiento de nuevas actividades (investigación científica, conocimiento, actividades creati- vas) o han renovado los modos de pr oducción de otras tradicionales (financie- ras, seguros), de tal forma que se ha generado un único proceso productivo bienes-servicios, integrado y continuo (Barcet, Bonamy et al. , 1984; Bailly y Coffey , 1994). Esta mayor fluidez hace que se difumine la tradicional especia- lización sectorial, que se desplaza hacia la especialización funcional definida por agrupamientos espaciales de funciones económicas determinadas (Duran- ton y Puga, 2002; Halbert, 2005). La difusión de las aplicaciones del conocimiento y de la innovación tecno- lógica ha impulsado cambios notables en los patrones de localización de mu- chas actividades económicas (Mandeville, 1983; Castells, 1995; Yigitcanlar , 2009). Las ciudades, por su considerable tamaño demográfico y económico, por su gran diversidad socioeconómica y su buena conectividad, son los lu- gares más adecuados para la localización de las actividades de la economía del conocimiento y para el desarrollo pleno del potencial de transformación social, económico y espacial que éstas llevan incorporado (Mitchell, 1995; Moss, 1998). La internacionalización de la economía y los avances tecnológicos conflu- yen también en la consolidación de otra característica fundamental de las eco- nomías urbanas como es el creciente peso económico de los servicios y su omnipresencia en la vida de las ciudades. Su pujanza se debe, entre otras cau- sas, al incremento de la demanda de servicios por los individuos, las familias y las empresas, a la externalización de servicios que antes formaban parte de la actividad industrial y agraria y al crecimiento de los servicios a la colectividad (educativos, sanitarios, culturales, asistenciales) prestados por las institucio- nes o por empresas. El grupo de los «servicios a las empresas» ha alcanzado también un notable desarrollo; por otro lado, los «servicios avanzados a la producción» (investigación, segur os, auditoría, asesoría jurídica, etc.) y los servicios financieros han adquirido una gran importancia estratégica, dada su contribución esencial a la mejora de la competitividad de las empresas. Las considerables implicaciones de los procesos señalados en las econo- mías urbanas avalan el empleo de la «intensidad de conocimiento y el tipo de tecnología» utilizada en la producción de bienes y ser vicios como criterios principales de la clasificación de actividades, combinados con la desagrega- POLARIZACIÓN DE LA ESTRUCTURA FUNCIONAL DE LAS CAPITALES DE PROVINCIA 143 Estudios Geográficos, V ol. LXXV , 276, pp. 139-175, enero-junio 2014 ISSN: 0014-1496, eISSN: 1988-8546, doi: 10.3989/estgeogr.201404 Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 143 ción de los servicios en varias categorías según su orientación al mercado final o a las empresas. Este enfoque permite la inclusión en los análisis de gran va- riedad de actividades económicas que representan la diversidad de la estruc- tura de las economías urbanas de forma bastante satisfactoria; la magnitud se ha medido mediante la población ocupada en cada rama de actividad. 2.2. Algunas tendencias de la localización de las actividades económicas en las ciudades El d esarr ollo conjunt o de las tend encias apun tadas y o tras han cread o nu evas lógicas de desc entrali zación y centra lizació n así co mo req uisito s de loca lizaci ón de las actividades económicas que, articulados con ciertas determinaciones de políticas nacionales, regionales y locales, han modificado la especialización económica de las ciudades y regiones. En general, los perfiles de especialización económica de las ciudades for- man parte de los patrones complejos de localización de actividades caracteri- zados, grosso modo , por la concentración espacial de ciertas actividades en grandes ciudades y por la dispersión selectiva de otras por ciudades medianas y espacios rurales. En consecuencia, determinadas actividades tienden a concentrarse en grandes áreas urbanas que ocupan los puestos de cabeza de las jerarquías ur- banas nacionales e internacionales, en tanto que otras se dispersan por ciuda- des más pequeñas, generalmente bien conectadas a las anteriores por modernos sistemas de transportes y comunicaciones. Abundantes investigaciones empíricas han mostrado la tendencia a la concentración en grandes ciudades de diversas actividades creativas y de la economía del conocimiento (May , 1997, p. 63; Scott, 1997; Acs, 2006; Gla- zer y Grimes, 2009), pero también han constatado su difusión selectiva por ciudades medias e incluso por espacios rurales (Méndez, Sánchez et al. , 2009; Clayton y Morris, 2010; Puissant y Lacour, 2011; Méndez, Michelini et al. , 2012). En el mismo sentido, el crecimiento y diferenciación de actividades de ser- vicios, los avances en las comunicaciones digitales y otros factores han pro- movido, simultáneamente, la revalorización de los centros urbanos como asiento de sedes de empresas, centros de decisión, oficinas, etc., y de áreas pe- riféricas bien comunicadas para la instalación de centros comerciales, oficinas administrativas, centros logísticos, conglomerados de industrias y servicios de alta tecnología y otras. Estas tendencias se plasman con desigual intensidad en SEVERINO ESCOLANO UTRILLA 144 Estudios Geográficos, V ol. LXXV , 276, pp. 139-175, enero-junio 2014 ISSN: 0014-1496, eISSN: 1988-8546, doi: 10.3989/estgeogr.201404 Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 144 el espacio urbano según el tamaño (demográfico, económico, espacial) de las ciudades y su posición en las redes urbanas: son muy nítidas en las grandes entidades urbanas (áreas metropolitanas, ciudades, región…) y se difuminan en las ciudades medianas y pequeñas. En resumen: los centros de las ciudades reúnen ventajas de localización para algunas actividades, como servicios avanzados a la producción, servicios financieros y actividades creativas y de la economía del conocimiento, mien- tras que diversos sectores de las periferias urbanas son más competitivos para la localización de actividades comerciales, de oficinas para desarrollar tareas administrativas, de diferentes tipos de industria, servicios de alta tecnología y centros logísticos. Esta organización espacial de las actividades económicas tiene consecuen- cias metodológicas en la delimitación de las unidades de análisis. El uso de los municipios, como en el presente estudio, sólo recoge la dinámica de las áreas centrales en el caso de las grandes áreas metr opolitanas y no la totalidad de los procesos espaciales y funcionales. A otra escala, la configuración de los perfiles de las actividades económicas de las ciudades está estrechamente asociada a los movimientos que se produ- cen en la jerarquía urbana. La articulación de la jerarquía urbana de las ciuda- des españolas está sujeta, por una parte, a la intervención de fuerzas de integración a escala global, europea, nacional y regional, que afectan con in- tensidad desigual a cada ciudad. Por otra, diversas actuaciones de variado al- cance impulsan también otros procesos de integración. Entre las principales cabe destacar la mejora de las infraestructuras y redes de trasportes y comuni- caciones, en espacial el desarrollo de la r ed ferroviaria de alta velocidad (A VE) (Ureña, 2012). La reor ganización territorial de la administración pública y del poder político (Moreno y Escolano, 1992, pp. 91-141) llevada a cabo con la creación del estado de las autonomías ha favor ecido la integración regional. La constitución de redes de ciudades interconectadas, de diversos niveles jerár- quicos y alcance funcional y espacial variable, ha generado ventajas y externa- lidades asociadas a la contigüidad y a la conectividad que conforman nuevos y cambiantes patrones espaciales de oportunidades para la localización de acti- vidades económicas. Para aprehender esta cualidad dinámica de las estructuras de las activida- des económicas de las ciudades, el presente trabajo se centra en el estudio de las trayectorias temporales e indaga, en la medida que los datos lo permiten, en los cambios recientes de la composición de las actividades económicas de las capitales de provincia y de autonomía y sus itinerarios de diferenciación que han dado lugar a la configuración actual de los perfiles de actividad. POLARIZACIÓN DE LA ESTRUCTURA FUNCIONAL DE LAS CAPITALES DE PROVINCIA 145 Estudios Geográficos, V ol. LXXV , 276, pp. 139-175, enero-junio 2014 ISSN: 0014-1496, eISSN: 1988-8546, doi: 10.3989/estgeogr.201404 Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 145 Los tipos de actividad se consideran como un datum , resultado de decisio- nes de localización. La investigación, de carácter eminentemente exploratorio y empírico, está guiada por tres hipótesis fundamentales que caracterizan las tendencias espaciales de los recientes procesos de restructuración y globaliza- ción socioeconómicos. La primera se refiere a la creciente concentración eco- nómica, política y cultural en las ciudades (metropolitanización) (V eltz, 1997, p. 82; Krätke, 2007), en especial de las actividades relacionadas con el conoci- miento, la cr eatividad, la investigación y la innovación tecnológica. La se- gunda, conectada con la anterior, denota las trayectorias diferenciadas que han seguido las capitales provinciales y autonómicas en la conformación de sus perfiles de especialización funcional: la capitalidad de autonomía figura entre los factores que inter vienen en la especialización económica. La tercera concierne a la escala de los procesos: la conformación de los per files de activi- dad de algunas ciudades no puede explicarse completamente si sólo se enmar- can a escala nacional o subnacional; ciertas actividades encuentran ventajas de localización en ciudades que forman parte de redes urbanas de alcance eu- ropeo o mundial. 3. M ETODOLOGÍA Y DA TOS Un estudio de carácter empírico con datos geográficos como el presente re- quiere que se justifiquen la delimitación de las unidades espaciales, los indica- dores del objeto de estudio y los procedimientos analíticos utilizados. La unidad de análisis empleada en este trabajo es el municipio. Su elec- ción se basa en la existencia de series de datos diacrónicos y sincrónicos con- sistentes. También es un individuo adecuado para reflejar el alcance de las políticas locales. Por otra parte, son bastantes los estudios de localización de actividades económicas que utilizan el municipio como unidad de análisis, pues permite comparar resultados producidos por diferentes enfoques (Mén- dez, Sánchez et al., 2009). Sin embargo, es necesario indicar que esta delimi- tación administrativa puede cercenar algunas conexiones en aquellas áreas urbanas compuestas por varios municipios que funcionan de forma unitaria, y por tanto el municipio solo refleja una imagen parcial del fenómeno estu- diado. La elección de los municipios capitales de provincia y de autonomía y las dos ciudades autónomas es congruente con los objetivos del trabajo, que bus- can identificar y delimitar la posible influencia de la capitalidad autonómica en la estructura de sus perfiles de actividad económica. Esta muestra de ciuda- SEVERINO ESCOLANO UTRILLA 146 Estudios Geográficos, V ol. LXXV , 276, pp. 139-175, enero-junio 2014 ISSN: 0014-1496, eISSN: 1988-8546, doi: 10.3989/estgeogr.201404 Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 146 des, que tienen en común su función administrativa, constituye un conjunto adecuado para la investigación. El tipo y magnitud de actividad económica se han medido por la población ocupada en ramas de actividad desglosadas a dos dígitos de la Clasificación Nacional de Actividades Económicas (CNAE-93, rev . 1) (INE, s/f). Se ha con- siderado que este nivel de detalle es suficiente para alcanzar los objetivos pro- puestos. Los datos de 2011 corresponden a los afiliados a todos los regímenes de la Seguridad Social. Para formar los perfiles funcionales de las capitales provinciales y autonó- economy”. Journal of The Economic Geography , 4, pp. 351-370. UNESCO (2005): T owar ds Knowledge Societies . Paris, UNESCO. POLARIZACIÓN DE LA ESTRUCTURA FUNCIONAL DE LAS CAPITALES DE PROVINCIA 173 Estudios Geográficos, V ol. LXXV , 276, pp. 139-175, enero-junio 2014 ISSN: 0014-1496, eISSN: 1988-8546, doi: 10.3989/estgeogr.201404 Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 173 Ureña, J. M. D. (ed.) (2012): Teritorial Implications of High Speed Rail. A Spanish Per- spective . Farnham (UK), Ashgate. Ureña, J. M. D.; Coronado, J. M.; Garmendia, M. ; et al. (2012): “T errotorial Implica- tions at national and Regional Scales of High-sèed Rail”, en Ureña, J. M. D. (ed.): T err otorial Implications of High Speed Rail. A Spanish perspective . Farnham (UK), Asghate, pp. 129-162. V arga, A. (ed.) (2009): Universities, Knowledge T ransfer and Regional Development. Ge- ography , Entrepr eneurship and Policy . Cheltenham, Inglaterra, Edward Elgar Publi- sing . V eltz, P . (1997): “The dinamics of production systems, territories and cities”, en Moulaert, F . y Scott, A. J. (eds.): Cities, enterprises and society on the eve of 21st cen- tury . London, Pinter , pp. 78-96. Yigitcanlar , T. (2009): “Spatial reestructuring of cities in the age of knowledge econ- omy: insights from Australian cities”, en 2nd Knowledge Cities Summit. Shenzhen, China, QUT Digital Repository . R ESUMEN Parte de la reorganización reciente de las actividades económicas en España se define por la concentración en determinadas áreas urbanas de ciertas actividades económi- cas, especialmente las relacionadas con la creación, gestión y uso de la innovación y el conocimiento, y por la descentralización selectiva de otras. La hipótesis principal de este trabajo asume que la capitalidad de autonomía es un factor que ejerce influencia en la estructura de las actividades económicas de una ciu- dad. En este marco se estudia el alcance de estas tesis referidas a los municipios capi- tales de provincia y de autonomía entre 1981 y 2011. El estudio permite constatar la tendencia a la concentración en determinadas capitales de las actividades de la «eco- nomía del conocimiento » . La buena conectividad de las ciudades o la cercanía a gran- des áreas urbanas son fuerzas de atracción de este tipo de actividades; la capitalidad de autonomía tiene una influencia limitada en núcleos de tamaño intermedio ubica- dos en contextos regionales dinámicos. P ALABRAS CLA VE : especialización; concentración; innovación; capitales; España. A BSTRACT Some fundamental trends of the recent reorganization of economic activities in Spain are defined by the growing concentration in certain urban areas of certain economic activities, especially those related to the creation, management and use of innovation and knowledge, and selective decentralization of others. The main hypothesis of this work assumes that capital of autonomy is a factor that exerts some influence on the structure of economic activities in a city . In this paper we study the scope of this thesis referred to municipalities and provincial capitals of autonomy between 1981 and 2011. The study conducted helps verify the trend to- SEVERINO ESCOLANO UTRILLA 174 Estudios Geográficos, V ol. LXXV , 276, pp. 139-175, enero-junio 2014 ISSN: 0014-1496, eISSN: 1988-8546, doi: 10.3989/estgeogr.201404 Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 174 wards concentration of capital in certain activities of the knowledge economy . The good connectivity of cities or the proximity to large urban areas are attractive forces; the capital of autonomy has a limited influence on intermediate sized nuclei located in dynamic regional contexts. K EY WORDS : specialization; concentration; innovation; capital; Spain. R ÉSUMÉ La réorganisation récente des activités économiques en Espagne est définie d’un côté par la concentration de certaines d’entre elles, en particulier celles liées à la création, gestion et utilisation de l’innovation et de la connaissance dans des zones urbaines concrètes, et de l’autre, par la décentralisation sélective d’autres activités. L ’hypothèse principale de cette recherche accepte que la «capitalité» d’une région au- tonome a des conséquences sur la structure des activités économiques de cette ville. Nous allons donc vérifier cette thèse référée aux municipalités capitales de province ou de région autonome dans la période 1981-2011. Cette analyse permettra de confir- mer la tendance à la concentration des activités de l’économie de la connaissance dans certaines de ces capitales. Une connectivité performante ou la pr oximité de grands ré- seaux urbains constituent des pôles d’attraction pour ces activités; la «capitalité» d’une région autonome a une influence limitée dans le cas de villes moyennes situées dans un contexte régional dynamique. M OTS - CLÈS : spécialisation; concentration; capital; innovation; l’Espagne. POLARIZACIÓN DE LA ESTRUCTURA FUNCIONAL DE LAS CAPITALES DE PROVINCIA 175 Estudios Geográficos, V ol. LXXV , 276, pp. 139-175, enero-junio 2014 ISSN: 0014-1496, eISSN: 1988-8546, doi: 10.3989/estgeogr.201404 Estudios Geograficos 276 Final_Estudios Geograficos 275 08/07/14 14:32 Página 175 ... As a result of the recent demographic growth of the city, it accounts for 57.5% of the total population of the province and 12.5% of the autonomous community. Valladolid ranks thirteenth among the most populated cities in Spain according to the Spanish National Statistics Institute (INE, for its acronym in Spanish), although it is classified among Spanish 'mediumsized cities' [34][35] [36] , which is why its study is interesting as an example for the urban planning of this type of city. Valladolid, as with other Spanish cities, has benefitted from the process of administrative decentralisation, which has mobilised a considerable amount of resources and personnel over the past 30 years [37]. ... ... The exploratory analysis conducted revealed that the census section provides sufficient detail for assessing the city model proposed by the AUE, due to the average dimensions of these spatial units. Census sections are commonly used in the research of different urban issues in Spain [36] as they allow analysis at city and district scales when aggregated and visualised as a whole, while also recognising the neighbourhood or urban sector scales. However, progress must be made towards achieving greater detail with scales that allow very specific decisions to be made for those areas where the planned action will have greater impact. ... Using Maps to Boost the Urban Proximity: Analysis of the Location of Public Facilities According to the Criteria of the Spanish Urban Agenda Developing analysis models that promote the sustainability, compactness and social balance of cities is particularly important in addressing post-pandemic urban planning. In this context, the population's proximity to public facilities is essential for achieving these objectives. Based on this framework, this paper analyses the city of Valladolid (Spain) under the criteria of distance between the population and public facilities proposed by the Spanish Urban Agenda. Specifically, the focus is on calculating the coverage of population with access to the facilities within the recommended distance thresholds using GIS techniques. The methods used relate the facilities with the distance to the population in the census sections, a highly detailed statistical unit. The results have been mapped as a decision making support tool for the city, and show how general coverage of access to facilities for the urban area as a whole is adequate, especially in terms of public transport services, and meets the recommendations of the Spanish Urban Agenda. Maps also reveal how some areas of the city are not covered by most public facilities.
https://www.researchgate.net/publication/268629622_Polarizacion_de_la_estructura_funcional_de_las_capitales_de_provincia_y_autonomia_en_Espana_1981-2011
Categories of Step-Up DC-DC Converters | Encyclopedia MDPI Encyclopedia is a user-generated content hub aiming to provide a comprehensive record for scientific developments. All content free to post, read, share and reuse. Categories of Step-Up DC-DC Converters : Comparison Please note this is a comparison between versions V1 by Marcelo Cavalcanti and V2 by Camila Xu. MICs can have either single-stage or two-stages conversion systems: single-stage MICs perform voltage boosting, MPPT and grid current control in a single DC-AC power conversion; two-stages MICs have a DC-DC stage to boost the PV module DC voltage (between 20 V–45 V) to a higher value (above 380 V, for instance) while tracking the PV module maximum power point, followed by a DC-AC stage, responsible to DC-link voltage regulation and the grid-tied functions. categories of DC-DC converters high step-up DC-DC converters microinverter 1. Introduction In recent years, the deployment of grid-connected photovoltaic (PV) system in large urban centers has increased significantly thanks to cost reductions and technological advances in PV module integrated converters (MICs), intended to perform maximum power point tracking (MPPT) per PV module [ 1 ] . Such feature, known as distributed MPPT, mitigates the power losses caused by PV module mismatch (e.g., manufacturing tolerance) [ 2 ] and enables the installation of PV panel on rooftop with different tilts and orientations, susceptible to partial shading caused by neighbouring buildings [ 3 ] . MICs can have either single-stage or two-stages conversion systems: single-stage MICs perform voltage boosting, MPPT and grid current control in a single DC-AC power conversion; two-stages MICs have a DC-DC stage to boost the PV module DC voltage (between 20 V–45 V) to a higher value (above 380 V, for instance) while tracking the PV module maximum power point, followed by a DC-AC stage, responsible to DC-link voltage regulation and the grid-tied functions [ 4 ] . The main drawback of single-stage MICs is that the double-line-frequency voltage ripples must be filtered by a bulky input electrolytic capacitors at the input side [ 5 ] , which affects the stable implementation of MPPT algorithms and reducing the life span of the entire system whereas two-stages MICs employ proper control strategies alongside small electrolytic capacitors in both conversion stages to eliminate it [ 6 ] . Compared to architectures with central inverter, MICs are inherently safer because the DC energy is converted to AC right at the site of the PV module [ 7 ] . Hence, they operate at the same low-voltage AC power as the grid utility, which means there is no long-distance high voltage DC cables [ 4 ] . Besides, since MICs are mounted in a single PV module and operate independently, system with MICs keeps delivering energy to the grid if one or more MICs fail while if a system with a central inverter fails, the energy production stops completely. Moreover, MICs allow simultaneously usage of different solar panels technology and faster and easier system expansion, possibly at any time, thanks to their plug-and-play technology [ 5 ] . Due to above-mentioned advantages provided for MICs, several high step-up DC-DC converters have been proposed in the literature for being employed as DC-DC power conversion stage in MICs. However, some of them do not meet the other necessary requirements such as high-efficiency, common ground, low input current ripple and reduced weight and volume. Thus, to assist researchers in developing module-level power electronics, this paper categorizes the DC-DC converters based on their constructive and operational characteristics. Then, the principles of elementary voltage-boosting techniques such as switched-capacitor, switched-inductor, magnetic coupling and voltage multiplier cells are approached, with their advantages and disadvantages stated. 2. Categories of Step-Up DC-DC Converters The DC-DC converters topologies proposed in the literature can be categorized according to their operational characteristics. Doing so, it becomes possible to evaluate which characteristics the step-up DC-DC converters intended for PV applications must feature. For this purpose, DC-DC converters can be essentially classified as ( Figure 1 ): isolated or non-isolated; unidirectional or bidirectional; current- or voltage-fed; and hard- or soft-switched. <here is a image a2342374adb46020-b3ebbe647ca77cf7> Figure 1.Categories of step-up DC-DC converters. 2.1. Isolated and Non-Isolated DC-DC Converters Regarding the presence of galvanic isolation, DC-DC converters can be classified into isolated or non-isolated. The isolated converters are characterized for using transformers to obtain the desired voltage gain. However, the leakage inductance of the transformer windings leads to high voltage spikes on the main switch and, consequently, high switching losses. In applications that do not demand high voltage gain or high efficiency, non-isolated converters without magnetic coupling can be a simple (since the design of the magnetic element is eliminated) and adequate solution. There are also non-isolated DC-DC converters that use built-in transformer and/or coupled inductor. These solutions are suitable candidates to be employed in applications where high voltage gain with high efficiency and reliability are required, such as microinverters and power optimizers. In both types of non-isolated DC-DC converters (with or without magnetic coupling), the negative terminal of the output voltage can either be connected to the negative terminal of the input voltage or be floating. However, in grid-connected PV applications where galvanic isolation is not mandatory, the first option can be used to improve system performance. In fact, it helps to reduce the leakage currents between the converter and the point of common coupling, which is grounded. 2.2. Unidirectional and Bidirectional DC-DC Converters In most DC-DC converters, the power flow is unidirectional (from input to output). This feature is required in applications where the input source should only supply power to the load, e.g., PV modules. On the other hand, in applications that have energy storage systems, DC-DC converters with the ability to transfer energy bidirectionally must be used. 2.3. Voltage- and Current-Fed DC-DC Converters With respect to the input filter, DC-DC converters can be classified into voltage- or current-fed. The first configuration is characterized for having a capacitive input filter while the second one has an inductive input filter. The use of an inductive input filter makes possible to attenuate the input current ripple, which is a desired feature to step-up DC-DC converters that are used in PV MICs. Furthermore, both configurations can operate with soft switching in applications with variable input voltage. Due to the characteristics described above, the current-fed DC-DC converters are very popular in PV applications, as PV modules behave as current sources. 2.4. Hard- or Soft-Switched DC-DC Converters The DC-DC converters can operate with hard- or soft-switching. In hard-switched DC-DC converters, the currents and voltages on the semiconductors during the turn-on and turn-off transitions are different from zero, causing switching losses. For this reason, the switching frequency in these converters must be limited, which commits the goals of minimizing the size of the energy storage elements. Besides, these converters are affected by electromagnetic interference problems due to the high current and voltage variation rates. In soft-switched DC-DC converters, the voltage on the switches falls to zero and, immediately after a short time interval—called dead time—the switches are turned on, mechanism known as “zero voltage switching” (ZVS). Furthermore, small capacitors can be added in series with the leakage inductance of the magnetic element to form resonant operation stages. In these stages, the current flowing through the diodes decreases naturally to zero before the diode becomes reverse-biased, mechanism known as “zero current switching” (ZCS). 2.5. Usual Requirements of DC-DC Converters for Microinverters From the evaluation of the operational characteristics presented in this section, the main requirements that DC-DC converters intended for PV microinverters should meet are: (i) Common ground, i.e., the DC-DC converter must be non-isolated; Common ground, i.e., the DC-DC converter must be non-isolated; (ii) High voltage gain capability, i.e., the DC-DC converter must be a step-up converter; and High voltage gain capability, i.e., the DC-DC converter must be a step-up converter; and (iii) unidirectional. unidirectional. It is important to point out that soft switching and resonant mechanisms can lead to reduced switching loss, which is desirable in PV microinverters. As indicated in the requirements described above, step-up DC-DC converters are the most commonly used solution for DC-DC power conversion stage in MICs. The most common converter that belongs to this category is the conventional boost converter. However, it has several drawbacks already observed in the literature, such as its non-capability to provide high voltage gain. Thus, before presenting some step-up DC-DC converters proposed in the literature for PV applications, it is extremely important to understand how basic voltage-boosting techniques work.
https://encyclopedia.pub/entry/history/compare_revision/41203
% households with a refrigerator - Area Database - Region Ranking - Global Data Lab Area Database (v4.2.1) % households with a refrigerator First decile Country / Region Afghanistan / Central Highlands (Bamyan Daikundi) Afghanistan / South East (Ghazni Paktya Paktika Khost) Benin / Atacora (incl Donga) Benin / Mono (incl Couffo) Burkina Faso / Boucle de Mouhoun Burkina Faso / Cascades Burkina Faso / Centre-Est Burkina Faso / Centre-Nord Burkina Faso / Centre-Ouest Burkina Faso / Centre-Sud Burkina Faso / Est Burkina Faso / Nord Burkina Faso / Plateau Central Burkina Faso / Sahel Burkina Faso / Sud-Ouest Burundi / East (Cankuzo, Rutana, Ruyigi ) Burundi / Middle (Gitega, Karuzi, Muramvya, Mwaro) Burundi / North (Kayanza, Kirundo, Muyinga, Ngozi) Burundi / South (Bururi, Makamba) Cambodia / Kampong Chhnang Cambodia / Kampong Spueu Cambodia / Pousat Cambodia / Svay Rieng Central African Republic CAR / RS I (Ombella Mpoko, Lobaye, Kemo, Nana Grebizi, Ouaka) Central African Republic CAR / RS II (Mambera Kadei, Nana Mambere, Sangha Mbaere) Central African Republic CAR / RS III (Ouham Pende, Ouham) Central African Republic CAR / RS IV (Haute-Kotto, Baminigui Bangoran, Vakaga) Central African Republic CAR / RS V (Basse Kotto, Mbornou, Houte Mbormou) Chad / Zone 2 (Borkou, Ennedi, Tibesti, Kanem, Barh El Gazal, Lac) Chad / Zone 3 (Guera, Batha, Salamat) Chad / Zone 4 (Ouaddai, Assongha, Sila, Biltine - Wadi Fira) Chad / Zone 5 (Chari-Baguimi, Dababa, Baguirmi, Hadjer Lamis) Chad / Zone 6 (Mayo-Kebbi Est and Ouest) Chad / Zone 7 (Logone Occidental & Oriental, Monts de Lam, Tandjile Est & Ouest) Chad / Zone 8 (Mandoul, Moyen-Chari, Bahr Koh, Lac Iro) Congo Democratic Republic / Bandundu Congo Democratic Republic / Equateur Congo Democratic Republic / Kasai Occidental Congo Democratic Republic / Kasai Oriental Congo Democratic Republic / Maniema Congo Democratic Republic / Orientale Congo Democratic Republic / Sud-Kivu Eritrea / Anseba Eritrea / Debub Eritrea / Gash-Barka Ethiopia / Amhara Country / Region Ethiopia / SNNP Ethiopia / Somali Guinea / N Zerekore Guinea Bissau / Bolama Guinea Bissau / Cacheu Guinea Bissau / Oio Guinea Bissau / Quinara Guinea Bissau / Tombali Kenya / Eastern Kenya / Western Kiribati / Central Gibert Kiribati / Southern Gilbert Liberia / North Central Liberia / North Western Liberia / South Eastern A Liberia / South Eastern B Liberia / Bong Liberia / Gbarpolu Liberia / Grand Bassa Liberia / Grand Cape Mount Liberia / Lofa Liberia / River Gee Madagascar / Alaotra Mangoro Madagascar / Analanjirofo Madagascar / Anamoroni Mania Madagascar / Androy Madagascar / Anosy Madagascar / Atsimo Andrefana Madagascar / Atsimo Atsinanana Madagascar / Betsiboka Madagascar / Bongolava Madagascar / Haute Matsiatra Madagascar / Itasy Madagascar / Melaky Madagascar / Menabe Madagascar / Sofia Madagascar / Vakinankaratra Madagascar / Vatovavy Fitovinany Malawi / Machinga Malawi / Other central (Nkhota Kota, Mchinji, Dowa, Ntchisi, Dedza, Ntcheu) Malawi / Thyolo Myanmar / Chin Niger / Dosso Niger / Maradi Niger / Tahoua Niger / Zinder Country / Region Panama / Ngobe Bugle Papua New Guinea / Hela Rwanda / East Rwanda / North Rwanda / South Rwanda / West Sierra Leone / Bonthe Sierra Leone / Kailahun Sierra Leone / Kambia Sierra Leone / Koinadugu Sierra Leone / Moyamba Sierra Leone / Pujehun Sierra Leone / Tonkolili Somalia / Bakool Somalia / Banadir Somalia / Bay Somalia / Galguduud Somalia / Gedo Somalia / Hiran Somalia / Lower Juba Somalia / Lower Shabelle Somalia / Middle Juba Somalia / Middle Shabelle Somalia / Sool South Sudan / Eastern Equatoria South Sudan / Jonglei South Sudan / Lakes South Sudan / Northern Bahr El Ghazal South Sudan / Unity South Sudan / Upper Nile South Sudan / Warrap South Sudan / Western Equatoria Tanzania / Dodoma Tanzania / Kagera Tanzania / Lindi Tanzania / Rukwa, Katavi Tanzania / Ruvuma Togo / Savanes Uganda / Eastern (Eastern, East Central) Uganda / Northern (North, Karamoja, West Nile) Uganda / Western (Western, Southwest) Uganda / Eastern (Bukedi, Bugishu, Teso) Uganda / North (Karamoja, Lango, Acholi) Uganda / Southwest (Ankole, Kigezi) Uganda / West Nile Uganda / Western (Bunyoro, Tooro) Second decile Country / Region Afghanistan / East (Nangarhar Kunar Laghman Nooristan) Angola / Bie Benin / Borgou (incl Alibori) Benin / Queme (incl Plateau) Benin / Zou (incl Collines) Bhutan / Gasa Burkina Faso / Hauts Bassins Burundi / West (Bubanza, Buja Rural, Cibitoke, Mairie de Bujumbura) Cambodia / Kampong Cham (incl Tboung Khmum) Cambodia / Kampong Thum Cambodia / Kandal Cambodia / Preah Vihear-Stueng Traeng-Kracheh Cambodia / Prey Veaeng Cambodia / Takaev Cameroon / Extreme Nord Cameroon / Nord Congo Brazzaville / Kouilou Congo Brazzaville / Lekoumou Congo Brazzaville / Likouala Congo Brazzaville / Pool Congo Democratic Republic / Katanga Congo Democratic Republic / Nord-Kivu Cote d'Ivoire / Centre Ouest Cote d'Ivoire / Nord Est Cote d'Ivoire / Ouest Cote d'Ivoire / Sud Ouest Eritrea / Semenawi Keih Bahri Ethiopia / Ben-Gumz Ethiopia / Oromiya Ethiopia / Tigray Guinea / Faranah Guinea / Labe Guinea / Mamou Guinea Bissau / Bafata Guinea Bissau / Gabu Haiti / Artibonite Haiti / Camps Haiti / Grande-Anse, Nippes Haiti / North-West Indonesia / East Timor Kenya / North Eastern Kenya / Nyanza Kenya / Rift Valley Kiribati / Northern Gilbert Lesotho / Thaba-Tseka Liberia / South Central Country / Region Liberia / Bomi Liberia / Grand Gedeh Liberia / Grand Kru Liberia / Margibi Liberia / Maryland Liberia / Nimba Liberia / River Cess Liberia / Sinoe Madagascar / Boeny Madagascar / Ihorombe Madagascar / Sava Malawi / Kasungu Malawi / Mangochi Malawi / Mulanje Malawi / Other northern (Chitipa, Karonga, Rumphi, Nkhata Bay) Malawi / Other southern (Balaka, Mwanza, Phalombe, Chiradzulu, Chikwawa, Nsanje, neno) Malawi / Salima Malawi / Zomba Mali / Gao and Kidal Mali / Kayes Mali / Mopti Mali / Segou Mali / Sikasso Mali / Tombouctou Mauritania / Gorgol Mauritania / Guidimagha Mauritania / Hodh Charghi Mauritania / Hodh Gharbi Mozambique / Cabo delgado Mozambique / Nampula Mozambique / Niassa Mozambique / Tete Mozambique / Zambezia Myanmar / Ayeyarwaddy Myanmar / Rakhine Myanmar / Taninthayi Namibia / Northeast Namibia / Northwest Nepal / Karnali Province Niger / Diffa Nigeria / Bauchi Nigeria / Jigawa Nigeria / Kebbi Nigeria / Sokoto Papua New Guinea / Autonomous Region of Bougainville Papua New Guinea / Enga Country / Region Papua New Guinea / Gulf Papua New Guinea / Jiwaka Papua New Guinea / Madang Papua New Guinea / Milne Bay Papua New Guinea / New Ireland Papua New Guinea / Northern, Oro Papua New Guinea / Southern Highlands Papua New Guinea / West Sepik, Sandaun Papua New Guinea / Western Philippines / ARMM Sierra Leone / Kono Sierra Leone / Port Loko Somalia / Awdal Somalia / Nugal Somalia / Sanaag Somalia / Togdhere South Sudan / Central Equatoria South Sudan / Western Bahr El Ghazal Sudan / North Darfur Sudan / South Darfur Sudan / South Kordofan Sudan / West Darfur Tanzania / Iringa, Njombe Tanzania / Kigoma Tanzania / Mara Tanzania / Mbeya Tanzania / Morogoro Tanzania / Mtwara Tanzania / Mwanza, Geita Tanzania / Pwani Tanzania / Shinyanga, Simiyu Tanzania / Singida Tanzania / Tabora Tanzania / Zanzibar North Timor Leste / Aileu Timor Leste / Ainaro Timor Leste / Ermera Togo / Centrale Togo / Kara Togo / Maritime Togo / Plateaux Uganda / Central (Central 1, Central 2, Kampala) Uganda / Central 2 (Central North) Uganda / East Central (Busoga) Zambia / Eastern Zambia / Northern Third decile Country / Region Afghanistan / North East (Baghlan Takhar Badakhshan Kunduz) Angola / Cunene Angola / Huambo Angola / Kuando Kubango Angola / Kuanza Sul Angola / Moxico Angola / Uige Bangladesh / Dinajpur, Nilphamari, Panchagarh, Thakurgaon Bangladesh / Khagrachhari, Rangamati (Chattagram) Bangladesh / Kurigram, Lalmonirhat, Rangpur Benin / Atlantique (incl Littoral (Cotonou)) Bhutan / Dagana Bhutan / Lhuntse Bhutan / Pemagatshel Bhutan / Trashigang Bhutan / Trashiyangtse Bhutan / Trongsa Bhutan / Tsirang Bolivia / Potosi Cambodia / Banteay Mean Chey Cambodia / Bat Dambang-Krong Pailin Cambodia / Kampot-Krong Kaeb-Krong Preah Sihanouk Cambodia / Mondol Kiri-Rotanak Kiri Cambodia / Siem Reab-Otdar Mean Chey Cameroon / Adamaoua Cameroon / Est Cameroon / Nord Ouest China / Xinjiang Congo Brazzaville / Bouenza Congo Brazzaville / Cuvette Ouest Congo Brazzaville / Plateaux Congo Democratic Republic / Bas-Congo Cote d'Ivoire / Centre Cote d'Ivoire / Centre Est Cote d'Ivoire / Nord Cote d'Ivoire / Nord Ouest Ethiopia / Affar Ethiopia / Gambela Gambia / Janjabureh Gambia / Kuntaur Guinea / Boke Guinea / Kankan Guinea / Kindia Guinea Bissau / Biombo Haiti / Centre Haiti / North Country / Region Haiti / North-East Haiti / South Haiti / South-East Honduras / Gracias a Dios India / Assam India / Bihar India / Jharkhand India / Meghalaya Kenya / Central Kenya / Coast Lesotho / Butha-Buthe Lesotho / Mokhotlong Lesotho / Quthing Liberia / Monrovia Madagascar / Antananarivo Madagascar / Antsiranana Madagascar / Fianarantsoa Madagascar / Mahajanga Madagascar / Toamasina Madagascar / Toliary Madagascar / Analamanga Madagascar / Atsinanana Madagascar / Diana Malawi / Lilongwe Malawi / Mzimba Mali / Koulikoro Mauritania / Assaba Mauritania / Brakna Mauritania / Tagant Mozambique / Inhambane Mozambique / Manica Mozambique / Sofala Myanmar / Bago Myanmar / Kachin Myanmar / Kayah Myanmar / Magway Myanmar / Sagaing Myanmar / Shan Namibia / Ohangwena Namibia / Omusati Nepal / Central Nepal / Sudoorpaschim Province Niger / Agadez Niger / Tillabery (incl Niamey) Nigeria / Adamawa Nigeria / Benue Fourth decile Country / Region Afghanistan / South (Uruzgan Helmand Zabul Nimroz Kandahar) Afghanistan / West (Ghor Herat Badghis Farah) Angola / Bengo Angola / Benguela Angola / Huila Angola / Kuanza Norte Angola / Lunda Norte Angola / Lunda Sul Angola / Malange Angola / Zaire Bangladesh / Bagerhat, Khulna, Satkhira Bangladesh / Bandarban, Cox s Bazar Bangladesh / Barguna, Bhola, Patuakhali Bangladesh / Bogra, Gaibandha, Jaypurhat Bangladesh / Chuadanga, Jhenaidah, Kushtia, Meherpur Bangladesh / Habiganj, Sunamganj Bangladesh / Jessore, Magura, Narail Bangladesh / Kishoreganj, Mymensingh, Netrakona Bangladesh / Naogaon, Nawabganj, Rajshahi Bangladesh / Natore, Pabna, Sirajganj Bhutan / Bumthang Bhutan / Haa Bhutan / Mongar Bhutan / Samdrup jongkhar Bhutan / Zhemgang Bolivia / Chuquisaca Bolivia / La Paz Bolivia / Oruro Burkina Faso / Centre (incl Ouagadougou) Cambodia / Kaoh Kong Cameroon / Ouest Central African Republic CAR / Bangui Chad / Zone 1 (N'Djamena) Comoros / Anjouan (Ndzouani) Comoros / Moheli Congo Brazzaville / Cuvette Congo Brazzaville / Niari Congo Brazzaville / Sangha Cote d'Ivoire / Centre Nord Cote d'Ivoire / Sud, Abidjan Djibouti / Other Districts Eritrea / Maekel Ethiopia / Dire Dawa Ethiopia / Harari Gambia / Kerewan Gambia / Mansakonko Country / Region Ghana / Brong Ahafo Ghana / Northern Ghana / Upper East Ghana / Upper West Ghana / Volta Guatemala / North Guatemala / North-Occidental Guyana / Barima-Waini Guyana / Potaro-Siparuni Guyana / Upper Takutu-Upper Essequibo Haiti / West (incl Metropolitain area) India / Arunachal Pradesh India / Chhattisgarh India / Madhya Pradesh India / Nagaland India / Orissa India / Tripura India / Uttar Pradesh India / West Bengal Indonesia / East Nusa Tenggara Kenya / Nairobi Kiribati / Line and Phoenix Group Lao / Huaphanh Lesotho / Leribe Lesotho / Mafeteng Lesotho / Mohale s Hoek Lesotho / Qasha s Nek Liberia / Montserrado Malawi / Blantyre Mauritania / Adrar Mozambique / Gaza Myanmar / Kayin Myanmar / Mandalay, NayPyitaw Myanmar / Mon Namibia / Central Namibia / Caprivi Namibia / Kavango Namibia / Oshikoto Nepal / Eastern Nepal / Far-western Nepal / Mid-western Nicaragua / Atlantico (Rio San Juan, Atlantico Norte (Raan), Atlantico Sur (Raas)) Nigeria / Akwa Ibom Nigeria / Bayelsa Nigeria / Borno Nigeria / Cross River Country / Region Nigeria / Ekiti Nigeria / Enugu Nigeria / Kaduna Nigeria / Kogi Nigeria / Kwara Nigeria / Nassarawa Nigeria / Niger Nigeria / Ondo Nigeria / Osun Nigeria / Oyo Pakistan / FATA Pakistan / Gilgit Baltistan Panama / Embera Wounaan Papua New Guinea / Central Papua New Guinea / Chimbu, Simbu Papua New Guinea / Morobe Peru / Central (Huancavelica, Huanuco, Junin, Pasco) Philippines / IVB-MIMAROPA Philippines / V-Bicol Philippines / XI-Davao Senegal / Diourbel Senegal / Fatick Senegal / Kaolack Senegal / Louga Senegal / Saint Louis Senegal / Tambacounda Senegal / Ziguinchor Sierra Leone / Western Rural Sudan / Kassala Sudan / Red Sea Sudan / Sinnar Sudan / White Nile Timor Leste / Baucau Timor Leste / Liquica Timor Leste / Manufahi Togo / Lome Uganda / Central 1 (Central South) Yemen / Beida (Al Bayda), Dhamar, Raimah Yemen / Hodeida (Al Hudaydah), Mahweit (Al Mahwit) Zambia / Central Zambia / North-Western Zimbabwe / Manicaland Zimbabwe / Mashonaland East Zimbabwe / Mashonaland West Zimbabwe / Matebeleland South Zimbabwe / Midlands Fifth decile Country / Region Afghanistan / Central (Kabul Wardak Kapisa Logar Parwan Panjsher) Afghanistan / North (Samangan Sar-e-Pul Balkh Jawzjan Faryab) Angola / Namibe Bangladesh / Barisal, Jhalokati, Pirojpur Bangladesh / Chittagong Bangladesh / Faridpur, Manikganj, Rajbari Bangladesh / Feni, Lakshmipur, Noakhali Bangladesh / Gopalganj, Madaripur, Munshiganj, Shariatpur Bangladesh / Jamalpur, Sherpur, Tangail Bangladesh / Maulvibazar, Sylhet Belize / Cayo Bhutan / Chukha Bhutan / Punakha Bhutan / Samtse Bhutan / Sarpang Bhutan / Wangdi Bolivia / Beni Bolivia / Cochabamba Bolivia / Pando Bolivia / Tarija Botswana / Central Botswana / Ghanzi Botswana / Kgalagadi Botswana / Kgatleng Botswana / Kweneng Botswana / North-West, Ngamiland Botswana / Southern Cambodia / Phnom Penh Cameroon / Centre (incl Yaounde) Cameroon / Littoral (incl Douala) Cameroon / Sud Cameroon / Sud Ouest Colombia / Guainja Colombia / Vaupis Comoros / Grande Comore (Ngazidja) Congo Brazzaville / Pointe Noire Congo Democratic Republic / Kinshasa Djibouti / Djibouti Eritrea / Debubawi Keih Bahri Eswatini / Lubombo Eswatini / Shiselweni Ethiopia / Addis Fiji / Cakaudrove, Bua Fiji / Kadavu, Lau, Lomaiviti, Rotuma Gabon / Ngounie Gabon / Nyanga Country / Region Gabon / Ogooue Ivindo Gabon / Woleu Ntem Gambia / Basse Gambia / Brikama Ghana / Ashanti Ghana / Central Ghana / Eastern Ghana / Western Guatemala / Central Guatemala / North-Oriental Guatemala / Peten Guatemala / South-Occidental Guatemala / South-Oriental Guinea Bissau / Bissau Honduras / El Paraiso Honduras / Intibuca Honduras / La Paz Honduras / Lempira India / Andhra Pradesh India / Dadra and Nagar Haveli India / Karnataka India / Maharashtra India / Manipur India / Rajasthan India / Sikkim India / Telangana Indonesia / Central Java Indonesia / Central Sulawesi Indonesia / Irian Jaya (Papua and Papua Barat) Indonesia / Maluku Indonesia / West Kalimantan Indonesia / West Nusa Tenggara Kiribati / Souyth Tarawa Lao / Luangnamtha Lao / Luangprabang Lao / Oudomxay Lao / Phongsaly Lao / Saravane Lao / Sekong Lesotho / Berea Lesotho / Maseru Malaysia / Sabah Mali / Bamako Mauritania / Inchiri Mauritania / Trarza incl Nouakchott Morocco / South Country / Region Morocco / Tensift Mozambique / Maputo Provincia Myanmar / Yangon Namibia / Kunene Namibia / Omaheke Namibia / Oshana Nepal / Western Nicaragua / Central-Norte (Boaco, Chontales, Jinotega, Matagalpa, Esteli, Madriz, Nueva Segovia) Nigeria / Abia Nigeria / Abuja FCT Nigeria / Anambra Nigeria / Delta Nigeria / Edo Nigeria / Imo Nigeria / Lagos Nigeria / Ogun Nigeria / Rivers Pakistan / Balochistan Pakistan / Sindh Panama / Bocas del Toro Peru / North (Tumbes, Piura, Lambayeque, Cajamarca, La Libertad) Peru / North East (Amazonas, Loreto, San Martin, Ucayali) Peru / South (Tacna, Moquegua, Arequipa, Ica, Ayacucho) Philippines / Cordillera Admin Region Philippines / I-Ilocos Philippines / II-Cagayan Valley Philippines / III-Central Luzon Philippines / IX-Zamboanga Peninsula Philippines / VI-Western Visayas Philippines / VII-Central Visayas Philippines / VIII-Eastern Visayas Philippines / X-Northern Mindanao Philippines / XII-SOCCSKSARGEN Philippines / XIII-Caraga Senegal / Thies Sierra Leone / Western Urban Sudan / Al Gezira Tanzania / Dar Es Salam Tonga / Ongo Niua Uganda / Kampala Uzbekistan / Central (Navoi, Bukhara, Samarkand) Uzbekistan / East (Namangan, Fergana, Andizhan) Uzbekistan / South (Kashkadarya, Surkhandarya) Yemen / Ibb Yemen / Taiz Zambia / Copperbelt Sixth decile Country / Region Angola / Cabinda Azerbaijan / Aran Azerbaijan / Dakhlik Shirvan Azerbaijan / Ganja Gazakh Azerbaijan / Lankaran Azerbaijan / Shaki Zaqatala Bangladesh / Brahmanbaria, Chandpur, Comilla Bangladesh / Dhaka Bangladesh / Gazipur, Narayanganj, Narsingdi Belize / Corozal, Orange Walk Bhutan / Paro Bhutan / Thimphu Bolivia / Santa Cruz Botswana / Chobe Botswana / North-East Botswana / South-East Chili / Arbucania China / Hainan China / Yunnan Colombia / Amazonas Colombia / Cauca Colombia / Choco Colombia / Guajira Colombia / Narino Colombia / Putumayo Congo Brazzaville / Brazzaville El Salvador / Central II El Salvador / Occidental El Salvador / Oriental Eswatini / Hhohho Eswatini / Manzini Fiji / Nadroga or Navosa Fiji / Ra Gabon / Estuaire Gabon / Haut Ogooue Gabon / Moyen Ogooue Gabon / Ogooue Lolo Gabon / Ogooue Maritime Gambia / Banjul Gambia / Kanifing Ghana / Greater Accra Guatemala / Metropolitan Guinea / Conakry Guyana / Cuyuni-Mazaruni Guyana / Pomeroon-Supenaam Honduras / Choluteca Country / Region Honduras / Colon Honduras / Comayagua Honduras / Copan Honduras / Ocotepeque Honduras / Olancho Honduras / Santa Barbara Honduras / Valle Honduras / Yoro India / Andaman and Nicobar Islands India / Daman and Diu India / Gujarat India / Himachal Pradesh India / Jammu and Kashmir India / Tamil Nadu India / Uttaranchal Indonesia / Bali Indonesia / Bengkulu Indonesia / Central Kalimantan Indonesia / DI Aceh Indonesia / DI Yogyakarta Indonesia / East Java Indonesia / Gorontalo Indonesia / Jambi Indonesia / Lampung Indonesia / North Sulawesi Indonesia / North Sumatra Indonesia / Riau (incl. Riau islands) Indonesia / South Kalimantan Indonesia / South Sulawesi (incl Sulawesi Barat) Indonesia / South Sumatra Indonesia / Southeast Sulawesi Indonesia / West Java Indonesia / West Sumatra Lao / Attapeu Lao / Bokeo Lao / Savannakhet Lao / Xiengkhuang Malaysia / Kelantan Malaysia / Sarawak Mauritania / Nouadhibou Mexico / Chiapas Mexico / Oaxaca Mexico / Puebla Mongolia / Khangai (Arkhangai, Bayankhongor, Bulgan, Uvurkhangai, Khuvsgul, Orkhon) Mongolia / Western (Bayan-Ulgii, Govi-Altai, Zavkhan, Uvs, Khovd) Morocco / Centre Country / Region Morocco / Centre north Morocco / Centre south Morocco / Eastern Morocco / North west Mozambique / Maputo Cidade Namibia / South Namibia / Erongo Namibia / Hardap Namibia / Karas Namibia / Khomas Namibia / Otjozondjupa Nicaragua / Pacifico (Chinandega, Leon, Managua, Masaya, Granada, Carazo, Rivas) Pakistan / AJK Pakistan / Khyber Pakhtunkhwa (NWFrontier) Pakistan / Punjab Panama / Cocle Panama / Darien Panama / Veraguas Peru / West (Ancash, Lima, Callao) Philippines / IVA-CALABARZON Philippines / National Capital Region Samoa / Savaii Sao Tome & Principe / Regiao Centro Sao Tome & Principe / Regiao Norte Sao Tome & Principe / Regiao Sul Senegal / Dakar South Africa / Eastern Cape Sudan / Khartoum Sudan / Nahr El Nil Suriname / Brokopondo and Sipaliwini Tajikistan / DRS Tajikistan / GBAO Tajikistan / Khatlon Tanzania / Zanzibar West Timor Leste / Dili Tonga / Ha-apai Uzbekistan / Central-East (Dzhizak, Syrdarya) Uzbekistan / West (Karakalpakstan, Khorezm) Venezuela / Apure Venezuela / Portuguesa Vietnam / Central Highlands Yemen / Abyan, Aden (town and countryside), Lahej, Ad Dali (Al Dhalih) Yemen / Sana a (capital; Al Amana), Sana a (governorate) Zambia / Lusaka Zimbabwe / Bulawayo Zimbabwe / Harare Seventh decile Country / Region Angola / Luanda Azerbaijan / Yukhari Karabakh Belize / Belize Belize / Stann Creek, Toledo Brazil / Amazonas Brazil / Para Chili / Aisen Chili / Atacama Chili / Bio Bio Chili / Coquimbo Chili / Los Lagos (incl Los Rios) Chili / Maule Chili / OHiggins Chili / Tarapaca (incl Arica and Parinacota) China / Chongqing, Sichuan, Guizhou, Yunnan, Tibet China / Gansu, Qinghai, Ningxia, Xinjiang China / Gansu China / Guangdong China / Guangxi Zhuang China / Guizhou China / Henan China / Jiangxi China / Ningxia China / Qinghai China / Shanxi China / Sichuan Colombia / Bolivar (Sur and Norte) Colombia / Boyaca Colombia / Caqueta Colombia / Cesar Colombia / Cordoba Colombia / Guaviare Colombia / Magdalena Colombia / Sucre Colombia / Tolima Colombia / Vichada Cuba / Camaguey Cuba / Granma Cuba / Guantanamo Cuba / Holguin Cuba / Las Tunas Cuba / Santiago de Cuba Dominican Republic / Region I (Peravia, San Cristobal, San Jose de Ocoa, Azua) Dominican Republic / Region II (Espaillat, Puerto Plata, Santiago) Dominican Republic / Region III (Duarte, Maria Trinidad Sanchez, Salcedo, Samana) Dominican Republic / Region IV (Independencia, Bahoruco, Barahona, Pedernales) Country / Region Dominican Republic / Region V (El Seibo, La Altagracia, La Romana, San Pedro de Macoris, Hato Mayor) Dominican Republic / Region VI (San Juan, Elias Pina) Dominican Republic / Region VII (Dajabon, Monte Cristi, Santiago Rodriguez, Valverde) Dominican Republic / Region VIII (La Vega, Monsenor Nouel, Sanchez Ramirez) Ecuador / Oriente El Salvador / Central I Fiji / Ba Fiji / Macuata Fiji / Rewa Fiji / Serua, Namosi Fiji / Tailevu Gabon / Libreville-Port Gentil Guyana / East Berbice-Corentyne Guyana / Mahaica-Berbice Honduras / Atlantida Honduras / Francisco Morazan Honduras / Islas de la Bahia India / Haryana India / Kerala India / Lakshadweep India / Mizoram India / New Delhi India / Puducherry Indonesia / Bangka Belitung Indonesia / Banten Indonesia / DKI Jakarta Indonesia / East Kalimantan Jamaica / Manchester, Clarendon Jamaica / St James, Hanover, Westmoreland Jamaica / St Thomas, Portland, St Mary Jamaica / Trelawny, St Elizabeth Lao / Champasack Lao / Khammuane Lao / Sayabury Lao / Vientiane Province Malaysia / Johor Malaysia / Kedah Malaysia / Kuala Lumpur Federal Territory Malaysia / Labuan Federal Territory Malaysia / Pahang Malaysia / Perak Malaysia / Perlis Malaysia / Terengganu Mauritania / Tiris-Zemmour Mexico / Centro (Guerrero, Morelos, Puebla, Tlaxcala, Hidalgo, Michoacan y Colima) Mexico / Sur (Campeche, Chiapas, Oaxaca, Quintana Roo, Tabasco, Veracruz y Yucatan) Country / Region Mexico / Campeche Mexico / Guerrero Mexico / Hidalgo Mexico / San Luis Potosi Mexico / Tlaxcala Mexico / Veracruz Mexico / Yucatan Moldova / Center Moldova / North Moldova / South Mongolia / Central (Dornogovi, Dundgovi, Umnugovi, Selenge, Tuv, Darkhan-Uul, Govisumber) Mongolia / Eastern (Dornod, Sukhbaatar, Khentii) Panama / Area Central Panama / Area Occidental Panama / Chiriqui Panama / Herrera Papua New Guinea / National Capital District Paraguay / North-West (Boqueron, Alto Paraguay, Presidente Hayes, Conception, Amambay, San pedro, Cordillera) Samoa / North West Upolu Samoa / Rest of Upolu Sao Tome & Principe / Regiao do Principe South Africa / Free State South Africa / Gauteng South Africa / KwaZulu Natal South Africa / Mpumalanga South Africa / North West South Africa / Northern Cape South Africa / Northern Province Sudan / Northern Tajikistan / Sughd (formerly Leninabad) Tonga / Vava-u Tuvalu / Nanumea, Nanumaga, Niutao Tuvalu / Vaitupu, Nui, Nukufetau Venezuela / Amacuros Delta Federal Territory Venezuela / Barinas Venezuela / Cojedes Venezuela / Falcon Venezuela / Guarico Venezuela / Lara Venezuela / Merida Venezuela / Monagas Venezuela / Sucre Venezuela / Trujillo Venezuela / Yaracuy Vietnam / North East, North West Yemen / Jawf, Hadramet, Shabda (Shabwah), Marib, Mohra (Al Mahrah) Eight decile Country / Region Albania / Diber Albania / Elbasan Albania / Kukes Azerbaijan / Absheron Azerbaijan / Guba Khachmaz Brazil / Acre Brazil / Alagoas Brazil / Amapa Brazil / Bahia Brazil / Ceara Brazil / Maranhao Brazil / Paraiba Brazil / Pernambuco Brazil / Piaui Brazil / Roraima Brazil / Sergipe Brazil / Tocantins Chili / Norte I - IV Chili / Sur VIII - XII Chili / Antofagasta Chili / Magallanes and La Antartica Chilena Chili / Region Metropolitana Chili / Valparaiso (former Aconcagua) China / Beijing, Tianjin, Hebei, Shandong China / Fujian, Guangdong, Hainan China / Henan, Shanxi, Shaanxi, Inner Mongolia China / Hubei, Jiangxi, Hunan, Guangxi China / Liaoning, Jilin, Heilongjiang China / Anhui China / Chongqing China / Fujian China / Hebei China / Heilongjiang China / Hubei China / Hunan China / Inner Mongolia China / Jilin China / Liaoning China / Shaanxi China / Shandong China / Zhejiang Colombia / Antioquia (incl Medellin) Colombia / Arauca Colombia / Atlantico (incl Barranquilla) Colombia / Bogota D.C. Colombia / Caldas Country / Region Colombia / Casanare Colombia / Cundinamarca Colombia / Huila Colombia / Meta Colombia / Norte de Santander Colombia / Quindio Colombia / Risaralda Colombia / Santander Cuba / Ciego de Avila Cuba / Cienfuegos Cuba / S.Spiritus Cuba / Villa Clara Dominican Republic / Region 0 (Distrito Nacional, Santo Domingo, Monte Plata) Ecuador / Coste Ecuador / Sierra Egypt / Assuit Egypt / Menya Fiji / Naitasiri Georgia / Guria Georgia / Kakheti Georgia / Mtskheta-Mtianeti Georgia / Samegrelo-Zemo Svateni Georgia / Samtskhe-Javakheti Georgia / Shida Kartli Guyana / Demerara-Mahaica Guyana / Essequibo Islands-West Demerara Guyana / Upper Demerara-Berbice Honduras / Cortes India / Chandigarth India / Goa India / Punjab Iraq / Anbar Jamaica / Kingston, St Andrew Jamaica / St Ann, St Catherine Kyrgyzstan / Jalal-Abad Kyrgyzstan / Naryn Kyrgyzstan / Talas Lao / Borikhamxay Malaysia / East Malaysia (Saba, Sarawak) Malaysia / Melaka Malaysia / Negeri Sembilan Malaysia / Pulau Pinang Malaysia / Selangor Mexico / CDMX-Edo Mexico Ciudad de Mexico (Estado de Mexico) Mexico / Noreste (Aguascalientes, Coahuila, Guanajuato, Nuevo Leon, Queretaro, San Luis Potosi, Tamaulipas, Mexico / Baja California Sur Country / Region Mexico / Colima Mexico / Durango Mexico / Guanajuato Mexico / Mexico Mexico / Michoacan de Ocampo Mexico / Morelos Mexico / Nayarit Mexico / Queretaro Mexico / Quintana Roo Mexico / Tabasco Mexico / Zacatecas Pakistan / Islamabad (ICT) Panama / Area Oriental Panama / Colon Panama / Los Santos Panama / Panama Paraguay / Central (Asuncion, Central) Paraguay / North-East (Caaguazu, Alto Parana, Canideyu) Paraguay / South-East (Guaira, Misiones, Paraguari, Neembucu) Paraguay / South-West (Caazapa, Itapua) Saint Lucia / St Lucia rural Saint Lucia / St Lucia urban Samoa / Apia Urban Area South Africa / Western Cape Suriname / Commewijne and Marowijne Syria / Al Raka-Raqqa Thailand / Bangkok Tonga / Eua Tonga / Tongatapu Trinidad & Tobago / East Tuvalu / Funafuti Uruguay / Norte (Artigas, Rivera, Cerro Largo and Trienta y Tres) Venezuela / Amazonas Federal Territory Venezuela / Anzoategui Venezuela / Aragua Venezuela / Bolivar Venezuela / Carabobo Venezuela / Miranda Venezuela / Tachira Venezuela / Vargas Venezuela / Zulia Vietnam / Mekong River Delta Vietnam / North Central Coast and South Central Coast Vietnam / Red River Delta Vietnam / South East Ninth decile Country / Region Albania / Fier Albania / Korce Albania / Lezhe Albania / Shkoder Algeria / Hauts Plateaux Centre (Djelfa, Laghouat, MSila) Algeria / Hauts Plateaux Ouest (Tiaret, Saida, Tissemsilt, Naama, El Bayadh) Argentina urban / Gran Buenos Aires Argentina urban / NEA Argentina urban / NOA Armenia / Ararat Armenia / Armavir Armenia / Gegharkunik Armenia / Lori Armenia / Shirak Armenia / Syunik Armenia / Tavush Armenia / Vayots Dzor Azerbaijan / Baku Barbados / St Michael Brazil / Goias Brazil / Mato Grosso Brazil / Mato Grosso do Sul Brazil / Minas Gerais Brazil / Parana Brazil / Rio Grande do Norte Brazil / Rondonia Chili / Centro V - VII China / Shanghai, Jiangsu, Zhejiang, Anhui China / Beijing China / Jiangsu China / Tianjin Colombia / San Andres Colombia / Valle (incl Cali) Costa Rica / Alajuela Costa Rica / Guanacaste Costa Rica / Heredia Costa Rica / Limon Costa Rica / Puntarenas Cuba / C. Habana Cuba / Isla Cuba / Matanzas Cuba / Pinar del Rio Cuba / Prov. Habana Egypt / Behera Egypt / Dakahlia Egypt / Fayoum
https://globaldatalab.org/areadata/rankings/fridge/?highlight=GINr102
D OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-09:56:42.414 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-09:59:42.418 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:03:12.430 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:06:42.438 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:10:12.449 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:13:42.457 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:17:12.469 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:20:12.480 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:23:42.484 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:26:42.492 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:30:42.500 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:33:42.508 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:37:12.520 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:40:42.527 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:44:12.543 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:47:12.547 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:51:42.559 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:54:42.563 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-10:58:42.574 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:01:42.582 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:05:42.594 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:08:42.605 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:12:12.613 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:15:42.617 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:17:42.625 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:20:42.633 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:23:42.645 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:27:12.652 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:30:12.660 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:33:42.668 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:37:12.680 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:40:12.688 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:43:42.695 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:47:12.707 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:50:42.711 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:53:42.719 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-11:57:12.730 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-12:00:42.738 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-12:04:12.750 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-12:07:12.762 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-12:10:42.770 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-12:14:12.781 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-12:17:42.785 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-12:21:12.801 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-12:24:12.805 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED 14/338-12:27:42.813 CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN CLOSED
https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20190820T173843/anc/eng/usm4/sci_anc_usm414_336_342.drf
Molar Mass of Unknown Gas Seth Hatfield - Copy.docx View Molar Mass of Unknown Gas Seth Hatfield - Copy.docx from CHM 151 at Richmond Community College. Determination of the Molar Mass of an Unknown LiquidBackgroundIn this lab, a volatile organic liqui Molar Mass of Unknown Gas Seth Hatfield - Copy.docx Determination of the Molar Mass of an Unknown Liquid Background In this lab, a volatile organic liquid is vaporized, and its molar mass determined using the Dumas method. The ideal-gas equation is used to calculate the molar mass of the vapor at room pressure and the boiling point of the water bath. Its identity will be determined from a given list of organic compounds and their molar masses. Once identified, a percentage of error will be calculated for the experimental molar mass. The Dumas method depends on vaporizing a small amount of a volatile organic substance in a known volume at a known temperature. This is typically done using a flask of known volume, adding a small amount of organic substance, and then placing the flask into boiling water until all the organic substance vaporizes. If done correctly, all the air and other gases in the flask are expelled and the flask contains only the organic substance as a gas at atmospheric pressure. The flask is cooled and the gas condenses back into a liquid; it is then weighed. Molar mass is defined as the mass in grams of 1 mole of a substance. If you determine the mass and moles you can determine the molar mass. You will determine the mass of gas on an analytical balance and use the ideal gas equation to determine the number of moles. We will use a version of the ideal gas equation to determine the molar mass of the gas. MM = mRT PV MM is the molar mass. m is the mass of liquid left after the experiment. R is the ideal gas constant (0.08206 L.atm/(mol.K)) T is the temperature in Kelvins P is the pressure (we will use 1.0 atm) V is the volume of the flask (you will have to measure this, not use the volume listed on the flask). Time Requirements ~60 – 75 minutes Materials Unknown liquid – Provided Laboratory balance – Provided 125-mL Erlenmeyer Flask – Provided Thermometer – Provided 50-mL Graduated cylinder – Provided 10-mL Graduated cylinder – Provided Ruler – Student Provided Pan – Student Provided Oven mitt, pot holder and/or Tongs - Student Provided 12 x 15” Aluminum foil – Student Provided Rubber band – Student Provided Safety Precautions  Wear safety glasses at all times while performing this experiment.  The unknown liquid and its vapors are flammable. Be sure to keep away from open flames.  Keep the unknown liquid away from children and pets. It should be stored in a cool, dark place away from heat and ignition sources. Use a hot pad or oven mitg to remove the flask from the boiling water.  Do not eat, drink, or chew gum while performing this experiment. Wash your hands with soap and water before and after performing this experiment. Clean the area with soap and water after performing and completing this experiment. Keep pets and children away from lab materials and equipment. Procedure 1. Record the unknown number in Data Table 1. 2. Cut tw0 7 x 7 cm squares of aluminum foil. 3. Weigh the empty 125-mL Erlenmeyer flask using the laboratory balance and record this in Data table 1. 4. Measure approximately 5 mL of the unknown liquid with a 10-mL graduated cylinder and pour the liquid into the Erlenmeyer flask. 5. Place the center of a 7-cm square of aluminum foil over the mouth of the flask and crimp the edges down over the rim. The foil should be tuat (pretty flat) across the mouth. 6. Secure the foil just below the rim with a rubber band. 7. Make a tiny hole in the center of the aluminum foil with a straight pin. 8. Place the flask in the middle of a saucepan. Hold the flask down with one hand (or some tongs) and add water to the saucepan until it rises to the 100-mL mar on the outside of the flask. 9. Remove the flask and set the pan of water on the burner of a stove. 10. Turn on the stove and heat the water in the pan to boiling. 11. Holding the flask with an oven mitt or pot holder, please the flask into the pan with the boiling water. You can hold the flask down with some tongs if you want or just let it tip to the side making sure it doesn’t tip over. 12. Heat the flask until you don’t see any more liquid in the bottom of the flask. If you can’t see if there is liquid or not, heat for a total of approximately 10 minutes. 13. Record the temperature of the boiling water. 14. Turn off the burner. 15. Using an oven mitt, pot holder or tongs remove the flask and place it on another pot holder or heat resistant surface to cool for a few minutes. 16. Hold the flask by the neck at a 45 o angle and place it under a stream of cool/cold water to continue cooling it to room temperature. Do not allow the running water to touch the aluminum foil cover. 17. Wipe the outside of the flask dry with a paper towel. 18. Remove the rubber band and aluminum foil. Dry any moisture from the outside of the flask neck with a paper towel. 19. Measure the mass of the flask and condensed vapor and record this value in Data Table 1 for Trial 1. 20. Rinse out the flask with tap water and thoroughly dry with paper towels. 21. Repeat this for 1 additional trial. Calculations 1. Determine the volume of the Erlenmeyer flask by filling it up with water. Pour the water from the flask into your 50-mL graduated cylinder as many times as necessary to determine the total volume of the flask. Record this volume in Data Table 1. Conversely, you can use the 50-mL graduated cylinder to add water to the Erlenmeyer flask until it is full making sure you keep a running total of all the water added. 2. You will use 1.00 atm as your atmospheric pressure. In NC, it is very rarely much different that that. Record this in Data Table 1. Possible Unknowns Unknown Molar mass (g/mol) Ethanol 46.07 Isopropyl alcohol 60.01 Hexane 86.18 Toluene 92.14 Data Table 1. Compound used ___#133__________ Trial 1 Trial 2 Mass empty flask (g) 84.82g 85.16g Mass of flask and condensed vapors after cooling (g) 84.92g 85.25 Mass of condensed vapor (g) 0.30g 0.32g Boiling water temperature ( o C) 100 Degrees C 100 Degrees C Boiling water temperature (K) 375.15 Degrees K 375.15 Degrees K Barometric Pressure (atm) 1 atm 1 atm Volume of Flask (mL) 155 mL 155 mL Volume of Flask (L) 0.155L 0.155L Molar mass of unknown MM = mRT PV 59.61 g/Mol 63.58 g/Mol Average Molar Mass 61.60 g/Mol % Error .902% Error 1. Show a calculation of molar mass using your data. ATTACHED ON NEXT PAGE, I HAD PRINTER ISSUES TODAY! 2. What is the chemical formula of your compound? 3. Calculate the molar mass (molecular weight) for your compound using the periodic table and based on the chemical formula.
https://www.cliffsnotes.com/file/188916291/Molar-Mass-of-Unknown-Gas-Seth-Hatfield-Copydocx/
JMIR Research Protocols - An Integrated Approach to Control Soil-Transmitted Helminthiasis, Schistosomiasis, Intestinal Protozoa Infection, and Diarrhea: Protocol for a Cluster Randomized Trial Background: The global strategy to control helminthiases (schistosomiasis and soil-transmitted helminthiasis) emphasizes preventive chemotherapy. However, in the absence of access to clean water, improved sanitation, and adequate hygiene, reinfection after treatment can occur rapidly. Integrated approaches might be necessary to sustain the benefits of preventive chemotherapy and make progress toward interruption of helminthiases transmission. Objective: The aim of this study was to assess and quantify the effect of an integrated control package that consists of preventive chemotherapy, community-led total sanitation, and health education on soil-transmitted helminthiasis, schistosomiasis, intestinal protozoa infection, and diarrhea in rural Côte d’Ivoire. Methods: In a first step, a community health education program was developed that includes an animated cartoon to promote improved hygiene and health targeting school-aged children, coupled with a health education theater for the entire community. In a second step, a cluster randomized trial was implemented in 56 communities of south-central Côte d’Ivoire with 4 intervention arms: (1) preventive chemotherapy; (2) preventive chemotherapy plus community-led total sanitation; (3) preventive chemotherapy plus health education; and (4) all 3 interventions combined. Before implementation of the aforementioned interventions, a baseline parasitologic, anthropometric, and hygiene-related knowledge, attitudes, practices, and beliefs survey was conducted. These surveys were repeated 18 and 39 months after the baseline cross-sectional survey to determine the effect of different interventions on helminth and intestinal protozoa infection, nutritional indicators, and knowledge, attitudes, practices, and beliefs. Monitoring of diarrhea was done over a 24-month period at 2-week intervals, starting right after the baseline survey. Results: Key results from this cluster randomized trial will shed light on the effect of integrated approaches consisting of preventive chemotherapy, community-led total sanitation, and health education against infections with soil-transmitted helminths, schistosomes, an intestinal protozoa and prevention of diarrhea in a rural part of Côte d’Ivoire. Conclusions: The research provided new insights into the acceptability, strengths, and limitations of an integrated community-based control package targeting helminthiases, intestinal protozoa infections, and diarrhea in rural communities of Côte d’Ivoire. In the longer term, the study will allow determining the effect of the integrated control approach on infection patterns with parasitic worms and intestinal protozoa, diarrheal incidence, anthropometric measures, and hygiene-related knowledge, attitudes, practices, and beliefs. Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN): 53102033; http://www.isrctn.com/ISRCTN53102033 (Archived by WebCite at http://www.webcitation.org/6wpnXEiHo) Registered Report Identifier: RR1-10.2196/9166 This paper is in the following e-collection/theme issue: RCTs - Protocols/Proposals (non-eHealth) (230) An Integrated Approach to Control Soil-Transmitted Helminthiasis, Schistosomiasis, Intestinal Protozoa Infection, and Diarrhea: Protocol for a Cluster Randomized Trial An Integrated Approach to Control Soil-Transmitted Helminthiasis, Schistosomiasis, Intestinal Protozoa Infection, and Diarrhea: Protocol for a Cluster Randomized Trial Authors of this article: Giovanna Raso 1, 2 ; Clémence Essé 3, 4 ; Kouassi Dongo 3, 4 ; Mamadou Ouattara 3, 4 ; Fabien Zouzou 3, 5 ; Eveline Hürlimann 1, 2 ; Veronique A Koffi 3, 4 ; Gaoussou Coulibaly 3, 4 ; Virginie Mahan 3, 4, 6 ; Richard B Yapi 3, 4 ; Siaka Koné 3 ; Jean Tenena Coulibaly 3, 4 ; Aboulaye Meïté 7 ; Marie-Claire Guéhi-Kabran 8 ; Bassirou Bonfoh 1, 2, 3 ; Eliézer Kouakou N'Goran 3, 4 ; Jürg Utzinger 1, 2 Marie-Claire Guéhi-Kabran 10 , MBA ; Bassirou Bonfoh 1, 2, 3 , PhD ; Eliézer Kouakou N'Goran 3, 6 , PhD ; Jürg Utzinger 1, 2 , PhD 1Swiss Tropical and Public Health Institute, Basel, Switzerland 2University of Basel, Basel, Switzerland 3Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Abidjan, Côte d'Ivoire 4Unité de Formation et de Recherche Sciences de l'Homme et de la Société, Université Félix Houphouët-Boigny, Abidjan, Côte d'Ivoire 5Unité de Formation et de Recherche Sciences de Terre et des Ressources Minières, Université Félix Houphouët-Boigny, Abidjan, Côte d'Ivoire 6Unité de Formation et de Recherche Biosciences, Université Félix Houphouët-Boigny, Abidjan, Côte d'Ivoire 7FAIRMED, Bern, Switzerland 8UNICEF Côte d'Ivoire, Abidjan, Côte d'Ivoire 9Programme National de Lutte contre les Maladies Tropicales Négligées à Chimiothérapie Préventive, Ministère de la Santé et de l'Hygiène Publique, Abidjan, Côte d'Ivoire 10Direction de l'Assainissement et du Drainage, Ministère de l'Urbanisme, Abidjan, Côte d'Ivoire Corresponding Author: Giovanna Raso, PhD Swiss Tropical and Public Health Institute Socinstrasse 57 Basel, CH-4002 Switzerland Phone: 41 61 2848307 Abstract Background:The global strategy to control helminthiases (schistosomiasis and soil-transmitted helminthiasis) emphasizes preventive chemotherapy. However, in the absence of access to clean water, improved sanitation, and adequate hygiene, reinfection after treatment can occur rapidly. Integrated approaches might be necessary to sustain the benefits of preventive chemotherapy and make progress toward interruption of helminthiases transmission. Objective:The aim of this study was to assess and quantify the effect of an integrated control package that consists of preventive chemotherapy, community-led total sanitation, and health education on soil-transmitted helminthiasis, schistosomiasis, intestinal protozoa infection, and diarrhea in rural Côte d’Ivoire. Methods:In a first step, a community health education program was developed that includes an animated cartoon to promote improved hygiene and health targeting school-aged children, coupled with a health education theater for the entire community. In a second step, a cluster randomized trial was implemented in 56 communities of south-central Côte d’Ivoire with 4 intervention arms: (1) preventive chemotherapy; (2) preventive chemotherapy plus community-led total sanitation; (3) preventive chemotherapy plus health education; and (4) all 3 interventions combined. Before implementation of the aforementioned interventions, a baseline parasitologic, anthropometric, and hygiene-related knowledge, attitudes, practices, and beliefs survey was conducted. These surveys were repeated 18 and 39 months after the baseline cross-sectional survey to determine the effect of different interventions on helminth and intestinal protozoa infection, nutritional indicators, and knowledge, attitudes, practices, and beliefs. Monitoring of diarrhea was done over a 24-month period at 2-week intervals, starting right after the baseline survey. Results:Key results from this cluster randomized trial will shed light on the effect of integrated approaches consisting of preventive chemotherapy, community-led total sanitation, and health education against infections with soil-transmitted helminths, schistosomes, an intestinal protozoa and prevention of diarrhea in a rural part of Côte d’Ivoire. Conclusions:The research provided new insights into the acceptability, strengths, and limitations of an integrated community-based control package targeting helminthiases, intestinal protozoa infections, and diarrhea in rural communities of Côte d’Ivoire. In the longer term, the study will allow determining the effect of the integrated control approach on infection patterns with parasitic worms and intestinal protozoa, diarrheal incidence, anthropometric measures, and hygiene-related knowledge, attitudes, practices, and beliefs. Trial Registration:International Standard Randomized Controlled Trial Number (ISRCTN): 53102033; http://www.isrctn.com/ISRCTN53102033 (Archived by WebCite at http://www.webcitation.org/6wpnXEiHo) Registered Report Identifier:RR1-10.2196/9166 JMIR Res Protoc 2018;7(6):e145 doi:10.2196/resprot.9166 Keywords community-led total sanitation ; Côte d’Ivoire ; diarrhea ; health education ; integrated control ; intestinal protozoa ; preventive chemotherapy ; schistosomiasis ; soil-transmitted helminthiasis Introduction The global strategy to control helminthiases (eg, schistosomiasis and soil-transmitted helminthiasis) emphasizes preventive chemotherapy, that is, the periodic administration of anthelmintic drugs to at-risk populations, most importantly school-aged children [ 1]. However, preventive chemotherapy does not prevent people from rapid reinfection with parasitic worms [ 2, 3]. In view of the current discussion and efforts to shift from morbidity control to interruption of transmission of helminthiases and other neglected tropical diseases, ongoing efforts need to be intensified, along with concurrent implementation of complementary interventions [ 4- 7]. Indeed, integrated approaches, combining preventive chemotherapy with water, sanitation, and hygiene and information, education, and communication, are necessary to sustain the gains made in the control of helminthiases and eventually break transmission [ 8- 11]. In 2015, an estimated 2.4 billion people globally lacked access to improved sanitation, and the absolute number of people practicing open defecation in Africa had increased since 1990 [ 12]. There is evidence that a considerable part of the global burden of disease is attributable to unsafe sanitation, poor water quality, and inadequate hygiene behavior [ 13, 14] and that improved sanitation and water supply are key factors for prevention, control, and elimination of helminthiases and diarrhea [ 11, 15- 18]. Yet, current control efforts do not take these aspects sufficiently into account. Combined interventions have shown around 35% reduction in the incidence of diarrheal diseases and helminthiases [ 15, 19, 20] with improved sanitation being particularly important [ 21]. Studies pertaining to the effect of improved sanitation combined with preventive chemotherapy suggest reductions of 75% and up to 90% for each of the 3 common soil-transmitted helminth species ( Ascaris lumbricoides, hookworm, and Trichuris trichiura) [ 22, 23]. Hence, sanitation and specific health education protect people from rapid reinfection, consolidate the gains of preventive chemotherapy, and are crucial for the sustainability of control programs [ 24- 26]. In 2013, a project was launched in south-central Côte d’Ivoire with the aim to assess and quantify the effect of preventive chemotherapy, combined with either community-led total sanitation (CLTS), or health education, or both measures combined, on reinfection with soil-transmitted helminths, schistosomes, intestinal protozoa, and the incidence of diarrhea, using a cluster randomized design. CLTS was initially designed to reduce diarrhea incidence; through a participatory grassroots approach, it aims to achieve and sustain an open defecation-free status of the target community [ 27]. In a first step, we developed a community health education program (CHEP), including an animated cartoon entitled Koko et les lunettes magiquesfor school-aged children [ 28] and a health education theater targeting the entire community. The emphasis of these health education tools is placed on improving people’s hygiene behavior to prevent the transmission of neglected tropical diseases and diarrhea. In a second step, a cluster randomized trial was implemented in 56 communities of the Taabo, Djékanou, and Toumodi departments in south-central Côte d’Ivoire. Here, we present the study protocol with particular consideration to the cluster randomized trial, whose aim was to assess the effect of preventive chemotherapy combined with either CLTS or CHEP, or both on infections with soil-transmitted helminths, schistosomes, and intestinal protozoa. Methods Ethics Approval and Consent to Participate Ethical clearance for the study was obtained from the Ethics Committee of Basel (EKBB; reference no. 300/13, date of approval: November 11, 2013) and from the ethics committee of the Ministry of Health and Public Hygiene in Côte d’Ivoire (reference no. 76-MSLS-CNER-dkn, date of approval: November 28, 2013). The trial is registered (ISRCTN53102033, date of approval: March 26, 2014). Written informed consent was obtained from each participant, with parents/guardians consenting on behalf of children younger than 18 years. Study Area and Participants Between July 2011 and December 2012, an 18-month pilot project, entailing a baseline parasitologic and knowledge, attitudes, practices, and beliefs (KAPB) cross-sectional survey, followed by a cross-sectional follow-up survey, was carried out to study the effect of an integrated disease control package, consisting of preventive chemotherapy, CLTS, and health education against helminthiases and intestinal protozoa infections in 9 communities of the Taabo health and demographic surveillance system in south-central Côte d’Ivoire [ 29- 32]. The results of this pilot project provided an indication that an integrated control package reduced the prevalence of helminth and intestinal protozoa infections and improved people’s hygiene knowledge and practice. In addition, the study results suggested that health education is an important complement, as it enhanced CLTS acceptance in the community [ 33]. Following this pilot project, a larger study was launched in 2013 to assess the effect of an integrated control package in a community cluster randomized trial with 4 intervention arms (preventive chemotherapy alone, or combined with either CLTS or CHEP, or both interventions simultaneously). This trial was implemented in 56 rural communities in 3 departments of south-central Côte d’Ivoire; namely, Taabo, Djékanou, and Toumodi. In this part of Côte d’Ivoire, people are mainly engaged in subsistence agriculture, whereas rubber, cocoa, and coffee are farmed as cash crops. Development and Validation of Health Education Tools Before starting the cluster randomized trial in the 3 departments, 2 types of health education tools were developed, refined, and tested—an animated cartoon entitled Koko et les lunettes magiques[ 28] and a community-based health theater. For the development of the animated cartoon, a formative research was conducted with school-aged children to identify key messages to improve hygiene behavior and to prevent transmission of neglected tropical diseases that were subsequently included in the video. The research was done with school-enrolled and nonenrolled children in 8 localities in south-central and western Côte d’Ivoire, in the same regions where further studies would take place [ 28]. Hence, the 8 localities were excluded from further research. The animated cartoon was produced by an Abidjan-based cartoon company, in collaboration with the research team, and was tested for comprehension and acceptance with school children. Subsequently, the cartoon was validated, and its effect on helminth infections and KAPB was determined in an intervention study comprising 25 schools of western Côte d’Ivoire from 2014 to 2015. This intervention study confirmed that knowledge of school children was improved after screening the cartoon, and hence, the cartoon was deemed a useful tool for health education. However, no significant effects on helminth infections were observed in the short term. As for the development of the animated cartoon, the health education theater was coupled to a KAPB survey in the community. Questionnaires and focus group discussions (FGDs) were administered to groups of women, men, young adults, and the elderly in 2 communities of the nearby Tiassalé department. In addition, direct observations were made with an emphasis on hygiene behavior and transmission of neglected tropical diseases. Community members constituted a theater group that was assisted by the research team who provided a health education session, according to KAPB survey results. The community theater members designed the sketches on their own and conveyed hygiene and health messages during their performance in front of the community. The health education theater was tested with 2 communities and then evaluated for its acceptance in the community in 2014. For this purpose, the team discussed with the community their opinion about the intervention, whether they liked it, if they thought it was helpful to improve their health knowledge, and whether they would welcome such kind of interventions. Figure 1summarizes the 3-step methodological approach for the development of health education tools, comprising identification of key messages, development, and refinement of the tool. Cluster Randomized Trial Design Once the health education tools had been developed and validated, a 4-armed cluster randomized trial was launched. The primary outcome of the trial was hookworm infection, as determined by the Kato-Katz method [ 34]. Secondary outcomes were other parasitic infections (ie, other soil-transmitted helminths, Schistosomaspp., and intestinal protozoa) and intensity of helminth infection, KAPB with regard to hygiene and intestinal parasitic infections, diarrhea incidence, and anthropometry of infants. Hookworm infection was chosen as primary outcome because of its endemicity across Côte d’Ivoire and the moderate to high prevalence in the study area [ 33, 35]. Details of the specific outcomes are provided in the following sections. In a first step, a baseline parasitologic, KAPB, and anthropometric survey was implemented in 56 communities (14 communities per arm). Sample size calculation was done using the Web-based sample calculator for cluster randomized trials presented elsewhere [ 36], assuming a baseline hookworm prevalence of 30% according to previous studies in the region [ 33, 37], a prevalence reduction of 50% after implementation of interventions [ 33], an intracluster correlation of .4 as we expected high correlation within the community because of the nature of community-based bottom-up interventions and mass drug administration within a community, and a dropout rate of 30% at each follow-up according to previous experience of the team, resulting in 152 individuals per cluster. In Côte d’Ivoire, the average number of people in a household is 7 (our assumption was 2 adults and 5 children). For a sample size of 152 children per community, we thus needed 30 households per community. The communities were selected based on their population size. We intended to include communities with at least 30 households and a population size not exceeding 600 individuals because this is the optimal recommended size for implementation of the CLTS intervention [ 27]. Given the demographic characteristics of the study area, somewhat smaller communities (slightly less than 30 households) and villages exceeding 600 individuals were also included. The selection of up to 30 households per community was done at random, according to the World Health Organization’s (WHO) Expanded Program on Immunization method [ 38]. ‎ Figure 1. Proposed 3-step process for the development and testing of health education tools for the control of neglected tropical diseases. KAPB: knowledge, attitudes, practices, and beliefs. Our main target group was children aged 5 to 15 years, on whom sample size calculation was based. In addition, whenever possible, 1 infant (aged 12-24 months) and 1 adolescent or adult (aged >15 years) from each household were also selected. Although all the 3 groups underwent parasitologic examinations, only infants were subjected to anthropometric measurements. Household heads (or their spouses/partners) were administered a questionnaire for KAPB, whereas direct observations occurred in each household to check for the presence, use, and maintenance of latrines as well as potential open defecation and waste disposal sites in close proximity. The questionnaire included a section reserved for these observations that were made by the interviewer during the interview. FGDs were conducted with selected groups (adult women, adult men, school-aged children, and the elderly), and in-depth interviews were conducted with head of communities and community health workers in 24 communities. The topics discussed during the FGDs were the same as for the questionnaires so that qualitative and quantitative results complemented each other. We monitored diarrhea over a 24-month period, determining the length and frequency of each episode, using a rapid assessment questionnaire carried out once every 2 weeks. The trial communities were assigned by restricted randomization to 1 of the 4 intervention arms with 14 communities per intervention arm based on baseline soil-transmitted helminth prevalence and population size [ 39]. The 4 intervention arms are as follows: (1) intervention arm 1: preventive chemotherapy only; (2) intervention arm 2: preventive chemotherapy plus CLTS; (3) intervention arm 3: preventive chemotherapy plus health education; and (4) intervention arm 4: all interventions combined. Figure 2shows the study area with the 56 selected rural communities, stratified by intervention arm. Interventions started right after randomization of the communities. A first follow-up parasitologic and KAPB survey was carried out 18 months after the baseline cross-sectional survey. A second follow-up survey was scheduled another 21 months later. At the end of the CLTS intervention, the communities were visited and inspected using standardized forms. Transects were done to assess whether open defecation and waste disposal spots were visible, and all households were inspected for the availability of latrines. A summary of the study design is presented in Figure 3. ‎ Figure 2. Map displaying communities included in the cluster randomized trial in 3 departments of south-central Côte d’Ivoire randomly assigned to one of 4 intervention arms. PC: preventive chemotherapy; CLTS: community-led total sanitation; CHEP: community health education program. ‎ Figure 3. Experimental design of the cluster randomized trial. The periodic cross-sectional surveys are highlighted in purple color, diarrhea monitoring is marked in blue, and interventions are highlighted in orange. CLTS: community-led total sanitation; CHEP: community health education program; KAPB: knowledge, attitudes, practices, and beliefs. Enrollment and Written Informed Consent For the whole study, including the parasitologic survey, preventive chemotherapy, the KAPB survey, and the interventions (CLTS and CHEP), village authorities were contacted once ethical approval had been granted. The objectives, procedures, and potential risks and benefits were explained. Subsequently, the community was informed about the aims and procedures. A patient information sheet was administered to all participants, explaining objectives, procedures, and potential risks and benefits of the study. Names and contact address of the main investigators were readily provided on this information sheet so that investigators could be contacted anytime if need be. For illiterate participants, the information sheet was read aloud, and, if necessary, an oral translation of the information into a local language was provided in the presence of a team member and a witness from the community. Written informed consent was obtained from each participant, with parents/guardians consenting on behalf of children (aged <18 years). It was emphasized that participation is voluntary, and hence, participants could withdraw from the study at any time without further obligation. Moreover, it was mentioned that preventive chemotherapy was provided to all people in the study area, not just those who decide to participate, free of charge through the national control program. Inclusion and Exclusion Criteria All household heads or their representatives of the selected households of the 56 communities were invited to participate in the questionnaire survey, and all children aged 5 to 15 years, 1 infant (aged 12-24 months), and 1 adolescent or adult (aged >15 years) from these households were invited for parasitologic examination, unless they met any of the following exclusion criteria: (1) no written informed consent or no parental/guardian’s permission to participate; and (2) too sick to participate in the study, as determined by qualified medical personnel. All members of the intervention communities were invited to participate in the implementation of CLTS and the CHEP sessions. Cross-Sectional Surveys Four teams were formed, each consisting of 1 driver, 2 laboratory technicians, 2 laboratory assistants, 3 field enumerators, 1 parasitologist/epidemiologist (team supervisor), and 1 social scientist. Each team was responsible for carrying out the cross-sectional parasitologic, anthropometric, and KAPB survey in their designated communities. The teams were based in 2 central laboratories of the study area, which are in close proximity to the survey locations. Moreover, 1 to 2 weeks before a cross-sectional survey, the study team visited the communities to announce the upcoming activities and to provide village authorities and inhabitants with exact dates and procedures of the survey. Parasitologic Surveys A day before the first sampling, the study team conducting the survey visited the selected households and distributed empty plastic containers for stool and urine collection. The team revisited the households to collect the samples early in the morning of the next day [ 40]. Stool and urine samples were transferred to laboratories at the general hospitals of Taabo and Djékanou, the community health center at Kpouèbo, or a mobile field laboratory set up at the dispensary of Léléblé. Participants’ infection status with helminths ( A. lumbricoides, hookworm, Schistosoma mansoni, and T. trichiura), pathogenic intestinal protozoa ( Giardia intestinalis, Entamoeba histolytica/E. dispar), as determined in stool samples, and S. haematobium,determined in urine samples, were recorded. From each stool sample, duplicate Kato-Katz thick smears were prepared, using a standard template holding 41.7 mg of feces [ 34]. The slides were allowed to clear for 30 to 45 min before examining under a microscope by experienced laboratory technicians. Helminth eggs were counted and recorded for each species separately. For quality control, approximately 10% of the slides, selected at random, were reexamined by a senior laboratory technician [ 41]. Urine samples were examined for microhematuria using reagent strips (Hemastix; Siemens Healthcare Diagnostics GmbH, Eschborn, Germany). A subsample of 10% of urine specimens was subjected to a filtration method for evaluation of the reagent strip results. Ten milliliters of vigorously shaken urine were pressed through a membrane (diameter: 13 mm; pore size: 30 µm; Sefar AG, Heiden, Switzerland) and the membrane placed on a microscope slide. A drop of Lugol’s iodine was added on the slide, and the number of S. haematobiumeggs was counted under a microscope by experienced laboratory technicians [ 42]. In addition, 1 to 2 g of stool from each specimen was transferred into small tubes, filled with 10 mL of sodium acetate-acetic acid-formalin (SAF) for subsequent diagnosis of intestinal protozoa. In short, the SAF-fixed stool samples were forwarded to a laboratory at the Université Félix Houphouët-Boigny in Abidjan and subjected to an ether-concentration method and examined under a microscope by experienced laboratory technicians. We adhered to a standard protocol [ 43]. Anthropometric Measurements In intervention arms 1 and 4, infants aged 12 to 24 months were assessed for standard anthropometric measures, including weight (to the nearest 0.1 kg; mothers holding their infant were weighed with a portable scale, and then the weight of the mother was subtracted to obtain the weight of the infant) and height (measured to the nearest cm using a portable centimeter scale). Nutritional status of children at baseline and follow-up was evaluated using the following indicators: underweight (weight for age), stunting (height for age), and wasting (weight for height). Knowledge, Attitudes, Practices, and Beliefs Surveys People’s KAPB were assessed, using a combination of direct observations and interviews (questionnaire surveys, in-depth interviews, and FGDs). All the components of the KAPB study were conducted in parallel to the baseline and follow-up parasitologic and anthropometric surveys. The main topics that were investigated in the KAPB survey pertained to perceived needs of sanitation facilities, common defecation practices, availability and use of latrines, associations of defecation and hygiene behavior (eg, washing hands), general knowledge of health risks associated with (open) defecation, signs and symptoms of parasite infections, and how such infections can be prevented and treated [ 24]. Direct observations and questionnaires were addressed to household heads or their representatives at the unit of the household in the 56 communities. Questionnaires were designed in a semistructured manner with mainly closed but also a few open-ended questions to gather quantitative and qualitative data for the analyses. All interviews were conducted by trained field enumerators in French or local languages. Before the start of the survey, the questionnaire and the direct observation checklist were pretested in neighboring communities that were not part of the study, as done in previous research [ 44, 45]. FGDs were conducted with different groups; namely (1) adult women; (2) adult men; (3) school-aged children; and (4) the elderly. FGDs were conducted in 8 villages; 2 villages per intervention arm. In each FGD, 8 to 10 individuals were invited to participate [ 46]. FGDs were tape-recorded for subsequent transcription and analysis. In-depth interviews were conducted with community health workers and traditional healers in the same 8 villages. Diarrhea Monitoring We monitored the incidence of diarrhea (duration and severity) over a 24-month period. Every second week, a short questionnaire was administered by community health workers to all members of the 30 selected households per community, starting right after the baseline cross-sectional survey. For the youngest children who were not able to answer the questionnaire, their mothers/caregivers were interviewed. Implementation of Interventions The interventions were implemented after the baseline cross-sectional survey. The CLTS intervention was started in the communities of intervention arms 2 and 4. Only after these communities had commenced building latrines, the CHEP was launched in the communities of intervention arms 3 and 4 to avoid interference with the methodological approach of the CLTS intervention (see section Community-Led Total Sanitation) in arm 4. Preventive chemotherapy was done according to ongoing activities of the national helminthiasis control program of the Ministry of Health in Côte d’Ivoire. These activities consist of community-based yearly mass administration of ivermectin and albendazole (against lymphatic filariasis) and yearly administration of praziquantel and albendazole (against schistosomiasis and soil-transmitted helminthiasis) to at-risk groups, adhering to WHO guidelines [ 47]. Preventive Chemotherapy After the baseline cross-sectional survey, in October 2014, all participants found positive for S. mansoni,or S. haematobium, or both, received a single 40 mg/kg oral dose of praziquantel using a dose pole for individuals aged 4 years and older, whereas albendazole (single 400 mg dose for participants aged >2 years and 200 mg for 1- to 2-years-old children) was administered against soil-transmitted helminths [ 48]. Thereafter, annual preventive chemotherapy was administered in the frame of the on-going helminthiasis control activities by the Ministry of Health in Côte d’Ivoire. Annual preventive chemotherapy against lymphatic filariasis was done between May and June and against schistosomiasis between October and November. Participants with persistent diarrhea identified during the diarrhea monitoring received oral rehydration solutions and, if needed, were referred to nearby health facilities. Community-Led Total Sanitation The CLTS approach is based on participatory rural appraisal that emphasizes that the learning effect is considerably higher if knowledge is acquired through self-experience and self-reflexion. It facilitates critical analysis by the community of their own sanitation profile, their practices of defecation, and the consequences, leading to collective action to become open defecation-free [ 49, 50]. The approach thus focuses on the whole community and their cooperation and interactions because the community only profits when every single community member cooperates and takes action [ 51]. CLTS is a grassroots, community-based, and community-led strategy that triggers community empowerment via feelings of shame and disgust induced through observation of the defecation situation in a specific setting and its environment, which is often missed by health education [ 52, 53]. Before the intervention, CLTS facilitators were trained and instructed during a 1-week workshop by certified national CLTS facilitators from the Ministry of Sanitation, UNICEF, and a Swiss-based nongovernmental organization (FAIRMED). Communities were contacted, and a first community meeting was organized. During this meeting, the ignition process of CLTS was started, which could include the following components according to Kar and Chambers [ 27]: (1) transect walk (“walk of shame”) through the open defecation areas and water points; (2) defecation map, mapping of defecation areas and defecation mobility; (3) identifying the dirtiest neighborhoods; (4) calculation of feces amount and medical expenses; and (5) triggering disgust pathways of fecal contamination (glass of water, feces to food exercise, flow diagrams of fecal-oral routes, etc). These components were used to initiate the ignition moment (we are eating each other’s feces!). When talking about feces, the term “caca” was employed, as “caca” had been identified as the most suited and culturally accepted term by CLTS facilitators in Côte d’Ivoire. Subsequently, 2 more steps were pursued that include the identification of natural leaders and the monitoring and sustaining of open defecation-free status or the process toward an open defecation-free community. Although CLTS encourages the communities to build basic sanitary facilities (ie, latrines), to change one’s hygiene behavior, and to alter people’s waste disposal practices, it does not impose standard designs and does not provide subsidies. Hence, for toilet construction, most communities used readily available local material, so that toilets were more affordable and accessible for rural communities. When a given community decided to go toward open defecation-free status, an implementation plan of community-based basic sanitation and hygiene services was elaborated. This community was frequently visited by the community development agents to ensure that the implementation of the different actions was done according to protocol. Community Health Education Program Once communities were well advanced or staggered with the construction of latrines, they were visited by the research team, and a first health education session was offered for the entire community, based on results from the preceding FGDs that facilitated the social science team to identify knowledge gaps and related key health messages. In each community, interested community members (up to 10) were identified (mostly by the village chief and other village authorities) and invited to form a community health theater group. In a further visit, the community theater group received an additional health education session by the team and was coached to develop its own sketch to deliver hygiene and health messages in front of the community. In a final visit, the theater group presented the sketch to the community, and during this visit, the animated cartoon was screen played to children, although adults were also invited to watch. After the theater and screening of the cartoon, people were grouped into adult women, adult men, school-aged children, and the elderly, and discussions about health and hygiene topics were pursued to determine their understanding. Statistical Analysis Data collected from the parasitologic and anthropometric surveys and the monitoring of diarrheal episodes were double entered and cross-checked in EpiInfo version 3.5.3 (Centers for Disease Control and Prevention; Atlanta, GA, USA). Household questionnaire data and direct observations were entered on tablets, using open data kit, and uploaded on a server hosted at the Swiss Tropical and Public Health Institute (Swiss TPH; Basel, Switzerland). Statistical analyses were done on STATA, version 14 (Stata Corp; College Station, TX, USA). To receive a standard infection intensity measure of eggs per 1 g (EPG) of stool, helminth species–specific egg counts from the individual Kato-Katz thick smears were multiplied by a factor of 24. For each individual, the arithmetic mean egg count was estimated. The geometric mean of the helminth infection at the population level was calculated from the arithmetic means of the individual infection intensities. To assess the effect of the interventions, helminth egg count reductions were determined as 1 − (geometric mean EPG after 1 year at follow-up/geometric mean EPG at baseline) multiplied by a factor 100and compared between intervention groups. The nutritional status for children aged <5 years was determined using available macros for STATA version 10.1 with child growth standards and references published by WHO [ 54] and means between intervention groups, compared between baseline and follow-up. The same approach was used for diarrheal episodes, whereas the prevalence is being defined as the percentage of days with diarrhea, calculated as the number of days with diarrhea divided by the total number of days of observation. Incidence is defined as the number of new episodes divided by the number of days at-risk, which is defined as the number of days of observation minus the number of days with diarrhea self-diagnosis, allowing for 2 illness-free days between episodes [ 55]. Random effect logistic regression models were used to assess the effect of interventions on infection, anthropometric, diarrhea, and KAPB outcomes, using a factorial design. Qualitative data gathered from the FGDs were transcribed and processed in MaxQDA 10/Atlas version 1 (VERBI Software Consult; Berlin, Germany). The coded data were analyzed for the frequency at which coded information and content categories occur. The most frequently occurring topics concerning the study population’s KAPB were analyzed for change after the implementation of CLTS and/or CHEP. Dissemination of Key Findings Progress and key results of this cluster randomized trial were communicated at annual workshops with key decision makers and other stakeholders, including community members. Results The project was funded in May 2013 and enrollment was completed in September 2014. Baseline, follow-up I, and follow-up II surveys were completed in September 2014, February 2016, and November 2017, respectively. Data analysis is currently under way, and the first results are expected to be submitted for publication in 2018. The findings will be published in peer-reviewed literature and presented at national and international conferences. Discussion Neglected tropical diseases, including soil-transmitted helminthiasis, schistosomiasis, giardiasis, and amoebiasis, are important public health issues in Côte d’Ivoire and elsewhere in low- and middle-income countries [ 14, 56- 58]. Indeed, a recent national school-based survey in 94 schools across Côte d’Ivoire revealed that 26% of children aged 5 to 15 years had a helminth infection [ 59]. Giardiasis and amoebiasis were reported from community- and school-based surveys in different parts of Côte d’Ivoire [ 30, 60, 61]. The aim of this project was to assess the effect of an integrated control package, consisting of preventive chemotherapy with either CLTS or CHEP, or all measures combined in 56 small rural communities of south-central Côte d’Ivoire, using a cluster randomized trial. The goal was to generate new evidence to determine whether an integrated control package, including community-based approaches, is useful for the control of helminth and intestinal protozoa infections and thus to assist decision making in translating global policy into local practice. A previous pilot study in Côte d’Ivoire revealed that CLTS coupled with health education and preventive chemotherapy has the potential to decrease the incidence of helminth and intestinal protozoa infection, although heterogeneity from one community to another rendered interpretation of the results somewhat difficult [ 33]. Notwithstanding, a recent cluster randomized study in Mali found no effect of CLTS on diarrhea 18 months after implementation of the intervention, but a significant beneficial effect on children’s anthropometric measures, as children from the intervention group were significantly less stunted [ 62]. Of note, the authors used a cross-sectional design for assessing diarrheal incidence at 2 time points (baseline and end line). In this protocol, diarrhea was monitored longitudinally over a 24-month period with 2-week intervals, which should capture subtle fluctuations. Two recent cluster randomized trials from India showed no effect on diarrhea, soil-transmitted helminths, and child malnutrition and highlighted the difficulty to achieve high coverage of latrine use at a large scale to demonstrate expected health outcomes [ 63, 64]. There is considerable interest in the scientific community and among disease control program managers to bring integrated approaches into action, although the challenges of scaling up such integrated, intersectoral, multidisease control approaches are recognized [ 65, 66]. CLTS holds promise to decrease diarrhea, helminthiases, and intestinal protozoa infections, yet, limitations with regard to achieving open defecation-free status and sustainability exist. Our previous work in Côte d’Ivoire has provided evidence that health education interventions can improve adherence of communities to CLTS and thus increase the success rate of such an intervention [ 33]. A further limitation of our study is that the distance between communities was sometimes relatively small, and contamination cannot be completely excluded. Although, it has to be emphasized that in this particular study area, the difficult physical accessibility to communities can limit contamination even if communities are relatively close. Furthermore, although during the CLTS and CHEP interventions, it was emphasized that a hand washing facility needs to be provided next to the latrines (eg, bucket with water and soap) and before eating, hands need to be washed with soap, no specific water access intervention was included in the study, which might have an impact on infection outcomes. Finally, sample size was limited by the size of the communities because of the methodological approach of CLTS. Indeed, communities up to a maximum size of 500 to 600 members are more likely to adhere to CLTS compared with larger communities. This study and experiences gained elsewhere [ 67] will shed new light on the effect of integrated approaches on different outcomes, including parasitic infections (soil-transmitted helminths, schistosomes, and intestinal protozoa), incidence of diarrhea, anthropometric measures, and KAPB of populations. Furthermore, this line of scientific inquiry will enhance our knowledge of community acceptance regarding integrated control approaches, including strengths and limitations, and provide important information for existing sanitation and health programs in Côte d’Ivoire and elsewhere. Acknowledgments The authors thank Dr Jan Hattendorf for carrying out the randomization and for inputs on the manuscript. The authors acknowledge financial support from UBS Optimus Foundation (Zurich, Switzerland) and the Rudolf Geigy Foundation (Basel, Switzerland). Authors' Contributions GR wrote the manuscript. GR and JU revised the manuscript. EH produced the map. GR, BB, EKN, and JU designed the study. All authors read and approved the manuscript. Conflicts of Interest None declared. References World Health Organization. Preventive chemotherapy in human helminthiasis; coordinated use of anthelminthic drugs in control interventions: a manual for health professionals and programme managers. 2006.   URL: http://apps.who.int/iris/bitstream/10665/43545/1/9241547103_eng.pdf [accessed 2018-05-12] [ WebCite Cache ] Quinnell RJ, Slater AF, Tighe P, Walsh EA, Keymer AE, Pritchard DI. Reinfection with hookworm after chemotherapy in Papua New Guinea. Parasitology 1993;106:379-385. [ Medline ] Jia TW, Melville S, Utzinger J, King CH, Zhou XN. Soil-transmitted helminth reinfection after drug treatment: a systematic review and meta-analysis. PLoS Negl Trop Dis 2012;6(5):e1621 [ FREE Full text ] [ CrossRef ] [ Medline ] Knopp S, Stothard JR, Rollinson D, Mohammed KA, Khamis IS, Marti H, et al. From morbidity control to transmission control: time to change tactics against helminths on Unguja Island, Zanzibar. Acta Trop 2013;128(2):412-422. [ CrossRef ] [ Medline ] Rollinson D, Knopp S, Levitz S, Stothard JR, Tchuem Tchuenté LA, Garba A, et al. Time to set the agenda for schistosomiasis elimination. Acta Trop 2013;128(2):423-440. [ CrossRef ] [ Medline ] Ross AG, Chau TN, Inobaya MT, Olveda RM, Li Y, Harn DA. A new global strategy for the elimination of schistosomiasis. Int J Infect Dis 2017;54:130-137 [ FREE Full text ] [ CrossRef ] [ Medline ] World Health Organization. Integrating Neglected Tropical Diseases in Global Health and Development. Geneva: World Health Organization; 2017.   URL: http://apps.who.int/iris/bitstream/handle/10665/255011/9789241565448-eng.pdf?sequence=1 [accessed 2018-05-12] [ WebCite Cache ] Mara D, Lane J, Scott B, Trouba D. Sanitation and health. PLoS Med 2010;7(11):e1000363 [ FREE Full text ] [ CrossRef ] [ Medline ] Knopp S, Mohammed KA, Ali SM, Khamis IS, Ame SM, Albonico M, et al. Study and implementation of urogenital schistosomiasis elimination in Zanzibar (Unguja and Pemba islands) using an integrated multidisciplinary approach. BMC Public Health 2012;12:930 [ FREE Full text ] [ CrossRef ] [ Medline ] Bieri FA, Gray DJ, Williams GM, Raso G, Li YS, Yuan L, et al. Health-education package to prevent worm infections in Chinese schoolchildren. N Engl J Med 2013;368(17):1603-1612. [ CrossRef ] [ Medline ] Strunz EC, Addiss DG, Stocks ME, Ogden S, Utzinger J, Freeman MC. Water, sanitation, hygiene, and soil-transmitted helminth infection: a systematic review and meta-analysis. PLoS Med 2014;11(3):e1001620 [ FREE Full text ] [ CrossRef ] [ Medline ] World Health Organization, United Nations International Children's Emergency Fund. Progress on Sanitation and Drinking Water: 2015 Update and MDG Assessment. Geneva: World Health Organization; 2015.   URL: https://data.unicef.org/wp-content/uploads/2015/12/Progress-on-Sanitation-and-Drinking-Water_234.pdf [accessed 2018-05-12] [ WebCite Cache ] Prüss-Üstün A, Bos R, Gore F, Bartram J. Safe water, better health: cost, benefits and sustainability of interventions to protect and promothe health. Geneva: World Health Organization; 2008. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388(10053):1545-1602 [ FREE Full text ] [ CrossRef ] [ Medline ] Esrey SA, Potash JB, Roberts L, Shiff C. Effects of improved water supply and sanitation on ascariasis, diarrhoea, dracunculiasis, hookworm infection, schistosomiasis, and trachoma. Bull World Health Organ 1991;69(5):609-621 [ FREE Full text ] [ Medline ] Bartram J, Cairncross S. Hygiene, sanitation, and water: forgotten foundations of health. PLoS Med 2010;7(11):e1000367 [ FREE Full text ] [ CrossRef ] [ Medline ] Grimes JE, Croll D, Harrison WE, Utzinger J, Freeman MC, Templeton MR. The relationship between water, sanitation and schistosomiasis: a systematic review and meta-analysis. PLoS Negl Trop Dis 2014;8(12):e3296 [ FREE Full text ] [ CrossRef ] [ Medline ] Freeman MC, Clasen T, Brooker SJ, Akoko DO, Rheingans R. The impact of a school-based hygiene, water quality and sanitation intervention on soil-transmitted helminth reinfection: a cluster-randomized trial. Am J Trop Med Hyg 2013;89(5):875-883 [ FREE Full text ] [ CrossRef ] [ Medline ] Fewtrell L, Kaufmann RB, Kay D, Enanoria W, Haller L, Colford JM. Water, sanitation, and hygiene interventions to reduce diarrhoea in less developed countries: a systematic review and meta-analysis. Lancet Infect Dis 2005;5(1):42-52. Cairncross S, Hunt C, Boisson S, Bostoen K, Curtis V, Fung IC, et al. Water, sanitation and hygiene for the prevention of diarrhoea. Int J Epidemiol 2010;39(Suppl 1):193-205. Prüss A, Kay D, Fewtrell L, Bartram J. Estimating the burden of disease from water, sanitation, and hygiene at a global level. Environ Health Perspect 2002;110(5):537-542 [ FREE Full text ] [ Medline ] Arfaa F, Sahba GH, Farahmandian I, Jalali H. Evaluation of the effect of different methods of control of soil-transmitted helminths in Khuzestan, southwest Iran. Am J Trop Med Hyg 1977;26(2):230-233. [ Medline ] Udonsi JK, Ogan VN. Assessment of the effectiveness of primary health care interventions in the control of three intestinal nematode infections in rural communities. Public Health 1993;107(1):53-60. [ Medline ] Asaolu SO, Ofoezie IE. The role of health education and sanitation in the control of helminth infections. Acta Trop 2003;86(2-3):283-294. [ Medline ] Albonico M, Montresor A, Crompton DW, Savioli L. Intervention for the control of soil-transmitted helminthiasis in the community. Adv Parasitol 2006;61:311-348 [ FREE Full text ] [ CrossRef ] [ Medline ] Acka CA, Raso G, N'Goran EK, Tschannen AB, Bogoch II, Séraphin E, et al. Parasitic worms: knowledge, attitudes, and practices in western Côte d'Ivoire with implications for integrated control. PLoS Negl Trop Dis 2010;4(12):e910 [ FREE Full text ] [ CrossRef ] [ Medline ] Kar K, Chambers R. Handbook on community-led total sanitation. London: Plan UK; 2008. Essé C, Koffi VA, Kouamé A, Dongo K, Yapi RB, Moro HM, et al. “Koko et les lunettes magiques”: an educational entertainment tool to prevent parasitic worms and diarrheal diseases in Côte d'Ivoire. PLoS Negl Trop Dis 2017;11(9):e0005839 [ FREE Full text ] [ CrossRef ] [ Medline ] Fürst T, Silué KD, Ouattara M, N'Goran DN, Adiossan LG, N'Guessan Y, et al. Schistosomiasis, soil-transmitted helminthiasis, and sociodemographic factors influence quality of life of adults in Côte d'Ivoire. PLoS Negl Trop Dis 2012;6(10):e1855. [ CrossRef ] Schmidlin T, Hürlimann E, Silué KD, Yapi RB, Houngbedji C, Kouadio BA, et al. Effects of hygiene and defecation behavior on helminths and intestinal protozoa infections in Taabo, Côte d'Ivoire. PLoS One 2013;8(6):e65722 [ FREE Full text ] [ CrossRef ] [ Medline ] Koné S, Baikoro N, N'Guessan Y, Jaeger FN, Silué KD, Fürst T, et al. Health & demographic surveillance system profile: the Taabo health and demographic surveillance system Côte d'Ivoire. Int J Epidemiol 2015(1):87-97. [ CrossRef ] [ Medline ] Koné S, Fürst T, Jaeger FN, Esso EL, Baïkoro N, Kouadio KA, et al. Causes of death in the Taabo health and demographic surveillance system, Côte d'Ivoire, from 2009 to 2011. Glob Health Action 2015;8(1):27271. [ CrossRef ] Hürlimann E, Silué KD, Zouzou F, Ouattara M, Schmidlin T, Yapi RB, et al. Effect of an integrated intervention package of preventive chemotherapy, community-led total sanitation and health education on the prevalence of helminth and intestinal protozoa infections in Côte d'Ivoire. Parasit Vectors 2018;11(1):115 [ FREE Full text ] [ CrossRef ] [ Medline ] Katz N, Chaves A, Pellegrino J. A simple device for quantitative stool thick-smear technique in schistosomiasis mansoni. Rev Inst Med Trop Sao Paulo 1972;14(6):397-400. [ Medline ] Yapi RB, Chammartin F, Hürlimann E, Houngbedji CA, N'Dri PB, Silué KD, et al. Bayesian risk profiling of soil-transmitted helminth infections and estimates of preventive chemotherapy for school-aged children in Côte d'Ivoire. Parasit Vectors 2016;9:162 [ FREE Full text ] [ CrossRef ] [ Medline ] Campbell MK, Thomson S, Ramsay CR, MacLennan GS, Grimshaw JM. Sample size calculator for cluster randomized trials. Comput Biol Med 2004;34(2):113-125. [ CrossRef ] Becker SL, Sieto B, Silué KD, Adjossan L, Koné S, Hatz C, et al. Diagnosis, clinical features, and self-reported morbidity of Strongyloides stercoralis and hookworm infection in a co-endemic setting. PLoS Negl Trop Dis 2011;5(8):e1292 [ FREE Full text ] [ CrossRef ] [ Medline ] Lemeshow S, Tserkovnyi AG, Tulloch JL, Dowd JE, Lwanga SK, Keja J. A computer simulation of the EPI survey strategy. Int J Epidemiol 1985;14(3):473-481. [ Medline ] Moulton LH. Covariate-based constrained randomization of group-randomized trials. Clin Trials 2004(3):297-305. [ CrossRef ] [ Medline ] Raso G, N'Goran EK, Toty A, Luginbühl A, Adjoua CA, Tian-Bi NT, et al. Efficacy and side effects of praziquantel against Schistosoma mansoni in a community of western Côte d'Ivoire. Trans R Soc Trop Med Hyg 2004;98(1):18-27. [ Medline ] Montresor A, Crompton DWT, Bundy DAP, Hall A, Savioli L. Guidelines for the evaluation of soil-transmitted helminthiasis and schistosomiasis at community level: a guide for managers of control programmes. Geneva: World Health Organization; 1998.   URL: http://apps.who.int/iris/bitstream/handle/10665/63821/WHO_CTD_SIP_98.1.pdf?sequence=1&isAllowed=y Savioli L, Hatz C, Dixon H, Kisumku U, Mott K. Control of morbidity due to Schistosoma haematobium on Pemba Island: egg excretion and hematuria as indicators of infection. Am J Trop Med Hyg 1990;43(3):289-295. Utzinger J, Botero-Kleiven S, Castelli F, Chiodini P, Edwards H, Köhler N, et al. Microscopic diagnosis of sodium acetate-acetic acid-formalin-fixed stool samples for helminths and intestinal protozoa: a comparison among European reference laboratories. Clin Microbiol Infect 2010;16(3):267-273 [ FREE Full text ] [ CrossRef ] [ Medline ] Utzinger J, N'Goran EK, Ossey YA, Booth M, Traoré M, Lohourignon KL, et al. Rapid screening for Schistosoma mansoni in western Côte d'Ivoire using a simple school questionnaire. Bull World Health Organ 2000;78(3):389-398 [ FREE Full text ] [ Medline ] Raso G, Luginbühl A, Adjoua CA, Tian-Bi NT, Silué KD, Matthys B, et al. Multiple parasite infections and their relationship to self-reported morbidity in a community of rural Côte d'Ivoire. Int J Epidemiol 2004;33(5):1092-1102. [ CrossRef ] [ Medline ] Dawson S, Manderson L, Tallo V. A manual for the use of focus groups: methods for social research in disease. Boston: International Nutrition Foundation for Developing Countries (INFDC); 1993. Keiser J, Utzinger J. Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis. J Am Med Assoc 2008;299(16):1937-1948. [ CrossRef ] [ Medline ] Chambers R. The origins and practice of participatory rural appraisal. World Dev 1994;22:953-969. Bongartz P, Musyoki SM, Milligan A, Ashley H. Tales of shit: community-led total sanitation in Africa. London: International Institute for Environment and Development; 2010.   URL: http://pubs.iied.org/pdfs/G02795.pdf [accessed 2018-05-12] [ WebCite Cache ] Kar K, Pasteur K. Subsidy or self-Respect? Community-led total sanitation. An update on recent developments. Brighton: Institute of Development Studies; 2005.   URL: http:/​/www.​communityledtotalsanitation.org/​sites/​communityledtotalsanitation.org/​files/​media/​wp257_0.​pdf [accessed 2018-05-12] [ WebCite Cache ] Jenkins MW, Curtis V. Achieving the 'good life': why some people want latrines in rural Benin. Soc Sci Med 2005;61(11):2446-2459. [ CrossRef ] [ Medline ] Jenkins MW, Scott B. Behavioral indicators of household decision-making and demand for sanitation and potential gains from social marketing in Ghana. Soc Sci Med 2007;64(12):2427-2442. [ CrossRef ] [ Medline ] Duggan MB. Anthropometry as a tool for measuring malnutrition: impact of the new WHO growth standards and reference. Ann Trop Paediatr 2010;30(1):1-17. [ CrossRef ] [ Medline ] Ruel MT, Rivera JA, Santizo MC, Lönnerdal B, Brown KH. Impact of zinc supplementation on morbidity from diarrhea and respiratory infections among rural Guatemalan children. Pediatrics 1997;99(6):808-813. [ Medline ] Tchuem-Tchuenté LA, N'Goran EK. Schistosomiasis and soil-transmitted helminthiasis control in Cameroon and Côte d'Ivoire: implementing control on a limited budget. Parasitology 2009;136(13):1739-1745. [ Medline ] Hotez PJ, Alvarado M, Basáñez MG, Bolliger I, Bourne R, Boussinesq M, et al. The Global Burden of Disease study 2010: interpretation and implications for the neglected tropical diseases. PLoS Negl Trop Dis 2014;8(7):e2865 [ FREE Full text ] [ CrossRef ] [ Medline ] Rogawski ET, Bartelt LA, Platts-Mills JA, Seidman JC, Samie A, Havt A, MAL-ED Network Investigators. Determinants and impact of Giardia infection in the first 2 years of life in the MAL-ED birth cohort. J Pediatric Infect Dis Soc 2017;6(2):153-160. [ CrossRef ] [ Medline ] Yapi RB, Hürlimann E, Houngbedji CA, N'Dri PB, Silué KD, Soro G, et al. Infection and co-infection with helminths and Plasmodium among school children in Côte d'Ivoire: results from a national cross-sectional survey. PLoS Negl Trop Dis 2014;8(6):e2913 [ FREE Full text ] [ CrossRef ] [ Medline ] Ouattara M, N'Guéssan NA, Yapi A, N'Goran EK. Prevalence and spatial distribution of Entamoeba histolytica/dispar and Giardia lamblia among schoolchildren in Agboville area (Côte d'Ivoire). PLoS Negl Trop Dis 2010 19;4(1):e574. [ CrossRef ] [ Medline ] Hürlimann E, Houngbedji CA, N’Dri PB, Bänninger D, Coulibaly JT, Yap P, et al. Effect of deworming on school-aged children's physical fitness, cognition and clinical parameters in a malaria-helminth co-endemic area of Côte d'Ivoire. BMC Infect Dis 2014;14(1):411. [ CrossRef ] Pickering AJ, Djebbari H, Lopez C, Coulibaly M, Alzua ML. Effect of a community-led sanitation intervention on child diarrhoea and child growth in rural Mali: a cluster-randomised controlled trial. Lancet Glob Health 2015;3(11):e701-e711. [ CrossRef ] Clasen T, Boisson S, Routray P, Torondel B, Bell M, Cumming O, et al. Effectiveness of a rural sanitation programme on diarrhoea, soil-transmitted helminth infection, and child malnutrition in Odisha, India: a cluster-randomised trial. Lancet Glob Health 2014;2(11):e645-e653. [ CrossRef ] Patil SR, Arnold BF, Salvatore AL, Briceno B, Ganguly S, Colford JM, et al. The effect of India's total sanitation campaign on defecation behaviors and child health in rural Madhya Pradesh: a cluster randomized controlled trial. PLoS Med 2014;11(8):e1001709 [ FREE Full text ] [ CrossRef ] [ Medline ] Nakagawa J, Ehrenberg JP, Nealon J, Fürst T, Aratchige P, Gonzales G, et al. Towards effective prevention and control of helminth neglected tropical diseases in the Western Pacific Region through multi-disease and multi-sectoral interventions. Acta Trop 2015;141(Pt B):407-418. [ CrossRef ] [ Medline ] Lo NC, Addiss DG, Hotez PJ, King CH, Stothard JR, Evans DS, et al. A call to strengthen the global strategy against schistosomiasis and soil-transmitted helminthiasis: the time is now. Lancet Infect Dis 2017;17(2):e64-e69. [ CrossRef ] [ Medline ] Nery SV, McCarthy JS, Traub R, Andrews RM, Black J, Gray D, et al. A cluster-randomised controlled trial integrating a community-based water, sanitation and hygiene programme, with mass distribution of albendazole to reduce intestinal parasites in Timor-Leste: the WASH for WORMS research protocol. BMJ Open 2015 30;5(12):e009293 [ FREE Full text ] [ CrossRef ] [ Medline ] Abbreviations Edited by G Eysenbach; submitted 12.10.17; peer-reviewed by S Nery, R Bergquist, I Suresh; comments to author 25.01.18; revised version received 05.03.18; accepted 10.03.18; published 12.06.18 Raso G , Essé C , Dongo K , Ouattara M , Zouzou F , Hürlimann E , Koffi VA , Coulibaly G , Mahan V , Yapi RB , Koné S , Coulibaly JT , Meïté A , Guéhi-Kabran M , Bonfoh B , N'Goran EK , Utzinger J An Integrated Approach to Control Soil-Transmitted Helminthiasis, Schistosomiasis, Intestinal Protozoa Infection, and Diarrhea: Protocol for a Cluster Randomized Trial JMIR Res Protoc 2018;7(6):e145 doi: 10.2196/resprot.9166 PMID: 29895511 PMCID: 6019843
https://www.researchprotocols.org/2018/6/e145
Motion-Secondary: Brett A. Phillips v. The Town Of Floyd, Patrick J Aughe, Joanne C Aughe, Lloyd A Miller | Trellis.Law Access the Motion-Secondary in the Brett A. Phillips v. The Town Of Floyd, Patrick J Aughe, Joanne C Aughe, Lloyd A Miller case on Trellis.Law. Review the document, case details, and relevant case updates to stay informed on this notable legal proceeding Motion-Secondary: Brett A. Phillips v. The Town Of Floyd, Patrick J Aughe, Joanne C Aughe, Lloyd A Miller Preview . . FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 STATE OF NEW YORK SUPREME COURT COUNTY OF ONEIDA ********************************************* BRETT A. PHILLIPS, RESPONSE TO DEMAND FOR Plaintiff, STATEMENTS, WITNESSES, -vs- ACCIDENT PHOTOGRAPHS, REPORTS, AND INSURANCE PATRICK J. AUGHE, JOANNE C. AUGHE, INFORMATION LLOYD A. MILLER, individually and acting on behalf of the Town of Floyd, TOWN OF FLOYD, Index No.: EFCA2017-001763 jointly and severally, Defendants ********************************************** Plaintiff, Brett A. Phillips, as and for a Response to Defendants', Patrick J. Aughe and Joanne C. Aughe, Demand for Statements, Witnesses, Photographs, Accident Reports, and Insurance, the Plaintiff, sets forth as follows: 1. There are no statements from the Defendants relating to the accident out of which this action arises. However, should any statements become available same will be Defendants' forwarded to the Attorney promptly. 2. The names and addresses of the following witnesses: a. Eyewitnesses to the incident alleged in the Complaint: The Plaintiff is unaware of any eyewitnesses to the incident. Should any witnesses become available same will be forwarded promptly to the Defendants' Attorney. b. Witnesses to any alleged defective conditions: The Plaintiff is unaware of any eyewitnesses to the incident. Should any witnesses become available same will be forwarded promptly to the Defendants' Attorney. 1 of 20 FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 c. To any notice to Defendants: The Plaintiff is unaware of any witnesses to any notice given to the Defendants. Should any witnesses become available same will be forwarded Defendants' promptly to the Attorney. d. To any admission by Defendants: The Plaintiff isunaware of any witnesses to any admission by the Defendants. Should any witnesses become available same will be forwarded promptly to Defendants' the Attorney. e. To any other element reflecting on liability: The Plaintiff is unaware of any witnesses to any other element reflecting on liability. Should any witnesses become available same will be forwarded Defendants' promptly to the Attorney. f. Pursuant to the Rule set forth in Troup vs Midland-Ross Corporation, 94 (4th A.D.2d 949, 464 N.Y.S.2d 74 Dept., 1983) and CPLR 3101, copies of statements, written or otherwise, of each and every other party to the instant litigation, their agents, servants and/or employees: The Plaintiff is unaware of any statements, written or otherwise. Should any statements, written or otherwise become available same will be forwarded Defendants' promptly to the Attorney. g. Witnesses in connection with any issues concerning damages: The Plaintiff is unaware of any witnesses in connection with any issues concerning damages. Should any witnesses become available same will be Defendants' forwarded promptly to the Attorney. 2 of 20 FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 "A" 3. Attached hereto and made a part hereof as Exhibit is a photograph of where the Defendant's, Lloyd A. Miller, truck was sitting in the road prior to the accident. Should any further photographs become available same will be provided promptly Defendants' to Attorney. "B" 4. Attached hereto and made a part hereof as Exhibit is a copy of the Police Accident Report and Accident Information Exchange Form. Should any further Defendants' reports become available same will be provided promptly to the Attorney. 5. The Plaintiff is not in possession of any data from any vehicle involved in the accident. Should any data become available same will be provided promptly to the Defendants' Attorney. "C" 6. Attached hereto and made a part hereof as Exhibit is a copy of the Estimate of Record for the repairs of Plaintiff's vehicle. Should any further documents become Defendants' available same will be forwarded promptly to the Attorney. Dated: gy y WILLIAM M. ESQ. BORRILL, Attorney for Plaintiff 23 Oxford Road New Hartford, New York 13413 (315) 223-3084 TO: BURGIO, CURVIN & BANKER JAMES P. BURGIO, ESQ. Attorney for the Defendants 496 Main Street Buffalo, New York 14202 (716) 854-1744 3 of 20 FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 VERIFICATION STATE OF NEW YORK) COUNTY OF ONEIDA ) ss.: BRETT A. PHILLIPS, being duly sworn, depose and say that deponent is the Plaintiff in the within action and have read the foregoing Response to Demand for Statements, Witnesses, Photographs, Accident Reports, and Insurance; that the contents of said Response to Demand for Statements, Witnesses, Photographs, Accident Reports, and Insurance are true to the knowledge of Plaintiff, except as to the matters therein stated to be alleged upon information and belief, and as to those matters deponent believes itto be true. /z~ /'~ BRETT A. PHILLIPS Subscribed and sworn to before me this day of f~ , 2018 Public- -Notary PAMELA RETTlG State of New York Notary Pubhcin the Oualifled in Oneida County 01RE60482 Sept,25, 20 My CommisatonExptrea 4 of 20 FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 CLIENT CERTIFICATION I, BRETT A. PHILLIPS, HEREBY CERTIFY, under penalty of perjury, that I have carefully read and reviewed the annexed Response to Demand for Statements, Witnesses, Photographs, Accident Reports, and Insurance and that all information contained in this document is true and accurate in all respects to the best of my knowledge and understanding. I FURTHER CERTIFY, under penalty of perjury, that neither my attorney, nor anyone action on my attorney's behalf, was the source of any of the information contained in the annexed document, that I provided all of the information contained in the annexed document to my attorney, and that I understand that my attorney, in executing the Attorney Certification required by 22 NYCRR 202 16(e), is relying entirely upon the information provided by me and upon my certification that allsuch information is true and accurate. I FURTHER CERTIFY, that the annexed document includes all information which provided to my attorney which is relevant to such document and that my attorney has not deleted, omitted or excluded any such information. I FURTHER CERTIFY, that my attorney has advised me that he isrequired to provide his own certification regarding the information contained in the annexed document. My attorney has advised me thathe is relying on the truth and accuracy of all information that I have given to him in executing that certification. Dated: '') /' BRETT A. PHILLIPS 5 of 20 FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 ATTORNEY CERTIFICATION I hereby certify to the best of my knowledge, information and belief, formed after an inquiry reasonable under the circumstances, the presentation of the Response to Demand for Statements, Witnesses, Photographs, Accident Reports, and Insurance or the contentions therein are not frivolous as defined in Part 130-1.1( c ) of the Rules of the Chief Administrator. Dated: g. Jg. @At WILLIAM M. BORRILL CERTIFICATION PURSUANT TO 22 N.Y.C.R.R. SECTION 130-1.1-a To the best of the undersigned's knowledge, information and belief, formed after an inquiry, reasonable after the circumstances, the presentation of the attached papers or the contentions therein are not frivolous, as that term is defined in 22 N.Y.C.R.R part 130. Date± ~ .gg WILLIAM M. BORRILL, ESQ. 6 of 20 FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 7 of 20 FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 8 of 20 FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 9 of 20 FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 Page 1 of 3 Pages New York StateDepartment of Motor Vehicles Local Codes ~ ~ POLICE ACCIDENT REPORT 17-02969 MV-104A (6/04)~x 13 J8P4576MHQ2P lAMEMD RE: I 2 AccidentDate Month 2 VEHlCLE Day 13 1- Dnver Year 2017 VEHICLE KS~MWW~W~I am~mwm~mm~m Day of Week Monday 1 1 Military Time 12:35 No of Vehicles 2 No Injured 1 No Killed jVr) VEHICLE 0 2 2( VEHICLE 2- Driver State of Lic Not Investigatedat Scene - - - - - - - - - - - - -- Accident Reconstructed BICYCLIST I ) PEDESTRIAN Left Scene i Police Photos YesE No OTHER PEDESTRIAN - State of Lic L 66 License ID Number ~ 245763652~~ ~ NY License ID Number 906685731 NY NY 21 Driver Name - exactly Driver Name - exactly as printed on license AUGHE, PATRICK J as printed on license PHILLIPS, BRETT A A m~ Address (include Number and Street) Apt.No Address (include Number and Street) Apt No W POBOX 173 2120 HIGHLAND AVE - 3 City or Town REMSEN State NY Zip Code City or Town UTICA State NY Zip Code 22 13438 135020000 1 Dateof Birth Sex Unhcensed No of Occupants Public Dateof Birth Sex unncensed No. of Occupants PI Public Month Uay Year -- Month Day Year -- Properly Property M __j 01 01 Damaged M [ 01 01 Damaged Name- pnnted exactly onregistration on Sex DateofBirth Name- exactlyasprintedonregistrallon Sex Dateof Birth Mo Day Year Month Da YearYear AUGHE, JOANNE C C F PHILLIPS, BRETT A M 1 Address(IncludeNumberandStreet) Apt No Haz | ReleasedAddress(IndudeNumberandStrcot) Haz Rele s Apt No ----12301230FRANCIS ST ST ~ i l 2120 HIGHLAND AVE ~ 24 Cityor Town State ZipCode ~~ CRyorTownTav/n StateSlala ~~ ZipCodeCade 5 UTICA NY 13502 I UTICA x NY NY 13502 5 1 PlateNumber Stateof Reg~ VehicleYear& MakeMake ~ van cie ype Ins Code PlateNumber Stateof Reg~ VehicleYear& MakeMakeVehicleType ype Ins.Code ~~ CZF5848 8Iflr)II~ NY NY 2002 PONT ~ 4 DSD DSD 356 GJF4754 NY NY 1996 DODG ~ ~ PICK 639 ~ ~ Ticket/Arrest Ticket/Arrest Number(s) Number(s) 6 ~ ~alion Violation ~ ~ Violation 13 Section(s)an(s) Section(s) Check d Involved vehicle rs ' ~ vehicle is check if~lnvalved ~ ~ ICircle the diagram below that describes the accident, or draw your own own ~ ~ more than than 95 inches w de, more than than 95 v wide; wide, diagram in space ¹9 the vehicles. cles ' long; ong, more than than ~ ~ more than than ~ ~ long; long, E .. E RearEnd LeftTum RightAngleRightTorn HeadOn 7 C H ~ operated operated overweight permit;H overdimension permit. C t ~ operated operated overweight permit; RWIH overdimension permit. 4- Sideewf LeftTum RR~m RightTum ---w Sidmip6 + 26 20 VEHICLE 1 DAMAGE CODES VEHICLE 2 DAMAGE CODES (same irection) (oppoonesection) L Box 1 - Point of Impact 3 1 2 L Box 1 - Point of Impact 1 2 t,g.,__ + E Box 2 - Most Damage E Box 2 - Most Damage ~ --- Enter up to three 3 4 5 Enter up to three 3 4 5 ACCIDENT DIAGRAM 27 1 -'--- more damagecodes 3 1 2 2 '' more damage --- codes 12 1 2 2 Vehicle By: NIMEY'S Towed To: ~NIMEY'S Vehicle By: Towed To: ~ See the last page of the MV-104A for the -m accident diagram. VEHICLEDAMAGECODING: 1-13SEEDIAGRAMONRIGHT. 14.UNDERCARRIAGE17.DEMOLISHED 2 is 8 ._ 15.TRAILER 18.NODAMAGE . - - to any one vehicle will Cost of repairs be morethan $1000 16,OVERTURNED~ 19.OTHER Unknown/Unableto determine Yes No Reference MarkerCoordinates (if available) Place Where Accident Occurred: Latitude/Northing i County ONEIDA ~ ' 1 City . - Village Town of ~ 3 6 5 FLOY D . Road on which accident occurred STATE ROUTE 3 65 I (RouteNumberorStreetName) Longitude/Easting ~ at 1) intersecting street . (RouteNumberorStreetName) or 2) -25 - ÏN S RITCHIE ROAD ~ 3 O 6 8 feet mtles E W Nearestintersecting (Milepost, RouteNumberorStreetName) Accident Description/Officer's notes 30 I Vehicle 1 was traveling west on State Route 365 when the operator observed a red pick-up truck operated by Lloyd A. Miller stopped in traffic. Vehicle ] attempted to pass the red pick-up on the right to avoid oncoming traffic. While overtaking the red pick-up, the snow caused the operator to lose control vehicle 1 and impact vehicle 2 causing damage to both vehicles. Operator of vehicle 2 was transported to Rome Memorial Hospital for a report ed 8 9 10 11 12 13 14 15 16 17 BY TO 18 Names of all involved Date of Death Only A 1 1 4 1 30 M - - AUGHE, PATRICK J J _ ... - B 2 1 4 1 58 OD M 06 12 6 9999 3204 PHILLIPS, iBRETT A A --- )m~~M~QMIR~~~ Imm Rl@ mal ~R~~MNS~ WWWW~~ O,'ficer's Rank Badge/ID No. ~NCIC No. ~ Precint/Post ~ Station/Beat Reviewing Officer Date/Time Reviewed~ DE PUTY and Signature Troop/Zone Sector STOCKHAUSER, 2/Ii]/2017 CRAIG 09:r)6 09: 46 10 of 20 . FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 Page 2 of 3 Pages New York StateDepartment of MolOr Vehicles Local Codes POLICE ACCIDENT REPORT 17 - 0 2 9 6 9 t,r.~ Ocr (S/04j J8P457 GNHQ2 P [-~} AMECED REPORT 1 - ccident ale Day of Week Military TimeNo. of No. Injured Not Investigated at Scene No. Killed ) ) Left Scene Police Photos Month av ear Vehicles - - - - - - - - - - - - - - 2 13 2017 Monday 12:35 2 1 0 Accident Reconstructed LI YesQ)vrNo VEHICLE VEHICLE ( BICYCLIST i,) ,'.BICYCLIST PEDESTRIAN OTHER PEDESTRIAN !+ 2 21 22 3 23 4 24 5 G Circle the diagram below that describes the accident, or draw your own V diagram in space #9. Number the vehicles E F RearEnd 1.eftTum ghtAngleRightTirn HeedOn 7 H H 5. 7. + + I LeftTum Right C C L L E E ACCIDENT DIAGRAM 27 VEHICLEDAMAGECODING: 4 ~ e 0 1 1-13SEEDIAGRAMONRIGHT. 9. 14.UNDERCARRIAGE17.DEMOLISHED a ta 15.TRAILER 18.NODAMAGE Cost of repairs to any one vehicle will be more than $1000 16.OVERTURNED 19.OTHER I a ,: Unknown/Unableto determine Yes No ls II IO Reference Marker Coordinates (if available) Place Where Accident Occurred: ' Latitude/Northing County ONE 1 DA City Village I Town of [-) ) I Poad on which accident occurred I \ I (HouteNumberor tree( smc) \ ~ Longitude/Easting at 1) intersecting street .., (RouteNumberor StreetName) • I or 2) N i S ) I i of feet miles( ,E E ';.W Nearestintersecting (Mdepost, RouteNumberor SheetName) Accident Description/Officer's notes 30 hack injury. Vehicle 1 was towed from scene. .".cene. WITNESS ill LLOYD A MILLER 8757 STATE RTE 365 STITTVl¯LLE, ) NY 3 34 ) )un G9 (315) & G5-5957 ) .).'DI N 8 9 , 10 11 12 13 14 15 16 17 BY TO 18 Names of all involved Date of Death Only A L L I N V - 0 L V JfficerRank -- 3adge/1 ) No. NCIC No. Precint/Postitation/Beat Reviewing Officer )ate/Time Reviewed E ind Signature Troop/Zone >ector D . 3TOCKHAUSER, 2/14/2017 11 of 20 . FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 F-age 3 of 3 Pages New York StateDepartment of Motor Vehicles Local Codes P RACCIDENT REPORT 17-02969 MV-104A (6/04) J8 P4576MHQ2P I I AMENDED REPORT cc eatoate Day omeek he No of Monlh Year May Ue°hices No InjuredNo. Killed Not Investigated at Scene( Left Scene Police Photos Day 2 13 2017 Monday 12:35 2 1 0 Accident ReconstructedI I Yes ]v'j No [Q [ 8767 State Route 365 V V1 ~+vtrl State Route 365 12 of 20 FILED: ONEIDA COUNTY CLERK 06/05/2018 08:55 AM INDEX NO. EFCA2017-001763 NYSCEF DOC. NO. 25 RECEIVED NYSCEF: 06/05/2018 ACCIDENT INFORMATION EXCHANGE FORM NY State Law that any accident requires in a fatality resulting . . damage to property of anyperson (including damage to your vehicle) or entity over be reported by YOU to the Departmentof Motor Ven .'-: i with o days after an accident Failure to report an accident or failure to give correct infor mation is a misdemeanorand may result in the suspend -. ation of yur driver's license(or oper ating priviledge in NYS) and all vehicle certifications or registrations. Veir- Report your Accident toDMV on DMV form MV-104 (Report ofMotor Vei,"le Accident).PoliceAccident Reports (DMV form MV-104A) DO NOT YOUR satisfy civilian reportingrequirement. Accident Report # LocalCodes Date Time # of Veh. Town, City,Road Nam J8P4576MHQ2P 17-02969 02/13/2017 12:35 PM 2 FLOYD. TOWN OF - 3358 STATE ROUTE 365 PoliceAgency Name/Badge Officer's ID# ONElDA CO. SHERIFF - 03200 BAXTER NICHOLAt J.I 28650 VEHICLE # 001 Operator'sName Date of Birth ~. ss AUGHE PATRICK J Case Info Judge David A Murad Track Judge’s New Case Case No. Document Filed Date June 05, 2018 Case Filing Date August 31, 2017 County Category Torts - Motor Vehicle Status BORRILL, WILLIAM MARKAttorney for the Plaintiff MULLIN, PAUL VINCENTAttorney for the Defendants BURGIO, JAMES PHILIPAttorney for the Defendants BURGIO, JAMES PHILIPAttorney for the Defendants KLUCSIK, JENNA WHITEAttorney for the Defendants MULLIN, PAUL VINCENTAttorney for the Defendants Brett A. PhillipsPlaintiff Lloyd A MillerDefendant Joanne C AugheDefendant Patrick J AugheDefendant The Town of FloydDefendant
https://trellis.law/doc/12964837/response-to-demand-exhibits-attached
(PDF) Hair follicle regional specificity in different parts of bay Mongolian horse by histology and transcriptional profiling PDF | Background: Different morphological structures of hairs having properties like defense and camouflage help animals survive in the wild... | Find, read and cite all the research you need on ResearchGate Hair follicle regional specificity in different parts of bay Mongolian horse by histology and transcriptional profiling DOI: 10.1186/s12864-020-07064-1 CC BY Authors: Wu Yihan Yiping Zhao Bei Li Bei Li Abstract and Figures Background: Different morphological structures of hairs having properties like defense and camouflage help animals survive in the wild environment. Horse is one of the rare kinds of animals with complex hair phenotypes in one individual; however, knowledge of horse hair follicle is limited in literature and their molecular basis remains unclear. Therefore, the investigation of horse hair follicle morphogenesis and pigmentogenesis attracts considerable interest. Result: Histological studies revealed the morphology and pigment synthesis of hair follicles are different in between four different parts (mane, dorsal part, tail, and fetlock) of the bay Mongolian horse. Hair follicle size, density, and cycle are strongly associated with the activity of alkaline phosphatase (ALP). We observed a great difference in gene expression between the mane, tail, and fetlock, which had a greater different gene expression pattern compared with the dorsal part through transcriptomics. The development of the hair follicle in all four parts was related to angiogenesis, stem cells, Wnt, and IGF signaling pathways. Pigmentogenesis-related pathways were involved in their hair follicle pigment synthesis. Conclusions: Hair follicle morphology and the activity of ALP differ among four body parts in bay Mongolian horse. Hair follicles of the different body parts of the are not synchronized in their cycle stages. GO terms show a regional specificity pattern between different skin parts of the bay Mongolian horse. These results provide an insight into the understanding of the biological mechanism of the hair follicle in other mammals. Hair length in different parts of horse showing differences among breeds. a is an Arabian horse (https://en.wikipedia.org/wiki/Arabian_horse). b is a Mongolian horse; the picture was taken in Inner Mongolia, China. The white arrows point four parts as following: mane, dorsal, tail, and fetlock. c is a Trait du Nord, a breed of heavy draft horse (https://en.wikipedia.org/wiki/Trait_du_Nord). a and c are from Wikimedia Commons under CC-BY-SA copyright, which can be used and adapted … Morphology of Mongolian bay horse hair follicle. From horizontal axis, mane (a1–5), body (b1–5), tail (c1–5), fetlock (d1–5); from longitudinal axis, (a1-d1) and (a4-d4) are anatomical lens images under 2X amplification. (a2-d2), (a3-d3) and (a5-d5) are microscope images of transparency stain or HE stain. Scale bars are, respectively, 100 μm, 200 μm, and 500 μm, as shown in pictures. e is the comparison of hair follicle dermal papilla diameter; f is the comparison of hair follicle density … ALP staining results. a, b, c and d represent four different parts, respectively, mane, dorsal part, tail and fetlock. Figures a1 ~ d1 are negative control (NC). Figures of a2 ~ d2 are ALP staining. Figures of a3 ~ d5 are the amplifications of ALP staining. a1, a2, × 18; b1, b2, × 40; c1, c2, × 20; d1, d2, × 25; scale bars,100 μm … Analysis of differential expression genes. a is a Venn diagram of differential expression analysis, different color indicates a different group. Green indicates mane, blue indicates dorsal part, pink indicates tail, and yellow indicates fetlock. b indicates the differentially expressed gene numbers between each group, red bars indicate gene numbers which up-regulated, while blue bars indicate down-regulated … GO enrichment annotated in the Hair Follicle Morphogenesis and Pigmentogenesis related signaling pathway between every two parts. Different color represents different kinds of pathways shown in the bottom left corner; dark blue refers pathways related to hair follicle morphogenesis to some extent but cannot be classified into one accurate function … Figures - available from: BMC Genomics Hair follicle regional specificity in different parts of bay Mongolian horse by histology and transcriptional profiling Ruoyang Zhao 1 , Wu Yihan 2 , Yiping Zhao 1 , Bei Li 1 , Haige Han 1 , Togtokh Mongke 1 , Tugeqin Bao 1 , Wenxing Wang 3 , Manglai Dugarjaviin 1 † and Dongyi Bai 1* † Abstract Background: Different mor phological str uctures of hair s having properti es like defense and ca mouflage help anim als survive in the wi ld environment . Horse is one of th e rare kinds of anim als with complex ha ir phenotype s in one individual ; however, know ledge of hors e hair follicle is limited in literature and their mole cular basis re mains unclear. Therefore, th e investigati on of horse hair follic le morphogene sis and pigmentog enesis attrac ts considerable in terest. Result: Histological stud ies revealed the morp hology and pigmen t synthesis of hair fo llicles are differ ent in between four differ ent parts (mane , dorsal part , tail, and fetl ock) of the bay Mo ngolian hors e. Hair follic le size, densit y, and cycle are strongl y associated wi th the activit y of alkaline ph osphatase (AL P). We observ ed a great differ ence in gene expression between the ma ne, tail, and fe tlock, which ha d a greater diff erent gene expr ession patter n compared wi th the dorsal pa rt through trans criptomic s. The developm ent of the hair fo llicle in all fo ur parts was rela ted to angiogene sis, stem cells, Wnt , and IGF signaling path ways. Pigmento genesis-rel ated pathways were in volved in their hair follicle pi gment synthesi s. Conclusion s: Hair follicle mo rphology and the act ivity of ALP differ amon g four body parts in bay Mongol ian horse. Hair follicle s of the different body pa rts of the are not synchron ized in their cycle sta ges. GO terms show a region al specificity pa ttern between di fferent skin part s of the bay Mongolian ho rse. These result s provide an insight in to the understand ing of the biological me chanism of the hair fo llicle in other mamma ls. Keywords: Mongolian horse, Skin , Hair follicle, Hist ology, Transcr iptome © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. * Correspondence: [email protected] † Manglai Dugarjaviin and Dongyi Bai contributed equally to this work. 1 lnner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Scientific Observing and Experimental Station of Equine Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs; Equine Research Center, College of animal science, Inner Mongolia Agricultural University, Zhao Wu Da Road, Hohhot 306 010018, Inner Mongolia, China Full list of author information is available at the end of the article Zhao et al. BMC Genomics (2020) 21:651 https://doi.org/10.1186/s12864-020-07064-1 Content courtesy of Springer Nature, terms of use apply. Rights reserved. Background Since about 5500 thousand years ago, horse ( Equus caballus ) has been domesticated as a crucial role in the agricultural industry, transportation, and military activ- ities [ 1 ]. Horse hair, with high regional specificity, can be mainly characterized at the mane, dorsal part, tail, and fetlock. Few mammals have such complex hair pheno- types on one individual body; therefore, the horse is a good model for studying hair follicle morphology and development due to the morphological differences exist- ing among breeds and even in the different body parts of the same animal (Fig. 1 ). Science and technology have led to the evolution of horse domestication and the production of diversified coat colors [ 2 ]. Horse coat color might be changing during the early ages to the adult stage, and also be influenced by environment and nutrition. Compared with young horses, adult horse coat color keeps rela- tively unchanged. Horse coat color is described as base colors, dilutions, and white spotting and depigmentation patterns [ 3 ]. The base color of a horse is ge nerally classi - fied into the black , chestnut, bay, or se al brown and is de- termined by two inte racting loci (exten sion and agouti) that affect melano cyte function [ 4 , 5 ]. These two loci de- termine if eumel anin or phaeomelan in will be produced in their correspo nding melanoso me. The extension loc us (E) encodes the melan ocortin-1 rece ptor (MC1R) and the agouti locus (A) enco des agouti signali ng protein (ASIP) which suppress es MC1R. Signal ing through MC1R with the agonist resul ts in the production of eume lanin, while antagonist bi nding (ASIP) resul ts in phaeomelanin pro- duction [ 6 ]. Ba y horse, the mos t common base co lor in horses, is the pr oduct of the domi nant wild type alle les at both loci (A, E). Bay hors es have a red body with blac k mane, tail, ear tips , and lower legs. Over the las t 70 years, human and mice hair fo llicles are extensi vely studied, and other animal mo dels include pi g, cattle, and sh eep were also used to study hair fol licle biology [ 7 ]. Al though there are some stud ies on the horse sk in [ 8 , 9 ], littl e is on horse hair follicle [ 10 , 11 ]. Understan ding the hair growth, cy cle, and melanogenes is in different part s of horse skin pro- vides insights an d valuable informat ion for studying the regional speci ficity of hair follic les in other mammals. Hair follicle undergoes lifelong cyclical transitions of anagen, catagen, telogen, and exogen (a stage which does not occur at every cycle), which is known as the hair cycle [ 12 ]. Through self-renewal and differentiation, stem cells are essential for hair follicle development and cycling, which involve many signaling pathways such as Wnt, Sonic Hedgehog, Notch, and bone morphogenetic protein (BMP). Some growth factors are also involv ed in the transition from telogen to anagen [ 13 , 14 ]. Wnt signals are considered to be the most important factor s during hair follicle morphogenesis. Wnt signaling path- way facilitates stem cell maintenance and proliferation. Wnt signaling activates the regeneration of hair follicles [ 15 , 16 ]. Dysregulation of this pathway often results in epithelial cancers [ 17 ]. Notch signaling also plays an im- portant role in hair follicle development by maintaining the follicular structure [ 18 , 19 ]. Notch participates in hair follicle development to control stem cell fate deter- mination [ 20 , 21 ]. Notch regulates cell differentiation and promotes boundary formation by altering the adhe- sive properties of keratinocytes [ 22 ]. The dermal Wnt pathway upregulates the epithelial Notch expression. Hair foll icle has two mes enchymal c omponen ts, in- cluding dermal papilla (DP) and dermal sheath. The DP is enveloped by keratinocytes at the anagen phase. DP releases insulin-like growth factors that are essen- tial for keratinocyte proliferation and differentiation [ 23 ]. Alkaline phosphatase (ALP) is detected in many tissues and organs [ 24 ]. ALP activity is also detected in the hair follicle during and after hair development, and this makes ALP a useful marker to indicate the location, shape, and size of the DP in skin specimens [ 25 ]. Over the years, scientists have continuously studied the expression pattern of ALP in the special- ized struc tures of hai r follicles i n various ma mmals and the detection of ALP expression is often used in developmental studies and clinical trials [ 26 ]. Fig. 1 Hair length in different parts of horse showing differences among breeds. a is an Arabian horse ( https://en.wikipedia.org/wiki/Arabian_ horse ). b is a Mongolian horse; the picture was taken in Inner Mongolia, China. The white arrows point four parts as following: mane, dorsal, tail, and fetlock. c is a Trait du Nord, a breed of heavy draft horse ( https://en.wikipedia.org/wiki/Trait_du_Nord ). a and c are from Wikimedia Commons under CC-BY-SA copyright, which can be used and adapted Zhao et al. BMC Genomics (2020) 21:651 Page 2 of 10 Content courtesy of Springer Nature, terms of use apply. Rights reserved. Our study aimed to reveal the morphological differ - ences and ALP expression patterns in hair follicles among four different body parts of the Mongoli an bay horse. We used transcriptome analysis to show the pathways relevant to hair follicle morphogenesis and pigmentogenesis. Results Morphological characteristics differ in hair follicles at four body parts The morphology differed in different parts of hair folli- cles (Fig. 2 a2, b2, c2, d2). Measurement of hair bulb (HB) diameter of four kinds of hair follicles showed that the tail and mane hair follicles had the biggest HB in diameter (Fig. 2 e). The hair density was visibly higher at the dorsal and fetlock regions than that of mane and tail regions (Fig. 2 a6, b6, c6, d6); Statistical analysis showed that hair follicles had the highest density at the fetlock part compared to that of the other body parts (Fig. 2 f). The tail hair follicles were highly keratinized compared to the hair follicles at the other body parts (Fig. 2 a3, a4, c3, c4). A cavity was observed in the hair matrix of the tail hair follicle (Fig. 2 c3). Based on the morphology of human and mouse hair follicles [ 12 , 27 ], either oval-shaped or onion-shaped DP suggests that the hair follicles in mane, tail, and fetlo ck regions were at late anagen. In dorsal hair follicles, together with a complete cessation of hair follicle pig- mentation and matrix volume loss in the HB, DP was condensed and almond-shaped (Fig. 2 b3), suggesting that most dorsal hair follicles were in early catag en, meanwhile, some follicles remain at late anagen (Fig. 2 b4, amplified in red rectangle). Smaller mid-anagen hair follicles were observed in between the large hair follicles in the fetlock region (Fig. 2 d2 with red arrows, ampli- fied in d4). Hairs in mane, tail, and fetlock of bay Inner Mongolian horse were observed to be all black, but hairs at the dor- sal part include both black and brownish-yellow so that the entire body of the horse showed a brown color (Fig. 2 a1 ~ d1). Paraffin sections with or without H&E stain- ing showed two kinds of pigment granules existed in the dorsal hair follicles (Fig. 2 b4, b6). These included the pheomelanin (amplified in a yellow rectangle), and the eumelanin (amplified in a red rectangle). There was only eumelanin deposition in the hair follicles of the other three parts. ALP expression patterns differed in hair follicles among four body parts ALP signals were detected in the vessel-like structures around the hair follicle (Fig. 3 a3, b3, c5, d5) among four body parts. ALP signals were also shown in the DP of mane, tail and fetlock follicles (Fig. 3 a4, a5, c3, c4, d5, red arrowheads), but not found in the dorsal hair folli- cles (Fig. 3 b4, b5). Different from the others, strong ALP signals were detected in papillary dermis in fetlock skin (Fig. 3 d3, red arrowhead). Meanwhile, ALP signals were also detected in the outer root sheath (O RS) of fetlock hair follicles (Fig. 3 d4, d5, red arrowhead). GO terms relevant to hair follicle morphogenesis and pigmentogenesis A total of 199.28G raw data and 196.49G valid data were obtained by transcriptome sequencing from twelve samples harvested from four different parts of the Inner Mongolian bay horse. Both G20 and G30 met the re- quirement of the following analysis (Additional file 1 ). All raw data fastq sequences were deposited at the Na- tional Center for Biotechnology Information ( http:// www.ncbi.nlm.nih.gov/ ) under BioProject PRJNA477743 with an SRA accession SRP151228. Dorsal skin had the most significant differential gene expression compared to that of skins from the other three parts ( p < 0.05, Fig. 4 a and b, Additional file 2 in detail). We selected all GO terms related to hair follicle morphogenesis and pigmentogenesis and found some Intriguingly patterns between every two parts (Fig. 5 and Additional file 3 ). Wnt, stem cell, and angiogenesis- related signaling pathways were enriched in GO terms with the comparison between the dorsal and tail skin. GO terms were mostly associated with melanogenesis and stem cells between mane and dorsal parts. The ma- jority of GO terms were classified in insulin-like growth factor-related signaling pathways and some stem cell signaling pathways between the dorsal part (or mane) and fetlock. Every two parts of mane, tail, and fetlock were all related to the angiogenesis pathway. An alkaline phosphatase pathway was selected between mane and tail. qRT-PCR was used to validate eight randomly se- lected genes that showed consistent expression tendency with the RNAseq data (Fig. 6 ). Discussion Histology of hair follicles in different parts of bay Mongolian horse was revealed for the first time. The results showed that mane and tail hair follicles have a similar morphology. Hair follicles in the dorsal part are very different in pigment, cycle stage, density, and size compared with the other three parts. It is obviously seen that two different kinds of hair follicles exiting in the fetlock skin, which might be considered as primary and secondary hair follicles. The density of hair follicles is very high in the fetlock skin suggesting that the horse needs more hairs to protect their knees. Mammalian hair growth is a dynamic process that depends on prolifera- tion, differentiation, and migration of the matrix cells within the bulb of the follicle, and the hair shape is Zhao et al. BMC Genomics (2020) 21:651 Page 3 of 10 Content courtesy of Springer Nature, terms of use apply. Rights reserved. Fig. 2 (See legend on next page.) Zhao et al. BMC Genomics (2020) 21:651 Page 4 of 10 Content courtesy of Springer Nature, terms of use apply. Rights reserved. programmed from the HB [ 28 ]. The size of HB deter- mines matrix volume, which may lead to the different hair follicle morphologies in different body parts. In the present study, we proposed that the HB diameter differ- ences may cause complex hair phenotypes in one indi- vidual horse. Hair follicle is a mini-organ that undergoes cyclic growth [ 12 ]. Different parts of mammals have different hair follicle cycling duration; hair follicle morphology changes during cyclic growth [ 27 ]. ALP activity is widely expressed in actively proliferating or remodeling tissues, as well as in cells with a high metabolic rate [ 29 ]. The expression pattern of ALP is slightly different at different hair cycle stages in different animals [ 26 , 30 , 31 ]. It has been reported that the ALP activity can last through the whole hair follicle cycle in mouse dorsal skin. But DP and ORS are only ALP-positive during late anagen and early catagen in rat hair follicles [ 32 ]. ALP activity changes dynamically in DP and dermal sheath in mou se vibrissa follicles, it reaches the highest level in the early anagen in DP, decreases by nearly half after the middle anagen, and even less in catagen [ 31 ]. ALP activities could also be detected at the proximal DS adjacent to DP, with the highest level at the early anagen [ 33 ]. In all, understanding of ALP patterns in horse skin and hair follicle helps to determine the hair cycle. Both H&E staining and ALP expression results showed that mane and tail hair follicles are at late anagen. Normally, horses shed twice a year in spring and fall. Our samples were taken in late fall, a season in the north of China when the hair coat of most mammals becomes thicker. Hair cycle of the animal body might be more closely related to season, the reason why hair follicles in the dorsal skin tend to enter catagen after shedding. Meanwhile, most fetlock follicles remain staying in anagen to produce more hairs to defense the strong northwest wind. Histology shows that the hair follicles of different parts of the horse body are not synchronized in their cycle stages, and the duration of the hair cycle in each of the body parts need further investigation. Due to the limited samples, the existing histological results cannot tell if all the hair follicles in the different four parts going through the same cycle stage simultan- eously (such as the first hair cycle in mouse), or they (See figure on previous page.) Fig. 2 Morphology of Mongolian bay horse hair follicle. From horizontal axis, mane ( a 1 – 5), body ( b 1 – 5), tail ( c 1 – 5), fetlock ( d 1 – 5); from longitudinal axis, ( a 1- d 1) and ( a 4- d 4) are anatomical lens images under 2X amplification. ( a 2- d 2), ( a 3- d 3) and ( a 5- d 5) are microscope images of transparency stain or HE stain. Scale bars are, respectively, 100 μ m, 200 μ m, and 500 μ m, as shown in pictures. e is the comparison of hair follicle dermal papilla diameter; f is the comparison of hair follicle density Fig. 3 ALP staining results. a , b , c and d represent four different parts, respectively, mane, dorsal part, tail and fetlock. Figures a1 ~ d1 are negative control (NC). Figures of a2 ~ d2 are ALP staining. Figures of a3 ~ d5 are the amplifications of ALP staining. a1, a2, × 18; b1, b2, × 40; c1, c2, × 20; d1, d2, × 25; scale bars,100 μ m Zhao et al. BMC Genomics (2020) 21:651 Page 5 of 10 Content courtesy of Springer Nature, terms of use apply. Rights reserved. are not synchronized like the hairs on a human scalp. This needs to be addressed in further studies on horse embryo skin in different gestational ages. The phenotypic differences among the four parts of bay Mongolian horse are significant, also with significant differential gene expression. The enrichment of differen- tial mRNAs and GO items is carried out by comparison between every two parts. In this way, within a certain range of p -values, the enriched pathway pattern is pre- liminarily revealed and summarized. Stem cell rele vant pathways are enriched in every two groups suggesting that stem cell signals are needed in the whole process of skin and hair follicle morphogenesis and pigment synthesis. The biggest difference between the dorsal part Fig. 4 Analysis of differential expression genes. a is a Venn diagram of differential expression analysis, different color indicates a different group. Green indicates mane, blue indicates dorsal part, pink indicates tail, and yellow indicates fetlock. b indicates the differentially expressed gene numbers between each group, red bars indicate gene numbers which up-regulated, while blue bars indicate down-regulated Fig. 5 GO enrichment annotated in the Hair Follicle Morphogenesis and Pigmentogenesis related signaling pathway between every two parts. Different color represents different kinds of pathways shown in the bottom left corner; dark blue refers pathways related to hair follicle morphogenesis to some extent but cannot be classified into one accurate function Zhao et al. BMC Genomics (2020) 21:651 Page 6 of 10 Content courtesy of Springer Nature, terms of use apply. Rights reserved. and tail is the shape of hair follicles, Wnt signals are considered to be mostly involved in its formation. GO terms enriched in melanogenesis is somewhat expected because it is obvious that the hair pigment is the most different phenotype between mane and dorsal part. In our study, an ALP pathway is enriched between the mane and tail, suggesting it can not only be used to determine the cycle stages in different parts of horse hair follicles. In association with the hair cycle, highly regen - erative hair follicles are known to express ALP. Regener- ation of hair follicles is governed by the reciprocal epithelial-mesenchymal interactions [ 34 ]. DP cells are critical to hair growth and regeneration of the HB has regressed in catagen by exhaustion and apoptosis of the bulbar epithelial cells. It has been described that hair inductivity of DP appears to be closely related to ALP activity [ 33 ]. Hair follicle is like other organs in need of rich nutrients supplement [ 35 ], especially, thick and strong hair follicles like mane and tail. Enough supply of nutrition must be accomplished by abundant capillaries and periodic angiogenesis around hair follicles to satisfy the demands of hair follicle cyclic growth. Therefore, ALP activity could have some other functions in hair fol- licles more than hair inductivity. Although the arteries and veins are located deep in the dermis, the dendritic capillaries are widely distributed above the bulge area, which provides nutrients, hormones, and immune cells to the skin and also plays an important role in heat transfer. These vascular tissues may affect the process of hair follicle regeneration. This is the reason why alkaline phosphatase, angiogenesis, and stem cell-related path- ways are enriched in the relatively thick hair follicles. Fig. 6 Validation of RNAseq data using qRT-PCR. The red line indicates qPCR results; while blue indicates FPKM values Zhao et al. BMC Genomics (2020) 21:651 Page 7 of 10 Content courtesy of Springer Nature, terms of use apply. Rights reserved. ALP activity shown in vessel-like structures around hair follicles in different parts might be directly related to angiogenesis and artery morph ogenesis. When angiogenesis is inhibited, the initiation of anagen will be delayed [ 35 ], which indicates that angiogenesis factors can regulate the activity of hair follicle stem cells and in turn to affect the expression of ALP. The relatio nship between ALP activity and cyclic hair regeneration and the exact roles of ALP in the horse hair follicles should be addressed by further inves- tigations. In DP cells, a variety of growth factors control the hair follicle cycle, including insulin-like growth factors [ 36 ]. GO terms are mostly enriched in IGF pathways between the fetlock and the other three parts. We could propose that IGF relevant pathways are closely related to horse hair cycle and hair density in accordance with histological results. These findings will provide some novel insights in horse hair follicle morphogenesis and melanogenesis. Conclusion Our study unveiled that hair follicles are in different morphology at different body parts of the Mongolian bay horse skin, with significant transcriptome level differences identified by RNA-seq analysis. The hair follicle size, density, and cycle among different types of hair follicles are suggested to be related to ALP activity, angiogenesis, stem cells, WNT, and IGF signaling pathways. These factors and pathways may regulate the regional specificity by control- ling the hair follicle morphogenesis and pigmentogenesis. Further studies are required to reveal the hair cycle stages and the molecular mechanism controlling the regional specificity at the different body parts of the Mongolian bay horse. Methods Sample collection Three male bay Mo ngolian hors es (10 years old) we re used in our experime nt (Fig. 1 b was one of the ho rses we used in this study) . Four kinds of skin sample s from mane, dorsal part, tail, and fetloc k were excised fr om each horse, and a total of twelve samp les were taken in Decembe r of 2017by trained ve terinary techni cians. The horses we re bought from compan y (CHINA HORSE INDUST RY GROUP CO., LIMITE D) and raised in the same en viron- ment (Hohhot, In ner Mongolia, Ch ina). All surger y was performed unde r combination anes thesia and all effort s were made to mini mize horses suff ering. Detomi dine (0.01 – 0.02 mg /kg, IV) combine d with butorpha nol (0.02 – 0.04 mg/kg, IV) was used for analgesia following standing surgery steps. Al l horses were still rear ed carefully after surgery. Sample s were collected follo wing the instituti onal, national, an d international gu idelines and ap proved by the Animal Ethica l Committee of Inner Mon golia Agricult ural University. Ha lf of the samples were pu t into liquid nitrogen immed iately then store d at − 80 °C. The other adjacent half were fixed in paraformaldehy de for 20 h, then were dehydrat ed with gradient etha nol (70, 80, 80, 100%) and cryo preserved in − 20 °C. Histological analysis Samples immersed in 100% ethanol were embedded into paraffin blocks and cut into sections (Leica RM 2245) of 5-7 μ m thickness, after being deparaffinized and rehy- drated, then stained with hematoxylin and eosin(H&E), or without any stain (transparency stain), for there were no other colors to disrupt observation of original pig- ment color) (Fig. 2 b4, a6, b6, c6, d6). We measured the HB diameter of 20 hair follicles under the same magnifi- cation from 5 locations from serial longitudinal slides each part and repeated in four parts of skin slides. We chose HBs which were cut right in the middle of hair follicles for measurements. The chosen HBs must be in- tegral and clear structured and the planes we measured the HB diameter are shown in figures (Red dashed lines in Fig. 2 a4, b3, c3 ~ 4, d3). Hair follicle density was mea- sured in 5 different fields using cross-sections and the planes we cut the cross-sections were shown in figures (Red dashed lines in Fig. 2 a1, b1, c1, d1). The method above was applied to a total of 12 samples. Data were made graphics using GraphPad (San Diego, CA, USA). Histochemistry Steps of alkali ne phosphatas e activity dete ction were as follows: the NB T/BCIP (Maixing , Fuzhou, China) wa s added on the tissue s after gradient al cohol rehydrat ion in the dark for 15 min until a dark blue sign al appeared an d was stopped by washing with PBS (pH 7.2 ~ 7.4). This was applied to the 12 sa mples. Signal s were detected an d mea- sured throug h digital photog raphs using the mi croscope imaging system (A xio Observer D1, ZEI SS). Library construction and sequencing Total RNA were extracted from twelve samples (three replicates from each of four parts) stored in − 80 °C in accordance with standard procedure of Trizol reagent (Invitrogen, CA, USA) and Animal Tissue RNA Purifica- tion Kit (LC Science, Houston, TX). The quantity and purity of RNA (RIN number > 7.0) were analyzed according to the previous research [ 37 ]. After, a certain amount of RNA was purified [ 37 ]. Following, the RNA fractions were fragmented by cations under suitable temperature. Finally, cDNA library was constructed using the stranded procedures of mRNA-seq Library Prep Kit (Illumina, San Diego, USA). An Illumina Hiseq 4000 platform was then performed the sequencing [ 37 ]. Transcripts assembly Cutadapt [ 38 ] was used to remove the low-quality frag- ments. There were two steps we used to wipe out low- Zhao et al. BMC Genomics (2020) 21:651 Page 8 of 10 Content courtesy of Springer Nature, terms of use apply. Rights reserved. quality reads to obtain clean reads. Firstly, we wiped out low reads with adapters and poly-N (N indicates that the base cannot be confirmed) over the rate of 10% using Cutadapt. Secondly, we wiped out paired reads with low-quality through single-ended sequencing (With low- quality bases over the rate of 50% of the whole reads were considered to be the low-quality paired reads). Then, Q20 and Q30 were calculated using q30.py ( https://github.com/d-ayedepps/q30 ). FastQC [ 37 ] was used to verify the sequence quality. High-quality clean data obtained were used to do mapping of Equus cabal- lus genome ( http://asia.ensembl.org/Equus_caballus/Info /Index) by Bowtie2 [ 39 ] and TopHat [ 40 ]. Reads mapped to the genome were assembled using StringTie [ 41 ] and generated a GTF file for each sample. Cuffmerge merges the GTF files into more comprehensive transcripts annotation results. Then, we used Cuffdiff to do gene expression difference analysis [ 42 ]. Expression analysis of mRNAs and GO enrichments StringTie [ 41 ] was used to perform expression level analysis for mRNAs by calculating FPKM [ 43 ]. The fragments per kilobase of transcript per million (FPKM) mapped reads was calculated for each gene based on the length of the gene and reads counts mapped to this gene. FPKM simultaneously considers the effect of sequencing depth and gene length for the reads count. The differentially expressed mRNAs were selected with |log 2 (fold change) | < 1 and with statistical significance ( p - value < 0.05) by R package Ballgown [ 44 ]. The Benjamin- Hochberg method wa s used to correct the P -val ue. GOseq R package was used to selected Gene Ontology (GO) enrichment of differentially expressed genes [ 45 ]w i t h a P -value of < 0.05. Quantitative real-time PCR (qRT-PCR) validation RNA was used to perform a reverse tr anscriptio n PCR using HiScri pt® II qRT Super Mix for qPCR (Vaz yme). Subsequentl y, qPCR was performe d using the primers (Additiona l file 4 ) from Invitro gen with SYBR®Pre mix Ex Taq ™ II (TaKaRa) . A total of 8 genes ( DKK1 , DK K2 , IGF1 , IGF1R , WNT5A , WNT5B , CD34 ,a n d SOX2 )w e r er a n - domly selecte d for qRT-PCR va lidation. Each sample has 3 replicates. GAP DH as the housekeeping ge ne was used to assess the leve l of RNA expressi on. Data collec tion and analysis were performed resp ectively by CF X96 Real-Time PCR Detection Syst em (Bio-Rad) and Mi crosoft Excel. Supplementary information Supplementary information accompanies this paper at https://doi.org/10. 1186/s12864-020-07064-1 . Additional file 1. The quality control of RNAseq data. Additional file 2. Gene differential expression results. Significant gene differential expression results between every two different parts. Additional file 3. GO enrichments. Significant GO enrichments between every two different parts. Additional file 4. Primers for qRT-PCR validation. Abbreviations DEGs: Differentially expressed genes; FDR: False discovery rate; FPKM: Fragments per kilobase of transcript per million fragments mapped; GO: Gene ontology; HE: Haematoxylin-eosin; PCA: Principal component analysis; q-PCR: Quantitative real-time PCR; RNA-Seq: RNA sequencing Acknowledgments Authors would like to thank prof. Mingxing Lei (Chongqing University, Chong Qing, China) for the excellent ideas of our work and support in the language improvement. We would like to thank Nei Mongol Bionew Technology Co. Ltd. for assistance of data analyzing. Authors ’ contributions RZ performed the most experiments, analyzed the data and wrote the manuscript. DB and MD were together conceived, revised and submitted the manuscript. WY and YZ helped with histological experiment and assisted with experimental design. BL interpreted morphological data. HH and WW helped with revising the manuscript. TM applied the Transcriptional Profiling. TB helped with analyzing Transcriptome data. All authors have read and approved the final version of the manuscript. Funding This work was supported by the National Natural Science Foundation of China (No.31960657,31961143025),National Basic Research Program of China (No.2017YFE0108700),Natural Science Foundation Special Project of Inner Mongolia (No.2017ZD06), Science and Technology major project of Inner Mongolia (No.ZD20190039),National Natural Science Foundation of Inner Mongolia (No.2019MS03064),and Youth Fund Project of Collage of Animal Science of Inner Mongolia Agricultural University (No.QN202006, QN201909). Availability of data and materials All raw data fastq sequences are deposited at the National Center for Biotechnology Information ( http://www.ncbi.nlm.nih.gov/ ) under BioProject PRJNA477743 with SRA accession SRP151228. All raw sequences are deposited as BioSamples SAMN09478216, SAMN09478217, SAMN09478218, SAMN09478219, SAMN09478220, SAMN09478221, SAMN09478222, SAMN09478223, SAMN09478224, SAMN09478225, SAMN09478226 and SAMN09478227 ( https://www.ncbi.nlm.nih.gov/sra/ PRJNA477743). Equus caballus genome ( http://asia.ensembl.org/Equus_caballus/Info /Index) was used to do mapping. Ethics approval and consent to participate The present study was carried out in strict accordance with relevant guidelines and regulations by the Ministry of Agriculture of the People ’ s Republic of China. Specimens were collected following the institutional, national, or international guidelines and approved by the Animal Ethical Committee of Inner Mongolia Agricultural University. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Author details 1 lnner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Scientific Observing and Experimental Station of Equine Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs; Equine Research Center, College of animal science, Inner Mongolia Agricultural University, Zhao Wu Da Road, Hohhot 306 010018, Inner Mongolia, China. 2 Inner Mongolia Center for Disease Comprehensive Control and Prevention, Hohhot 010030, China. 3 Inner Mongolia Zhong Yun Horse Industry Group, Xilinhot 026000, China. Zhao et al. BMC Genomics (2020) 21:651 Page 9 of 10 Content courtesy of Springer Nature, terms of use apply. Rights reserved. Received: 10 December 2019 Accepted: 10 September 2020 References 1. Outram AK, St ear NA, Bendr ey R, Olsen S, Ka sparov A, Za ibert V, Thor pe N, Evershed RP. The earliest horse harnessing and milking. Science. 2009;323:1332 – 5. 2. Ludwig A, Pruvost M, Reissmann M, Benecke N, Brockmann GA, Castanos P, Cieslak M, Lippold S, Llorente L, Malaspinas AS, et al. Coat color variation at the beginning of horse domestication. Science. 2009;324:485. 3. Sponenberg DP, Bellone R. Equine color genetics, 4th edition. London: Blackwell Publishers; 1996. 4. Rees JL. Genetics of hair and skin color. Annu Rev Genet. 2003;37:67 – 90. 5. Chen Y, Duhl DM, Barsh GS. Opposite orientations of an inverted duplication and allelic variation at the mouse agouti locus. Genetics. 1996; 144:265 – 77. 6. Rieder S, Taourit S, Mariat D, Langlois B, Guerin G. Mutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotypes in horses (Equus caballus). Mamm Genome. 2001;12:450 – 5. 7. Bernard BA. The hair follicle enigma. Exp Dermatol. 2017;26:472 – 7. 8. Cerrato S, Ramio-Lluch L, Brazis P, Rabanal RM, Fondevila D, Puigdemont A. Development and characterization of an equine skin-equivalent model. Vet Dermatol. 2014;25:475 – e77. 9. Tomich LM, Pieper JB, Stern AW. Comparing dermoscopy and histological examination of normal equine skin. Vet Dermatol. 2018;29:170 – e63. 10. Imsland F, McGowan K, Rubin CJ, Henegar C, Sundstrom E, Berglund J, Schwochow D, Gustafson U, Imsland P, Lindblad-Toh K, et al. Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation that underlies dun camouflage color in horses. Nat Genet. 2016;48:152 – 8. 11. Morgenthaler C, Diribarne M, Capitan A, Legendre R, Saintilan R, Gilles M, Esquerre D, Juras R, Khanshour A, Schibler L, et al. A missense variant in the coil1A domain of the keratin 25 gene is associated with the dominant curly hair coat trait (Crd) in horse. Genet Sel Evol. 2017;49:85. 12. Oh JW, Kloepper J, Langan EA, Kim Y, Yeo J, Kim MJ, Hsi TC, Rose C, Yoon GS, Lee SJ, et al. A guide to studying human hair follicle cycling in vivo. J Invest Dermatol. 2016;136:34 – 44. 13. Rishikaysh P, Dev K, Diaz D, Qureshi WM, Filip S, Mokry J. Signaling involved in hair follicle morphogenesis and development. Int J Mol Sci. 2014;15: 1647 – 70. 14. Hwang I, Choi KA, Park HS, Jeong H, Kim JO, Seol KC, Kwon HJ, Park IH, Hong S. Neural stem cells restore hair growth through activation of the hair follicle niche. Cell Transplant. 2016;25:1439 – 51. 15. Andl T, Reddy ST, Gaddapara T, Millar SE. WNT signals are required for the initiation of hair follicle development. Dev Cell. 2002;2:643 – 53. 16. Lo Celso C, Prowse DM, Watt FM. Transient activation of beta-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development. 2004;131:1787 – 99. 17. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434: 843 – 50. 18. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770 – 6. 19. Pan Y, Lin MH, Tian X, Cheng HT, Gridley T, Shen J, Kopan R. Gamma- secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell. 2004;7:731 – 43. 20. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7:678 – 89. 21. Hurlbut GD, Kankel MW, Lake RJ, Artavanis-Tsakonas S. Crossing paths with notch in the hyper-network. Curr Opin Cell Biol. 2007;19:166 – 75. 22. Watt FM. Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J. 2002;21:3919 – 26. 23. Stenn KS, Pau s R. Controls o f hair folli cle cycling. Physiol Rev . 2001;81: 449 – 94. 24. Stefkova K, Prochazkova J, Pachernik J. Alkaline phosphatase in stem cells. Stem Cells Int. 2015;2015:628368. 25. Muller-Rover S, Handjiski B, van der Veen C, Ei chmuller S, Foitzik K, McKay IA, Stenn KS, Paus R. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest Dermatol. 2001;117:3 – 15. 26. Al-Bagdadi FK, Titkemeyer CW, Lovell J. Alkaline phosphatase reaction in hair follicles of male beagle dogs during hair cycle stages. Anat Histol Embryol. 1978;7:245 – 52. 27. Paus R, Muller-Rover S, Van Der Veen C, Maurer M, Eichmuller S, Ling G, Hofmann U, Foitzik K, Mecklenburg L, Handjiski B. A comprehensive guide for the recognition and classification of distinct stages of hair follicle morphogenesis. J Invest Dermatol. 1999;113:523 – 32. 28. Thibaut S, Gaillard O, Bouhanna P, Cannell DW, Bernard BA. Human hair shape is programmed from the bulb. Br J Dermatol. 2005;152:632 – 8. 29. Kopf AW. The distribution of alkaline phosphatase in normal and pathologic
https://www.researchgate.net/publication/344366375_Hair_follicle_regional_specificity_in_different_parts_of_bay_Mongolian_horse_by_histology_and_transcriptional_profiling
CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial Oki Y, Kelly KR, Flinn I, Patel MR, Gharavi R, Ma A, Parker J, Hafeez A, Tuck D, Younes A. CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial. Haematologica. 2017 Nov;102(11):1923-1930. doi: 10.3324/haematol.2017.172882. Epub 2017 Aug 31. Yasuhiro Oki, Kevin R Kelly, Ian Flinn, Manish R Patel, Robert Gharavi, Anna Ma, Jefferson Parker, Amir Hafeez, David Tuck, Anas Younes, Yasuhiro Oki, Kevin R Kelly, Ian Flinn, Manish R Patel, Robert Gharavi, Anna Ma, Jefferson Parker, Amir Hafeez, David Tuck, Anas Younes Abstract CUDC-907 is a first-in-class, oral small molecule inhibitor of both HDAC (class I and II) and PI3K (class Iα, β, and δ) enzymes, with demonstrated anti-tumor activity in multiple pre-clinical models, including MYC-driven ones. In this report, we present the safety and preliminary activity results of CUDC-907, with and without rituximab, in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), with a particular focus on those with MYC-altered disease. Thirty-seven DLBCL patients were enrolled, 14 with confirmed MYC-altered disease. Twenty-five patients received monotherapy treatment, and 12 received the combination of CUDC-907 with rituximab. CUDC-907 monotherapy and combination demonstrated similar safety profiles consisting primarily of Grade 1/2 hematologic and gastrointestinal events. The most frequently reported Grade ≥3 treatment-related events were thrombocytopenia, neutropenia, diarrhea, fatigue, and anemia. Eleven responses (5 complete responses and 6 partial responses) were reported, for a response rate of 37% (11 out of 30) in evaluable patients [30% (11 out of 37) including all patients]. The objective response rate in evaluable MYC-altered DLBCL patients was 64% (7 out of 11; 4 complete responses and 3 partial responses), while it was 29% (2 out of 7) in MYC unaltered, and 17% (2 out of 12) in those with unknown MYC status. Median duration of response was 11.2 months overall; 13.6 months in MYC-altered patients, 6.0 months in MYC unaltered, and 7.8 months in those with MYC status unknown. The tolerable safety profile and encouraging evidence of durable anti-tumor activity, particularly in MYC-altered patients, support the continued development of CUDC-907 in these populations of high unmet need. ( clinicaltrials.gov identifier: 01742988). Trial registration:ClinicalTrials.govNCT01742988. Copyright© Ferrata Storti Foundation. Figures Figure 1. Extended progression-free survival (PFS) in MYC-altered patients. Kaplan-Meier PFS curve for all patients (n=37) on the trial (solid black line) along with subsets based on MYC status. MYC-altered patients (n=14, blue dotted line), MYC negative patients (n=8, red dashed line) and MYC unknown (n=15, green dash-dotted line). Median PFS was 2.9 months for all diffuse large B-cell lymphoma (DLBCL) patients and 21.8 months for the MYC-altered patients, respectively. x-axis in months; y-axis is the proportion of patients. Figure 2. Extended duration of response in MYC-altered patients. Kaplan-Meier duration of response curve for all responding patients (n=11) on the trial (solid black line) along with subsets based on MYC status. MYC-altered patients (n=7, blue dotted line), MYC negative patients (n=2, red dashed line) and MYC unknown (n= 2, green dash-dotted line). x-axis in months; y-axis is the proportion of patients. References Colosia A, Njue A, Trask PC, et al. Clinical efficacy and safety in relapsed/refractory diffuse large B-cell lymphoma: a systematic literature review. Clin Lymphoma Myeloma Leuk. 2014;14(5):343–355.e6. de Jonge AV, Roosma TJA, Houtenbos I, et al. Diffuse large B-cell lymphoma with MYC gene rearrangements: Current perspective on treatment of diffuse large B-cell lymphoma with MYC gene rearrangements; case series and review of the literature. Eur J Cancer. 2016;55:140–146. Rosenthal A, Younes A. High grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6: Double hit and triple hit lymphomas and double expressing lymphoma. Blood Rev. 2017;31(2):37–42. Miyazaki K. Treatment of Diffuse Large B-Cell Lymphoma. J Clin Exp Hematop. 2016;56(2):79–88. Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012;30(36):4462–4469. NCCN Clinical Practice Guidelines. Non-Hodgkin’s Lymphomas. V 4.2014. Van Den Neste E, Schmitz N, Mounier N, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplant. 2016;51(1):51–57. Younes A, Berdeja JG, Patel MR, et al. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2016;17(5):622–631. Elstrom RL, Martin P, Ostrow K, et al. Response to second-line therapy defines the potential for cure in patients with recurrent diffuse large B-cell lymphoma: implications for the development of novel therapeutic strategies. Clin Lymphoma Myeloma Leuk. 2010;10(3):192–196. Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28(20):3360–3365. Zhou K, Xu D, Cao Y, Wang J, Yang Y, Huang M. C-MYC aberrations as prognostic factors in diffuse large B-cell lymphoma: a meta-analysis of epidemiological studies. PloS One. 2014;9(4):e95020. Cuccuini W, Briere J, Mounier N, et al. MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation. Blood. 2012;119(20):4619–4624. Nitsu N, Okamoto M, Miura I, Hirano M. Clinical significance of 8q24/c-MYC translocation in diffuse large B-cell lymphoma. Cancer Sci. 2009;100(2):233–237. Savage KJ, Johnson NA, Ben-Neriah S, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009;114(17):3533–3537. Horn H, Ziepert M, Becher C, et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013;121(12):2253–2263. Valera A, López-Guillermo A, Cardesa-Salzmann T, et al. MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Haematologica. 2013;98(10):1554–1562. Landsburg D, Falkiewicz M, Petrich A, et al. Sole rearrangement but not amplification of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma and B cell lymphoma unclassifiable. Br J Haematol. 2016;175(4):631–640. Sun K, Atoyan R, Borek MA, et al. Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers. Mol Cancer Ther. 2017;16(2):285–299. Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lymphomas. Blood. 2011;117(8):2319–2331. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3452–3459. Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3460–3467. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–2390. West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124(1):30–39. Crump M, Coiffier B, Jacobsen ED, et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Ann Oncol. 2008;19(5):964–969. Kurland JF, Tansey WP. Myc-mediated transcriptional repression by recruitment of histone deacetylase. Cancer Res. 2008;68(10):3624–3629. Zhang X, Zhao X, Fiskus W, et al. Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell. 2012;22(4):506–523. Chambers AE, Banerjee S, Chaplin T, et al. Histone acetylation-mediated regulation of genes in leukaemic cells. Eur J Cancer. 1990 2003;39(8):1165–1175. Gui C-Y, Ngo L, Xu WS, Richon VM, Marks PA. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci USA. 2004;101(5):1241–1246. Duan H, Heckman CA, Boxer LM. Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol Cell Biol. 2005;25(5):1608–1619. Kenney AM, Widlund HR, Rowitch DH. Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle progression in cerebellar neuronal precursors. Development. 2004;131(1):217–228. Asano T, Yao Y, Zhu J, Li D, Abbruzzese JL, Reddy SAG. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells. Oncogene. 2004;23(53):8571–8580. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378(6559):785–789. Qian C, Lai C-J, Bao R, et al. Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin Cancer Res. 2012;18(15):4104–4113. Rahmani M, Aust MM, Benson EC, Wallace L, Friedberg J, Grant S. PI3K/mTOR inhibition markedly potentiates HDAC inhibitor activity in NHL cells through BIM- and MCL-1-dependent mechanisms in vitro and in vivo. Clin Cancer Res. 2014;20(18):4849–4860. Mondello P, Derenzini E, Asgari Z, et al. Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma. Oncotarget. 2017;8(8):14017–14028. Wendel H-G, De Stanchina E, Fridman JS, et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature. 2004;428(6980):332–337. Sander S, Calado DP, Srinivasan L, et al. Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis. Cancer Cell. 2012;22(2):167–179. Chapuy B, McKeown MR, Lin CY, et al. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell. 2013;24(6):777–790. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014;124(15):2354–2361. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–586. HDAC Inhibitors in Cancer Care | Cancer Network. Available from: [Last accessed 27 March 2017] Aggarwal R, Thomas S, Pawlowska N, et al. Inhibiting Histone Deacetylase as a Means to Reverse Resistance to Angiogenesis Inhibitors: Phase I Study of Abexinostat Plus Pazopanib in Advanced Solid Tumor Malignancies. J Clin Oncol. 2017;35(11):1231–1239. Farydak (panobinostat) Product Characteristics leaflet. Chia S, Gandhi S, Joy AA, et al. Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer. Curr Oncol. 2015;22(1):33–48. Barr PM, Saylors GB, Spurgeon SE, et al. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood. 2016;127(20):2411–2415. Assouline SE, Nielsen TH, Yu S, et al. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood. 2016;128(2):185–194. Sun K, Atoyan R, Borek MA, et al. The Combination of Venetoclax and CUDC-907 Exhibits Synergistic Activity in Venetoclax-Refractory DLBCL. Blood. 2016;128(22):4184–4184. Source:PubMed
https://ichgcp.net/clinical-trials-registry/publications/138903-cudc-907-in-relapsed-refractory-diffuse-large-b-cell-lymphoma-including-patients-with-myc
Multi-Scale Mass Transfer Processes Controlling Natural Attenuation and Engineered Remediation: An IFRC Focused on Hanford’s 300 Area Uranium Plume (Technical Report) | OSTI.GOV The U.S. Department of Energy's Office of Scientific and Technical Information Title: Multi-Scale Mass Transfer Processes Controlling Natural Attenuation and Engineered Remediation: An IFRC Focused on Hanford’s 300 Area Uranium Plume The Integrated Field-Scale Subsurface Research Challenge (IFRC) at the Hanford Site 300 Area uranium (U) plume addresses multi-scale mass transfer processes in a complex hydrogeologic setting where groundwater and riverwater interact. A series of forefront science questions on mass transfer are posed for research which relate to the effect of spatial heterogeneities; the importance of scale; coupled interactions between biogeochemical, hydrologic, and mass transfer processes; and measurements and approaches needed to characterize and model a mass-transfer dominated system. The project was initiated in February 2007, with CY 2007 and CY 2008 progress summarized in preceding reports. The site has 35 instrumented wells, and an extensive monitoring system. It includes a deep borehole for microbiologic and biogeochemical research that sampled the entire thickness of the unconfined 300 A aquifer. Significant, impactful progress has been made in CY 2009 with completion of extensive laboratory measurements on field sediments, field hydrologic and geophysical characterization, four field experiments, and modeling. The laboratory characterization results are being subjected to geostatistical analyses to develop spatial heterogeneity models of U concentration and chemical, physical, and hydrologic properties needed for reactive transport modeling. The field experiments focused on: (1) physical characterization of the groundwater flow field during amore » period of stable hydrologic conditions in early spring, (2) comprehensive groundwater monitoring during spring to characterize the release of U(VI) from the lower vadose zone to the aquifer during water table rise and fall, (3) dynamic geophysical monitoring of salt-plume migration during summer, and (4) a U reactive tracer experiment (desorption) during the fall. Geophysical characterization of the well field was completed using the down-well Electrical Resistance Tomography (ERT) array, with results subjected to robust, geostatistically constrained inversion analyses. These measurements along with hydrologic characterization have yielded 3D distributions of hydraulic properties that have been incorporated into an updated and increasingly robust hydrologic model. Based on significant findings from the microbiologic characterization of deep borehole sediments in CY 2008, down-hole biogeochemistry studies were initiated where colonization substrates and spatially discrete water and gas samplers were deployed to select wells. The increasingly comprehensive field experimental results, along with the field and laboratory characterization, are leading to a new conceptual model of U(VI) flow and transport in the IFRC footprint and the 300 Area in general, and insights on the microbiological community and associated biogeochemical processes. A significant issue related to vertical flow in the IFRC wells was identified and evaluated during the spring and fall field experimental campaigns. Both upward and downward flows were observed in response to dynamic Columbia River stage. The vertical flows are caused by the interaction of pressure gradients with our heterogeneous hydraulic conductivity field. These impacts are being evaluated with additional modeling and field activities to facilitate interpretation and mitigation. The project moves into CY 2010 with ambitious plans for a drilling additional wells for the IFRC well field, additional experiments, and modeling. This research is part of the ERSP Hanford IFRC at Pacific Northwest National Laboratory.« less Authors: Zachara, John M ; Bjornstad, Bruce N ; Christensen, John N ; Conrad, Mark E ; Fredrickson, Jim K ; Freshley, Mark D ; Haggerty, Roy ; Hammon, Glenn ; Kent, Douglas B ; Konopka, Allan ; Lichtner, Peter C ; Liu, Chongxuan ; McKinley, James P ; Murray, Christopher J ; Rockhold, Mark L ; Rubin, Yoram ; Vermeul, Vincent R ; Versteeg, Roelof J ; Ward, Anderson L ; Zheng, Chunmiao Publication Date: 2010-02-01 Research Org.: Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL) Sponsoring Org.: USDOE OSTI Identifier: 1033090 Report Number(s): PNNL-19209 34494; KP1702030; TRN: US1200280 DOE Contract Number: AC05-76RL01830 Resource Type: Technical Report Country of Publication: United States Language: English Subject:
https://www.osti.gov/biblio/1033090
Debate: Waste and Environmental Protection (Amendment) (Northern Ireland) (EU Exit) Regulations 2019 - 23rd Oct 2019 - Baroness Chisholm of Owlpen extracts Wed 23rd Oct 2019 - Lords - Waste and Environmental Protection (Amendment) (Northern Ireland) (EU Exit) Regulations 2019 debate Baroness Chisholm of Owlpen contributions to the 23rd October 2019 Waste and Environmental Protection (Amendment) (Northern Ireland) (EU Exit) Regulations 2019 debate Waste and Environmental Protection (Amendment) (Northern Ireland) (EU Exit) Regulations 2019 Debate Waste and Environmental Protection (Amendment) (Northern Ireland) (EU Exit) Regulations 2019 Baroness Chisholm of Owlpen Excerpts Lords Chamber My Lords, the regulations make corrections to three other Northern Ireland EU exit instruments and amend one piece of Northern Ireland primary legislation to address failures of retained EU law to operate effectively with regard to Northern Ireland waste legislation, arising from the withdrawal of the United Kingdom from the European Union. Part 2 of the instrument amends the Waste and Contaminated Land (Northern Ireland) Order 1997. Part 3 amends three Northern Ireland EU exit SIs to correct some earlier operability changes made to primary and secondary waste legislation in Northern Ireland. This is considered necessary to ensure that a consistent approach is taken to address operability issues identified across the relevant Northern Ireland waste legislation. All the amendments are to provisions which relate to the interpretation and application of article 16 of the waste framework directive, once the UK exits the European Union. The amendments ensure that the requirement on the United Kingdom to move towards the aim of becoming self-sufficient in waste disposal and in the recovery of waste is adequately and accurately reflected in domestic legislation. The amendments also ensure that the relevant legislation in Northern Ireland is updated to ensure there are no inoperable references to “best available techniques”. The amendments are therefore primarily corrections which are technical in nature. Importantly, there are no policy changes and there is no reduction in the environmental standards or obligations to which Northern Ireland is currently subject. The regulations are made under Section 8 of, and paragraph 21 of Schedule 7 to, the European Union (Withdrawal) Act 2018. The Act retains EU-derived legislation in UK law. Section 8 of the Act enables regulations, such as those we are considering, to be made to address deficiencies in EU-derived legislation that arise from the UK leaving the European Union. The regulations extend and apply solely to Northern Ireland. They concern matters which would normally be dealt with by the Northern Ireland devolved Administration. The Government’s preference is that these Northern Ireland regulations be made and scrutinised by the devolved institutions in Belfast. However, there is no sitting Assembly in Northern Ireland and it would not be possible to make the regulations. The Government are committed to the restoration of devolved government in Northern Ireland but, given existing circumstances, we have decided to process these and other Northern Ireland regulations made under the withdrawal Act through Parliament in order to maintain the integrity of the Northern Ireland statute book. In pursuing this course, we have worked closely with the Northern Ireland Department of Agriculture, Environment and Rural Affairs. As with other regulations made under the withdrawal Act, these regulations have been drafted on the basis of leaving the EU without an agreement. It is, of course, the Government’s preference that there will be an agreed basis for leaving the EU. The Secondary Legislation Scrutiny Committee highlighted this SI as an instrument of interest. The committee published comments by Green Alliance which highlight the group’s concerns about the removal of references to “bestavailable techniques” in Northern Ireland legislation. They fear that this could lower environmental standards. I categorically reassure noble Lords that there is absolutely no risk of any lowering of standards. Notwithstanding the Government’s repeated commitments to protect environmental standards, the Government are already bound by other legislation to take best available techniques into account. This SI does not change that. The Waste Management Licensing Regulations (Northern Ireland) 2003 set out these requirements in the context of establishing an adequate network of installations for waste disposal and for the recovery of mixed municipal waste from households in Northern Ireland. The corrections and amendments in this instrument remove the requirement to take best available techniques into account in the context of article 16.1 of the waste framework directive. We are doing so to ensure that the United Kingdom can set its own best available technique requirements and emission limits going forward, rather than having to comply with those which may be produced by the European Commission after the UK exits the European Union. In respect of the amendment to the Waste and Contaminated Land (Northern Ireland) Order 1997, the reference to best available techniques in Schedule 3, which was directly copied from article 16 of the waste framework directive, has been omitted because the term is not defined or used elsewhere in the order. This would render the term inoperable. The Government have committed to putting a process in place for determining future UK best available technique conclusions for industrial emissions post the UK’s exit from the European Union. This is being developed with the devolved Administrations and competent authorities across the UK. Legislative changes may be required to reflect the agreed process in due course. If so, your Lordships and, where appropriate, the devolved Parliaments and Assemblies, will be able to scrutinise these at the appropriate time. No comments were raised by the JCSI in respect of the regulations. As the purpose of the regulations is to make corrections and minor technical amendments, no consultation was undertaken in respect of the provisions. The regulations will not have any significant impact on business, charities, voluntary bodies or the public sector, but will help ensure legal certainty for regulators, stakeholders and the Government and prevent any ambiguity around environmental obligations. Similar legislative updates to those contained in this instrument have already been extended to England and Wales through the Environment and Rural Affairs (Amendment) (EU Exit) Regulations 2019, which amended the Waste (Miscellaneous Amendments) (EU Exit) Regulations 2019 and the Waste (Miscellaneous Amendments) (EU Exit) (No. 2) Regulations 2019. These regulations maintain the integrity of the Northern Ireland statute book, ensure legal certainty as we approach our exit from the EU and ensure that we maintain environmental standards and protections across the UK. I beg to move. My Lords, I thank the Minister for her extensive introduction. I am grateful to her and her officials for their time in providing a briefing. I am reassured that this SI makes no changes to the regulations covering waste and ensures that the law around waste disposal, installations and the recovery of mixed municipal waste collected from private households after Brexit will now be exactly the same over the whole of the UK. More importantly, perhaps, for Northern Ireland, it will be the same across the whole island of Ireland, as the UK and the EU statutes will be identical, so there will be no issues should a border ever be reintroduced. This SI covers contaminated land and the supply and storage of prescribed substances and potentially hazardous substances. This could include asbestos. Can the Minister say whether this might also include, as a hazardous substance, nuclear waste, and, if so, whether that might now or in the future be nuclear waste created in England, Wales or Scotland and shipped to Northern Ireland for safe disposal? As this SI transfers current EU law directly into UK and Northern Ireland law, I am confident that there will be no additional costs on local authorities as they already carry out duties under waste disposal, noise and environmental liabilities. In the Explanatory Memorandum, paragraph 2.6 refers to the Environment (Miscellaneous Amendments) (Northern Ireland) (EU Exit) Regulations 2019, which have already been debated. Since SIs which have been debated are then allocated an official number, it would be helpful for this number to be used. For those of us grappling with numerous SIs, many with what appear to be the same long titles with only one word different, if where they have a number it is quoted each time they are referred to, this would make life far less confusing. That is a very minor point, but it would certainly assist the process if it were to happen. Apart from that, I am happy to support this SI.
https://www.parallelparliament.co.uk/lord/baroness-chisholm-of-owlpen/debate/2019-10-23/lords/lords-chamber/waste-and-environmental-protection-amendment-northern-ireland-eu-exit-regulations-2019
U.S. v. SHAFFER EQUIPMENT CO., (S.D.W.Va. 1994) | Civ. A. No. 5:90-1195. | S.D.W. Va. | Judgment | Law | CaseMine Get free access to the complete judgment in U.S. v. SHAFFER EQUIPMENT CO., (S.D.W.Va. 1994) on CaseMine. U.S. v. SHAFFER EQUIPMENT CO., (S.D.W.Va. 1994) United States District Court, S.D. West Virginia, Beckley Division Sep 27, 1994 Judgment Subsequent References Case Information CITATION CODES DOCKET NO. Civ. A. No. 5:90-1195. ATTORNEY(S) Richard B. Stewart, Asst. Atty. Gen., Michael D. Goodstein, Sr. Atty., Robert H. Oakley, Sr. Counsel, Environmental Enforcement Section, Environment and Natural Resources Div., U.S. Dept. of Justice, Washington, DC, Carol A. Casto, Asst. U.S. Atty., Charleston, WV, for the U.S. Johnnie E. Brown, Cynthia M. Salmons, McQueen Law Offices, L.C., Anthony P. Tokarz, Bowles, Rice, McDavid, Graff and Love, Charleston, WV, for Shaffer Equip. Co. Anna Shaffer. John H. Tinney, Spilman, Thomas, Battle Klostermeyer, Charleston, WV, for Berwind Corp. Robert A. Lockhart, Robert G. McLusky, Barbara D. Little, Jackson Kelly, Charleston, WV, for Johns Hopkins University. JUDGES Elizabeth Virginia Hallanan ACTS The Public Health And Welfare — Comprehensive Environmental Response, Compensation, And Liability — Hazardous Substances Releases, Liability, Compensation — Settlements The Public Health And Welfare — Comprehensive Environmental Response, Compensation, And Liability — Hazardous Substances Releases, Liability, Compensation — Definitions The Public Health And Welfare — Comprehensive Environmental Response, Compensation, And Liability — Hazardous Substances Releases, Liability, Compensation — Liability Crimes And Criminal Procedure — Perjury — Crimes — False Declarations Before Grand Jury Or Court MEMORANDUM OPINION AND ORDER HALLANAN, District Judge. I. BACKGROUND This matter is before the Court via the United States of America's Motion to Enter Proposed Consent Decrees. On July 8, 1994 consent decrees between the United States of America (United States) and Defendants Anna Shaffer and Shaffer Equipment Company (Shaffer), the United States and Defendant Berwind Land Company (Berwind), and the United States and Defendant Johns Hopkins University (Johns Hopkins) were lodged with this Court. Public notice of their lodging was published in the Federal Register on July 21, 1994 and a thirty day comment period began on that date (See 59 Fed.Reg. 37265 ), pursuant to the policy of the United States Department of Justice and consistent with 28 C.F.R. § 50.7 and 42 U.S.C. § 9622(d)(2) . The comment period closed on August 22, 1994 and no comments were received on the proposed consent decrees. Therefore, the Court is now prepared to rule on the instant Motion. The approval of a CERCLA (Comprehensive Environmental Response, Compensation, and Liability Act of 1980, 42 U.S.C. § 9601 , et seq., as amended) consent decree is committed to the informed discretion of the District Court. United States v. Akzo Coatings of America, Inc., 949 F.2d 1409, 1423-24 (6th Cir. 1991); United States v. Cannons Engineering Corp., 899 F.2d 79, 84 (1st Cir. 1990); United States v. Hooker Chemical Plastics Corp., 776 F.2d 410, 411 (2d Cir. 1985). "Before approving a CERCLA settlement the Court must be convinced that it is fair, adequate, and reasonable, and consistent with the Constitution and the mandate of Congress." City of New York v. Exxon Corp., 697 F. Supp. 677, 692 (S.D.N.Y. 1988), citing United States v. Conservation Chemical Co., 628 F. Supp. 391, 400 (W.D.Mo. 1985). The District Court, however, must accord deference to the EPA's expertise and its determination that the settlement is appropriate. United States v. Cannons Engineering Corp., 720 F. Supp. 1027, 1036 (D.Mass. 1989), aff'd, 899 F.2d at 84 . The Court, therefore, "does not have the power to modify a consent decree; it may only approve or reject it." Id. citing United States v. Jones Laughlin Steel Corp., 804 F.2d 348 (6th Cir. 1986); Walsh v. Great Atlantic Pacific Tea Co., 726 F.2d 956, 965 (3rd Cir. 1983); Officers for Justice v. Civil Service Commission, 688 F.2d 615, 630 (9th Cir. 1982). A. THE MINDEN SITE CLEANUP At the outset, the Court will comment that it fully recognizes that this whole matter began with the release and threatened release of polychlorinated biphenyls (PCBs) at the Shaffer Equipment Site in Minden, West Virginia, for which these Defendants are by all accounts responsible. Unfortunately, this matter does not end, as it should have, with the named Defendants in this case. The Environmental Protection Agency (EPA) and the Department of Justice (DOJ) have incurred at least six million four hundred seventy-five thousand dollar's ($6,475,000) in response costs for attempting to eliminate the release or threatened release of hazardous substances from the Shaffer Equipment Site in Minden, Fayette County, West Virginia (the Site). Under CERCLA, the United States sought reimbursement for the full amount of these response costs from Defendants Shaffer, Berwind, and Johns Hopkins. At the outset of this action, the United States appeared to have a good case for reimbursement of their removal, remedial and other costs as the Defendants are arguably persons liable under CERCLA. In its complaint the United States alleged, among other allegations, that Shaffer, the current owner of the Site, and Berwind are liable persons "who at the time of disposal of any hazardous substance owned or operated a facility in which hazardous substances were disposed of." 42 U.S.C. § 9607(a)(2) . The United States also alleged that Johns Hopkins is a "person who by contract, agreement, or otherwise arranged for disposal or treatment . . . of hazardous substances owned or possessed by such a person." 42 U.S.C. § 9607(a)(3) . The consent decrees that the United States moves the Court to enter reflect a total monetary settlement value of seven hundred twenty-five thousand dollars ($725,000). This amount is substantially less than the costs incurred by the United States in cleaning up the Site. II. REASONS TO ACCEPT SETTLEMENT Although the Court is prepared to enter the proposed consent decrees, it feels compelled to comment on the vast discrepancy between costs incurred and those recovered. It is the Court's opinion that in the case of each Defendant, the United States' mismanagement of this entire matter sabotaged its potential recovery of response costs from responsible persons, leaving the bulk of these costs to be born by the Superfund as established by CERCLA. See Superfund Amendments and Reauthorization Act of 1986, Pub.L. 99-499, Oct. 17, 1986, 100 Stat. 1613 (codified as amended in scattered sections of 10 U.S.C. § 26 U.S.C. § 29 U.S.C. and 42 U.S.C.), as amended. The Court has observed a tendency on the part of the EPA to treat this appropriation as though it is manna from heaven to be thrown around at will. The Court would like to remind all who are involved in this case that the Superfund is nothing more than an environmental tax on certain corporations which ultimately lands squarely on the rest of us. See Superfund Revenue Act of 1986, Pub.L. 99-499, Title V, Oct. 17, 1986, 100 Stat. 1760 (codified as amended in scattered sections of 26 U.S.C. and 42 U.S.C.), as amended. A. THE "CARON PROBLEM" Not the slightest in a series of blunders by the EPA is the fact that the EPA's first chosen method for removal of hazardous substances from the Site, solvent extraction, proved unsuccessful, after an expenditure of one million two hundred thirty five thousand dollars ($1,235,000). The solvent extraction method, a new and relatively unestablished technology, was chosen by Robert E. Caron, the EPA's "On Scene Coordinator." Mr. Caron is a man who has misrepresented his academic credentials and achievements throughout his career and subsequent to this case was convicted of perjury, specifically making material false declarations in violation of 18 U.S.C. § 1623 . At the time of Mr. Caron's decision to use solvent extraction, solvent extraction had only been pilot tested. At that time the EPA was directed to utilize "established technology when feasible and cost-effective." 40 C.F.R. § 300.61(c)(4) (1982). Another decision made by Mr. Caron was raised as a challenge by Defendants when this case first came before this Court. This was the decision to exceed the one million dollar ($1,000,000) ceiling in place at the time for removal actions. See 40 C.F.R. § 300.66 (1985). This could best be described as the first step in a series of many missteps by an inept and deceitful "On Scene Coordinator" who seems to have been let loose in Minden, West Virginia with a virtually unbounded authority to spend federal money. Defendants have also challenged eight hundred eighty thousand dollars ($880,000) in initial costs as excessive. These expenditures were all approved by Mr. Caress. Defendants also question Mr. Caron's decision to ship contaminated soil off-Site at a cost of approximately one million nine hundred thousand dollars ($1,900,000). Defendants argue that once the soil had been consolidated and covered, the risk posed by the Site was minimal and the expense unnecessary. Because of Mr. Caron's misconduct in this case, Defendants can seek de nova review of Mr. Caron's decisions, among them the decisions to use solvent extraction and to exceed the $1,000,000 limit, as hereinbefore noted, if the Court rejects the Proposed Consent Decrees. In that event, the United States will not be able to rely on Mr. Caron's testimony regarding these expenses. These combined factors pose substantial risks to the United States' ability to prevail in this litigation and are compelling conditions which force this Court to accept the Proposed Consent Decrees. B. ANNA SHAFFER AND SHAFFER EQUIPMENT COMPANY In addition to the arguments raised above Shaffer and Berwind have asserted counterclaims against the United States Department of the Interior (DOI) as a current owner of a portion of the site. The portion allegedly owned by the DOI is a railroad right-of-way conveyed to the DOI by deed dated September 27, 1985 by West Virginia's Public Land Corporation to be part of the New River Gorge National River Park, a Park administered by the DOI's Park Service. Shaffer and Berwind assert that the DOI is liable for a portion of the response costs under CERCLA, 42 U.S.C. § 9607(a) . The United States moved for summary judgment on this counterclaim, claiming that the DOI does not own any portion of the Site. In an alternative argument, the United States maintains it is not liable for any response costs because cleanup was completed before the property was conveyed to the DOI. This motion is still pending before this Court. Shaffer also asserts no liability for contamination cleaned up in 1990, costing an additional three hundred eighty thousand dollars ($380,000), claiming this was new contamination caused by vandals. Additionally, Shaffer Equipment Company is no longer an operating company, with no real assets besides its insurance policies which contain pollution exclusion clauses. Anna Shaffer, sole shareholder of Shaffer Equipment Company, does not have sufficient assets to contribute in any significant way to the EPA's response costs either. Given Shaffer's limited ability to pay, their arguments concerning the EPA's response action, and the fact that the United States cannot use Mr. Caron's testimony to defend their response costs, Shaffer's offer of six hundred thousand dollars ($600,000) in settlement of past claims appears reasonable to the Court. C. BERWIND LAND COMPANY Although Berwind has owned a portion of the Site since at least 1971 when it acquired its interest from its parent corporation, Berwind Corporation, Berwind argues it is an innocent landowner under CERCLA, 42 U.S.C. § 9607(b)(3) . Berwind claims it has a third party defense to liability. While the United States believes it can prove Berwind had actual knowledge of how its property was being used, if successful, this defense would relieve Berwind of all liability. Berwind also raises a defense to joint and several liability, relying on a letter from EPA Assistant Regional Counsel dated February 15, 1992 in which Berwind was invited to clean up its portion of the Site. The letter states that Berwind should expect to pay between one hundred fifty and two hundred thousand dollars ($150,000-$200,000) when the EPA cleans up Berwind's portion. Berwind maintains that this letter implies that the EPA believed the environmental harm to be divisible and that Berwind was only liable for its portion of the Site. This contention is also supported by the testimony of Berwind employees and can apparently only be rebutted by Mr. Caron. Additionally, Berwind Corporation, Berwind Land Company's parent, has filed a motion under Rule 11 of the Federal Rules of Civil Procedure against the United States for naming Berwind Corporation as a defendant without sufficient evidence. In light of Berwind's claims and defenses, resolved under its Proposed Consent Decree, and other provisions of the Proposed Consent Decrees including a reopener for future release of hazardous substances caused by Berwind, the Court believes Berwind's settlement offer of seventy five thousand dollars ($75,000) for reimbursement of past response costs is reasonable. D. JOHNS HOPKINS UNIVERSITY The basis for Johns Hopkins' liability are three large used transformers, admittedly filled with PCBs, which Johns Hopkins contends it sent to the Site for re-use by Shaffer Equipment Company. Johns Hopkins has a number of defenses to liability, many of which relate to actions taken by the EPA in cleanup efforts. At either Mr. Carons or the EPA counsel's direction, the EPA removed the Johns Hopkins transformers from the Site and destroyed them before contacting Johns Hopkins. The EPA was required to notify Johns Hopkins, having identified Johns Hopkins as a "potentially responsible person" under CERCLA. The transformers, relevant evidence, were also destroyed without ascertaining in any verifiable manner that they were leaking at the time they were removed from the Site. Regarding these actions taken by the EPA, Johns Hopkins has asserted a claim of governmental misconduct as part of its motion for Summary Judgment. If granted in relation to this part of the motion, this claim would entitle Johns Hopkins to an evidentiary presumption fatal to much of the United States' case. McGuire v. Sigma Coatings, Inc., No. 91-2076, 1993 U.S.Dist. LEXIS 19174 (E.D.La. Nov. 1, 1993). Johns Hopkins contends that if it had received notice that its transformers were at the Site at the time of cleanup, it would have removed them at a fraction of the cost incurred by the EPA. Johns Hopkins argues that it has thereby also been deprived of an opportunity to show that its transformers did not leak. If the transformers did not leak, Johns Hopkins would only be responsible for disposal of the transformer. Therefore, destruction of the transformers also deprived Johns Hopkins of the opportunity to argue that harm was divisible. Johns Hopkins further maintains it sent the transformers to Shaffer for re-use and not disposal, and was not an "arranger for disposal" under CERCLA, Section 107(a)(3). See United States v. Gordon Stafford, Inc., 810 F. Supp. 182 (N.D.W. Va.1993); Chesapeake and Potomac Telephone Company of Virginia v. Peck Iron Metal Co., 814 F. Supp. 1269, 1275 (E.D.Va. 1992) (conveyance of usable equipment to be used for its originally intended purpose not "arrangement for disposal.") If it were to prevail in this argument, Johns Hopkins would have no liability. Johns Hopkins also has a third party defense under CERCLA Section 107(b)(3) for Shaffer's handling of the transformers which if successful would also relieve Johns Hopkins of all liability. Johns Hopkins can demonstrate that the maximum cost to the United States for removing the transformers in question and their contents was fifty seven thousand four hundred seventy-five dollars ($57,475), including a proportionate share of overhead costs. Given the EPA's mishandling of the transformers, Johns Hopkins' limited involvement and its arguments against all liability, particularly against joint and several liability, the Court believes Johns Hopkins' settlement offer of fifty thousand dollars ($50,000) to be more than reasonable. E. THE "CARON PROBLEM:" SNYDER AND HUTCHINS As the United States admits in its Additional Information Regarding Proposed Settlements, no small part of its mismanagement of this matter was the so-called "Caron Problem," in which it was discovered that Mr. Caron had been substantially misrepresenting his credentials and had given perjured testimony in other matters. Compounding this problem was the fact that the United States' attorneys, J. Jared Snyder and William A. Hutchins, violated their duty of candor to this Court with respect to the "Caron Problem" by repeatedly obstructing Defendants' attempts to uncover Mr. Caron's perjury and failing to reveal what they knew of Mr. Caron's misrepresentation once they learned of it. See United States v. Shaffer Equipment Co., 11 F.3d 450, 461 (4th Cir. 1993). See also Rules of Professional Conduct, Rule 3.3(a)(2) (W.Va. 1989) ("A lawyer shall not knowingly fail to disclose a material fact to the tribunal when disclosure is necessary to avoid assisting in a criminal or fraudulent act by the client"). In all appearances, actions and proceedings in and within the jurisdiction of this Court, attorneys shall conduct themselves in accordance with the ethical considerations and disciplinary rules of the Model Federal Rules of Disciplinary Enforcement and the said Codes of Professional Responsibility, being subject at all times to the statutes, rules and orders applicable to and controlling the procedures and practice of law in this Court. Attorneys should remember that said codes and rules and orders are minimal standards. The Court encourages counsel to strive to reach the highest standards of ethical conduct. Local Rules of the United States District Court for the Southern District of West Virginia, Rule 1.03(h) (effective through September 1, 1994). This violation, in fact, compromised the United States to the extent that this Court dismissed the case and awarded attorney fees and costs to Defendants. Indeed, the Court felt compelled to take this severe action, because, as it said, "there is no price tag that comes with the duty of candor charged by the courts and the applicable "rules of professional responsibility" United States v. Shaffer Equipment Co., 796 F. Supp. 938, 953 (S.D.W. Va. 1992) (emphasis in original), aff'd in part, rend in part, remanded, 11 F.3d 450 (4th Cir. 1993). Upon appeal the United States Court of Appeals for the Fourth Circuit (Fourth Circuit) found that the sanction of dismissal was too severe and remanded the case on that issue. However, the Fourth Circuit agreed with this Court that Mr. Hutchins and Mr. Snyder had violated their duty of candor to the Court, "exposing themselves and their employer to sanctions." U.S. v. Shaffer at 461 (emphasis added). Neither Mr. Hutchins nor Mr. Snyder can claim ignorance of an attorney's duty of candor to the Court. Both attended law-school and are members of the bar where the Court must assume they have learned something about legal ethics or have been at least exposed to the subject. In an example of how much damage the "Caron Problem," including the roles played by Mr. Snyder and Mr. Hutchins, may have contributed to the outcome of this litigation, the Fourth Circuit suggested that an appropriate sanction might be the denial of the government's "right to claim any expertise which may have been tainted by Caron's misconduct." U.S. v. Shaffer, 11 F.3d at 463 . By the United States' own admission, the total amount of these expenses, incurred while Mr. Caron was overseeing the Site cleanup, is approximately five million two hundred thirty thousand dollars ($5,230,000), which is approximately eighty percent (80%) of the total cleanup cost of $6,475,000, leaving the United States with a remaining claim against Defendants for only one million two hundred forty-five thousand dollars ($1,245,000). This remaining claim is the maximum the United States would be able to recover under this scenario. However, as hereinbefore noted, each Defendant in this case has significant defenses to their respective liability. III. AUTHORITY TO SANCTION A. ABUSE OF DISCOVERY The Court must point out that when Mr. Hutchins and Mr. Snyder breached their duty of candor to the Court they also flagrantly abused the discovery process. In failing to supplement Defendants' discovery requests regarding Mr. Caron's credentials with information that Mr. Snyder admitted was relevant, Mr. Snyder and his immediate supervisor, Mr. Hutchins, violated Rule 26(e) of the Federal Rules of Civil Procedure. Mr. Snyder and Mr. Hutchins violated Rule 26(e)(1) and Rule 26 (a)(2)(C) by failing to supplement information on an expert witness. Rule 26(e)(2) was ignored when Mr. Snyder failed to amend his prior objection to an interrogatory regarding Mr. Caron after he learned that the matter was indeed relevant and his previous objection to the questions was incorrect. This Court's discretion to impose sanctions for abuse of discovery is quite broad under its inherent power and under Federal Rule of Civil Procedure 26(e) which itself furnishes fair warning of the Court's power to impose sanctions. Thibeault v. Square D Co., 960 F.2d 239, 245 (1st Cir. 1992). The Rules permit the imposition of a sanction in the form of a fine, paid to the court and not to the opposing party. A finding of contempt is not a prerequisite to the imposition of such a sanction. Pereira v. Narragansett Fishing Corp., 135 F.R.D. 24 (D.C.Mass. 1991). Monetary sanctions in the form of attorney fees for litigation abuse in this case would not be barred by sovereign immunity because a sufficiently explicit rule authorizing such an award exists, namely Federal Rule of Civil Procedure 26(e). See United States v. Horn, 29 F.3d 754 (1st Cir. 1994). B. DUTY OF CANDOR The Court has the inherent authority to discipline all attorneys who appear before it and "the inherent power extends to the full range of litigation abuses." U.S. v. Shaffer, 11 F.3d at 457 . See Chambers v. NASCO, 501 U.S. 32, 111 S.Ct. 2123, 115 L.Ed.2d 27 (1991) citing Anderson v. Dunn, 6 Wheat 204, 5 L.Ed. 242 (1821). Therefore, this Court possesses the inherent authority to fashion a sanction for attorneys violating the duty of candor in a manner it finds appropriate. See Chambers, 501 U.S. at 44-45, 111 S.Ct. at 2132-33 . The duty of candor to the tribunal is a widely recognized one within the legal profession, United States v. Associated Convalescent Enterprises, Inc., 766 F.2d 1342, 1346 (9th Cir. 1985), and government attorneys, like all attorneys, have a duty to conform to the ethical guidelines of their profession. In so failing to conform, Mr. Hutchins and Mr. Snyder were not acting within the directives of their employment and therefore cannot claim any exemption from sanction for their actions by way of sovereign immunity. Sovereign immunity is not a bar to personal sanctions on government attorneys for their ethical violations because these sanctions do not come from the public coffers. See U.S. v. Horn, 29 F.3d at 754. IV. SANCTIONS ORDERED Despite the Fourth Circuit's opinion, the U.S. Department of Justice, Office of Professional Responsibility, has refused to find misconduct" by Mr. Snyder and Mr. Hutchins, instead characterizing their behavior as "repeated exercises of poor judgment." Letter from Michael E. Shaheen Jr. to Mr. John Tinney, Attorney and Mr. Richard Rivers, Vice President and General Counsel of Berwind Corporation. To demonstrate the cursory attitude of this in-house investigation, the full letter, dated July 19, 1994 is herein quoted: Dear Messrs. Tinney and Rivers: This is in final response to your letter of complaint dated February 10, 1992, concerning Justice Department Attorney Jared Snyder and his handling of United States v. Shaffer Equipment, et al., Civil Action No. 5:90-1195 (S.D.W.Va). Subsequently, the U.S. District Court for the Southern District of West Virginia dismissed Shaffer on the basis of its findings that Jared Snyder and his supervisor, ENRD senior trial attorney had engaged in intentional misconduct. On appeal, the Fourth Circuit affirmed the district court's findings of misconduct, but reversed and remanded for a sanction short of dismissal. It is our understanding that the matter is presently pending before the district court. We have carefully reviewed your allegations of misconduct against Mr. Snyder and the court's findings of misconduct against Mr. Snyder and Mr. Hutchins. We find that Mr. Snyder and Mr. Hutchins engaged in repeated exercises of poor judgment in their handling of aspects of Shaffer. We do not, however, find they engaged in intentional misconduct [emphasis added]. We have advised the Acting Assistant Attorney General of the Environment and Natural Resources Division of our findings. We are now closing our file in this matter. If you have any questions, please contact me or Assistant Counsel Rob Lyon on 202-514-3365. Sincerely, Michael E. Shaheen Jr. Counsel "And thereby hangs a tale." With such perfunctory treatment, two complete sentences, given to matters of ethics found to be worthy of at least a dozen paragraphs by the Fourth Circuit, it is no small wonder, but no excuse, that these attorneys behaved as they did. Quite frankly, it shocked this Court to learn of the Department of Justice's superficial investigation and evaluation of the conduct of these attorneys. We are dealing here with a hodgepodge of bureaucratic bungling and cover up of abysmal proportions. William Shakespeare, As You Like It, Act II, scene vii. Be that as it may, as directed by the Fourth Circuit, this case is again before this Court to resolve its merits, which it will do by entering the consent decrees, and to sanction the United States, short of outright dismissal, in such a way as to deter future violations of the duty of candor by government attorneys. U.S. v. Shaffer, 11 F.3d at 462-63 . Therefore, IT IS ORDERED that Mr. J. Jared Snyder shall pay from his personal funds the amount of two thousand dollars ($2,000) and Mr. William A. Hutchins shall pay from his personal funds the amount of two thousand five hundred dollars ($2,500) to reimburse the Superfund (to be deposited into Department of Justice lockbox bank, referencing CERCLA number 03D8, DOJ Case Number 90-11-2-649 and US Attorney Office file number 90V0304) as sanctions for their respective breaches of ethical conduct, namely for violation of the duty of candor to the Court. In determining the amount of sanction the Court deemed appropriate, the Court considered, inter alia, the salary levels of these attorneys. Further, IT IS ORDERED that neither Mr. Hutchins or Mr. Snyder shall seek reimbursement for these sanctions from their employer. See Chilcutt v. United States, 4 F.3d 1313, 1362 (5th Cir. 1993) (Assistant United States Attorney (AUSA) ordered to personally reimburse plaintiffs for attorney fees which arose from AUSA's discovery abuses). See also J.M. Cleminshaw Co. v. City of Norwich, 93 F.R.D. 338 (D.C.Conn. 1981) (discovery sanction assessed against attorney to be paid to the clerk of the court out of attorney's personal funds). Payment of personal assessments directly into the Superfund is an appropriate way for these attorneys to make some restitution toward this pyramid of errors which ultimately collapsed upon itself, resulting in serious and costly consequences to all those involved in the Minden cleanup debacle. V. VALUE OF THE CONSENT DECREES Without the substantial cost to the United States of attorney fees previously awarded, totalling one hundred ninety three-thousand nine hundred thirty-six dollars and fifteen cents ($193,936.15), and with provisions in the consent decrees governing maintenance of the response actions and access to the Site, and provisions allowing the United States to reopen this matter against Shaffer for future response costs and against Berwind for future releases of hazardous substances, the consent decrees actually have a greater value than $725,000. This value could range from as low as nine hundred eighteen thousand nine hundred thirty-six dollars and fifteen cents ($918,936.15) (the total of the $725,000 settlement and $193,936.15 in previously awarded attorney fees) to millions of dollars if there are future releases and response costs. In addition to the sanctions ordered above and consistent with the consent decrees, IT IS ORDERED that those portions of this Court's July 31, 1992 and October 29, 1992 Orders awarding Defendants attorney fees totalling one hundred thirty-three thousand five hundred four dollars and fifty-two cents ($133,504.52) to Berwind's counsel, twenty-four thousand seven hundred seventy-one dollars and fifty-six cents ($24,771.56) to Shaffer's counsel and thirty-five thousand six hundred sixty dollars and seven cents ($35,660.07) to Johns Hopkins' counsel are VACATED. VI. MOTION TO ENTER CONSENT DECREES GRANTED Due in part to the fact that the consent decrees are more significant than their face monetary value would indicate and due primarily to the mismanagement of this matter which severely weakened the United States' chances for recovery of any substantial portion of its response costs and the conceivably enormous expenses for all parties involved in proceeding with this litigation, the United States' Motion to Enter Proposed Consent Decrees is GRANTED. The Court will enter the decrees by executing them in the space provided at the end of each decree. The Clerk is directed to send a copy of this Order and the executed consent decrees between the United States and Anna Shaffer and Shaffer Equipment Company, the United States and Berwind Land Company, and the United States and Johns Hopkins University to all counsel of record. IT IS SO ORDERED.
https://www.casemine.com/judgement/us/5914bdcaadd7b049347a46d3/amp
The substrate-binding pocket. aAtNIT4 structure showing two dimers... | Download Scientific Diagram Download scientific diagram | The substrate-binding pocket. aAtNIT4 structure showing two dimers interacting across the C-interface, the position of the catalytic site is indicated by a square. b The active-site pocket, the catalytic residues (E76, K163, E170, and C197) are shown (**), residues conserved in all plant NITs (*). A loop (tan) arising from the adjacent monomer (between α2 and α3) extends over the entrance to the active-site pocket. c As expected, the amino acid residues surrounding the binding pocket correlate with substrate specificity. Three amino acid positions in particular are responsible for the majority of the variation between known plant NITs: 169, 224, and 95 (numbered according to AtNIT4). d A lid (tan), formed by the loop, limits the length of the binding pocket (#). R95 is in the lid loop; S224 is on the outer border of the binding pocket and L169 points toward the light green subunit across the C-interface from publication: Cryo-EM and directed evolution reveal how Arabidopsis nitrilase specificity is influenced by its quaternary structure | Nitrilases are helical enzymes that convert nitriles to acids and/or amides. All plants have a nitrilase 4 homolog specific for ß-cyanoalanine, while in some plants neofunctionalization has produced nitrilases with altered specificity. Plant nitrilase substrate size and... | Directed Evolution, Arabidopsis and Secondary Metabolism | ResearchGate, the professional network for scientists. The substrate-binding pocket. aAtNIT4 structure showing two dimers interacting across the C-interface, the position of the catalytic site is indicated by a square. b The active-site pocket, the catalytic residues (E76, K163, E170, and C197) are shown (**), residues conserved in all plant NITs (*). A loop (tan) arising from the adjacent monomer (between α2 and α3) extends over the entrance to the active-site pocket. c As expected, the amino acid residues surrounding the binding pocket correlate with substrate specificity. Three amino acid positions in particular are responsible for the majority of the variation between known plant NITs: 169, 224, and 95 (numbered according to AtNIT4). d A lid (tan), formed by the loop, limits the length of the binding pocket (#). R95 is in the lid loop; S224 is on the outer border of the binding pocket and L169 points toward the light green subunit across the C-interface Nitrilases are helical enzymes that convert nitriles to acids and/or amides. All plants have a nitrilase 4 homolog specific for ß-cyanoalanine, while in some plants neofunctionalization has produced nitrilases with altered specificity. Plant nitrilase substrate size and specificity correlate with helical twist, but molecular details of this relatio... Citations ... The contact interfaces between the monomers in a helical oligomer are designated A, C, D, and E, whereas in nitrilase Nit4 from Arabidopsis thaliana, the F interface has also been found, which depends on oligomer termination [54] . The positions of A, C, and D surfaces for Cyn pum are shown in Figure 5a (the E interface is formed by the rotation of the terminal dimers in the helix). ... ... The C-termini, which are part of the A interface, also maintain interactions required for the formation of the quaternary structure in nitrilases. They span at least two adjacent dimers in Nit4 from Arabidopsis thaliana (pdb 6i00) [54] and the nitrilase from Pseudomonas fluorescens EBC191 (pdb 6zby). The orientation of the C-terminus in the dimer of the recently reported structure of CynD pum is shown in Figure 5b. ... ... The C-terminus in CynH homologs has a conserved motif (DXXGHY) similar to that of CynDs ( Figure 5c). C, D, and E, whereas in nitrilase Nit4 from Arabidopsis thaliana, the F interface has also been found, which depends on oligomer termination [54] . The positions of A, C, and D surfaces for Cynpum are shown in Figure 5a (the E interface is formed by the rotation of the terminal dimers in the helix). ... Nitrilases have a high potential for application in organic chemistry, environmental technology, and analytics. However, their industrial uses require that they are produced in highly active and robust forms at a reasonable cost. Some organic syntheses catalyzed by nitrilases have already reached a high level of technological readiness. This has been enabled by the large-scale production of recombinant catalysts. Despite some promising small-scale methods being proposed, the production of cyanide-converting nitrilases (cyanide hydratase and cyanide dihydratase) is lagging in this regard. This review focuses on the prospects of cyanide(di)hydratase-based catalysts. The current knowledge of these enzymes is summarized and discussed in terms of the origin and distribution of their sequences, gene expression, structure, assays, purification, immobilization, and uses. Progresses in the production of other nitrilase catalysts are also tackled, as it may inspire the development of the preparation processes of cyanide(di)hydratases. ... In CynD C1 and CynD from P. stutzeri, mutations in the C-terminal region decrease oligomerization (14,36,37). The C-terminal region of nitrilases stabilizes the spiral structure through criss-crossed beta sheets in the center of the oligomer (8, 40) . Also, Acidic pH has been shown to promote higher-order oligomerization states of CynDs (12,36); however, the effects of pHs greater than 9 have not been reported. ... (Mulelu et al. 2019) . The structure was repaired by FoldX. ... ... On the other hand, in the B subunit of H90M, three new hydrogen bonds in the C-terminal tail that are relevant in the spiral oligomer to form the C-surface were formed. The C-surface is the major region that contributes to the formation of the larger spiral structure of nitrilases (Mulelu et al. 2019) ... Central to the discussion of the reaction mechanism is the correct identification of the reaction catalyzed by any particular member of the superfamily as this will enable an understanding of the subtle effects of the differences in active site conformation. In particular, there are only two published intermediate-resolution structures of verified nitrilases (Mulelu et al., 2019; Zhang et al., 2014) that have not yet led to a satisfactory explanation of the differences between the active sites of amidases and nitrilases. ... ... Several attempts to co-crystallize the C146A variant of the P. horikoshii amidase with all the nitriles that we tested failed in our hands. Although the mode of binding suggested by Raczynska et al. (2011) seems plausible, further discussion of nitrile binding should await experimental visualization of the bound substrate, perhaps in the active site of an enzyme that has been shown to have nitrilase activity of which two structures are now published (Mulelu et al., 2019; The nitrilase superfamily enzymes from Pyrococcus abyssi and Pyrococcus horikoshii hydrolyze several different amides. No nitriles that we tested were hydrolyzed by either enzyme. Propionamide and acetamide were the most rapidly hydrolyzed of all the substrates tested. Amide substrate docking studies on the wild-type and C146A variant P. horikoshii enzymes suggest a sequence in which the incoming amide substrate initially hydrogen bonds to the amino group of Lys-113 and the backbone carbonyl of Asn-171. When steric hindrance is relieved by replacing the cysteine with alanine, the amide then docks such that the amino group of Lys-113 and the backbone amide of Phe-147 are hydrogen-bonded to the substrate carbonyl oxygen, while the backbone carbonyl oxygen of Asn-171 and the carboxyl oxygen of Glu-42 are hydrogen-bonded to the amino group of the substrate. Here, we confirm the location of the acetamide and glutaramide ligands experimentally in well-resolved crystal structures of the C146A mutant of the enzyme from P. horikoshii. This ligand location suggests that there is no direct interaction between the substrate amide and the other active site glutamate, Glu-120, and supports an active-site geometry leading to the formation of the thioester intermediate via an attack on the si-face of the amide by the sulfhydryl of the active site cysteine. [84] revel substrate specificity, binding pocket and binding mode of Arabidopsis nitrilase. ... Nitrilase enzyme catalyze conversion of nitrile compounds to its corresponding carboxylic acid and ammonia. With the rise of digital era, the use of computational analysis to revel hidden characteristics of enzymes is continuously growing because of its cost effectiveness and faster output. Highly developed sequencing technology provides an opportunity to conduct virtual studies and explore unique properties and applications of various enzymes. Physico-chemical properties of aliphatic nitrilase evaluated results show quite similar properties of all 13 studied aliphatic nitrilase. The 3D structures of aliphatic nitrilase were generated by using Swiss-Model server and validated using different tools describes that quality of 3D structure of all 13 protein is good. Docking of 13 nitriles with all 13 aliphatic nitrilase was done by using Autodock v4.2.6 software, reveals that cis-cis Mucononitrile has highest binding affinity with most of studied protein, while Glycolonitrile and Propionitrile has less binding affinity toward major studied nitrilase. ... Details related to the helical twisted nature of these enzyme has received considerable attention of late because of its demonstrated importance in determining substrate specificity [12]. In the absence of available crystal structures the recent application of cryoEM has proven itself useful for these studies [13] ... Recent studies have shown that a significant factor contributing to the substrate specificity of Branch1 nitrilases is their quaternary structure consisting of oligomeric left-handed helical spirals or twisted filaments comprised of interacting dimers [11][12] [13] . Nit6803, for example, has been described as a spiral with a small twist (relaxed) (Δ Ψ ~ − 60 • ) which has been equated with broad specificity for relatively larger substrates [12]. In contrast, other nitrilases such as the Arabidopsis thaliana Nit4 (AtNit4) enzyme, exhibits a large twist (tight) (Δ Ψ ~ − 73 • ), has a narrow substrate specificity, and acts mainly on smaller substrates. ... ... In contrast, other nitrilases such as the Arabidopsis thaliana Nit4 (AtNit4) enzyme, exhibits a large twist (tight) (Δ Ψ ~ − 73 • ), has a narrow substrate specificity, and acts mainly on smaller substrates. AtNit4, for example, is specific for relatively small compounds such as β-cyanoalanine which is thought to be the physiological substrate [13] . We may predict that Nit11764 would also assume a small helical twist in its quaternary state because of its close homology to Nit6803. ... Characterization of the Nit6803 nitrilase homolog from the cyanotroph Pseudomonas fluorescens NCIMB 11764 We report the purification and characterization of a nitrilase (E.C. 3.5.5.1) (Nit11764) essential for the assimilation of cyanide as the sole nitrogen source by the cyanotroph, Pseudomonas fluorescens NCIMB 11764. Nit11764, is a member of a family of homologous proteins (nitrile_sll0784) for which the genes typically reside in a conserved seven-gene cluster known as Nit1C. The physical properties and substrate specificity of Nit11764 resemble those of Nit6803, the current reference protein for the family, and the only true nitrilase that has been crystallized. The substrate binding pocket of the two enzymes places the substrate in direct proximity to the active site nucleophile (C160) and conserved catalytic triad (Glu44, Lys126). The two enzymes exhibit a similar substrate profile, however, for Nit11764, cinnamonitrile, was found to be an even better substrate than fumaronitrile the best substrate previously identified for Nit6803. A higher affinity for cinnamonitrile (Km 1.27 mM) compared to fumaronitrile (Km 8.57 mM) is consistent with docking studies predicting a more favorable interaction with hydrophobic residues lining the binding pocket. By comparison, 3,4-dimethoxycinnamonitrile was a poorer substrate the substituted methoxyl groups apparently hindering entry into the binding pocket. in situ ¹H NMR studies revealed that only one of the two nitrile substituents in the dinitrile, fumaronitrile, was attacked yielding trans-3-cyanoacrylate (plus ammonia) as a product. The essentiality of Nit11764 for cyanotrophy remains uncertain given that cyanide itself is a poor substrate and the catalytic efficiencies for even the best of nitrile substrates (~5 × 10³ M⁻¹ s⁻¹) is less than stellar. ... (Figure 1). All nitrilases showed complete conservation of the catalytic tetrad Cys-Glu-Glu-Lys (CEEK) [20] . In addition, 79 residues in NitAF were conserved in the sequences of the aligned nitrilases. ... ... Nitrilases, as thiol enzymes, form covalent thioimidate complexes by attacking the carbon of nitriles (R-CN). The catalytic tetrad of nitrilase consists of CEEK; the cysteine carries out a nucleophilic attack on the cyanocarbon, the glutamate functions by mediating the transfer of a proton as a general base, and the lysine plays an essential role in the stabilization of a tetrahedral intermediate [20, 21,24]. Although previous investigations have aimed to elucidate the role of an amino acid residue in the substrate specificity of nitrilases using mutational and computational approaches, its role in the catalytic efficiency has not been reported; thus, a comprehensive understanding of the factors contributing to the catalytic efficiency of nitrilases remains elusive. ... ... The homology model of NitTv1 was constructed previously [18]. Since then, a new template NIT4 in A. thaliana (pdb code 6i00) [21] emerged. In this study, this template was used for multiple sequence alignment ( Figure S3) along with the previously used template [18], i.e., the NLase from Synechocystis sp. ... ... However, as this information on the active form of NitAb or NitTv1 has not been available yet, we used both the monomer and an oligomer (tetramer) for the docking studies ( Figures S7 and S8 in Supplementary Materials). The recently reported structure of NIT4 [21] allowed a precise modeling of loop HL1 and hence improved prediction and characterization of ligand binding in the NLase oligomers. ... ... The model of NitTv1 was previously constructed [18] and the model of NitAb was made analogously. The templates for homology modeling of NitAb were the recently released cryo-EM structure of NIT4 from A. thaliana (pdb code 6i00 [21] ) and crystal structure of the NLase from Synechocystis sp. (pdb code 3wuy [22]). ...
https://www.researchgate.net/figure/The-substrate-binding-pocket-aAtNIT4-structure-showing-two-dimers-interacting-across-the_fig3_334519175
Dentistry Journal | Free Full-Text | A Longitudinal Study on the Relationship of Oral Health at 4 Years of Age with That in Adulthood This longitudinal study aimed to clarify the relationship of oral health in infancy with that in adulthood among participants who were the subjects of the oral health promotion project (OHPP) conducted in Miyako Island, Okinawa Prefecture, Japan, since 1984. Twenty-seven subjects, around 35 years of age, were examined for dental caries, periodontal diseases (community periodontal index), dental plaque, occlusion, and bite-force and compared with those at 4 and 13–15 years of age. The dental caries status and maximum bite force in adulthood was significantly reflected for those at 4 and 13–15 years of age (p 0.05). Most of the normal occlusion at 4 years of age became normal permanent occlusion in adulthood (88.9%). Most of the cases involving the discrepancy factor retained the same condition in both the deciduous and permanent dentitions (83.3%) (p < 0.001). Those who participated in the OHPP soon after birth showed significantly fewer DMFT (p < 0.05) compared with those who did not. This study revealed that oral health at 4 years of age was related to that in adulthood, suggesting that fostering good oral health soon after birth is of great importance. Open Access Article A Longitudinal Study on the Relationship of Oral Health at 4 Years of Age with That in Adulthood by Sho Yamada 1 , Reiko Sakashita 2,* , Mikinori Ogura 3 , Eiko Nakanishi 2 and Takuichi Sato 4 1 2 College of Nursing Art and Science, University of Hyogo, Akashi 673-8588, Japan 3 Maxillofacial Unit, Oita Oka Hospital, Oita 870-0192, Japan 4 Division of Clinical Chemistry, Niigata University Graduate School of Health Sciences, Niigata 951-8518, Japan * Author to whom correspondence should be addressed. Dent. J. 2021 , 9 (2), 17; https://doi.org/10.3390/dj9020017 Received: 28 December 2020 / Revised: 18 January 2021 / Accepted: 23 January 2021 / Published: 1 February 2021 (This article belongs to the Section Oral Hygiene, Periodontology and Peri-implant Diseases ) Abstract : This longitudinal study aimed to clarify the relationship of oral health in infancy with that in adulthood among participants who were the subjects of the oral health promotion project (OHPP) conducted in Miyako Island, Okinawa Prefecture, Japan, since 1984. Twenty-seven subjects, around 35 years of age, were examined for dental caries, periodontal diseases (community periodontal index), dental plaque, occlusion, and bite-force and compared with those at 4 and 13–15 years of age. The dental caries status and maximum bite force in adulthood was significantly reflected for those at 4 and 13–15 years of age ( p < 0.05). CPI in adulthood was related to the dental caries status at 4 and 13–15 years of age but not to the gingival score at 4 years of age, and it was weakly related to the gingival score at 13–15 years (r = 0.264, p > 0.05). Most of the normal occlusion at 4 years of age became normal permanent occlusion in adulthood (88.9%). Most of the cases involving the discrepancy factor retained the same condition in both the deciduous and permanent dentitions (83.3%) ( p p < 0.05) compared with those who did not. This study revealed that oral health at 4 years of age was related to that in adulthood, suggesting that fostering good oral health soon after birth is of great importance. Keywords: oral health ; dental caries ; periodontal disease ; occlusion ; bite-force ; infant ; longitudinal study 1. Introduction It has been suggested that the underdevelopment of the masticatory system will increase among young Japanese population [ 1 , 2 ]. For example, 63.1% of young Japanese people (n = 495) have crowding of teeth [ 3 ], and Japanese children currently show a narrowing of the dental arch width as compared with those in 1964 [ 4 ], and 34.6% of children aged 3 to 5 years (n = 107) have problem in eating such as slow eating and less function [ 5 ]. The present diet, with its soft and nutritious food, bottle feeding, and long-lasting pureed baby food, has been suspected to be the cause of these problems [ 6 ]. Experiments have shown that breast-fed mice have a better developed masticatory system than bottle-fed ones. A diet of liquidized or pureed food reduces the height of the mandible, the length of the body of the mandible, and the condylar width, and widens the gonial angle [ 7 ]. It also reduces the size of the masseter and temporal muscles as well as of the salivary glands [ 8 ]. Experiments with rats have also shown that the feeding of a liquid diet after being weaned may alter the motor output of jaw and tongue muscles and obstruct the functional transition from suckling to mastication, and jaw elevators that develop without motor learning of mastication are inefficiency when performing functionally [ 9 ]. Hence, if diet can be the main cause of not only dental diseases but also insufficient development of the masticatory system, healthy oral conditions can possibly be brought about by a change in the dietary regime from a young age. Hoping to reduce the insufficient development of the masticatory system and to prevent dental problems through health education focusing on diet, we set up the Oral Health Promotion Project (OHPP) and a longitudinal study in selected districts on Miyako Island, Okinawa Prefecture, Japan, in 1984 [ 10 ]. The OHPP lasted eight years, with another nine years of follow-up, and completed in the year 2000. Positive effects of this project were reported on dental occlusion, masticatory function, and dental caries in the participants at 4 and 13–15 years of age [ 11 , 12 ]. After graduating from junior high school, many participants left this remote island for study or work, but some of them were expected to return for the reunion to celebrate the 20th anniversary of graduating from junior high school in Karimata on Miyako Island, when they were about 35 years old. On this and on other occasions, such as New Year’s and Homecoming, this study aimed to clarify the relationship between the oral conditions at 4 years of age (completed deciduous dentition [Hellman’s dental age, IIA]), 13–15 years old (permanent dentition [IVA]), and in adulthood. 2. Methods 2.1. Study Design This prospective, longitudinal study was based on three examinations conducted in Ikema and Karimata district, remote Island Miyako, Okinawa, Japan. 2.2. The Oral Health Promotion Project (OHPP) The Project began in April 1984. During the first eight years, the OHPP intervention focused mainly on health education, with special emphasis on diet and thrice-yearly dental examinations and treatments such as cavity restoration [ 10 ]. Participants were followed up, including an assessment of their oral health, once a year until the year 2000. Children born in the district between 1979 and 1992 were enrolled in the OHPP. Based on previous studies [ 6 , 10 , 13 ], the guidelines for oral health promotion were developed [ 1 ]. At the first stage of the lactation period, ‘breast feeding’ was recommended; at the second step of the transition from milk to solid food, ‘natural weaning’, i.e., the introduction of food at the proper time was advised. In the third step, after approximately three years of age, when the deciduous dentition was complete, establishment of a good dietary style was suggested. Two small communities, Ikema and Karimata, Miyako Island, Okinawa, where no regular dentist served and public health nurses requested for help in improving the poor oral condition of the population in 1984, were selected as model venues for the OHPP. 2.3. Subjects The subjects who participated in the OHPP had records at two periods, namely at 4 years of age (completed deciduous dentition [IIA]) and at 13–15 years (permanent dentition [IVA]). The main targets were 39 participants born between 1982 and 1985 in Karimata, who would possibly return for the 20th anniversary reunion around 35 years of age. In addition, invitation cards were sent to the 70 expected participants to inform them of dental surveys and to request their participation. However, 46 cards (65.7%) were returned as the addresses were unknown. 2.4. Examinations 2.4.1. Oral Health Examinations Dentists examined each participant to determine the oral condition, including dental caries, periodontal diseases [ 14 ], dental plaque [ 15 ], and occlusion [ 11 ], according to the criteria shown in Table 1 . This was done using a mouth mirror and an explorer, with careful consideration of the lighting conditions. Dentists assessed the dental caries status as intact, decayed, missing, or filled teeth, and DMF (number of decayed, missing, or filled permanent teeth) was used as an index. The previous data at 4 years and 13–15 years of age contained the Gingival Score (GS), in which the areas of greatest gingivitis progression were scored following Dunning’s criteria [ 16 ]. For the deciduous dentition, pseudo-normal occlusion, which is a deciduous normal occlusion with closed dental arches, was used to determine occlusion [ 11 ]. 2.4.2. Bite-Force Measurements The bite-force was measured using a bite-force transducer (Occluser, Nagano Seiki Co., Tokyo, Japan). The block portion of the transducer was inserted into the subject’s mouth. The bite block was positioned parallel to the occlusal plane and was centered on the mandibular second molar. Maximum bites on both sides were measured, and the maximum value was used as the maximum bite force. 2.5. Data Analysis Methods The data of this study were compared with that at 4 and 13–15 years of age. The relationship of the oral condition in adulthood with that at 4 and 13–15 years of age was examined [ 11 , 12 ]. Spearman’s correlation coefficient among quantitative variables was performed to examine the relationship among variables. Chi-squared tests were performed to examine the relationship among age-related occlusion. In previous studies [ 11 , 12 ], a major improvement of oral health has been observed in children born after the OHPP started (1984). Thus, the oral conditions were compared between those born before 1984 and in or after 1984 using t-tests for quantitative variables and the Chi-squared test for nominal scale. Differences in the bite force by age and sex were tested using repeated measures ANOVA with post hoc multiple comparison by Bonferroni. Statistical analysis software (SPSS PASW Statistics 24, Tokyo, Japan) was used for testing. 2.6. Ethical Approval This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Research Ethics Committee of the College of Nursing Art and Science, University of Hyogo (KYOUIN20) on 13 December 2017. Written informed consent was obtained from the participants. 3. Results 3.1. Subjects’ Characteristics The demographic data of the subjects are shown in Table 2 . A total of 27 subjects (mean age, 34.5 ± 1.5 years; 66.7% male) participated in this study. As there were no significant sex differences except for the bite-force, males and females were analyzed together, except for the analysis of bite-force. 3.2. Longitudinal Change in Oral Conditions The high values of the DMF (number of decayed, missing, or filled deciduous teeth) at 4 years (11.6 ± 5.3) dropped to 5.7 ± 3.1 at 13–15 years of age, with the replacement to permanent teeth; however, it went up to 12.2 ± 5.7 around 35 years of age ( Table 3 ). Participants born in and after 1984 had significantly lower DMF levels compared to those born before 1984 ( p < 0.05). The CPI scores were also lower among those born in/after 1984, although the difference was not significant ( Table 3 ). The percentage of normal occlusion increased from 33.3% at 4 years to 44.4% around 35 years of age. Less crowding was found in those born in/after 1984 (11.1%) compared to those born before 1984 (44.4%), although the difference was not significant. More significant functional factors were found in those born in 1984 (33.3%) compared to those born before 1984 (0.0%) ( p < 0.05) as causative factors ( Table 3 ). 3.3. Longitudinal Change in the Maximum Bite Force Significant differences were observed among all age groups and sexes ( p < 0.001). The maximum bite force increased significantly with age and the sex gap, and it was the largest around 35 years of age ( Table 4 ). 3.4. Correlation among Variables The dental caries status and the maximum bite force in adulthood significantly reflected those at 4 and 13–15 years of age ( Table 5 ). The CPI in adulthood was related to the DMF and number of untreated teeth at 4 years and the DMF at 13–15 years, whereas it was not related to the GS at 4 years of age and only weakly related to the GS at 13–15 years ( Table 5 ). The number of untreated teeth at 4 years of age was strongly related to the DMF and the CPI in adulthood ( p < 0.001–0.01). Dental caries, periodontal status, and dental plaque scores were significantly related to each other in adulthood ( Table 5 ). 3.5. Distribution of Occlusion at 4 Years of Age and in Adulthood Most of the subjects with normal occlusion at 4 years of age (88.9%) had normal permanent occlusion in adulthood, whereas only 16.7% of the subjects with pseudo-normal deciduous occlusion had normal permanent occlusion ( Table 6 ). Most of the cases involving the discrepancy factor (83.3%) retained the same conditions in both the deciduous and permanent dentitions ( p < 0.001) ( Table 7 ). Two deciduous open-bite malocclusions, which were caused by thumb-sucking, disappeared in the permanent dentition, since the habit stopped with the eruption of the permanent teeth. One permanent posterior cross-bite malocclusion seemed to be caused by a tongue habit ( Table 7 ). 4. Discussion Dental caries and periodontal diseases are the two most important causes for extraction in Japan [ 18 ]. Dental caries develops in both the crowns and roots of teeth, and it can arise in early childhood as aggressive tooth decay affecting the deciduous teeth of infants [ 19 ]. In the present study, as in a previous study [ 12 ], differences in dental caries prevalence were found in those born before the onset of the OHPP compared to those born after the onset of the OHPP, and these conditions continued through adolescence (age 13–15 years) into adulthood (age 35 years) ( Table 3 ). The causes associated with early childhood caries are multifactorial, including infant feeding habits, dietary habits, consumption of sugary foods, oral hygiene procedures, use of fluoride, and psycho-social factors [ 20 ]. Among them, Sheiham and James [ 21 ] indicated that the consumption of sugars was a major etiological factor for dental caries. In the present study, those born after 1984 had good eating habits, such as less snack intake and greater intake of fiber-rich food [ 12 ], and this may have reflected in the low caries rate in adults born after 1984. Several recent studies have provided evidence suggesting that periodontitis may increase the risk of systemic disorders such as cardiovascular diseases and premature low birth weight infants [ 22 ]. As oral conditions affect systemic conditions, such as atherosclerotic vascular, pulmonary disease, diabetes, pregnancy, low birth weight, osteoporosis, and kidney diseases either coincidentally or causally [ 23 ], it is very important to maintain good oral health throughout life. In this study, the gingivitis status at 4 years of age and at middle school correlated strongly with dental caries from the age of 4 to adulthood and seemed to reflect the oral hygiene status, but was not related to the CPI status of adults ( Table 5 ). Conversely, the caries status at 4 years of age showed a strong correlation with the periodontal disease status in adults. Although the disease states of gingivitis and periodontal disease in young people are suggested to be different [ 24 ], maintaining a caries-free oral condition soon after birth may reduce the risk of periodontal disease in the future. This study revealed that oral conditions in childhood were strongly related with those in adulthood ( Table 3 and Table 5 ). Many studies indicate that the caries status in the deciduous dentition is related to that in the permanent dentition, although the subjects’ age was under 20 years in most of the studies [ 25 , 26 , 27 ]. There are a few longitudinal studies from childhood to adulthood, although epidemiological studies suggest that gingivitis is common in children, and the untreated cases may progress to severe breakdown of the periodontium and loss of teeth in adults [ 28 ]. Prevention should start when deciduous teeth change into permanent teeth. However, this study confirms that the condition of the deciduous teeth is passed on to the permanent teeth ( Table 5 ). This is because the oral condition is greatly influenced by diet. Previous studies comparing the secular changes in the rates of carious teeth and the prevalence of malocclusion of discrepancy type showed that both would be expected to grow in severity as the economy progressed, with a resultant influence on dietary regimes [ 3 , 10 , 29 , 30 ]. Fiber-rich food has been seen to be most effective in dealing with this problem, as it produces a greater load on the jaws during mastication and promotes a self-cleansing system, reducing oral pollution [ 30 , 31 ]. The two main points of the OHPP dietary instructions after transition to solid food were: 1) stop drinking large amounts of high-calorie drinks like juice, especially before meals; and 2) eat fiber-rich food such as vegetables at all meals. The consumption of high-calorie drinks reduce appetite and result in not eating enough fibrous vegetables. [ 12 ]. As a result of inadequate meals, infants soon become hungry again and more juice and snacks are given. To break this vicious circle, mothers must regulate their infants’ and children’s intake so that they have empty stomachs at mealtimes. This promotes the development of the chewing system, chewing ability, and salivary secretion. Both brushing of teeth and the application of fluoride reduce dental caries [ 32 , 33 ]. However, it is not expected to have significant effects on the development of oral morphology and function. Therefore, we focused on dietary instructions and did not introduce fluoride mouth rinses. Previous studies showed a decrease in crowding with the type of discrepancy, and dental caries could be seen among those born after the establishment of the OHPP [ 11 , 12 ]. There was less improvement in children born in 1979–1980, whose deciduous dentitions were already fully developed at the beginning of the project. Considering that the DMF improved significantly, according to the findings of this study ( Table 3 ), the developmental “direction” and risk of dental diseases would be difficult to change with increasing age. Children’s dietary intake has been shown to be strongly associated with their mother’s dietary intake [ 34 ], and the children’s own dietary habits develop early in life [ 35 , 36 ]. Thus, the suckling and weaning stages seem to be the key periods. Experiments on mice have shown that the masticatory muscles and jaw bone in breast-fed mice developed better than those in mice fed maternal milk through artificial teats [ 37 ]. In human babies, the activity of the masticatory muscles was reduced in bottle-fed babies compared to that in breast-fed babies [ 6 , 38 ]. Rats or mice fed on soft or liquid food showed a lower percentage of oxidative fibers in the ascending rami, and it has been demonstrated that altered muscular function can influence craniofacial morphology [ 8 , 39 , 40 ]. A constant liquid diet reduces the size of the masseter and temporal muscles, and even of the salivary glands. It also affects the chewing pattern [ 8 , 9 ]. Several experiments on rats have shown that insufficient mechanical stress in the growth process results in the underdevelopment of the masticatory system, the weight of the masseter muscles, and the size of the jaw bone and condylar head [ 41 , 42 , 43 ]. Based on the above findings, we recommend breast feeding and natural weaning processes, such as baby-led weaning [ 44 ], through the OHPP. The main dietary instructions in the OHPP, as described above, are important not only for the masticatory system but also for the life-long health of the whole body. Experiences in early life influence later dietary regimes [ 45 ] and could help decrease metabolic risk factors leading to obesity and obesity-related diseases [ 46 , 47 , 48 ]. In this study, we tried to confirm the relationship between feeding and weaning processes, but in vain, due to the lack of records. One of the limitations of the present study was the small sample size, which was a consequence of the relatively small number of participants in the OHPP, as most of the young people moved out of the region in search of education and jobs, and it was difficult to track them. There was also sex bias, as female candidates tended to be less likely to participate in this research because they were too shy to let their mouth be examined. Although there have been significant advances in treatment methods over the past 30 years, the diagnostic criteria for health screening have not changed. Thus the same criteria were used in this study. 5. Conclusions The dental caries status and maximum bite force in adulthood was significantly reflected for those at 4 and 13–15 years of age. Periodontal diseases in adulthood was related to the dental caries status at 4 and 13–15 years of age but not to the gingival score at 4 years of age, and it was weakly related to the gingival score at 13–15 years. Most of the normal occlusion at 4 years of age became normal permanent occlusion in adulthood. Most of the cases involving the discrepancy factor retained the same condition in both the deciduous and permanent dentitions. Those who participated in the OHPP soon after birth showed significantly fewer DMF compared with those who did not. Thus, this study revealed that oral health at 4 years of age was related to that in adulthood, suggesting that fostering good oral health and dietary habits soon after birth is of substantial importance. The authors would like to express their sincere appreciation to participants in the study. Conflicts of Interest The authors declare no conflict of interest. References Inoue, N. Collapse of dentition in Japan. In Culture of Food and Oral Health in Maori ; Therapeia Publishing Co.: Tokyo, Japan, 1993; pp. 67–78. [ Google Scholar ] Hayashi, R.; Kawamura, A.; Kasai, K. Relationship between Masticatory Function, Dental Arch Width, and Bucco-Lingual Inclination of the First Molars. Orthod. Waves 2006 , 65 , 120–126. [ Google Scholar ] [ CrossRef ] Sakashita, R.; Inoue, M.; Inoue, N.; Pan, Q.; Zhu, H. Dental Disease in the Chinese Yin-Shang Period with Respect to Relationships between Citizens and Slaves. Am. J. Phys. Anthropol. 1997 , 103 , 401–408. [ Google Scholar ] [ CrossRef ] Kasai, K.; Negishi, S.; Hayashi, R.; Saitoh, K.; Kanazawa, E. Growth Change of Dental Arch Form in Mixed Dentition. Orthod. Waves-Jpn. Ed. 2010 , 69 , 23–35. [ Google Scholar ] [ CrossRef ] Yokomizo, M. Research on Development of Masticatory Behavior in kindergarteners. J. Dent. Health 1992 , 42 , 277–306. [ Google Scholar ] [ CrossRef ][ Green Version ] Inoue, N.; Sakashita, R.; Inoue, M.; Kamegai, T.; Ohashi, K.; Katsivo, M. Ritual Ablation of Front Teeth in Modern and Recent Kenyans. Anthropol. Sci. 1995 , 103 , 263–277. [ Google Scholar ] [ CrossRef ][ Green Version ] Ito, G.; Kuroe, K.; Yasuda, H.; Inoue, N.; Kamegai, T. Experimental study on jaw reduction. Orthod. Waves-Jpn. Ed. 1982 , 41 , 708–715. [ Google Scholar ] Ikeda, K. Development of Jaw Muscles’ Function in Rats Fed a Kneaded Diet. Orthod. Waves J. Jpn. Orthod. Soc. 1998 , 57 , 163–172. [ Google Scholar ] Liu, Z.J.; Ikeda, K.; Harada, S.; Kasahara, Y.; Ito, G. Functional Properties of Jaw and Tongue Muscles in Rats Fed a Liquid Diet after Being Weaned. J. Dent. Res. 1998 , 77 , 366–376. [ Google Scholar ] [ CrossRef ] Inoue, N. Report on the Improvement of Maternal and Child Care-1986: Studies on Maternal and Child Health Administration ; The Ministry of Health and Welfare: Tokyo, Japan, 1986. [ Google Scholar ] Sakashita, R.; Inoue, N. Can Oral Health Promotion Help Develop Occlusion? Orthod. Waves-Jpn. Ed. 2002 , 61 , 426–434. [ Google Scholar ] Sakashita, R.; Inoue, N.; Kamegai, T. Can Oral Health Promotion Help Develop Masticatory Function and Prevent Dental Caries? Community Dent. Health 2006 , 23 , 107–115. [ Google Scholar ] Ito, G.; Mitani, S.; Kim, J.H. Effect of Soft Diets on Craniofacial Growth in Mice. Anat. Anz. 1988 , 165 , 151–166. [ Google Scholar ] [ PubMed ] Ainamo, J.; Barmes, D.; Beagrie, G.; Cutress, T.; Martin, J.; Sardo-Infirri, J. Development of the World Health Organization (WHO) Community Periodontal Index of Treatment Needs (CPITN). Int. Dent. J. 1982 , 32 , 281–291. [ Google Scholar ] [ PubMed ] Greene, J.C.; Vermillion, J.R. The Oral Hygiene Index: A Method for Classifying Oral Hygiene Status. J. Am. Dent. Assoc. 1960 , 61 , 172–179. [ Google Scholar ] [ CrossRef ] Dunning, J.M. Principles of Dental Public Health , 4th ed.; Harvard University Press: London, UK, 1986; ISBN 978-0-674-70550-0. [ Google Scholar ] Sakashita, R.; Inoue, N.; Watanabe, K.; Watanabe, M.; Kamegai, T. Electromyographic Evidence for Sufficient and Insufficient Developmental Space in Juvenile Jaws. Orthod. Waves-Jpn. Ed. 1998 , 57 , 409–416. [ Google Scholar ] Ministry of Health, Labour and Welfere Survey of Dental Diseases 2016. Available online: https://www.mhlw.go.jp/toukei/list/62-17.html (accessed on 28 November 2020). Selwitz, R.H.; Ismail, A.I.; Pitts, N.B. Dental Caries. Lancet 2007 , 369 , 51–59. [ Google Scholar ] [ CrossRef ] Thitasomakul, S.; Piwat, S.; Thearmontree, A.; Chankanka, O.; Pithpornchaiyakul, W.; Madyusoh, S. Risks for Early Childhood Caries Analyzed by Negative Binomial Models. J. Dent. Res. 2009 , 88 , 137–141. [ Google Scholar ] [ CrossRef ] Sheiham, A.; James, W.P.T. Diet and Dental Caries: The Pivotal Role of Free Sugars Reemphasized. J. Dent. Res. 2015 , 94 , 1341–1347. [ Google Scholar ] [ CrossRef ] Fowler, E.B.; Breault, L.G.; Cuenin, M.F. Periodontal Disease and Its Association with Systemic Disease. Mil. Med. 2001 , 166 , 85–89. [ Google Scholar ] [ CrossRef ][ Green Version ] Kane, S.F. The Effects of Oral Health on Systemic Health. Gen. Dent. 2017 , 65 , 30–34. [ Google Scholar ] Pihlstrom, B.L.; Michalowicz, B.S.; Johnson, N.W. Periodontal Diseases. Lancet 2005 , 366 , 1809–1820. [ Google Scholar ] [ CrossRef ][ Green Version ] Gray, M.M.; Marchment, M.D.; Anderson, R.J. The Relationship between Caries Experience in the Deciduous Molars at 5 Years and in First Permanent Molars of the Same Child at 7 Years. Community Dent. Health 1991 , 8 , 3–7. [ Google Scholar ] [ PubMed ] Li, Y.; Wang, W. Predicting Caries in Permanent Teeth from Caries in Primary Teeth: An Eight-Year Cohort Study. J. Dent. Res. 2002 , 81 , 561–566. [ Google Scholar ] [ CrossRef ] [ PubMed ] Skeie, M.S.; Raadal, M.; Strand, G.V.; Espelid, I. The Relationship between Caries in the Primary Dentition at 5 Years of Age and Permanent Dentition at 10 Years of Age—A Longitudinal Study. Int. J. Paediatr. Dent. 2006 , 16 , 152–160. [ Google Scholar ] [ CrossRef ] [ PubMed ] Ketabi, M.; Tazhibi, M.; Mohebrasool, S. The Prevalance and Risk Factors of Gingivitis Among the Children Referred to Isfahan Islamic Azad University (Khorasgan Branch) Dental School, In Iran. Dent. Res. J. 2008 , 3 , 33–36. [ Google Scholar ] Hanihara, K.; Inoue, N.; Ito, G.; Kamegai, T. Microevolution and Tooth to Denture Base Discrepancy in Japanese Dentition. J. Anthropol. Soc. Nippon 1981 , 89 , 63–70. [ Google Scholar ] [ CrossRef ][ Green Version ] Sakashita, R.; Inoue, N.; Pan, Q.; Zhu, H. Diet and Discrepancy between Tooth and Jaw Size in the Yin-Shang Period of China. Am. J. Phys. Anthropol. 1997 , 103 , 497–505. [ Google Scholar ] [ CrossRef ] Sakashita, R.; Inoue, N. On Bi-Polarization of Gingivitis in Infants. Child Health Res. 1989 , 48 , 359–363. [ Google Scholar ] Curnow, M.M.T.; Pine, C.M.; Burnside, G.; Nicholson, J.A.; Chesters, R.K.; Huntington, E. A Randomised Controlled Trial of the Efficacy of Supervised Toothbrushing in High-Caries-Risk Children. Caries Res. 2002 , 36 , 294–300. [ Google Scholar ] [ CrossRef ] Marinho, V.C.C.; Higgins, J.P.T.; Logan, S.; Sheiham, A. Fluoride Mouthrinses for Preventing Dental Caries in Children and Adolescents. Cochrane Database Syst. Rev. 2003 , CD002284. [ Google Scholar ] [ CrossRef ] Oliveria, S.A.; Ellison, R.C.; Moore, L.L.; Gillman, M.W.; Garrahie, E.J.; Singer, M.R. Parent-Child Relationships in Nutrient Intake: The Framingham Children’s Study. Am. J. Clin. Nutr. 1992 , 56 , 593–598. [ Google Scholar ] [ CrossRef ] Rossow, I.; Kjaernes, U.; Holst, D. Patterns of Sugar Consumption in Early Childhood. Community Dent. Oral Epidemiol. 1990 , 18 , 12–16. [ Google Scholar ] [ CrossRef ] [ PubMed ] Ismail, A.I. The Role of Early Dietary Habits in Dental Caries Development. Spec. Care Dent. Off. Publ. Am. Assoc. Hosp. Dent. Acad. Dent. Handicap. Am. Soc. Geriatr. Dent. 1998 , 18 , 40–45. [ Google Scholar ] [ CrossRef ] [ PubMed ] Oseko, T.; Kuroe, K.; Matsuo, H.; Utsu, H.; Ono, H.; Oshikawa, S.; Yamagata, K.; Ito, G. An Experimental Study on Feeding Style and Development of Jaws. Orthod. Waves-Jpn. Ed. 1988 , 33 , 33–38. [ Google Scholar ] Sakashita, R.; Kamegai, T.; Inoue, N. Masseter Muscle Activity in Bottle Feeding with the Chewing Type Bottle Teat: Evidence from Electromyographs. Early Hum. Dev. 1996 , 45 , 83–92. [ Google Scholar ] [ CrossRef ] Kiliaridis, S.; Shyu, B.C. Isometric Muscle Tension Generated by Masseter Stimulation after Prolonged Alteration of the Consistency of the Diet Fed to Growing Rats. Arch. Oral Biol. 1988 , 33 , 467–472. [ Google Scholar ] [ CrossRef ] Kim, J.H. The Effects of Solid or Liquified Diet on the Submandibular Condyles and Fossae. J. Jpn. Orthod. Soc. 1990 , 49 , 73–86. [ Google Scholar ] Watt, D.G.; Williams, C.H.M. The Effects of the Physical Consistency of Food on the Growth and Development of the Mandible and the Maxilla of the Rat. Am. J. Orthod. 1951 , 37 , 895–928. [ Google Scholar ] [ CrossRef ] Beecher, R.M.; Corruccini, R.S. Effects of Dietary Consistency on Craniofacial and Occlusal Development in the Rat. Angle Orthod. 1981 , 51 , 61–69. [ Google Scholar ] [ CrossRef ] Kuroe, K. Effect of Masticatory Function on the Age Changes of Mandibular Condyle and Fossae. J. Jpn. Orthod. Soc. 1991 , 50 , 196–209. [ Google Scholar ] Rapley, G.; Murkett, T. Baby-Led Weaning: The Essential Guide to Introducing Solid Foods—And Helping Your Baby to Grow Up a Happy and Confident Eater ; The Experiment: London, UK, 2010. [ Google Scholar ] Westenhoefer, J. Establishing Good Dietary Habits—Capturing the Minds of Children. Public Health Nutr. 2001 , 4 , 125–129. [ Google Scholar ] [ CrossRef ][ Green Version ] James, W.P.; Nelson, M.; Ralph, A.; Leather, S. Socioeconomic Determinants of Health. The Contribution of Nutrition to Inequalities in Health. BMJ 1997 , 314 , 1545–1549. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Pereira, M.A.; Ludwig, D.S. Dietary Fiber and Body-Weight Regulation. Observations and Mechanisms. Pediatr. Clin. N. Am. 2001 , 48 , 969–980. [ Google Scholar ] [ CrossRef ] Rolland-Cachera, M.F.; Deheeger, M.; Bellisle, F. Nutrient Balance and Body Composition. Reprod. Nutr. Dev. 1997 , 37 , 727–734. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Table 1. Assessment scores for oral conditions. Table 1. Assessment scores for oral conditions. Community Periodontal Index (CPI) [ 14 ] A special probe was used to determine the probing depth, bleeding response, and presence of calculus. Six areas were measured (upper and lower central incisors, and the upper and lower, left and right first molars) and the highest applicable number was used. 0: Healthy periodontal tissues 1: Bleeding after gentle probing 2: Supragingival or subgingival calculus or defective margin of filling or crown 3: 4 mm or 5 mm periodontal pocket 4: 6 mm or deeper pathologic periodontal pocket Dental plaque index (DPI) The teeth with the most plaque were scored according to Greene & Vermillion’s criteria [ 15 ]. 0: No plaque present 1: Plaque covering not more than one-third of the exposed tooth surface 2: Plaque covering more than one third, but not more than-two thirds of the exposed tooth surface 3: Plaque covering more than two-thirds of the exposed tooth surface Categories of occlusion [ 17 ] Each occlusion was examined and classified into one of the following categories: (1) Normal occlusion: The upper and lower molars were in a relationship whereby the mesiobuccal cusp of the upper molar occluded in the buccal grove of the lower molar and the teeth were arranged in a smoothly curving line of occlusion. (2) Crowding: Crowded arrangement of the teeth. (3) Maxillary protrusion: Protruding anterior maxillary teeth. (4) Anterior cross-bite: Reversed occlusion of the anterior teeth, i.e., one or more mandibular teeth biting in front of the maxillary teeth. (5) Open bite: A partial gap of 2 mm or more between the anterior maxillary and mandibular teeth when in occlusion. (6) Others: Occlusion that does not meet the above criteria Causative factors Four main causative factors were seen in the cases of malocclusion, and these were used in combination to describe each case (e.g., anterior cross-bite with skeletal discrepancy factors): (1) Skeletal factor: Skeletal imbalance in size and/or shape between the maxilla and mandible. (2) Functional factor: Functional interference in occlusion, e.g., abnormal movement of the mandible. (3) Discrepancy factor: Tooth-to-denture base discrepancy. (4) Habitual factor: Thumb sucking or other habit. Table 2. Subjects’ characteristics. Table 2. Subjects’ characteristics. Variable Age in years (Mean (SD)) 34.5 (1.5) Sex (n, %) Male 18 (66.7%) Female 9 (33.3%) Employment (n, %) Full-time 23 (85.1%) Part-time 2 (7.4%) Missing 2 (7.4%) Table 3. Longitudinal change in oral conditions. Table 3. Longitudinal change in oral conditions. Variables 4 Years’ Old n = 27 13–15 Years’ Old n = 27 Adulthood n = 27 Adulthood, Born before 1984, n = 18 Adulthood, Born in/after 1984, n = 9 dmf, DMF Mean (SD) 11.6 (5.3) 5.7 (3.1) 12.2 (5.7) 14.2 (5.3) * 8.3 (4.7) * Number of untreated teeth, Mean (SD) 5.0 (4.7) 0.9 (1.7) 1.6 (2.7) 1.6 (1.9) 1.6 (4.1) GS < 15 years, CPI at 35 years, Mean (SD) 1.1 (0.5) 1.2 (0.6) 1.9 (1.2) 2.1 (1.2) 1.3 (1.3) DPI Mean (SD) 0.6 (0.6) 0.9 (0.5) 0.9 (0.7) 0.9 (0.6) 0.9 (0.8) Occlusion (1) (1) Normal 9 (33.3%) 10 (37.0%) 12 (44.4%) 8 (44.4%) 4 (44.4%) Pseudo normal 13 (48.1%) - - - - Crowding 0 (0.0%) 10 (37.0%) 9 (33.3%) 8 (44.4%) 1 (11.1%) Maxillary protrusion 0 (0.0%) 2 (7.4%) 2 (7.4%) 0 (0.0%) 1 (11.1%) Anterior cross-bite 3 (11.1%) 5 (18.5%) 1 (3.7%) 0 (0.0%) 2 (22.2%) Others 2 (7.4%) 0 (0.0%) 1 (3.7%) 0 (0.0%) 1 (11.1%) Causative factors Skeletal 1 (3.7%) 2 (7.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Functional 2 (7.4%) 5 (18.5%) 3 (12.0%) 0 (0.0%) 3 (33.3) * Discrepancy 14 (51.9%) 14 (51.9%) 12 (40.7%) 8 (44.4%) 3 (33.3) Habitual 2 (7.4%) 1 (3.7%) 1 (8.0%) 0 (0.0%) 1 (11.1%) * A significant difference p < 0.05 was observed between the two groups: born before and in/after 1984. (1) Two cases were excluded in which normal occlusion was achieved after orthodontic treatment. Table 4. Longitudinal change in maximum bite force. Table 4. Longitudinal change in maximum bite force. Max Bite Force (kg) 4 Years Old 13–15 Years Old Adulthood Adulthood, Born before 1984 Adulthood, Born in/after 1984 n Mean (SD) n Mean (SD) n Mean (SD) n Mean (SD) n Mean (SD) Male 18 15.9 (7.3) 18 44.3 (15.9) 18 78.5 (22.5) 10 78.6 (23.8) 8 78.4 (22.3) Female 9 9.6 (5.4) 9 38.6 (5.8) 9 38.2 (12.6) 7 35.7 (11.4) 1 55.3 (-) Repeated measures ANOVA p < 0.001, sex factor p < 0.001. Table 5. Correlation among variables. Table 5. Correlation among variables. Adulthood DMF Untreated Carious Teeth CPI DPI Maximum Bite Force Age 4 years DMF 0.504 ** 0.414 * 0.392 * 0.220 −0.104 Untreated carious teeth 0.610 ** 0.256 0.675 *** 0.064 −0.133 GS 0.579 ** 0.163 0.073 0.143 −0.297 DPI 0.068 0.167 0.078 0.020 −0.083 Max bite force −0.230 −0.014 −0.317 −0.031 0.443 * Age 13–15 years DMF 0.651 ** 0.378 0.447 * 0.248 −0.289 Untreated carious teeth 0.501 ** 0.492 ** 0.298 0.592 ** 0.057 GS 0.537 ** 0.393 * 0.264 0.504 ** −0.156 DPI 0.447 * 0.305 0.264 0.510 ** 0.078 Max bite force −0.297 −0.172 −0.319 0.044 0.451 * Adulthood DMF 0.504 ** 0.580 ** 0.413 * −0.094 Untreated carious teeth 0.536 ** 0.551 ** −0.173 CPI 0.534 ** −0.200 DPI 0.110 CPI: Community Periodontal Index, DPI: Dental plaque index, GS: Gingival Score. * p < 0.05, ** p < 0.01. *** p < 0.001. Table 6. Distribution of occlusion at 4 years of age and in adulthood. Table 6. Distribution of occlusion at 4 years of age and in adulthood. Adulthood Age 4 Years Normal Crowding Maxillary Protrusion Anterior Cross-Bite Others Total Normal n 8 1 0 0 0 9 % 88.9% 11.1% 0.0% 0.0% 0.0% 100.0% Pseudo normal n 2 8 1 0 1 12 % 16.7% 66.7% 8.3% 0.0% 8.3% 100.0% Maxillary protrusion n 0 0 0 2 0 2 % 0.0% 0.0% 0.0% 100.0% 0.0% 100.0% Open bite n 2 0 0 0 0 2 % 100.0% 0.0% 0.0% 0.0% 0.0% 100.0% χ2 test, p < 0.001. Table 7. Distribution of causative factors at 4 years of age and in adulthood (around 35 years). Table 7. Distribution of causative factors at 4 years of age and in adulthood (around 35 years). Adulthood Skeletal Functional Discrepancy *** Habitual Age 4 Years − + − + − + − + Skeletal − 24 0 % 100.0% 0.0% + 1 0 % 100.0% 0.0% Functional − 22 0 % 100.0% 0.0% + 2 1 % 66.7% 33.1% Discrepancy − 12 1 % 93.3% 7.7% + 1 10 % 16.7% 83.3% Habitual − 22 1 % 95.1% 4.3% + 2 0 % 100.0% 0.0% *** A significant relationship was observed between the discrepancy type at 4 years old and that in adulthood ( p < 0.001). n = 26; Two were excluded because of orthodontic treatment. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
https://www.mdpi.com/2304-6767/9/2/17/xml
Remote Sensing | Free Full-Text | Fusion of China ZY-1 02D Hyperspectral Data and Multispectral Data: Which Methods Should Be Used? ZY-1 02D is China’s first civil hyperspectral (HS) operational satellite, developed independently and successfully launched in 2019. It can collect HS data with a spatial resolution of 30 m, 166 spectral bands, a spectral range of 400~2500 nm, and a swath width of 60 km. Its competitive advantages over other on-orbit or planned satellites are its high spectral resolution and large swath width. Unfortunately, the relatively low spatial resolution may limit its applications. As a result, fusing ZY-1 02D HS data with high-spatial-resolution multispectral (MS) data is required to improve spatial resolution while maintaining spectral fidelity. This paper conducted a comprehensive evaluation study on the fusion of ZY-1 02D HS data with ZY-1 02D MS data (10-m spatial resolution), based on visual interpretation and quantitative metrics. Datasets from Hebei, China, were used in this experiment, and the performances of six common data fusion methods, namely Gram-Schmidt (GS), High Pass Filter (HPF), Nearest-Neighbor Diffusion (NND), Modified Intensity-Hue-Saturation (IHS), Wavelet Transform (Wavelet), and Color Normalized Sharping (Brovey), were compared. The experimental results show that: (1) HPF and GS methods are better suited for the fusion of ZY-1 02D HS Data and MS Data, (2) IHS and Brovey methods can well improve the spatial resolution of ZY-1 02D HS data but introduce spectral distortion, and (3) Wavelet and NND results have high spectral fidelity but poor spatial detail representation. The findings of this study could serve as a good reference for the practical application of ZY-1 02D HS data fusion. Fusion of China ZY-1 02D Hyperspectral Data and Multispectral Data: Which Methods Should Be Used? by Han Lu 1,2,3,† , Danyu Qiao 1,2,3,† , Yongxin Li 4 , Shuang Wu 1,2,3 and Lei Deng 1,2,3,* Author to whom correspondence should be addressed. † Co-first author. Remote Sens. 2021 , 13 (12), 2354; https://doi.org/10.3390/rs13122354 Received: 12 May 2021 / Revised: 14 June 2021 / Accepted: 14 June 2021 / Published: 16 June 2021 (This article belongs to the Special Issue Remote Sensing Data Fusion as a Strategy to Add Value to Earth Observation Data ) Abstract ZY-1 02D is China’s first civil hyperspectral (HS) operational satellite, developed independently and successfully launched in 2019. It can collect HS data with a spatial resolution of 30 m, 166 spectral bands, a spectral range of 400~2500 nm, and a swath width of 60 km. Its competitive advantages over other on-orbit or planned satellites are its high spectral resolution and large swath width. Unfortunately, the relatively low spatial resolution may limit its applications. As a result, fusing ZY-1 02D HS data with high-spatial-resolution multispectral (MS) data is required to improve spatial resolution while maintaining spectral fidelity. This paper conducted a comprehensive evaluation study on the fusion of ZY-1 02D HS data with ZY-1 02D MS data (10-m spatial resolution), based on visual interpretation and quantitative metrics. Datasets from Hebei, China, were used in this experiment, and the performances of six common data fusion methods, namely Gram-Schmidt (GS), High Pass Filter (HPF), Nearest-Neighbor Diffusion (NND), Modified Intensity-Hue-Saturation (IHS), Wavelet Transform (Wavelet), and Color Normalized Sharping (Brovey), were compared. The experimental results show that: (1) HPF and GS methods are better suited for the fusion of ZY-1 02D HS Data and MS Data, (2) IHS and Brovey methods can well improve the spatial resolution of ZY-1 02D HS data but introduce spectral distortion, and (3) Wavelet and NND results have high spectral fidelity but poor spatial detail representation. The findings of this study could serve as a good reference for the practical application of ZY-1 02D HS data fusion. Keywords: ZY-1 02D ; hyperspectral remote sensing ; multispectral remote sensing ; data fusion Graphical Abstract 1. Introduction The ZY-1 02D Satellite, also known as a 5-m optical satellite, is the first operational civil hyperspectral (HS) satellite, independently developed and successfully operated by China as the China–Brazil Earth Resources Satellite. It was launched on 12 September 2019, and one of the three main payloads is an advanced HS imager developed by the Shanghai Institute of Technical Physics (SITP), Chinese Academy of Sciences. The ZY-1 02D HS imager has 166 spectral bands ranging from 400 nm to 2500 nm, a spatial resolution of 30 m, and a swath width of 60 km, allowing it to provide detailed spectral information about ground features. Compared with other on-orbit or planned satellites (e.g., Environmental Mapping and Analysis Program, Precursore Iperspettrale della Missione Applicativa, and DLR Earth Sensing Imaging Spectrometer), the spectral resolution and the swath width of the ZY-1 02D are more advantageous. Unfortunately, due to the unavoidable trade-offs between spectral resolution, spatial resolution and signal-to-noise ratio [ 1 , 2 ], the ZY-1 02D HS data cannot directly make full use of its advantages in some specific applications [ 3 , 4 , 5 , 6 , 7 ]. In this case, a simple and feasible solution that improves spatial resolution while preserving spectral fidelity is required. Nowadays, data fusion has become an important data processing method for achieving the aforementioned goal, as it can fuse HS data with MS data to combine the benefits of both [ 8 ]. Given the availability of ZY-1 02D MS data and the benefits of imaging under the same conditions as HS data, this paper focuses on fusing ZY-1 02D HS data with ZY-1 02D MS data to fully excavate and effectively use its internal information [ 9 , 10 ]. In recent years, with the development of high-precision quantitative remote sensing applications, a large amount of remote sensing data with both high spatial resolution and high spectral resolution has become urgently needed [ 11 , 12 , 13 , 14 ]. To address this issue, domestic and international researchers have conducted a lot of research in the hopes of improving spatial resolution and enriching information while preserving the spectral fidelity of the original image [ 15 ]. Data fusion technology can synthesize the effective information of various image data, eliminate the redundancy and contradictions between multiple sources of information, and produce a composite image with improved interpretability [ 16 , 17 ]. So far, several mature image fusion methods have been developed, including the Gram-Schmidt (GS) transform [ 18 ], Intensity-Hue-Saturation (IHS) [ 19 ], High-Pass Filter (HPF) [ 20 ], Nearest-Neighbor Diffusion (NND) [ 21 ], Wavelet Transform (Wavelet) [ 22 ], Principal Component Analysis (PCA) [ 23 ], Color Normalized Spectral Sharpening (CNSS) [ 24 ] and Color Normalized Sharping (Brovey) [ 25 ], etc. To evaluate the quality of the fused result, statistical indicators (mean, standard deviation, and mean gradient, etc.) or ground object classification accuracy, and target extraction accuracy are typically used [ 26 , 27 , 28 , 29 ]. Among the numerous studies, Huang et al. [ 30 ] compared the performance of HPF, IHS and super-resolution Bayesian (Pansharp) in the image fusion application of Mapping Satellite-1 (TH-1) and found that HPF is the best. Sun et al. [ 31 ] made a performance comparison of five different fusion methods to find a suitable method for GaoFen-2 (GF-2), and the results show that the fused images transformed by HCS and GS have good performance in both visual interpretation analysis and ground object classification. Du et al. [ 32 ] used four methods including Pansharp, GS and Wavelet to carry out data fusion on GaoFen-1 (GF-1), finding that the GS method could effectively improve the spatial resolution and enrich the texture information. Huang et al. [ 33 ] fused the ZiYuan-3 (ZY-3) satellite data with a variety of commonly used image fusion methods and evaluated the fusion results from both qualitative and quantitative aspects. Obviously, it can be seen that these fusion methods have good performance in high-spatial-resolution satellite data fusion. In addition, there have also been some studies considering the use of multi-source data fusion to explore the best fusion method for different data, such as Ren et al. [ 34 ], who conducted a comprehensive evaluation study on the fusion results of GF-5 HS data with three MS data (namely GF-1, GF-2 and Sentinel-2A), and the results showed that LANARAS, Adaptive Gram-Schmidt (GSA), and modulation transfer function (MTF)-generalized Laplacian pyramid (GLP) methods were more suitable for fusing GF-5 with GF-1 data, while MTF-GLP and GSA methods were recommended for fusing GF-5 with GF-2 data, and GSA and smoothing filtered-based intensity modulation (SFIM) could be used to fuse GF-5 with S2A data. Ghimire et al. [ 35 ] also created an optimal image fusion and quality evaluation strategy for various satellite image data (GF-1, GF-2, GF-4, Landsat-8 OLI, and MODIS). The preceding studies point us in the right direction for data fusion. It can be found that different fusion methods have different fusion performance when applied to remote sensing data. This disparity can be attributed to the characteristics of remote sensing data as well as the fusion method. As a result, in practice, it is critical to select the appropriate fusion method according to the image characteristics and application purpose [ 36 ]. Given the short launch time of the ZY-1 02D satellite, there are currently few related research and results regarding image fusion of ZY-1 02D data. Because the fusion methods suitable for existing satellite data are not necessarily suitable for the ZY-1 02D, it is critical to investigate its suitable fusion methods, and this is of great significance for future application and research using ZY-1 02D data. Furthermore, when compared to multi-source remote sensing data, ZY-1 02D provides HS and MS data under the same imaging conditions, reducing the uncertainty caused by input data. The fusion results of ZY-1 02D will have more application value. For these reasons, we will look into image fusion on ZY-1 02D HS and ZY-1 02D MS data. There are numerous fusion methods available for us to use in this research [ 37 , 38 , 39 , 40 , 41 , 42 ], but many of them are not user-friendly in terms of operability, computing resource requirements, and professional requirements. Taking into account the needs of users in practical applications, the focus of this research is to identify suitable methods for ZY-1 02D data among the existing well-known methods. The objective of this paper is to find appropriate methods for fusing ZY-1 02D HS and ZY-1 02D MS data from among some well-known methods. To meet the main objective, we test six common image fusion methods (i.e., GS, HPF, IHS, Wavelet, NND, and Brovey) and use a comprehensive evaluation framework to evaluate their performance, including aspects of their visual interpretation and quantitative metrics. This study will serve as a reference for the choice of fusion methods for the ZY-1 02D data, thereby further broadening its application in a variety of fields. 2. Materials and Methods 2.1. ZY-1 02D Data At 11:26 a.m. on 12 September 2019, the ZY-1 02D satellite was launched into the planned orbit by a Long March-4B carrier rocket from the Taiyuan Satellite Launch Center in China’s Shanxi Province. It is currently in a solar synchronous orbit 778 km above the earth, with a five-year expected lifespan. The two sensors on board enable it to effectively acquire 8-band MS data with a width of 115 km and 166-band HS data with a width of 60 km. Specifically, the spatial resolution of the MS data is 10 m, the HS data is 30 m, and the spectral resolution of the HS reaches 10 nm and 20 nm in the visible-near infrared (VIS-NIR) and short-wave infrared (SWI) ranges. The main parameters of the ZY-1 02D HS and MS sensors are shown in Table 1 . Figure 1 shows the spectral response function of MS sensor. Figure 1. Spectral response function of multispectral sensor. Table 1. Parameters of ZY-1 02D hyperspectral and multispectral sensors. For the experiment, the ZY-1 02D HS image and MS image covering Anxin County, Baoding City, Hebei Province, China were used ( Figure 2 ). They were collected on 7 October 2020. There are several common surface types in the area, mainly artificial buildings, farmland, vegetation, and water. Figure 2. Location of study area. ( a ) hyperspectral image; ( b ) multispectral image. 2.2. Data Preprocessing The preprocessing of the data was divided into two sections: (1) MS data preprocessing, and (2) HS data preprocessing. MS data preprocessing included image mosaicking, image clipping and image registration. First, the two MS images were mosaicked into one image, and then the part that overlapped with the HS image was clipped out (the size of the clipped image was 7670 × 8291 pixels). Then, the automatic registration tool in ENVI (i.e., Image Registration Workflow) was used to register it with the HS image (RMS Error: 0.31), and the processed MS image was used as input data for the fusion experiment. HS data preprocessing included radiometric calibration, atmospheric correction, and band extraction. Radiation calibration was used to covert the gray value (digital number, DN) into top of atmosphere (TOA) reflectance. FLAASH model was used for atmospheric correction. The atmospheric model was set to mid-latitude summer, and the aerosol model parameters were set to city. Since the spectral range of the HS image (396~2501 nm) was wider than that of the MS (452–1047 nm), a subset of the data spanning the range 452~1047 nm was extracted from the HS data, and the bands were grouped to match specific MS bands ( Table 2 ), and the processed HS image was used as the input data of the fusion experiment. All of the preceding procedures were carried out using the ENVI 5.3 software. Table 2. Correspondence between the eight MS bands and seventy-five HS bands. 2.3. Fusion Method In this experiment, six commonly used fusion methods were compared, namely GS, HPF, NND, IHS, Wavelet, and Brovey. The methodological flowchart is shown in Figure 3 . In the fusion experiment, 8 MS bands and their corresponding 75 HS bands (as shown in Table 2 ) were input into different algorithms, respectively. Figure 3. Methodological flowchart of the research. GS: Gram-Schmidt; HPF: High-Pass Filter; NND: Nearest-Neighbor Diffusion; IHS: Intensity-Hue-Saturation; Wavelet: Wavelet Transform; Brovey: Color Normalized Sharping. 2.3.1. Gram-Schmidt (GS) GS transform can remove redundant information by converting an HS image to orthogonal space. The transformed components are orthogonal in the orthogonal space, and the degree of information retention varies little between them. Compared with PCA transform, this method avoids the problem of information over-concentration [ 43 , 44 ]. Its advantage is that the process is simple, there are no restrictions on the number of input bands, and the spectral information of the original low-spatial-resolution image can be well preserved. During the experiment, the HS data was input as a low-resolution image, and the MS data were input as a high-resolution image (the following methods also used the same setting). The resampling method was set to nearest neighbor. This method was implemented in ENVI 5.3. 2.3.2. High-Pass Filter (HPF) The HPF fusion method extracts structural detail information from the high-spatial-resolution image using a high-pass filter operator and then superimposes the detail information on the low-spatial-resolution image to achieve a combination of the two [ 45 ]. The advantages of this method include a simple algorithm, a small amount of calculation, and no limit on the number of input bands. The keral size and weighting factor were set to 5 × 5 and the minimum value, respectively, while the other parameters remained unchanged. This method was implemented in ERDAS IMAGINE 2014. 2.3.3. Nearest-Neighbor Diffusion (NND) NND was proposed by the Rochester Institute of Technology (RIT) in the United States, which uses the Nearest-Neighbor Diffusion pan-sharpening algorithm for fusion [ 21 ]. The principle is to first perform down-sampling processing on the high-spatial-resolution image to make the spatial resolution consistent with the low-spatial-resolution image data; then, the spectral band contribution vector is calculated via linear regression, obtaining the nearest super-pixel difference factor of each pixel in the original high-spatial-resolution image; and finally, the linear mixed model is used to obtain the fused image. It is characterized by fast operation speed and high spectral fidelity. This method was implemented in ENVI 5.3. 2.3.4. Modified Intensity-Hue-Saturation (IHS) IHS is a color representation system that employs intensity, hue, and saturation. When using this method for image fusion, it is primarily divided into the following three steps: (1) Resampling the low-spatial-resolution image to match the spatial resolution of the high-spatial-resolution image, then converting it from RGB space to IHS space; (2) histogram matching the high-resolution image and the I component of the low-resolution image, then replacing the I component of the low-resolution image with the new luminance component; (3) inverse transformation of the above result and its restoration to RGB space. This method has been widely used because of its high spatial detail enhancement capabilities. Compared with the traditional IHS, modified IHS overcomes the limitation of three input bands by fusing multi-band data via multiple iterations. In the B03 band, for an example, a combination of 13-14-15 and 16-17-18 is used for two iterations of fusion to produce a fused result of 13-18. The resampling method was set to nearest neighbor, and the ratio celling was set to 2.0. Because there is no ZY-1 02D in the sensor options, the band information (including center wavelength, wavelength, etc.) was customized according to the provided data file. This method was implemented in ERDAS IMAGINE 2014. 2.3.5. Wavelet Transform (Wavelet) Wavelet transform is a spatial signal decomposition and reconstruction fusion technology. Its basic principle is to perform wavelet forward transformation on a low-spatial-resolution image and a high-resolution image to obtain high-frequency information from the high-resolution image and low-frequency information from the low-resolution image, respectively, and then generate a fused image using inverse wavelet transformation [ 46 ]. The spectral transform and resampling method were set to single band and nearest neighbor, respectively. This method was implemented in ERDAS IMAGINE 2014. 2.3.6. Color Normalized Sharping (Brovey) The Brovey fusion method first normalizes the high-spectral-resolution data, before multiplying it by the high-spatial-resolution image to obtain the fusion result. Each band in the RGB image is multiplied by the ratio of the high-resolution data to the RGB data, and the RGB image is then resampled to the high-resolution pixel size. The resampling method was set to nearest neighbor. This method was implemented in ERDAS IMAGINE 2014. 2.4. Quality Evaluation Methods We evaluate the quality of fusion results using two criteria: qualitative evaluation (i.e., visual interpretation) and quantitative evaluation (i.e., statistical metrics). 2.4.1. Qualitative Evaluation Visual interpretation is the method used in qualitative evaluation, and it refers to the observer’s subjective evaluation of the fusion result with respect to both the overall effect and the local effect via visual perception. Qualitative evaluation has become an indispensable part of the quality evaluation of remote sensing fusion images due to its quick and simple advantages. 2.4.2. Quantitative Evaluation The use of various remote sensing image statistical metrics to evaluate the quality of the fusion results is referred to as quantitative evaluation. The advantages and disadvantages of various fusion methods can be discovered through statistics and analysis of the aforementioned metrics. In this experiment, five statistical metrics (i.e., mean, standard deviation, entropy, mean gradient, and correlation coefficient) were selected to quantitatively evaluate the fused results from the four aspects of brightness, clarity, information content, and spectral fidelity ( Figure 4 ). The calculations of the five metrics are performed as follows. Figure 4. Structure of the fused image quality evaluation system. The gray mean value is primarily used to describe the average brightness of the image. When the gray mean value of the fused image is close to that of the original multispectral image, it indicates that the fusion effect is good. It is defined as Mean = 1 M × N ∑ i = 1 M ∑ j = 1 N I ( i , j ) (1) where M and N are the total number of rows and columns of the image, i and j are the pixel positions, I ( i , j ) indicates the gray value of the pixel located in the i -th row and j -th column of the image. The standard deviation is frequently used to describe the uniformity of image grayscale. The larger the standard deviation, the more dispersed the grayscale distribution of the image and the higher the image contrast. It is defined as Std = 1 M × N ∑ i = 0 M − 1 ∑ j = 0 N − 1 ( I ( i , j ) − I ) 2 (2) where I represents the gray mean value of the image. The entropy is an important indicator for measuring the richness of image information because it reflects the average information content in the image. It is defined as Entropy = − ∑ P ( x i ) log ( 2 , p ( x i ) ) (3) where x i represents the random variable, and P ( x i ) is the output probability function. The mean gradient refers to the obvious difference in the gray scale near the border or both sides of the shadow line of the image, indicating that the gray scale change rate is high, and the magnitude of this change rate can be used to express the clarity of the image. It can sensitively reflect the rate at which the image expresses the contrast of small details and characterize the relative clarity and texture of the image. The larger the mean gradient, the clearer the image is. It is defined as G = 1 ( M − 1 ) ( N − 1 ) ∑ i = 1 M ∑ j = 1 N ( ( ∂ Z ( x i , y j ) ∂ x i ) 2 + ( ∂ Z ( x i , y j ) ∂ y j ) 2 ) 2 (4) where ∂ Z ( x i , y j ) ∂ x i represents the gradient in the horizontal direction, and ∂ Z ( x i , y j ) ∂ y j represents the gradient in the vertical direction. The correlation coefficient indicates how similar the images were before and after fusion. A high correlation coefficient indicates that the fused image is close to the original image and has good spectral fidelity. It is defined as C = ∑ i = 1 M ∑ j = 1 N [ R ( i , j ) − F ˉ R ] [ F ( i , j ) − F ˉ ] ∑ i = 1 M ∑ j = 1 N [ R ( i , j ) − F ˉ R ] 2 ∑ i = 1 M ∑ j = 1 N [ F ( i , j ) − F ˉ ] 2 (5) In addition to the statistical metrics listed above, the spectral curve of typical ground objects can also be used to evaluate the quality of the fusion results [ 47 ]. In this experiment, the spectral curves of typical ground objects (vegetation, water, and artificial building) are extracted, and a comparison is drawn between the original HS image and the fused image, respectively, to quantify the benefits and drawbacks of the fusion methods. 3. Results 3.1. Qualitative Evaluation Figure 5 shows false-color images of the original HS image, the six fused results (R: 954 nm; G: 765 nm; B: 482 nm), and the original MS image (R: B09; G: B08; B: B02). There are some color differences between different fused images and the original HS image from the perspective of the entire image, but they all retain the main spectral characteristics of the original HS image. The colors of the HPF and Wavelet images are the closest to the original HS image, and the tone of the two is lighter than that of the original HS image, with almost no difference between the HPF and the Wavelet images. When compared to the original HS image, the color of the NND and GS images is more orange, and the contrast between adjacent objects in the two is not as clear, indicating that the NND and GS fusion methods perform worse than the above two methods. The IHS image and the original HS image have a distinct spectral difference, which is reflected in the darker tone of the IHS image as well as the spectral distortion phenomenon. Nevertheless, IHS images possess clarity. The color deviation between the Brovey image and the original HS image is the greatest, indicating that the Brovey image has significant spectral distortion. Figure 5. Experimental results of ZY-1 02D hyperspectral and multispectral data fusion. ( a ) ZY-1 02D hyperspectral image; ( b ) Brovey image; ( c ) GS image; ( d ) HPF image; ( e ) ZY-1 02D multispectral image; ( f ) IHS image; ( g ) NND image; ( h ) Wavelet image. To further evaluate the visual interpretation effect of the fused images, especially the enhancement effect of the spatial details, Figure 6 and Figure 7 show the detail of several typical ground objects, namely artificial buildings, farmland, vegetation and water. Figure 6. The details of farmland and artificial buildings. ( a ) ZY-1 02D original hyperspectral image; ( b ) GS image; ( c ) HPF image; ( d ) IHS image; ( e ) NND image; ( f ) Wavelet image; ( g ) Brovey image. Figure 7. The details of vegetation and water.( a ) ZY-1 02D original hyperspectral image; ( b ) GS image; ( c ) HPF image; ( d ) IHS image; ( e ) NND image; ( f ) Wavelet image; ( g ) Brovey image. When the edge and texture differences between the original HS image and fused image are compared, it can be found that, with the exception of the Wavelet image, the clarity of the other five fused images is higher than that of the original HS image, indicating that the above five fusion methods are able to improve the spatial resolution of the original HS image, thereby improving the accuracy and reliability of the visual interpretation. The IHS image has the best clarity and good spatial sharpening effect. The boundaries between building, road, and farmland are the clearest, and the outlines of vegetation and artificial fences in the water are the most visible, indicating that the IHS fusion method improves the spatial details of the original image the most. Unfortunately, the IHS image contains some spectral distortions, resulting in significant color differences between the IHS image and the original HS image. HPF and GS fusion methods are second only to IHS in terms of spatial detail enhancement. Specifically, the contours of aquatic vegetation are more visible in the HPF fused image, and the details of some buildings and farmland features are blurred. The detailed spatial information of the Brovey fused image is slightly lost, which is reflected in the fact that the artificial fence edge in the water is difficult to identify, and its spectral distortion is more pronounced. The spatial resolutions of the NND and Wavelet fused images are low, and the visual interpretation effect is not optimal. Between them, the Wavelet image has the closest color match to the original HS image, but the effect of its spatial detail representation is poor, and there are some obvious distortions and unclear texture features in the buildings. 3.2. Quantitative Evaluation 3.2.1. Statistical Metrics Considering a large number of HS bands, eight HS bands are quantitatively accounted for this experiment, corresponding to the center wavelength positions of the eight MS bands. Table 3 shows the mean, standard deviation, entropy, mean gradient, and correlation coefficient of the original HS image and six fused images. Table 3. Quantitative evaluation statistics metrics. By comparing the statistical metric values of the six fused images in Table 3 with the original HS image, the following five results can be obtained. (1) The HPF and GS fused images (gray mean value of the HPF image: 101~160; GS: 96~154) had high brightness similarity with the original HS image (100~155); the NND image (103~147) and Wavelet image (99~166) were second to them; the IHS image (73~131) had some spectral distortion when compared to the original HS image; the mean value of the Brovey image (29~49) was much lower than that of the original HS image, the mean value between the two had the largest deviation, and the spectral distortion of the Brovey image was the most significant. (2) The standard deviations of HPF, IHS and GS fused images were relatively large. Among them, the HPF image had the largest standard deviation in the visible light (standard deviation of the HPF fused image: 23~27), and the IHS image had the biggest standard deviations in the near-infrared and red edge bands (IHS image: 22~24), and the standard deviations of the three fused images were higher than the original HS image, greatly improving the information richness of the original HS image; the standard deviations of the NND and Wavelet images were slightly lower than those of the above three fused images. The standard deviation of the Wavelet image (16~21) was slightly higher than that of the NND (12~22); the standard deviation of the Brovey image (6~8) was much lower than that of the original image, indicating that the gray level of the fused image after Brovey transformation was not sufficiently dispersed and the tone tended to be single. (3) Except for the Brovey image, the entropy of the other five fused images was improved when compared to the original HS image, and there was no significant difference in the entropy of different fusion images (5–7). Among them, the entropy of the Wavelet image was the highest, followed by the HPF and GS images. The information content of the three was nearly identical, with the exception of the IHS, which was slightly lower; the information content of Brovey fusion images was lower than that of the original HS images. (4) The mean gradient of the fused image was higher than that of the original HS image, indicating that the six fusion methods were able to improve the original image’s ability to represent spatial details. The mean gradients of HPF and IHS fused images were larger, and their spatial detail information enhancement effects were the best, as shown in Table 3 . Between them, the mean gradient of HPF image was more visible in the visible light band (mean gradient of HPF fusion image: 47~61). The IHS fusion image outperformed the other two fusion methods in the red edge and near-infrared bands (55~57); the mean gradient of GS and Brovey fused images were slightly lower than the above two fused images. Between them, the mean gradient of Brovey image (43~57) was slightly higher than GS image (41~58); the mean gradient of NND and Wavelet fused was the lowest, indicating that the spatial resolution of these two fused images was low. (5) Similar to the visual interpretation result, the correlation coefficients of Wavelet, HPF and NND were relatively large, indicating that they have excellent spectral fidelity performance. Except for the red band, the correlation coefficients of Wavelet and HPF fused images were all greater than 0.9; the correlation coefficient between the IHS fusion image and the original image was second only to HPF and Wavelet, but it performed poorly in the blue and red bands; and the Brovey fused image had the lowest correlation coefficient, indicating that there was a large spectral difference between it and the original HS image. To summarize, the HPF image not only preserved the spectral characteristics of the original HS image to a large extent, but also improved the spatial resolution of the HS data, making it the best choice for ZY-1 02D HS data enhancement; although Wavelet and NND fused images had a large amount of information and a high spectral fidelity, the spatial detail representation effect of the two was not satisfactory; the IHS fused image was clear and rich in texture information, but there was obvious spectral distortion; the performance of the GS fusion image was at a medium level; the Brovey transform had a mediocre performance in spectral fidelity and spatial detail representation, and had a serious spectral distortion problem, making it far inferior to the above five methods. 3.2.2. The Spectral Curves of Typical Ground Objects To more intuitively evaluate the spectral fidelity of the different fused images, this experiment takes typical objects (i.e., vegetation, artificial building, and water) as examples to compare the differences between the six fused results and the original HS image. To ensure that the results are representative, the spectral curves of the three objects are averaged over three homogeneous areas with 5 × 5 pixels. As shown in Figure 8 , the left column is the three spectral curves of six fused images and HS image. In addition, the spectral differences between the six fused images and the original HS image are also shown (the right column of Figure 8 ), which is convenient for identifying the differences in the spectral fidelity of the different fusion methods. Figure 8. Spectral curves of typical objects. Top: vegetation spectral curves of six fused images and HS image ( a ), difference between fused images and HS image in vegetation spectral curve ( d ); Middle: artificial building spectral curves of six fused images and HS image ( b ), difference between fused images and HS image in building spectral curve ( e ); Bottom: water spectral curves of six fused images and HS image ( c ), difference between fused images and HS image in water spectral curve ( f ). By comparing the spectral curves of different fused images and the original HS image, we can obtain similar results to those presented above. Overall, the HPF, Wavelet, NND and GS fused images possessed high spectral fidelity; while the IHS and Brovey fused images exhibited significant spectral distortion. The spectral curves of the fused images have roughly the same trend as the original HS image and fluctuate around the original HS spectral curve with slight variations. In the spectral curves of vegetation, the difference between the Wavelet and HPF fused image and the original HS image was the smallest, indicating that the two fusion methods had the best spectral fidelity. Between them, the Wavelet fused image was more prominent in the visible light band, while the HPF fused image was more prominent in the visible light and near-infrared (NIR) bands; the spectral fidelity of the NND and GS fused images were second, with a lager difference between their spectral curves. In the spectral curves of the building, the Wavelet fused image had a higher degree of overlap and a smaller difference with the original HS image; the spectral curves of HPF and GS fused images basically fitted the original HS image after about 510 nm; and the performance of NND was quite different in the NIR band (approximately 765 nm). The curve in the second half of the spectral curve was very similar to that of the original HS image, whereas the curve in the first half was quite different from the gray value of the original HS image. This result is consistent with the color deviation of the building in the visual interpretation effect. In the spectral curves of water, the NND and the original HS image were highly overlapped; the difference between Wavelet and GS was slightly larger; the change trend of the HPF fused image was the same as the original image, but compared to the above fused methods, there was a larger difference between HPF and the original HS, which is slightly different from the high correlation coefficient obtained for the HPF method in the metric statistical results. This may have been caused by the small amount of water in the entire image. Similar to the visual interpretation results, the IHS and Brovey fused images were significantly different from the original HS image with respect to the spectral curves of the three ground objects. There were obvious spectral distortions in the two fused images, particularly the Brovey image, which had the lowest spectral fidelity. In conclusion, the HPF, Wavelet, NND, and GS fusion methods performed well, and different fusion methods performed differently when confronted with different ground objects. HPF and Wavelet had the best spectral fidelity in the vegetation and building areas, respectively, while NND had the best spectral fidelity in the water area. It can be found that the HPF, Wavelet, NND and GS fusion methods have good performance, and different fusion methods have different performance when facing different ground objects. Specifically, HPF and Wavelet have the best spectral fidelity in vegetation and building areas, and NND has the best spectral fidelity in the water area. 4. Discussion 4.1. Performance of Fusion Methods In this paper, six well-known fusion methods were successfully used to enhance the spatial resolution and the information of ZY-1 02D data. Compared to the original HS data, the six fused images were clearer and easier to visually interpret. Furthermore, there were also some noticeable differences among the six fused results. HPF, in particular, demonstrated excellent performance with respect to both spectral fidelity and spatial resolution enhancement. The reason for this could be that the HPF injects the spatial details of the MS data into the HS data via a high-pass filter and has a low-pass filter to maintain the spectral separation of HS data. This result was also discovered in the fusion experiment of Mapping Satellite-1 by Huang et al. [ 30 ]. The difference is that the research object of this study is HS data with high spectral resolution, which are better suited to narrow-band spectroscopy research. Aside from HPF, Wavelet and NND exhibited high robustness in terms of spectral fidelity. Between them, the spatial resolution of the Wavelet fused image was slightly lower, and the boundary between different features was not significant, but it was always clearer than the original HS data. As concluded by Sun et al. [ 31 ] and Du et al. [ 32 ], GS performs well when applied to remote sensing data. On the contrary, the spectral fidelity performances of IHS and Brovey were slightly inferior, and there is still room for improvement in spatial resolution [ 48 , 49 ]. The spectral distortion of IHS is mainly caused by the forced direct replacement of the I component [ 50 ], whereas the spectral distortion of Brovey was affected by the simple multiplication of HS and MS [ 25 ]. It is worth noting that these two methods are simple in terms of theory, simple to implement, and quick to calculate, and so can be used for some low-demand applications. 4.2. Selection of Quantitative Metrics The quality evaluation of the fused results in remote sensing data fusion research is too complicated to establish a unified standard. Until now, it has been performed using a combination of visual interpretation and quantitative metrics [ 51 ]. As a result, we used the same method to evaluate the quality of six fused images. The five quantitative metrics selected for this paper adhered to three principles: (1) they were able to evaluate the quality of fused images with respect to different aspects (typically spatial resolution enhancement capability and spectral fidelity); (2) they were able to distinguish the performance differences of the six fusion methods; and (3) they were simple and easy to calculate. The comparison results also demonstrate the applicability of the five metrics. In addition to the common metrics listed above, many researchers have attempted to supplement the quality evaluation system by improving or proposing new metrics [ 52 , 53 , 54 ]. There is still a long way to go before we establish a unified evaluation standard. In practical applications, appropriate quantitative metrics should be selected based on geographic conditions, application requirements, and data sources. 4.3. Limitations The study was carried out on a single date in a single study area with four typical surface types; it would be preferable if different study areas with more surface types in different periods were used [ 55 ]. Because the spectral range of the HS image is wider than that of the MS, this study only performed fusion processing on the HS data in the 452~1047 nm range. In subsequent research, we will fully exploit the advantages of the wide spectral range to investigate suitable fusion methods for shortwave of infrared band, as well as extending the practical application of ZY-1 02D data. In reality, the primary purpose of data fusion is to prepare for remote sensing image applications such as image classification [ 56 ], change detection [ 57 ], and so on. As a result, more research into the application of fused images is required in the future to obtain better results and conclusions. 5. Conclusions Six fusion methods, GS, HPF, IHS, NND, Wavelet, and Brovey, were used in this paper to realize the fusion of ZY-1 02D HS data and MS data. The six fusion results were compared and analyzed using a combination of qualitative and quantitative evaluation methods, and the following conclusions were drawn: (1) Considering the three aspects of visual effect, spectral fidelity, and spatial detail expression, the HPF method was the most suitable for the fusion of ZY-1 02D HS data and MS data. In comparison to the original HS image, the HPF fused image maintained its spectral characteristics while improving its spatial resolution, enriching its information, and providing the best fusion performance. (2) Different fusion methods perform differently for different datasets. In practice, appropriate data fusion methods should be selected according to the data type and specific needs. Six commonly used fusion methods were used in this study for fusion processing of ZY-1 02D satellite HS and MS images, providing a significant reference for future ZY-1 02D data processing and application-related research. Author Contributions H.L., D.Q. and L.D. designed and developed the research idea. H.L., D.Q. and S.W. conducted the field data collection. H.L., D.Q., Y.L. and S.W. processed all remaining data. H.L. and D.Q. performed the data analysis and wrote the manuscript. H.L., D.Q., Y.L., S.W. and L.D. contributed to result and data interpretation, discussion, and revision of the manuscript. All authors have read and agreed to the published version of the manuscript. Funding This research was funded by the landscape plant maintenance monitoring and intelligent diagnosis model development of Capital Normal University (no. 21220030003). Acknowledgments The authors are very thankful for Zou Hanyue, Fan Tianxing and Chen Yong for their valuable support. Conflicts of Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. References Zhang, L.; Shen, H. Progress and future of remote sensing data fusion. J. Remote Sens. 2016 , 20 , 1050–1061. [ Google Scholar ] Xie, Q.; Zhou, M.; Zhao, Q.; Meng, D.; Zuo, W.; Xu, Z. Multispectral and Hyperspectral Image Fusion by MS/HS Fusion Net. In Proceedings of the 2019 IEEE/CVF Conference on Computer Vision and Pattern Recognition (CVPR), Long Beach, CA, USA, 15–20 June 2019; pp. 1585–1594. [ Google Scholar ] Ma, Y.; Zhang, Y.; Mei, X.; Dai, X.; Ma, J. Multifeature-Based Discriminative Label Consistent K-SVD for Hyperspectral Image Classification. IEEE J. Stars. 2019 , 12 , 4995–5008. [ Google Scholar ] [ CrossRef ] Qu, Y.; Qi, H.; Ayhan, B.; Kwan, C.; Kidd, R. DOES multispectral/hyperspectral pansharpening improve the performance of anomaly detection? In Proceedings of the 2017 IEEE International Geoscience and Remote Sensing Symposium (IGARSS), Fort Worth, TX, USA, 23–28 July 2017; pp. 6130–6133. [ Google Scholar ] Li, W.; Wu, G.; Zhang, F.; Du, Q. Hyperspectral Image Classification Using Deep Pixel-Pair Features. IEEE Trans. Geosci. Remote Sens. 2017 , 55 , 844–853. [ Google Scholar ] [ CrossRef ] Ferraris, V.; Dobigeon, N.; Qi, W.; Chabert, M. Robust Fusion of Multi-Band Images with Different Spatial and Spectral Resolutions for Change Detection. IEEE Trans. Comput. Imaging 2017 , 3 , 175–186. [ Google Scholar ] [ CrossRef ][ Green Version ] Gómez-Chova, L.; Tuia, D.; Moser, G.; Camps-Valls, G. Multimodal classification of remote sensing images: A review and future directions. Proc. IEEE 2015 , 103 , 1560–1584. [ Google Scholar ] [ CrossRef ] Fauvel, M.; Tarabalka, Y.; Benediktsson, J.A.; Chanussot, J.; Tilton, J.C. Advances in Spectral-Spatial Classification of Hyperspectral Images. Proc. IEEE 2013 , 101 , 652–675. [ Google Scholar ] [ CrossRef ][ Green Version ] Ghassemian, H. A review of remote sensing image fusion methods. Inf. Fusion 2016 , 32 , 75–89. [ Google Scholar ] [ CrossRef ] Pandit, V.R.; Bhiwani, R.J. Image Fusion in Remote Sensing Applications: A Review. Int. J. Comput. Appl. 2015 , 120 , 22–32. [ Google Scholar ] Huang, B.; Zhao, Y. Research Status and Prospect of Spatiotemporal Fusion of Multi-source Satellite Remote Sensing Imagery. Acta Geod. Cartogr. Sin. 2017 , 46 , 1492–1499. [ Google Scholar ] Wang, H.; Peng, J.; Wu, W. Remote Sensing Image Fusion Using Wavelet Packet Transform. J. Image Graph. 2002 , 9 , 68–73. [ Google Scholar ] Zhou, F.; Hang, R.; Liu, Q.; Yuan, X. Pyramid Fully Convolutional Network for Hyperspectral and Multispectral Image Fusion. IEEE J. Sel. Top. Appl. Earth Obs. Remote. Sens. 2019 , 12 , 1–10. [ Google Scholar ] [ CrossRef ] Yokoya, N.; Grohnfeldt, C.; Chanussot, J. Hyperspectral and Multispectral Data Fusion: A comparative review of the recent literature. IEEE Geosci. Remote Sens. Mag. 2017 , 5 , 29–56. [ Google Scholar ] [ CrossRef ] Shao, Y.; Zhu, C.; Zhang, X.; Shen, Q. Comparison of diffirent fusion methods and their performance evaluation to high spatial resolution remote sensing data of GF. Bulletin Surv. Mapp. 2019 , 5 , 5–10. [ Google Scholar ] Wang, G.; Li, Y.; Zeng, Y.; Jin, L. Comparison and analysis is of pixel level image fusion algorithms application to ALOS data. Sci. Surv. Mapp. 2008 , 33 , 121–124. [ Google Scholar ] Kaczynski, R.; Donnay, J.P.; Muller, F. Satellite image maps of Warsaw in the scale 1:25,000. Earsel Adv. Remote Sens. 1995 , 4 , 100–103. [ Google Scholar ] Aiazzi, B.; Baronti, S.; Selva, M. Improving Component Substitution Pansharpening Through Multivariate Regression of MS +Pan Data. IEEE Trans. Geosci. Remote Sens. 2007 , 45 , 3230–3239. [ Google Scholar ] [ CrossRef ] Tu, T.; Huang, P.S.; Hung, C.; Chang, C. A fast intensity-hue-saturation fusion technique with spectral adjustment for IKONOS imagery. IEEE Geosci. Remote Sens. 2004 , 1 , 309–312. [ Google Scholar ] [ CrossRef ] Metwalli, M.R.; Nasr, A.H.; Allah, O.S.F.; El-Rabaie, S. Image fusion based on principal component analysis and high-pass filter. In Proceedings of the 2009 International Conference on Computer Engineering & Systems, Cairo, Egypt, 14–16 December 2009; pp. 63–70. [ Google Scholar ] Sun, W.; Chen, B.; Messinger, D.W. Nearest-neighbor diffusion-based pan-sharpening algorithm for spectral images. Opt. Eng. 2013 , 53 , 13107. [ Google Scholar ] [ CrossRef ][ Green Version ] Zhou, J.; Civco, D.L.; Silander, J.A. A wavelet transform method to merge Landsat TM and SPOT panchromatic data. Int. J. Remote Sens. 1998 , 19 , 743–757. [ Google Scholar ] [ CrossRef ] Shah, V.P.; Younan, N.H.; King, R.L. An Efficient Pan-Sharpening Method via a Combined Adaptive PCA Approach and Contourlets. IEEE Trans. Geosci. Remote 2008 , 46 , 1323–1335. [ Google Scholar ] [ CrossRef ] Klonus, S.; Ehlers, M. Image Fusion Using the Ehlers Spectral Characteristics Preserving Algorithm. GISci. Remote Sens. 2007 , 44 , 93–116. [ Google Scholar ] [ CrossRef ] Tu, T.; Lee, Y.C.; Chang, C.P.; Huang, P.S. Adjustable intensity-hue-saturation and Brovey transform fusion technique for IKONOS/QuickBird imagery. Opt. Eng. 2005 , 44 , 116201. [ Google Scholar ] [ CrossRef ][ Green Version ] Zeng, Y.; Huang, W.; Liu, M.; Zhang, H.; Zou, B. Fusion of satellite images in urban area: Assessing the quality of resulting images. In Proceedings of the 2010 18th International Conference on Geoinformatics, Beijing, China, 18–20 June 2010; pp. 1–4. [ Google Scholar ] Teo, T.; Fu, Y. Spatiotemporal Fusion of Formosat-2 and Landsat-8 Satellite Images: A Comparison of “Super Resolution-Then-Blend” and “Blend-Then-Super Resolution” Approaches. Remote Sens. 2021 , 13 , 606. [ Google Scholar ] [ CrossRef ] Amarsaikhan, D.; Saandar, M.; Ganzorig, M.; Blotevogel, H.H.; Egshiglen, E.; Gantuyal, R.; Nergui, B.; Enkhjargal, D. Comparison of multisource image fusion methods and land cover classification. Int. J. Remote Sens. 2012 , 33 , 2532–2550. [ Google Scholar ] [ CrossRef ] Karathanassi, V.; Kolokousis, P.; Ioannidou, S. A comparison study on fusion methods using evaluation indicators. Int. J. Remote Sens. 2007 , 28 , 2309–2341. [ Google Scholar ] [ CrossRef ] Huang, H.; Feng, Y.; Zhang, M.; Li, M. Research on Fusion of Mapping Satellite-1 Imagery and Its Evaluation. Bulletin Surv. Mapp. 2013 , 430 , 6–9. [ Google Scholar ] Sun, P.; Dong, Y.; Chen, W.; Ma, J.; Zou, Y.; Wang, J.; Chen, H. Research on fusion of GF-2 imagery and quality evaluation. Remote Sens. Land Resour. 2016 , 28 , 108–113. [ Google Scholar ] Du, Y.; Zhang, X.; Mao, Z.; Chen, J. Performances of conventional fusion methods evaluated for inland water body observation using GF-1 image. Acta Oceanol. Sin. 2019 , 38 , 172–179. [ Google Scholar ] [ CrossRef ] Huang, X.; Wen, D.; Xie, J.; Zhang, L. Quality Assessment of Panchromatic and Multispectral Image Fusion for the ZY-3 Satellite: From an Information Extraction Perspective. IEEE Geosci. Remote Sens. 2014 , 11 , 753–757. [ Google Scholar ] [ CrossRef ] Ren, K.; Sun, W.; Meng, X.; Yang, G.; Du, Q. Fusing China GF-5 Hyperspectral Data with GF-1, GF-2 and Sentinel-2A Multispectral Data: Which Methods Should Be Used? Remote Sens. 2020 , 12 , 882. [ Google Scholar ] [ CrossRef ][ Green Version ] Ghimire, P.; Lei, D.; Juan, N. Effect of Image Fusion on Vegetation Index Quality—A Comparative Study from Gaofen-1, Gaofen-2, Gaofen-4, Landsat-8 OLI and MODIS Imagery. Remote Sens. 2020 , 12 , 1550. [ Google Scholar ] [ CrossRef ] Li, L.; She, M.; Luo, H. Comparison on fusion algorithms of ZY-3 panchromatic and multi-spectral images. Trans. Chin. Soc. Agric. Eng. 2014 , 30 , 157–165. [ Google Scholar ] Liu, Z.; Zheng, Y.; Han, X. Unsupervised Multispectral and Hyperspectral Image Fusion with Deep Spatial and Spectral Priors ; Springer International Publishing: Cham, Switzerland, 2021; Volume 12628, pp. 31–45. [ Google Scholar ] Dian, R.; Li, S.; Kang, X. Regularizing Hyperspectral and Multispectral Image Fusion by CNN Denoiser. IEEE Trans. Neural Netw. Learn. Syst. 2021 , 32 , 1124–1135. [ Google Scholar ] [ CrossRef ] Shao, Z.; Cai, J. Remote Sensing Image Fusion With Deep Convolutional Neural Network. IEEE J. Sel. Top. Appl. Earth Obs. Remote Sens. 2018 , 11 , 1656–1669. [ Google Scholar ] [ CrossRef ] Kwan, C.; Choi, J.H.; Chan, S.; Jin, Z.; Budavari, B. Resolution enhancement for hyperspectral images: A super-resolution and fusion approach. In Proceedings of the ICASSP 2017–2017 IEEE International Conference on Acoustics, Speech and Signal, New Orleans, LA, USA, 5–9 March 2017; pp. 6180–6184. [ Google Scholar ] Loncan, L.; de Almeida, L.B.; Bioucas-Dias, J.M.; Briottet, X.; Chanussot, J.; Dobigeon, N.; Fabre, S.; Liao, W.; Licciardi, G.A.; Simoes, M.; et al. Hyperspectral Pansharpening: A Review. IEEE Geosci. Remote Sens. Mag. 2015 , 3 , 27–46. [ Google Scholar ] [ CrossRef ][ Green Version ] Lillo Saavedra, M.; Gonzalo, C. Spectral or spatial quality for fused satellite imagery? A trade-off solution using the waveletà trous algorithm. Int. J. Remote Sens. 2007 , 27 , 1453–1464. [ Google Scholar ] [ CrossRef ] Jelének, J.; Kopačková, V.; Koucká, L.; Mišurec, J. Testing a Modified PCA-Based Sharpening Approach for Image Fusion. Remote Sens. 2016 , 8 , 794. [ Google Scholar ] [ CrossRef ][ Green Version ] Laben, C.A.; Brower, B.V. Process for Enhancing the Spatial Resolution of Multispectral Imagery Using Pan-Sharpening. U.S. Patent 6,011,875, 4 January 2000. [ Google Scholar ] Schowengerdt, R.A. Reconstruction of multispatial, multispectral image data using spatial frequency content. Photogramm. Eng. Rem. Sens. 1980 , 46 , 1325–1334. [ Google Scholar ] Nunez, J.; Otazu, X.; Fors, O.; Prades, A.; Pala, V.; Arbiol, R. Multiresolution-based image fusion with additive wavelet decomposition. IEEE Trans. Geosci. Remote 1999 , 37 , 1204–1211. [ Google Scholar ] [ CrossRef ][ Green Version ] Chen, Y.; Sun, K.; Bai, T.; Peng, Y. Quality assessment on image fusion methods for GF-2 data. Sci. Surv. Mapp. 2017 , 42 , 35–40. [ Google Scholar ] Choi, M. A new intensity-hue-saturation fusion approach to image fusion with a tradeoff parameter. IEEE Trans. Geosci. Remote Sens. 2006 , 44 , 1672–1682. [ Google Scholar ] [ CrossRef ][ Green Version ] Zhou, H.; Shuang, W.U.; Mao, D.; Wang, A.; Bingyang, Y.U. Improved Brovey method for multi-sensor image fusion. J. Remote Sens. 2012 , 16 , 343–360. [ Google Scholar ] El-Mezouar, M.C.; Taleb, N.; Kpalma, K.; Ronsin, J. An IHS-Based Fusion for Color Distortion Reduction and Vegetation Enhancement in IKONOS Imagery. IEEE Trans. Geosci. Remote Sens. 2011 , 49 , 1590–1602. [ Google Scholar ] [ CrossRef ] Pei, W.; Wang, G.; Yu, X. Performance evaluation of different references based image fusion quality metrics for quality assessment of remote sensing Image fusion. Geosci. Remote Sens. Symp. 2012 , 2280–2283. [ Google Scholar ] [ CrossRef ] Sengupta, A.; Seal, A.; Panigrahy, C.; Krejcar, O.; Yazidi, A. Edge Information Based Image Fusion Metrics Using Fractional Order Differentiation and Sigmoidal Functions. IEEE Access 2020 , 8 , 88385–88398. [ Google Scholar ] [ CrossRef ] Rodriguez-Esparragon, D.; Marcello, J.; Eugenio, F.; Garcia-Pedrero, A.; Gonzalo-Martin, C. Object-based quality evaluation procedure for fused remote sensing imagery. Neurocomputing 2017 , 255 , 40–51. [ Google Scholar ] [ CrossRef ] Rodríguez-Esparragón, D. Evaluation of the performance of spatial assessments of pansharpened images. Geosci. Remote Sens. Symp. 2014 , 1619–1622. [ Google Scholar ] [ CrossRef ] Lu, H.; Fan, T.; Ghimire, P.; Deng, L. Experimental Evaluation and Consistency Comparison of UAV Multispectral Minisensors. Remote Sens. 2020 , 12 , 2542. [ Google Scholar ] [ CrossRef ] Seal, A.; Garcia-Pedrero, A.; Bhattacharjee, D.; Nasipuri, M.; Gonzalo-Martin, C. Multi-scale RoIs selection for classifying multi-spectral images. Multidimens. Syst. Sign. Process 2020 , 31 , 745–769. [ Google Scholar ] [ CrossRef ] Wang, B.; Jaewan, C.; Seokeun, C.; Soungki, L.; Wu, P.; Yan, G. Image Fusion-Based Land Cover Change Detection Using Multi-Temporal High-Resolution Satellite Images. Remote Sens. 2017 , 9 , 804. [ Google Scholar ] [ CrossRef ][ Green Version ] Figure 1. Spectral response function of multispectral sensor. Figure 2. Location of study area. ( a ) hyperspectral image; ( b ) multispectral image. Figure 3. Methodological flowchart of the research. GS: Gram-Schmidt; HPF: High-Pass Filter; NND: Nearest-Neighbor Diffusion; IHS: Intensity-Hue-Saturation; Wavelet: Wavelet Transform; Brovey: Color Normalized Sharping. Figure 4. Structure of the fused image quality evaluation system. Figure 5. Experimental results of ZY-1 02D hyperspectral and multispectral data fusion. ( a ) ZY-1 02D hyperspectral image; ( b ) Brovey image; ( c ) GS image; ( d ) HPF image; ( e ) ZY-1 02D multispectral image; ( f ) IHS image; ( g ) NND image; ( h ) Wavelet image. Figure 6. The details of farmland and artificial buildings. ( a ) ZY-1 02D original hyperspectral image; ( b ) GS image; ( c ) HPF image; ( d ) IHS image; ( e ) NND image; ( f ) Wavelet image; ( g ) Brovey image. Figure 7. The details of vegetation and water.( a ) ZY-1 02D original hyperspectral image; ( b ) GS image; ( c ) HPF image; ( d ) IHS image; ( e ) NND image; ( f ) Wavelet image; ( g ) Brovey image. Figure 8. Spectral curves of typical objects. Top: vegetation spectral curves of six fused images and HS image ( a ), difference between fused images and HS image in vegetation spectral curve ( d ); Middle: artificial building spectral curves of six fused images and HS image ( b ), difference between fused images and HS image in building spectral curve ( e ); Bottom: water spectral curves of six fused images and HS image ( c ), difference between fused images and HS image in water spectral curve ( f ). Table 1. Parameters of ZY-1 02D hyperspectral and multispectral sensors. Sensors Bands Spectral Range/nm Spatial Resolution/m Spectral Resolution/nm Swath Width/km MS B02 452~521 10 115 B03 522~607 B04 635~694 B05 776~895 B06 416~452 B07 591~633 B08 708~752 B09 871~1047 HS VIS-NIR 396~1039 30 10 60 SWI 1056~2501 20 Table 2. Correspondence between the eight MS bands and seventy-five HS bands. Spectral Range/nm Bands of MS (HS) 452~521 B02 (4~12) 522~607 B03 (13~18) 635~694 B04 (22~33) 776~895 B05 (40~55) 416~452 B06 (1~3) 591~633 B07 (19~21) 708~752 B08 (34~39) 871~1047 B09 (56~75) Table 3. Quantitative evaluation statistics metrics. Number of Bands (Wavelength) Fusion Method Mean Standard Deviation Entropy Mean Gradient Correlation Coefficient B02 (48 nm) Original HS 100.3648 12.7672 6.0404 26.8851 1.0000 GS 96.9338 19.6723 6.1241 47.8024 0.9027 HPF 103.5575 24.3926 6.0896 54.4626 0.9448 IHS 73.1858 24.1157 5.2708 49.4911 0.8613 NND 103.8201 14.2127 6.0183 29.0472 0.9237 Wavelet 102.7105 18.2765 6.1112 38.4877 0.9711 Brovey 29.6865 6.3760 4.9725 46.1580 0.7841 B03 (56 nm) Original HS 109.7536 14.0712 6.0792 30.4275 1.0000 GS 108.7666 21.017 6.0606 54.8879 0.8979 HPF 113.8481 25.3081 6.1309 58.9571 0.9479 IHS 104.0233 22.5063 6.0326 52.4368 0.8986 NND 111.2329 15.7797 6.0458 32.9132 0.9501 Wavelet 112.7678 19.1729 6.1322 41.9692 0.9682 Brovey 33.6375 6.7881 5.037 51.8042 0.7923 B04 (66 nm) Original HS 105.6488 15.0996 6.1017 32.1022 1.0000 GS 103.7238 22.5502 6.1283 55.0825 0.8966 HPF 108.9427 26.6834 6.1284 60.8555 0.9426 IHS 104.1239 23.5609 6.0404 54.7468 0.8995 NND 108.6382 16.4924 6.0502 33.9025 0.9411 Wavelet 111.4921 20.2655 6.1502 44.3468 0.9664 Brovey 32.2769 7.2767 5.0268 53.6661 0.7904 B05 (83 nm) Original HS 148.1834 10.9544 5.7649 24.2174 1.0000 GS 147.7579 17.8605 5.9226 56.4583 0.9281 HPF 148.4721 19.7851 6.0258 49.2987 0.9095 IHS 129.5685 23.5102 5.8911 56.8161 0.9252 NND 138.3355 14.0712 5.8797 30.2696 0.9403 Wavelet 156.0215 16.0169 5.8548 34.2237 0.9813 Brovey 48.5566 5.9984 4.9162 47.4623 0.8193 B06 (43 nm) Original HS 98.2831 11.9164 6.0626 25.3595 1.0000 GS 104.1284 15.3213 6.1055 41.8993 0.8887 HPF 101.6062 24.5561 6.0715 55.1704 0.9341 IHS 79.5842 22.2562 5.6839 44.5485 0.8834 NND 115.3039 19.2873 6.0474 45.6413 0.8802 Wavelet 99.2973 17.6968 6.0998 37.4642 0.9696 Brovey 33.4879 5.6296 5.0001 43.9359 0.7811 B07 (61 nm) Original HS 107.9341 14.5122 6.0967 31.1587 1.0000 GS 105.9264 22.2558 6.1283 54.5936 0.8972 HPF 110.5961 26.2106 6.1309 60.1416 0.9442 IHS 104.6792 22.3629 6.0433 55.7009 0.8985 NND 109.8163 15.9687 6.0527 33.1166 0.9502 Wavelet 112.5107 20.2215 6.1508 44.2971 0.9688 Brovey 32.2255 7.2689 5.0279 53.6364 0.8894 B08 (76 nm) Original HS 147.6844 11.2318 5.7661 24.9981 1.0000 GS 147.2125 17.7753 5.9252 57.0881 0.9289 HPF 139.327 21.3667 6.0161 53.9328 0.8806 IHS 116.0493 22.1731 6.0229 55.1546 0.6981 NND 127.7334 21.6202 5.9381 56.6921 0.8184 Wavelet 134.6255 20.4686 6.0776 45.9071 0.8207 Brovey 48.9651 6.0844 4.9028 56.1831 0.8106 B09 (95 nm) Original HS 154.8327 9.9505 5.7401 22.1483 1.0000 GS 153.1369 18.2631 5.8793 51.5527 0.9529 HPF 159.3981 18.0164 6.0258 47.0832 0.9775 IHS 130.1481 22.2889 5.8911 55.1831 0.9226 NND 146.2381 12.7801 5.8583 27.7978 0.9461 Wavelet 159.3499 15.8887 5.8548 36.2066 0.9832 Brovey 48.0108 6.1852 4.8995 46.1493 0.8071 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Lu, H.; Qiao, D.; Li, Y.; Wu, S.; Deng, L. Fusion of China ZY-1 02D Hyperspectral Data and Multispectral Data: Which Methods Should Be Used? Remote Sens. 2021, 13, 2354. https://doi.org/10.3390/rs13122354 Lu H, Qiao D, Li Y, Wu S, Deng L. Fusion of China ZY-1 02D Hyperspectral Data and Multispectral Data: Which Methods Should Be Used? Remote Sensing. 2021; 13(12):2354. https://doi.org/10.3390/rs13122354 Lu, Han, Danyu Qiao, Yongxin Li, Shuang Wu, and Lei Deng. 2021. "Fusion of China ZY-1 02D Hyperspectral Data and Multispectral Data: Which Methods Should Be Used?" Remote Sensing13, no. 12: 2354. https://doi.org/10.3390/rs13122354 Article Metrics
https://www.mdpi.com/2072-4292/13/12/2354/html
Pictures of parabolic dunes (a) and transverse dunes (b) at the Grande... | Download Scientific Diagram Download scientific diagram | Pictures of parabolic dunes (a) and transverse dunes (b) at the Grande beach, São Francisco do Sul Island. The recognition of large blowouts on parabolic dunes is easily appreciable, as is the difference in vegetation cover between the two dune types. from publication: Morpho-sedimentological and vegetational characterization of Grande beach at São Francisco do Sul Island (Santa Catarina, Brazil) | A multidisciplinary study based on several digital (geology, lithology, shoreline evolution, photo-interpretation of aerial and ortho-photographs) and field (topographic and vegetational surveys, grain-size analysis) datasets prompted new insights to a better definition of... | Beach, Islands and Vegetation | ResearchGate, the professional network for scientists. Pictures of parabolic dunes (a) and transverse dunes (b) at the Grande beach, São Francisco do Sul Island. The recognition of large blowouts on parabolic dunes is easily appreciable, as is the difference in vegetation cover between the two dune types. Source publication Morpho-sedimentological and vegetational characterization of Grande beach at São Francisco do Sul Island (Santa Catarina, Brazil) A multidisciplinary study based on several digital (geology, lithology, shoreline evolution, photo-interpretation of aerial and ortho-photographs) and field (topographic and vegetational surveys, grain-size analysis) datasets prompted new insights to a better definition of the processes in action at the Grande beach at São Francisco do Sul Island (... Contexts in source publication Context 1 ... width of the Grande beach, which averages about 20 m, is quite constant throughout the entire length of the beach. The beach is subjected to erosion processes that at times produced the destruction of the frontal dune and the generation of a steep scarp at the transition between the backshore and the dunes. The erosion is uniform throughout the length of the beach; no particular accumulation or retreat areas are detectable. The littoral drift is northwards trending (Zular, 2011). Parabolic dunes up to 15 m high characterize the northern sector of the Grande beach (Zone A). They are well developed, but wide blowouts interrupt their regularity ( Figure 2 (a)). In addition, human interference is significant in this por- tion of the beach. In the central sector of the beach (Zone B), the dunes are transverse. They are character- ized by lower height (hardly over 7 m) and less human impact, likely due to their major distance from the vil- lages ( Figure 2 (b)). Close to Praia do Ervino village, human interference increases ... Context 2 ... width of the Grande beach, which averages about 20 m, is quite constant throughout the entire length of the beach. The beach is subjected to erosion processes that at times produced the destruction of the frontal dune and the generation of a steep scarp at the transition between the backshore and the dunes. The erosion is uniform throughout the length of the beach; no particular accumulation or retreat areas are detectable. The littoral drift is northwards trending (Zular, 2011). Parabolic dunes up to 15 m high characterize the northern sector of the Grande beach (Zone A). They are well developed, but wide blowouts interrupt their regularity ( Figure 2 (a)). In addition, human interference is significant in this por- tion of the beach. In the central sector of the beach (Zone B), the dunes are transverse. They are character- ized by lower height (hardly over 7 m) and less human impact, likely due to their major distance from the vil- lages ( Figure 2 (b)). Close to Praia do Ervino village, human interference increases ... Full-text available May 2019 Youn Kyung Song Jens Figlus Patricia Chardon-Maldonado JACK A. PULEO Influences of Beach Replenishment on Seawall Engineering Article Full-text available May 2020 Kaiwen Huang Shaoyi Zheng Citations ... Epiphytic bromeliads and parasitic Loranthaceae and Viscaceae also prevail (Ziffer-Berger, 2008). The beach dune environments contain succulent plants with creeping roots, such as Hydrocotyle (Apiaceae) and Ipomoea (Covolvulaceae) (Alquini et al., 2018) . ... Poleward mangrove expansion in South America coincides with MCA and CWP: A diatom, pollen, and organic geochemistry study QUATERNARY SCI REV Erika Rodrigues Marcelo Cancela Lisboa Cohen Carlos R Pessenda Qiang Yao The projected warming trend in the 21st century is likely to alter the global distribution of mangroves. However, the migratory pattern of different mangrove species is still unclear, especially in the subtropical Brazilian littoral. This study utilizes pollen, diatom, and organic geochemistry to document the late Holocene morphological and ecological transformation in São Francisco do Sul Bay, the mangrove sub-range limit in south Brazil. This multi-proxy dataset indicates the establishment of saltmarshes and mangroves on muddy tidal flats at~1720 and~870 cal yr BP, and Laguncularia, Avicennia, and Rhizophora colonized the study area at~870,~390, and~70 cal yr BP, respectively. This stepwise succession of three mangrove species in São Francisco do Sul Bay, and poleward mangrove expansion toward the austral mangrove range limit, indicate that the migratory histories of different mangrove species were not synchronized during the late Holocene, and temperature is the primary climatic factor regulating the mangrove distribution in south Brazil. More importantly, the Medieval Climate Anomaly and the Current Warm Period were clearly registered in the pollen record, suggesting that the two climate anomalies likely facilitated the mangroves colonization into higher latitudes in south Brazil. Overall, our dataset indicates that mangrove expansion into more temperate zones will likely accelerate in South America. ... Nevertheless, CVIs are limited in effectiveness if they are not contextualized within thematic maps of coastal areas. Geological, and particularly morphodynamic and litho-sedimentological, maps constitute complementary tools to give a full meaning and efficacy to CVIs (Alquini, Bertoni, Sarti, Vieira, & Melo Júnior, 2018) . These approaches are tightly intertwined, and development of accurate maps is needed to represent the first order of data to design and integrate the CVI approach. ... ... These maps act as a grounding database that can be progressively integrated and revised as new data and observations are acquired. As already pointed out in the scientific literature, maps are of great support for coastal management as they provide the chance to visualize in single documents many aspects related to the morphodynamic processes acting on the coast (Alquini et al., 2018; De Muro, Pusceddu, Buosi, & Ibba, 2017;Sabato, Longhitano, Gioia, Cilumbriello, & Spalluto, 2012). Recent approaches to coastal management that emphasize multidisciplinarity (e.g. ... Litho-sedimentological and morphodynamic characterization of the Pisa Province coastal area (northern Tuscany, Italy) Full-text available Dec 2019 J MAPS Duccio Bertoni Serena Giacomelli Lorenzo Ciulli Giovanni Sarti In this paper litho-sedimentological and morphodynamic maps of the coastal sector belonging to the Pisa Province are presented as an example of how increasing the accessibility to data on lithology, sedimentology, and morphodynamics may lead to a better approach to coastal management. The database used to build the maps includes an original rendering of remote sensing data (aerial imagery) and new field data (geologic survey), as well as data retrieved from the scientific literature (grain-size and past coastline positions). The maps show that the geometry of beach ridges is an indication of the evolution of the Arno River delta in the last 3000 years, highlighting the relationships between geological aspects and morphodynamic features. The maps represent the synthesis of different data available in the database, and they may be a useful support to coastal management as they are more easily understandable and straightforward than the database from which are created. ... The complexity of this environment justifies the worldwide concern about the rising sea level in the coming decades, which will intensify the impact of coastal erosion and flooding on coastal communities (Rao et al., 2008;USAID, 2009;Özyurt and Ergin, 2010;IPCC, 2014;Germani et al., 2015;Alsahli and Alhasem, 2016). Brazil is one example of the detrimental effects of the erosion process, and has been struggling to manage the effects all along its coasts (Mazzer, 2007;Mazzer and Dillenburg, 2009;Figueiredo, 2013;Ribeiro et al., 2013;Lima and Amaral, 2015; Alquini et al., 2018) . In Brazil, 50.7 million people occupy coastal areas or areas near the coast (IBGE, 2011). ... Implementing a coastal dune vulnerability index (CDVI) to support coastal management in different settings (Brazil and Italy) Article OCEAN COAST MANAGE Duccio Bertoni Giovanni Sarti Fernanda Alquini Daniela Ciccarelli In this paper, the vulnerability of two dune fields located in southern Brazil (São Francisco do Sul Island) and western Italy (Tuscany) has been defined through the implementation of a Coastal Dune Vulnerability Index (CDVI). As the sites belonged to settings characterized by huge differences in terms of physical processes (Atlantic Ocean and Mediterranean Sea), the index has been adapted accordingly to minimize the influence of the dissimilarities in an attempt to define potential vulnerability parameters they might have in common. Five main groups of factors were taken into account in the design of the index: Geomorphological Condition of the Dune system (GCD), Marine Influence (MI), Aeolian Effect (AE), Vegetation Condition (VC), and Human Effect (HE) for a total of 51 variables. A total vulnerability index was calculated for each site. Cluster analysis and non-metric multidimensional scaling identified two main groups characterized by medium values of vulnerability (0.32-0.49): as a result, the vulnerability of both sites can be defined as "medium". In more detail, GCD turned out to be the most influent factor on both settings; subordinately, marine influence also resulted relevant on the Oceanic site. The CDVI proved to be a flexible tool, as it was easily adjusted to work on such different sites. In this sense it will be of great support to increase the awareness of coastal managers and decision makers about the mutual interactions of many factors and processes that contribute to the evolution of coastal dunes regardless of the geographical setting. ... Several multi-thematic coastal maps have been developed over the last few years as reliable tools to support decision-makers in making better choices with respect to the development of sustainable beach management plans (e.g. Alquini, Bertoni, Sarti, Vieira, & Melo Júnior, 2018; Sabato, Longhitano, Gioia, Cilumbriello, & Spalluto, 2012). These maps can support critical planning decisions like potential land use, the vulnerability to beach erosion and the identification of areas designated for protection/conservation. ... Geomorphology, beach classification and seasonal morphodynamic transition of a Mediterranean gravel beach (Sardinia, Gulf of Cagliari) Article Full-text available Mar 2019 J MAPS Carla Buosi Angelo Ibba Marinella Passarella Marco Porta Sandro De Muro This paper presents an innovative multi-thematic map (1:2500) that integrates morpho-sedimentological data, hydrodynamic processes, seasonal morphodynamic transitions and the distribution of the benthic habitat of a Mediterranean microtidal, wave-dominated gravel beach system. It is part of a larger cartography of coastal areas, and is based on an interdisciplinary sea-land approach that is applicable worldwide and aims to facilitate coastal management practices and future scientific research. The applications to coastal management include: the facilitation of coastal vulnerability assessments; easy-to-access, up-to-date digital geospatial data; and baseline studies for the future assessment and monitoring of environmental changes. The main environmental features that control the marine processes of this gravel beach appear to be linked to geological and morphological contexts such as the presence of the river mouth, the outcropping of a beach-rock along the coastline, the deposition of gravelly sediment in the beachface and the seagrass cover. Palaeoenvironmental reconstruction through phytolith analysis in the Casa de Pedra shell mound archaeological site, São Francisco do Sul, Santa Catarina, Brazil Article Full-text available Nov 2022 VEG HIST ARCHAEOBOT David Oldack Barcelos Ferreira Machado Heloisa Helena Gomes Coe Dione Da Rocha Bandeira Rosa Souza Júlio César De Sá Shell mounds, or middens, are artificial accumulations of food remains such as shells, sediments, artefacts and remains from daily life and funerary rituals, which were deposited in our study area by groups of Sambaquian fisher-hunter-gatherers. These mounds contain remains, which are representative of the fauna and flora at the time they were formed, enabling the recovery of palaeoenvironmental data related to biodiversity of taxa and biogeography, 14C dating and analysis of changes in the patterns of marine biodiversity and ocean circulation. This paper uses the Casa de Pedra shell mound rock shelter, located in São Francisco do Sul, state of Santa Catarina, southeastern Brazil, to study aspects of the palaeoenvironment through analyses of the archaeological material of the site, which contains well-preserved phytoliths and sponge spicules. Among the phytoliths, those from grasses predominate and some trees and palms were present, with no variation in vegetation type during the period of site occupation, between 5,470 and 4,460 years bp. Despite the general stability of the vegetation, a small increase in the density of the tree cover was identified from the base to the top, which may be related to an increase in precipitation, and is in agreement with other palaeoenvironmental studies carried out in southern Brazil. Get access to 30 million figures
https://www.researchgate.net/figure/Pictures-of-parabolic-dunes-a-and-transverse-dunes-b-at-the-Grande-beach-Sao_fig1_323369135
(PDF) Pyrolysis temperature during biochar production alters its subsequent utilization by microorganisms in an acid arable soil PDF | Biochar amendment of agricultural soils can have a significant impact on microbial carbon (C) metabolism by providing C substrates and altering... | Find, read and cite all the research you need on ResearchGate Pyrolysis temperature during biochar production alters its subsequent utilization by microorganisms in an acid arable soil December 2017 Land Degradation and Development29(7) DOI: 10.1002/ldr.2846 Authors: <here is a image 8803396064767379-503d5972e156d9f2> Yu Luo Zhejiang University <here is a image a16004bec8f403ca-9426a3434be6d484> Jennifer Dungait University of Exeter <here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Xiaorong Zhao China Agricultural University <here is a image c8477ea08d4ff0f5-abe0a1c0933ac387> Philip Brookes Institute of soil and water resourcesand Environmental Sciences Abstract and Figures Biochar amendment of agricultural soils can have a significant impact on microbial carbon (C) metabolism by providing C substrates and altering soil properties, including amelioration of soil acidity. It remains unclear whether available C of biochar or its pH effects determines the utilization of biochar by microorganisms. Compound-specific stable 13C isotope analysis of phospholipid fatty acids (13C-phospholipid fatty acid analysis) was used to explore which microbial group utilized biochar distinguished with pHs and C availability. C4 Miscanthus biochar (δ13C = −12.2‰) was prepared at 2 pyrolysis temperatures (350 °C and 700 °C) and applied (50 mg C g−1 soil) to a very acid soil (pH 3.7, δ13C = −27.7‰), which was sampled from the long term Hoosfield Acid Strip experiment at Rothamsted Research, and incubated for 14 months. Biochar700 increased soil pH to 5.1 and biochar350 increased soil pH to 4.3. All microbial groups (Gram-positive bacteria, Gram-negative bacteria, actinobacteria, and fungi) were more abundant in the biochar-treated soils. The 13C values of biomarker phospholipid fatty acid analysis suggested that all groups of microorganisms, and especially Gram-positive bacteria, were using the C from the biochar350, but not the biochar700, as a substrate. We conclude that its utilization of biochar by microorganisms after 14 months was largely determined by the pyrolysis temperature controlling the availability of biochar C, instead of the pH effects, in a very acidic soil. <here is a image 474a0f5663cebbab-259330c2795b5510> Mean contents (μg C g −1 soil; n = 3, ±1 SE) of biomarker phospholipid fatty acid analysis (PLFA; Gram-positive bacteria, Gramnegative bacteria, actinobacteria, and fungi) in low pH soils treated with BC350, BC700 or no biochar (control) after 431 days. Error bars represent standard errors of the means (n = 3). Different letters indicate significant difference at p < .05 between treatments (control, BC350 and BC700) … <here is a image 737c627fa5705af9-342662906a0f0dd6> The incorporation (a) of labelled biochar 13 C into biomarker phospholipid fatty acid analysis (Gram-positive bacteria, Gramnegative bacteria, actinobacteria, and fungi) and mean δ 13 C values (b) in low pH soils treated with BC350, BC700 or no biochar (control) after 431 days. Error bars represent standard errors of the means (n = 3). Different letters indicate significant difference at p < .05 between treatments (BC350 and BC700) … <here is a image 93ac0e49392a487d-f34f4ffc03ff5e0e> Microbial colonization and its utilization of biochar350 and biochar700. Colonization images were obtained from Luo et al. (2013) [Colour figure can be viewed at wileyonlinelibrary.com] … <here is a image e89aad44535b4495-ea856a1ea4f19c9a> Figures - uploaded by Yu Luo SPECIAL ISSUE ARTICLE Pyrolysis temperature during biochar production alters its subsequent utilization by microorganisms in an acid arable soil substrates, such as sucrose and plant straw (Luo, Lin, Durenkamp, Dungait, & Brookes, 2017; Luo, Zang, et al., 2017). The preparation (pyrolysis) temperature of biochar is a major factor for determining its organic chemistry: biochars produced at higher pyrolysis temper- atures have significantly increased pH values (Xu, Zhao, Yuan, & Jiang, 2012) and more condensed polyaromatic structures, compared to biochars produced at lower temperatures that are more likely to retain labile fractions available fo r subsequent microbial utilization after application to soils, but wi th reduced pH effects on the func- tioning of microorganisms in acidic soils. The question is, which fac- tor, pH effects or available C determines its microbial utilization of biochar in a highly acidic soil? The combined effects of C ‐ availability and pH amelioration have not been explored explicitly in the same experiment. A shift of the primary effect of biochar on soil microbial processes from providing C (short term) to pH effects (relatively long term) might occur when the small fraction of labile biochar ‐ Cis depleted and becomes barely bioavailable in the late stage of incubation. Direct evidence of the microbial utilization of biochar have been proven using 14 C and 13 C labelled biochar ‐ C to investigate routing of biochar C into the microbial biomass C (Kuzyakov et al., 2009) and microbial phospholipid fatty acid analyses (PLFAs; Steinbass et al., 2009). Relatively short ‐ term incubations and pot experiments (up to 175 days) have been conducted to examine the fate of 13 C ‐ labelled biochar ‐ C made from contrasting plant ‐ derived feedstocks using 13 C ‐ PLFA analyses to investigate the functional groups of soil microorganisms utilising biochar ‐ C as a substrate (Farrell et al., 2013; Watzinger et al., 2014). Gram ‐ negative bacteria, (Watzinger et al., 2014), Gram ‐ positive bacteria and fungal PLFAs (Farrell et al., 2013) were observed to incorporate biochar ‐ C. The difference in the activity of different microbial groups between studies corresponds to biochar preparation and incubation time (early or late stage). Biochars pro- duced at lower temperatures have less condensed structures and are more likely to retain labile fractions available for microbial utilization by r ‐ strategists typified by Gram ‐ negative bacteria directly after appli- cation to soils, whereas biochar produced at high temperatures is more likely to be utilized by spore ‐ forming, K ‐ strategists. However, these studies were relatively short term (less than 3 months), and whether soil microbial groups utilize biochar C in the relatively long term (above 1 year) remains unclear. Our hypothesis was that the microbial utilization of biochar in a very acid arable soil was largely de termined by the pyrolysis temper- ature that controls both the availability of biochar ‐ CanditspH,and the biochar ‐ C availability will be overwhelmed by its pH effects in the late stage of above 1 year. Thus, we used the same C4 feedstock (Miscanthus grass) to produce biochar350 and biochar700at two temperatures (350 °C and 700 °C), which gave biochars with differ- ent pH (7.8 and 10.8, respectively). Biochar350 and biochar700 were applied (50 mg C g − 1 soil) to a very acid C3 soil (pH 3.7) from the Hoosfield Acid Strip experim ent at Rothamsted Research. The difference in the 13 C values of the biochar (C4) and SOC (C3) enabled the use of biochar ‐ C by soil microorganisms to be identified. We chose a long incubation (14 months) to explore the response of the soil microbial biomass to the combined effect of pH and biochar C availability. 2 | MATERIALS AND METHODS 2.1 | Soil sampling Full details of soil sampling, preparation, and chemical properties are given in Luo, Durenkamp, De Nobili, Lin, and Brookes (2011). In brief, soil of pH 3.7 was sampled (0 – 23 cm, plough layer depth) with a Dutch auger from the Hoosfield acid strip at Rothamsted Research, UK. The soil samples were hand ‐ picked to remove visible plant debris and roots, sieved at field moisture (<2 mm) and subsequently adjusted to 40% of water holding capacity. The soils were then preincubated at 25 °C for 7 days before starting the experiments. The soil contained 0.90% total C and 0.1% total N, microbial biomass C (Cmic) was 62.9 μ gg − 1 , and the bulk δ 13 C value was − 27.7 ‰. 2.2 | Biochar production Full details of biochar preparation are given by Luo et al. (2011). In brief, two biochars were prepared from the same source material ( Miscanthus giganteus straw; δ 13 C= − 11.8 ‰ ) at two temperatures (350 °C and 700 °C) in a Carbolite CWF 1200 furnacewith a sealable retort (Carbolite, Hope, UK) flushed with argon. Hereafter, the two biochar treatments are referred to as biochar350 and biochar700, respectively. The total C of biochar350 and biochar700 were 65.5% and 83.9%, total N were 3.8% and 0.7%, respectively, and the corre- sponding δ 13 C values for biochar350 and biochar700 were − 12.0 ‰ and − 12.3 ‰ , and pH values were 7.8 and 10.8, respectively (Luo, Lin, et al., 2017). 2.3 | Soil incubation The preincubated soil were mixed with no biochar (control) or 50 mg Cg − 1 soil (on a soil dry weight basis) of either biochar350 or bio- char700 and incubated for 14 months (431 days) at 25 °C in the dark at 40% water holding capacity. NH 4 NO 3 (170 μ gNg − 1 soil) was added to avoid N limitation. After 431 days, the biochar350 ‐ and biochar700 ‐ treated soil both contained 5.29% total C and 0.12% total N and had a pH values of 4.3 and 5.1, respectively. Further properties are described in Luo, Lin et al. (2017). 2.4 | Compound ‐ specific stable isotope analysis of PLFAs A modified Bligh Dyer extraction procedure was applied for the extrac- tion of PLFA (Dungait et al., 2013). In brief, Bligh Dyer solvent (KH 2 PO 4 ‐ buffered H 2 O, pH 7.2 MeOH:CHCl 3 in 4:10:5 v:v:v) was used to liberate a total lipid extract from freeze ‐ dried soils. A normal pressure chromatography was used to separate the phospholipid frac- tion from the total lipid extract. The polar lipids were saponified (0.5 M methanolic NaOH; 1 hr, 80 °C) and acidified (1 M HCl), and the liber- ated PLFAs were methylated with acidified dry MeOH (1 hr; 80 °C). The PLFA were analysed as their methyl esters using gas chromatogra- phy – mass spectrometry (GC – MS; Rothamsted Research North Wyke, Okehampton, UK) and gas chromatography combustion isotope ratio mass spectrometry (GC/C/IRMS; James Hutton Institute, Aberdeen, Scotland). PLFA biomarkers were grouped as Gram ‐ positive bacteria 2 LUO ET AL. ( i 15:0, a15:0, i16:0, i17:0, a 17:0), Gram ‐ negative bacteria (16:1 ω5, 16:1 ω 7, 17:1 ω 8, cy17:0, 18:1 ω 7, cy19:0, 19:1), actinobacteria (10Me16:0, 10Me17:0, 10Me18:0), and fungi (18:2 ω 6; Zelles, 1999). 2.5 | Calculation of biochar ‐ 13 C incorporation into PLFAs The fractional abundance expresses the concentration of 13 C as a pro- portion of the total concentration of C in the PLFA using the equation described by Nold, Boschker, Pel, and Laanbroek (1999) F ¼ 13 C = 13 C þ 12 C   (1) The fractional abundance (F) of 13 C in the control (Fc) and enriched (Fe) PLFA were used to calculate the concentration of 13 C incorporated into PLFA from the total PLFA concentration, using the equation 13 C PLFA ¼ Fe −Fc ðÞ  PLFAs (2) The percentage of biochar ‐ 13 C incorporation into the various PLFAs groups was calculated according to Gunina, Dippold, Glaser, and Kuzyakov (2014) 13 C incorporation ¼13 C PLFA =13 C Applied  100 %(3) 2.6 |Statistics Data meeting assumptions of normality and equality of variances were analysed by analysis of variance. A 1 ‐ way analysis of variance was undertaken to determine the significance ( p < .05) of differences between the treatments of without, with biochar350and biochar700. Least significant difference was chosen for the comparisons between different treatments. Data were performed using GenStat software (13th edition). 3 | RESULTS Total PLFA content was more than doubled in the biochar ‐amended soils, but there was no significant difference between biochar350 and biochar700 (Figure 1). All groups of microorganisms identified by PLFA biomarkers were significantly more abundant in the biochar ‐ amended soils (Figure 1). All soils were dominated by Gram ‐positive bacteria, but the content of Gram ‐ negative bacteria, actinobacteria, and fungi biomarkers were increased in the biochar ‐ amended soils, with the largest increases of both groups in the biochar700 amended soils. The fungal to bacterial ratio (f:b) was significantly greater in the biochar ‐ treated soils (control = 0.06; biochar350 = 0.11; biochar700 = 0.18). The δ 13 C values of the biomarker PLFAs revealed significant incor- poration of 13 C from biochar350 into Gram ‐ positive bacteria, followed by actinobacteria, Gram ‐ negative bacteria, and fungi after 431 days (Figure 2). However, the total amount of the initial applied 13 Cof biochar700 incorporated to PLFA was very small (less than 0.01%) even though a substantial amount of biochar700 ‐ C was added (50 mg C g − 1 soil, equivalent roughly to 5 times of SOC). 4 | DISCUSSION Changes in the activity and community structure of the soil microbial biomass after biochar addition have been reported, e.g. Kolb, FIGURE 1 Mean contents ( μ gCg − 1 soil; n = 3, ±1 SE) of biomarker phospholipid fatty acid analysis (PLFA; Gram ‐ positive bacteria, Gram ‐ negative bacteria, actinobacteria, and fungi) in low pH soils treated with BC350, BC700 or no biochar (control) after 431 days. Error bars represent standard errors of the means ( n = 3). Different letters indicate significant difference at p < .05 between treatments (control, BC350 and BC700) FIGURE 2 The incorporation (a) of labelled biochar 13 C into biomarker phospholipid fatty acid analysis (Gram ‐ positive bacteria, Gram ‐ negative bacteria, actinobacteria, and fungi) and mean δ 13 C values (b) in low pH soils treated with BC350, BC700 or no biochar (control) after 431 days. Error bars represent standard errors of the means ( n = 3). Different letters indicate significant difference at p < .05 between treatments (BC350 and BC700) LUO ET AL . 3 Fermanich, and Dornbush (2009). Increased CO 2 emissions have been observed immediately after biochar addition but these diminished in days to weeks (Luo et al., 2011; Zimmerman, Gao, & Ahn, 2011) and were largely attributed to a small fraction of available C contained within the biochar (Smith, Collins, & Bailey, 2010). The soil microbial communities of the biochar ‐ treated soils, quantified as PLFA, were sig- nificantly larger than the control soil after 431 days (Figure 1). It has been suggested that, such as all particulate organic matter, the large surface area of biochar serves as an adsorption site for water, soluble carbon, and nutrients that is favourable for microbial colonisation (Pietikäinen et al., 2000; Saito et al., 2002), which was previously described as the ‘ Charsphere ’ (Luo et al., 2013). PLFA is used to sepa- rate out broad groups of soil microorganisms with different morphol- ogies that tend to have the same functional ecologies (Wixon & Balser, 2013). In this study, the content of Gram ‐ positive bacteria, Gram ‐ negative bacteria, actinobacteria, and fungi biomarkers increased in the biochar ‐ treated soils. The large f:b (Fungi:Bacterial) of the biochar ‐ treated soils indicates the importance of fungal coloni- sation of biochar to decompose the polyaromatic structure of biochar and to make it available to other microbial groups as a substrate, although its contents of PLFA was still limited. Gram ‐ positive bacteria were the largest group in the biochar ‐ treated and control soils, and the greatest relative increase was in the actinobacteria. Gram ‐ positive bac- teria and actinobacteria (that are a subgroup of Gram ‐ positive bacteria) are described as K ‐ strategists that are associated with slow and persis- tent growth on more resistant organic residues (Blagodataskaya et al., 2008; Dungait et al., 2011, 2013) that are typified by the characteris- tically condensed structure of biochars. Although the increase in the abundance of total and biomarker PLFA was similar in soils treated with biochar350 or biochar700, 13 C ‐ PLFA analysis revealed that all groups of microorganisms were only using biochar ‐ C as a substrate in the biochar350 treatment after 431 days (Figure 2a), suggesting that C from the biochar700 was less available for microbial utilization. This does not mean that no bio- char700 had been utilised, but maybe that it was below detection for the natural abundance 13 C labelling technique used herein. There was significant incorporation of biochar350 ‐ C into all PLFAs, especially within Gram ‐ positive bacteria (Figure 2a), although the most 13 C ‐ enriched values were determined in the Gram ‐ negative bacteria (Figure 2b). Farrell et al. (2013) also observed significant 13 C ‐ enrich- ments in Gram ‐ positive bacteria ( K ‐ strategists) after 3 days and fungal PLFAs in the latter stages of the incubations (up to 74 days) of biochars from different feedstocks. However, a short term ‐incubation experiment (up to 35 days) by Watzinger et al. (2014) showed a signif- icant 13 C ‐ enrichment of Gram ‐ negative bacteria ( r ‐ strategists). The overall % incorporation of applied 13 C into PLFA was very small, but similar to that previously observed (< 1% added 13 C as a range of sub- strates) by Dungait et al. (2011, 2013). Farrell et al. (2013) attributed the incorporation of biochar into PLFAs biomarker to direct uptake of biochar ‐ C, or from the turnover of microorganisms as Gram ‐positive bacteria continuously decompose biochar labile C or even recalcitrant C. This may suggest routing of biochar ‐ C into the microbial biomass had occurred, but that its provenance may have been the biochar350 itself, or a secondary metabolite of another organism within the soil food web that was using biochar350 after 14 months. However, this needs further research to clarify the microbial succession at different stages along incubation time. The effect of biochar pH effects on the incorporation of biochar ‐C remains unclear. Previous investigations of the soil microbial dynamics along the pH gradient of the Hoosfield acid strip experiment (the source of the very acid experimental soil) determined thatthe microbial community changed in composition because the soil organic carbon decreased as the pH declined (Rousk, Bååth, et al., 2010a; Rousk, Brookes, & Bååth, 2010), whereas concentrations of NH 4 + ─ N and extracted toxic elements (Al, Mn) tended to increase (Aciego Pietri & Brookes, 2008a, 2008b). Farrell et al. (2013) attributed the significant and rapid changes in the soil microbial community after biochar appli- cation to both addition of labile C and increased soil pH. In this lon- ger ‐ term study, the initial very acid soil pH (3.7) that was increased to 4.3 and 5.1 more than a year after the addition of biochar. These pH values are the rangeregularly measured in agricultural soils (e.g., http://esdac.jrc.ec.europa.eu/Library/Data/PH/Documents/pH_Pub. FIGURE 3 Microbial colonization and its utilization of biochar350 and biochar700. Colonization images were obtained from Luo et al. (2013) [Colour figure can be viewed at wileyonlinelibrary.com] 4 LUO ET AL. pdf). The incorporation of biochar350 ‐ C into all groups of PLFAs was greater than for biochar700 ‐ C after 431 days, suggesting that (a) its incorporation of biochar ‐ C into PLFA was governed by its chemical structure, thatis, biochars producedathigher temperatures have more condensed structures which are more recalcitrant,and (b) the pH effects of biochar was secondary to the available biochar ‐ Ccon- tent (Figure 3). Although less incorporation of biochar700 ‐ Cinto PLFAs, we found biochar700 increased total PLFAs with almost the same extend as biochar350 (Figure 1), which can be mainly attributed to more alkaline pH within biochar700 compared with biochar350. Moreover, the alkaline conditions imposed by biochar addition was suggested to be more favourable forGram ‐ positive bacteria than for Gram ‐ negative bacteria (Gul et al., 2015). This agreed with our finding that Gram ‐ positive bacteria dominated biochar ‐ C utilization (Figure 2), suggesting that biochar exert pH effects on microbial uti- lization within certain microbialgroups although a comparatively limited effect compared with its C availability effects. Overall, when considering the microbial utilization of biochar within PLFAs, it appeared that the content of available C in biochar after 14 months, which was dictated by the pyrolysis temperature in this study, was more important than its effects on soil pH (Figure 3). In the biochar350 amended soil, the microorganisms (Gram ‐ positive, actinobacteria, Gram ‐ negative bacteria, and Fungi) used labile biochar C and the activated microorganisms might further utilize SOC due tothe co ‐ metabolisms, causing soil priming effects (Figure 4). Biochar700 increased the total PLFAs via affecting soilpH (Figure 1), and the enhanced microorganisms (Gram ‐ positive, actinobacteria, Gram ‐ negative bacteria, and Fungi) by biochar700might utilize otherC sources, instead of recalcitrant biochar700 ‐ C, to maintain its growth. This was attributed to the preferential utilization of relatively labile C sources, also leading to the soil priming effects, but with relatively smaller scale (Figure 4). How- ever, the mechanisms (or hypothesis) need further research, adopting Iso- tope techniques and DNA/PLFA ‐SIP (Stable Isotope Probing), to clarify. 5 | CONCLUSION In conclusion, (a) the addition of biochars, regardless of produced tem- peratures, to very acidic soils caused an increase in the content of all PLFA; (b) biochar produced by pyrolysis at lower temperatures (biochar350) was more likely to be used as a substrate by all soil micro- organisms, especially Gram ‐ positive bacteria after 14 months; (c) the content of available C, rather than altering soil pH, is the mainmecha- nism determining the microbial utilization of biochar ‐ C in acidic soils; (d) biochar can be used for soil C sequestration as most of recalcitrant biochar C is resistant to microbial attack, even biochar induced higher microbial biomass and activity. ACKNOWLEDGEMENTS We thank J. Zhou for chemical analyses and A. Duffey for bulk stable isotope analyses. This study was supported by the National Science Foundation of China (41671233, 41520104001) and National Basic Research Program of China (2014CB441003). This work represents part of the BBSRC ‐ funded programme “ Soil to Nutrition ”(BB/ P01268X/1) at Rothamsted Research. ORCID Yu Luo http://orcid.org/0000-0002-3834-498X REFERENCES Aciego Pietri, J. C., & Brookes, P. C. (2008a). Relationships between soil pH and microbial properties in a UK arable soil. Soil Biology & Biochemistry, 40 , 1856 –1861. Aciego Pietri, J. C., & Brookes, P. C. (2008b). Nitrogen mineralisation along a pH gradient of a silty loam UK soil. Soil Biology & Biochemistry , 40, 797 –802. Blagodatskaya, Е ., & Kuzyakov, Y. (2008). Mechanisms of real and apparent priming effects and their dependence on soil microbial biomass and FIGURE 4 Conceptual graph of microbial phospholipid fatty acid analyses utilizing biochar and inducedsoil priming effects (refer to Luo et al., 2011), mediated by biochar C availability and its pH effects [Colour figure can be viewed at wileyonlinelibrary.com] LUO ET AL . 5 community structure: Critical review. Biology and Fertility of Soils , 45, 115 –131. Dungait, J. A. J., Kemmitt, S. J., Michallon, L., Guo, S., Wen, Q., Brookes, P. C., & Evershed, R. P. (2011). Variable responses of the soil microbial bio- mass to trace concentrations of 13 C ‐ labelled glucose, using 13 C ‐PLFA analysis. European Journal of Soil Science , 62 , 117 –126. Dungait, J. A. J., Kemmitt, S. J., Michallon, L., Guo, S., Wen, Q., Brookes, P. C., & Evershed, R. P. (2013). The variable response of soil microorganisms to trace concentrations of low molecular weight organic substrates of increasing complexity. Soil Biology & Biochemistry , 64 ,57 – 64. Farrell, M., Kuhn, T. K., Macdonald, L. M., Maddern, T. M., Murphy, D. V., Hall, P. A., … Baldock, J. A. (2013). Microbial utilisation of biochar ‐ derived carbon. Scienceofthe Total Environment , 465 , 288 –297. Frostegård, A., Bååth, E., & Tunlid, A. (1993). Shifts in the structure of soil microbial communities in limed forests as revealed by phospholipid fatty acid analysis. Soil Biology & Biochemistry , 25 , 723 –730. Gul, S., Whalen, J. K., Thomas, B. W., Sachdeva, V., Deng, H., (2015). Physico ‐ chemical properties and microbial responses in biochar- amended soils: Mechanisms and future directions. Agriculture Ecosystems & Environment , 206 ,46 – 59. Gunina, A., Dippold, M. A., Glaser, B., & Kuzyakov, Y. (2014). Fate of low molecular weight organic substances in an arable soil: From microbial uptake to utilisation and stabilisation. Soil Biology & Biochemistry , 77, 304 –313. Jeffery, S., Verheijen, F. G. A., van der Velde, M., & Bastos, A. C. (2011). A quantitative review of the effects of biochar application to soils on crop productivity using meta ‐ analysis. Agriculture, Ecosystems & Environment, 144 , 175 – 187. Kolb, S. E., Fermanich, K. J., & Dornbush, M. E. (2009). Effect of charcoal quantity on microbial biomass and activity in temperate soils. Soil Sci- ence Society of America Journal , 73 , 1173 –1181. Kuzyakov, Y., Subbotina, I., Chen, H., Bogomolova, I., & Xu, X. (2009). Black carbon decomposition and incorporation into soil microbial biomass estimated by 14 C labeling. Soil Biology & Biochemistry , 41 , 210 –219. Luo, Y., Durenkamp, M., De Nobili, M., Lin, Q., & Brookes, P. C. (2011). Short term soil priming effects and the mineralisation of biochar follow- ing its incorporation to soils of different pH. Soil Biology & Biochemistry, 43 , 2304 – 2314. Luo, Y., Durenkamp, M., De Nobili, M., Lin, Q., Devonshire, B. J., & Brookes, P. C. (2013). Microbial biomass growth, following incorporation of bio- chars produced at 350 °C or 700 °C, in a silty ‐ clay loam soil of high and low pH. Soil Biology & Biochemistry , 57 , 513 –523. Luo, Y., Lin, Q., Durenkamp, M., Dungait, A. J., & Brookes, P. C. (2017). Soil priming effects following substrates addition to biochar ‐ treated soils after 431 days of pre ‐ incubation. Biology and Fertility of Soils , 53, 315 –326. Luo, Y., Zang, H., Yu, Z., Chen, Z., Gunina, A., Kuzyakov, Y., … Brookes, P. C. (2017). Priming effects in biochar enriched soils using a three ‐ source‐ partitioning approach: 14 C labelling and 13 C natural abundance. Soil Biology and Biochemistry , 106 ,28 – 35. Nold, S. C., Boschker, H. T. S., Pel, R., & Laanbroek, H. J. (1999). Ammonium addition inhibits 13c ‐ methane incorporation into Methanotroph membrane lipids in a freshwater sediment. FEMS Microbiology Ecology, 29 ,81 – 89. Pietikäinen, J., Kiikkilä, O., & Fritze, H. (2000). Charcoal as a habitat for microbes and its effect on the microbial community of the underlying humus. Oikos , 89 , 231 –242. Rousk, J., Bååth, E., Brookes, P. C., Lauber, C. L., Lozupone, C., Caporaso, J. G., … Fierer, N. (2010a). Soil bacterial and fungal communities across a pH gradient in an arable soil. The ISME Journal , 4 , 1340 –1351. Rousk, J., Brookes, P. C., & Bååth, E. (2010). The microbial PLFA composi- tion as affected by pH in an arable soil. Soil Biology & Biochemistry , 42, 516 –520. Saito, M., & Marumoto, T. (2002). Inoculation with arbuscular mycorrhizal fungi: The status quo in Japan and the future prospects. Plant and Soil, 244 , 273 –279. Smith, J. L., Collins, H. P., & Bailey, V. L. (2010). The effect of young biochar on soil respiration. Soil Biology & Biochemistry , 42 , 2345 –2347. Spokas, K. A., Cantrell, K. B., Novak, J. M., Archer, D. W., Ippolito, J. A., Col- lins, H. P., … Nichols, K. A. (2012). Biochar: A synthesis of its agronomic impact beyond carbon sequestration. Journal of Environmental Quality, 41 , 973 –989. Steinbeiss, S., Gleixner, G., & Antonietti, M. (2009). Effect of biochar amendment on soil carbon balance and soil microbial activity. Soil Biol- ogy & Biochemistry , 41 , 1301 –1310. Watzinger, A., Feichtmair, S., Kitzler, B., Zehetner, F., Kloss, S., Wimmer, B., … Soja, G. (2014). Soil microbial communities responded to biochar application in temperate soils and slowly metabolized 13 C ‐ labelled bio- char as revealed by 13 C PLFA analyses: Results from a short ‐term incubation and pot experiment. European Journal of Soil Science , 65, 40 –51. Wixon, D. L., & Balser, T. C. (2013). Toward conceptual clarity: PLFA in warmed soils. Soil Biology & Biochemistry , 57 , 769 –774. Woolf, D., Amonette, J. E., Street ‐ Perrott, F. A., Lehmann, J., & Joseph, S. (2010). Sustainable biochar to mitigate global climate change. Nature Communications , 1 , 56. Xu, R. ‐ K., Zhao, A. ‐ Z., Yuan, J. ‐ H., & Jiang, J. (2012). pH buffering capacity of acid soils from tropical and subtropical regions of China as influenced by incorporation of crop straw biochars. Journal of Soils and Sediments, 12 , 494 –502. Zelles, L. (1999). Fatty acid patterns of phospholipids and lipopolysaccha- rides in the characterisation of microbial communities in soil: A review. Biology and Fertility of Soils , 29 , 111 –129. Zimmerman, A. R., Gao, B., & Ahn, M. ‐ Y. (2011). Positive and negative car- bon mineralization priming effects among a variety of biochar ‐amended soils. Soil Biology & Biochemistry , 43 , 1169 –1179. How to cite this article: Luo Y,DungaitJAJ,ZhaoX,etal. Pyrolysis temperature during biochar production alters its sub- sequent utilization by microorganisms in an acid arable soil. Land Degrad Develop . 2017;1 – 6. https://doi.org/10.1002/ldr.2846 6 LUO ET AL. ... A previous study indicated that the abundances of both fungi and bacteria were increased in soils amended with biochar and that both microbial groups used the C from the added biochar as a substrate (Luo et al., 2017) . The results of the current study are consistent with this previous study because the abundances of fungi (F 3,12 = 7.2, P < 0.01) as well as of G + bacteria (F 3,12 = 5.9, P < 0.05) and actinobacteria (F 3,12 = 5.2, P < 0.05) were higher in the biochar treatment than in the noaddition treatment (Fig. 3). ... ... The only exception were G − bacteria, whose abundance was not affected by treatments (F 3,12 = 2.7, P > 0.05) (Fig. 3). Fungi, G + bacteria, and actinobacteria derive greater benefit from biochar than G − bacteria because biochar commonly lacks easily available substrates, which are essential for the growth of G − bacteria (Farrell et al., 2013;Zhang et al., 2018), and because biochar only provides less degradable substances that tend to support the growth of fungi (Luo et al., 2017) , G + bacteria (Farrell et al., 2013), and actinobacteria (Watzinger et al., 2014). The rapid depletion of readily available compounds might also explain the generally lower abundances of fungi, G + bacteria, and actinobacteria in the compost treatment than in the biochar treatment and the lack of differences in the abundance of G − bacteria among treatments. ... Biochar and compost amendments to a coarse-textured temperate agricultural soil lead to nutrient leaching Article May 2022 APPL SOIL ECOL <here is a image e49c7766f5f855df-e498965e9a384584> V. Jílková <here is a image edf3aa5a9706f46f-bf95f47efb05c6dd> Gerrit Angst Organic soil amendments benefit agricultural soils depleted in soil organic matter because they improve soil chemical and biological properties. Biochar and compost, used as organic amendments, differ in their contents of total vs. available nutrients and may therefore differ in their effects on soil properties. The effects of these amendments have seldom been assessed in coarse-textured temperate soils and in no-tillage agriculture. In this study, we conducted a 6-month laboratory experiment with a coarse-textured temperate soil with a history of conventional farming to determine the effects of biochar, compost, and their combination, which were spread evenly on the soil surface, on microbial activity and biomass, and nutrient release and leaching. Both biochar and compost increased microbial activity and nutrient release compared to the no-addition treatment, but compost effects were relatively short term (<two months), and biochar effects were relatively long term (>six months). Biochar and compost had additive effects on all properties when added in combination. Biochar addition to soil increased soil pH, microbial biomass, and the abundance of fungi, G⁺ bacteria, and actinobacteria after 6 months of incubation compared to the compost treatment and the no-addition treatment. Although biochar was expected to reduce loss of nutrients through leaching, the short exposure time and disturbance of the soil probably hindered its capacity to adsorb nutrients and to thereby limit leaching; as a consequence, the biochar acted only as a slow-release nutrient fertilizer during the 6-month incubation. ... (Arriagada et al., 2014) and can provide essential support for achieving crop yield and ecosystem services (Knoblauch et al., 2021). Biochar amendments to soil have been previously shown to increase OM and available nutrient contents (Abujabhah et al., 2016;Cooper et al., 2020; Jílková & Angst, 2022) as well as soil microbial activity and biomass (Abujabhah et al., 2016;Jílková & Angst, 2022; Luo et al., 2018) . Based on recent meta-analyses, these effects are especially evident in coarsetextured, acidic soils (Liu et al., 2016;Zhang et al., 2018). ... Biochar‐application rate and method affect nutrient availability and retention in a coarse‐textured, temperate agricultural Cambisol in a microcosm experiment Article Feb 2023 <here is a image e49c7766f5f855df-e498965e9a384584> V. Jílková Agricultural soils often require organic amendments, which improve crop yield and ecosystem services. Biochar has been proven to increase nutrient availability and retention in fine‐textured, tropical soils. Here we determine how coarse‐textured, temperate soils react to different biochar‐application rates in different tillage systems. We conducted a 6‐month laboratory incubation experiment in microcosms filled with a coarse‐textured, temperate agricultural soil to determine the effects of biochar‐application rate (none, low, or high, i.e., 0, 20, or 40 t dw ha−1, respectively) and application method (mixed into the soil or applied to the soil surface) on microbial activity and biomass, and nutrient availability and leaching. Microbial activity and biomass and contents of carbon, nitrogen, and phosphorus in leachates were higher in biochar‐addition treatments (by 134%, 37%, 372%, 28%, and 801%, respectively) than in the no‐addition treatment. The effect was stronger with the low than with the high biochar‐application rate. Biochar applied by both methods acted as a slow‐release fertilizer, but this effect was stronger when biochar was mixed into the soil. Although available nutrient contents in the soil remained high, nutrient leaching decreased with incubation time. This effect was especially evident when biochar was mixed into the soil. Biochar is an effective organic amendment in coarse‐textured soils providing available nutrients. On the other hand, nutrient‐retention mechanisms develop slowly after biochar application and may be greater when biochar is mixed into the soil than applied on the soil surface. Graphical Abstract: ... Thirdly, the organic matrix of biochar acts as promising habitat for plant growth promoting bacteria (PGPB) (Bertola et al. 2019). Again, low-temperature biochars with low aromaticity are good candidates because bacteria can utilize aliphatic moieties much easier than aromatic ones (Luo et al. 2018; Zhong et al. 2020). Stimulated microbial activities within the charosphere account for improved soil health within the rhizosphere, thus leading to an elevated plant biomass yield (Dissanayake et al. 2022;Weralupitiya et al. 2022). ... Role of biochar toward carbon neutrality Article Full-text available Jan 2023 Liuwei Wang <here is a image c04546fa1991f4a8-8743dd001bd31ba4> Jiayu Deng Xiaodong Yang <here is a image 3fb4ba50142c86d5-6a0cc0df6fc96c43> Deyi Hou Carbon neutrality by the mid-twenty-first century is a grand challenge requiring technological innovations. Biochar, a traditional soil amendment which has been used for fertility improvement and contaminant remediation, has revealed new vitality in this context. In this review we highlight the huge potential of biochar application in different fields to mitigate as high as 2.56 × 10 ⁹ t CO 2 e total greenhouse gas (GHG) emissions per year, accounting for 5.0% of the global GHG emissions. Soil applications of biochar as either a controlled-release fertilizer or an immobilization agent offer improved soil health while simultaneously suppressing the emissions of CH 4 and N 2 O. Non-soil applications of biochar also contribute to carbon neutrality in unique ways. Firstly, biochar application as a ruminant feed decreases CH 4 emissions via physical sorption and enhanced activities of methanotrophs. Secondly, biochar can be used as a green catalyst for biorefinery. Besides, biochar as an additive to Portland cement and low impact development (LID) infrastructure lowers the carbon footprint and builds resilience to climate change. Furthermore, biochar can be used as novel batteries and supercapacitors for energy storage purposes. Finally, the high CO 2 adsorption capacity makes it possible for biochar being used as a sorbent for carbon capture, utilization, and storage (CCUS). We advocate that future research should further explore the effectiveness of biochar systems for climate change mitigation in large scale applications, and assess the economic and social viability of local biochar systems to combat climate change. Graphical Abstract ... "Increased enzyme activity of dehydrogenase, βglucosidase, and urease in a red soil of China was recorded when amended with an oak wood or bamboo biochar at 0.5, 1.0, and 2.0% after 372 days of incubation" [31]. Luo et al. [32] showed that "all microbial groups (Gram positive and Gram-negative bacteria, Actinobacteria and Fungi) were more abundant in the biochar treated soil after 14 months of incubation". Similar findings were reported by Gomez et al. [33] in a study using four soils from the Midwest, USA, and concluded that biochar stimulated microbial activity and growth. ... Biochar: An Emerging Soil Amendment for Sustaining Soil Health and Black Gold for Indian Agriculture Full-text available <here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Vikram N Shiyal <here is a image 9861eb773076b9d7-22b6a57dbbb769fd> Vinaykumar Patel <here is a image fa41d0bc505f9a36-5219690e1e8bb4f5> Hiren Patel <here is a image 8ac39acab7c2774b-04ac4e53e3b5b21a> Piyush H. Patel At the international level, improving soil with coal is seen as a means to increase soil productivity, fertility and also to mitigate climate change. Biochar, which is used to increase land fertility and store carbon, is currently gaining scientific attention and popularity in the agriculture sector. It is a solid material made by pyrolysis process of any biomass, including weeds, agricultural leftovers and other plant wastes, to carbonise it and use it as a soil amendment and carbon sequestration medium. Biochar is a viable option for enhancing soil chemical properties such as cation exchange capacity (CEC) and soil pH, as well as lowering exchangeable acidity. Biochar was also discovered to boost soil biota by boosting nutrient availability, improving habitat appropriateness, increasing water retention and aeration as well as lowering harmful compounds in the soil. Also, it can help to mitigate climate change by sequestering carbon in the soil and reducing nitrous oxide (N2O) and methane (CH4) gas emissions to the environment by enhancing soil absorption. ... To lessen the PS's microbial toxicity, SBB could boost adsorption and enhance soil quality. The soil microorganisms could receive nutrition and protection directly from biochar (Jia et al. 2018; Luo et al. 2018) or a more favorable habitat by altering the soil's physical characteristics. Biochar could release dissolved organic carbon (DOC) into the soil solution after application and directly alter the DOC's properties (Dittmar et al. 2012). ... Methane emissions and rice yield in a paddy soil: the effect of biochar and polystyrene microplastics interaction
https://www.researchgate.net/publication/321578113_Pyrolysis_temperature_during_biochar_production_alters_its_subsequent_utilization_by_microorganisms_in_an_acid_arable_soil
RIDGEWAY v. UNITED STATES | 558 F.2d 357 | 6th Cir. | Judgment | Law | CaseMine Get free access to the complete judgment in RIDGEWAY v. UNITED STATES on CaseMine. RIDGEWAY v. UNITED STATES 558 F.2d 357 Case Information CITATION CODES 558 F.2d 357 DOCKET NO. No. 76-2145. ATTORNEY(S) Ovid C. Lewis, Covington, Ky. (Court-appointed), for defendant-appellant. Philip M. Van Dam, U.S. Atty., Peter M. Rosen, Detroit, Mich., Dana D. Biehl, Washington, D.C., for plaintiff-appellee. JUDGES Harry Phillips ACTS Food And Drugs — Drug Abuse Prevention And Control — Import And Export — Attempt And Conspiracy Food And Drugs — Drug Abuse Prevention And Control — Import And Export — Importation Of Controlled Substances Food And Drugs — Drug Abuse Prevention And Control — Control And Enforcement — Offenses And Penalties — Attempt And Conspiracy Food And Drugs — Drug Abuse Prevention And Control — Control And Enforcement — Offenses And Penalties — Prohibited Acts A Smart Summary Important Paras Against this background of the origin and purpose of the Agreement, we turn now to the writ of habeas corpus ad prosequendum and its origins. A federal writ of habeas corpus ad prosequendum is a court order directing the production of a prisoner to stand trial in federal court. A history of the writ in American jurisprudence is presented in Carbo v. United States, 364 U.S. 611, 81 S.Ct. 338, 5 L.Ed.2d 329 (1961). The writ of habeas corpus ad prosequendum is one of the oldest writs available to the judiciary. Blackstone described the writ in his Commentaries on English law. In the United States the writ traces its origins from § 14 of the First Judiciary Act, 1 Stat. 81-82 (1789), and it is now incorporated in 28 U.S.C. § 2241(c)(5) . For almost 200 years the United States has utilized the writ in cases where a State prisoner was facing federal charges. Nowhere have we found any expression of Congressional intent to modify or change the writ. Go to Since the Congressional history does not answer our question, we look to the origins of the Agreement. A detainer is simply a notice to prison authorities that charges are pending against an inmate elsewhere, requesting the custodian to notify the sender before releasing the inmate. The detainer itself does nothing to affect the prosecution of an inmate. Filing a detainer is an informal process which does not bind the authorities to act. Generally, a penal institution will recognize a detainer lodged by any person who has authority to take an inmate into custody. In most instances, the prosecutor charged with the task of bringing the case to disposition files the detainer, but, if the case has not yet reached the stage of a formal indictment or information, the detainer may be filed by the police. Go to The Agreement was first promulgated by the Council of State Governments in 1957. It was adopted by Congress in 1970, and 46 states, the District of Columbia and the United States are signatories. The Agreement was designed to facilitate the disposition of charges in one jurisdiction when the accused is incarcerated in another jurisdiction. Some of the reasons for the agreement are set forth in Article I: Go to See United States v. Ford, supra, 550 F.2d 732 (2d Cir. 1977). Go to The Agreement is applicable to situations in which one participating jurisdiction has lodged a detainer for a prisoner in another participating jurisdiction where the prisoner is incarcerated. Article III provides that a prisoner can demand to be brought to trial within 180 days on any untried indictment, information or complaint which is the basis for a detainer lodged against him. If the prisoner is not brought to trial within the 180 day limit, the appropriate court of the jurisdiction in which the outstanding charge is pending is required to dismiss the charge with prejudice and the detainer thereupon ceases to have effect. The time limit can be extended for good cause in open court, if either the prisoner or his counsel are present. Thus, Article III provides a prisoner with a procedure for bringing about a prompt disposition of detainers placed against him. Go to The Agreement also provides a method under Article IV whereby prosecutors can secure prisoners serving sentences in other jurisdictions for a prompt trial. Unless a request is disapproved by the Governor of the State having custody (or in an appropriate case by the Attorney General of the United States) within 30 days, temporary custody of the prisoner is given to the requesting prosecutor. Trial must commence within 120 days of the arrival of the prisoner in the jurisdiction requesting him, unless a continuance is granted for good cause in open court with the prisoner or his counsel present. Article IV(e) mandates that: Go to First we consider the question of whether a writ of habeas corpus ad prosequendum is a detainer under the Interstate Agreement on Detainers (Agreement). Go to The party States find that charges outstanding against a prisoner, detainers based on untried indictments, informations, or complaints and difficulties in securing speedy trial of persons already incarcerated in other jurisdictions, produce uncertainties which obstruct programs of prisoner treatment and rehabilitation. Accordingly, it is the policy of the party States and the purpose of this agreement to encourage the expeditious and orderly disposition of such charges and determination of the proper status of any and all detainers based on untried indictments, informations, or complaints. The party States also find that proceedings with reference to such charges and detainers, when emanating from another jurisdiction, cannot properly be had in the absence of cooperative procedures. It is the further purpose of this agreement to provide such cooperative procedures. If a trial is not had on any indictment, information, or complaint . . . prior to the prisoner's being returned to the original place of imprisonment . . . the court shall enter an order dismissing the [indictment, information or complaint] with prejudice. Dictum in United States v. Roberts, 548 F.2d 665, 670 (6th Cir. 1977) indicated that this court might find a writ of habeas corpus ad prosequendum to be a detainer under the Agreement. However, in view of this court's ultimate conclusion in Roberts that the Agreement did not apply to a prisoner in Roberts' situation, the dictum is not binding upon this court when we are faced squarely with the issue. Go to We have reviewed the legislative history of the Agreement and find no conclusive answer to the question before us. The Senate Report defined a detainer as "a notification filed with the institution in which a prisoner is serving a sentence, advising that he is wanted to face pending criminal charges in another jurisdiction" Nowhere in the legislative history do we find any express reference to a writ of habeas corpus ad prosequendum. Go to The effects of a detainer on an inmate can be profound. Extensive delay in bringing the prisoner to trial is only one of the problems. Many prison authorities regard convicts subject to detainers as potential escape risks, and, therefore, restrict their activities and privileges. An inmate may be denied institutional privileges resulting in decreased freedom of movement, and he may be precluded from preferred living quarters such as dormitories. Such an inmate may be denied trusty status, or he may be considered ineligible to reside on an "honor farm" or to take part in a furlough program. Detainers may be taken into account by parole boards and thus may affect the length of a sentence. A detainer can also have a psychological effect upon an inmate, thus frustrating rehabilitation. As the Senate Report noted: Detainers, separate and distinct from the writ of habeas corpus ad prosequendum, continue to be used by federal authorities. We refuse to interpret the word "detainer" to include the writ of habeas corpus ad prosequendum. Go to The abuses of detainers designed to be corrected by the Agreement are not present in the use of the writ. The writ is a federal court order. It can be issued only by the court, unlike a detainer which can be filed by police authorities and prosecutors. The primary emphasis of the proponents of the Agreement was on the anti-rehabilitative effect of longstanding detainers. Note, Effective Guaranty of a Speedy Trial for Convicts in Other Jurisdictions, supra note 5, 77 Yale L.J. at 775. The writ is not subject to this objection because it is executed expeditiously, unlike a detainer which can lay dormant for many years. Go to The interpretation of the Agreement proposed by appellant would implicitly repeal § 2241(c)(5) and runs counter to fundamental rules of statutory construction. Where Congress has enacted legislation on a particular subject, as it has for a writ of habeas corpus ad prosequendum, subsequent legislation will not be construed to modify, repeal or supplant the legislation, particularly where both statutes serve distinct purposes. Rosencrans v. United States, 165 U.S. 257, 17 S.Ct. 302, 41 L.Ed. 708 (1897). Rather, the courts will reconcile the earlier statute and the later legislation if possible. McCool v. Smith, 66 U.S. (1 Black) 459, 17 L.Ed. 218 (1861). We re-emphasize that the legislative history of the Agreement in Congress does not even mention the writ of habeas corpus ad prosequendum. It would be error to conclude that § 2241(c)(5) incorporating the writ in the current code was modified by the Agreement. Go to RIDGEWAY v. UNITED STATES PHILLIPS, Chief Judge. The principal question raised on this appeal is whether a writ of habeas corpus ad prosequendum is a detainer under the Interstate Agreement on Detainers. We hold that it is not. Robert Lee Ridgeway was indicted and convicted on one count of conspiracy to import, possess and distribute cocaine. On appeal he raises four grounds for reversal: (1) That a writ of habeas corpus ad prosequendum is a detainer under the Interstate Agreement on Detainers and that the federal indictment against him should have been dismissed with prejudice when he was not tried within 120 days after his arrival within federal jurisdiction, and when he was returned to his incarceration in a State institution prior to trial on the federal charges; (2) That an in-court identification was improperly admitted into evidence; (3) That the evidence was insufficient to support the conviction; and (4) That he was denied the effective assistance of counsel. We conclude that all four of these contentions are without merit and affirm the conviction. I. On August 8, 1975, Ridgeway was charged under a federal indictment with one count of conspiracy. The count charged appellant and others under the conspiracy provision,21 U.S.C. § 963, with having conspired to smuggle cocaine knowingly and intentionally into the United States in violation of21 U.S.C. § 952(a)and under the conspiracy provision21 U.S.C. § 846, with having conspired to distribute or possess with intent to distribute, cocaine in violation of21 U.S.C. § 841(a)(1). A second count charged appellant with possession of cocaine with the intent to distribute it in violation of21 U.S.C. § 841(a)(1). When the indictment was filed appellant was serving a sentence in a Michigan prison for an unrelated state charge. He was brought to the United States District Court for the Eastern District of Michigan pursuant to a writ of habeas corpus ad prosequendum for his arraignment and plea of not guilty on August 14, 1975. From the arraignment and throughout the proceedings, appellant and the Government agreed that appellant would be placed on personal bond rather than having a detainer filed against him with the State prison authorities.This arrangement was requested by appellant so that he could maintain his trustee status and be eligible for benefits he might not have had if he had been held in a federal facility or had a detainer filed against him while awaiting trial. He was returned to the Michigan state prison until November 20, 1975, when he was brought back to the district court for trial pursuant to another writ of habeas corpus ad prosequendum. During the trial, appellant, his attorney and the Government agreed that in return for appellant's waiver of a jury trial the Government would drop the substantive possession charge against him. Appellant's counsel then requested a continuance so that he could obtain certain scientific evidence. Appellant was returned to the Michigan State prison while the trial of his co-defendants continued. He was brought before the court for trial pursuant to yet another writ of habeas corpus ad prosequendum on March 5, 1976. Appellant was indicted as a member of the Robert Wind cocaine smuggling conspiracy, alleged to have involved shipments of cocaine from South America in large quantities for distribution in the Detroit area for a period of almost two years from mid-1973 to mid-1975. Seventeen persons were named as co-conspirators, fifteen of whom were indicted. The district court sentenced appellant to twelve years imprisonment running consecutively with his State sentence. In addition, the court imposed a special parole term of ten years. This appeal was then filed. II. First we consider the question of whether a writ of habeas corpus ad prosequendum is a detainer under the Interstate Agreement on Detainers (Agreement). The Agreement was first promulgated by the Council of State Governments in 1957.It was adopted by Congress in 1970, and 46 states, the District of Columbia and the United States are signatories. The Agreement was designed to facilitate the disposition of charges in one jurisdiction when the accused is incarcerated in another jurisdiction. Some of the reasons for the agreement are set forth in Article I: Council of State Governments Suggested Legislation 167 (1959). The party States find that charges outstanding against a prisoner, detainers based on untried indictments, informations, or complaints and difficulties in securing speedy trial of persons already incarcerated in other jurisdictions, produce uncertainties which obstruct programs of prisoner treatment and rehabilitation. Accordingly, it is the policy of the party States and the purpose of this agreement to encourage the expeditious and orderly disposition of such charges and determination of the proper status of any and all detainers based on untried indictments, informations, or complaints. The party States also find that proceedings with reference to such charges and detainers, when emanating from another jurisdiction, cannot properly be had in the absence of cooperative procedures. It is the further purpose of this agreement to provide such cooperative procedures. The Agreement is discussed in United States v. Ford,550 F.2d 732(2d Cir. 1977), petition for cert. filed,46 U.S.L.W. 3056(U.S. Aug. 16, 1977, No. 77-52). The Agreement is applicable to situations in which one participating jurisdiction has lodged a detainer for a prisoner in another participating jurisdiction where the prisoner is incarcerated. Article III provides that a prisoner can demand to be brought to trial within 180 days on any untried indictment, information or complaint which is the basis for a detainer lodged against him. If the prisoner is not brought to trial within the 180 day limit, the appropriate court of the jurisdiction in which the outstanding charge is pending is required to dismiss the charge with prejudice and the detainer thereupon ceases to have effect. The time limit can be extended for good cause in open court, if either the prisoner or his counsel are present. Thus, Article III provides a prisoner with a procedure for bringing about a prompt disposition of detainers placed against him. The Agreement also provides a method under Article IV whereby prosecutors can secure prisoners serving sentences in other jurisdictions for a prompt trial. Unless a request is disapproved by the Governor of the State having custody (or in an appropriate case by the Attorney General of the United States) within 30 days, temporary custody of the prisoner is given to the requesting prosecutor. Trial must commence within 120 days of the arrival of the prisoner in the jurisdiction requesting him, unless a continuance is granted for good cause in open court with the prisoner or his counsel present. Article IV(e) mandates that: If a trial is not had on any indictment, information, or complaint . . . prior to the prisoner's being returned to the original place of imprisonment . . . the court shall enter an order dismissing the [indictment, information or complaint] with prejudice. In addressing the issue of whether a writ of habeas corpus ad prosequendum is a detainer under the Agreement, we note that there is a split of authority among the other Circuits. The Second Circuit in United States v. Mauro,544 F.2d 588(2d Cir. 1976) (Mansfield, J., dissenting) and the Third Circuit in United States ex rel. Esola v. Groomes,520 F.2d 830(3rd Cir. 1975), held that the writ is a detainer under the Agreement, while the Fifth Circuit has recently reached the opposite conclusion in United States v. Scallion,548 F.2d 1168(5th Cir. 1977). Dictum in United States v. Roberts,548 F.2d 665, 670(6th Cir. 1977) indicated that this court might find a writ of habeas corpus ad prosequendum to be a detainer under the Agreement. However, in view of this court's ultimate conclusion in Robertsthat the Agreement did not apply to a prisoner in Roberts' situation, the dictum is not binding upon this court when we are faced squarely with the issue. We have reviewed the legislative history of the Agreementand find no conclusive answer to the question before us. The Senate Reportdefined a detainer as "a notification filed with the institution in which a prisoner is serving a sentence, advising that he is wanted to face pending criminal charges in another jurisdiction"Nowhere in the legislative history do we find any express reference to a writ of habeas corpus ad prosequendum. S.Rep. No. 91-1356, 91st Cong., 2d Sess. (1970), reprinted in [1970] U.S. Code Cong. Ad. News, p. 4864; H.R. Rep. No. 91-1018, 91st Cong., 2d Sess.; 116 Cong. Rec. 13999-14000 (remarks of Rep. Kastenmeier and Rep. Poff), 3884-85 (remarks of Sen. Hruska) (1970). S.Rep. No. 91-1356, supra,n. 2 at 4865. See also116 Cong.Rec. 13999 (1970) (remarks of Rep. Kastenmeier). Since the Congressional history does not answer our question, we look to the origins of the Agreement.A detainer is simply a notice to prison authorities that charges are pending against an inmate elsewhere, requesting the custodian to notify the sender before releasing the inmate. The detainer itself does nothing to affect the prosecution of an inmate. Filing a detainer is an informal process which does not bind the authorities to act.Generally, a penal institution will recognize a detainer lodged by any person who has authority to take an inmate into custody. In most instances,the prosecutor charged with the task of bringing the case to disposition files the detainer, but, if the case has not yet reached the stage of a formal indictment or information, the detainer may be filed by the police. See generally,Meyer, Effective Utilization of Criminal Detainer Procedures, 61 Ia.L.Rev. 659 (1976); Yackle, Taking Stock of Detainer Statutes, 8 Loy.L.A.L.Rev. 88 (1975); Dauber, Reforming the Detainer System: A Case Study, 7 Crim.L.Bull. 669 (1971); Wexler Hershey, Criminal Detainers in a Nutshell, 7 Crim.L.Bull. 753 (1971); Note, Extending the Smith v. HooeyDuty to the Holding Jurisdiction, 23 Me. L.Rev. 201 (1971); Note, The Interstate Criminal Detainer and the Sixth Amendment, 23 Ark.L.Rev. 634 (1970); Note, Effective Guaranty of a Speedy Trial for Convicts in Other Jurisdictions, 77 Yale L.J. 767 (1968); Schindler, Interjurisdictional Conflicts and the Right to a Speedy Trial, 35 U.Cin.L.Rev. 179 (1966); Note, Detainers and the Correctional Process, 1966 Wn.U.L.Q. 417; Comment, The Detainer System and the Right to a Speedy Trial, 31 U.Chi.L.Rev. 535 (1964); Note, Convicts — The Right to Speedy Trial and the New Detainer Statutes, 18 Rut.L.Rev. 828 (1964). Note, Detainers and the Correctional Process, supranote 5, 1966 Wn.U.L.Q. at 417. Yackle, Taking Stock of Detainer Statutes, supranote 5, 8 Loy.L.A.L.Rev. at 90. Detainers have been filed with little consideration of whether the inmate will be brought to trial. In some cases they may be withdrawn as a matter of prosecutorial discretion. Some detainers apparently have been filed for punitive reasons.They are withdrawn shortly before the inmate's release, having served their purpose by limiting his prison privileges and preventing parole. The dangers in this practice were discussed by Judge Sobeloff in Pitts v. North Carolina,395 F.2d 182, 187(4th Cir. 1968): Note, Effective Guaranty of a Speedy Trial for Convicts in Other Jurisdictions, supranote 5, 77 Yale L.J. at 773. Detainers, informal aides in interstate and intrastate criminal administration, often produce serious adverse side-effects. The very informality is one source of the difficulty. Requests to an imprisoning jurisdiction to detain a person upon his release so that another jurisdiction may prosecute or incarcerate him may be filed groundlessly, or even in bad faith, as suspected by the appellant in this case. The accusation in a detainer need not be proved; no judicial officer is involved in issuing a detainer. As often happens, the result of the then unestablished charge upon which the detainer in this case rested was that the detainee was seriously hampered in his quest for a parole or commutation. The effects of a detainer on an inmate can be profound. Extensive delay in bringing the prisoner to trial is only one of the problems. Many prison authorities regard convicts subject to detainers as potential escape risks, and, therefore, restrict their activities and privileges.An inmate may be denied institutional privileges resulting in decreased freedom of movement, and he may be precluded from preferred living quarters such as dormitories.Such an inmate may be denied trusty status,or he may be considered ineligible to reside on an "honor farm" or to take part in a furlough program. Detainers may be taken into account by parole boards and thus may affect the length of a sentence. A detainer can also have a psychological effect upon an inmate, thus frustrating rehabilitation. As the Senate Report noted: [W]hen detainers are filed against a prisoner he sometimes loses interest in institutional opportunities because he must serve his sentence without knowing what additional sentences may lie before him, or when, if ever, he will be in a position to employ the education and skills he may be developing. Although a majority of detainers filed by States are withdrawn near the conclusion of the Federal sentence, the damage to the rehabilitation program has been done because the institution staff has not had sufficient time to develop a sound pre-release program. Note, Detainers and the Correctional Process, supranote 5, 1966 Wn.U.L.Q. at 419. Yackle, Taking Stock of Detainer Statutes, supranote 5, 8 Loy.L.A.L.Rev. at 91. Note, Detainers and the Correctional Process, supranote 5, 1966 Wn.U.L.Q. at 419. Sometimes the inmate would be automatically held under maximum security or be declared ineligible for special work programs, athletic programs, release for visits to relatives' death beds, or funerals. United States v. Ford,550 F.2d 732(2d Cir. 1977). S.Rep. No. 91-1356 supra,n. 2 at 4866. Against this background of the origin and purpose of the Agreement, we turn now to the writ of habeas corpus ad prosequendum and its origins. A federal writ of habeas corpus ad prosequendum is a court order directing the production of a prisoner to stand trial in federal court. A history of the writ in American jurisprudence is presented in Carbo v. United States,364 U.S. 611,81 S.Ct. 338,5 L.Ed.2d 329(1961). The writ of habeas corpus ad prosequendumis one of the oldest writs available to the judiciary. Blackstone described the writ in his Commentaries on English law.In the United States the writ traces its origins from § 14 of the First Judiciary Act, 1 Stat. 81-82 (1789), and it is now incorporated in28 U.S.C. § 2241(c)(5). For almost 200 years the United States has utilized the writ in cases where a State prisoner was facing federal charges. Nowhere have we found any expression of Congressional intent to modify or change the writ. 3 Blackstone, Commentaries [*] 129. Detainers, separate and distinct from the writ of habeas corpus ad prosequendum, continue to be used by federal authorities.We refuse to interpret the word "detainer" to include the writ of habeas corpus ad prosequendum. See United States v. Ford, supra,550 F.2d 732(2d Cir. 1977). The abuses of detainers designed to be corrected by the Agreement are not present in the use of the writ. The writ is a federal court order. It can be issued only by the court, unlike a detainer which can be filed by police authorities and prosecutors. The primary emphasis of the proponents of the Agreement was on the anti-rehabilitative effect of longstanding detainers. Note, Effective Guaranty of a Speedy Trial for Convicts in Other Jurisdictions, supranote 5, 77 Yale L.J. at 775. The writ is not subject to this objection because it is executed expeditiously, unlike a detainer which can lay dormant for many years. The interpretation of the Agreement proposed by appellant would implicitly repeal § 2241(c)(5) and runs counter to fundamental rules of statutory construction. Where Congress has enacted legislation on a particular subject, as it has for a writ of habeas corpus ad prosequendum, subsequent legislation will not be construed to modify, repeal or supplant the legislation, particularly where both statutes serve distinct purposes. Rosencrans v. United States,165 U.S. 257,17 S.Ct. 302,41 L.Ed. 708(1897). Rather, the courts will reconcile the earlier statute and the later legislation if possible. McCool v. Smith,66 U.S. (1 Black) 459,17 L.Ed. 218(1861). We re-emphasize that the legislative history of the Agreement in Congress does not even mention the writ of habeas corpus ad prosequendum. It would be error to conclude that § 2241(c)(5) incorporating the writ in the current code was modified by the Agreement. We agree with the Fifth Circuit that the legislative history shows no intent to make the Agreement the exclusive means by which a state prisoner can be brought to trial in federal court. United States v. Scallion, supra,548 F.2d at 1171. Further evidence that Congress did not intend to equate federal writs of habeas corpus with detainers is provided by a statement of the Senate Committee on the Judiciary issued to clarify this matter: Federal prosecution authorities and all Federal defendants have always had and continue to have recourse to a speedy trial in a Federal court pursuant to 28 U.S.C. § 2241(c)(5) , the Federal writ of habeas corpus ad prosequendum. The Committee does not intend, nor does it believe that the Congress in enacting the [Interstate Agreement on Detainers] in 1970 intended, to limit the scope and applicability of that writ. S. 1, 94th Cong., 1st Sess. (1975). Since we conclude that a writ of habeas corpus ad prosequendum is not a detainer, it follows that the charges against Ridgeway are not required to be dismissed under the terms of the Agreement. III. We have considered Ridgeway's other contentions and find them to be without merit. Specifically, we hold that the district court did not err in admitting an incourt identification into evidence; that the evidence is sufficient to support the conviction; and that Ridgeway was not denied effective assistance of counsel. Affirmed.
https://www.casemine.com/judgement/us/5914c5c1add7b049347d65d9
(!) Cephalic Index vs. Y-haplogroups in Europe [Archive] - Eupedia Forum Hello everybody, Is anybody familiar with any study on the relationship of the Cephalic Index vs. Y-haplogroups in Europe? Thank you. (!) Cephalic Index vs. Y-haplogroups in Europe Hello everybody, Is anybody familiar with any study on the relationship of the Cephalic Index vs. Y-haplogroups in Europe? Thank you. I think it will be a waste of time to study such a relationship unless u focus on a single region of a country where Y haplogroups could be correlated to the migration of a group from another area and so on. Take a look at R1b for instance, its linked to brachycephaly in Anatolia and Balkans, while its farther branches in Scotland and Ireland or Iberia are dolichocephals. I think mtdna is a better candidate for the cephalic index than ydna. The cephalic index could vary from brachy to dolicho and vice-versa over time. It was studied already in the mid XX-th century and from that point the cephalic index was dropped out from most of the study fields. So, yes, don't waste your time with that. ... I think mtdna is a better candidate for the cephalic index than ydna. Thank you.Would you be kind to refer to any study you are aware of? The cephalic index could vary from brachy to dolicho and vice-versa over time. It was studied already in the mid XX-th century and from that point the cephalic index was dropped out from most of the study fields. So, yes, don't waste your time with that. Thank you.Would you be kind to refer to any such studies? The cephalic index could vary from brachy to dolicho and vice-versa over time. It was studied already in the mid XX-th century and from that point the cephalic index was dropped out from most of the study fields. So, yes, don't waste your time with that. very simplistic answer for a genetic trait: don't mistake long term collective variations of diverse origins (often cultural, environmental) and genetic basis of individual CI differences - that said, it's evident Y-HG's don't play a big role in this (as in other genetic traits), here I do the same answer as others forumers, it is not very new -I wait for true Albanians with a mean CI of 72 as among 1930's Pathans, even now in the 2010's spite the dolichocephalicizing trend - Thank you.Would you be kind to refer to any such studies? very simplistic answer for a genetic trait: don't mistake long term collective variations of diverse origins (often cultural, environmental) and genetic basis of individual CI differences - that said, it's evident Y-HG's don't play a big role in this (as in other genetic traits), here I do the same answer as others forumers, it is not very new -I wait for true Albanians with a mean CI of 72 as among 1930's Pathans, even now in the 2010's spite the dolichocephalicizing trend - There were several studies in the past from which I can recall the study of Franz Boas on Jewish emigrants in America that observed how there was a complete reverse in the cephalic index of the generation born on American soil. Also, there's another study on Czech bone material which states that the medieval Czechs were dolichocephalic and gradually unto XIX century they went through brachycephalization that characterize them now. Another or maybe the same study, stated that the so-called Baltic phenotype was a reduced form of a Nordic prototype, (i.e. from dolicho to brachy). Furthermore there's some information about the brachy processes that happen when a population is living in mountainous area for long time. Also, you can see how the PIE Kurgan people were dolichocephalic cro-magnids and now this type and features almost don't exist.So, I am saying that the cephalic index is not a constant and I don't think it correlates well with anything. MOESAN, what are you implying? I agree the CI does not correlate with Y-dna and it is something connected to many different things. I found this archived thread:http://www.eupedia.com/forum/archive/index.php/t-27058.html Is anybody aware of anything new? I wait for true Albanians with a mean CI of 72 as among 1930's Pathans, even now in the 2010's spite the dolichocephalicizing trend -Well 72 is too extreme but better nutrition and no cradling for babies did reduce the extreme brachycephaly among Tosk Albanians. But you're right that even after 100 years we can probably see a maximum of 3-4 decrease in CI, not a shift from brachy to dolicho. I'm more interested in facial index. I've noticed that Haplogroup J corresponds to higher facial index in Asia for one thing. From my observation south,east Europeans tend to have more broad brachy heads and faces than north, west Europeans. I even mentioned this to my mom once, and she said maybe they sleep more on their side. IMO there is no relation whatsoever between cephalic index and Y-DNA. Any correlation would be fortuitous. The best proof is that Swiss and North Italians have mostly brachycephalic, while Spanish, British and Irish people are more dolicocephalic, despite both having high percentages of R1b. Likewise, most Slavs are brachycephalic, but Norwegians, who also have high levels of R1a, are dolicocephalic. From my observation south,east Europeans tend to have more broad brachy heads and faces than north, west Europeans. I even mentioned this to my mom once, and she said maybe they sleep more on their side. I agree with east vs west, but I've seen the opposite in north vs south. I think of long, narrow faces as typical of the Mediterranean more than Northern Europe. Spaniards and Italians seem to typify this. Here in the Balkans in Southeastern Europe South Slavs have this facial type combined with a brachycephalic head ("Dinaric"-type craniofacial profile). Likewise, most Slavs are brachycephalic, but Norwegians, who also have high levels of R1a, are dolicocephalic.The region in Norway where R1a is highest is brachycephalic, which was observed by early anthropologists. Cephalic index in France differs from village to village, so we don't know whether North Italians who are R1b lean brachycephalic or dolicocephalic. IMO there is no relation whatsoever between cephalic index and Y-DNA. Any correlation would be fortuitous. The best proof is that Swiss and North Italians have mostly brachycephalic, while Spanish, British and Irish people are more dolicocephalic, despite both having high percentages of R1b. Likewise, most Slavs are brachycephalic, but Norwegians, who also have high levels of R1a, are dolicocephalic. Thank you.I know the thread specifically targets at Y-DNA in Europe, but how about this relation occuring in other regions? in the historical context, males who succeeded in conquering people often took concubines and multiple wives from the conquered or tributary people, resulting overtime, in mixed phenotypes. A perfect example is the Yamna culture which had more than 90% of its males belonging to haplogroup R1b. These then should have been predominantly red-haired but because of the high incidence of foreign mtDNA belonging to NE. Caucasian/Iranian Plateau people as well as European hunter-gatherer lines, the population ended up having dark hair in most cases. I suppose same thing goes for the cephalic index.One thing I a having a hard time with understanding this whole Haplogroup I2 with its variants I2a1 an I2a2 because the names were changed so many times.Apparently, I2a2 is bracycephalic originally and is most likely the old Borreby type Coon talked about. As far as the Balkans and Sardinia however, I am confused as they seem to represent a similar type but the Balkans are brachycephalic while Sardinia I exactly the opposite. Any thoughts? what about claims of an increase in dolicho and mesocephalic trends in the Balkans and in German Saxony? Are these correct? I think that skull shape is determined mostly by autosomal genes not haplogroup, nutrition and other external factors could also play a role I looked up for CI in web yet to my surprise the data was very old and there weren't no new maps, and if regions like Nordica is so mix in ydna then why data shows only doliocephalic and other regions too are titled certain CI as if they are completely homogenous which I don't think they are! and is there link between height and CI? Oh I just saw maps of CI in Europe and the lowest rates in Europe are above 75(Iberia, UK) so they fall under Mesocephalic then why people term them Doliocephalic? Hello everybody, Is anybody familiar with any study on the relationship of the Cephalic Index vs. Y-haplogroups in Europe? Thank you. There should be no relations of y-dna to cephalic index. It makes no sense, as that is not how those things work.There might be relation to auDNA haplogroups, though, but that is not what you are looking for... ;) The y-chromosome carries important genes for brain development and Y-DNA haplogroups are strongly correlated with intelligence.
https://www.eupedia.com/forum/archive/index.php/t-33965.html?s=ae010b9cba55c93677d36fe6a2c9729e
Mask Detection Using IoT - A Comparative Study of Various Learning Models | Request PDF Request PDF | On Jun 17, 2022, Mohamed Amine Meddaoui and others published Mask Detection Using IoT - A Comparative Study of Various Learning Models | Find, read and cite all the research you need on ResearchGate Mask Detection Using IoT - A Comparative Study of Various Learning Models University Sultan Moulay Slimane IMT-Atlantique Novel Face Mask Detection Technique using Machine Learning to control COVID’19 pandemic Article Full-text available S. V. N. Sreenivasu Kuldeep Chouhan Ravindra Manohar Potdar The COVID-19 pandemic has been scattering speedily around the world since 2019. Due to this pandemic, human life is becoming increasingly involutes and complex. Many people have died because of this virus. The lack of antiviral drugs is one of the reasons for the spreading of COVID-19 virus. This disease is spreading continuously and easily due to some common mistakes by people, like breathing, coughing and sneezing by infected persons. The main symptom is the normal flu. Therefore, in the present condition, the best precaution for this disease is the face mask, which covers both areas of mouth & nose. According to the government and the World Health Organization, everyone should wear a face mask in busy places like hospitals and marketplaces. In today's environment, it's difficult to tell if someone is wearing a mask or not, and physical inspection is impractical since it adds to labour costs. In this research, we present a mask detector that uses a machine learning facial categorization system to determine whether a person is wearing a mask or not, so that it may be connected to a CCTV system to verify that only persons wearing masks are allowed in. Covid-19 Face Mask Detection Using TensorFlow, Keras and OpenCV Conference Paper Full-text available Dec 2020 Arjya Das Mohammad Wasif Ansari Rohini Basak Thor: A Deep Learning Approach for Face Mask Detection to Prevent the COVID-19 Pandemic Conference Paper Mar 2021 Shay E. Snyder Ghaith Husari Face Mask Detection Using MobileNetV2 in The Era of COVID-19 Pandemic Conference Paper Oct 2020 Samuel Ady Sanjaya Suryo Adi Rakhmawan Fighting against COVID-19: A novel deep learning model based on YOLO-v2 with ResNet-50 for medical face mask detection Nov 2020 Mohamed Loey Gunasekaran Manogaran Mohamed Hamed N. Taha Nour Eldeen Khalifa Deep learning has shown tremendous potential in many real-life applications in different domains. One of these potentials is object detection. Recent object detection which is based on deep learning models has achieved promising results concerning the finding of an object in images. The objective of this paper is to annotate and localize the medical face mask objects in real-life images. Wearing a medical face mask in public areas, protect people from COVID-19 transmission among them. The proposed model consists of two components. The first component is designed for the feature extraction process based on the ResNet-50 deep transfer learning model. While the second component is designed for the detection of medical face masks based on YOLO v2. Two medical face masks datasets have been combined in one dataset to be investigated through this research. To improve the object detection process, mean IoU has been used to estimate the best number of anchor boxes. The achieved results concluded that the adam optimizer achieved the highest average precision percentage of 81% as a detector. Finally, a comparative result with related work has been presented at the end of the research. The proposed detector achieved higher accuracy and precision than the related work. A Hybrid Deep Transfer Learning Model with Machine Learning Methods for Face Mask Detection in the Era of the COVID-19 Pandemic Article Jan 2021 MEASUREMENT Mohamed Loey Gunasekaran Manogaran Mohamed Hamed N. Taha Nour Eldeen Khalifa The coronavirus COVID-19 pandemic is causing a global health crisis. One of the effective protection methods is wearing a face mask in public areas according to the World Health Organization (WHO). In this paper, a hybrid model using deep and classical machine learning for face mask detection will be presented. The proposed model consists of two components. The first component is designed for feature extraction using Resnet50. While the second component is designed for the classification process of face masks using decision trees, Support Vector Machine (SVM), and ensemble algorithm. Three face masked datasets have been selected for investigation. The Three datasets are the Real-World Masked Face Dataset (RMFD), the Simulated Masked Face Dataset (SMFD), and the Labeled Faces in the Wild (LFW). The SVM classifier achieved 99.64 % testing accuracy in RMFD. In SMFD, it achieved 99.49%, while in LFW, it achieved 100% testing accuracy. MobileNetV2: Inverted Residuals and Linear Bottlenecks Conference Paper Jun 2018 Mark Sandler Andrew Howard Z Wang Lin, T.-Y., et al.: Microsoft COCO: common objects in context. In: Fleet, D., Pajdla, T., Schiele, B., Tuytelaars, T. (eds.) ECCV 2014. LNCS, vol. 8693, pp. 740-755. Springer, Cham (2014). https://doi.org/10.1007/978-3-319-10602-1 48 Face mask detection using deep learning during COVID-19 Jan 2021 S Taneja A Nayyar P Nagrath Taneja, S., Nayyar, A., Nagrath, P.: Face mask detection using deep learning during COVID-19. In: International Conference on Computing, Communications and Cyber-Security (2021). https://doi.org/10.1007/978-981-16-0733-2 3 Mohamed Amine Meddaoui Mohammed Erritali
https://www.researchgate.net/publication/362536576_Mask_Detection_Using_IoT_-_A_Comparative_Study_of_Various_Learning_Models
Processes | Free Full-Text | Transient Characteristics of Three-Dimensional Flow in a Centrifugal Impeller Perturbed by Simple Pre-Swirl Inflow The pre-swirl inflow generated by guide vanes could improve the hydrodynamic performances of centrifugal pumps as long as the inflow matches the patterns of internal flow of the impeller. In this work, we present a numerical investigation on the internal flow in a centrifugal impeller subjected to inflow artificially constructed with simple pre-swirling; unsteady Reynolds-Averaged Navier-Stokes (URANS) simulations are performed at the designed flow rate with five values of rotating velocity of the inflow, i.e., Urot/Uref = & minus;0.5, & minus;0.3, 0.0, 0.3 and 0.5, where Urot and Uref denote the rotating and normal velocity component at the entrance of the inflow tube, respectively. The primary objective of this work is to reveal the three-dimensional characteristics of internal flow of the impeller as influenced by the superimposed pre-swirl inflow, and to identify the propagation of inflow within the impeller. The numerical data are presented and analyzed in terms of the streamline fields, the distributions of various velocity components along the circumferential and axial directions, the pressure distribution and limiting streamlines on the surfaces of a blade. Numerical results reveal that separation occurs around the leading edge of the blades and occasionally at the trailing edge, and the internal flow is more uniform in the central region of the channels. A noticeable fluctuation of both radial and circumferential velocities is observed at the outlet of the impeller as it is subjected to counter-rotating inflow, and the greatest fluctuation is close to the hub instead of the middle channel and shroud as for the co-rotating inflow. The boundary layer flow of suction surface is more sensitive to the inflow; occasional small-scale separation bubble occurs on the suction surface around the leading edge for some blades, and reattachment of separated flow is reduced for the counter-rotating inflow. Transient Characteristics of Three-Dimensional Flow in a Centrifugal Impeller Perturbed by Simple Pre-Swirl Inflow by Ze Wang and Wei Zhang * Key Laboratory of Fluid Transmission Technology of Zhejiang Province, Zhejiang Sci-Tech University, Hangzhou 310018, China Author to whom correspondence should be addressed. Processes 2022 , 10 (10), 2007; https://doi.org/10.3390/pr10102007 Received: 6 September 2022 / Revised: 26 September 2022 / Accepted: 27 September 2022 / Published: 5 October 2022 Abstract : The pre-swirl inflow generated by guide vanes could improve the hydrodynamic performances of centrifugal pumps as long as the inflow matches the patterns of internal flow of the impeller. In this work, we present a numerical investigation on the internal flow in a centrifugal impeller subjected to inflow artificially constructed with simple pre-swirling; unsteady Reynolds-Averaged Navier-Stokes (URANS) simulations are performed at the designed flow rate with five values of rotating velocity of the inflow, i.e., U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5, where U rot and U ref denote the rotating and normal velocity component at the entrance of the inflow tube, respectively. The primary objective of this work is to reveal the three-dimensional characteristics of internal flow of the impeller as influenced by the superimposed pre-swirl inflow, and to identify the propagation of inflow within the impeller. The numerical data are presented and analyzed in terms of the streamline fields, the distributions of various velocity components along the circumferential and axial directions, the pressure distribution and limiting streamlines on the surfaces of a blade. Numerical results reveal that separation occurs around the leading edge of the blades and occasionally at the trailing edge, and the internal flow is more uniform in the central region of the channels. A noticeable fluctuation of both radial and circumferential velocities is observed at the outlet of the impeller as it is subjected to counter-rotating inflow, and the greatest fluctuation is close to the hub instead of the middle channel and shroud as for the co-rotating inflow. The boundary layer flow of suction surface is more sensitive to the inflow; occasional small-scale separation bubble occurs on the suction surface around the leading edge for some blades, and reattachment of separated flow is reduced for the counter-rotating inflow. Keywords: centrifugal impeller ; pre-swirl inflow ; three-dimensional flow 1. Introduction Centrifugal pumps are widely used for liquid transportation applications in many fields, such as thermal power plants, metallurgical production, and processing industries. The performances of the centrifugal pumps, i.e., head and efficiency which represent the work and loss during energy transfer, are greatly determined by the centrifugal impeller in terms of the patterns of its internal flow. Since energy transfer between the impeller and fluid is crucial for the implementation of the pumps, the characteristics of internal flow within the impeller and even the whole pump system have been investigated in many works, even for the simplest working conditions as steady and uniform fluid enters the pump. However, in a lot working circumstances, the flow patterns are rather complex as they are affected by certain influential factors, such as unsteady and/or non-uniform inflow, during a start/stop stage where the rotation speed varies, and in a multi-stage pump. The flow in the channels of the impeller may separate from the solid walls and result in separation bubbles which block the channel, and the interactions between the flows in the impeller and inflow tube or diffusers are consequently affected. To understand the mechanisms of flow in a centrifugal impeller, a large number of numerical and experimental investigations have been carried out with the consideration of various influential factors. Byskov et al. [ 1 , 2 ] performed large-eddy simulation (LES) on the internal flow of a six-blade impeller for a centrifugal pump. The LES approach is capable of accurately predicting the hydrodynamic performances of the impeller and capturing the transient flow field compared with the experimental result. No significant separation is observed at designed flow rate, while notable differences are shown for flows in neighboring channels at a quarter flow rate. A steady non-rotating stall was observed at the entrance of one channel and relative vortices were observed for the rest channels. Zhang et al. [ 3 , 4 ] analyzed the transient evolutions of stalled structures in a low specific speed centrifugal pump based on coherent analysis of pressure signals, and presented and explored the unsteady evolution of flow and pressure pulsation in the stagnant state by using the DDES method. Krause et al. [ 5 ] and Ullum et al. [ 6 ] successfully captured the rotating stall flow using the time-resolved particle image velocimetry (PIV) technique. Zhou et al. [ 7 , 8 ] studied stalled flow in a centrifugal pump using LES approach. As the flow rate decreases, the stalled cell grows in size and occupies the channel. The pressure fluctuation caused by the evolution of stalled cell is analyzed, and the peak value of the pressure fluctuation at quarter designed flow rate is obviously greater than that at half designed flow rate. Pei et al. [ 9 ] carried out numerical simulations on flow in a centrifugal pump with a volute under partial load to analyze the three-dimensional periodic flow in all channels of the impeller. Li et al. [ 10 ] measured the internal flow in the impeller of a low specific speed centrifugal pump using the PIV technique to quantify the energy conversion characteristics as determined by the internal flow patterns. Westra et al. [ 11 ] analyzed the effect of secondary flow in the impeller of a low specific speed centrifugal pump with vane-less diffuser under designed and off-designed conditions. The patterns of inflow at the entrance of the centrifugal impeller have a substantial impact on the hydrodynamic performance of the impeller, as revealed in some works. Song et al. [ 12 ] studied the influence of different pre-swirl inflows on the aerodynamic performances of the impeller in a centrifugal compressor. Xiao et al. [ 13 ] conducted numerical simulations on the internal flow of a single-stage centrifugal compressor with inflow following pre-swirl patterns; numerical results showed that the inflow pre-swirling directly affects the circumferential distribution of flow parameters in the impeller. Gish et al. [ 14 ] studied the effect of the geometry of inlet stators on the performances of a hydro-turbine under different Reynolds numbers, and found the proper geometry has the potential to improve the performance. Danlos et al. [ 15 ] investigated flow in a compressor impeller and analyzed the influence of pre-swirling on the instability of the compressor system with emphasis on the surge line. Amin and Xiao [ 16 ] conducted numerical simulations on flow through a horizontal-axis tidal turbine with or without the pre-swirl stator. It was found that the velocity field around the turbine can be improved by using the pre-swirl stator, and the turbine efficiency can be increased by about 13% at a certain blade tip velocity ratio. Mohseni et al. [ 17 ] conducted numerical and experimental studies on the effect of guide blade profiles in terms of the setting angle and positive or negative inlet swirling, and found that series profiles showed better aerodynamic performance than S-profile under negative inlet swirls. Zhang et al. [ 18 ] studied the clocking effect in a multi-stage centrifugal pump in terms of the velocity field and hydrodynamic performances of the pump; it was found that at the appropriate clocking position, the guide vanes could effectively reduce the size and intensity of vortices between neighboring stages of the pump. Zhao et al. [ 19 ] applied the inlet guide vane in a centrifugal compressor to improve its performance and studied the flow patterns in the impeller. Xu et al. [ 20 ] studied the influence of chord length and installation angle of guide vanes on the efficiency and internal flow field of an axial-flow pump, and found that the efficiency can be improved under low flow rates by rotating the guide vanes in the counter-clockwise direction. Poujol et al. [ 21 ] studied the effect of staggered inlet guide vanes on the stability of a centrifugal compressor. The increased staggered angle moves the surge line towards the left, and rotating instability occurs at a lower mass flow rate. Zhong et al. [ 22 ] experimentally tested the performance characteristics of an axial-flow pump with and without guide vanes to explore the patterns of flow in the impeller. Liu et al. [ 23 ] conducted numerical calculations using the steady and unsteady Reynolds-averaged Navier-Stokes (RANS and URANS) simulation approaches to investigate the internal flow in a centrifugal fan under the condition of incoming flow from an upstream bended inflow tube of various radii and demonstrated the effects of the non-axisymmetric pre-swirl flow generated due to the curvature of the bended inflow tube. Heidarian et al. [ 24 ] modelled shark’s skin for the first time, and analyzed the effects of riblet on a submerged flat plate. Jiang et al. [ 25 ] presented a review on two phase performances from various centrifugal pumps designs, mainly based on experimental results and detected the significant geometrical parameters. Heidarian et al. [ 26 ] presented calculations on the Clark-Y wing section of the Reynolds-averaged Navier-Stokes (RANS) equations solver and verified the numerical results of lift and drag of the rectangular airfoil at ground effect. Xu et al. [ 27 ] developed a wind turbine rotor blade design and optimization method and introduced a propeller-turbine rotor code coupling aerodynamic and structural properties. It is revealed in the above reviewed literature that the characteristics of inflow of the centrifugal impeller greatly determine the patterns of flow within the impeller and consequently the performances of the pump system. In most of the existing studies, the centrifugal impeller of the pump or compressor system is equipped with an upstream guide vane or stator system to be compatible to different working conditions, thus the pre-swirl flow is generated and the inflow of the centrifugal impeller rotates in the circumferential direction and is spatially non-uniform. It is already known that the pre-swirl inflow affects the internal flow of the impeller and determines the hydrodynamic performances of the impeller, however, the transient characteristics of the internal flow is not revealed in terms of the three-dimensionality, which represents the temporal unsteadiness and spatial non-uniformity that are crucially related with significant flow phenomena such as boundary layer separation and stall. In this work, we performed a numerical investigation on the transient flow in a centrifugal impeller at the designed flow rate under the influence of pre-swirl inflow. Different from the models in existing works where the pre-swirl flow is generated by the inlet guide vanes or a stator of specific geometry, we artificially constructed the pre-swirl flow in a simple way without the consideration of certain geometries that the inflow rotates in the circumferential direction. The benefit of this model is that the essential influence of the pre-swirl flow on the internal flow of impeller is considered, while the particular effect associated with the specific geometry or installation of guide vanes or stator is omitted, thus the present model reflects the general influence from the pre-swirl flow. The objective of our work is to demonstrate the effect of pre-swirl inflow, in both magnitude and direction, on the transient three-dimensional flow within the impeller. The three-dimensionality of the internal flow are presented and analyzed mainly in terms of the distributions of radial, circumferential and axial velocities within the channels of the impeller. Moreover, we discuss the boundary layer flow on the blade surfaces in terms of the limiting streamlines and pressure field. The paper is organized as follows. Section 2 introduces the physical models, the formulation of the pre-swirl inflow, the numerical simulation and grid independence verification. Section 3 presents and analyzes the numerical results. Section 4 gives some conclusions. 2. Numerical Setup 2.1. Physical Model In this work, we investigate the flow in a six-blade centrifugal impeller which is introduced in the work of Byskov et al. [ 1 , 2 ], as shown in Figure 1 a. The geometrical and operational parameters of the impeller are listed Table 1 and Table 2 respectively. Byskov et al. [ 2 ] have carried out a detailed experimental study on the internal flow of this centrifugal impeller at designed and off-designed flow rates using the PIV technique, and the transient flow patterns are revealed and compared with the numerical data obtained by LES approach. Since our objective is to explore the patterns of flow in the impeller subjected to pre-swirl inflow, an extended inflow tube is applied upstream of the impeller to permit the development of swirling flow; its radius is the same as that of the impeller and extends in the streamwise (axial) direction for a length of 2.1 D 1 . An outflow section is placed at the outlet of the impeller to prevent the occurrence of backflow; the inner and outer diameters are D 2 and 1.36 D 2 , respectively, and the width is the same as that of the impeller, i.e., b 2 . The computational domain is shown in Figure 1 b. The centrifugal impeller is geometrically axisymmetric and the blades are backward-curved, thus the direction of swirling of the inflow determines the patterns of internal flow of the impeller. The fluid at the entrance of the inflow tube has two velocity components. The uniform streamwise velocity is along the axial direction towards the impeller whose magnitude is defined as U ref as determined by the volume flow rate. The circumferential velocity defined as U rot is applied perpendicular to the streamwise velocity. The direction of inflow could be either clockwise or counterclockwise, i.e., in contrary or aligned with the direction of rotation of the impeller, and is termed as counter-rotating and co-rotating inflow as exemplified in Figure 2 . The magnitude of circumferential velocity is set as zero, 0.3 U ref and 0.5 U ref , and is represented as positive or negative depending on the direction. 2.2. Numerical Methods The time-dependent incompressible flow is governed by the conservation of mass and momentum equations [ 28 ]: ∂ u i ∂ x i = 0 (1) ∂ u i ∂ t + u j ∂ u i j = f i − 1 ρ ∂ P ∗ ∂ x i + ν ∂ 2 u i ∂ x x j (2) where x i is the components of the Cartesian coordinate system; u i is the velocity component; P * represents the pressure considering the conversion of turbulent kinetic energy and centrifugal force; f i is the component of volume force. Since the SST k - ω turbulence model [ 29 ] has good results in the simulation of boundary layer flows near the wall [ 30 ], the SST k - ω turbulence model is chosen to simulate the impeller numerically in this paper. The transport equations of the turbulent kinetic energy k and the turbulent dissipation rate ω [ 31 ] are as follows: ∂ k ∂ t + ∇ ⋅ ( u k ) = P u ω = δ S 2 − β ω 2 + ∇ ⋅ ν + σ w ν T ∇ ω 1 − F σ ω 2 ω ∇ k ⋅ ∇ ω T (4) ν T = a 1 k max ω ; S F 2 (5) where P k = min ν T ∇ × u ⋅ ∇ × u T β ∗ k ω , S is the absolute value of the vorticity. The constants of the SST k - ω turbulence model in the present study [ 32 ] are: σ k 1 = 0.85, σ k 2 = 1.0, σ ω 1 = 0.5, σ ω 2 = 0.856, β 1 = 0.075, β 2 = 0.0828, α 1 = 0.31, δ 1 = 0.5532, δ 2 = 0.440, β * = 0.09. In this work, the simulations are performed for the centrifugal impeller operated under designed flow rate Q d = 3.06 L/s, which is used to compute the magnitude of streamwise velocity imposed at the entrance of the inflow tube (U ref ). The UDF program is set in the inlet boundary condition to control the rotation direction of the fluid. The circumferential velocity of the inflow is set as U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5 in which the value of 0.0 denotes zero-swirling inflow. Zero gauge pressure is set at the outlet of the outflow section. No-slip condition is applied for velocity components on all solid walls. The unsteady Reynolds-averaged Navier-Stokes (URANS) simulations were performed using ANSYS-Fluent. The governing equations are discretized by second-order central difference scheme in space and second-order implicit scheme in time. The SIMPLEC algorithm is used to decouple the solutions of velocity and pressure. The time step size of the unsteady simulation is fixed at 2.3 × 10 −4 s as the impeller rotates for one degree. The maximum number of iterations in one physical step is 20 and the convergence criterion of all equation is 10 −5 . To ensure the fully development of flow within the impeller, we first carried out the simulation for ten revolutions of the impeller, and subsequently the production simulation as the impeller rotates for another revolution that the results are saved for following analysis and discussions. 2.3. Grid Sensitivity Study The structured grid of the model is generated using ANSYS-ICEM CFD, as shown in Figure 3 a. To resolve the boundary layer flow, the grid is refined in the near-wall region of all solid walls especially around the leading and trailing edges of the blades, as given in Figure 3 b,c. The value of y+ on the surfaces of blade, shroud and hub is generally lower than 10, and is slightly higher as <15 at the outlet of impeller. We performed grid sensitivity study to evaluate the influence of grid number on the accuracy of simulation results. Four sets of grids are generated and the head of the impeller for the zero-swirling inflow case is calculated and listed in Table 3 . It is seen that the relative difference is less than 5% for grid 3 and the experimental data. To balance the computational cost and numerical accuracy, we chose to use grid 3 for following simulations. 3. Results and Discussion 3.1. Development of Pre-Swirl Inflow Although swirling is imposed at the entrance of the inflow tube, the circumferential velocity of the inflow, representing the intensity of swirling, is attenuated during its motion into the interior of the finite-length tube along with the formation of boundary layer. It is necessary to quantify the intensity of pre-swirl flow at the exit of the inflow tube (inlet of the impeller). Figure 4 shows the distribution of axial and circumferential velocities in the radial direction at the exit of the inflow tube. Since the inflow tube is axisymmetric in geometry, the distributions are the same at any circumferential position. It is seen in the figure that the uniform inflow, in both axial and circumferential directions, gradually develops and presents a parabolic distribution after the fluid moves through the inflow tube. The distribution of axial velocity is obviously affected by the value of U rot in that the velocity of near-wall flow close to the inner wall (shaft of the impeller) is comparably smaller at certain radial positions for the U rot /U ref = −0.5 and 0.5 cases. The nearly identical distributions reflect that the rotating flow in the impeller has no influence on the flow in the upstream region. The swirling of the inflow is notably attenuated as the flow develops towards the impeller. The maximum magnitude of circumferential velocity reduces to around 0.24 U ref and 0.40 U ref for the U rot /U ref = ±0.3 and ±0.5 cases, in which the difference denotes the attenuation. As the value of U rot increases, the maximum magnitude of axial and circumferential velocities appears close to the outer wall of the inflow tube because of centrifugal force. The effective Reynolds number for flow near the inner wall of the tube gets lower, thus a thick boundary layer develops. 3.2. General Flow Patterns To demonstrate the general patterns of flow in the impeller, we present the instantaneous distribution of streamlines at three axial cross-sections in Figure 5 . The cross-sections are labeled as Z/b 2 = 0.1, 0.5 and 0.9 as measured from the hub of the impeller, i.e., close to the hub, at the middle and close to the shroud of the impeller. In general, the streamline field is quite similar for the several cases with different pre-swirl inflows. Small-scale vortices appear at the leading edge of the suction side of the blade, and no reversed flow is observed within the channels. On the cross-sections at Z/b 2 = 0.5 and 0.9, tiny vortices may also appear around the trailing edge of some blades. The boundary layer flow is found to detach from the pressure surface in the upstream part of the blade. As the fluid moves towards the outlet of impeller, the significant Coriolis force drives the fluid towards the pressure surface where the magnitude of velocity increases, and the flow at the outlet of impeller is getting uniform. It is observed that for co-rotating inflow (U rot < 0), the detachment of boundary layer flow on the pressure surface is relatively weak compared with the counter-rotating inflow (U rot > 0) cases, especially for the Z/b 2 = 0.1 cross-section. 3.3. Three-Dimensional Flow: Blade-to-Blade Distribution The three-dimensionality of internal flow of the impeller is presented and analyzed by the blade-to-blade distribution of velocity components. We define the normalized radial position as r* = (r − r 1 )/(r 2 − r 1 ) in which r 1 and r 2 are the radii of inlet and outlet of the channels, respectively. Three radial positions for the cross-sections are chosen for further analysis which locate at the inlet, middle and outlet of the channels, i.e., r* = 0.0, 0.5 and 1.0, as exemplified in Figure 6 . The distributions of normalized radial velocity V r in the circumferential direction across all channels are presented in Figure 7 . The curves are obtained at the intersection line formed by the axial cross-section at Z/b 2 = 0.5 and the respective constant-r* cross-section, and for six moments during the impeller rotates for 60° which is termed as period T. The distributions are generally similar at the leading edge of blades for cases of inflows of different swirling, and the temporal fluctuation is minor as observed by the overlapping curves. The magnitude of V r reduces substantially at the middle and outlet of the channels because of the diverging of the channel, and significant temporal fluctuation is seen for all channels. The distribution of V r around the leading edge of the blades (r* = 0.0) is quite similar for the several channels. The magnitude of V r gradually increases from the pressure surface and abruptly decreases close to the suction surface, and could even be negative as a result of the formation of vortices for cases of zero-swirling (U rot = 0.0) and counter-rotating (U rot > 0) inflows, and the reversed flow is more obvious for the U rot = 0.3 and 0.5 cases. For co-rotating inflow cases, the peak magnitude of Vr observed near the suction surface gets smaller compared with other cases. In the middle of the channels (r* = 0.5), the flow within the same channel is more non-uniform and the temporal fluctuation is strong. There is both abrupt increasing and decreasing close to the pressure and suctions surfaces of the blades, while an additional fluctuation appears at the center of the channel for all cases. It is observed that as U rot increases from negative to positive, i.e., from co-rotating to counter-rotating inflow, the position for the peak magnitude of V r moves from the suction surface to pressure surface for all channels, and the fluctuating amplitude at any circumferential position greatly increases, reflecting stronger unsteady behaviors of internal flow. The temporal fluctuation of V r at the outlet of the impeller (r* = 1.0) is much stronger than flow in the center of the channels. Except for the drastic variation in velocity magnitude on the surfaces of the blades, the internal flow in the central region of all channels exhibits significant temporal variation. It is seen that the magnitude of V r varies a lot especially for inflow with strongly swirling inflow U rot /U ref = ±0.5, while the position of the peak magnitude also moves in time, although the motion is asynchronous for the various channels. The magnitude of V r is greatly different for flow in various channels. In the case of U rot /U ref = 0.3, abnormal fluctuation of V r is found in channel-I and channel-II with mild fluctuation and relatively small peak magnitude, especially in channel-II. The three-dimensionality of flow from a blade-to-blade view is further presented and analyzed by the distribution of circumferential velocity V θ on the intersecting lines between the axial cross-section at Z/b 2 = 0.5 and radial cross-sections at r* = 0.0, 0.5 and 1.0, as shown in Figure 8 . The flow is quite stable and there is almost no temporal variation in velocity magnitude at the inlet of channels, and the distribution is quite similar for the various channels. A minor fluctuation is observed at the middle of the channels, and the largest magnitude reduces; the distribution is still similar for the various channels. Great fluctuations form at the outlet of the channels especially in the central region. The circumferential velocity shows almost no temporal fluctuation at the leading edge of the blades especially close to the surfaces, and the distributions in various channels are similar. The maximum magnitude for the negative velocity appears close to the suction surface and the value increases with U rot which is the same as that of V r . Moreover, a positive value of V θ is clearly observed close to the suction surface for zero-swirling (U rot = 0.0) and counter-rotating (U rot > 0) inflow cases, and it gradually becomes obvious as U rot increases. This is generated by the small-scale vortices at the inlet of the channels which restrain the development of flow in the channels and produce the weak circumferential motion of local flow, as is also seen in Figure 5 . In the middle region of the channels, the maximum magnitude of negative V θ reduces compared with flow at the inlet of the channels, and the difference among the various peaks is minor. There is one local peak in the central region of the channel whose magnitude decreases with the value of U rot ; for high values of U rot , the fluctuation tends to occupy the whole channel, as revealed by the fluctuation around the suction surface. The flow at the outlet of the channels is highly fluctuating in time for the majority of the channel, and the fluctuation is especially remarkable for the counter-rotating (U rot > 0) inflow cases. For the co-rotating (U rot < 0) inflow cases, the temporal fluctuation is notably non-uniform especially for the U rot = −0.5 case, i.e., strong in channel-I, channel-II, channel-III and channel-VI but relatively weak in channel-IV and channel-V. 3.4. Three-Dimensional Flow: Hub-to-Shroud Distributions Since there is a transition of direction for flow from axial to radial in the impeller, the patterns of flow close to the hub and shroud of the impeller differ because of the inertia of flow and possible separation of boundary layer flow on the curved surfaces. The three-dimensionality of internal flow is also reflected by the non-uniformity of velocity across the meridian section of the impeller. In this section, we analyze the three-dimensional flow by its hub-to-shroud distributions of velocity components at two positions as given in Figure 6 ; the two hub-to-shroud lines locate at r* = 0.5 close to the pressure and suction surfaces of the same channel. The non-dimensional quantity b* is used to denote the local coordinate as the distance measured from the hub, and b* = 0.0 and 1.0 denote the hub and shroud, respectively. Figure 9 shows the distributions of instantaneous radial velocity V r on the two hub-to-shroud lines at six equally spaced moments as the impeller rotates for 60°. The curves exhibit temporal variations which are greatly dependent on U rot , and the curves representing flow adjacent to the surfaces are drastically different depending on the position (pressure or suction surface). For the near-wall flow of pressure surface, the curves vary gently for the co-rotating inflow cases (U rot < 0), although the amplitude of variation is noticeable mainly in the central region across the channel. For the zero-swirling inflow case (U rot = 0.0), the fluctuation is the most significant at around b* = 0.3, i.e., close to the hub, while it is much smaller in the region close to the shroud. As U rot further increases, the magnitude of instantaneous V r generally increases in the near-wall regions of hub and shroud, and presents a great fluctuation in the central region of the channel, resulting in an uneven double-peak pattern. The radial velocity of flow near the hub is higher than that of the shroud; this is attributed to the inertia of fluid during the transition of direction as it moves through the channel. The radial velocity in the central region can be nearly zero at a certain moment; we believe that this is induced by the weakly separated flow in the upstream region. The magnitude of V r for flow close to the suction surface is generally higher. The fluctuating amplitude is quite small in the region very adjacent to the hub and shroud surfaces, while it rapidly increases for flow away from the surfaces. The fluctuation is strongest in the central region of the channel for the co-rotating inflow cases (U rot < 0) and comparably weak for the zero-swirling inflow case (U rot = 0.0). For counter-rotating inflow cases (U rot > 0), the radial velocity fluctuates notably near the hub, and reversed local flow with negative value of V r appears at certain moments due to the transient evolution of separated vortex. The distributions of circumferential velocity V θ in the hub-to-shroud direction are presented in Figure 10 . The temporal variations of V θ at the two positions differ a lot in terms of the magnitude, fluctuating amplitude and distribution. The magnitude and temporal variation of V θ is more uniform for flow near the pressure surface. For flow near the pressure surface, the distribution of V θ is generally uniform through the whole channel in the hub-to-shroud direction; the magnitude of velocity increases or decreases as a whole such that the fluctuating amplitude at different positions is not substantially different. As U rot increases, the amplitude first decreases until the zero-swirling inflow case and then increases, thus the fluctuation is the most notable for cases of U rot /U ref = ±0.5. For flow near the suction surface, the distribution of V θ is obviously non-uniform and the maximum magnitude of negative V θ generally appears close to the hub. It is found that the co-rotating inflow (U rot < 0) results in great fluctuation in the central region and close to the shroud of the channel, while counter-rotating inflow (U rot > 0) produces strong fluctuation in the central region and close to the hub of the channel. A consistent reduction in both circumferential and radial velocities is observed for the counter-rotating inflow (U rot > 0) cases which is induced by a small-scale vortex generated in the upstream part of the channel and restrains the development of flow towards the outlet. 3.5. Pressure Gradient Field on the Blade Surfaces The patterns of near-wall flow of the blade are affected by the pressure gradient field on the surfaces; positive and negative pressure gradient could accelerate and decelerate the local flow. To analyze how the pre-swirl inflow affect the near-wall flow of the blade, Figure 11 presents the distributions of instantaneous pressure coefficient on the mid-span cross-section (Z/b 2 = 0.5) from the inlet to outlet of the blade separating channel-I and channel-II at six moments. A local coordinate S is defined on the curved surface of the blade which starts from the leading edge of the blade and ends at the trailing edge, and S 0 is the arc length of the curve, thus S/S 0 = 0.0 and 1.0 represent the leading and trailing edges of the blade, respectively. It is seen that both the pressure and suction surfaces of the blade are occupied by the adverse pressure gradient (APG) field. On the pressure surface, the pressure coefficient monotonically increases from the leading edge and reaches maximum at around S/S 0 = 0.8–0.9, and then slightly decreases until the trailing edge. However, it is observed in Figure 5 that there is no separation because of the weak APG field. The fluctuation of pressure coefficient is relatively strong for cases of inflow with higher Urot, especially in the upstream and middle section of the pressure surface S/S 0 = 0.0–0.7, while the pre-swirl inflow has no obvious influence on the pressure coefficient in the remained part of the surface. The pressure coefficient on the suction surface of the blade exhibit entirely different distributions. It decreases right at the leading edge and then recovers until the trailing edge, thus the suction surface is almost entirely occupied by APG which decelerates the boundary layer flow along with the viscous drag. It is seen in Figure 5 that small-scale vortices are generated on the suction surface of the leading edge, and moves towards the outlet of impeller while the size and intensity do not vary a lot. 3.6. Topology of Limiting Streamlines The three-dimensionality of boundary layer flow on the surfaces of the blade reflects the patterns of possible separation and reattachment. Figure 12 shows the distribution of instantaneous limiting streamlines on the pressure and suction surfaces of the blade located between channel-I and channel-II. The sinks and sources of the streamlines represent the separation and reattachment of local boundary layer flow. It is seen that separation and reattachment of flow, although weak as seen in Figure 5 , occur around the leading edge of the blade, while the boundary layer flow in the middle and downstream sections of the blade is stable. The pre-swirl inflow does not have any noticeable effect on the patterns of separation and reattachment, especially for the pressure surface. However, the patterns of reattachment on the suction surface are also determined by the corner flow between the surface and the hub/shroud of the impeller. It is noticed that for the zero-swirling inflow case (U rot = 0.0), reattachment also occurs at the central region of the suction surface. Therefore, it is believed that for the counter-rotating inflow cases (U rot > 0), the separation and reattachment on the blade surfaces can be effectively reduced which improves the uniformity of the flow. 4. Conclusions This work presents a numerical investigation on the transient characteristics of three-dimensionality of internal flow in a centrifugal impeller perturbed by simple pre-swirl inflow. The influences of co-rotating and counter-rotating inflow under the designed flow rate are explored using the URANS approach. The following conclusions are obtained: (1) The temporal fluctuation of flow is weak at the inlet of the blade channels (r* = 0.0). Close to the suction surface, the magnitude of radial velocity V r for the counter-rotating inflow is 15–25% larger compared to the co-rotating inflow cases. The peak magnitude reaches the maximum about 2.5 m/s near the suction surface. In the middle of the channels (r* = 0.5), the peak magnitude of V r moves from suction to pressure surface as the inflow gets from co-rotating to counter-rotating, and the fluctuating amplitude greatly increases, and the magnitude of V r varies from 0 to 1.2 m/s. The fluctuation is highest at the outlet of the channels (r* = 1.0) especially for the counter-rotating inflow cases. The magnitude of circumferential velocity V θ reaches the minimum in the central channel for the counter-rotating inflow cases, and the minimum value reaches about 2.2 m/s. (2) The internal flow of the impeller is highly three-dimensional in the hub-to-shroud direction. The strongest fluctuation of V r occurs in the central region of the channel for the co-rotating inflow cases, while the peak is observed close to the hub for the counter-rotating inflow cases which can be negative as a result of the separated vortex. Close to the hub, compared to the zero-swirling inflow, the magnitude of V r near the pressure surface is smaller for the co-rotating inflow cases and the degree of reduction increases with the increase in rotating speed, while for the counter-rotating inflow cases the magnitude of V r reaches 1.25 m/s, which is 25% larger for the zero-rotating inflow cases. On the contrary, near the suction surface the magnitude of V r is smaller for the counter-rotating inflow cases about 50–75%, compared to the co-rotating cases. For the circumferential velocity V θ , great fluctuation appears in the central region and close to the shroud for the co-rotating inflow cases, while in the central region and close to the hub for the counter-rotating cases. (3) Both pressure and suction surfaces of the blade are mainly occupied by an adverse pressure gradient field. There is no obvious separation on the pressure surfaces because of the weak APG, and small-scale vortices appear on the suction surface around the leading edge. (4) Three-dimensional separation and reattachment of flow occur around the leading edge of the blade are observed by the limiting streamlines, while the internal flow is quite stable and uniform in the middle and downstream sections of the channels. Reattachment also occurs at the central region of the suction surface for the zero-swirling inflow, and the counter-rotating inflow could reduce the reattachment which improves the uniformity of the internal flow. The primary objective of this work was to present and analyze the transient characteristics of three-dimensional internal flow of a centrifugal impeller as perturbed by simply constructed pre-swirl inflow, and to reveal the influence of the pre-swirl inflow. The findings and conclusions may be helpful in the design of a pump system involving a curved inflow tube or guide vanes system for the improved efficiency and operational stability of the impeller. Since the pre-swirl inflow is simple in pattern, the significance of present study is limited, and we would analyze the influence of realistic guide vanes which generate non-uniform and fluctuating wake flow in future works. Author Contributions Conceptualization, Z.W. and W.Z.; data curation, Z.W.; formal analysis, Z.W. and W.Z.; funding acquisition, W.Z.; investigation, Z.W. and W.Z.; methodology, Z.W.; project administration, W.Z.; resources, W.Z.; software, Z.W.; supervision, W.Z.; validation, Z.W.; visualization, Z.W.; writing—original draft, Z.W.; writing—review and editing, W.Z. All authors have read and agreed to the published version of the manuscript. Funding This work was supported by Natural Science Foundation of China (52176047), Zhejiang Province Science and Technology Plan Project (2020C04011, 2022C01227) and 111 Project (D21011). Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. References Byskov, R.K.; Jacobsen, C.B.; Pedersen, N. Flow in a centrifugal pump impeller at design and off-design conditions-Part I: Particle image velocimetry (PIV) and laser Doppler velocimery (LDV) measurements. J. Fluids Eng. 2003 , 125 , 61–72. [ Google Scholar ] [ CrossRef ] Byskov, R.K.; Jacobsen, C.B.; Pedersen, N. Flow in a centrifugal pump impeller at design and off-design conditions-Part II: Large eddy simulations. J. Fluids Eng. 2003 , 125 , 73–83. [ Google Scholar ] [ CrossRef ] Zhang, N.; Jiang, J.; Gao, B.; Liu, X. DDES analysis of unsteady flow evolution and pressure pulsation at off-design condition of a centrifugal pump. Renew Energ. 2020 , 153 , 193–204. [ Google Scholar ] [ CrossRef ] Zhang, N.; Gao, B.; Ni, D.; Liu, X. Coherence analysis to detect unsteady rotating stall phenomenon based on pressure pulsation signals of a centrifugal pump. Mech. Syst. Signal Pract. 2021 , 148 , 107161. [ Google Scholar ] [ CrossRef ] Krause, N.; Zähringer, K.; Pap, E. Time-resolved particle imaging velocimetry for the investigation of rotating stall in a radial pump. Exp. Fluids 2005 , 39 , 192–201. [ Google Scholar ] [ CrossRef ] Ullum, U.; Wright, J.; Dayi, O.; Ecder, A.; Soulaimani, A.; Piché, R.; Kamath, H. Prediction of rotating stall within an impeller of a centrifugal pump based on spectral analysis of pressure and velocity data. Phys. Conf. Ser. 2006 , 52 , 004. [ Google Scholar ] [ CrossRef ] Zhou, P.; Dai, J.; Yan, C.; Zheng, S.; Ye, C.; Zhang, X. Effect of Stall Cells on Pressure Fluctuations Characteristics in a Centrifugal Pump. Symmetry 2019 , 11 , 1116. [ Google Scholar ] [ CrossRef ][ Green Version ] Zhou, P.-J.; Wang, F.-J.; Yang, Z.-J.; Mou, J.-G. Investigation of rotating stall for a centrifugal pump impeller using various SGS models. J. Hydrodyn. Ser. B 2017 , 29 , 235–242. [ Google Scholar ] [ CrossRef ] Pei, J.; Yuan, S.-Q.; Li, X.-J.; Yuan, J.-P. Numerical prediction of 3-D periodic flow unsteadiness in a centrifugal pump under part-load condition. J. Hydrodyn. 2014 , 26 , 257–263. [ Google Scholar ] [ CrossRef ] Li, X.; Chen, B.; Luo, X.; Zhu, Z. Effects of flow pattern on hydraulic performance and energy conversion characterisation in a centrifugal pump. Renew Energ. 2020 , 151 , 475–487. [ Google Scholar ] [ CrossRef ] Westra, R.W.; Broersma, L.; Van Andel, K.; Kruyt, N.P. Secondary flows in centrifugal pump impellers: PIV measurements and CFD computations. In Proceedings of the ASME 2009 Fluids Engineering Division Summer Meeting, Vail, CO, USA, 2–6 August 2009; Volume 43727, pp. 305–314. [ Google Scholar ] [ CrossRef ] Song, Z.; Li, X.; Liu, Z. Research on the mechanism of the influence of inlet pre-rotation on the aerodynamic performance of centrifugal impeller. Chin. J. Appl. Mech. 2021 , 38 , 53–59. [ Google Scholar ] [ CrossRef ] Xiao, J.; Gu, C.; Gao, C.; Shu, X.W. Numerical analysis of the flow in centrifugal compressor in consideration of inlet pre-whirl. Chin. J. Power Eng. 2008 , 28 , 400–403. [ Google Scholar ] [ CrossRef ] Gish, L.A.; Carandang, A.; Hawbaker, G. Experimental evaluation of a shrouded horizontal axis hydrokinetic turbine with pre-swirl stators. J. Ocean Eng. 2020 , 204 , 107252. [ Google Scholar ] [ CrossRef ] Danlos, A.; Podevin, P.; Toussaint, M. Pre-swirl mechanism in front of a centrifugal compressor: Effects on surge line and on unsteady phenomena in surge area. MATEC Web Conf. 2017 , 133 , 04002. [ Google Scholar ] [ CrossRef ][ Green Version ] Amin, I.; Xiao, Q. Numerical simulation of a horizontal axis tidal turbine with a pre-swirl stator. Dev. Marit. Transp. Exploit. Sea Resour. 2014 , 2014 , 863–869. [ Google Scholar ] [ CrossRef ] Mohseni, A.; Goldhahn, E.; Van den Braembussche, R.A.; Seume, J.R. Novel IGV designs for centrifugal compressors and their interaction with the impeller. J. Turbomach. 2012 , 134 , 021006. [ Google Scholar ] [ CrossRef ] Zhang, K.; Tan, M.; Wu, X.; Ma, H.; Liu, X. Clocking effect of guide vane in multi-stage centrifugal pump. J. Drain. Irrig. Mach. Eng. 2021 , 39 , 663–670. Available online: https://t.cnki.net/kcms/detail/32.1814.th.20210624.1113.006.html (accessed on 24 July 2021). Zhao, J.; Wang, Z.; Xi, G.; Zhao, Y. Improvements of inlet structure and sweep-angle of guide vane inside a centrifugal compressor at large pre-swirl. J. Xi’an Jiaotong Univ. 2017 , 54 , 1–6. [ Google Scholar ] [ CrossRef ] Xu, L.; Ji, D.; Shi, W.; Xu, B.; Lu, W.; Lu, L. Influence of inlet angle of guide vane on hydraulic performance of an axial flow pump based on CFD. Shock Vib. 2020 , 2020 , 8880789. [ Google Scholar ] [ CrossRef ] Poujol, N.; Trébinjac, I.; Duquesne, P. Effects of inlet guide vanes on the performance and stability of an aeronautical centrifugal compressor. J. Turbomach. 2021 , 143 , 101010. [ Google Scholar ] [ CrossRef ] Zhong, L.; Min, G.; Xiao, K. Experimental study of guide vane influence on performance of axial-flow pump. J. Drain. Irrig. Mach. Eng. 2009 , 27 , 15–18. Available online: https://www.researchgate.net/publication/286887847 (accessed on 30 January 2009). Liu, Z.; Yang, H.; He, H.; Yu, P.; Wei, Y.; Zhang, W. Flow instability in a volute-free centrifugal fan subjected to non-axisymmetric pre-swirl flow from upstream bended inflow tube. Proc. Inst. Mech. Eng. Part A J. Power Energy 2022 , 236 , 689–713. [ Google Scholar ] [ CrossRef ] Heidarian, A.; Ghassemi, H.; Liu, P. Numerical Analysis of the Effects of Riblets on Drag Reduction of a Flat Plate. Appl. Fluid Mech. 2018 , 11 , 3. [ Google Scholar ] [ CrossRef ] Jiang, Q.; Heng, Y.; Liu, X.; Zhang, W.; Bois, G.; Si, Q. A Review of Design Considerations of Centrifugal Pump Capability for Handling Inlet Gas-Liquid Two-Phase Flows. Energies 2019 , 12 , 1078. [ Google Scholar ] [ CrossRef ][ Green Version ] Heidarian, A.; Ghassemi, H.; Liu, P. Numerical Aerodynamic of the Rectangular Wing Concerning to Ground Effect. Am. J. Mech. Eng. 2018 , 6 , 43–47. [ Google Scholar ] [ CrossRef ] Xu, Y.; Liu, P.; Penesis, I.; He, G.; Heidarian, A.; Ghassemi, H. Energy Generation Efficiency and Strength Coupled Design and Optimization of Wind Turbine Rotor Blades. J. Energ. Eng. 2019 , 145 , 04019004. [ Google Scholar ] [ CrossRef ] Cai, J.; Wang, Y.; Yu, S. The Recent Progress and the State-of-art Applications of Navier Stokes Equation. Highlights Sci. Eng. Technol. 2022 , 12 , 114–120. [ Google Scholar ] [ CrossRef ] Menter, F.R.; Kuntz, M.; Langtry, R. Ten years of industrial experience with the SST turbulence model. Turbul. Heat Mass Transf. 2003 , 4 , 625–632. Available online: https://www.researchgate.net/publication/228742295 (accessed on 30 January 2003). Menter, F.R. Influence of freestream values on k-omega turbulence model predictions. AIAA J. 1992 , 30 , 1657–1659. [ Google Scholar ] [ CrossRef ] Menter, F.R. Two-equation eddy-viscosity turbulence models for engineering applications. AIAA J. 2012 , 32 , 8. [ Google Scholar ] [ CrossRef ][ Green Version ] Wilcox, D.C. Reassessment of the scale-determining equation for advanced turbulence models. AIAA J. 2012 , 26 , 11. [ Google Scholar ] [ CrossRef ] Figure 1. The geometry of the centrifugal impeller; ( a ) configuration of six-blade impeller; ( b ) computational domain. Figure 1. The geometry of the centrifugal impeller; ( a ) configuration of six-blade impeller; ( b ) computational domain. Figure 2. Definition of the direction of pre-swirl inflow. The clockwise and counterclockwise directions are termed as counter−rotating and co−rotating inflows, respectively. Figure 2. Definition of the direction of pre-swirl inflow. The clockwise and counterclockwise directions are termed as counter−rotating and co−rotating inflows, respectively. Figure 3. ( a ) Gird of the whole model; ( b ) enlarged view at the leading edge of the blade; ( c ) enlarged view at the trailing edge of the blade. Figure 3. ( a ) Gird of the whole model; ( b ) enlarged view at the leading edge of the blade; ( c ) enlarged view at the trailing edge of the blade. Figure 4. Distributions of axial velocity (V z ) and circumferential velocity (V θ ) at the exit of the inflow tube. Figure 4. Distributions of axial velocity (V z ) and circumferential velocity (V θ ) at the exit of the inflow tube. Figure 5. ( a – e ) Distribution of instantaneous streamlines for (from top to bottom): U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. The left, middle and right columns represent the distributions on the cross-sections at Z/b 2 = 0.1. 0.5 and 0.9, respectively. Figure 5. ( a – e ) Distribution of instantaneous streamlines for (from top to bottom): U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. The left, middle and right columns represent the distributions on the cross-sections at Z/b 2 = 0.1. 0.5 and 0.9, respectively. Figure 6. Definitions of radial cross-sections at r* = 0.0, 0.5 and 1.0. Figure 7. ( a – e ) Distributions of instantaneous normalized radial velocity along the circumferential direction at r* = 0.0 (left), r* = 0.5 (middle) and r* = 1.0 (right) for (from top to bottom) U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. Figure 7. ( a – e ) Distributions of instantaneous normalized radial velocity along the circumferential direction at r* = 0.0 (left), r* = 0.5 (middle) and r* = 1.0 (right) for (from top to bottom) U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. Figure 8. ( a – e ) Distributions of instantaneous normalized circumferential velocity along the circumferential direction at r* = 0.0 (left), r* = 0.5 (middle) and r* = 1.0 (right) for (from top to bottom) U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. Figure 8. ( a – e ) Distributions of instantaneous normalized circumferential velocity along the circumferential direction at r* = 0.0 (left), r* = 0.5 (middle) and r* = 1.0 (right) for (from top to bottom) U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. Figure 9. ( a – e ) Distributions of instantaneous normalized radial velocity along the hub-to-shroud direction for flow near the pressure surface (left) and suction surface (right) for (from top to bottom) U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. Figure 9. ( a – e ) Distributions of instantaneous normalized radial velocity along the hub-to-shroud direction for flow near the pressure surface (left) and suction surface (right) for (from top to bottom) U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. Figure 10. ( a – e ) Distributions of instantaneous normalized circumferential velocity along the hub-to-shroud direction for flow near the pressure surface (left) and suction surface (right) for (from top to bottom) U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. Figure 10. ( a – e ) Distributions of instantaneous normalized circumferential velocity along the hub-to-shroud direction for flow near the pressure surface (left) and suction surface (right) for (from top to bottom) U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. Figure 11. ( a – e ) Distribution of pressure coefficient at the mid-span (Z/b 2 = 0.5) of pressure surface (left) and suction surface (right) from inlet to outlet of the channel. The curves are plotted (from top to bottom) at U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. Figure 11. ( a – e ) Distribution of pressure coefficient at the mid-span (Z/b 2 = 0.5) of pressure surface (left) and suction surface (right) from inlet to outlet of the channel. The curves are plotted (from top to bottom) at U rot /U ref = −0.5, −0.3, 0.0, 0.3 and 0.5. Figure 12. Instantaneous limiting streamlines on the pressure ( top ) and suction ( bottom ) surfaces of the blade for (from ( a – e )) U rot /U ref = −0.5, 0.5, −0.3, 0.3 and 0.0. Figure 12. Instantaneous limiting streamlines on the pressure ( top ) and suction ( bottom ) surfaces of the blade for (from ( a – e )) U rot /U ref = −0.5, 0.5, −0.3, 0.3 and 0.0. Table 1. Geometric specifications of the centrifugal impeller. Table 1. Geometric specifications of the centrifugal impeller. Parameter Value Inlet Diameter, D 1 (mm) 71.0 Outlet Diameter, D 2 (mm) 190.0 Inlet height, b 1 (mm) 13.8 Outlet height, b 2 (mm) 5.8 Blade thickness, t (mm) 3.0 Number of blades, Z 6 Inlet angle, β 1 (deg) 19.7 Outlet angle, β 2 (deg) 18.4 Blade curvature radius, Rb (mm) 70.0 Specific speed, N s 26.3 Table 2. Flow specifications of working condition. Table 2. Flow specifications of working condition. Parameter Value Q/Q d 1.0 Flow rate, Q 3.06 Head, H 1.75 Rotation speed, n 725 Reynolds number, Re 1.4 × 106 Table 3. Head of the impeller obtained using different number of grid. Table 3. Head of the impeller obtained using different number of grid. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
https://www.mdpi.com/2227-9717/10/10/2007/htm
Text of H.R. 4364 (116th): Taxpayer Fairness for Resource Development Act of 2019 (Introduced version) - GovTrack.us Text of H.R. 4364 (116th): Taxpayer Fairness for Resource Development … as of Sep 17, 2019 (Introduced version). H.R. 4364 (116th): Taxpayer Fairness for Resource Development Act of 2019 The text of the bill below is as ofSep 17, 2019(Introduced). The bill was not enacted into law. I 116th CONGRESS 1st Session H. R. 4364 IN THE HOUSE OF REPRESENTATIVES Mr. McAdams(for himself and Mr. Rooney of Florida) introduced the following bill; which was referred to the Committee on Natural Resources A BILL To amend the Mineral Leasing Act to make certain adjustments to the fiscal terms for fossil fuel development and to make other reforms to improve returns to taxpayers for the development of Federal energy resources, and for other purposes. 1. Short title This Act may be cited as the Taxpayer Fairness for Resource Development Act of 2019. 2. Table of contents The table of contents for this Act is the following: Sec. 1. Short title. Sec. 2. Table of contents. Sec. 3. Onshore fossil fuel royalty rates. Sec. 4. Minimum bid amount. Sec. 5. Onshore oil and gas rental rates. Sec. 6. Penalties. Sec. 7. Royalty relief. Sec. 9. Royalty in kind. Sec. 10. Amendments to definitions. Sec. 11. Compliance reviews. Sec. 12. Liability for royalty payments. Sec. 13. Recordkeeping. Sec. 14. Adjustments and refunds. Sec. 15. Obligation period. Sec. 16. Tolling agreements and subpoenas. Sec. 17. Appeals. Sec. 18. Assessments. Sec. 19. Pilot project on automatic data transfer. Sec. 20. Penalty for late or incorrect reporting of data. Sec. 21. Required recordkeeping for natural gas plants. Sec. 22. Shared penalties. Sec. 23. Applicability to other minerals. Sec. 24. Entitlements. Sec. 25. Royalties on all extracted methane. 3. Onshore fossil fuel royalty rates The Mineral Leasing Act ( 30 U.S.C. 181et seq.) is amended— (1) in section 7— (A) by striking 12 1/2and inserting 18.75; and (B) by adding at the end the following: (d) Periodic evaluation of royalty rates The Secretary shall establish a periodic process of evaluating increases in royalty rates to achieve a fair market value return for the public. The process should include: (1) publishing annually the average, weighted by relative production per State, of the top fossil fuel royalty rates charged by States for fossil fuels production on State-owned public lands; (2) evaluating triennially increases in the Federal fossil fuel royalty rates above the minimum rates required under this Act to match the production-weighted average of State royalty rates. The triennial review shall include and benefit from public participation through written comment, public hearings and other meetings open to all interested parties; and (3) submitting the triennial evaluation to Congress, including a summary of the views expressed in the public participation processes related to the evaluation. . (2) in section 17, by— (A) striking 12.5each place such term appears and inserting 18.75; and (B) striking 12 1/2each place such term appears and inserting 18.75; and (3) in section 31(e), by striking 16 2/3both places such term appears and inserting 25. 4. Minimum bid amount Section 17 of the Mineral Leasing Act ( 30 U.S.C. 226) is amended— (1) in subsection (b)(1)(B)— (A) by striking $2 per acreand inserting $5 per acre, except as otherwise provided by this paragraph; and (B) by striking Federal Onshore Oil and Gas Leasing Reform Act of 1987and inserting Taxpayer Fairness for Resource Development Act of 2019; (2) in subsection (b)(2)(C), by striking $2 per acreand inserting $5 per acre; and (3) by adding at the end the following: (q) Inflation adjustment The Secretary shall— (1) by regulation, at least once every 4 years, adjust each of the dollar amounts that apply under subsections (b)(1)(B), (b)(2)(C), and (d) to reflect the change in the Consumer Price Index for All Urban Consumers published by the Bureau of Labor Statistics; and (2) publish each such regulation in the Federal Register. . 5. Onshore oil and gas rental rates The Mineral Leasing Act ( 30 U.S.C. 181et seq.) is amended— (1) in section 17(d)— (A) by striking $1.50 per acreand inserting $3 per acre; and (B) by striking $2 per acreand inserting $5 per acre; and (2) in section 31(e), by striking $10and inserting $20. 6. Penalties (a) Mineral Leasing Act Section 41 of the Mineral Leasing Act ( 30 U.S.C. 195) is amended— (1) in subsection (b), by striking $500,000and inserting $1,000,000; and (2) in subsection (c), by striking $100,000and inserting $250,000. (b) Federal Oil and Gas Royalty Management Act of 1982 The Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1701et seq.) is amended— (1) in section 109— (A) in subsection (a), by striking $500and inserting $1,500; (B) in subsection (b), by striking $5,000and inserting $15,000; (C) in subsection (c), by striking $10,000and inserting $25,000; and (D) in subsection (d), by striking $25,000and inserting $75,000; and (2) in section 110, by striking $50,000and inserting $150,000. (c) Outer Continental Shelf Lands Act (1) Civil penalty, generally Section 24(b) of the Outer Continental Shelf Lands Act ( 43 U.S.C. 1350(b)) is amended to read as follows: (b) Civil penalties (1) In general Except as provided in paragraph (2), any person who fails to comply with any provision of this Act, or any term of a lease, license, or permit issued pursuant to this Act, or any regulation or order issued under this Act, shall be liable for a civil administrative penalty of not more than $75,000 for each day of the continuance of such failure. The Secretary may assess, collect, and compromise any such penalty. (2) Opportunity for a hearing No penalty shall be assessed until the person charged with a violation has been given an opportunity for a hearing. (3) Adjustment for inflation The Secretary shall, by regulation at least every 3 years, adjust the penalty specified in this paragraph to reflect any increases in the Consumer Price Index (all items, United States city average) as prepared by the Department of Labor. (4) Threat of harm If a failure described in paragraph (1) constitutes or constituted a threat of harm or damage to life, property, any mineral deposit, or the marine, coastal, or human environment, a civil penalty of not more than $150,000 shall be assessed for each day of the continuance of the failure. . (2) Knowing and willful violations Section 24(c) of the Outer Continental Shelf Lands Act ( 43 U.S.C. 1350(c)) is amended by striking $100,000and inserting $1,000,000. (3) Officers and agents of corporations Section 24(d) of the Outer Continental Shelf Lands Act ( 43 U.S.C. 1350(d)) is amended by striking knowingly and willfully authorized, ordered, or carried outand inserting authorized, ordered, carried out, or through reckless disregard of the law caused. 7. Royalty relief (a) Gulf of Mexico royalty relief The following provisions of the Energy Policy Act of 2005 ( 42 U.S.C. 15801et seq.) are hereby repealed: (1) Section 344 ( 42 U.S.C. 15904) (relating to incentives for natural gas production from deep wells in the shallow waters of the Gulf of Mexico). (2) Section 345 ( 42 U.S.C. 15905) (relating to royalty relief for deep water production). (b) Alaska royalty relief (1) Provisions relating to planning areas offshore Alaska Section 8(a)(3)(B) of the Outer Continental Shelf Lands Act ( 43 U.S.C. 1337(a)(3)(B)) is amended by striking and in the Planning Areas offshore Alaskaafter West longitude. (2) Provisions relating to naval petroleum reserve in Alaska Section 107 of the Naval Petroleum Reserves Production Act of 1976 ( 42 U.S.C. 6506a) is amended— (A) in subsection (i)— (i) by striking (1) In general; and (ii) by striking paragraphs (2) through (6); and (B) by striking subsection (k). 8. Revision of Royalty Policy Committee charter Not later than one year after the date of enactment of this Act, or March 29, 2021, whichever is earlier, the Secretary of the Interior shall revise the charter of the Royalty Policy Committee (as signed on March 29, 2017) to— (1) require that of the 6 members of such Committee who are representatives of the Governors of States, no more than 4 members may be representatives of Governors of the same political party; (2) increase to 6 the number of members who are representatives of academia or the public, of whom— (A) 2 members shall be representatives of academia; (B) 2 members shall be representatives of public interest groups; and (C) 2 members shall be representatives of nonprofit environmental groups; and (3) require that for a person to be eligible to serve as a member who is a representative of a person who is a mineral stakeholder or energy stakeholder (or both) in Federal and Indian royalty policy, the employer of that member shall provide to the Secretary, who shall publish— (A) for the preceding 10-year period— (i) aggregated information on all Federal royalty payments made by the employer, by year and by commodity; (ii) conclusions from compliance reviews and audits conducted by Federal or State revenue collection entities; and (iii) a description of all enforcement actions taken against the employer regarding payment of Federal or State royalties; and (B) records of— (i) prices charged by the employer for sales of minerals to captive affiliates of the employer; and (ii) prices charged by such affiliates for subsequent resales of such minerals. 9. Royalty in kind (a) Onshore oil and gas lease royalties Section 36 of the Mineral Leasing Act ( 30 U.S.C. 192) is amended by inserting , except that the Secretary may not demand such payment in oil or gas if the amount of such payment would exceed the amount necessary to fill the strategic petroleum reserveafter in oil or gas. (b) Offshore oil and gas lease royalties Section 27(a)(1) of the Outer Continental Shelf Lands Act ( 43 U.S.C. 1353(a)) is amended by striking the period at the end and inserting , except that the Secretary may not demand such payment in oil or gas if the amount of such payment would exceed the amount necessary to fill the strategic petroleum reserve.. 10. Amendments to definitions Section 3 of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1702) is amended— (1) in paragraph (20)(A), by striking : Provided, Thatand all that follows through subject of the judicial proceeding; (2) in paragraph (20)(B), by striking (with written notice to the lessee who designated the designee); (3) in paragraph (23)(A), by striking (with written notice to the lessee who designated the designee); (4) by amending paragraph (24) to read as follows: (24) designeemeans a person who pays, offsets, or credits monies, makes adjustments, requests and receives refunds, or submits reports with respect to payments a lessee must make pursuant to section 102(a); ; (5) in paragraph (25), in subparagraph (B)— (A) by striking (subject to the provisions of section 102(a) of this Act); and (B) in clause (ii), by striking subclause (IV) and all that follows through the end of the subparagraph and inserting the following: (IV) any assignment, that arises from or relates to any lease, easement, right-of-way, permit, or other agreement regardless of form administered by the Secretary for, or any mineral leasing law related to, the exploration, production, and development of oil and gas or other energy resource on Federal lands or the Outer Continental Shelf; ; (6) in paragraph (29), by inserting or permitafter lease; and (7) by striking andafter the semicolon at the end of paragraph (32), by striking the period at the end of paragraph (33) and inserting a semicolon, and by adding at the end the following new paragraphs: (34) compliance reviewmeans an examination of a lessee’s lease accounts to compare one or all elements of the royalty equation (volume, value, royalty rate, and allowances) against anticipated elements of the royalty equation to test for variances; and (35) marketing affiliatemeans an affiliate of a lessee whose function is to acquire the lessee’s production and to market that production. . 11. Compliance reviews Section 101 of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1711) is amended by adding at the end the following new subsection: (d) The Secretary may, as an adjunct to audits of accounts for leases, conduct compliance reviews of accounts. Such reviews shall not constitute nor substitute for audits of lease accounts. The Secretary shall immediately refer any disparity uncovered in such a compliance review to a program auditor. The Secretary shall, before completion of a compliance review, provide notice of the review to designees whose obligations are the subject of the review. . 12. Liability for royalty payments Section 102(a) of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1712(a)) is amended to read as follows: (a) Liability for royalty payments (1) Time and manner of payment In order to increase receipts and achieve effective collections of royalty and other payments, a lessee who is required to make any royalty or other payment under a lease, easement, right-of-way, permit, or other agreement, regardless of form, or under the mineral leasing laws, shall make such payment in the time and manner as may be specified by the Secretary or the applicable delegated State. (2) Designee Any person who pays, offsets, or credits monies, makes adjustments, requests and receives refunds, or submits reports with respect to payments the lessee must make is the lessee’s designee under this Act. (3) Liability Notwithstanding any other provision of this Act, a designee shall be liable for any payment obligation of any lessee on whose behalf the designee pays royalty under the lease. The person owning operating rights in a lease and a person owning legal record title in a lease shall be liable for that person’s pro rata share of payment obligations under the lease. . 13. Recordkeeping Section 103(b) of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1713(b)) is amended by striking 6and inserting 7. 14. Adjustments and refunds Section 111A of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1721a) is amended— (1) in subsection (a)— (A) by amending paragraph (3) to read as follows: (3) (A) An adjustment or a request for a refund for an obligation may be made after the adjustment period only upon written notice to and approval by the Secretary or the applicable delegated State, as appropriate, during an audit of the period which includes the production month for which the adjustment is being made. (B) Except as provided in subparagraph (C), no adjustment may be made with respect to an obligation after the completion of an audit or compliance review of such obligation unless such adjustment is approved by the Secretary or the applicable delegated State, as appropriate. (C) If an overpayment is identified during an audit, the Secretary shall allow a credit in the amount of the overpayment. ; and (B) in paragraph (4)— (i) by striking six-yearand inserting four-year; and (ii) by striking period shalland inserting period may; and (2) in subsection (b)(1)— (A) in subparagraph (C), by striking and; (B) in subparagraph (D), by striking the period and inserting ; and; and (C) by adding at the end the following: (E) is made within the adjustment period for that obligation. . 15. Obligation period Section 115(c) of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1724(c)) is amended by adding at the end the following new paragraph: (3) Adjustments In the case of an adjustment under section 111A(a) in which a recoupment by the lessee results in an underpayment of an obligation, the obligation becomes due on the date the lessee or its designee makes the adjustment. . 16. Tolling agreements and subpoenas (a) Tolling agreements Section 115(d)(1) of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1724(d)(1)) is amended by striking (with notice to the lessee who designated the designee). (b) Subpoenas Section 115(d)(2)(A) of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1724(d)(2)(A)) is amended by striking (with notice to the lessee who designated the designee, which notice shall not constitute a subpoena to the lessee). 17. Appeals Section 115(h) of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1724(h)) is amended— (1) in paragraph (1), in the heading, by striking 33-monthand inserting 48-month; (2) by striking 33 monthseach place it appears and inserting 48 months; and (3) by striking 33-montheach place it appears and inserting 48-month. 18. Assessments Section 116 of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1724) is repealed. 19. Pilot project on automatic data transfer (a) Pilot project Not later than 2 years after the date of enactment of this Act, the Secretary of the Interior shall complete a pilot project with willing operators of oil and gas leases on the outer Continental Shelf (as such term is defined in the Outer Continental Shelf Lands Act ( 43 U.S.C. 1331et seq.)) that assesses the costs and benefits of automatic transmission of data regarding the volume and quality of oil and gas produced under Federal leases on the outer Continental Shelf in order to improve the production verification systems used to ensure accurate royalty collection and audit. (b) Report The Secretary shall submit to Congress a report on findings and recommendations based on the pilot project not later than 3 years after the date of enactment of this Act. 20. Penalty for late or incorrect reporting of data (a) In general The Secretary of the Interior shall issue regulations by not later than 1 year after the date of enactment of this Act that establish a civil penalty for late or incorrect reporting of data under the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1701et seq.). (b) Amount The amount of the civil penalty shall be— (1) an amount (subject to paragraph (2)) that the Secretary determines is sufficient to ensure filing of data in accordance with that Act; and (2) not less than $10 for each failure to file correct data in accordance with that Act. (c) Content of regulations Except as provided in subsection (b), the regulations issued under this section shall be substantially similar to section 216.40 of title 30, Code of Federal Regulations, as most recently in effect before the date of enactment of this Act. 21. Required recordkeeping for natural gas plants Not later than 1 year after the date of enactment of this Act, the Secretary of the Interior shall publish final regulations with respect to required recordkeeping of natural gas measurement data as set forth in section 250.1203 of title 30, Code of Federal Regulations (as in effect on the date of enactment of this Act), to include operators and other persons involved in the transporting, purchasing, or selling of gas under the requirements of that rule, under the authority provided in section 103 of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1713). 22. Shared penalties Section 206 of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1736) is amended by striking Any payments under this section shall be reduced by an amount equal to any payments provided or due to such State or Indian tribe under the cooperative agreement or delegation, as applicable, during the fiscal year in which the civil penalty is received, up to the total amount provided or due for that fiscal year.. 23. Applicability to other minerals Section 304 of the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1753) is amended by adding at the end the following new subsection: (e) Applicability to other minerals (1) Notwithstanding any other provision of law, sections 107, 109, and 110 of this Act and the regulations duly promulgated with respect thereto shall apply to any lease authorizing the development of coal or any other solid mineral on any Federal lands or Indian lands, to the same extent as if such lease were an oil and gas lease, on the same terms and conditions as those authorized for oil and gas leases. (2) Notwithstanding any other provision of law, sections 107, 109, and 110 of this Act and the regulations issued under such sections shall apply with respect to any lease, easement, right-of-way, or other agreement, regardless of form (including any royalty, rent, or other payment due thereunder)— (A) under section 8(k) or 8(p) of the Outer Continental Shelf Lands Act ( 43 U.S.C. 1337(k)and 1337(p)); or (B) under the Geothermal Steam Act ( 30 U.S.C. 1001et seq.), to the same extent as if such lease, easement, right-of-way, or other agreement were an oil and gas lease on the same terms and conditions as those authorized for oil and gas leases. (3) For the purposes of this subsection, the term solid mineralmeans any mineral other than oil, gas, and geo-pressured-geothermal resources, that is authorized by an Act of Congress to be produced from public lands (as that term is defined in section 103 of the Federal Land Policy and Management Act of 1976 ( 43 U.S.C. 1702)). . 24. Entitlements (a) Directed rulemaking Not later than 180 days after the date of enactment of this Act, the Secretary of the Interior shall publish final regulations prescribing when a Federal lessee or designee must report and pay royalties on— (1) the volume of oil and gas such lessee or designee produces or takes under a Federal lease or Indian lease; or (2) the volume of oil and gas that such lessee or designee is entitled to based on its ownership interest under a unitization agreement for Federal leases or Indian leases. (b) 100 percent entitlement reporting and paying The Secretary shall give consideration to requiring 100 percent entitlement reporting and paying based on Federal or Indian oil and gas lease ownership. 25. Royalties on all extracted methane (a) Assessment on all production (1) In general Except as provided in paragraph (2), royalties otherwise authorized or required under the mineral leasing laws (as that term is defined in the Federal Oil and Gas Royalty Management Act of 1982 ( 30 U.S.C. 1701et seq.)) to be paid for gas shall be assessed on all gas produced under the mineral leasing laws, including— (A) gas used or consumed within the area of the lease tract for the benefit of the lease; and (B) all gas that is consumed or lost by venting, flaring, or fugitive releases through any equipment during upstream operations. (2) Exception Paragraph (1) shall not apply with respect to— (A) gas vented or flared for not longer than 48 hours in an acute emergency situation that poses a danger to human health; and (B) gas injected into the ground on a lease tract in order to enhance production of an oil or gas well or for some other purpose. (b) Conforming amendments (1) Mineral Leasing Act The Mineral Leasing Act is amended— (A) in section 14 ( 30 U.S.C. 223), by adding at the end the following: Notwithstanding any other provision of this Act (including this section), royalty shall be assessed with respect to oil and gas, other than gas described in section 124(a)(2) of the Sustainable Energy Development Reform Act , without regard to whether oil or gas is removed or sold from the leased land.; (B) in section 17 ( 30 U.S.C. 226), by striking removed or soldeach place it appears; (C) in section 31 ( 30 U.S.C. 188), by striking removed or soldeach place it appears. (2) Outer Continental Shelf Lands Act The Outer Continental Shelf Lands Act is amended— (A) in section 6(a)(8) ( 43 U.S.C. 1335(a)(8)), by striking saved, removed, or soldeach place it appears; and (B) in section 8(a) ( 43 U.S.C. 1337(a))— (i) in paragraph (1), by striking saved, removed, or soldeach place it appears; and (ii) by adding at the end the following: (9) Notwithstanding any other provision of this Act (including this section), royalty under this Act shall be assessed with respect to oil and gas, other than gas described in section 124(a)(2) of the Sustainable Energy Development Reform Act, without regard to whether oil or gas is removed or sold from the leased land. . (c) Application The provisions of this section and the amendments made by this section shall apply only with respect to leases issued on or after the date of the enactment of this Act.
https://www.govtrack.us/congress/bills/116/hr4364/text
Publications - Global Disability Innovation Hub The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good. Type Conference Paper Themes Assistive & Accessible Technology Culture and Participation The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya Giulia Barbareschi,Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, Joyce Olenja We present the findings of a case study of mobile technology use by People with Visual Impairment (VIPs) in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted. CHI '20: Proceedings of the 2020 CHI Conference; 2020 Abstract The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya Living in an informal settlement with a visual impairment can be very challenging resulting in social exclusion. Mobile phones have been shown to be hugely beneficial to people with sight loss in formal and high-income settings. However, little is known about whether these results hold true for people with visual impairment (VIPs) in informal settlements. We present the findings of a case study of mobile technology use by VIPs in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted. Cite The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya Giulia Barbareschi, Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, and Joyce Olenja. 2020. The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya. In Proceedings of the 2020 CHI Conference on Human Factors in Computing Systems (CHI '20). Association for Computing Machinery, New York, NY, USA, 1–15.https://doi.org/10.1145/331383... The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya Type Conference Paper Disability design and innovation in computing research in low resource settings Dafne Zuleima Morgado-Ramirez,Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney,Catherine Holloway 80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes. ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020 Abstract Disability design and innovation in computing research in low resource settings 80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes. In short, researchers rarely examine what was challenging in the process of collaboration. We present reflections from the field across four studies. Our contributions are: (1) an overview of past work in computing with a focus on disability in low resource settings and (2) learnings and recommendations from four collaborative projects in Uganda, Jordan and Kenya over the last two years, that are relevant for future HCI studies in low resource settings with communities with disabilities. We do this through a lens of Disability Interaction and ICT4D. Disability design and innovation in computing research in low resource settings Dafne Zuleima Morgado-Ramirez, Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney, and Catherine Holloway. 2020. Disability design and innovation in computing research in low resource settings. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 11, 1–7.https://doi.org/10.1145/337362... Disability design and innovation in computing research in low resource settings Type Article Themes Assistive & Accessible Technology These tools help visually impaired scientists read data and journals Alla Katsnelson This article was featured in Nature and discusses tools that help visually impaired scientists read data and Journals. Innovation Manager, Daniel Hajas, was interviewed as part of this piece and highlights the need for an ecosystem approach, and access to data / visualisations for blind members of the research and science community. Nature; 2023 Type Book Research Group Disability Interactions Disability Interactions Creating Inclusive Innovations Catherine Holloway,Giulia Barbareschi ; 2021 Disability Interactions Creating Inclusive Innovations Disability interactions (DIX) is a new approach to combining cross-disciplinary methods and theories from Human Computer Interaction (HCI), disability studies, assistive technology, and social development to co-create new technologies, experiences, and ways of working with disabled people. DIX focuses on the interactions people have with their technologies and the interactions which result because of technology use. A central theme of the approach is to tackle complex issues where disability problems are part of a system that does not have a simple solution. Therefore, DIX pushes researchers and practitioners to take a challenge-based approach, which enables both applied and basic research to happen alongside one another. DIX complements other frameworks and approaches that have been developed within HCI research and beyond. Traditional accessibility approaches are likely to focus on specific aspects of technology design and use without considering how features of large-scale assistive technology systems might influence the experiences of people with disabilities. DIX aims to embrace complexity from the start, to better translate the work of accessibility and assistive technology research into the real world. DIX also has a stronger focus on user-centered and participatory approaches across the whole value chain of technology, ensuring we design with the full system of technology in mind (from conceptualization and development to large-scale distribution and access). DIX also helps to acknowledge that solutions and approaches are often non-binary and that technologies and interactions that deliver value to disabled people in one situation can become a hindrance in a different context. Therefore, it offers a more nuanced guide to designing within the disability space, which expands the more traditional problem-solving approaches to designing for accessibility. This book explores why such a novel approach is needed and gives case studies of applications highlighting how different areas of focus—from education to health to work to global development—can benefit from applying a DIX perspective. We conclude with some lessons learned and a look ahead to the next 60 years of DIX. Type Conference Paper Themes Assistive & Accessible Technology Value beyond function: analyzing the perception of wheelchair innovations in Kenya Barbareschi, G; Daymond, S; Honeywill, J; Singh, A; Noble, D; Mbugua, N; Harris, I;Austin, V;Holloway, C The World Health Organization (WHO) defines Assistive Technology (AT) as “an umbrella term covering the systems and services related to the delivery of assistive products and services” [6]. This definition highlights how AT encompasses not only the physical and digital products used by millions of persons with disabilities (PWDs) worldwide, but also the systems and services that accompany the provision of these devices [78]. ASSETS '20: The 22nd International ACM SIGACCESS Conference on Computers and Accessibility.; 2020 Abstract Value beyond function: analyzing the perception of wheelchair innovations in Kenya Innovations in the field of assistive technology are usually evaluated based on practical considerations related to their ability to perform certain functions. However, social and emotional aspects play a huge role in how people with disabilities interact with assistive products and services. Over a five months period, we tested an innovative wheelchair service provision model that leverages 3D printing and Computer Aided Design to provide bespoke wheelchairs in Kenya. The study involved eight expert wheelchair users and five healthcare professionals who routinely provide wheelchair services in their community. Results from the study show that both users and providers attributed great value to both the novel service delivery model and the wheelchairs produced as part of the study. The reasons for their appreciation went far beyond the practical considerations and were rooted in the fact that the service delivery model and the wheelchairs promoted core values of agency, empowerment and self-expression. Value beyond function: analyzing the perception of wheelchair innovations in Kenya Type Conference Paper Themes Assistive & Accessible Technology Culture and Participation Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh Nusrat Jahan,Giulia Barbareschi, Clara Aranda Jan, Charles Musungu Mutuku, Naemur Rahman,Victoria Austin,Catherine Holloway Worldwide it is estimated that there are over a billion people who live with some form of disability[1]. Approximately 80% of people with disabilities live in low-and-middle income countries (LMICs). The combination of an inaccessible environment compounded by socio-economic factors such as poverty and stigma, makes it more likely for people with disabilities to be marginalised and excluded from society[1]. Assistive Technologies (ATs) are known to bridge the accessibility gaps and allow for greater social inclusion. However, there is a lack of adequate access to ATs in LMICs, combined with often poorly designed services, which only magnifies these challenges, thus limiting the opportunities for persons with disabilities to live an independent life[2]. Despite the importance of AT, access to AT globally is inadequate with only 10 percent of those in need having access to the ATs that they need[2]. 2020 IEEE Global Humanitarian Technology Conference Abstract Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh Globally, mobile technology plays a significant role connecting and supporting people with disabilities. However, there has been limited research focused on understanding the impact of mobile technology in the lives of persons with disabilities in low or middle- income countries. This paper presents the findings of a participatory photovoice study looking at the role that mobile phones play in the daily lives of 16 persons with disabilities in Kenya and Bangladesh. Participants used a combination of pictures and voice recordings to capture their own stories and illustrate the impact that mobile phone use has on their lives. Through thematic analysis, we categorized the benefits of mobile phones captured by participants as 1) Improved social connection; 2) Increased independence and 3) Access to opportunities. While mobile phones are ubiquitously used for communication, for persons with disabilities they become essential assistive technologies that bridge barriers to opportunities which are not accessible otherwise. Our paper adds evidence to the need for mobile phones for persons with disabilities to enable communication and connectivity in support of development. Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh N. Jahan et al., "Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh," 2020 IEEE Global Humanitarian Technology Conference (GHTC), Seattle, WA, USA, 2020, pp. 1-8, doi: 10.1109/GHTC46280.2020.9342934. Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh Type Conference Paper Themes Assistive & Accessible Technology Research Group Local Productions A Preliminary Study to Understand How Mainstream Accessibility and Digital Assistive Technologies Reaches People in Lower- and Middle-Income Countries Tigmanshu Bhatnagar, George Torrens, Ben Oldfrey, Priya MorjariaFelipe Ramos Barajas, Katherine PerryandCatherine Holloway Access to information on digital platforms not only facilitates education, employment, entertainment, social interaction but also facilitates critical governmental services, ecommerce, healthcare services and entrepreneurship [1]. Article 9 of United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) enforces its signatories to commit to provide full accessibility to every citizen of the nation [2]. This has helped to spearhead accessibility directives such as the European Accessibility Act [3] that aims to improve the functioning of markets for accessible products and services. Such directives contribute to ensure that mainstream digital technologies (smartphones, computers etc.) are accessible for everyone and without being socially remarkable, they are able to assist in daily living. Additionally, there is evidence that improving access in mainstream technologies improves product experience and usability for everyone [4]. However, mainstream access has not been fully realized, leading to inferior opportunities for people with disabilities, a disparity which is more prominent in lower and middle-income countries [5]. RESNA Annual Conference; 2021 A Preliminary Study to Understand How Mainstream Accessibility and Digital Assistive Technologies Reaches People in Lower- and Middle-Income Countries Type Working Paper Themes Culture and Participation Research Group Disability Interactions Barriers to Access and Retain Formal Employment for Persons with Disabilities in Bangladesh and Kenya Nusrat Jahan andCatherine Holloway This working paper was developed to support the development of challenge statements for a GDI Hub innovation challenge fund call related to improving access to and retention of employment for persons with disabilities in Kenya and Bangladesh and is written by GDI Hub's Nusrat Jahan andProfessor Catherine Holloway. The issue of disability and employment has taken centre stage on the global arena in part because it is recognised across several areas of the United Nations Sustainable Development Goals, in which confrontation of extreme poverty in its many manifestations is the number one goal [2]. The World Health Organization (2011) reports about 15 percent of the world’s population has a disability [1]. In developing countries, 80 to 90 percent of people with disabilities of working age are unemployed. Abstract Barriers to Access and Retain Formal Employment for Persons with Disabilities in Bangladesh and Kenya Globally persons with disabilities have lower employment rates compared to the general population due to systemic barriers particularly in the formal sector. In developing countries, 80 percent to 90 percent of people with disabilities of working age are unemployed. There has been limited research in low-income and middle-income countries focused on the barriers to access and retain formal employment for persons with disabilities. The aim of this paper, based on desk research, is to analyse the barriers to access and retain formal employment of persons with disabilities which are framed in three categories according to where the barriers primarily manifest: 1. In the workplace among employers and co-workers without disabilities, 2. Among persons with disabilities seeking or engaged in formal employment and 3. In the wider social, physical and policy environment. Although the study mainly focuses on Kenya and Bangladesh other countries’ literature on access to and retention of employment of persons with disabilities were reviewed where relevant. In the current context where the global pandemic is breaking barriers to remote working one part of the solution will be to empower persons with disabilities with appropriate access to Information and Communication Technology, assistive devices and services, digital skills, creating more accessible and inclusive digital platforms for persons with disabilities which also hold the potential to improve working conditions and productivity for the whole workforce as well as enhancing resilience to potential future shocks. Cite Barriers to Access and Retain Formal Employment for Persons with Disabilities in Bangladesh and Kenya Jahan & Holloway, 2020, Barriers to Access and Retain Formal Employment for Persons with Disabilities in Bangladesh and Kenya, GDI Hub Working Paper Series Issue 01 Barriers to Access and Retain Formal Employment for Persons with Disabilities in Bangladesh and Kenya Type Conference Paper Themes Assistive & Accessible Technology Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People Maryam Bandukda,Catherine Holloway, Aneesha Singh,Giulia Barbareschi, Nadia Berthouze We conducted semi-structured interviews with 20 BPS people and 8 Mobility and Orientation Trainers (MOT). The interviews were thematically analysed and organised into four overarching themes discussing factors influencing the self-efficacy belief of BPS people: Tools and Strategies for O&M training, Technology Use in O&M Training, Changing Personal and Social Circumstances, and Social Influences. We further highlight opportunities for combinations of multimodal technologies to increase access to and effectiveness of O&M training. ASSETS '21: Proceedings of the 23rd International ACM SIGACCESS Conference on Computers and Accessibility Abstract Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People Orientation and mobility (O&M) training provides essential skills and techniques for safe and independent mobility for blind and partially sighted (BPS) people. The demand for O&M training is increasing as the number of people living with vision impairment increases. Despite the growing portfolio of HCI research on assistive technologies (AT), few studies have examined the experiences of BPS people during O&M training, including the use of technology to aid O&M training. To address this gap, we conducted semi-structured interviews with 20 BPS people and 8 Mobility and Orientation Trainers (MOT). The interviews were thematically analysed and organised into four overarching themes discussing factors influencing the self-efficacy belief of BPS people: Tools and Strategies for O&M training, Technology Use in O&M Training, Changing Personal and Social Circumstances, and Social Influences. We further highlight opportunities for combinations of multimodal technologies to increase access to and effectiveness of O&M training. Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People Type Conference Paper Themes Assistive & Accessible Technology What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT Giulia Barbareschi, Norah Shitawa Kopi,Ben Oldfrey,Catherine Holloway In this paper, we examine how young Kenyans without disabilities view people with disabilities and AT users. Findings show that while the portrayal of disability is often shaped by negative emotion, participants felt that many of the barriers affecting people with disabilities were created by society. Perceptions of AT differed –devices were not only seen as a mark of disability but also as a sign of access to resources. Therefore, what we see is an emergent picture where social barriers can be reinforced by poverty, and where poverty reinforces social barriers faced by people with disabilities. We conclude that access to appropriate technology alongside societal interventions tackling incorrect beliefs about disability can help to overcome the stigma faced by people with disabilities. ASSETS '21: Proceedings of the 23rd International ACM SIGACCESS Conference on Computers and Accessibility Abstract What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT Most research which investigates stigma towards with people with disabilities and the use of Assistive Technology (AT) are based in the Global North and focus on the experiences of people with disabilities and the consequences that stigma has on choices surrounding AT. However, stigma is a societal construct rooted in the attitude and beliefs that people without disabilities hold on disability and AT. Furthermore, the portrayal of people with disabilities and AT is dependent on the social context. In this paper, we examine how young Kenyans without disabilities view people with disabilities and AT users. Findings show that while the portrayal of disability is often shaped by negative emotion, participants felt that many of the barriers affecting people with disabilities were created by society. Perceptions of AT differed –devices were not only seen as a mark of disability but also as a sign of access to resources. Therefore, what we see is an emergent picture where social barriers can be reinforced by poverty, and where poverty reinforces social barriers faced by people with disabilities. We conclude that access to appropriate technology alongside societal interventions tackling incorrect beliefs about disability can help to overcome the stigma faced by people with disabilities. What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT Giulia Barbareschi, Norah Shitawa Kopi, Ben Oldfrey, and Catherine Holloway. 2021. What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT. In The 23rd International ACM SIGACCESS Conference on Computers and Accessibility( ASSETS '21). Association for Computing Machinery, New York, NY, USA, Article 18, 1–13. DOI:https://doi.org/10.1145/3441852.3471226 What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT Type Conference Paper Themes Assistive & Accessible Technology Inclusive Educational Technology Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution Tigmanshu Bhatnagar, Nicolai Marquardt, Mark Miodownik,Catherine Holloway Shape changing materials create a unique opportunity to design reconfigurable tactile display actuators. In this paper, we present a method that transforms a single thin monolithic sheet of Nitinol into a passive reconfigurable tactile pixel array at Braille resolution. We have designed a 27x27 tactile pixel array in which each pixel can be selectively actuated with an external source of heat. The pixels rise 0.4mm vertically with a peak blocked force of 0.28kg and have an average blocked force of 0.23kg at room temperature. After cooling, the pixels can be mechanically reconfigured back to their flat state for repeatable actuation. We demonstrate this actuator’s interactive capabilities through a novel erasable tactile drawing interface. IEEE World Haptics Conference; 2021 Abstract Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution Shape changing materials create a unique opportunity to design reconfigurable tactile display actuators. In this paper, we present a method that transforms a single thin monolithic sheet of Nitinol into a passive reconfigurable tactile pixel array at Braille resolution. We have designed a 27x27 tactile pixel array in which each pixel can be selectively actuated with an external source of heat. The pixels rise 0.4mm vertically with a peak blocked force of 0.28kg and have an average blocked force of 0.23kg at room temperature. After cooling, the pixels can be mechanically reconfigured back to their flat state for repeatable actuation. We demonstrate this actuator’s interactive capabilities through a novel erasable tactile drawing interface. Cite Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution T. Bhatnagar, N. Marquardt, M. Miodownik and C. Holloway, "Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution," 2021 IEEE World Haptics Conference (WHC), 2021, pp. 409-414, doi: 10.1109/WHC49131.2021.9517239. Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
https://www.disabilityinnovation.com/publications?page=9&type=working-paper+article+book+conference-paper
Let's Talk Kitty Litter!? - Pet forum for dogs cats and humans - Pets.ca Let's Talk Kitty Litter!? Cat behavior forum - cat training # 1 April 4th, 2008, 10:17 AM zztopp Member Join Date: Dec 2007 Location: Black River Posts: 79 Let's Talk Kitty Litter!? We live on a small farm (9 acres) and do our best to be environmentally friendly, which also helps with our land management. We use a straw-based bedding for the horses that breaks down fully in two weeks. Meaning, after 2 weeks we can spread it on our fields, which helps with space constraints, etc. The barn cats and the house cats each have kitty litter boxes .. and we use a clay based litter. Bad me, bad me ... I know!! We can't dispose of the kitty litter on the horsey manure pile, since they don't break down at the same rate. And I DON'T want to be spreading kitty litter on the fields that the horses eat from ... ick. Plus, our garbage bag limit is two bags a week ... and all that kitty litter takes up alot of space!! So, what are my choices for both economical and environmental kitty litters? Thanks everyone! -- zztopp __________________ "Say what you mean, mean what you say, do what you said you were going to do!" -- DJ, the best dog trainer ever <3 Owned by a very cute golden retriever; Kassie!! <3 # 2 April 4th, 2008, 10:22 AM SARAH Senior Contributor Join Date: Nov 2006 Posts: 1,718 Before the store I got it from closed (without warning!) I would get wood-chip/sawdust litter. It clumped and was flushable. Frankly, I wish I could find it again, because the clay, although scoopable is easier to clean than the non scoopable, does smell more and takes space in the garbage can (don't use a full bag/week though, and no limit here, so that's not the issue). See if you can find the wood stuff, it's worth it. # 3 April 4th, 2008, 10:31 AM phoozles proud to be a cat slave Join Date: Oct 2007 Location: Southwestern Ontario Posts: 1,420 Thanks to growler I was recently introduced to Feline Fresh - it's a pine litter that comes in either pellet or scoopable form - it's a lot like sawdust, it clumps and is flushable.. It's also the same price as the clay stuff, which works well in my books! Here's their website: http://www.planetwiseproducts.com/feline.htm - they even have a rebate for a free first bag! Thanks again growler for the tip! __________________ Taken over by: Jake - grey DSH (Aug '98) Alley - spazzy grey tabby (Aug '07) # 4 April 4th, 2008, 10:34 AM Kristin7 Senior Member Join Date: Jul 2006 Location: US Posts: 857 I have used a pine litter before, called Feline Pine. It was pretty good, flushable and I think clumpable too, though this was several years back. Now I use a wheat based litter called Sweat Scoop, which is clumping and flushable too. The cats like it and so do I __________________ http://www.catster.com/cats/702907 http://www.catster.com/cats/703259 http://www.catster.com/cats/703269 http://www.dogster.com/dogs/669963 # 5 April 4th, 2008, 10:36 AM sugarcatmom Senior Contributor Join Date: May 2007 Location: Calgary, AB Posts: 5,357 There's pine litter, which you can get in both pellet form (but not every cat likes it, although mine does) and in clumping format. Brands would be Feline Pine, Feline Fresh, Exquisicat, etc. There's also recycled newspaper pellets, like Yesterday's News (which also comes in a softer texture pellet that some cats might take to easier than the harder pine pellets). Then there's clumping wheat litter like Swheat Scoop, and clumping corn litter like World's Best Cat litter. I've also heard of corn cob litter (by One Earth). Here's an article on cat litter with links to many of the brands I mentioned: http://www.greenlivingonline.com/Hom...ty-litter-bad/ What I do is mix half pine pellets with half Yesterday's News. My cat loves this combo so much that he'll even come in from outside (where he has access to a gynormous dirt vegetable garden), to use the litter box. But then he's kinda weird. __________________ "To close your eyes will not ease another's pain." ~ Chinese Proverb “We must not refuse to see with our eyes what they must endure with their bodies.” ~ Gretchen Wyler # 6 April 4th, 2008, 10:51 AM Chris21711 - Join Date: Apr 2007 Location: Queensville, Ontario Posts: 8,992 We can put cat litter in our Green Bin along with the dog poop. # 7 April 4th, 2008, 10:57 AM ancientgirl Senior Contributor Join Date: May 2007 Location: Miami, FL Posts: 15,069 I use Swheat Scoop which is wheat based, as you may have guessed. It's clumping and flushable. Swheat Scoop __________________ There are only two rules at my house: House rule #1. Cats rule. House rule #2. See rule #1. http://nuriaandthegang.shutterfly.com/ # 8 April 4th, 2008, 11:16 AM sugarcatmom Senior Contributor Join Date: May 2007 Location: Calgary, AB Posts: 5,357 Depending on where you live, it may not be a good idea to flush cat litter: Quote: Although most of these green litters are septic- and sewer-safe, it’s best not to flush them into our waterways. Cat feces contains the Toxoplasmosis gondii (TG) parasite, dangerous to pregnant women and marine life, particularly sea otters. Unfortunately TG is not filtered out in most water treatment plants, so don’t flush your used litter. __________________ "To close your eyes will not ease another's pain." ~ Chinese Proverb “We must not refuse to see with our eyes what they must endure with their bodies.” ~ Gretchen Wyler # 9 April 4th, 2008, 11:38 AM Kristin7 Senior Member Join Date: Jul 2006 Location: US Posts: 857 No sea otters around here! Regardless, I don't flush the litter but instead throw it in the garbage. The flushability is a good indicator that the litter biodegrades. Not sure, but I think cat litter waste can be composted, depending on type of litter? At least, only the urine part, probably not good to put the poop of a meat eater in the compost bin.... __________________ http://www.catster.com/cats/702907 http://www.catster.com/cats/703259 http://www.catster.com/cats/703269 http://www.dogster.com/dogs/669963 # 10 April 4th, 2008, 12:22 PM ancientgirl Senior Contributor Join Date: May 2007 Location: Miami, FL Posts: 15,069 Sugarcatmom, thanks for posting that. I'd read that a long time ago. We don't have any sea otters here, but I also throw mine in it's own little bin. I put it in a zip lock bag then place it in a small garbage pail next to the regular garbage. __________________ There are only two rules at my house: House rule #1. Cats rule. House rule #2. See rule #1. http://nuriaandthegang.shutterfly.com/ # 11 April 4th, 2008, 01:08 PM sugarcatmom Senior Contributor Join Date: May 2007 Location: Calgary, AB Posts: 5,357 Quote: Originally Posted by ancientgirl We don't have any sea otters here, Ha ha, ya I didn't think you did, but just in case anyone else reading thought flushing was a good idea....... Apparently this is a real problem on the California coast. Lots of sea otters dying from TG. __________________ "To close your eyes will not ease another's pain." ~ Chinese Proverb “We must not refuse to see with our eyes what they must endure with their bodies.” ~ Gretchen Wyler # 12 April 4th, 2008, 01:15 PM SARAH Senior Contributor Join Date: Nov 2006 Posts: 1,718 Quote: Originally Posted by Chris21711 We can put cat litter in our Green Bin along with the dog poop. I only wish we did have a green bin. Only paper/plastic/glass/metal recyclable bin (huuuge) and a regular grabage bin for everything else, which is silly really, because a lot of it is bio degradable, except the styrofoam ... # 13 April 4th, 2008, 01:31 PM ancientgirl Senior Contributor Join Date: May 2007 Location: Miami, FL Posts: 15,069 Quote: Originally Posted by sugarcatmom Ha ha, ya I didn't think you did, but just in case anyone else reading thought flushing was a good idea....... Apparently this is a real problem on the California coast. Lots of sea otters dying from TG. I did some snooping around and yeah, those poor little guys. Not to mention, a lot of people are still using that nasty clay stuff. I used to use clay until I started to do a little reading and because as a kitty Vlad had taken to laying in the litter. That was one of the main reasons I wanted to get him something natural enough so that if he ate it, it wouldn't make him sick. __________________ There are only two rules at my house: House rule #1. Cats rule. House rule #2. See rule #1. http://nuriaandthegang.shutterfly.com/ # 14 April 4th, 2008, 02:57 PM Jim Hall Kitty pimp Join Date: Jul 2007 Location: paterson new jersey Posts: 4,788 uhh whats wrong with clay litter? # 15 April 4th, 2008, 03:09 PM sugarcatmom Senior Contributor Join Date: May 2007 Location: Calgary, AB Posts: 5,357 Quote: Originally Posted by Jim Hall uhh whats wrong with clay litter? From my link above: Quote: Clumping is bad for the health... The main culprit is sodium bentonite, a natural clay ingredient that expands into a hard mass when it comes into contact with moisture. While this is convenient for cleaning, it’s not great for kitty. Cats inhale fine sodium bentonite particles when they dig in the litter. Once inhaled, the clay expands when it hits their lungs, causing asthma and other lung problems. Cats can also ingest the clay while cleaning their paws and some even develop sores on their pads from it. Silica-based litters are not much better. This porous granular form of sodium silicate absorbs odours and moisture but is also easily inhaled by humans and felines. It’s been linked to lung cancer, bronchitis and tuberculosis. Some cats can end up with a fatal form of pulmonary tuberculosis called silico-tuberculosis. ...and bad for the planet Both these conventional litters have an adverse effect on the environment. Produced by the destructive method of strip-mining, clay and silica litter can’t decompose any further because they are already in their natural state. When you consider that we send about two million tons of cat litter every year to the landfill that adds up to a lot of fecal feline matter hanging around. __________________ "To close your eyes will not ease another's pain." ~ Chinese Proverb “We must not refuse to see with our eyes what they must endure with their bodies.” ~ Gretchen Wyler # 16 April 4th, 2008, 04:16 PM zztopp Member Join Date: Dec 2007 Location: Black River Posts: 79 Wow! Thanks everyone for your help! And espcially to sugarcatmom for that link ... pretty scary how bad -- and common! -- clay cat litter is!! I can't find a website for Simply Pine -- ??!! I've found Feline Pine but still want to do some comparing We are leaning towards the pine based litters, for various reasons including human allergies. Thanks!! __________________ "Say what you mean, mean what you say, do what you said you were going to do!" -- DJ, the best dog trainer ever <3 Owned by a very cute golden retriever; Kassie!! <3 # 17 April 4th, 2008, 04:16 PM chico2 Senior Contributor Join Date: Jan 2004 Location: Oakville Ontario Posts: 26,591 I change my clumping clay-litter every 2 weeks,I would love to change it to something that's environmentally better and safer for the boys(kitties). Also every 2 weeks I have superheavy garbage-bags.. Swheat Scoop,Yesterdays News which I tried was a no go,but maybe I'll try the clumping Pine,first I have to find a place who sells it There was also another that was recommended to me,it was called something like"Best ever something..." but at $39 bag,was out of the question __________________ "The cruelest animal is the Human animal" 3 kitties,Rocky(r.i.p my boy),Chico,Vinnie # 18 April 4th, 2008, 04:25 PM sugarcatmom Senior Contributor Join Date: May 2007 Location: Calgary, AB Posts: 5,357 Quote: Originally Posted by chico2 There was also another that was recommended to me,it was called something like"Best ever something..." but at $39 bag,was out of the question Probably World's Best Cat Litter, the corn-based one. It is expensive, but you typically use less of it because it clumps super well. I used to really like it, but when my cat started peeing massive amounts from diabetes, it wouldn't soak up his urine fast enough so it would pool around his feet. He hated that and started using the living room floor instead. I switched to the pellets, and he went back to using the box. Even though his urine amounts are normal now, he still prefers the pellets. __________________ "To close your eyes will not ease another's pain." ~ Chinese Proverb “We must not refuse to see with our eyes what they must endure with their bodies.” ~ Gretchen Wyler # 19 April 4th, 2008, 05:06 PM duttypaws head in the clouds Join Date: Nov 2007 Location: Bonnie Banks of Loch Lomond Posts: 464 Quote: Originally Posted by SARAH Before the store I got it from closed (without warning!) I would get wood-chip/sawdust litter. It clumped and was flushable. Frankly, I wish I could find it again, because the clay, although scoopable is easier to clean than the non scoopable, does smell more and takes space in the garbage can (don't use a full bag/week though, and no limit here, so that's not the issue). See if you can find the wood stuff, it's worth it. you can buy Felinefresh in Canadian Tire its clumpable and flushable __________________ (>'.'<) "Princess" Lola ~ 5yrs black and white long hair (>'.'<) PoppyCat ~ 6 yrs grey and white short hair (>'.'<) Buffy ~ 14 yrs Calico (>'.'<) Zena ~ 14 yrs Calico long hair & Hugo ~ 10 yrs GBGV # 20 April 4th, 2008, 06:02 PM clm Senior Contributor Join Date: Feb 2007 Location: Mississauga, Ontario Posts: 3,333 I use the Max cat multi cat litter. Non clumping. The boxes get totally changed out every week. We have a 2 bag limit here as well. We have to pay $1.00 apiece for tags for any additional bags. Now I'm forever cleaning out something in this house, and normally I'm over the 2 bag limit anyway. Cindy # 21 April 5th, 2008, 12:46 AM growler~GateKeeper Moderator Join Date: May 2007 Posts: 17,568 Quote: Originally Posted by Kristin7 No sea otters around here! Regardless, I don't flush the litter but instead throw it in the garbage. The flushability is a good indicator that the litter biodegrades. Not sure, but I think cat litter waste can be composted, depending on type of litter? At least, only the urine part, probably not good to put the poop of a meat eater in the compost bin.... Toxoplasmosis is dangerous to all marine life so please don't flush it no matter where you live, whether you have sea otters or not, it will affect other species too. (not directed specifically @ you Kristin7) With the Pine litters of which I use Feline Fresh (your welcome Phoozles ) it is competely compostable only you would use it for flower beds etc not for veggie gardens, hay fields etc where someone would be eating from that land. __________________ Avoid biting when a simple growl will do The Spirit Lives As Long As Someone Who Lives Remembers You - Navaho Saying # 22 April 5th, 2008, 06:25 AM Kristin7 Senior Member Join Date: Jul 2006 Location: US Posts: 857 Unfortunately I did used to flush it when I lived in San Diego, though never would have if I had known back then. Poor otters (and other species) :sad: I don't live near the ocean anymore and the waters in my state are very polluted, as in, it is recommended to not eat fish out of any of the waters. Still, I don't flush it, mostly because I am afraid it would clog my toilet. What is a green bin? is that a compost bin? Someday I'd like to start composting, no idea why I don't now. Do animals get in the bins?? __________________ http://www.catster.com/cats/702907 http://www.catster.com/cats/703259 http://www.catster.com/cats/703269 http://www.dogster.com/dogs/669963 # 23 April 5th, 2008, 09:54 AM krdahmer ~Cat Servent~ Join Date: Jul 2004 Location: Niagara Falls, Ontario Posts: 5,229 I use the swwheat scoop as well. Love the new multi-cat formula... clumps harder and faster. And I have never had a problem with stink. I do not flush it here, simply for the sheer amount I would be flushing... pee and poo times 6 really adds up! (Guess that's a good thing after all! Poor otters!:sad I dispose of it in the doggy poop bags every night when I scoop and then into the regular garbage. I only do a big clean out every two months and all that gets put in seperate bags and tagged. Ya Chico, at first the cost really put me off, but even though I spend $100 on litter, that's only once every two months (8-10 wks), and for 6 cats that's not bad. This litter clumps better so scooping is easier and cleaner and it also controls the smell a lot better than any clay I ever used. With my asthma I really had to look for a litter with no harmful dusts. I did also use the World's Best corn stuff, but didn't like the smell of it with the pee. The corn had a very sty type scent when used, and the swwheat is more of a bakery smell. Not a bakery I'd ever eat at mind you... __________________ Windy~Smoke~Buddy~Palomine~Fagan~Asker~Mickey Blue Eyes Venus “The greatness of a nation and its moral progress can be judged by the way its animals are treated” -Mahatma Gandhi "We're the renegades, we're the people; With our own philosophies; We change the course of history; Everyday people like you and me"- R A T M # 24 April 5th, 2008, 11:36 AM ancientgirl Senior Contributor Join Date: May 2007 Location: Miami, FL Posts: 15,069 I wasn't able to find any Swheat Scoop at the market last week, which usually sells it for less than the pet store. Since I was on a very tight budget I went with the only other natural litter they had. Some corn based litter I'd never heard of. OMG, I can't wait to get paid again, because this stuff is terrible. I will never buy another corn litter again. What I saved by not going to the pet store and getting the SS isn't worth the smell. It's not pungent, but when I walk into my apartment I can smell there are cats living here, whereas with the SS there is no odor. I'd love to try the Feline Fresh, but I can't find it anywhere here and I've looked online on Petco and Petsmart and they don't sell it either. I'm going to try ordering it from the actual site to give it a try. In my opinion though, of all the litters I've used so far, Swheat Scoop is the best for me. __________________ There are only two rules at my house: House rule #1. Cats rule. House rule #2. See rule #1. http://nuriaandthegang.shutterfly.com/ # 25 April 7th, 2008, 10:02 PM katie&thecrew Slave to the fur Join Date: Feb 2008 Location: Sooke, BC Posts: 16 I used to swear by Swheat Scoop, but then I found that it wasn't clumping as well and there was a distinct smell that turned my stomach...I now use Nature's Miracle litter and whooooa boy!!! LOVE IT!! Better clumping, distinct pine smell (which I personally love)...I have turned on some old co workers at the humane society to it as well!! I think it's the best out there, and I find it has even less dust than swheat scoop (I am a sensitive soul ) # 26 April 8th, 2008, 10:07 AM krdahmer ~Cat Servent~ Join Date: Jul 2004 Location: Niagara Falls, Ontario Posts: 5,229 I would have given the pine a shot too.... but alas I am really really allergic to pine! __________________ Windy~Smoke~Buddy~Palomine~Fagan~Asker~Mickey Blue Eyes Venus “The greatness of a nation and its moral progress can be judged by the way its animals are treated” -Mahatma Gandhi "We're the renegades, we're the people; With our own philosophies; We change the course of history; Everyday people like you and me"- R A T M # 27 April 10th, 2008, 06:20 PM zztopp Member Join Date: Dec 2007 Location: Black River Posts: 79 Awesome!! Just to update ... we went and bought some EnviroLitter, which is a pelleted pine-based litter. It's awesome!! Our cats eyeballs almost popped out when he caught a whiff of it ... he promptly left. Later that day I checked the box and there was, uh, evidence of him being in there! Have seen both cats happily coming and going, so I think they are happy. The farm house now has a lovely pine scent to it ... Also noticed that the kitties now have fresh, pine smelling toes LOL __________________ "Say what you mean, mean what you say, do what you said you were going to do!" -- DJ, the best dog trainer ever <3 Owned by a very cute golden retriever; Kassie!! <3 # 28 April 10th, 2008, 06:40 PM onster Senior Contributor Join Date: Feb 2007 Posts: 4,842 ok im sold, gonna try some pine stuff next time i go to buy litter. swheatscoop just isnt cutting it anymore. Doesnt clump well enough and i have the moral dilemna of my cats pooping in wheat when theres wheat shortages elsewhere in the world. I know its supposed to be non human grade, but still.... # 29 April 10th, 2008, 07:08 PM 14+kitties 150% PRO S/N Join Date: Nov 2007 Location: MYOB Posts: 15,408 Ok so...... silly question. I know this pine based litter says it will last forever and it's great for the environment. Great btw!! I have done some "googleing" (so not a word!) on it and they all say they are 100% recycled pine. Great again!!! My question is........... If this pine stuff is made with 100% pine than why pay the money for a small bag ($7.99 up) when you can go and buy 100% pine based softwood bedding (shavings) in a huge bag at hardware stores (78litres I think which expands 3 times the size) for $5.25? Is it the pellet shape? I am using the shavings out in the catuary. The kitties have an area they use and I just cover it with the shavings and clean as necessary. Then I can use the shavings as compost or mulch. I also have it in one litter box until they are used to it and then it will be in all of them. __________________ Assumptions do nothing but make an ass out of u and me. We can stick our heads in the sand for only so long before it starts choking us. Face it folks. The pet population is bad ALL OVER THE WORLD!
http://www.pets.ca/forum/showthread.php?p=574583
Why so few women training? | Iain Abernethy Why so few women training? Why so few women training? This is a conversation I've been trying to have for some time now and I can't seam able to develop it. As a good example, the majority of people actually active here in the forum are men. The few women I was actually able to talk directly are already practitioners and their answers were not very insightful. So, why does most martial arts gyms have so few women training? The most common answer I found is, they don't feel safe. This is the strange thing though, most people don't feel safe around martial arts gyms either. Most of my friends and random people I try to invite to come by have the same VERY immediate response "But I don't know anything, you people are going to hurt me!" and it doesn't matter what I say after....at least I never found a way around this. Ok, sure, I get it, it's not the same for women, when they feel threatened is for very different and, most of the time, much more real and imminent reasons. I don't like to frame the question like this at all, but.... What does a more "feminine friendly" martial arts environment would look like? What would we need to change in order to be at least more open and address those concerns face on? I have some theories of my own, but I would like to hear your thoughts about it. I'm sure there must be some among you with a very balanced presence of all sorts of people in your schools, so your experience would be very welcome. And maybe a woman or two hiding here in the forum that could better guide this conversation??? Edit: maybe we should make clear from which country we are from? There may be some very interesting patterns there for us to dig deeper. I'm from Brasil o/ It's eternally vexing to me that the very people who may most benefit from self defence training and self confidence building are the same people who will often be most put off walking into a martial arts place. While young fit active blokes are ten-a-penny. Although arguably they are among the most at risk demographic of being a victim of physical violence (at the hands of other young fit blokes!). I got into martial arts as a very nervous young man looking to build confidence and it took weeks of build up and failed attempts at walking into a gym (I'll go next week...I'm busy tonight....I wasn't busy!) before I actually did it. I can see why it can be an intimidating undertaking. I'm not sure I have the answers. "Combat fitness" type classes (body-combat, etc) and boxercise have a more representative demographic as far as I can see (more women than men in some cases) so there must be something to the atmosphere and epxectations of those types of activities compared to a "regular" martial arts class? Maybe because you can't fail a bodycombat grading or boxercise class and know you won't be hit or hurt? I hate gradings personally. I know enough to know what I'm crap at and don't need someone officially reminding me of that! One thing that came up talking to an instructor mate of mine was his decision (based on talking to his female students) to make his optional club uniforms a dark colour rather than the plain white he was going to go for. They have official grading/competition uniforms that are white. So that at "certain times of the month" the female students could wear something suitable for training and not worry about it. If you get my meaning. White uniforms are not the best choice in that regard and yet they seem to be the default. It's a bit of a catch 22 situation. I think any club wishing to attract more women (and keep them) needs women prominently in its identity and branding. Female safeguarding and child protection officers, female high grades, female only classes or starter classes. "Family" sessions perhaps? That kind of thing. But you can't do any of that unless women join your club in the first place! Women would definitely be better contributors to this, but I can throw in my two cents. For what it's worth, though, the majority of my students are women and girls, and at both of the schools I have trained at as a student, the student population was close to 50% women and girls, so my experience may be a bit skewed. Bear in mind that I make the following statements as a cisgender, heterosexual male, so the female perspective is what I have learned from talking to women, and reading articles that women have written on such subjects, but but I am absolutely not the best source. First, I feel it's important to clarify your point about people not feeling safe in a martial arts gym: Men don't feel safe going to martial arts gyms because they are afraid of being embarrassed, or potentially injured. Women don't feel safe going to martial arts gyms because, in addition to the potential of embarrassment (the white uniforms don't help) or injury, there are likely to be a lot of men at martial arts gyms (as you've alluded to), which in their experience means that they are at much higher risk of being harrassed or assaulted, because that is what they experience on a day-to-day basis. Additionally, martial arts training can be very triggering for someone who has been assaulted, before, which is approximately 25% of women. Now, as to how to make a martial arts gym more inclusive? Well, I have some ideas but, again, it would be better to get input from women and girls, and members of the LGBTQIA+ community, so these are just a start. • Don't embrace toxic masculinity, and don't use or reward outward displays of machismo or vulgarity • Don't allow disrespectful, misogynistic, sexist, bigoted, or otherwise harmful speech/jokes/behavior • Don't shame people for what they wear/how they look • Don't tell women and girls they are "distracting," or otherwise sexualize them • Allow dark colored uniforms that won't become see-through when sweaty, and won't show blood as easily • Make sure students are communicating with each other and getting consent before making contact or engaging in a training exercise, and enforce that consent (this includes trying to make them do things they don't feel comfortable with in the name of "pushing them out of their comfort zone," unless you have explicitly discussed this ahead of time and gotten consent, and make it clear they have the right to revoke that consent at any point) • Educate yourself about the dangers and issues women and girls face on a daily basis, and be open to having discussions with them to see how you can improve your understanding and your approach to training • Be a safe space/person for your students to come to with concerns, and really listen to what they have to say • Encourage the women and girls in your gym to lead, and be sure you are using them as examples as much as you use the men and boys • Encourage students to have their parents and friends come in to watch training • Participate in family-type activities as a gym (park outings, cookouts, etc.) PASmith wrote: "Combat fitness" type classes (body-combat, etc) and boxercise have a more representative demographic as far as I can see (more women than men in some cases) so there must be something to the atmosphere and epxectations of those types of activities compared to a "regular" martial arts class? Maybe because you can't fail a bodycombat grading or boxercise class and know you won't be hit or hurt? I hate gradings personally. I know enough to know what I'm crap at and don't need someone officially reminding me of that! Actually, here in Brasil, Muay Thai and Jiujitsu have lot's of women on some academies. I don't believe it's 50/50 but it's quite close overall. I could rationalize Muay Thai as being visually aggressive all the time may have an appeal for people looking to "feel" hipper aggressive as a self defense response. But Jiujitsu?? You are constantly rolling in close proximity with someone trying to dominate you by "any means necessary".....I don't get it! I did Judo for 6 months (planing to try again at some point) and I found the ground work to be EXTREMELY psychologically demanding, you need a lot of trust on your fellow practitioners specially wile training chokes. PASmith wrote: It's a bit of a catch 22 situation. I think any club wishing to attract more women (and keep them) needs women prominently in its identity and branding... But you can't do any of that unless women join your club in the first place! I see that too, in the place I traine, the doughter of the instructor were there form the begining and this makes a difference in helping other women to come by the door just to chat and sse whats going on. Wastelander wrote: First, I feel it's important to clarify your point about people not feeling safe in a martial arts gym: Men don't feel safe going to martial arts gyms because they are afraid of being embarrassed, or potentially injured. Women don't feel safe going to martial arts gyms because, in addition to the potential of embarrassment (the white uniforms don't help) or injury, there are likely to be a lot of men at martial arts gyms (as you've alluded to), which in their experience means that they are at much higher risk of being harrassed or assaulted, because that is what they experience on a day-to-day basis. Additionally, martial arts training can be very triggering for someone who has been assaulted, before, which is approximately 25% of women. I thought I have said that, but thank you for explaining it much better than I did. You are right, of course. I was luck to train my hole life with incredible teachers more than incredible athletes or martial artists and for sure! The instructors behavior defines the overall pace of the school in every single aspect of it. Being inclusive and creating a safe environment is their responsibility in first place. But it's like PASmith said, we need first those people in the gym to than be able to apply any guidelines we may feel are needed. I've never run things like ladies-only classes and currently have no intention of doing so. And yet around three years I found that one of my adult classes was 100% female with an age range of 15 to 30. Why? Let's be honest I'm no Jason Statham or Brad Pitt. I could claim it's my GSOH of course? My suspicion is that it was the material that I was teaching especially given the honesty of their specific risks which we all know very few martial arts do. I suspect my occupation paid a part as there was no overt masculine ego at play. I talked freely about what my job had taught me about the reality of violence including for that group specifically. As a result all of these girls/ladies had gravitated towards me. My question should therefore have been to the effect of why I wasn't attracting men into class. I've just checked my class database and discovered that currently 56% of my students are male. I suspect the 44% female number is unusual. The environments many male martial arts teachers create are anathema to many women, that's the gist of it. At least this is the answer I've recevied when I've had candid conversations about this with the women I've taught. In addition the concerns mentioned about possible abuse and general poor treatment are (unfortunately) very realistic and reasonable concerns. I will note that funnily enough my original Karate dojo in the 80's and 90's was nearly half female. Since then I've only seen numbers dwindle in the dojos I've been part of. This was also in the state of New Mexico, now a somewhat famous place for MMA training, and martial arts have always been popular there, as well as a bit of a "family" thing. So, at my dojo growing up there were many couples and families training together. My Stepfather still runs a dojo (well, dojang) there and it sounds like it is much the same. Also notable, the boxing gym I attended recently seems to have had a fair number of female attendees. Where I live now in the state of Washington the ratio of women I have seen training at various dojos (and running my own) is much smaller, maybe 1 out of 5, if that. I think Wastelander's post has some excellent suggestions, I have tried to follow some these over the years. PASmith wrote: It's eternally vexing to me that the very people who may most benefit from self defence training and self confidence building are the same people who will often be most put off walking into a martial arts place. While young fit active blokes are ten-a-penny. Although arguably they are among the most at risk demographic of being a victim of physical violence (at the hands of other young fit blokes!). I got into martial arts as a very nervous young man looking to build confidence and it took weeks of build up and failed attempts at walking into a gym (I'll go next week...I'm busy tonight....I wasn't busy!) before I actually did it. I can see why it can be an intimidating undertaking. One thing I always try to keep in mind is that it is generally more difficult by orders of magnitude for a woman to walk into a martial arts Dojo or Gym than it is for a man. There are far more social, interpersonal, communication, and safety issues that a woman has to worry about when looking for training the first time. There is simply is no comparison between their experience and ours. I have a physical disablity, which is part of what brought me to Karate training when I was young. Even with that, I would wager that my experience (primarily due to my gender and size) is somehow more overtly "welcomed" when I walk into a gym or Dojo than it is for many women. How much of that is the place and how much is the individual is of course different in each circumstance, and could be debated. However, I am personally convinced this is the case. Tau wrote: My suspicion is that it was the material that I was teaching especially given the honesty of their specific risks which we all know very few martial arts do. I suspect my occupation paid a part as there was no overt masculine ego at play. I talked freely about what my job had taught me about the reality of violence including for that group specifically. As a result all of these girls/ladies had gravitated towards me. I'm new here and don't know anybody yet, would you mind elaborating? What kind of explanation do you give? Whats is your job exactly? There would remain the need to bring someone through the door to have this conversations, but your particular situation may give us some very good ideas about how to create a more credible relation with newcomers from the start. Frazatto wrote: Tau wrote: My suspicion is that it was the material that I was teaching especially given the honesty of their specific risks which we all know very few martial arts do. I suspect my occupation paid a part as there was no overt masculine ego at play. I talked freely about what my job had taught me about the reality of violence including for that group specifically. As a result all of these girls/ladies had gravitated towards me. I'm new here and don't know anybody yet, would you mind elaborating? What kind of explanation do you give? Whats is your job exactly? There would remain the need to bring someone through the door to have this conversations, but your particular situation may give us some very good ideas about how to create a more credible relation with newcomers from the start. I'm a nurse. Much of my career was spent as an Emergency Nurse Practitioner and still is when I do agency shifts for some extra money. Essentially I'm a nurse but with specialist training to the point that these days I work essentially as a Dr. Working in emergency care means I got an insight into violence from different perspectives as I would treat the perpetrators of violence with the Police accompanying them and I would treat the victims. I'm trained to spot signs of abuse and to ask about it. It is thought that it takes something like an average of 37 encounters with a health care professional for a victim of domestic abuse to disclose that that is what is happening and I've been the "37th" encounter as it were. This has directly influenced how I teach pragmatic self protection skills and increased the setting on my bullshit filter. I think my students see and respect that. #11 So, why does most martial arts gyms have so few women training? The most common answer I found is, they don't feel safe. This is the strange thing though, most people don't feel safe around martial arts gyms either. Most of my friends and random people I try to invite to come by have the same VERY immediate response "But I don't know anything, you people are going to hurt me!" and it doesn't matter what I say after....at least I never found a way around this. Ok, sure, I get it, it's not the same for women, when they feel threatened is for very different and, most of the time, much more real and imminent reasons. I don't like to frame the question like this at all, but.... What does a more "feminine friendly" martial arts environment would look like? And maybe a woman or two hiding here in the forum that could better guide this conversation??? Edit: maybe we should make clear from which country we are from? There may be some very interesting patterns there for us to dig deeper. I'm from Brasil o/ Well, one of the possible reasons is that their idea of Martial Arts might be different than what you think. When someone who is into Martial Arts are asked to associate something to the idea of Martial Arts to a lay person. They are thinking Mr. Miyagi, Bruce Lee, some old wise dude with a Fu Machu. But to someone who has no interest but is being talked to about martial arts. Those might be something they think of. Or they might be thinking Warmachine and Christy Mack. Or any other big MMA person that abused their significant other. So it can be a image thing, how to sell a traditional art to someone that will accomplish someome's goals but doesn't appear too agressive and scary. Which is why family martial arts works so well, because its not scary or intimidating.
https://iainabernethy.co.uk/comment/18500
Why you need to move on mobile app testing - Information Age Mobile app testing is perceived as expensive and time consuming, but it’s vital to ensure users have a positive experience. It helps identify navigation a Why you need to move on mobile app testing Mobile app testing is perceived as expensive and time consuming, but it’s vital to ensure users have a positive experience. It helps identify navigation and presentation errors, controls usage problems, and provides feedback about the apps general appeal and engagement level. Unfortunately, a lot of marketers launching mobile apps take shortcuts to skimp on testing, or use a reactive approach and only worry about what users think once the app hits the market. They often put far too much emphasis on time-to-market, citing competitive reasons and the rapid technological pace of mobile as justification to get their mobile app out there fast. Mobile apps should be tested proactively, not reactively. A Localytics study shows that 24% of users try out a downloaded app only once. That’s because when users find fault with an app, they simply don’t use it again. The goal of testing efforts should not be just to find errors, but to understand the quality of the app. Does it work? Does it function as it was designed? Will it meet the needs of your users so that they come back, again and again? A Perfecto Mobile benchmark survey this year found that users and not testers identify almost half of mobile application issues. In essence, that means users are the final QA step – obviously this is not the desired course of action. That means testing must be proactive to catch issues before the user experiences them. The report also identified the top three challenges in mobile testing: insufficient coverage (63%), lack of reliable automation (48%), and needing more coverage to execute test scenarios than time permits (47%). Respondents said that in order to reduce mobile app defects, more functional testing, device/OS coverage, and performance testing were needed. Usability testing is not just a backend activity, it should occur throughout the development process from initial design to just before an app is released to allow you to address issues. By testing an app prior to its release and during development, it is exponentially easier to fix problems. Addressing the issues discovered in the early stages of development will not only save the higher costs of fixing them post-release, but also avoid potential damage to a brand as a result of the bad reviews it will likely receive. Testing should also be done at every phase of development, and user interaction should be recorded. Monitoring mobile apps is essential to examining their performance; it’s vital to monitor continuously, especially during performance testing so to isolate trends and differentiate between systems and root causes. User testing vs. beta testing While any testing is a both necessary and positive, beta testers get so familiar with a mobile app that they develop a kind of ‘white line fever’ – a fixation on a single point and lack fresh eyes – making them less likely to spot usability problems. User testing, on the other hand, gives feedback from typical users who aren’t familiar with an app and have no bias or emotional attachment to it. These user tests help understand the needs and reactions of normal users, the types of people who write reviews in the app store. Mobile apps differ from Web applications in their specific purpose. As such, when an app is created and deployed, there needs to be more upfront planning specific to the utilisation of the app – not simply a scaled-down version of the website. Mobile apps are used under much different conditions than a website, so they must facilitate this with ease. It’s important to remember that mobile consists of two devices: smartphones and tablets. If an app is designed to run on both, tests should be run on both because a screen layout may look good on a smartphone but cumbersome or unappealing on a tablet, or visa-versa. Additionally, user behavior on the two devices has subtle, yet distinct, differences. Testing is often considered logical, planned and predictable, full of processes, test scripts, passes and fails – but this is not the full extent of what it encompasses. Businesses need to do more than just test cases and find bugs; they need to find the issues that matter to users, and provide information of value that determines when it is okay to release an app and mitigates any issues beforehand. By testing apps within the target audience during development, they are more likely to be not only wanted by the user but also engaging. Testing helps avoid naval gazing (looking at your own needs only); it gives the insights into what the users want and the type of app that will enhance the brand. Sourced from Gregg Guzman, associate director of planning, Sq1 Applications Development Process
https://www.information-age.com/why-you-need-move-mobile-app-testing-30208/
Prognostic models for patients with brain metastases after stereotactic radiosurgery with or without whole brain radiotherapy: a validation study - [scite report] Mentioning: 5 - All models under-predicted MS and only the BSKN and Lung-molGPA model stratified patients into three risk groups with statistically significant actual MS. The prognostic groupings of the adenocarcinoma Lung-molGPA group was the best predictor of MS, and showed that we are making improvements in our prognostic ability by utilizing molecular information that is much more widely available in the current treatment era. Prognostic models for patients with brain metastases after stereotactic radiosurgery with or without whole brain radiotherapy: a validation study et al. Abstract: All models under-predicted MS and only the BSKN and Lung-molGPA model stratified patients into three risk groups with statistically significant actual MS. The prognostic groupings of the adenocarcinoma Lung-molGPA group was the best predictor of MS, and showed that we are making improvements in our prognostic ability by utilizing molecular information that is much more widely available in the current treatment era. Retrospective Study of hypofractionated stereotactic radiotherapy Combined with whole brain radiotherapy for Patients with Brain Metastases Peng 2 , Zhang 3 et al. 2022 Preprint Background and purpose To evaluate the clinical outcomes of hypofractionated stereotactic radiotherapy (HFSRT) combined with whole brain radiotherapy (WBRT) in patients with brain metastases (BMs). Materials and methods From May 2018 to July 2020, 50 patients (111 lesions) received HFSRT (18Gy/3F) + WBRT (40Gy/20F). The RECIST 1.1 and RANO-BM criteria were used to evaluate treatment efficacy. Five prognostic indexes (RPA, GPA, SIR, BS-BM, and GGS) were applied. The primary endpoint was intracranial local control (iLC). Secondary endpoints were overall survival (OS) and the safety of treatment. Results Intracranial objective response rates (iORR) using the RECIST 1.1 and RANO-BM criteria were 62.1% and 58.6%, respectively. The iLC rate was 93.1%, the 6- and 12-month iLC rates were 90.8% and 57.4%, respectively. The median intracranial progression-free survival (iPFS) was not reached (range 0 − 23 months). The 6-, 12-, and 24-month OS rates were 74.2%, 58.2%, and 22.9%, respectively. The KPS score showed statistical significance in univariate analysis of survival. The 6, 12, and 24 month OS rates for patients with KPS ≥ 70 were 83.8%, 70.5%, and 29.7%, respectively. The median survival time (MST) for all patients and for patients with KPS ≥ 70 were 13.6 and 16.5 months, respectively. Sex, KPS score, and gross tumor volume were significant factors in the multivariate analysis of survival. OS was significantly associated with RPA, SIR, BS-BM, and GGS classes. No acute toxicities of grade 3 or higher were noted. Conclusion HFSRT combined with WBRT is a safe and effective local treatment modality for BM patients. “…In addition, we found that the PIs in our study were not uniformly recommended in different studies, and there was a large discrepancy between the expected and actual survival[18, [40] [41] [42] . This nding supports the need for a better prognostic tool or index.…” Section : Discussion mentioning confidence: 59% Retrospective Study of hypofractionated stereotactic radiotherapy Combined with whole brain radiotherapy for Patients with Brain Metastases Xie 1 , Peng 2 , et al. 2022 Preprint Background and purpose To evaluate the clinical outcomes of hypofractionated stereotactic radiotherapy (HFSRT) combined with whole brain radiotherapy (WBRT) in patients with brain metastases (BMs). Materials and methods From May 2018 to July 2020, 50 patients (111 lesions) received HFSRT (18Gy/3F) + WBRT (40Gy/20F). The RECIST 1.1 and RANO-BM criteria were used to evaluate treatment efficacy. Five prognostic indexes (RPA, GPA, SIR, BS-BM, and GGS) were applied. The primary endpoint was intracranial local control (iLC). Secondary endpoints were overall survival (OS) and the safety of treatment. Results Intracranial objective response rates (iORR) using the RECIST 1.1 and RANO-BM criteria were 62.1% and 58.6%, respectively. The iLC rate was 93.1%, the 6- and 12-month iLC rates were 90.8% and 57.4%, respectively. The median intracranial progression-free survival (iPFS) was not reached (range 0 − 23 months). The 6-, 12-, and 24-month OS rates were 74.2%, 58.2%, and 22.9%, respectively. The KPS score showed statistical significance in univariate analysis of survival. The 6, 12, and 24 month OS rates for patients with KPS ≥ 70 were 83.8%, 70.5%, and 29.7%, respectively. The median survival time (MST) for all patients and for patients with KPS ≥ 70 were 13.6 and 16.5 months, respectively. Sex, KPS score, and gross tumor volume were significant factors in the multivariate analysis of survival. OS was significantly associated with RPA, SIR, BS-BM, and GGS classes. No acute toxicities of grade 3 or higher were noted. Conclusion HFSRT combined with WBRT is a safe and effective local treatment modality for BM patients. “…In the only study to date that validated the molGPA score, 70% of patients received WBRT and concurrent systemic therapy was likewise not recorded [18] . Other available scores have been shown to underestimate OS as these were all developed before widespread implementation of TT/IT [19] . Two studies have aimed to validate prognostic scores in TT/IT-treated patient cohorts that received concomitant SRT to date, albeit omitting the most widely used molGPA score [20, 21] .…” Section : Introduction mentioning confidence: 99% Schaule 1 , Kroeze 2 , Blanck 3 et al. 2020 Background: Melanoma patients frequently develop brain metastases. The most widely used score to predict survival is the molGPA based on a mixed treatment of stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT). In addition, systemic therapy was not considered. We therefore aimed to evaluate the performance of the molGPA score in patients homogeneously treated with SRT and concurrent targeted therapy or immunotherapy (TT/IT). Methods: This retrospective analysis is based on an international multicenter database (TOaSTT) of melanoma patients treated with TT/IT and concurrent (≤30 days) SRT for brain metastases between May 2011 and May 2018. Overall survival (OS) was studied using Kaplan-Meier survival curves and log-rank testing. Uni-and multivariate analysis was performed to analyze prognostic factors for OS. Results: One hundred ten patients were analyzed. 61, 31 and 8% were treated with IT, TT and with a simultaneous combination, respectively. A median of two brain metastases were treated per patient. After a median follow-up of 8 months, median OS was 8.4 months (0-40 months). The molGPA score was not associated with OS. Instead, cumulative brain metastases volume, timing of metastases (syn-vs. metachronous) and systemic therapy with concurrent IT vs. TT influenced OS significantly. Based on these parameters, the VTS score (volume-timing-systemic therapy) was established that stratified patients into three groups with a median OS of 5.1, 18.9 and 34.5 months, respectively (p = 0.001 and 0.03). “…Ideally, patients with limited prognosis would not be exposed to the unnecessary burden of intense treatment, whereas those with better prognosis would receive the therapeutic measures required to prevent neurologic death [11, 12] . Several tools (prognostic scores and nomograms with survival and other endpoints) have been developed to support decision-making [13] [14] [15] [16] [17] . Initially, they were heavily based on performance status and extracranial disease extent or control, and not stratified by primary cancer type.…”
https://scite.ai/reports/prognostic-models-for-patients-with-RVGAGRN
A low power and low distortion VCO based ADC using a pulse frequency modulator | Request PDF Request PDF | A low power and low distortion VCO based ADC using a pulse frequency modulator | This paper shows a novel VCO based ADC which uses an inverter delay line as a monostable to implement a pulse frequency modulator. The inverter... | Find, read and cite all the research you need on ResearchGate Conference Paper A low power and low distortion VCO based ADC using a pulse frequency modulator August 2014 DOI: 10.1109/MWSCAS.2014.6908458 Conference: 2014 IEEE 57th International Midwest Symposium on Circuits and Systems (MWSCAS) Authors: University Carlos III de Madrid University Carlos III de Madrid Sergio Walter Abstract This paper shows a novel VCO based ADC which uses an inverter delay line as a monostable to implement a pulse frequency modulator. The inverter delay line doubles as a Time to Digital converter, providing a multibit digital output similar to a ring oscillator. The pulse frequency modulator is based on a gm-C integrator, operating as a closed loop transconductor for the low bandwidth input signal path and as a charge pump for the monostable feedback. This way a high linearity is achieved while the total power consumption is kept on the order of a calibrated VCO-ADC. The paper shows the basic system level operation and behavioral simulations, and also a transistor level design example in 0.25μm CMOS technology. 0.04-mm² 103-dB-A Dynamic Range Second-Order VCO-Based Audio Σ Δ ADC in 0.13-μm CMOS Feb 2018 IEEE J SOLID-ST CIRC Fernando Cardes Eric Gutierrez Andres Quintero Luis Hernandez This paper presents a compact-area, low-power, highly digital analog-to-digital converter (ADC) for audio applications. The proposed converter is implemented using only oscillators and digital circuitry, without operational amplifiers nor other highly linear circuits. The ADC consists of two twin secondorder ΣA modulators, which can work both individually or in a pseudodifferential configuration. The proposed system has been implemented in a 0.13-μm standard CMOS technology. The single-ended configuration occupies an active area of 0.02 mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> , is powered at 1.8 V with a current consumption of 155 μA, and achieves an A-weighted dynamic range (DR) of 98 dB-A. The pseudodifferential configuration achieves 103 dB-A of A-weighted DR at the expense of doubling the area and power consumption. A Pulse Frequency Modulation Interpretation of VCOs Enabling VCO-ADC Architectures With Extended Noise Shaping Aug 2017 IEEE T CIRCUITS-I Eric Gutierrez L. Hernandez Fernando Cardes Pieter Rombouts In this paper, we propose to study voltage controlled oscillators (VCOs) based on the equivalence with pulse frequency modulators (PFMs). This approach is applied to the analysis of VCO-based analog-to-digital converters (VCO-ADCs) and deviates significantly from the conventional interpretation, where VCO-ADCs have been described as the first-order ΔΣ modulators. A first advantage of our approach is that it unveils systematic error components not described by the equivalence with a conventional ΔΣ modulator. A second advantage is that, by a proper selection of the pulses generated by the PFM, we can theoretically construct an open loop VCO-ADC with an arbitrary noise shaping order. Unfortunately, with the exception of the first-order noise shaping case, the required pulse waveforms cannot easily be implemented on the circuit level. However, we describe circuit techniques to achieve a good approximation of the required pulse waveforms, which can easily be implemented by practical circuits. Finally, our approach enables a straightforward description of multistage ΔΣ modulator architectures, which is an alternative and practically feasible way to realize a VCO-ADC with extended noise shaping. A digitally corrected ADC using a passive pulse frequency modulator Feb 2015 Eric Gutierrez L. Hernandez Ulrich Gaier Liang Zou Pulse Frequency Modulators have been proposed recently as an alternative to ring oscillators in the implementation of Voltage-Controlled-Oscillators Analog to Digital Converters (VCO-ADC). In this paper, we propose a passive pulse frequency modulator in terms of the integration process that uses digital inverters only and provides a polyphase output similar to a ring oscillator. Oscillation depends on a passive RC circuit acting as oscillator time constant. The voltage-to-frequency characteristic of this oscillator shows a nonlinear relationship respect to the input voltage in a similar way as classical ring oscillators. However, in the proposed circuit the nonlinearity depends mainly in a predictable way from the RC product instead of supply voltage (Vdd), temperature or mismatch. We show in this paper how the nonlinearity can be corrected in the signal post-processing by a simple algorithm depending only on the RC time constant operating on the decimated data and circuit parameters that could be known. A 12-Bit, 10-MHz Bandwidth, Continuous-Time ADC With a 5-Bit, 950-MS/s VCO-Based Quantizer May 2008 IEEE J SOLID-ST CIRC M.Z. Straayer Michael H. Perrott The use of VCO-based quantization within continuous-time (CT) SigmaDelta analog-to-digital converter (ADC) structures is explored, with a custom prototype in 0.13 mum CMOS showing measured performance of 86/72 dB SNR/SNDR with 10 MHz bandwidth while consuming 40 mW from a 1.2 V supply and occupying an active area of 640 mum times 660 mum. A key element of the ADC structure is a 5-bit VCO-based quantizer clocked at 950 MHz which achieves first-order noise shaping of its quantization noise. The quantizer structure allows the second-order CT SigmaDelta ADC topology to achieve third-order noise shaping, and direct connection of the VCO-based quantizer to the internal DACs of the ADC provides intrinsic dynamic element matching of the DAC elements. Oversampled ADC based on pulse frequency modulator and TDC Mar 2014 Eric Gutierrez L. Hernandez
https://www.researchgate.net/publication/286679443_A_low_power_and_low_distortion_VCO_based_ADC_using_a_pulse_frequency_modulator
(PDF) Epidemiological and immunological features of obesity and SARS-CoV-2 PDF | Obesity is established as a key correlate of severe SARS-CoV-2 outcomes. Multiple other epidemiological and immunological features are less... | Find, read and cite all the research you need on ResearchGate Epidemiological and immunological features of obesity and SARS-CoV-2 November 2020 DOI: 10.1101/2020.11.11.20229724 Abstract and Figures Obesity is established as a key correlate of severe SARS-CoV-2 outcomes. Multiple other epidemiological and immunological features are less well-defined including if obesity enhances susceptibility to SARS-CoV-2 infection, influences symptom phenotype, or impedes or alters the immune response to infection. Given the substantial global burden of obesity and given these uncertainties, we examined the epidemiology and immunology of obesity and SARS-CoV-2. Methods Industry employees were invited to participate in a prospective SARS-CoV-2 serology-based cohort study. Blood and baseline survey measures that included demographics, comorbidities, and prior COVID-19 compatible symptoms were collected. Serological testing and interim symptom reporting were conducted monthly. SARS-CoV-2 immunoassays included an IgG ELISA targeting the spike RBD, multiarray Luminex targeting 20 viral antigens, pseudovirus neutralization, and T cell ELISPOT assays. Unadjusted and adjusted analyses were used to identify differences in seroprevalence, clinical features, and immune parameters by BMI. Results Of 4469 individuals enrolled, 322 (7.21%) were seropositive. Adjusted seroprevalence was non-significantly lower with higher BMI. Obesity was associated with increased reporting of fever (OR 3.43 [95% CI 1.58-7.60]) and multiple other symptoms and aggregate measures. There were no identifiable differences in immune response between obese and non-obese individuals. Discussion We present benchmark data from a prospective serology-based cohort on the immunoepidemiology of BMI and SARS-CoV-2. Our findings suggest obesity is not linked to an increased risk of SARS-CoV-2 infection; that symptom phenotype is strongly influenced by obesity; and that despite evidence of obesity-associated immune dysregulation in severe COVID-19, there is no evidence of a muted or suppressed immune response across multiple immune measures among non-severe infections. 1 Epidemiological and immunological features of obesity and SARS-CoV- 2 1 Brigham and Women’s Hospital, Boston, MA 2 Harvard Medical School, Boston, MA 3 Harvard Humanitarian Initiative, Boston, MA 4 Massachusetts Consortium on Pathogen Readiness, Boston, MA 6 Broad Institute of MIT and Harvard, Cambridge, MA. 8 Space Exploration Technologies Corp, Hawthorne, CA 9 Harvard T.H. Chan School of Public Health, Boston, MA 10 Howard Hughes Medical Institute, Chevy Chase, MD 11 Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 12 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 13 London School of Hygiene and Tropical Medicine, London # Correspondence : Eric J Nilles: [email protected] ; Galit Alter: [email protected] ; Anil S Menon: [email protected] . CC-BY-NC-ND 4.0 International license It is made available under a Abstract Obesity is established as a key correlate of severe SARS-CoV-2 outcomes. Multiple other epidemiological and immunological features are less well-defined including if obesity enhances susceptibility to SARS- CoV-2 infection, influences symptom phenotype, or impedes or alters the immune response to infection. Given the substantial global burden of obesity and given these uncertainties, we examined the epidemiology and immunology of obesity and SARS-CoV-2. Methods: Industry employees were invited to participate in a prospective SARS-CoV-2 serology-based cohort study. Blood and baseline survey measures that included demographics, comorbidities, and prior COVID-19 compatible symptoms were collected. Serological testing and interim symptom reporting were conducted monthly. SARS-CoV-2 immunoassays included a n IgG ELISA targeting the spike RBD, multiarray Luminex targeting 20 viral antigens, pseudovirus neutralization, and T cell ELISPOT assays . Unadjusted and adjusted analyses were used to identify differences in seroprevalence, clinical features, Results: Of 4469 individuals enrolled, 322 (7.21%) were seropositive. Adjusted seroprevalence was non- significantly lower with higher BMI. Obesity was associated with increased reporting of fever (OR 3. 43 [95% CI 1. 58 -7.60]) and multiple other symptoms and aggregate measures. There were no identifiable differences in immune response between obese and non-obese individuals. Discussion: We present benchmark data from a prospective serology-based cohort on the immunoepidemiology of BMI and SARS-CoV-2. Our findings suggest obesity is not linked to an increased risk of SARS-CoV-2 infection; that symptom phenotype is strongly influenced by obesity; and that despite evidence of obesity-associated immune dysregulation in severe COVID- 19 , there is no evidence of a muted or suppressed immune response across multiple immune measures among non-severe infections. . CC-BY-NC-ND 4.0 International license It is made available under a 3 Background Obesity is a key risk factor for severe disease and death from novel coronavirus disease 2019 (COVID- 19) , 1,2 the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) . With over 1.9 billion people overweight or obese globally, 3 implications for SARS-CoV-2 pandemic morbidity and mortality are substantial . Even after adjusting for age and obesity-related comorbidities such as diabetes, hypertension and coronary heart disease, obesity remains a strong independent predictor of excess morbidity and mortality. 1,4,5 Th ese findings although concerning are not entirely unexpected. 6 Obesity and poor clinical outcomes ha ve been described with other viral pathogens, most notably influenza A (H1N1) during the 2009 pandemic, when obesity was associated with increased hospitalizations, need for intensive care support, and deaths. 4,7,8 In addition to the relationship between obesity and clinical outcomes, emerging evidence suggests a link between higher body mass index (BMI ) and higher incidence rates of COVID-19 or SARS-CoV-2 infection 4,9,10 suggesting increased BMI may enhance susceptibility to infection . If correct, there would be important implications for individual-level risks and population-level transmission dynamics, particularly among populations with high rates of obesity. 4 However, data supporting this association is limited, and given the absence of convincing precedent from other pathogens additional evidence is required to confirm these findings. The influence of obesity specifically on the immune response to SARS-CoV-2 has also been the focus of intense recent attention. 4,11 Obesity has been linked to less robust and/or effective immune response after natural influenza infection 12 or vaccination, 13 raising concerns about diminished protective immunity following natural SARS-CoV-2 infection or vaccination. 4,14 This is particularly relevant given multiple phase II and III vaccine trials are underway, and the outcomes of these trials are likely to reframe the pandemic trajectory. However, again, the immunological features of SARS-CoV-2 infection and obesity are poorly characterized with limited directly relevant data. . CC-BY-NC-ND 4.0 International license It is made available under a 4 Thus, given the essential connection between the epidemiology and immunology of infectious pathogens including SARS-CoV-2 and given substantial uncertainly about multiple features of obesity and SARS-CoV-2 we conducted an integrated immunoepidemiological investigation of obesity and SARS- CoV- 2 through a prospective multi-site cohort study. This study aimed to identify if BMI is associated with (i) differential risks of testing positive for anti-SARS-CoV-2 IgG antibodies among a population unbiased to serostatus at study entry, (ii) variable reporting of COVID-19 compatible symptoms, and (iii) measurable differences in adaptive immune features. Methods Ethical Disclosures The study protocol was approved by the Western Institutional Review Board. The use of de -identified data and biological samples was approved by the Mass General Brigham Healthcare Institutional Review Board. All participants provided written informed consent. Study design, setting and study population This is a prospective observational cohort study using serial serological assessment to characterize the immunoepidemiology of SARS-CoV-2 infection among a cohort of industry employees. Serostatus was unknown at the time of subject enrollment. The study population was comprised of Space Exploration Technologies Corporation employees, all of whom were invited to participate. A total of 44 69 participants were enrolled out of a total of ~8400 employees from seven primary work locations in four U.S. states including California, Texas, Florida, and Washington. Study enrollment commenced 20 April and employees were invited to participate on a rolling basis through 28 July 2020. Serial blood sampling and interim symptom reporting were performed monthly. Covariates All participants completed a standardized baseline study survey that included demographic data (age, sex, race, ethnicity, primary work location, and number of individuals and children <18 years living in the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 5 subject household), medical history (weight, height, diabetes, asthma, chronic obstructive pulmonary disease, other lung disease, coronary heart disease, heart failure, high blood pressure, chronic kidney disease, stroke, any immunocompromised condition, any other significant medical condition, and smoking status), and COVID-19 compatible symptoms between March 1, 2020, and study enrollment including primary symptoms (fever, chills or feverish, cough, anosmia, ageusia) and other compatible symptoms (body or muscle aches, sore throat, nausea or vomiting, diarrhea, congestion, and increased fatigue/generalized weakness). Composite symptom measures included (i) any symptom, (ii) number o f symptoms, (iii) ≥3 symptoms; (iv) ≥6 symptoms, (v) any primary symptom (v i) number of primary symptoms and (v ii ) ≥3 primary symptoms. Sequential blood sampling and interim symptom reporting using a standardized survey were performed monthly. The number of participants with missing data by covariate is listed in Table 1. Laboratory analys es Serological analyses were performed on sera using the Ragon/MGH enzyme-linked immunosorbent assay, which detects IgG against the receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein using a previously described method 15 (Supplemental 1). Assay performance has been externally validated in a blinded fashion at 99·6% specific and benchmarked against commercial EUA approved assays. 16 Immune profiling methods are detailed in Supplement 1. Briefly, specific antibody subclasses, isotypes and FcγR binding against SARS-CoV-2 RBD, nucleocapsid and full spike proteins were assessed using a custom Luminex multiplexed assay (Luminex Corp, TX, USA). Viral neutralization was assessed on a 2019-nCoV pseudovirus neutralization assay, as described previously 17 with neutralization titer defined as the sample dilution associated with a 50% reduction in luminescent units. The presence of neutraliz ing activity was defined as a titer >20. T cell activity was assessed on an enzyme-linked interferon-gamma immunospot assay (ELISPOT) with > 25 spot forming cells (SPC) per 10 6 peripheral blood mononuclear cells (PBMCs) considered positive. . CC-BY-NC-ND 4.0 International license It is made available under a 6 Data classification and analyses Serostatus was determined by the presence or absence of IgG against SARS-CoV-2 RBD. BMI was calculated by dividing weight in kilograms by height in meters squared and categorized by underweight (<18·5 kg/m 2 ), normal weight (18·5 to 24 kg/m 2 ; reference), overweight (25 to 29 kg/m 2 ), obesity class 1 (30 to 34 kg/m 2 ), obesity class 2 (35 to 39 kg/m 2 ), and obesity class 3 or severe obesity (≥40 kg/m 2 ) according to the World Health Organization . We performed discrete analyses to address the three aims of the study. For assessment of risk of seropositivity by BMI, the primary exposure of interest was BMI and the outcome variable of interest was seropositivity at any time point. We assessed the unadjusted and adjusted association between a range of demographic (n=7) and medical history (n=17) covariates using χ2 to compare proportions and ANOVA or Kruskal-Wallis tests to compare means. For adjusted analyses, we constructed a multivariable logistic regression model that included, in addition to BMI and serostatus, age, sex, ethnicity, race, comorbidities, primary work location, number of individuals in the household, and children in the household. To understand if obesity status is associated with differential reporting of symptoms, we computed the proportion of seropositive individuals reporting each of 11 COVID-19 compatible symptoms stratified by obesity status. Symptoms were analyzed from the period preceding the first seropositive result. For example, if an individual w as seronegative at baseline and seropositive at the subsequent time point, the symptoms reported between those timepoints were analyzed. The primary exposure of interest was obesity, and the outcome variables of interest were symptoms and composite symptom measures. Given recent data suggest ing the adverse impact of obesity on COVID- 19 mortality may decline with age, 9 we assessed if similar age-dependent obesity risk may be observed for symptom reporting by conducting subgroup analysis stratified by < or ≥ 40 years, with categorization selected due to sparsity of older participants. . CC-BY-NC-ND 4.0 International license It is made available under a 7 Lastly, given an accumulation of evidence that obesity impairs the immune response to a range of pathogens 6,13,18 – 20 we stratified 20 discrete immune features by obesity status to identify univariate differences. We also performed uniform manifold approximation and projection (UMAP) 21 a mathematical approach for exploratory analyses that constructs a visualizable summary of multiple subjects' characteristics, with each point representing an individual and clusters representing underlying uniformities in subject characteristics. Binomial exact 95% confidence intervals were calculated and p-values < 0·05 were considered statistically significant· For adjusted analyses, variables with a p-value <0·10 were assessed by backward elimination and excluded if the p-value was >0· 10 and did not meaningfully alter the point estimates of the remaining variables. Luminex UMAP and Mann-Whitney U Tests were conducted using scikit-learn, a machine learning toolkit for the Python programming language. Analyses were performed using the R sof tware package (Version 4·0, www.R-project.org/) or the Python programming language (Version 3·7, python.org). Results A total of 44 69 Space Exploration Technologies Corporation employees out of a total of ~ 84 00 employees (53%) were enrolled. Baseline characteristics are included in Table 1 . Mean BMI was 27·1 kg/m 2 (SD 5·4) with a median of 25· 8 kg/m 2 (range 15·6 — 60 ·9). Most subjects were normal weight (18 ·5 — 24 kg/m 2 ) ( 16 86 , 39·5%) or overweight (25 — 29 kg/m 2 ) (1523, 35·7%), and 24·1% and 0· 80 % met criteria for obese (≥30 kg/m 2 ) and underweight (≤18 · 5 kg/m 2 ) respectively. IgG against the SARS-CoV-2 spike RBD protein was detected in 32 2/4469 (7·21%) of study participants . Of the 322 seropositive individuals, five (1 ·6%) were hospitalized and none required critical care support or died . Unadjusted seropositivity rates are detailed in Table 1; they were higher in South Texas (O dd Ratio 4· 28 [95% CI, 2·54 to 7·21), p<0·0001]) and among Hispanics (2 · 91 [95% CI 2· 22 6 — 3· 75 ], p<0·0001); and they were lower in Seattle, Washington (0·30 [95% CI, 0·11 to 0· 82 ], p=0·02]), and in the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 8 30 — 39 year compared to the 18 — 29 year age group (0 ·72 [ 95% CI, 0·56 to 0·94, p=0·02). Adjusted associations for all covariates are listed in Table 1 ; only primary work location was retained as significantly associated with serostatus with increased OR in South Texas (OR 4·28 [2·54 — 7·21], p<0·0001) and lower in Seattle (OR 0·30 [0· 11 — 0·82], p=0·02 ) largely reflecting local transmission rates. The strong univariate association between Hispanic ethnicity and serostatus was not retained after adjusting for work location (OR 1·27 [0· 94 — 1·73], p=0·12). BMI and serostatus Of the 4469 participants, 4270 (9 5·5 %) provided weight and height data and are included in BMI analyses. The unadjusted risks of seropositivit y stratified by BMI are listed in the Table 1; only BMI 30 to 34 kg/m 2 (versus normal/healthy weight, 18·5 — 24 kg/m 2 ) was associated with differential serostatus (OR 1· 48 [1 ·06 to 2· 05 ], p<0·02). However, after adjusting for all candidate variables (Table 1 ), no association was detected . In fact, higher BMI and in particular severe obesity (BMI ≥40 kg/m 2 ) trended non-significantly to lower seroprevalence (Figure 1A) . Subgroup analysis from a single high prevalence location where, given the high force of infection as evidenced by high seroprevalence (22·5% versus 4·2% for all other sites combined), we predict risks for infection — including any effect of BMI — would be more clearly delineated (Supplementary 2) . Findings were similar to the primary analysis with no evidence of increased seroprevalence with increasing BMI. Rather, point prevalence measures consistently trend ed lower than normal/healthy weight (Figure 1B ). BMI and COVID-19 compatible symptoms Of 26 2 seropositive participants with complete symptom data, three (1 ·1%) were underweight (BMI<18·5 kg/m 2 ), 89 (3 4·0%) normal weight (BMI 18·5 — 24 kg/m 2 ), 89 (34·0%) overweight (BMI 25 — 29 kg/m 2 ), and 81 (3 0·9%) obese (BMI ≥ 30 kg/m 2 ) . A total of 106/262 (4 0·5%) reported one or more of 11 COVID- 19 - compatible symptoms and 68 /262 (2 6·0%) reported one or more of five primary COVID- 19 symptom. When comparing symptoms between normal weight and overweight (but not obese) . CC-BY-NC-ND 4.0 International license It is made available under a 9 individuals, there were no meaningful differences or trends (Supplementary 3) and therefore subsequent analyses were stratified by obese versus non-obese. Obesity was associated with increased reporting of multiple symptoms including fever (OR 3· 43 [95% CI 1· 58 — 7· 60 ]), chills or feverish but no measured fever (OR 2· 64 [1 ·33 — 5·27]), myalgias (OR 2· 29 [1 ·18 — 4· 42 ]), and ≥6 symptoms ( OR 2· 26 [1 · 10 — 4· 64 ]). With the exception of congestion (0·87 [0· 43 — 1·70]), a similar and consistent but non-significant trend was observed for all symptoms (Figure 2) . Overall, obese individuals registered more symptoms (2 · 26 versus 1·40, OR 1·10 [1 ·02 — 1 ·22]) and more primary symptoms (1· 05 versus 0· 58 , OR 1·24 [1 ·04 — 1·48] ) than non-obese. Differential symptom reporting was mo re pronounced in those under 40 years of age. Fever was more commonly reported among obese vs non-obese individuals under 40 years of age (OR 4· 99 [1 · 97 — 13· 35 ]) but not over 40 years (OR 1· 32 [0 ·30 — 5· 57 ]) . Similarly, reporting ≥6 symp toms was more common among obese vs non— obese unde r 40 years (OR 3·0 [1· 32 — 6·85]) but not for those greater than 40 years (OR 0·94 [0· 18 — 4·26]). A strikingly similar trend was observed for the majority of other symptoms and aggregate symptom measures (Figure 3). No similar age-dependent effect on obesity and symptomatology was observed among age groups < 40 years of age (Supplementary 4). Obesity and functional immune response Among the same 26 2 seropositive individuals, peak SARS-CoV-2 RBD IgG titers were 0·92 ug/ml (SD 2·47 ) among obese (n=81) and 1· 12 ug/ml (SD 3·21 ) among non-obese (n=181) participants (p=0·601). Deep immune profiling was performed among a subset of 77 participants including 25 obese and 52 non-obese individuals. Me an ELISA nucleocapsid titers were 0· 35 (SD 0·48 ) among obese individuals and 0· 30 (0· 34 ) for non-obese individuals (p=0· 57) . Viral neutralization activity (titer >20) was detected in 3/25 (12·0%) and 6/52 (11·5%) of obese and non-obese individuals respectively (p=0·95) . When assessing 20 immune features measured by Luminex, n o univariate differences were observed between obesity categories, with sparse levels across both obese and non-obese individuals tightly linked to . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 10 antibody titers (Figure 4A, Supplementary 5). Similarly, no clustering or trends between BMI and immunological features were identifiable either by UMAP (Figure 4B) or Spearman’s correlation (Figure 4C). Lastly, given evidence that T cells may be key mediators of adaptive immunity in SARS-CoV-2, we examined responses to nucleocapsids protein or spike protein overlapping peptide pools quantified by IFN-g ELISpot among 12 obese and 28 non-obese individuals. There was no difference in the proportion with SARS-CoV- 2 T cell activity (≥25 SFC/10 6 PBMCs) against nucleocapsid peptides (3/12 [25%] versus 7/28 [25·0%]) or spike peptides (3/12 [25%] versus 7/28 [25·0%]). In fact, the only difference observed was higher SFC against nucleocapsid (mean 124 SFC /10 6 PBMCs [SD 77] versus 47 SFC/10 6 PBMCs [SD 14], p=0· 02 ) but not spike (44 SFC/10 6 PBMCs [SD 4·0] versus 44 SFC/10 6 PBMCs [SD 20·0], p=1· 00) among obese versus non-obese individuals with T cell activity . Discussion We present data from a large multi-site prospective cohort of non-hospitalized individuals unbia sed to serostatus at study entry to investigate the association between BMI, SARS-CoV-2 serostatus, COVID- 19 compatible symptoms, and functional and non-functional immune measures . Given the prevalence of overweight/obese among adults is close to 70% in most high income countries and ≥50%, in many lower and middle income countries, the scientific and public health implications for the current pandemic are substantial 4 . Unlike prior studies, we did not observe an increase in infection or COVID- 19 prevalence with increasing BMI but rather identified a trend to decreasing risk among the highest BMI classes . We also provide benchmark data on the association between reported COVID- 19 symptoms and BMI, identifying evidence for more frequent reporting of multiple symptoms including fever, myalgia, chills, and total COVID-19 compatible symptoms among obese individuals. Finally, we examined immune features of infection to probe for differential immune signatures associated with obesity status. By . CC-BY-NC-ND 4.0 International license It is made available under a 11 combining traditional epidemiological approaches with deep immun e profiling, we provide new insights into the epidemiology and immune characteristics of obesity in SARS-CoV-2 infections. Prior studies that report an association between increased risk of COVID-19 or SARS-CoV-2 infection with higher BMI are intriguing and raise important questions about factors driving transmission. Given the enormous global burden of overweight and obese adults, delineating risks for infection is a public health priority. Interestingly, our findings appear to diverge from recent data that examines the risk for COVID- 19 by BMI including a nationwide case-control study from South Korea 9 and a cross-sectional study from a primary care surveillance network in the United Kingdom 22 that identify a n increased risk of COVID-19 with increasing BMI; and a recent meta-analysis of 20 studies that reported a pooled increased risk of 46·0% (OR = 1·46; 95% CI, 1· 30 – 1·65; p < 0·0001) with 18 of 20 studies demonstrating higher COVID- 19 risk among obese individuals. 4 Our study did not identify an increase in adjusted seroprevalence with increasing BMI and conversely identified a trend to lower infection risk with high er obesity classes. This trend was consistent when both considering all data and when performing subgroup analysis on a high transmission site where the increased force of infection would be expected to more precisely delineate heterogeneity in infection risks. Reasons for the difference between our and prior study outcomes may be multifactorial with differences in study design and population behaviors likely influencing findings. However, we believe the primary difference is we examined SARS-CoV- 2 infection risk using serological methods unbiased to exposure risks or presence or absence of symptoms at study entry versus other studies examining risks for clinically apparent infection (i.e. COVID- 19 ). Given obese individuals exhibit more pronounced symptomatology including fever, as our data indicates, this population is more likely to meet testing criteria, more likely to be tested and therefore more likely to be over-represented in studies that identify cases through routine surveillance approaches. 23,24 As such, although our study findings appear inconsistent with most prior studies of obesity risk, in fact the question being asked was different. Our study examined SARS-CoV-2 infection risk, as measured by the . CC-BY-NC-ND 4.0 International license It is made available under a 12 presence of SARS-CoV-2 antibodies, while prior studies examined the risk of clinical disease. Unfortunately, conflation of COVID-19 with SARS-CoV- 2 infection is commonplace, as evidenced by confusion over case- versus infection-fatality rate. 24 Our finding that obesity is associated with increased COVID-19 compatible symptoms among SARS-CoV- 2 seropositive individuals provides benchmark data for understanding symptom heterogeneity in mild infections by BMI. We demonstrate that not only are well established measures of severe disease such as hospitalization, intensive care requirements and death more common among obese individuals 5,25,26 , but that obesity is also an important driver of increased symptomatology in non-severe infections . While our data does not provide insights into the mechanism driving th ese findings, it informs our understanding of symptomatology and obesity, guides our interpretation of epidemiological data, and highlights the potential implication of using passively collected symptom-driven surveillance data to characterize the epidemiology of infectious pathogens. We also identify an interesting influence of age on obesity symptom reporting, with a compelling association below 40 years of age but near complete absence of effect in older adults. These findings are notable given they imply the established interaction between obesity and age on COVID-19 morbidity and mortality, with obesity disproportionately driving increased disease severity among younger age groups, 5,25 extend throughout the spectrum of disease and are not restricted to severe disease. The reasons for this phenomenon are unclear and deserve study but do fit with in the broader understanding of obesity and age in which the all-cause relative risk of death associated with increasing BMI decreases with age. 27 Given the fundamental role of the adaptive immune response in both the resolution of infection and the severity of disease, 11 we also probed multiple binding and functional immune markers to assess differential immune responses between obese and non-obese individuals . While, previous studies noted poor seroconversion and inadequate seroprotection across vaccine trials, 28 we did not detect meaningful differences in binding or neutralizing antibodies, T cell activity, or other functional humoral . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 13 measures by BMI. These findings, while notable, should be considered in the context of this largely asymptomatic and pauci-symptomatic cohort, that may not capture the full range of disease burden associated with SARS-CoV-2 infection. Yet, the overlapping and indistinguishable antibody and T-cell helper profiles point to unaltered adaptive immunity with BMI, raising the possibility that BMI-driven immunological changes during SARS-CoV-2 infection may manifest largely within the innate immune response. Significant alterations in chronic inflammation, particularly driven by persistent innate cytokine responses from adipocytes, have been noted in the setting of obesity. 29 Dissecting the influence of adipocyte inflammatory responses, associated cytokine storm, and enhanced symptomatology, particularly among individuals with a high BMI, may point to mechanistic differences in viral sensing across populations. These data point to remaining knowledge gaps on the relative importance and interplay of the humoral, cellular and innate immunity in SARS-CoV-2 infection and disease. 30 Limitations Although this study is unique in combining a large prospective, multisite serology-based SARS-CoV- 2 cohort with deep immune profiling, there are limitations. The study population are industry employees with over-representation – compared to the US population -- of persons of Hispanic ethnicity, white race, male sex, and younger individuals with lower rates of comorbidities including obesity and as such findings may not be generalizable. Given 53% of the invited employee s participated in the study, a n unmeasured selection bias may have been introduced. Several additional potential study limitations should be noted but any impact of these limitations would be expected to be evenly distributed across cohort participants and therefore not introduce a systematic bias and impact study findings. These include (i) limited recall of COVID-19 compatible symptoms, (ii) delayed seroconversion relative to reported symptoms, so depending on timing of infection and blood sampling, some registered symptoms may not be due to SARS-CoV-2 infection, and (ii) false positive serological results. Lastly, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 14 behavioral factors, which can be critical drivers of transmission, and may be influenced by BMI, were not assessed in this study. Conclusion We demonstrate that obesity is associated with increased symptomatology in mild COVID-19 infections, suggesting obesity impacts the pathophysiology of COVID-19 throughout the spectrum of disease severity. Our findings do not, however, suggest that obesity increases susceptibility to SARS-CoV- 2 infection, nor did we identify immunological features differentiating obese from non-obese individuals in mild and asymptomatic infection. Acknowledgements We acknowledge support from Space Exploration Technologies Corporation, the Brigham and Women’s Department of Emergency Medicine, the Ragon Institute of MGH, MIT and Harvard, the Massachusetts Consortium on Pathogen Readiness (MassCPR), the NIH (3R37AI080289-11S1), FDA HHSF223201810172C, and the Gates foundation Global Health Vaccine Accelerator Platform funding. We thank Nancy Zimmerman, Mark and Lisa Schwartz, an anonymous donor (financial support), Terry and Susan Ragon, and the SAMANA Kay MGH Research Scholars award for their support. EJN is supported by the CDC (U01 GH002238). SMS was partially supported by the US Food and Drug Administration (HHSF223201810172C). DAL was partially supported by the National Institute for Allergy and Infectious Disease (U19 AI135995). We would also like to thank Eric Fischer for S protein production efforts and Jared Feldman, Blake Marie Hauser, Tim Caradonna and Aaron Schmidt for generating receptor binding domain antigen. Author contribution EJN, GZ, SMS, AK, DAL, and GA analyzed and interpreted the data. YCB, SF, CA, MJG, ALZ, JB and MS performed Systems Serology and ELISA assays. JY, MGe, and DHB performed the neutralization assay. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 15 YCB, ZC and BDJ performed and analyzed T cell experiments. MG, SB, JR, EP, BM, ML, MSA, MAH, GJ, EB, ERM, ASM, GJ, and EJN managed sample and data collection. EJN, ERM, ASM, and GA designed the study. EJN drafted the manuscript. All authors critically reviewed the manuscript Conflict of interest GA is a founder of Seromyx Systems Inc., a company developing platform technology that describes the antibody immune response. GA’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. PS is a co-founder of, shareholder in, and advisor to Sherlock Biosciences, Inc, as well as a Board member of and shareholder in Danaher Corporation. MJG, SB, YH, JR, EP, BM, A SM and E RM are employees of Space Exploration Technologies Corp. All other authors have declared that no conflict of interest exists. References 1. Hamer M, Gale CR, Kivimäki M, Batty GD. Overweight, obesity, and risk of hospitalization for COVID-19: A community-based cohort study of adults in the United Kingdom. Proc Natl Acad Sci . 2020;117(35):21011-21013. doi:10.1073/pnas.2011086117 2. Seidu S, Gillies C, Zaccardi F, et al. The impact of obesity on severe disease and mortality in people with SARS-CoV-2: A systematic review and meta-analysis. Endocrinol Diabetes Metab . 2020. doi:10.1002/edm2.176 3. WHO. Obesity and overweight: Fact sheet. WHO Media Cent . 2020. https://www.who.int/news- room/fact-sheets/detail/obesity- and -overweight. 4. Popkin BM, Du S, Green WD, et al. Individuals with obesity and COVID-19: A global perspective on the epidemiology and biological relationships. Obes Rev . doi:10.1111/obr.13128 5. Tartof SY, Qian L, Hong V, et al. Obesity and Mortality Among Patients Diagnosed With COVID-19: Results From an Integrated Health Care Organization. Ann Intern Med . doi:10.7326/m20-3742 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 16 6. Falagas ME, Kompoti M. Obesity and infection. Lancet Infect Dis . 2006. doi:10.1016/S1473- 3099(06)70523-0 7. Kwong JC, Campitelli MA, Rosella LC. Obesity and respiratory hospitalizations during influenza seasons in Ontario, Canada: A cohort study. Clin Infect Dis . 2011;53(5):413-421. doi:10.1093/cid/cir442 8. Centers for Disease Control and Prevention (CDC). Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009. MMWR Morb Mortal Wkly Rep . 2009;58:749-752. 9. Jung C-Y, Park H, Kim DW, et al. Association between Body Mass Index and Risk of COVID-19: A Nationwide Case-Control Study in South Korea. Clin Infect Dis . 2020. doi:10.1093/cid/ciaa1257 10. Ghoneim S, Umer Butt M, Hamid O, Shah A, Asaad I. The incidence of COVID-19 in patients with metabolic syndrome and non-alcoholic steatohepatitis: A population-based study. Metab Open . doi:https://doi.org/10.1016/j.metop.2020.100057 11. García LF. Immune Response, Inflammation, and the Clinical Spectrum of COVID-19. Front Immunol . 2020. doi:10.3389/fimmu.2020.01441 12. Karlsson EA, Sheridan PA, Beck MA. Diet-Induced Obesity Impairs the T Cell Memory Response to Influenza Virus Infection. J Immunol . 2010;184(6):3127-3133. doi:10.4049/jimmunol.0903220 13. Neidich SD, Green WD, Rebeles J, et al. Increased risk of influenza among vaccinated adults who are obese. Int J Obes . 2017;41(9):1324-1330. doi:10.1038/ijo.2017.131 14. Wadman M. Why COVID-19 is more deadly in people with obesity —even if they’re young. Science . https://www.sciencemag.org/news/2020/09/why-covid- 19 -more-deadly-people- obesity- even - if -theyre-young. 15. Roy V, Fischinger S, Atyeo C, et al. SARS-CoV-2-specific ELISA development. J Immunol Methods . 2020. doi:10.1016/j.jim.2020.112832 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 17 16. Nilles EJ, Karlson EW, Norman M, et al. Evaluation of two commercial and two non-commercial immunoassays for the detection of prior infection to SARS-CoV-2. medRxiv . 2020. doi:10.1101/2020.06.24.20139006 17. Atyeo C, Fischinger S, Zohar T, et al. Distinct Early Serological Signatures Track with SARS-CoV- 2 Survival. Immunity . 2020. doi:10.1016/j.immuni.2020.07.020 18. Milner JJ, Sheridan PA, Karlsson EA, Schultz-Cherry S, Shi Q, Beck MA. Diet-Induced Obese Mice Exhibit Altered Heterologous Immunity during a Secondary 2009 Pandemic H1N1 Infection. J Immunol . 2013;191(5):2474-2485. doi:10.4049/jimmunol.1202429 19. Sheridan PA, Paich HA, Handy J, et al. Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obes . 2012;36(8):1072-1077. doi:10.1038/ijo.2011.208 20. Zimmermann P, Curtis N. Factors that influence the immune response to vaccination. Clin Microbiol Rev . 2019;32(2):e00084-18. doi:10.1128/CMR.00084- 18 21. Becht E, McInnes L, Healy J, et al. Dimensionality reduction for visualizing single-cell data using UMAP. Nat Biotechnol . 2019. doi:10.1038/nbt.4314 22. de Lusignan S, Dorward J, Correa A, et al. Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study. Lancet Infect Dis . 2020. doi:10.1016/S1473-3099(20)30371-6 23. Gibbons CL, Mangen MJJ, Plass D, et al. Measuring underreporting and under-ascertainment in infectious disease datasets: A comparison of methods. BMC Public Health . 2014;14(147). doi:10.1186/1471-2458- 14 - 147 24. Lipsitch M, Donnelly CA, Fraser C, et al. Potential biases in estimating absolute and relative case- fatality risks during outbreaks. PLoS Negl Trop Dis . 2015. doi:10.1371/journal.pntd.0003846 25. Kass DA, Duggal P, Cingolani O. Obesity could shift severe COVID-19 disease to younger ages. Lancet . 2020;395(10236):1544-1545. doi:10.1016/S0140-6736(20)31024-2 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 18 26. Deng M, Qi Y, Deng L, et al. Obesity as a Potential Predictor of Disease Severity in Young COVID- 19 Patients: A Retrospective Study. Obesity . doi:10.1002/oby.22943 27. Villareal DT, Apovian CM, Kushner RF, Klein S. Obesity in older adults: Technical review and position statement of the American Society for Nutrition and NAASO, The Obesity Society. Am J Clin Nutr . 2005;82(5):923-934. doi:10.1093/ajcn/82.5.923 28. Painter SD, Ovsyannikova IG, Poland GA. The weight of obesity on the human immune response to vaccination. Vaccine . 2015. doi:10.1016/j.vaccine.2015.06.101 29. Méry G, Epaulard O, Borel AL, Toussaint B, Le Gouellec A. COVID-19: Underlying Adipokine Storm and Angiotensin 1-7 Umbrella. Front Immunol . 2020. doi:10.3389/fimmu.2020.01714 30. Moderbacher CR, Ramirez SI, Dan JM, et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell . doi:10.1016/j.cell.2020.09.038 . CC-BY-NC-ND 4.0 International license It is made available under a 19 Table 1. Characteristics and serostatus of study participants (n=44 69 ) (n=4469) N N % Age group 18-29 y 1668 133 8.0% ref 40-49 y 584 50 8.6% 1.08 (0.77 to 1.5 2) 0.6 545 50-59 y 315 26 8.3% 1.04 (0.67 to 1.6 1) 0.8 666 60+ y 85 2 2.4% 0. 28 (0.0 7 to 1.1 4) 0.0 76 BMI <18.5 34 3 8.8% 1.44 (0.43 to 4.8 0) 0.5 500 18.5 -<25 1686 106 6.3% ref 25-<30 1523 101 6.6% 1. 06 (0.8 0 to 1.4 0) 0 .6916 30-<35 676 61 9.0% 1.48 (1.06 to 2. 05) 0 .01 96* 35-<40 246 23 9.3% 1.54 (0.96 to 2. 47) 0.0 742 ≥ 40 105 5 4.8% 0. 75 (0.3 0 to 1.8 7) 0 .53 08 Ethnici ty Not Hispanic/Not Latinx 2492 113 4.5% ref Hispanic/L atinx 1274 155 12. 2% 2.91 (2.26 to 3. 75) <0.00 01**** Race White 2862 185 6.5% ref Ameri ca n Indian/Alaska N ative 32 3 9.4% 1. 50 (0.4 5 to 4.9 6) 0 .50 92 Asian 442 18 4.1% 0.61 (0.37 to 1.01 ) 0. 053 5 Black 72 2 2.8% 0. 41 (0.1 0 to 1.7 0) 0 .2207 Native Hawa iian/Pacific Islander 29 2 6.9% 1. 07 (0.2 5 to 4.5 4) 0 .92 49 More than one race 292 13 4.5% 0.67 (0.38 to 1.20 ) 0 .179 6 Sex2 Female 600 40 6.7% ref Childr en ≤ 18 y in household No 3014 204 6.8% ref Yes 1342 106 7.9% 1 .18 (0.93 to 1.5 1) 0.1 808 No. in household 1 640 41 6.4% ref 2-4 3027 214 7.1% 1.11 (0.79 to 1.5 7) 0.54 90 >4 659 51 7.7% 1.2 3 (0.80 to 1.88 ) 0. 349 9 Primary work location Cape Canaveral, Florida 268 17 6.3% ref Hawthorne, California 2859 111 3.9% 0 .60 (0.35 to 1.0 1) 0.05 44 McGre g or, Texas 257 21 8.2% 1.31 (0.6 8 to 2.5 5) 0 .42 02 Seattle, Was hington 253 5 2.0% 0.3 0 ( 0.11 to 0.82 ) 0.0 190 * South Texas, Texas 712 160 22.5% 4 .28 (2.54 to 7.2 1) <0.00 01**** Other 69 1 1.4% 0 .23 (0.03 to 1.7 9) 0.1 623 Comorbid itie s3,4 Asthma 368 20 5.4% 0.72 (0.45 to 1.1 5) 0.1 721 Hyperte nsion 356 26 7.3% 1.02 (0.67 to 1.5 4) 0.94 05 Diabete s mellitus 101 11 10.9% 1.59 (0.8 4 to 3.01) 0 .1509 Coronary heart disease 17 1 5.9% 0 .80 (0.11 to 6. 08) 0.8 329 Stroke 9 2 22.2% 3.70 (0.76 to 17 .87 ) 0.1 039 Emphysema/COPD 9 1 11.1% 1.61 (0.20 to 12 .93 ) 0.65 32 Cancer - not recei ving treatment 39 2 5.1% 0.69 (0.17 to 2.8 9) 0.61 63 Other immunoc ompromise d 61 4 6.6% 0.92 (0.33 to 2. 55) 0.8 710 Other chroni c medic al conditi on 176 9 5.1% 0.7 2 ( 0.36 to 1.43 ) 0. 347 1 Smoking history Never 3769 263 7.0% ref Prior 367 24 6.5% 0.93 (0.61 to 1. 44) 0.7 514 Curren t 229 23 10.0% 1.49 (0.9 5 to 2.33) 0 .0826 2 Four (4) reported "other s ex", none we re s eropositi ve 3 For comorb idi ties refe rence value for OR is no. COPD chron ic obstu cti ve pulmonary disease 5 P-values unadjusted for multip le hypothesis testing: * < 0.05 . **< 0.01 , *** <0.001 , *** *< 0.00 01 1 Not reported data: age group (n=56), BMI (199), ethni city (703), race (740), sex ( 139 ), child ren in HH (113), No. in HH (143 ), primary loc ation (51), co morbi dit ies (105) 4 Other comorbi dities with no seropositi ve particip ants: chroni c kidney disease (10), Heart f ailur e ( 4), Cancer receiving treatment (3), Other heart disea se (22). P-Value5 OR (95% CI) Seropo sitive participant s (n=322) Charact eristic1 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 20 Figure 1. Forest plots of adjusted odds ratio for seropositivity by BMI as a categorical variable with normal BMI (18·5-<25) as reference . (A) Includes participants with BMI measures and demonstrates a non-significant trend to declining seroprevalence with BM I ≥40 kg/m 2 when compared to normal/healthy weight (BMI 18·5-24 kg/m 2 ) (n=4270) . (B) Includes only participants from a single high seroprevalence (22·5%) location in South Texas where the high force of infection may more clearly delineate infection risks (n=629). Odds ratio, log 10 scale . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 21 Figure 2. Forest plot of odds ratios of reported COVID-19 compatible symptoms among obese (n=85) versus non-obese (n=179) SARS-CoV-2 seropositive individuals Odds ratio, log 10 scale . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 22 Figure 3. Forest plot of odds ratios of COVID-19 compatible symptoms among obese versus non-obese SARS-CoV-2 seropositive individuals stratified by (A) <40 years (n=195) and (B) ≥ 40 years (n=67) Odds ratio, log 10 scale . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint 23 Figure 4. Limited influence of BMI on SARS-CoV-2 antibody profiles (n=77) . (A) The dot plots show similar mean fluorescent intensity levels of IgG1, IgM, IgG3, and IgA levels across individuals classified as normal weight (n=29), overweight (n=23), and obese (n=25). (B) The uniform manifold approximation and projection (UMAP) shows the relationship between antibody profiles and BMI (dot size, color intensity), highlighting the limited influence of BMI on shaping SARS-CoV-2 antibody responses. (C) Correlation plot of shows limited correlation between BMI and 20 immunological features. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.11.20229724 doi: medRxiv preprint ... The two symptoms that were more frequent in patients with obesity were also the two most frequent in the general population 19 . The prospective cohort study by Nilles et al. 20 , which collected BMI information, sociodemographic data, comorbidities, and symptoms from patients with COVID-19, showed that obesity was associated with an increase in the reporting of symptoms, mainly selfreported fever, but not measured. Another interesting finding from the work of Nilles et al. 20 was that the clinical condition is strongly influenced by obesity among younger age groups. ... ... The prospective cohort study by Nilles et al. 20 , which collected BMI information, sociodemographic data, comorbidities, and symptoms from patients with COVID-19, showed that obesity was associated with an increase in the reporting of symptoms, mainly selfreported fever, but not measured. Another interesting finding from the work of Nilles et al. 20 was that the clinical condition is strongly influenced by obesity among younger age groups. The scientific literature says that patients with obesity have more expressive clinical conditions since the onset of symptoms and this is a possible explanation to justify the greater risk of hospitalization 5 . ... Clinical, Laboratory and Tomographic characteristics associated with obesity and BMI at Hospital admission in adult patients with COVID-19: a cross-sectional study Introduction: The pathological status of obesity can influence COVID-19 from its initial clinical presentation, therefore, the identification of clinical and laboratory parameters most affected in the presence of obesity can contribute to improving the treatment of the disease. Objective: To identify the clinical, laboratory, and tomographic characteristics associated with obesity and BMI at t hospital admission in adult patients with COVID-19. Methods: This is a cross-sectional observational study with a total of 315 participants with COVID-19 confirmed by rt-PCR. The participants were divided into non-Obese (n=203) and Obese (n=112). Physical examinations, laboratory tests, and computed tomography of the chest were performed during the first 2 days of hospitalization. Results: Patients with obesity were younger, and they had higher systolic and diastolic blood pressure, higher frequency of alcoholism, fever, cough, and headache, higher ALT, LDH, and red blood cell count (RBC), hemoglobin, hematocrit, and percentage of lymphocytes. Also, they presented a lower value of leukocyte count and Neutrophil/Lymphocyte Ratio (RNL). The parameters positively correlated with BMI were alcoholism, systolic and diastolic blood pressure, fever, cough, sore throat, number of symptoms, ALT in men, LDH, magnesium, RBC, hemoglobin, hematocrit, and percentage of lymphocytes. The parameters negatively correlated with the BMI were: age and RNL. Conclusion: Several parameters were associated with obesity at hospital admission, revealing better than expected results. However, these results should be interpreted with great caution, as there may be some influence of a phenomenon called the Obesity Paradox that can distort the severity and prognosis of the patient. ... A strong association between obesity, obesity-associated comorbidities, and severe outcomes of COVID-19 has indeed been shown [16], with adult COVID-19 symptomatic patients with Body Mass Index (BMI) >30 showing higher admission to acute and critical care compared to lean and overweight individuals (BMI < 30) [17]. These results have been confirmed in part in a multi-site prospective cohort of non-hospitalized individuals in which obesity was found to be associated with the presence of multiple COVID-19 symptoms [18] However, in this cohort obesity was not associated with increased risk of infection. ... ... The results from this study show that the majority of COVID-19 patients with obesity make almost undiscernible amounts of neutralizing anti-SARS-CoV-2 antibodies, suggesting that obese individuals may be at a higher risk to respond poorly to SARS-CoV-2 infection. Our results are in disagreement with another study in which obesity was associated with increased fever and multiple severe symptoms of disease caused by SARS-CoV-2 infection but not with dysfunctional B and T cell immune responses [18] . These differences may depend on the characteristics of the different cohorts recruited in the two studies. ... The majority of SARS-CoV-2-specific antibodies in COVID-19 patients with obesity are autoimmune and not neutralizing Daniela Frasca Lisa Reidy Maria Romero Bonnie B Blomberg Background/objectives Obesity decreases the secretion of SARS-CoV-2-specific IgG antibodies in the blood of COVID-19 patients. How obesity impacts the quality of the antibodies secreted, however, is not understood. Therefore, the objective of this study is to evaluate the presence of neutralizing versus autoimmune antibodies in COVID-19 patients with obesity. Subjects/methods Thirty serum samples from individuals who tested positive for SARS-CoV-2 infection by RT-PCR were collected from inpatient and outpatient settings. Of these, 15 were lean (BMI < 25) and 15 were obese (BMI ≥ 30). Control serum samples were from 30 uninfected individuals, age-, gender-, and BMI-matched, recruited before the current pandemic. Neutralizing and autoimmune antibodies were measured by ELISA. IgG autoimmune antibodies were specific for malondialdehyde (MDA), a marker of oxidative stress and lipid peroxidation, and for adipocyte-derived protein antigens (AD), markers of virus-induced cell death in the obese adipose tissue. Results SARS-CoV-2 infection induces neutralizing antibodies in all lean but only in few obese COVID-19 patients. SARS-CoV-2 infection also induces anti-MDA and anti-AD autoimmune antibodies more in lean than in obese patients as compared to uninfected controls. Serum levels of these autoimmune antibodies, however, are always higher in obese versus lean COVID-19 patients. Moreover, because the autoimmune antibodies found in serum samples of COVID-19 patients have been correlated with serum levels of C-reactive protein (CRP), a general marker of inflammation, we also evaluated the association of anti-MDA and anti-AD antibodies with serum CRP and found a positive association between CRP and autoimmune antibodies. Conclusions Our results highlight the importance of evaluating the quality of the antibody response in COVID-19 patients with obesity, particularly the presence of autoimmune antibodies, and identify biomarkers of self-tolerance breakdown. This is crucial to protect this vulnerable population at higher risk of responding poorly to infection with SARS-CoV-2 than lean controls. ... This study aimed to evaluate the characteristics of the hospitalized patients, finding that severe obesity (≥ 35 kg / m 2 ), older age, and male sex were independently associated with mortality, the need for intubation, and oxygen requirement during hospital stay. Nilles et al. [38] conducted a prospective cohort study with 4469 non-hospitalized employees of Space Exploration Technologies Corporation; the most important finding was the association of obesity with the increase in symptoms of mild COVID-19 infections, otherwise not having an association with the increase of the susceptibility to infection by COVID-19. There were also no different immunological characteristics between obese and non-obese patients. ... Covid obesity: A one-year narrative review Susana Rodrigo-Cano Aránzazu González Jose M Soriano On 11 March 2020, coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization (WHO). This study focuses on a narrative review about the illness during the first year of the pandemic in relation to obesity. Databases were used to search studies published up to 8 December 2020. In total, 4430 articles and other scientific literature were found, and 24 articles were included in this one-year narrative review. The mean BMI value of severe COVID-19 patients ranged from 24.5 to 33.4 kg/m2, versus <18.5 to 24.3 kg/m2 for non-severe patients. Articles using the terms obesity or overweight without indicating the BMI value in these patients were common, but this is not useful, as the anthropometric parameters, when not defined by this index, are confusing due to the classification being different in the West compared to among Asian and Korean criteria-based adults. We proposed a new term, called COVID obesity, to define the importance of this anthropometric parameter, among others, in relation with this pandemic. ... A prospective seroprevalence survey in the US analyzing the presence of antibodies against multiple SARS-CoV-2 antigens in 4,469 people (24.1% with obesity) with a 7.2% rate of seropositivity did not detect any evidence for increased rates of SARS-CoV-2 infection in people with overweight or obesity. Furthermore, humoral immunity and helper T cell activity were not different in seropositive individuals with obesity (Nilles et al., 2020) . Analysis of anti-IgG responses directed against the S1 domain in 2,112 persons with confirmed symptomatic SARS-CoV-2 infection at~63 days after symptom onset revealed that people with overweight or obesity were less likely to be antibody-negative . ... Diabetes, obesity, metabolism and SARS-CoV-2 infection: The end of the beginning CELL METAB The increased prevalence of obesity, diabetes and cardiovascular risk factors in people hospitalized with severe COVID-19 illness has engendered considerable interest in the metabolic aspects of SARS-CoV-2-induced pathophysiology. Here, I update concepts informing how metabolic disorders and their comorbidities modify the susceptibility to, natural history and potential treatment of SARS-CoV-2 infection, with a focus on human biology. New data informing genetic predisposition, epidemiology, immune responses, disease severity and therapy of COVID-19 in people with obesity and diabetes are highlighted. The emerging relationships of metabolic disorders to viral-induced immune responses and viral persistence, and the putative importance of adipose and islet ACE2 expression, glycemic control, cholesterol metabolism, and glucose- and lipid-lowering drugs is reviewed, with attention to controversies and unresolved questions. Rapid progress in these areas informs our growing understanding of SARS-CoV-2 infection in people with diabetes and obesity, while refining the therapeutic strategies and research priorities in this vulnerable population. Kinetics of the SARS-CoV-2 antibody response in immunocompetent convalescent patients: nationwide multicenter 15-month follow-up cohort study Preprint Full-text available Armine Chopikyan Irina Kasparova Konstantin Yenkoyan The comprehension of a long-term humoral immune response against the SARS-CoV-2 virus can shed light on the treatment and vaccination of the disease, improve the control of the pandemic infection. We assessed the antibodies against SARS-CoV-2 nucleocapsid (N) protein in 1441 COVID-19 convalescent patients within 15 months longitudinal nationwide multicenter study from middle-developed country. 92.7 % of convalescent patients’ serum contained antibodies against N protein and only 1.3% of patients had a delayed antibody response. In the majority of convalescent patients’ the durability of antibodies lasted more than one year. The kinetics of neutralizing antibodies took a bell-shaped character – increased first 25-30 weeks, then started to decrease, but were still detectable for more than 15 months. Summing up, we found that anti-SARS-CoV-2 humoral response levels, in particular the level of peak antibodies, correlate with age, older patients developing more robust humoral response independently from sex, disease severity and BMI. Obesity and COVID19 Chapter Umair Mallick Global statistics indicate a high prevalence of obesity, and elevated body mass index (BMI), across the regions, with increasing trends that have reached a pandemic level. Adipose tissue is no longer considered a structural support element of the body, but a complex organ with a diversity of metabolic, endocrine, and immune related functions, and is a potent risk factor. The risks and comorbidities associated with obesity and correlated conditions are likely to aggravate the impact of the CoViD19 pandemic across the populations. Several studies describe the associations of raised BMI and obesity in CoViD19 and possible risks. Although data show that the association of CoVID19 with obesity has a deleterious impact and robustly designed studies exploring obesity, associated factors, and pathogenetic mechanisms may be lacking, the impact of obesity in CoViD19 appears significant. This chapter is intended to provide a better understanding of obesity in CoViD19. We provide an overview of the epidemiological evidence linking obesity with CoViD19, risks, and the associated variabilities. We explore the pathological mechanisms associated with obesity and CoViD19 that may facilitate the harmful impact of obesity observed in CoViD19 patients. We highlight the need for further exploration of the epidemiological and pathogenetic links that determine the criticality of CoViD19 in obese patients.KeywordsIncidence obesity and CoViD19Raised BMI and CoViD19Obesity and CoViD19Obesity and severe CoViD19Obesity and mortalityVariations obesity incidenceObesity and critical CoViD19Inflammation and obesityImmune mechanisms and obesityObesity and thrombosisObesity and cardiovascular diseaseObesity and lung diseaseObesity challenges and CoViD19Increased BMIDefinition obesityPathogenetic mechanisms and obesityAdipose tissue and CoViD19Confounding in CoViD19 obesity studies Journal Pre-proof Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals > 65 years old. Scarcity of naive T cells was also associated with ageing and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between ageing and impaired adaptive immune responses to SARS-CoV-2. The incidence of COVID-19 in patients with metabolic syndrome and non-alcoholic steatohepatitis: A population-based study Background The novel coronavirus disease (COVID-19) emerged from China in 2019 and rapidly spread worldwide. Patients with metabolic comorbid conditions are more susceptible to infection by COVID-19. Metabolic syndrome is a constellation of interlinked metabolic risk factors that predispose patients to increased risk of complications. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and non-alcoholic steatohepatitis (NASH) is the aggressive form of NAFLD. Objective The aim of this study is to determine the relationship between metabolic syndrome components and the risk of COVID-19. Methods We reviewed data from a large commercial database (Explorys IBM) that aggregates electronic health records from 26 large nationwide healthcare systems. Using systemized nomenclature of clinical medical terms (SNOMED-CT), we identified adults with the diagnosis of metabolic syndrome and its individual components from 1999-2019. We included patients with the diagnosis of COVID-19 from December 2019 to May 2020. Comorbidities known to be associated with COVID-19 and metabolic syndrome such as obesity, diabetes mellitus, dyslipidemia, smoking, male gender, African American, and hypertension were collected. Univariable and multivariable analyses were performed to investigate whether metabolic syndrome or its individual components are independently associated with the risk of COVID-19. Results Out of 61.4 million active adult patients in the database, 8,885 (0.01%) had documented COVID-19. The cumulative incidence of COVID-19 was higher if metabolic syndrome was the primary diagnosis (0.10% vs 0.01% OR 7.00 [6.11–8.01]). The adjusted odds (aOR) of having COVID-19 was higher in patients if they were African Americans (OR 7.45 [7.14- 7.77]), hypertensive (aOR 2.53 [2.40 - 2.68]), obese (aOR 2.20 [2.10 2.32]) , diabetic (aOR 1.41 [1.33- 1.48]), hyperlipidemic (OR 1.70 [1.56-1.74]), or diagnosed with NASH (OR 4.93 [4.06- 6.00]). There was a slight decrease in adjusted odds of having COVID-19 in males as compared to females (aOR 0.88 [0.84- 0.92]). Conclusion The incidence of COVID-19 in patients with metabolic syndrome is high. Among all comorbid metabolic conditions, NASH had the strongest association with COVID-19. Association between Body Mass Index and Risk of COVID-19: A Nationwide Case-Control Study in South Korea
https://www.researchgate.net/publication/346881504_Epidemiological_and_immunological_features_of_obesity_and_SARS-CoV-2
MATTER OF EWALD | 174 Misc. 939 | N.Y. Misc. | Judgment | Law | CaseMine Get free access to the complete judgment in MATTER OF EWALD on CaseMine. MATTER OF EWALD Surrogate's Court of the City of New York, New York County. Aug 12, 1940 MATTER OF EWALD 174 Misc. 939 22 N.Y.S.2d 299 Case Information CITATION CODES 174 Misc. 939 22 N.Y.S.2d 299 ATTORNEY(S) Margaret Mary J. Mangan, for the administratrix. Morris L. Gussow, for Robert Hoffman, as receiver of George F. Ewald, distributee. Benjamin Bernstein, for Robert E. McFadden, a judgment creditor of George F. Ewald, distributee. William J. McArthur, for the United States Fidelity and Guaranty Company, surety. Reisner Shenk, for Mae E. Walsh, claimant. Barnett Shapiro, for Mary A. Betzag and Katherine Ewald Anderson. Kupfer Levine, for Peter Eckert, assignee of George F. Ewald. Martin S. Blate, for Charles Sobelson, assignee of Charles Ewald. JUDGES FOLEY, S. ACTS No Acts See more information ... Important Paras The note was concededly executed in January, 1932, and was payable on demand, since no time for payment was expressed. (Neg. Inst. Law, § 26.) The check for $500 was dated January 15, 1932. It was never presented for payment and was evidently regarded by the payee as merely security for the loan. The decedent died June 19, 1939, and there can be no doubt that at the time of his death his right of action against his brother on these two claims was barred by the Statute of Limitations. It is well settled, however, that the statute does not extinguish the debt but merely bars the remedy. The defense is one that must be pleaded by the debtor in order to be available and in the event of suit thereon a failure to plead the statute would result in making the obligations enforcible at law. It is possible also to revive the right of action on such debts by a written acknowledgment or by a promise contained in writing and signed by the party to be charged. (Civ. Prac. Act, § 59; Manchester v. Braedner, 107 N.Y. 346 ; Connecticut Trust S.D. Co. v. Wead, 172 id. 497; Lincoln-Alliance Bank Trust Co. v. Fisher, 247 A.D. 465 .) In order to constitute such an acknowledgment, "the writing must recognize an existing debt, and should contain nothing inconsistent with an intention on the part of the debtor to pay it. * * * The document need contain nothing more than `a clear recognition of the claim as one presently existing.'" ( Lincoln-Alliance Bank Trust Co. v. Fisher, supra, p. 466.) In his letter to the administratrix, the debtor not only recognized his obligation in a specific amount but gave her express authority to liquidate the debt by applying a portion of his share to it. Go to (1) The main controversy revolves around the one-seventh distributive share of George F. Ewald, a brother of the intestate. The questions here presented for determination involve, first, the right of the administratrix to set off against this distributive share the amount of several loans made by the decedent to the distributee; second, the interest of one Peter Eckert under an instrument of assignment in which the distributee assigned to him all of the money, property or other interest in this estate which was due him or to become due him to the extent of $11,000; and, finally, the rights and interest of the receiver of the property of the distributee, appointed in proceedings supplementary to execution on two judgments against him. Go to It is clear, therefore, that the receiver of the property of the distributee has no standing in law to object to the transaction between the distributee and the estate whereby the debts were revived and the bar of the statute lifted. That transaction was not fraudulent because the debts were bona fide obligations. The Statute of Limitations does not discharge a debt but merely bars the remedy thereon; and the waiver of the statute does not create a new obligation, but simply permits enforcement of the old promise. ( Central Hanover Bank Trust Co. v. United Traction Co., supra; Hulbert v. Clark, 128 N.Y. 295 ; House v. Carr, 185 id. 453.) The right of an executor or administrator to set off an enforcible debt owing to decedent by a legatee or distributee, against his legacy or distributive share, is firmly established. ( Smith v. Kearney, 2 Barb. Ch. 533, 547 ; Close v. Van Husen, 19 Barb. 505, 509 ; Ferris v. Burrows, 34 Hun, 104; affd., 99 N.Y. 616 ; Matter of James, 149 Misc. 135, 136 ; Matter of Flint, 120 id. 230; affd., 206 A.D. 778 ; Matter of Grifenhagen, 174 Misc. 559 ; Matter of Macneal, Id. 947.) Go to MATTER OF EWALD FOLEY, S. In this contested accounting proceeding the issues are disposed of as follows: (1) The main controversy revolves around the one-seventh distributive share of George F. Ewald, a brother of the intestate. The questions here presented for determination involve, first,the right of the administratrix to set off against this distributive share the amount of several loans made by the decedent to the distributee; second,the interest of one Peter Eckert under an instrument of assignment in which the distributee assigned to him all of the money, property or other interest in this estate which was due him or to become due him to the extent of $11,000; and, finally,the rights and interest of the receiver of the property of the distributee, appointed in proceedings supplementary to execution on two judgments against him. The decedent had on numerous occasions made loans to his brother George F. After the former's death on June 19, 1939, certain instruments evidencing indebtedness to him were discovered among his effects. The administratrix, after examination of the intestate's records, made demand upon George F. Ewald for repayment of sums which she believed to be due the estate from him by reason of these loans. On July 29, 1939, George F. Ewald wrote a letter to the administratrix apparently in response to her oral demands upon him. He denied that the amount owing by him was as large as that claimed by her, and he disclaimed certain particular obligations charged against him. He expressly admitted, however, specific loans that were made to him by the deceased. One was in the sum of $3,000, as security for which the decedent had received a promissory note signed by George F. Ewald and his wife in which neither the amount nor the date was filled in. This note was stated by Ewald to have been executed in January, 1932. Another obligation was evidenced by a check in the sum of $500, representing a loan made January 15, 1932, and conceded by George F. Ewald to be his obligation. He further admitted that he had received other smaller loans in the form of checks amounting to not more than $100. He stated that all of these loans had been made to him and that he had intended to repay them, and he suggested that the administratrix deduct from his share the sum of $3,600 in payment of these debts. The administratrix accepted the amounts thus stated to be due. She has listed them in her account as assets of the estate and has charged against the share of George F. Ewald the sum of $3,600 as suggested in his letter. George F. Ewald was called as a witness in this proceeding, and he affirmed his obligations to the decedent in the amount which has been charged against his share. It is apparent from his testimony that he had borrowed from his brother even larger sums than those admitted by him, but he claimed that deduction of certain sums in payment of legal services performed by him for his brother reduced the indebtedness to the amount conceded due by him. He described the various loans, and he reiterated his intention and desire to repay them. The surrogate finds upon the evidence that George F. Ewald borrowed from the decedent, and has never repaid, the sums admitted in his letter of July 29, 1939, aggregating in amount $3,600. The receiver of the property appointed under two judgments obtained against George F. Ewald has filed objections to the account, in which he attacks the inclusion of the $3,000 note and the $500 check as assets of the estate and the charging of those amounts against the distributive share of George F. Ewald. The basis of his objection is that both of those claims have been barred by the Statute of Limitations, and that they cannot be revived, particularly where the rights of creditors of the distributee intervene. The note was concededly executed in January, 1932, and was payable on demand, since no time for payment was expressed. (Neg. Inst. Law, § 26.) The check for $500 was dated January 15, 1932. It was never presented for payment and was evidently regarded by the payee as merely security for the loan. The decedent died June 19, 1939, and there can be no doubt that at the time of his death his right of action against his brother on these two claims was barred by the Statute of Limitations. It is well settled, however, that the statute does not extinguish the debt but merely bars the remedy. The defense is one that must be pleaded by the debtor in order to be available and in the event of suit thereon a failure to plead the statute would result in making the obligations enforcible at law. It is possible also to revive the right of action on such debts by a written acknowledgment or by a promise contained in writing and signed by the party to be charged. (Civ. Prac. Act, § 59; Manchesterv. Braedner,107 N.Y. 346; Connecticut Trust S.D. Co.v. Wead,172 id. 497; Lincoln-Alliance Bank Trust Co.v. Fisher,247 A.D. 465.) In order to constitute such an acknowledgment, "the writing must recognize an existing debt, and should contain nothing inconsistent with an intention on the part of the debtor to pay it. * * * The document need contain nothing more than `a clear recognition of the claim as one presently existing.'" ( Lincoln-Alliance Bank Trust Co.v. Fisher, supra,p. 466.) In his letter to the administratrix, the debtor not only recognized his obligation in a specific amount but gave her express authority to liquidate the debt by applying a portion of his share to it. The receiver contends that there was no clear and unqualified acknowledgment of an existing debt, but that there was at most an offer to compromise a demand barred by the statute. Without conceding that there is any force in this argument, it is a sufficient answer to point out that both the debtor and creditor interpret the letter as an acknowledgment of the debt, as well as authority to make the setoff, and that the liquidation of his debts by means of the charge against his distributive share as set forth in the account meets with the satisfaction of both debtor and creditoralike. This is evident not only from the debtor's written acknowledgment, but from his testimony given from the witness stand. In view of the permission thus granted by the debtor to retain a sufficient part of his distributive share to extinguish his indebtedness to the estate, it becomes necessary to determine whether the receiver appointed on behalf of the judgment creditors of the distributee has any basis in law for attacking that transaction. The rule appears firmly to be established that the creditors of a person have no standing to object to his failure to plead the Statute of Limitations against the stale claim of another against him, or to his waiving of the statute or revival of the claim. ( Allenv. Smith,129 U.S. 465; Central Hanover Bank Trust Co.v. United Traction Co.,95 F. [2d] 50; Del Vallev. Hyland,76 Hun, 493; affd.,148 N.Y. 751; McConnellv. Barber,86 Hun, 360, 362; Livermorev. Northrup,44 N.Y. 107; Matter of Sheppard,180 Penn. St. 57;36 A. 422; Brookville Nat. Bankv. Kimble,76 Ind. 195.) In Central Hanover Bank Trust Co.v. United Traction Co.( supra) Judge SWAN said: "It has never been deemed a fraudulent conveyance to pay an honest debt or to perform an obligation which the obligor was under a moral duty to perform, although the debt or obligation was legally unenforceable because of some statutory provision." Judge LEARNED HAND, in concurring, said: "I agree that, as the law stands, we cannot hold that the revival by an insolvent of a debt barred by the statute of limitations is a fraudulent conveyance." The decision of the Supreme Court of Pennsylvania, in Matter of Sheppard( supra) is particularly in point. There a judgment on confession was entered by the executrix against a distributee on a claim against which the Statute of Limitations had run. Attachment creditors of the distributee contended that, by reason of their prior attachment, they acquired a lien upon the share of their debtor in the estate which deprived him of the power to waive the statute. In the opinion of the lower court, which was approved by the Supreme Court, it was said: "The attachment binds only the interest of the debtor in the estate of the testator, and the interest does not arise until it has been ascertained how much of the estate has already been received by him. The lien does not extend to the conscience of the debtor. If, instead of obtaining the confession of judgment, the executrix had brought suit for recovery of the debt, nothing short of the pleading of the statute could have prevented an adverse judgment. It can scarcely be pretended that an attaching creditor of the defendant to the suit would have the right to intervene, and make defense." In Allenv. Smith(129 U.S. 465) certain judgment creditors of one Todd brought a proceeding against his administrator and heirs in an effort to have set aside a certain judgment obtained against him by his son-in-law on the ground that it was collusively obtained and was in fraud of his creditors. The United States Supreme Court held that the plaintiffs had not sustained their burden of proving that the judgment was dishonestly obtained. In language particularly pertinent to the situation in the pending proceeding, the court said: "Much comment is made on the fact that Todd did not plead the statute of limitations of the State to a part of Smith's claim. But this is not an objection of which the plaintiffs can avail themselves. Todd was at liberty to waive the plea, and there was evidently sufficient in the relations of the parties and in the circumstances of the case to warrant him in doing so" (p. 470). It is clear, therefore, that the receiver of the property of the distributee has no standing in law to object to the transaction between the distributee and the estate whereby the debts were revived and the bar of the statute lifted. That transaction was not fraudulent because the debts were bona fideobligations. The Statute of Limitations does not discharge a debt but merely bars the remedy thereon; and the waiver of the statute does not create a new obligation, but simply permits enforcement of the old promise. ( Central Hanover Bank Trust Co.v. United Traction Co., supra; Hulbertv. Clark,128 N.Y. 295; Housev. Carr,185 id. 453.) The right of an executor or administrator to set off an enforcible debt owing to decedent by a legatee or distributee, against his legacy or distributive share, is firmly established. ( Smithv. Kearney,2 Barb. Ch. 533, 547; Closev. Van Husen,19 Barb. 505, 509; Ferrisv. Burrows,34 Hun, 104; affd.,99 N.Y. 616; Matter of James,149 Misc. 135, 136; Matter of Flint,120 id. 230; affd.,206 A.D. 778; Matter of Grifenhagen,174 Misc. 559; Matter of Macneal,Id. 947.) The surrogate, therefore, holds that the setoff of the debts against the distributive share of George F. Ewald must be allowed. There remains for consideration the relative rights of the assignee and the receiver to the balance of the distributive share that is left over and above the amount set off by the administratrix. The assignment by George F. Ewald to Peter Eckert of all his property and interest in this estate to the extent of $11,000 was executed on June 27, 1939, and was recorded in the office of the clerk of this court on June 30, 1939. This assignment was made for the purpose of reimbursing the assignee for loans made to the distributee, who was his son-in-law. The property of George F. Ewald did not vest in the receiver until after the recording of the above assignment. The property of a judgment debtor, whether acquired before or after the appointment of a receiver, is vested in the receiver from the time of filing the order appointing him, or extending his receivership, as the case may be. (Civ. Prac. Act, § 807.) Where the receiver's title has become vested, it may extend back by relation, for the benefit of the judgment creditor, to the time of the service of the order or subpoena upon the judgment debtor in supplementary proceedings, or to the time of the service of a third-party order. (Civ. Prac. Act, § 808.) In the latter case the receiver's title extends to the personal property of the judgment debtor which was in the hands or under the control of the person thus required to attend and be examined at the time of the service of the order or subpoena. Tested by these rules, the receiver's title vested on February 27, 1940, the date of the filing of the order appointing him under the Herold judgment. The order extending the receivership to include the McFadden judgment was filed April 18, 1940. The earliest that the title of the receiver can be made to extend back is August 1, 1939, when the administratrix was served with a subpoena for examination as a third party in proceedings supplementary to the execution of the McFadden judgment. No order or subpoena for his examination was ever served upon the judgment debtor personally. He voluntarily appeared and submitted to examination. It thus becomes evident that at the earliest date on which title can be said to have vested in the receiver, even under the theory of relation back, the judgment debtor had no interest in this estate. The assignment, which had been theretofore duly recorded, disposed of his interest to the extent of $11,000, an amount greatly in excess of any possible interest he might have had. The title had, therefore, passed to the assignee before any title had vested in the receiver. The receiver can take priority over the assignee only if he can impeach the assignment as a fraudulent conveyance. That George F. Ewald was insolvent at the time he made this assignment cannot be doubted. It is clear, too, that the assignment was made for the purpose of preferring the assignee over other creditors of the assignor. This, however, is not decisive of the question. "That a debtor has the right to pay the claim of one creditor in preference to and to the exclusion of all the others, has been many times decided." ( Del Vallev. Hyland,76 Hun, 493; affd.,148 N.Y. 751.) The important consideration is whether it was made to defraud the other creditors. Every conveyance made by an insolvent person is fraudulent as to creditors without regard to his actual intent if the conveyance is made without a fair consideration.(Debtor and Creditor Law, § 273.) "Fair consideration is given for property, or obligation, (a) When in exchange for such property, or obligation, as a fair equivalent therefor, and in good faith, * * * an antecedent debt is satisfied, or (b) when such property, or obligation, is received in good faith to secure a present advance or antecedent debt in amount not disproportionately small as compared with the value of the property, or obligation obtained." (Debtor and Creditor Law, § 272.) Prior to the assignment to Peter Eckert, the distributee, George F. Ewald, was indebted to him in the sum of approximately $11,000. He had borrowed large sums from Mr. Eckert, who was his father-in-law, and had never repaid them. The total indebtedness was far greater than any sum the distributee might receive from the estate. The assignment was, therefore, based upon a fair consideration, and was not fraudulent as to other creditors. The assignee is entitled to receive any money due on account of the distributive share over and above that necessary to effect the setoff of the estate. (2) The written agreement of settlement of the debt of Charles Ewald, one of the distributees, is approved and an appropriate provision may be included in the decree to that effect. (3) The claim of Mae E. Walsh is disallowed upon the merits. (4) The objections to the account filed by Robert Hoffman, receiver of the property of George F. Ewald, are disposed of as follows: Objections 1, 2, 3, 4(a), 4(b) and subdivisions a, b and c of objection 6 are overruled. Objection 5 and subdivisions d and e of objection 6 have been withdrawn. (5) Schedule A of the account sets forth the total sum of $3,590 as due from George F. Ewald. The total should read $3,600. The corresponding amount of $3,590 deducted in Schedule B-1 as uncollectible debts must be eliminated from the account and from the summary statement in the decree. In other words, by the foregoing disposition as to the indebtedness of George F. Ewald, gross assets must be increased by the sum of $3,600. The shares of the various distributees must be computed upon the net estate after the proper deductions are made from the gross estate.
https://www.casemine.com/judgement/us/5914cbe0add7b04934805ef9
Bendamustine Hydrochloride and Rituximab With or Without Bortezomib Followed by Rituximab With or Without Lenalidomide in Treating Patients With High-Risk Stage II, Stage III, or Stage IV Follicular Lymphoma - Full Text View - ClinicalTrials.gov Bendamustine Hydrochloride and Rituximab With or Without Bortezomib Followed by Rituximab With or Without Lenalidomide in Treating Patients With High-Risk Stage II, Stage III, or Stage IV Follicular Lymphoma ClinicalTrials.gov Identifier: NCT01216683 Recruitment Status : Completed First Posted : October 7, 2010 Results First Posted : February 23, 2021 Last Update Posted : January 17, 2023 Sponsor: National Cancer Institute (NCI) Information provided by (Responsible Party): Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group ) Study Details Study Description Brief Summary: RATIONALE: Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether giving bendamustine hydrochloride and rituximab together alone is more effective than giving bendamustine hydrochloride and rituximab together with bortezomib or lenalidomide in treating follicular lymphoma. PURPOSE: This randomized phase II trial is studying giving bendamustine hydrochloride and rituximab together with or without bortezomib followed by rituximab with or without lenalidomide to see how well they work in treating patients with high-risk stage II, stage III, or stage IV follicular lymphoma. Condition or disease Intervention/treatment Phase Lymphoma Biological: rituximab Drug: Bendamustin Drug: bortezomib Drug: lenalidomide Phase 2 Detailed Description: OBJECTIVES: Primary To compare the complete remission rate in patients with high-risk follicular lymphoma receiving induction therapy comprising bendamustine hydrochloride and rituximab with vs without bortezomib. Secondary To determine the 3-year progression-free survival and the 5-year overall survival of these patients. To evaluate patient-reported outcomes at baseline and during treatment to determine differences in symptom palliation, treatment-related symptoms, and overall health-related quality of life. To examine the association between baseline Follicular Lymphoma International Prognostic Index (FLIPI) information and outcome of these patients. To examine the association between baseline and end-of-treatment patient comorbidities assessed by the Cumulative Illness Rating Scale (CIRS) and outcome. To create an image and tissue bank including serial PET/CT scans, diagnostic paraffin-embedded tissue, germline DNA, and serial blood and bone marrow samples sufficient to support proposed and future studies of tumor and host characteristics that may predict for clinical outcome, including treatment arm effects, and enhance existing prognostic indices. (exploratory) To evaluate the rate of peripheral neuropathy associated with subcutaneous and intravenous bortezomib. OUTLINE: Patients are stratified according to FLIPI-1score (0-2 vs 3 vs 4-5) and Groupe d'Etude des Lymphomes Folliculaires (GELF) tumor burden (low vs high). Patients are randomized to 1 of 3 treatment arms. Arm A then Arm D Arm A (induction): Patients receive rituximab intravenously (IV) on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Arm D (continuation): Beginning 4 weeks after the completion of induction therapy, patients who have stable disease or better at time of post-induction restaging receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Arm B then Arm E Arm B (induction): Patients receive rituximab IV on day 1; bortezomib IV on days 1, 4, 8, and 11; and bendamustine hydrochloride IV over 1 hour on days 1 and 4. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Arm E (continuation): Beginning 4 weeks after the completion of induction therapy, patients who have stable disease or better at time of post-induction restaging receive rituximab as in arm D. Arm C then Arm F Arm C (induction): Patients receive rituximab IV on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Arm F (continuation): Immediately after completing induction therapy, patients who have stable disease or better at time of post-induction restaging receive oral lenalidomide on days 1-21. Treatment repeats every 4 weeks for 13 courses in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of induction therapy, these patients receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Quality of life (including fatigue, neurotoxicity, anxiety, and depression) is assessed by questionnaire at baseline and periodically during study therapy. Blood, bone marrow, and tissue samples may be collected periodically for correlative studies and for a repository. After completion of study therapy, patients are followed up periodically for 15 years. Study Design Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Layout table for study information Study Type : Interventional  (Clinical Trial) Actual Enrollment : 289 participants Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment Official Title: A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by Lenalidomide/Rituximab in High Risk Follicular Lymphoma Actual Study Start Date : December 13, 2010 Actual Primary Completion Date : December 2, 2019 Actual Study Completion Date : December 2, 2019 Resource links provided by the National Library of Medicine MedlinePlus related topics: Lymphoma Drug Information available for: Bendamustine hydrochloride Bendamustine Rituximab Bortezomib Lenalidomide Genetic and Rare Diseases Information Center resources: Lymphosarcoma Follicular Lymphoma U.S. FDA Resources Arms and Interventions Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Arm Intervention/treatment Experimental: Arm A then Arm D (Induction with Bendamustine + Rituximab; Continuation with Rituximab)Arm A (induction): Patients receive rituximab intravenously (IV) on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.Arm D (continuation): Beginning 4 weeks after the completion of induction therapy, patients who have stable disease or better at time of post-induction restaging receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Biological: rituximab Given IV Other Names: IDEC-C2B8 Chimeric anti-CD20 monoclonal antibody Rituxan Drug: Bendamustin Given IV Other Names: Bendamustine hydrochloride CEP-18083 TREANDA Experimental: Arm B then Arm E (Induction with Bendamustine + Rituximab + Bortezomib; Continuation with Rituximab)Arm B (induction): Patients receive rituximab IV on day 1; bortezomib IV on days 1, 4, 8, and 11; and bendamustine hydrochloride IV over 1 hour on days 1 and 4. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.Arm E (continuation): Beginning 4 weeks after the completion of induction therapy, patients who have stable disease or better at time of post-induction restaging receive rituximab as in arm D. Biological: rituximab Given IV Other Names: IDEC-C2B8 Chimeric anti-CD20 monoclonal antibody Rituxan Drug: Bendamustin Given IV Other Names: Bendamustine hydrochloride CEP-18083 TREANDA Drug: bortezomib Given IV Other Names: MLN341 LDP-341 Velcade® PS-341 Experimental: Arm C then Arm F (Induction with Bendamustine+Rituximab; Continuation with Lenalidomide + Rituximab)Arm C (induction): Patients receive rituximab IV on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.Arm F (continuation): Immediately after completing induction therapy, patients who have stable disease or better at time of post-induction restaging receive oral lenalidomide on days 1-21. Treatment repeats every 4 weeks for 13 courses in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of induction therapy, these patients receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Biological: rituximab Given IV Other Names: IDEC-C2B8 Chimeric anti-CD20 monoclonal antibody Rituxan Drug: Bendamustin Given IV Other Names: Bendamustine hydrochloride CEP-18083 TREANDA Drug: lenalidomide Given orally Other Names: IMiD compound CC-5013 Revlimid® Outcome Measures Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Primary Outcome Measures : Complete Remission (CR) Rate [ Time Frame: Assessed every 4 weeks during induction treatment and every 8 weeks during continuation treatment, up to 2 years ] Complete remission is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. This analysis was conducted among 222 evaluable patients for the primary analysis. The purpose of this analysis is to compare the complete remission rate of rituximab + bendamustine vs. bortezomib + rituximab + bendamustine as induction therapy, therefore, the proportion of patients with complete remission was compared between Arm B (bortezomib + rituximab + bendamustine) and Arms A and C combined (rituximab + bendamustine). 1-year Post-induction Disease-free Survival (DFS) Rate [ Time Frame: Assessed at 1 year post-induction, approximately 1.5 years ] 1-year post induction disease-free survival rate is defined as the proportion of patients achieving complete remission during induction treatment and are alive and maintaining complete remission at 1 year after induction completion. The purpose of this analysis is to compare the 1-year post-induction disease-free survival (DFS) rate with rituximab plus lenalidomide to rituximab alone as continuation therapy following induction treatment of bendamustine+rituximab, therefore, patients with induction treatment of bendamustine + rituximab + bortezomib were not included in this analysis. Secondary Outcome Measures : 3-year Progression-free Survival Rate [ Time Frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry ] Progression-free survival is defined as the time from registration of induction treatment to progression, relapse or death, whichever occurs first. Patients alive without documented progression are censored at last disease assessment. 3-year progression-free survival rate is the proportion of patients who were progression-free and alive at 3 years estimated using the method of Kaplan-Meier. Progression/relapse is defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, >=50% increase from nadir in the SPD of any previously involved nodes or extranodal masses or the size of other lesions, or >=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. 5-year Overall Survival Rate [ Time Frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry ] Overall survival is defined as the time from randomization to death or date last known alive. 5-year overall survival rate is the proportion of patients who were alive at 5 years estimated using the method of Kaplan-Meier. Complete Remission (CR) Rate [ Time Frame: Assessed every 4 weeks during induction treatment and every 8 weeks during continuation treatment, up to 2 years ] Complete remission is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. This analysis was conducted among 222 evaluable patients. The proportion of patients with complete remission was compared between patients with Follicular Lymphoma International Prognostic Index (FLIPI) of 3-5 and patients with FLIPI of 0-2/unknown. The FLIPI was developed in order to predict prognosis of patients with newly diagnosed follicular lymphoma (FL). The five FLIPI risk factors were: age > 60 years, Ann Arbor stage III-IV, hemoglobin level < 12 gm/dL, >4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis. 1-year Disease-free Survival (DFS) Rate [ Time Frame: Assessed at 1 year post-induction, approximately 1.5 years ] 1-year post induction disease-free survival rate is defined as the proportion of patients achieving complete remission during induction treatment and are alive and maintaining complete remission at 1 year after induction completion. This analysis was conducted among 203 evaluable patients in the continuation treatment portion of the study. The 1-year post induction disease-free survival rate was compared between patients with FLIPI of 3-5 and patients with FLIPI of 0-2/unknown. The FLIPI was developed in order to predict prognosis of patients with newly diagnosed follicular lymphoma (FL). The five FLIPI risk factors were: age > 60 years, Ann Arbor stage III-IV, hemoglobin level < 12 gm/dL, >4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis. Progression-free Survival [ Time Frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry ] Progression-free survival is defined as the time from registration of induction treatment to progression, relapse or death, whichever occurs first. Patients alive without documented progression are censored at last disease assessment. Progression/relapse is defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, >=50% increase from nadir in the SPD of any previously involved nodes or extranodal masses or the size of other lesions, or >=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. The five FLIPI risk factors were: age > 60 years, Ann Arbor stage III-IV, hemoglobin level < 12 gm/dL, >4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis. 5-year Overall Survival Rate [ Time Frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry ] Overall survival is defined as the time from randomization to death or date last known alive. 5-year overall survival rate is the proportion of patients who were alive at 5 years estimated using the method of Kaplan-Meier. The FLIPI was developed in order to predict prognosis of patients with newly diagnosed follicular lymphoma (FL). The five FLIPI risk factors were: age > 60 years, Ann Arbor stage III-IV, hemoglobin level < 12 gm/dL, >4 nodal areas, and serum LDH level above normal. The FLIPI score was calculated by summing the number of risk factors. The higher the FLIPI score, the worse the prognosis. Complete Remission (CR) Rate [ Time Frame: Assessed every 4 weeks during induction treatment and every 8 weeks during continuation treatment, up to 2 years ] Complete remission is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy. This analysis was conducted among 250 evaluable patients with Cumulative Illness Rating Scale (CIRS) data available. The proportion of patients with complete remission was compared between patients with CIRS <10 and patients with CIRS >=10. Higher CIRS scores indicate higher severity with max score of 56 points. 1-year Disease-free Survival (DFS) Rate [ Time Frame: Assessed at 1 year post-induction, approximately 1.5 years ] 1-year post induction disease-free survival rate is defined as the proportion of patients achieving complete remission during induction treatment and are alive and maintaining complete remission at 1 year after induction completion. This analysis was conducted among 250 evaluable patients with Cumulative Illness Rating Scale (CIRS) data available. The proportion of patients disease-free and alive at 1 year post induction treatment was compared between patients with CIRS <10 and patients with CIRS >=10. Higher CIRS scores indicate higher severity with max score of 56 points. 3-year Progression-free Survival Rate [ Time Frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry ] Progression-free survival is defined as the time from registration of induction treatment to progression, relapse or death, whichever occurs first. Patients alive without documented progression are censored at last disease assessment. 3-year progression-free survival rate is the proportion of patients who were progression-free and alive at 3 years estimated using the method of Kaplan-Meier. Progression/relapse is defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, >=50% increase from nadir in the SPD of any previously involved nodes or extranodal masses or the size of other lesions, or >=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. The 3-year progression-free survival rate is reported by Cumulative Illness Rating Scale (CIRS) score (<10 vs. >=10). Higher CIRS scores indicate higher severity with max score of 56 points. 5-year Overall Survival Rate [ Time Frame: Assessed every cycle during treatment and every 6 months between 2 and 5 years from study entry ] Overall survival is defined as the time from randomization to death or date last known alive. 5-year overall survival rate is the proportion of patients who were alive at 5 years estimated using the method of Kaplan-Meier. The 5-year overall survival rate is reported by Cumulative Illness Rating Scale (CIRS) score (<10 vs. >=10). Higher CIRS scores indicate higher severity with max score of 56 points. Proportion of Patients With Grade 3 or Higher Peripheral Neuropathy [ Time Frame: Assessed every cycle during treatment and for 30 days after discontinuation of treatment, up to 15 years ] Peripheral neuropathy was assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Proportion of patients with grade 3 or higher peripheral neuropathy was compared between patients with subcutaneous bortezomib and patients with intravenous bortezomib. Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Baseline [ Time Frame: Assessed at baseline ] The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-G total score ranges between 0 and 108. The higher the score, the better the quality of life. Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Mid-treatment [ Time Frame: Assessed at cycle 3 or cycle 4, approximately 3 or 4 months ] The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-G total score ranges between 0 and 108. The higher the score, the better the quality of life. FACT-G total score at cycle 3 is considered as mid-treatment score. If FACT-G total score at cycle 3 is not available, the score at cycle 4 will be used as the mid-treatment score. Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at End of Induction Treatment [ Time Frame: Assessed at cycle 6, approximately 6 months ] The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-G total score ranges between 0 and 108. The higher the score, the better the quality of life. Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Baseline [ Time Frame: Assessed at baseline ] The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is a 15-item questionnaire that evaluates disease-related symptoms and concerns specific to lymphoma with a scale of 0-4. The FACT-Lym subscale score ranges between 0 and 60. The higher the score, the better the quality of life. Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at Mid-induction Treatment [ Time Frame: Assessed at cycle 3 or cycle 4, approximately 3 or 4 months ] The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is a 15-item questionnaire that evaluates disease-related symptoms and concerns specific to lymphoma with a scale of 0-4. The FACT-Lym subscale score ranges between 0 and 60. The higher the score, the better the quality of life. FACT-Lym subscale score at cycle 3 is considered as mid-treatment score. If FACT-Lym subscale score at cycle 3 is not available, the score at cycle 4 will be used as the mid-treatment score. Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale Score at End of Induction Treatment [ Time Frame: Assessed at cycle 6, approximately 6 months ] The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is a 15-item questionnaire that evaluates disease-related symptoms and concerns specific to lymphoma with a scale of 0-4. The FACT-Lym subscale score ranges between 0 and 60. The higher the score, the better the quality of life. Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Baseline [ Time Frame: Assessed at baseline ] The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) is comprised of 13 items that assess fatigue and its impact with a scale of 0-4. The FACIT-Fatigue subscale score ranges between 0 and 52. The higher the score, the better the quality of life. Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at Mid-induction Treatment [ Time Frame: Assessed at cycle 3 or cycle 4, approximately 3 or 4 months ] The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) is comprised of 13 items that assess fatigue and its impact with a scale of 0-4. The FACIT-Fatigue subscale score ranges between 0 and 52. The higher the score, the better the quality of life. FACIT-Fatigue subscale score at cycle 3 is considered as mid-treatment score. If FACIT-Fatigue subscale score at cycle 3 is not available, the score at cycle 4 will be used as the mid-treatment score. Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Subscale Score at End of Induction Treatment [ Time Frame: Assessed at cycle 6, approximately 6 months ] The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) is comprised of 13 items that assess fatigue and its impact with a scale of 0-4. The FACIT-Fatigue subscale score ranges between 0 and 52. The higher the score, the better the quality of life. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Baseline [ Time Frame: Assessed at baseline ] The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) subscale is comprised of 11 items that assess neurotoxicity with a scale of 0-4. The FACT-GOG-NTX subscale score ranges between 0 and 44. The higher the score, the better the quality of life. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at Mid-induction Treatment [ Time Frame: Assessed at cycle 3, approximately 3 months ] The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) subscale is comprised of 11 items that assess neurotoxicity with a scale of 0-4. The FACT-GOG-NTX subscale score ranges between 0 and 44. The higher the score, the better the quality of life. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) Subscale Score at the End of Induction Treatment [ Time Frame: Assessed at end of induction treatment (cycle 6), approximately 6 months ] The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) subscale is comprised of 11 items that assess neurotoxicity with a scale of 0-4. The FACT-GOG-NTX subscale score ranges between 0 and 44. The higher the score, the better the quality of life. Eligibility Criteria Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Layout table for eligibility information Ages Eligible for Study: 18 Years and older   (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No Criteria Inclusion Criteria (Induction): Histologically confirmed (biopsy-proven) diagnosis of follicular B-cell non-Hodgkin lymphoma with no evidence of transformation to large cell histology Patients having both diffuse and follicular architectural elements are eligible if the histology is predominantly follicular (i.e., ≥ 50% of the cross-sectional area) and there is no evidence of transformation to a large cell histology Diagnostic confirmation (i.e., core needle or excisional lymph node biopsy) required if the interval since tissue diagnosis of low-grade malignant lymphoma is > 24 months Bone marrow biopsy alone not acceptable Stage II, III, or IV AND grade 1, 2, or 3a disease Must meet criteria for High Tumor Burden (higher risk) as defined by either the Groupe D'Etude des Lymphomes Follicularies (GELF) criteria OR the follicular lymphoma international prognostic index (FLIPI) as defined below: Patient must meet ≥ 1 of the following GELF criteria: Nodal or extranodal mass ≥ 7 cm At least 3 nodal masses > 3.0 cm in diameter Systemic symptoms due to lymphoma or B symptoms Splenomegaly with spleen > 16 cm by CT scan Evidence of compression syndrome (e.g., ureteral, orbital, gastrointestinal) or pleural or peritoneal serous effusion due to lymphoma (irrespective of cell content) Leukemic presentation (≥ 5.0 x 10^9/L malignant circulating follicular cells) Cytopenias (polymorphonuclear leukocytes < 1.0 X 10^9/L, hemoglobin < 10 g/dL, and/or platelets < 100 x 10^9/L) Patient must have a FLIPI-1 score of 3, 4, or 5 (1 point per criterion below): Age ≥ 60 years Stage III-IV disease Hemoglobin level < 12 g/dL > 4 nodal areas Serum lactate dehydrogenase (LDH) level above normal At least 1 objective measurable disease parameter Baseline measurements and evaluations (PET and CT) obtained within 6 weeks of randomization Measurable disease in the liver is required if the liver is the only site of lymphoma HIV-positive patients must meet all of the following criteria: HIV is sensitive to antiretroviral therapy Must be willing to take effective antiretroviral therapy if indicated No history of CD4 < 300 cells/mm³ prior to or at the time of lymphoma diagnosis No history of AIDS-defining conditions If on antiretroviral therapy, must not be taking zidovudine or stavudine Must be willing to take prophylaxis for Pneumocystis jiroveci pneumonia (PCP) during therapy and ≥ 2 months following completion of study therapy or until the CD4 cells recover to over 250 cells/mm³ ECOG performance status 0-2 Absolute neutrophil count (ANC) ≥ 1,500/mm³ (includes neutrophils and bands) Platelet count ≥ 100,000/mm³ Creatinine ≤ 2.0 mg/dL Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 5 x upper limit of normal (ULN) Alkaline phosphatase ≤ 5 x ULN Total bilirubin ≤ 1.5 x ULN (patients with known Gilbert disease should contact the study PI) Negative pregnancy test Fertile patients must use 2 effective methods (1 highly effective and 1 additional effective method) of contraception ≥ 28 days before, during, and for ≥ 28 days after completing study treatment Must register into the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist® (for patients randomized to arm C and proceed onto arm F) Exclusion Criteria (Induction): Prior chemotherapy, radiotherapy, or immunotherapy for lymphoma Prednisone or other corticosteroids used for non-lymphomatous conditions will not be considered as prior chemotherapy A prior/recent short course (< 2 weeks) of steroids for symptom relief of lymphoma-related symptoms is allowed Recent history of malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for ≥ 2 years Pregnant or nursing Active, uncontrolled infections (afebrile for > 48 hours off antibiotics) ≥ grade 2 neuropathy Myocardial infarction within the past 6 months NYHA class III-IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities Serious medical or psychiatric illness likely to interfere with participation in this clinical study Known hypersensitivity to boron or mannitol Chronic carriers of hepatitis B virus (HBV) with positive hepatitis surface antigen (HBsAg +) Inclusion Criteria (Continuation): Patient must have improved their response or have had no interval change in their tumor measurements with restaging from Induction cycle 3 to 6 as determined at Cycle 6 restaging. Adequate organ function ECOG performance status 0-2 Patients with a prior history of HBV infection, but immune, with only IgG hepatitis core antibody positive (HBcAb+), must receive antiviral prophylaxis (e.g., lamivudine 100 mg po daily) for ≥ 1 week prior to course 1 and throughout induction and continuation therapy and for ≥ 12 months after the last rituximab dose Additional requirements for Arm C induction patients registering to arm F: Patients must be willing to take deep vein thrombosis (DVT) prophylaxis. Subjects with a history of a thrombotic vascular event will be required to have full anticoagulation, therapeutic doses of low molecular weight heparin or warfarin to maintain an INR between 2.0 - 3.0, or any other accepted full anticoagulation regimen (e.g. direct thrombin inhibitors or Factor Xa inhibitors) with appropriate monitoring for that agent. Subjects without a history of a thromboembolic event are required to take a daily aspirin (81 mg or 325 mg) for DVT prophylaxis. Subjects who are unable to tolerate aspirin should receive low molecular weight heparin therapy or warfarin treatment or another accepted full anticoagulation regimen. Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study/lenalidomide: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation/stopping lenalidomide. The two methods of reliable contraception must include one highly effective method (i.e. intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal ligation, partner's vasectomy) and one additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods if needed. Patient must agree to abstain from donating blood during study participation and for at least 28 days after discontinuation from protocol treatment. All males, regardless of whether they have undergone a successful vasectomy, must agree to use a latex condom during sexual contact with a female of childbearing potential, or to practice complete abstinence from heterosexual intercourse with any female of childbearing potential during the cycles of continuation therapy of which lenalidomide are taken and for at least 28 days after discontinuation/stopping lenalidomide. Patient must agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from protocol treatment. Must register into the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist® Exclusion Criteria (Continuation): Active, uncontrolled infections (afebrile for > 48 hours off antibiotics) ≥ grade 2 neuropathy Additional requirements for Arm C induction patients registering to arm F: Not pregnant or breast-feeding Study Documents (Full-Text) Documents provided by Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group ): Study Protocol and Statistical Analysis Plan [PDF] June 15, 2016 Publications of Results: Evens AM, Hong F, Habermann TM, Advani RH, Gascoyne RD, Witzig TE, Quon A, Ranheim EA, Ansell SM, Cheema PS, Dy PA, O'Brien TE, Winter JN, Cescon TP, Chang JE, Kahl BS. A Three-Arm Randomized Phase II Study of Bendamustine/Rituximab with Bortezomib Induction or Lenalidomide Continuation in Untreated Follicular Lymphoma: ECOG-ACRIN E2408. Clin Cancer Res. 2020 Sep 1;26(17):4468-4477. doi: 10.1158/1078-0432.CCR-20-1345. Epub 2020 Jun 12. Layout table for additonal information Responsible Party: ECOG-ACRIN Cancer Research Group ClinicalTrials.gov Identifier: NCT01216683 History of Changes Other Study ID Numbers: E2408 E2408 ( Other Identifier: ECOG-ACRIN ) NCI-2011-02644 ( Other Identifier: NCI ) CDR0000683312 ( Other Identifier: NCI ) First Posted: October 7, 2010 Key Record Dates Results First Posted: February 23, 2021 Last Update Posted: January 17, 2023 Last Verified: January 2023 Individual Participant Data (IPD) Sharing Statement: Plan to Share IPD: Yes Plan Description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy. Layout table for additional information Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No Keywords provided by Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group ): contiguous stage II grade 1 follicular lymphoma contiguous stage II grade 2 follicular lymphoma contiguous stage II grade 3 follicular lymphoma noncontiguous stage II grade 1 follicular lymphoma noncontiguous stage II grade 2 follicular lymphoma noncontiguous stage II grade 3 follicular lymphoma stage III grade 1 follicular lymphoma stage III grade 2 follicular lymphoma stage III grade 3 follicular lymphoma stage IV grade 1 follicular lymphoma stage IV grade 2 follicular lymphoma stage IV grade 3 follicular lymphoma Additional relevant MeSH terms: Layout table for MeSH terms Lymphoma Lymphoma, Follicular Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, Non-Hodgkin Rituximab Lenalidomide Bortezomib Bendamustine Hydrochloride Antineoplastic Agents, Immunological Antineoplastic Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Growth Inhibitors Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action
https://clinicaltrials.gov/ct2/show/study/NCT01216683?show_desc=Y
Heritage | Free Full-Text | Deep Water Archaeology in Italy and in the Tyrrhenian Sea This paper presents an overview of the history of the research in deep water archaeology in Italy and the recent activities carried out by Fondazione Azionemare, in collaboration with the Dipartimento di Studi Umanistici of the Università Ca’ Foscari Venezia, in the Tyrrhenian Sea. Through a preliminary presentation of some shipwrecks dated to the Roman period, discovered by the Fondazione Azionemare and investigated, thanks also to photogrammetry, with the archaeologists of the Venetian university, this article analyses the characteristics and the potentialities of these contexts, which present an excellent level of conservation. Deep Water Archaeology in Italy and in the Tyrrhenian Sea by Carlo Beltrame 1,* , Elisa Costa 1 and Guido Gay 2 Dipartimento di Studi Umanistici, Università Ca’ Foscari Venezia, Dorsoduro 3484/D, 30123 Venezia, VE, Italy Fondazione Guido Gay Azionemare, via Lavizzari 4, 6900 Lugano, Switzerland Heritage 2022 , 5 (3), 2106-2122; https://doi.org/10.3390/heritage5030110 Abstract : This paper presents an overview of the history of the research in deep water archaeology in Italy and the recent activities carried out by Fondazione Azionemare, in collaboration with the Dipartimento di Studi Umanistici of the Università Ca’ Foscari Venezia, in the Tyrrhenian Sea. Through a preliminary presentation of some shipwrecks dated to the Roman period, discovered by the Fondazione Azionemare and investigated, thanks also to photogrammetry, with the archaeologists of the Venetian university, this article analyses the characteristics and the potentialities of these contexts, which present an excellent level of conservation. Keywords: underwater archaeology ROV deep wreck shipwreck conservation 1. Introduction Underwater archaeology is traditionally very permeable to technologies that it is able to acquire from other disciplines. Indeed, technology offers a great opportunity to go beyond the limits of submerged environments (depth, visibility, etc.) and to reduce working time, which consequently saves money and reduces risks [ 1 ]. Therefore, whereas technology is simply an opportunity when working in shallow waters, the same technology becomes indispensable when investigating deep waters. Marine technology offers more and more opportunities for the deep water exploration of our cultural heritage. Compared to the past, such technology is also becoming more accessible for archaeologists, because costs are progressively diminishing. In many cases, this kind of research is possible thanks to the collaboration of specialized private companies, trusts, or other better-equipped and resource-rich institutions, which see in these activities the chance to conduct research and improve visibility. Although the chances for archaeological institutions to use this technology can be quite frequent, it is of course desirable, in the future, for diminishing costs and increased simplicity in the use of these tools to encourage independent research activity. 2. Potentialities of Deep Water Shipwreck Investigation Deep water contexts are of great interest for many reasons. They are very important to the study of direct and offshore routes [ 2 ] given that 98% of known shipwrecks lie a few miles from the coast, which means that known sites in deep waters, far from the coast, are still very rare. On the other hand, the location of a shipwreck more than 4 or 5 miles from the coast does not automatically mean that the ship was sailing an offshore route without the possibility of visually following the coast. Instead, storms or the loss of the ability to control the route, because of the rudder or the sail breaking, could push the ship adrift. An example is the story of the Querina ship which, in 1431, after a storm that dismantled its rudder and its sails, was pushed by the sea from the Channel to the coasts of Norway after more than one month of sailing without any control [ 3 ]. 1 Shipwrecks located offshore can also be useful in studying the techniques of sailing and navigation. This is particularly interesting for the Ancient and Medieval periods of which we have poor information from traditional sources. For example, it seems very important to understand whether the ships that frequented the Mediterranean in the Greek and in the Early Medieval periods, which, according to what we know, had a limited tonnage, were technically able to sail for long distances offshore, like the Roman onerariae represented by the Madrague de Giens and the Albenga shipwrecks, and by many ships carrying marble stones [ 6 ]. Deep shipwrecks often retain a relatively “good” level of conservation. Given that these ships did not impact against reefs or crags, and that they usually sank intact, their aspect is seldom compromised by the dynamic of the shipwreck. Indeed, the ships can reach the sea bottom in correspondence with the position of navigation, and remain intact on the sand, often with the cargo in a whole state, as it had been on the surface. This is evident from the observation of hundreds of shipwrecks, especially ancient cargos of amphoras, stones blocks, or building materials dated from the Greek to the Medieval period. The depth, then, permits relatively good protection from treasure hunters, who can seldom exceed a depth of 100 metres, although very well-equipped pirates, breaking national laws and the UNESCO Convention on the Protection of the Underwater Cultural Heritage (2001), visited deeper sites such as the 1000 m deep wreck of the Nuestra Senora de las Mercedes [ 7 ] and the Spanish galleon San José , sunk off Columbia on a seabed at 600 m deep ( https://www.cbsnews.com/news/san-jose-shipwreck-colombia-200-tons-treasure/ (accessed on 20 July 2022)). The depth also provides protection from the impact of trawling nets. In the Mediterranean, down to many hundreds of metres, these are the most devastating actors for shipwrecks [ 8 ]. The depth can permit the survival of the sites, which either are sufficiently deep or are protected by the morphology of the seabed or are in an area not attended by fishing vessels. On the other hand, the experience of the shipwrecks of the Adriatic demonstrates that, in shallow waters, underwater sites can survive only thanks to the protection of very irregular rocky sea bottoms, with deep cavities, or the covering of a thick layer of sand [ 9 ]. Xylophaga 10 11 Xylophaga 12 A totally different case can be found in the formation processes in the deep sea bottoms of the Baltic Sea [ 13 , 14 ] and the Black Sea [ 15 ], where recent and less recent discoveries have returned shipwrecks with wood in excellent states of conservation. 3. The First Steps of the Deep Water Archaeology in Italy and Tuscany Asherad 16 Deutsches Archäologisches Institut 17 In the same years, another Italian company, the Snamprogetti, in the Sicily Channel, made a quick survey, through images and remote sensing for the position, with a mini submarine of a shipwreck with 5th century BC amphoras at a depth of 530 m [ 18 ]. After these cases, we had to wait many years before an Italian company or institution carried out other missions of this kind. At the end of the 1980s, the French technical service Infremer, while engaged in the recovery of pieces of the DC 9 airplane off Ustica on a sea bottom that was 3200 m deep, happened to discover a cargo of the 6th century AD with African amphoras [ 19 ]. This find offered us the first evidence of the potentialities of deep-water archaeology, albeit as the result of a non-scientific mission. 7 2 20 A study carried out quite close to the Italian coast, and which left its mark on the discipline, was the JASON project, coordinated by the oceanographer R.D. Ballard and the archaeologist A.M. McCann on the Skerki Bank in the Channel of Sicily [ 21 ]. Here, in 1989, a US mission using a ROV on a sea bottom of 818 m recovered some finds in international waters. This mission then continued over several years, also along the Italian coasts [ 4 ], and received critical reactions among some Italian archaeologists (La Repubblica, 2.8.1997, https://ricerca.repubblica.it/repubblica/archivio/repubblica/1997/08/02/america-ruba-nostri-tesori.html (accessed on 20 July 2022)). Ballard’s team, in 1999, west of Israel, surveyed also two 400 m deep Phoenician shipwrecks of the 8th century AD [ 22 ]. 23 24 www.archeomedia.net dolia 25 Other Italian superintendencies, such as the Soprintendenza del Mare of Sicily, collaborated with the Aurora Trust Foundation to carry out investigations on deep shipwrecks at Ventotene (2008–9), Capri (2010–11), Panarea (2010 and 2015) and Messina [ 25 , 26 ] ( www.auroratrust.com , accessed on 20 July 2022). Since 2005, the Soprintendenza del Mare, thanks to the collaboration of the RPM Foundation, has also worked with ROVs on the 90 m deep sea bottom of the Favignana island where the rostra were found [ 26 ]. In this case, technology was used to assist the work of technical divers at a depth that could be reached by human divers. The same kind of experience of ROVs in collaboration with divers was carried out, in 2009–2010, on the 65 m-deep shipwrecks with dolia of Marciana Marina (LI) by the Soprintendenza of Tuscany and the Politecnico della Marche [ 24 ]. With the exception of the latter, all these studies undertaken by Italian institutions were possible thanks to the collaboration of French and USA companies and trusts—sometimes under contract, as in the case of the Archeomar project. Other discoveries and investigations were made by chance on the occasion of offshore works, such as the recently explored Archaic shipwreck investigated at 780 m in the Canale d’Otranto under the coordination of the Soprintendenza Nazionale per il Patrimonio Culturale Subacqueo during the installation of pipes ( www.ansa.it , accessed on 16 October 2021); www.patrimoniosubacqueo.it/il-relitto-alto-arcaico-del-canale-di-otranto/ (accessed on 20 July 2022)). 4. Experiences of Deep Water Investigation by ROVs in the Tyrrenian Sea with the Azionemare Foundation In recent years, ROVs have been increasingly used to explore the depths, playing an important role in various fields of marine scientific research, and allowing the broadening of knowledge in the field of maritime archaeology [ 27 , 28 ]. ROVs suitable for deep water investigations (>300 m) are generally heavy and bulky, and must be supported by large expensive survey vessels, the associated costs being well beyond the reach of scientific researchers who, in most cases, do not have adequate funds. The Azionemare Foundation has tackled the problem and has adopted non-standard and intelligent solutions. The main tools needed for the research and study of a wreck at depths between 150 and 1000 m are: - a long-range sonar able to detect the morphology of the bottom and the presence of any object; - capacity for georeferencing a particular anomaly detected by the sonar on the seabed; - a vessel equipped with dynamic positioning, capable of moving to the vertical above the anomaly and remaining stationary, automatically controlled by a computer; - an ROV to be sent to the bottom to recognize the nature of the anomaly and to study it in the case of an ancient wreck. Guido Gay has created a company that, for 40 years, has been producing Pluto ROVs ( Figure 1 ) used by the Military in mine-hunting jobs. Years ago, he had the opportunity to build a vessel also suitable for experimenting with the Plutos. Among various solutions, he chose to design and build a sailing catamaran. Thus was born the Daedalus, a 21 m long catamaran completely different from the shapes currently in use ( Figure 2 ). This was a fast, stable, spacious and comfortable boat, equipped with dynamic positioning and all the instruments necessary to explore the deep seabed, as well as a workshop-laboratory and a control room ( Figure 3 ) for working with two Pluto wire-guided submarine vehicles. Automatisms and servos allow a single person to maneuver the whole boat. Figure 4 Figure 5 Except in difficult weather conditions, the long-range sonar is always activated when underway. The emission occurs with a 50 kHz ultrasound beam in the shape of a vertical fan oriented laterally perpendicular to the motion of the boat, so as to strike a strip of seabed about one kilometer wide on the left side of the catamaran. The beam is quite narrow, at about two degrees, and the advancement of the boat allows one to construct an image of the bottom seen not perpendicularly downwards but in profile; in this way any objects stand out very clearly. Generally speaking, only medium or large vessels specialized for research or underwater work are equipped with this system. In Italy, none of the research vessels available are equipped with dynamic positioning. Only oil works vessels or military mine-hunters are fitted with dynamic positioning capabilities. The Daedalus catamaran has been designed as an innovative sailing pleasure yacht with the addition of several features designed and built in house, suitable for scientific activity. One of them is the DP, a propeller that is normally hidden in the hull, which can extend out into the water when necessary. The computer controls its orientation and rotation speed in order to keep the boat steady against the current and against the wind. This is a job that could also be done manually but would require a dedicated person. The DP will maintain the position of Daedalus under the conditions of 12-knot wind and 2-knot tide, in seastate 3. The project concepts of the Pluto Palla and Multipluto are original and unusual. The original idea behind these developments lies in the extreme homogeneity of the project, which includes the development and production of most of the subsystems, to better match the characteristics of each other and to obtain a vehicle with maximum performance with the lowest mass, as well as a very compact footprint. In fact, nothing exists today that comes close to the performance of the Pluto, which can explore as deep as 2000 m with a 60 kg vehicle, as well as another 60 kg remote-controlled cable drum, and which remains there to work for 8 h. Normally, to go down to depths of, for example, a thousand meters, heavy equipment must be used that can only be installed on ships of adequate tonnage, for example the André Malraux of the French DRASSM (233 tons versus 29 tons of the Daedalus); the Plutos, on the other hand, is battery-powered, thus eliminating the large umbilical cable that carries energy from the surface down to the vehicle. The roller of this cable constitutes the bulk and is the most important weight of all the other vehicles, which imposes the use of ships. The potential benefits of such a light and compact instrument are many, such as for the recovery of instrumentation (in one case, Multipluto recovered a disabled Hugin AUV from 700 m, and in another a military object of 500 kg from 1000 m depth), as well as for the identification and inspection of ancient and modern wrecks, as in the case of the cruiser Giovanni dalle Bande Nere sunk in World War II and lying at a depth of 1750 m. The Multipluto ROV can be transported in a normal car, loaded by hand on boats and used without the need for system installation. Recovery and deployment can be done by sliding the vehicle by hand or using a small davit. All these tools make the Daedalus catamaran capable of replacing an expensive research vessel for exploration, investigation, surveying and study at great depth, which may also involve light manipulation. In ten years of navigation exploring the Ligurian and the Tyrrhenian Seas, the Daedalus has discovered 43 wrecks from the Roman era lying at depths between 150 m and 900 m, as well as 24 modern wrecks including the Battleship Roma at 1200 m deep. By considering only the 43 ancient Roman wrecks, Azionemare has located, inspected and identified each and all of them. In general, it was immediately realized that all but three had been affected by damage due to the passage of trawling nets. Many deposits have been totally devastated by the fishing nets, while others show only the first layer of amphorae upset and crushing. This was believed to be the most serious conservation problem, as opposed to looting on coastal deposits accessible to scuba divers. Studies and samplings have been carried out on some of these wrecks in collaboration with the competent authorities. For example, on the Daedalus 26 wreck located south of Portofino at a depth of 710 m, two photomosaics were made at a two-year interval: they were almost unrecognizable, so significant was the upheaval and the dispersion of the amphorae [ 29 ]. Sampling operations of finds were carried out on about ten wrecks thanks to the use either of a special hook, carried out by the ROV and linked to the boat by a thin line capable of lifting a maximum of one hundred kilos of weight, and to the manipulator arm, which can tighten with delicately adjustable force in order not to damage fragile objects. When it has been planned to recover a certain number of small finds, the manipulator can place a container on the bottom, and each object can be deposited inside it; when full, the same manipulator can grab the container and bring it back to the surface together with the vehicle. 5. Experience of Photogrammetric Documentation on Tyrrhenian Deep Shipwreck ROVs are widely used for mapping and monitoring cultural and natural heritage, or to document the phases of the work of archaeologist during excavation; their main application is linked to photogrammetric surveys for documentation [ 15 , 30 , 31 ]. Important results of the application of the photogrammetric technique in deep waters have been obtained from recent studies through collaboration with the Azionemare Foundation. After some short studies with low-cost self-built ROVs, in which the quality of the underwater photogrammetric survey was tested through an accurate comparison between images and video footage of different cameras [ 32 ], the team of the Ca’ Foscari University of Venice had the opportunity to create synergy between its photogrammetric skills and the most advanced technologies of Azionemare. As part of the projects “The routes of ancient marble” and “Digital photogrammetry in underwater archaeology”, it was possible to document and study two important wrecks in the Tyrrhenian Sea, Dae37 and Dae27 3 . The documentation of the two shipwrecks was realized using a professional camera directly mounted inside the head of the ROV with the support of eight lateral external lights for environmental illumination. The processing and the alignment of extrapolated frames (831 for Dae37 and 3668 for Dae27) from the videos was realized with Agisoft Metashape and resulted in an accurate photogrammetric model. The versatility of photogrammetry allows the application of this technique in contexts where natural light is totally absent and the archaeological site is visible only with powerful artificial lights; the effect of the changing shadows on the subject is reduced thanks to the wide overlap between the strips, realized in a bustrophedic way, and it is largely resolved through the algorithms of the latest generation of photogrammetric software [ 15 , 30 , 33 ]. The first experimentation of the photogrammetric technique was carried out on Dae37, a large cargo of 17 lithic (presumably marble) blocks, with dimensions from 2 to 4 m, with a minimum thickness of 20 to 100 cm and Dressel two to four amphoras dated to the 1st century AD, which sank a few miles northwest of the island of Gorgona at a depth of 280 m ( Figure 6 ). The survey was carried out with the use of Multipluto which, through remote-controlled navigation, documented the site with parallel and overlapping strips realized in both directions (longitudinal and transversal to the shape of the site) in order to represent the details of the blocks and obtain an accurate model of the complete cargo. 6 34 With this technique, it was possible to weigh the biggest block, which was 100 tons, and then double the weight of all the other blocks, resulting in an apparently unbalanced configuration and assessment of the marble cargo, with much more weight on one extremity than on the other one. A second mission was carried out on the Dae27 wreck, a cargo of Roman Dressel 1 amphoras and tiles, sunk at a depth of 640 m off the island of Pianosa. This archaeological site is really important for different reasons: the cargo is preserved inside a pit, probably created by the impact of the shipwreck on the sea bottom, presenting an interesting situation regarding the formation process of shipwrecks, and it represents rare evidence of the long-range transport of material for roof construction. The shipwreck could be dated around the 2nd or 1st century BC, but extensive study and analysis will be conducted after the recovery of an amphora and a tile during the next campaign. This survey, as for the Dae37, was made using the images taken by the Multipluto, which, in this case, made radial and concentric strips following the mound conformation of the wreck; the survey was particularly difficult due to the numerous objects and the conformation of the finds, which required thousands of frames to represent the cargo in detail ( Figure 7 and Figure 8 ). The photogrammetric 3D model provided documentary evidence of the characteristic of the mound of the cargo and the pit that contains the shipwreck, thus allowing important analysis of the shipwreck; it is possible to approximately calculate the number of amphoras and tiles and the hypothetical volume and weight of the cargo, as completed in other contexts [ 9 ]. 6. Aspect of the Mediterranean Deep Shipwrecks When observing the ancient shipwrecks investigated by the Azionemare Foundation, we can make some interesting observations regarding their aspect in comparison with other shipwrecks of the Mediterranean. Indeed, the facies of these sites are similar, with most of them being dated to the Greek or Roman period; they are cargoes of non-perishable goods, such as amphoras, stone blocks, tiles, pottery and metal ingots. These are of course the less perishable materials, but also the more visible cargoes. Their appearance is often coherent, retaining the organization they had aboard. The result of the disappearance of the wooden deck is particularly evident in the Dae 39 shipwreck, a cargo of Dressel 1B amphoras preliminarily dated to between the end of the 2nd and the end of the 1st century BC. The location on the top of the amphoras cargo of a doliolum ( Figure 9 a), a few tiles ( Figure 9 b) and a rotary milestone (made by meta and catillus ) ( Figure 9 b) indicates that, originally, these objects were, of course, on the deck and that, after the degradation of the wood, they collapsed. The location of the rotary millstone on the top of the cargo can also be seen on other Mediterranean archaeological sites, such as the Roman cargo documented by the Aurora Trust off Messina ( www.auroratrust.com (accessed on 20 July 2022)) or the wreck at Skerki bank [ 21 ]. We know that millstones were often used aboard to mill the grain, and that they were not merely the object of trading [ 35 ]. The location on an extremity of the shipwreck of lead stocks of unpreserved wooden anchors is evidence of their original position on the presumed bow of the ship [ 36 ]. This is a frequently recurring situation, which can be seen in the Dae 22, 33/34, but which is particularly evident on the Dae 27, on the Dae 42 ( Figure 10 a) and on the Dae 39. On this last shipwreck, the extremity of the presumed bow also hosts an iron arrow-shaped anchor ( Figure 9 c). The presence of the anchors in this position is fairly frequent on other deep shipwrecks. A careful observation of these sites sometimes allows pottery items to be identified, which were presumably part of the crew’s equipment. The distinction between this pottery and the cargo is possible thanks to the limited numbers of pieces and their isolated position on an extremity. This can be appreciated on the Dae 42 shipwreck, a cargo of Dressel 1C, Brindisine and Lamboglia 2 amphoras, preliminarily dated between the end of the 2nd and the middle of the 1st century BC ( Figure 10 a–c). On this site, it is also possible to see some lead ingots, which could be a secondary part of the cargo ( Figure 10 b). On none of these sites did we recognize organic finds, a situation that confirms the fact that, aboard an ancient ship, differently to what happened on Late-Medieval or later vessels, both the equipment and the personal belongings, except for very small objects, which are not easy to recognize on the seabed, and the pottery, were mainly made of perishable materials [ 37 ]. The recent discovery of Roman ships in excellent conditions in the deep waters of the Black Sea confirms this image, because its preliminary observation does not show objects made with materials different from wood and ropes, such as metal [ 15 ] and the numerous images and videos on the web]. Among the post-depositional formation processes of these deep shipwrecks, we can include the entrapment of garbage. Indeed, the shipwreck is a trap on the seabed for plastic, glass, ropes and any kind of garbage lost by fishing boats and other vessels ( Figure 11 ). 7. Conclusions The deep waters of the Tyrrhenian Sea conserve a significant number of shipwrecks, mainly from the Roman period, of great interest both due to the quality of their conservation and because of the historical information they can offer us. One of them has a precious cargo of tiles useful for reconstructing the dynamic of traffic of this product; another one has a cargo of stone blocks (possibly marble blocks) offering exceptional data, which need to be better investigated. The others present interesting information for the study both of the traffic of goods in amphoras, and of navigation and life aboard in antiquity. They also offer important data, helping us to better know the formation processes of the archaeological record at this depth. This developing frontier raises important challenges that nautical archaeologists can take on thanks to collaborations with institutions and private entities, such as the Azionemare Foundation, equipped with technology still not available to archaeological institutions. This collaboration allows us to both develop new practices in deep-water research and to acquire precious archaeological data. It also would be a significant help for institutions working on the monitoring and safeguarding of submerged heritage, as in the Italian archaeological superintendency. While we wait for increased autonomy in such institutes (working both in the research and in the safeguarding of the heritage), which too often suffer because of the very limited budget available for research, the collaboration between these two realities, which would place them in a position to share technology and historical research, if carried out according to modern archaeological practices and respecting the UNESCO Convention on the Protection of the Cultural Heritage, will play an important part in documenting and reconstructing, over the decades to come, the technological and economic history of the Mediterranean. Thanks to this collaboration, deep water sites are no longer off limit for archaeological institutions. Author Contributions Introduction, history of the research, shipwrecks analysis, C.B.; ROV technique, G.G.; photogrammetry, E.C. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Informed Consent Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. References Beltrame, C.; Costa, E. Make visible the invisible. La rivoluzione copernicana della ricerca e della comunicazione del patrimonio sommerso. In Traces of Complexity ; Magnini, L., Bettineschi, C., Burigana, L., Eds.; Studi in onore di A. De Guio, SAP Società Archeologica: Mantova, Italy, 2021; pp. 441–449. [ Google Scholar ] Arnaud, P. Les Routes de la Navigation Antique ; Errance: Paris, France, 2020. [ Google Scholar ] Querini, P.; De Michiele, N.; Fioravante, C. Il Naufragio Della Querina. Veneziani nel Circolo Polare Artico ; Nutrimenti srl: Rome, Italy, 2007. [ Google Scholar ] McCann, A.M.; Oleson, J.P. Deep-Water Shipwrecks off Skerki Bank: The 1997 Survey ; Journal of Roman Archaeology: Portsmouth, UK, 2004; Suppl. S58. [ Google Scholar ] Royal, J.; Tusa, S. The Levanzo I Wreck, Sicily: A 4th-century AD merchantman in the service of the annona? Int. J. Naut. Archaeol. 2012 , 41 , 26–55. [ Google Scholar ] [ CrossRef ] Parizzi, S.; Beltrame, C. Calculating the Tonnage and the Dimension of the Cargoes of Marble of Roman Period. Digit. Appl. Archaeol. Cult. Herit. 2020 , 18 , e00153. [ Google Scholar ] [ CrossRef ] Long, L. L’archéologie sous-marine à grande profondeur: Fiction ou réalité. In Archeologia Subacquea. Come Opera L’archeologo sott’acqua. Storie Dalle Acque, VIII Ciclo di Lezione Sulla Ricerca Applicata in Archeologia, Certosa di Pontignano (Siena), 1996 ; Volpe, G., Ed.; All’Insegna del Giglio: Firenze, Italy, 1998; pp. 341–380. [ Google Scholar ] Kingsley, S.A. Fishing and Shipwreck Heritage ; Bloomsbury: London, UK; New Delhi, India; New York, NY, USA; Sydney, Australia, 2016. [ Google Scholar ] Beltrame, C.; Costa, E.; Medas, S. I relitti “dei mattoni” e di San Nicoletto (Hellmuth?) del mare di Venezia. Archeol. Postmediev. 2020 , 24 , 14–26. [ Google Scholar ] Mc Koy, J.L. Distribution of shipworms (Bivalvia: Teredinidae) in the New Zeland region. J. Mar. Freshw. Res. 1980 , 14 , 263–275. [ Google Scholar ] [ CrossRef ] Palma, P.; Santhakumaran, L.N. Shipwrecks and Global ‘Worming’ ; Blackwell’s: Oxford, UK, 2014. [ Google Scholar ] Piechota, D. Laboratory conservation. In Deep Water Archaeology. A Late-Roman Ship from Carthage and an Ancient Trade Route near Skerki Bank off Northwest Sicily ; Mc Cann, A.M., Freed, J., Eds.; Journal of Roman Archaeology: Ann Arbor, MI, USA, 1994; Volume XIII, pp. 103–107. [ Google Scholar ] Gjelstrup Björdal, C.; Gregory, D. Wreck Protect. In Decay and Protection of Archaeological Wooden Shipwrecks ; Archaeo Press: London, UK, 2012. [ Google Scholar ] Eriksson, N.; Roennby, J. Mars (1564): The initial archaeological investigations of a great 16th-century Swedish warship. Int. J. Naut. Archaeol. 2017 , 46 , 92–107. [ Google Scholar ] [ CrossRef ][ Green Version ] Pacheco-Ruiz, R.; Adams, J.; Pedrotti, F.; Grant, M.; Holmlund, J.; Bailey, C. Deep sea archaeological survey in the Black Sea—Robotic documentation of 2,500 years of human seafaring. Deep-Sea Res. Part I (Oceanogr. Res. Pap.) 2019 , 152 , 103087. [ Google Scholar ] [ CrossRef ] Bass, G.F. The Turkish Aegean. Proving Ground for Underwater Archaeology. Expedition 1968 , 10 , 3–10. [ Google Scholar ] Frey, D.; Hentschel, F.; Keith, D. Deepwater Archaeology: The Capistello Wreck Excavation, Lipari, Aeolian Islands. Int. J. Naut. Archaeol. 1978 , 7 , 279–300. [ Google Scholar ] [ CrossRef ] Barbieri, A.; Purpura, G. Un giacimento archeologico in acque profonde nel Canale di Sicilia. Sicil. Archeol. 1977 , 34 , 55–58. [ Google Scholar ] Volpe, G. Archeologia subacquea e commerci di età tardoantica. In Archeologia Subacquea. Come Opera L’archeologo Sott’acqua. Storie Dalle Acque ; Volpe, G., Ed.; All’Insegna del Giglio: Firenze, Italy, 1998; pp. 614–616. [ Google Scholar ] Drap, P.; Long, L. Towards a digital excavation data management system: The “Grand Ribaud F” Estruscan deep-water wreck. In VAST‘01: Proceedings of the 2001 Conference on Virtual Reality, Archeology, and Cultural Heritage, Glyfada, Greece, 28–30 November 2001 ; Association for Computing Machinery: New York, NY, USA, 2001; pp. 17–26. [ Google Scholar ] [ CrossRef ] McCann, A.M.; Freed, J. Deep Water Archaeology: A Late-Roman Ship from Carthage and an Ancient Trade Route near Skerki Bank off Northwest Sicily ; Journal of Roman Archaeology: Ann Arbor, MI, USA, 1994; Suppl. S13. [ Google Scholar ] Ballard, R.D.; Stager, L.E.; Master, D.; Yoerger, D.; Mindell, D.; Whitcomb, L.L.; Singh, H.; Piechota, D. Iron Age Shipwrecks in Deep Water off Ashkelon, Israel. Am. J. Archaeol. 2002 , 106 , 151–168. [ Google Scholar ] [ CrossRef ] Gambogi, P. Strumenti per la tutela e la ricerca del patrimonio sommerso in Toscana. In Comunicare la Memoria del Mediterraneo. Atti del Convegno Internazionale di Pisa Organizzato Dalla Regione Toscana ; Gravina, F., Ed.; Publications du Centre Jean Bérard: Naples, Italy, 2007; pp. 177–188. [ Google Scholar ] Gambogi, P. Quale futuro per i beni culturali sommersi a grande profondità? In Conoscenza e Tutela del Patrimonio Sommerso, Atti del Convegno Scuola Normale Superiore, 2012 ; Botarelli, L., La Monica, D., Eds.; Aracne ed.: Rome, Italy, 2013; pp. 199–225. [ Google Scholar ] Ritondale, M. Deep discoveries from the seabed of the Pontine Islands: The shipwrecks of Ventotene, Santo Stefano and Zannone. Assemblage 2014 , 13 , 26–38. [ Google Scholar ] Tusa, S. Sistemi elettroacustici di prospezione subacquea e il SIT per il patrimonio culturale sommerso della Regione Siciliana. In Conoscenza e Tutela del Patrimonio Sommerso, Atti del Convegno Scuola Normale Superiore, 2012 ; Botarelli, L., La Monica, D., Eds.; Aracne ed.: Rome, Italy, 2013; pp. 15–30. [ Google Scholar ] Ballard, R.D. Archaeological Oceanography. Oceanography 2007 , 20 , 62–67. [ Google Scholar ] [ CrossRef ] Brennan, M.L.; Cantelas, F.; Elliott, K.; Delgado, J.P.; Bell, K.L.C.; Coleman, D.; Fundis, A.; Irion, J.; Van Tilburg, H.K.; Ballard, R.D. Telepresence-Enabled Maritime Archaeological Exploration in the Deep. J. Marit. Archaeol. 2018 , 13 , 97–121. [ Google Scholar ] [ CrossRef ] Costa, E.; Gay, G. La tutela del patrimonio archeologico in acque profonde. L’archeologo Subacqueo 2020 , 72 , 3–8. [ Google Scholar ] Drap, P.; Merad, D.; Hijazi, B.; Gaoua, L.; Motasem, N.; Saccone, M.; Chemisky, B.; Seinturier, J.; Sourisseau, J.-C.; Gambin, T.; et al. Underwater photogrammetry and object modelling: A case study of Xlendi Wreck in Malta. Sensors 2015 , 15 , 30351–30384. [ Google Scholar ] [ CrossRef ] [ PubMed ] Sedlazeck, A.; Köser, K.; Koch, R. 3D reconstruction based on underwater video from ROV Kiel 6000 considering underwater imaging conditions. In Oceans 2009-Europe ; IEEE Press: New York, NY, USA, 2009; pp. 1–10. [ Google Scholar ] [ CrossRef ] Costa, E.; Guerra, F.; Vernier, P. Self-assembled ROV and photogrammetric surveys with low cost techniques. Int. Arch. Photogramm. Remote Sens. Spat. Inf. Sci. 2018 , XLII-2 , 275–279. [ Google Scholar ] [ CrossRef ][ Green Version ] Nornes, S.T.; Ludvigsen, M.; Odegard, O.; Sorensen, A. Underwater photogrammetric mapping of an intact standing steel wreck with ROV. IFAC—Pap. OnLine 2015 , 48 , 206–211. [ Google Scholar ] [ CrossRef ] Beltrame, C.; Costa, E. 3D survey and modelling of shipwrecks in different underwater environments. J. Cult. Herit. 2017 , 29 , 82–88. [ Google Scholar ] [ CrossRef ] Beltrame, C.; Boetto, G. Macine da relitti. Archeol. Subacquea 1997 , 2 , 167–196. [ Google Scholar ] Beltrame, C. Interpretazione della distribuzione spaziale dei reperti e riconoscimento di processi formativi nel relitto. In Atti del Convegno Nazionale di Archeologia Subacquea, Anzio 1996 ; Edipuglia: Bari, Italy, 1997; pp. 333–340. [ Google Scholar ] Beltrame, C. Vita di Bordo in età Romana ; Istituto Poligrafico e Zecca dello Stato: Rome, Italy, 2002. [ Google Scholar ] Notes 1 There are a pair of shipwrecks sunk in the channel of Sicily that have been tentatively interpreted as evidence of the annona [ 4 , 5 ]. 2 ROVs (Remote Operated Vehicles) are underwater vehicles with no crew on board, which are remote controlled from the surface and which have reached such perfection and dexterity that they can replace humans in complex jobs up to depths exceeding 3000 m. 3 We want to thanks dott. Andrea Camilli (Soprintendenza Archeologia Belle Arti e Paesaggio per le Provincie di Pisa e Livorno) for the permission to carry out research activities on these two sites. Figure 1. The ROV MultiPluto in action (Photo: G. Gay). Figure 1. The ROV MultiPluto in action (Photo: G. Gay). Figure 2. The 29-tonne catamaran Daedalus ready to dive the ROV Pluto palla (Photo: G. Gay). Figure 2. The 29-tonne catamaran Daedalus ready to dive the ROV Pluto palla (Photo: G. Gay). Figure 3. Guido Gay piloting a ROV in the control room of the Daedalus (Photo: C. Lucarini). Figure 3. Guido Gay piloting a ROV in the control room of the Daedalus (Photo: C. Lucarini). Figure 4. The ROV Pluto palla on the Dae 27 Roman shipwreck (Photo: G. Gay). Figure 5. The ROV Multipluto using its arm for the recovery of pottery (Photo: G. Gay). Figure 5. The ROV Multipluto using its arm for the recovery of pottery (Photo: G. Gay). Figure 6. Orotophoto from the photogrammetry made on the Dae 37 Roman shipwreck with a cargo of stone blocks (off Gorgona Island) (Photo: E. Costa). Figure 6. Orotophoto from the photogrammetry made on the Dae 37 Roman shipwreck with a cargo of stone blocks (off Gorgona Island) (Photo: E. Costa). Figure 7. Orotophoto from the photogrammetry made on the Dae 27 Roman shipwreck with a cargo of tiles (off Pianosa Island) (Photo: E. Costa). Figure 7. Orotophoto from the photogrammetry made on the Dae 27 Roman shipwreck with a cargo of tiles (off Pianosa Island) (Photo: E. Costa). Figure 8. Frames from the photogrammetry of the Dae 27 shipwreck (Photo: E. Costa). Figure 8. Frames from the photogrammetry of the Dae 27 shipwreck (Photo: E. Costa). Figure 9. Cargo of the Dae 39 (north of Corsica) shipwreck: ( a ) Doliolum. ( b ) Tile and millstone. ( c ) Iron arrow shape anchor (from top to bottom is ( a – c ), Photo: G. Gay). Figure 9. Cargo of the Dae 39 (north of Corsica) shipwreck: ( a ) Doliolum. ( b ) Tile and millstone. ( c ) Iron arrow shape anchor (from top to bottom is ( a – c ), Photo: G. Gay). Figure 10. Cargo of Dae 42 (East of Corsica) shipwreck: ( a ) Lead anchor stocks and pottery vessels. ( b ) Lead ingots. ( c ) Dressel 1C amphoras (from top to bottom is ( a – c ), Photo: G. Gay). Figure 10. Cargo of Dae 42 (East of Corsica) shipwreck: ( a ) Lead anchor stocks and pottery vessels. ( b ) Lead ingots. ( c ) Dressel 1C amphoras (from top to bottom is ( a – c ), Photo: G. Gay). Figure 11. Plastic and other garbage in the Dae 37 shipwreck (Photo: G. Gay). Figure 11. Plastic and other garbage in the Dae 37 shipwreck (Photo: G. Gay). Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
https://www.mdpi.com/2571-9408/5/3/110#fn002-heritage-05-00110
Sexual Dysfunction in Infertile Women With PCOS Undergoing Fertility... Infertility, defined as the inability to become pregnant after one year of regular unprotected sexual intercourse. It is estimated that around 20 % of... Sexual Dysfunction in Infertile Women With PCOS Undergoing Fertility Treatment Phase: | Start Date: January 1, 2022 Overall Status: Recruiting | Estimated Enrollment: 186 Overview Infertility, defined as the inability to become pregnant after one year of regular unprotected sexual intercourse. It is estimated that around 20 % of couples suffer from infertility with prevalence rates of infertility differing substantial among countries . Sexual function in females is very complex and is affected by many factors. The prevalence of sexual dysfunction is higher in infertile patients compared to the normal population . Whether sexual dysfunction is the cause or consequence of subfertility is difficult to establish. For instance, sexual dysfunction might result in decreased coital frequency compounding the issue of subfertility due to reduced exposure. On the other hand, the psychological pressure to get pregnant stemming from sex on demand could result in a reduction in enjoyment of sex aggravating sexual dysfunction. Indeed, situational sexual dysfunction and loss of a couple's intimacy may occur as a consequence of timed intercourse where focus for coitus is no longer pleasure but conception . Study Type Study Type: Observational Study Design Time Perspective: Cross-Sectional Study Primary Completion Date: June 1, 2022 Detailed Description Our work is an observational analytic cross-sectional study that included an Egyptian convenient sample of 186 females with primary infertility due to polycystic ovary syndrome. Patients aged 18-35 were recruited from Kasr Al-Ainy Gynecology Clinic (Infertility Clinic) Medicine Hospital, Faculty of Medicine, Cairo University. They were diagnosed with primary infertility and polycystic ovary by Rotterdam criteria . Patients with medical conditions (apart from PCOS complications like type II diabetes, obesity and metabolic syndrome) or receiving antidepressant therapy were excluded. Females with other causes of infertility associated with PCOS (e.g uterine factors, tubal factors) were not included. Patients with history of psychotic disorders or substance abuse were excluded. All patients approved to participate in the study and signed an informed consent to confirm this approval. Intervention : A- Gynecological Assessment : Using Kasr Al Ainy infertility sheet that include clinical history taking of amenorrhea or oligomenorrhea. assessment of age years and type of infertility, medical history, surgical history, weight , height, history of hirsutism, ultrasound finding, speculum examination and hormonal profile including (FSH, LH, E2, Prolactin, TSH and progesterone) also history of any surgical intervention and type of fertility treatment were obtained . Vaginal ultrasound and speculum examination were done to every patient. PCOS was diagnosed using Rotterdam criteria based on identifying at least two of the following three features: oligo/anovulation , hyperandrogenism: clinical (hirsutism or male pattern alopecia) or biochemical (raised free androgen index or free testosterone) & polycystic ovaries on ultrasound (a follicle number per ovary of > 10). Other etiologies must be excluded such as congenital adrenal hyperplasia, androgen secreting tumours, Cushing syndrome, thyroid dysfunction and hyperprolactinaemia . Laboratory work up including : 1. LH/FSH ratio: Many women with PCOS have LH and FSH levels still within the 5-20 mlU/ml range, but their LH level is often two or three times that of the FSH level 2. Prolactin level: (1-20 ng/mL) 3. Estradiol level : (ranging from 20-400 pg/mL in healthy normal women) 4. TSH level : (normally 0.35- 5 μU/mL). TSH is checked to rule out other problems, such as an underactive or overactive thyroid, which often cause irregular or lack of periods and anovulation . All blood samples (FSH-LH- E2 -PRL-TSH) were obtained at the second day of menstrual cycle in all women within the last six months before the interview B-Data collection tool was a questionnaire completed through interviews in private meetings by the researcher. The questionnaire was composed of two parts: demographic characteristics and information about sexual relationship (such as frequency of sexual contacts per week, satisfaction with sexual and non-sexual relationships). Sexual dysfunction measurement were done by gynecologists/sexologists in infertility center on the basis of a diagnostic interview according to the Female Sexual Functioning Index (FSFI) The FSFI is a reliable test for the assessment of sexual function in women. The Arabic version of this test, was used. The FSFI is comprised of six domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) with score ranges of 0 (or 1) to 5. The total FSFI score ranges from 2.0 to 36. The translated version of the FSFI test was used in this study. All questions in the FSFI questionnaire were explained by the physician one by one, and they were filled in a suitable and silent environment where patients could comfortably share such intimate information. Analysis of data will be done by using SPSS ( statistical program for social science version 23 ) . Quantitative data will be statistically represented in terms of mean ± standard deviation (± SD) while categorical data will be represented as frequency and percentage. Comparison of quantitative data will be done using (Mann Whitney U ) test for independent samples while categorical data will be compared using ( Chi squared test ) or ( Fisher exact test ) when appropriate. Correlation coefficient test will be used to rank different variables against each other where a probability value (p value) > 0.05 will be considered statistically insignificant , a probability value (p value) < 0.05 will be considered statistically significant & a probability value (p value) < 0.001 will be considered statistically highly significant. Interventions Other: FSFI questionnaire The FSFI is a reliable test for the assessment of sexual function in women. The Arabic version of this test, was used. The FSFI is comprised of six domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) with score ranges of 0 (or 1) to 5. The total FSFI score ranges from 2.0 to 36. The translated version of the FSFI test was used in this study. All questions in the FSFI questionnaire were explained by the physician one by one, and they were filled in a suitable and silent environment where patients could comfortably share such intimate information Clinical Trial Outcome Measures Primary Measures prevalence of sexual dysfunction in PCOS Time Frame: 6 months prevalence of sexual dysfunction in PCOS Secondary Measures Risk factors for sexual dysfunction in PCO Time Frame: 6 months Risk factors for sexual dysfunction in PCO Relation of sexual dysfunction to different fertility treatments in PCO Time Frame: 6 months Relation of sexual dysfunction to different fertility treatments in PCO Participating in This Clinical Trial Inclusion Criteria 1. Infertility . 2. PCOS. 3. Age from 18-35 years Exclusion Criteria: 1. chronic medical condition previously associated with FSD (e.g. diabetes mellitus and cardiovascular diseases, such as hypertension) or using antidepressant medications. 2. Refusing participation in study. 3. Other causes of infertility Gender Eligibility: Female Minimum Age: 18 Years Maximum Age: 35 Years Are Healthy Volunteers Accepted: Accepts Healthy Volunteers Investigator Details Lead Sponsor Cairo University Provider of Information About this Clinical Study Principal Investigator: Bassiony Dabian, lecturer of obstetrics and gynecology – Cairo University References World Health Organization. Report of a WHO meeting. In: Vayena E, Rowe PJ, Griffin PD, editors. Current practices and controversies in assisted reproduction. Geneva: Byword Editorial Consultants; 2002. p. 1-396 Fassino S, Piero A, Boggio S, Piccioni V, Garzaro L. Anxiety, depression and anger suppression in infertile couples: a controlled study. Hum Reprod. 2002 Nov;17(11):2986-94. doi: 10.1093/humrep/17.11.2986. Malin M, Hemmink E, Raikkonen O, Sihvo S, Perala ML. What do women want? Women's experiences of infertility treatment. Soc Sci Med. 2001 Jul;53(1):123-33. doi: 10.1016/s0277-9536(00)00317-8. Ercan CM, Coksuer H, Aydogan U, Alanbay I, Keskin U, Karasahin KE, Baser I. Sexual dysfunction assessment and hormonal correlations in patients with polycystic ovary syndrome. Int J Impot Res. 2013 Jul-Aug;25(4):127-32. doi: 10.1038/ijir.2013.2. Epub 2013 Feb 14. Keye WR Jr. Psychosexual responses to infertility. Clin Obstet Gynecol. 1984 Sep;27(3):760-6. doi: 10.1097/00003081-198409000-00024. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004 Jan;81(1):19-25. doi: 10.1016/j.fertnstert.2003.10.004. 2 June 2022 Conditions in This Trial Sexual Dysfunction PCOS Interventions in This Trial FSFI questionnaire Condition MeSH Term(s) Infertility Information Source ID Number: 12A34 NCT Identifier: NCT05402800 NCT05402800, June 28, 2023
https://trialbulletin.com/lib/entry/ct-05402800
(PDF) Psychological distress, depression and generalised anxiety in Turkish and Moroccan immigrants in Belgium PDF | This study assesses the prevalence of and risk and protective factors for common mental health complaints in a general population sample of... | Find, read and cite all the research you need on ResearchGate Psychological distress, depression and generalised anxiety in Turkish and Moroccan immigrants in Belgium September 2008 Social Psychiatry and Psychiatric Epidemiology 44(3):188-97 DOI: 10.1007/s00127-008-0431-0 Abstract This study assesses the prevalence of and risk and protective factors for common mental health complaints in a general population sample of Turkish and Moroccan immigrants living in Belgium. Focus is on between- and within-group variation. The study is based on pooled data from the Belgian Health Interview Surveys 2001 and 2004 and focuses on the Turkish and Moroccan immigrant population aged 18-65 (N = 147 Turks, N = 359 Moroccans). Mental health status is assessed with the General Health Questionnaire-12 and the Symptom Checklist 90-R subscales for depression and generalised anxiety. Risk and protective factors considered are gender, age, household type, labor market position, educational level, household income, homeownership, being foreign- or native born and social support. Between-group variance was not significant. Within-group analysis showed significant effects of gender and social support. Although not significant, the results suggested positive associations between social adversity and mood status. In addition, there was a tendency for higher risks for psychological distress, depression and generalised anxiety in foreign-born as compared to Belgian-born Turkish and Moroccan immigrants. ORIGINAL PAPER Katia Levecque Æ Ina Lodewyckx Æ Piet Bracke Psychological distress, depression and generalised anxiety in Turkish and Moroccan immigrants in Belgium A general population study Received: 2 January 2008 / Accepted: 31 July 2008 / Published online: 25 August 2008 j Abstract Background This study assesses the prevalence of and risk and protective factors for common mental health complaints in a general population sample of Turkish and Moroccan immi- grants living in Belgium. Focus is on between- and within-group variation. Methods The study is based on pooled data from the Belgian Health Interview Surveys 2001 and 2004 and focuses on the Turkish and Moroccan immigrant population aged 18–65 ( N = 147 Turks, N = 359 Moroccans). Mental health status is assessed with the General Health Questionnaire—12 and the Symptom Checklist 90-R subscales for depression and generalised anxiety. Risk and protec- tive factors considered are gender, age, household type, labor market position, educational level, house- hold income, homeownership, being foreign- or native born and social support. Results Between-group variance was not significant. Within-group analysis showed significant effects of gender and social sup- port. Although not significant, the results suggested positive associations between social adversity and mood status. In addition, there was a tendency for higher risks for psychological distress, depression and generalised anxiety in foreign-born as compared to Belgian-born Turkish and Moroccan immigrants. j Key words depression – anxiety – community sample – risk factors – immigrants Introduction In the United States, early population studies on the relationship between migration and mental health suggested that there was a strong association between migrant status and psychological disorder, but more recent research reveals contradictory results, with some studies suggesting an increased risk, whereas others demonstrating a lower risk for psychiatric dis- order among immigrants than among native-born [ 28 , 46 ]. The early studies highlighted the stresses of migration and the disadvantages faced by immigrants, contrasting these with the positive effects of accultur- ation and assimilation into mainstream society of the United States [ 20 ]. More recent findings however, challenge these long standing tenets in psychiatry and psychology by finding lower levels of psychopathology in first-generation immigrants as compared to immi- grants born in the host country [e.g. 10 ]. This rising new evidence suggest that the intergenerational process of adjustment to American society leads to increasing risk for psychiatric disorder, while retention to the cultural traditions socialized into in the home country has a positive effect on mental health [ 21 ]. European research on mental disorders in immi- grants is less developed. Most studies carried out are clinical, mostly limited to private medical practices or health care facilities and usually reveal higher preva- lences and higher admission rates in (some) immi- grant groups [ 13 , 33 ]. Most studies are directed at less common conditions such as schizophrenia [e.g. 27 ]; for mood disorders, empirical evidence is more limited and inconclusive [a.o. 53 , 58 , 65 ]. Knowledge on mental health gathered through patient studies SPPE 431 K. Levecque Research Foundation – Flanders Brussels, Belgium K. Levecque ( & ) Æ P. Bracke Dept. of Sociology, Faculty of Political and Social Sciences University of Ghent Korte Meer 3-5 9000 Ghent, Belgium Tel.: +32-9/264-8436 Fax: +32-9/264-9198 E-Mail: [email protected] I. Lodewyckx Centre for Migration and Intercultural Studies University of Antwerp Antwerp, Belgium Soc Psychiatry Psychiatr Epidemiol (2009) 44:188–197 DOI 10.1007/s00127-008-0431-0 should be seen as having some limitations due to the use of small and, frequently, biased samples [ 14 ]. Bias may, among others, be related to group differences in treatment-seeking and admission practices [ 65 ]. Epidemiological studies informing on the mental health status of immigrants in the general population of European countries are still very scant [ 14 ]. According to Carta et al. [ 14 ] there is little data at our disposal with regard to the level of mental health among those who are culturally different owing to inadequate systems of registration. These systems have recently started to be modified in some coun- tries in order to provide with useful data. Never- theless, some epidemiological non-patient studies on the mental health status of immigrants do exist, but its distribution across European countries is patchy [ 14 , 16 ] and only a few studies actually inform about depression and anxiety [see e.g. 5 , 15 , 34 ] for exceptions. Those that do, usually report higher prevalence rates of affective problems in immigrants than in natives. Mavreas and Bebbington [ 44 ] sug- gest a greater risk of anxiety disorders in southern and of depression in northern European countries. Only in a handful of countries, nationwide or re- gional epidemiological studies are available on immigrants [ 14 ]. Recently, an epidemiological study by Levecque et al. [ 38 ] reported on generalised anxiety and depression in the native and immigrant general population in Belgium. The data used was the nationally representative Health Interview Survey conducted in 2001. It was found that all European immigrant groups considered showed no differential pattern in mental health status as compared to Bel- gian natives, but immigrants originating from Turkey and Morocco reported significantly higher levels of depression and anxiety (as assessed with the relevant SCL 90-R subscales) [ 37 ]. Multivariate analyses showed the higher risk for anxiety to be attributable to lower socioeconomic status, suggesting a signifi- cant role for stress-related conditions and processes such as social exclusion, impoverishment, discrimi- nation and racism. In the case of depression, multi- variate findings showed only a partial decrease in risk, leaving a significant association with Turkish or Moroccan origin. In the Netherlands, a neighbouring country of Belgium, a similar finding was reported for Turkish and Moroccan elderly immigrants [ 68 ]. In the present study we use the same dataset as Levecque et al. [ 38 ], but extend their analysis in several ways. First, focus will not only be on depres- sion and generalised anxiety as assessed with the relevant subscales of the Symptom Checklist 90-R, but also on mental health complaints indicated by the 12- item version of the General Health Questionnaire. Second, we consider the same classic list of risk fac- tors (i.e. gender, age, household type, educational le- vel, labor market position, home ownership and income), but in line with more recent American evi- dence on the link between migration and mental health, we add information on nativity, indicating whether one is foreign-born or born in Belgium. Third, as international epidemiological research has consistently shown social support to be a significant protective factor in the development of common mental health problems, we add information on per- ceived social support. As a buffering factor, social support may be especially relevant in immigrant communities [ 12 ]. Finally, we concentrate solely on the Turkish and Moroccan immigrant population, as former analysis has shown these groups to be espe- cially at risk for depression and anxiety. Focussing on the Turkish and Moroccan immigrants, we first assess whether the between-group variation in mental health is significant, thus asking whether differentiation between both immigrant communities in further mental health analysis is necessary. Although there are many similarities in migration history and in the current cultural, demographic and socioeconomic profile of Turkish and Moroccan immigrants, critical differences remain that might be relevant for the development of common mental problems [ 7 , 8 , 35 ]. Similarities in patterns of migration history, for example, show both groups to come from mainly rural areas in an Islamic country of origin. Originally, migration to Belgium started in the 1960s within the context of labor market shortage, but since 1973 most migration flows from Turkey and Morocco are mainly organized within the context of family reunions and marriage [ 52 , 64 ]. Most immi- grants from the same region in the home country have moved to the same region of destination in Belgium, resulting in ‘transplanted communities’. According to Surkyn and Reniers [ 63 ], Turkish immigrants believed in the temporary character of their stay in Belgium, while Moroccans saw it as a steadier move. As concerns marriage migration and second generation immigrants of Turkish and Moroccan origin, recent findings show that both communities differ significantly in the choice of marriage partner: nearly 70% of the Turkish immi- grants choose a partner from the country of origin, while almost 50% of the Moroccan second generation immigrants opt for an inter-ethnic marriage [ 64 , 66 ]. Concerning motherhood, Turkish mothers begin and end the family-forming process earlier, resulting in lower Turkish fertility rates [ 41 , 57 ]. Concerning socioeconomic status, research has shown significant between-group differences on some aspects (e.g. higher illiteracy rates in first generation Morrocans, 50% home owners in the Turkish community versus 29% in the Moroccan) [ 48 , 69 ], but a lack of differ- entiation on others (e.g. poverty rate, housing and living conditions, educational level in second gener- ation migrants, labor market position) [ 49 , 69 ]. In addition, there is a strong gender dimension on the labor market, resulting in an extremely low activity rate for Turkish and Moroccan women. 189 Methods j Sample Analyses are based on the pooled data of the 2001 and 2004 health interview survey (HIS), which are the second and third national health surveys to be organised in the general population in Bel- gium. An extensive description of the methods, sampling frame and respondents of both surveys is provided elsewhere [ 61 ]. Suffice it to say that these cross-sectional surveys are representative of the population in private and collective households and that they are based on a multistage stratified cluster sample (pooled N = 12,057 households, 26,601 individuals). Both surveys provide information on respondents physical and mental health and on their use of healthcare resources. Household characteristics are assessed with a household questionnaire; individual characteristics are assessed by means of a verbal and written questionnaire administered to up to three additional household members. Household members in psychiatric care were not contacted. All questionnaires are available in Dutch, French, German and English, but when necessary, help with translation was provided. Response rate at household level is 61.4% in both survey years. Information on mental health is col- lected by written questionnaire for all participating respondents aged 15 or more. Proxies were not allowed. In our analysis, we restrict the sample to the population aged 18–65 because of the small number of elderly immigrants. This restriction results in a sample of N = 147 Turkish and N = 359 Moroccans immigrants. j Mental health status Mental health is assessed with the 12-item version of the general health questionnaire (GHQ) and the symptom checklist (SCL) 90-R subscales for depression and anxiety. All scales are frequently used in international epidemiology and have shown good psychometric properties within a general population context e.g. [ 39 , 45 , 56 ]. The GHQ asks about symptoms that are experienced more or less than usual in the recent few weeks [ 22 ], while the SCL-R subscales tap the severity of symptoms suffered by an individual in the week prior to the interview [ 18 ]. In the present study, we use the 12-item version of the GHQ, which has several indicators of severe depression. From the SCL-R, we use the depression subscale (13 items) and the subscale for generalised anxiety (10 items). (Sub)- scale scores are computed as advised by their developers. Reli- ability of the GHQ and both SCL-R-subscales in our sample was accurate, as indicated by a Cronbach alpha of at least 0.85 for the GHQ and at least 0.92 for both SCL-R-subscales in the two immi- grant groups. Cultural validity of the scales is assumed based on published GHQ- and SCL - research in Turkey [e.g. 23 , 25 , 30 , 31 , 50 ]. Except for Levecque et al. [ 28 ], no study for Moroccan immigrants or for the Moroccan context could be found. Although both the GHQ and the SCL-R are dimensional scales, we opt for the use of thresholds in order to focus at the most severe mental health complaints in the Turkish and Moroccan immigrant population. For the GHQ-12, international literature suggests a cut- off at a crude scale score of 2, indicating psychological distress [ 22 ]. For the SCL-R-subscales, there are no validly established cut-offs [ 55 ]. We therefore opt for a 90% severity threshold: if a subscale score is above the 90th percentile in the scale score distribution in the general population in Belgium, we consider the complaints to be severe and label them as expressions of depression or anxiety [see also 38 ]. j Risk factors Turkish or Moroccan immigrant status is the main variable in our study. In health research, migrant status is often determined based on nationality [e.g. 29 ], but since the drastic change in the 1990s to Belgian legislation on naturalisation, current nationality is no longer a good indicator for the identification of one’s foreign roots. Under the new law, large numbers of immigrants from Turkey and Morocco have acquired Belgian nationality and descendents of immigrants now automatically receive Belgian nationality when they are born on Belgian soil. An alternative way of differentiating according to region of origin is to consider country of birth [e.g. 47 ], but if research focus is not on first-generation immigrants only, this too is an inadequate strategy since it would categorise large numbers of individuals with Turkish or Moroccan roots as Belgian. In the present study, we opt for a combination of infor- mation on current nationality and country of birth in order to get a more accurate identification of Turkish and Moroccan immigrants [see also 38 , 42 ]. Next to immigrant status, we look at eight additional risk fac- tors, which previous research has found to be relevant for common mental health problems in the general population in Belgium and elsewhere [see 7 , 9 , 35 , 36 , 43 , 70 ]. We consider three sociodemo- graphic factors: gender (two categories: male, female), age (in years) and household type (five categories, combining information on cohabitation status and dependent children). As for the socio- economic risk factors, we look at educational attainment (four categories: low/none, medium, high and still studying), labor market position (four categories: employed, unemployed, sick/ disabled, other inactive), homeownership (two categories: owners, renters) and equivalent household income (five categories: <750, 750–1,000, 1,000–1,500, 1,500–2,500, > 2,500 EURO). Adjustments for differences in the size and composition of households were made using the modified organization for economic cooperation and development (OECD) equivalence scale. In addition to these ‘classic’ risk factors, we also consider country of birth, indicating whether the Turkish and Moroccan immigrants were foreign-born or born in Belgium. One of the best known protective factors in the development of mental health problems, namely social support, is measured with the medical outcome social support scale (MOSS) [ 59 ]. This scale measures the perception of social support based on combined information on emotional, instrumental and affective support and positive social interaction. Scale scores range from 0 to 100, with higher scores indicating a more positive perception of social sup- port. International literature reports the scale to be highly reliable and valid [e.g. 60 , 72 ]. j Analysis procedure Prevalence rates are assessed with percentages; between-group differences were calculated with v 2 analyses, using P = 0.05 as the level set to determine statistical significance. Profiles of risk and protective factors are established using multivariate logistic regression. Odds ratios (ORs) are calculated, as are 95% confidence intervals (CIs). In order to ensure that the sample data represents the general population of interest, weights are applied to adjust for the probability of selection within the household, for municipality, province and region and for interview timing [ 61 ]. The significance of individual indicators is assessed by means of the Wald v 2 test. The overall goodness of model fit is assessed on the basis of the Likelihood Ratio v 2 test [ 26 ]. We also report the Nagelkerke R 2 [ 1 ]. Results j Prevalence As Table 1 shows, Turks and Moroccans are worse of in terms of psychological distress, severe depression and severe generalised anxiety as compared to the Belgian population. Differences between the Turkish and Moroccan immigrant population are not signifi- cant. 190 j Risk and protective factors Next, we consider whether the classic risk and pro- tective factors identified in international mental health research, are also relevant in explaining mental health complaints in Turkish and Moroccan immi- grants. Comparisons in terms of these factors are reported in Table 2 . As in Table 1 , we add informa- tion on the native population. Table 2 shows that Turkish and Moroccan immi- grants are significantly younger, less single and/or childless and have a lower socioeconomic status as compared to the native population. There is no sig- nificant difference in gender composition or in per- ceived social support. When looking at the between- group variation, the Turkish and Moroccan commu- type, educational level and home-ownership. There is no significant difference in terms of gender, age, labor market position, income and the percentage of for- eign-born migrants. Because of the small number of retired immigrants in our sample, the categories ‘re- tired’ and ‘non-active’ are combined in further analyses, of which results are shown in Table 3 . This table informs on the risk and protective factors in the development of psychological distress, depression and anxiety in the Turkish and Moroccan immigrant community. Table 3 shows that for all common mental health problems considered, only gender and social support are statistically significant. In the case of social sup- port, results confirm the international pattern that suggests lower prevalence rates of psychological dis- tress, depression and anxiety when affective, instru- mental and emotional support and possibilities for positive interaction are available [e.g. 17 , 32 ]. Con- cerning gender, Table 3 reports a partial OR = 2.20 for psychological distress, and OR = 3.82 and OR = 4.47 for depression and anxiety respectively. These gender differences in mental health complaints [ 51 ], but compared to former evidence for the general population in Belgium [ 7 , 8 , 36 , 70 ], the ORs in the Turkish and Moroccan immigrant population are much larger, especially for depression and generalised anxiety. Although the other risk factors in Table 3 are not statistically significant, a similar pattern for all three mental health statuses can be observed for country of birth: a tendency to more mood problems in foreign- born as compared to Belgian-born immigrants. In terms of socioeconomic status, our findings suggest a small but positive association with educational level, a higher risk of complaints when sick or handicapped, and less mood problems when financially better off. Discussion j Key findings In this study, we concentrated on psychological dis- tress, depression and generalised anxiety in the Turkish and Moroccan immigrant population that has settled in Belgium. We first assessed prevalence rates and confirmed the finding by Levecque et al. [ 38 ] that rience higher levels of psychopathology as compared to Belgian natives. The within-group variation in the immigrant sample was found to be non-significant for all health indicators used. Levels of psychological distress, as assessed with the GHQ-12, were found to be as high as 32%, a percentage resembling the 33.4% reported for the same scale for a general population sample of Turkish immigrants in the Netherlands, a neighbouring country of Belgium [ 5 ]. In the second phase of our study, we tested whe- ther the classic risk and protective factors identified in international epidemiology were also significant determinants for psychopathology in Turkish and Moroccan immigrants. In line with international lit- erature, our findings for gender as a risk factor, and social support as a protective factor, were statistically significant. All other covariates in our model missed significance at the P < 0.05-level, due to a limited statistical power. However, the findings suggest some tendencies in the risk profile for all three mental health problems considered. of psychological distress, depression and anxiety in the adult population (aged 18–65) in Belgium, 2001 and 2004: differentiated according to region of origin (absolute N , weighted %) Region of origin Belgium (B) ( N = 11,747) Turkey (T) ( N = 147) Morocco (M) ( N = 359) Difference (B–T–M) ( P > v 2 ) Difference (T–M) ( P > v 2 ) Psychological distress (GHQ 2+) 26.42 31.90 32.05 # NS Depression (SCL-R subscale 90% severity threshold) 9.14 15.41 14.21 * NS Anxiety (SCL-R 90% severity threshold) 10.41 17.04 15.17 * NS Belgian Health Interview Survey 2001 and 2004—own calculations NS not significant # P < 0.05; * P < 0.01 a Age and sex direct standardization with the Belgian population as reference 191 Concerning age, the findings suggest no effect, which is consistent with prior research based on the same data-set in different population groups in Bel- gium [e.g. 35 , 36 ] and with Dutch empirical evidence on severe depression and anxiety in Turkish non- patients living in the Netherlands [ 5 ]. This lack of an age-effect should be considered independent of the generation-effect that was tested based on knowledge of one’s country of birth. While early American re- search of ethnic variation in health highlighted the positive effects of acculturation and assimilation into mainstream society [ 20 ], more recent studies chal- lenge this hypothesis by reporting lower levels of psychopathology in first-generation immigrants as compared to immigrants born in the host country [e.g. 10 , 21 ]. Our findings do not support the more recent idea of deleterious effects of acculturation since ORs for first-generation immigrants were systemati- cally higher than for immigrants born in Belgium. When turning to the tendencies reported for socioeconomic status, the pattern for educational le- vel was similar for all three emotional problems: lower health risks for individuals at school compared to adults who have already finished education. For the latter, higher educational levels seem to increase the risk for psychological distress, depression and gen- eralised anxiety. In the case of home ownership, re- sults show renters to be less depressed or experiencing generalised anxiety, but they report slightly more psychological distress as assessed with the GHQ-12. In a Dutch study on psychological dis- tress in Turkish immigrants [ 5 ], poor housing was modelled as a risk factor, but no significant effect was found. Both other socioeconomic status variables in Table 2 Characteristics of the adult population (aged 18–65) in Belgium, 2001 and 2004: differentiated according to region of origin (absolute N , weighted %, weighted mean and standard deviation SD) Region of origin Belgium (B) ( N = 11747) Turkey (T) ( N = 147) Morocco (M) ( N = 359) Difference (B–T–M) ( P > v 2 ) Difference (T–M) ( P > v 2 ) Gender (%) NS NS Male 48.05 54.42 51.81 Female 51.95 45.58 48.19 Age *** NS Mean age (year) 41.98 36.81 38.74 SD age (year) 13.12 10.24 10.89 Household type (%) *** # Single, no children 17.14 11.56 14.21 Single, with children 5.18 3.40 5.01 Couple, no children 29.07 6.80 15.60 Couple, with children 33.28 58.50 46.80 Other household type 15.32 19.73 18.38 Educational level (%) *** # None/low 31.55 54.01 41.42 Middle 32.73 16.79 21.36 High 28.44 22.63 24.60 Studying 7.28 6.57 12.62 Labor market position (%) *** NS Employed 69.02 43.07 44.51 Unemployed 7.31 25.55 18.81 Retired 10.68 0.73 4.39 Sick/handicapped 3.72 5.84 4.70 Other inactive 9.28 24.82 27.59 Equivalent income *** NS <750 EURO 4.25 6.98 5.21 750–1,000 EURO 7.01 19.38 19.94 1,000–1,500 EURO 20.04 31.78 35.28 1,500–2,500 EURO 36.13 36.43 33.13 >2,500 EURO 32.56 5.43 6.44 Home ownership (%) *** ** Owner 72.69 48.28 30.40 Renter 27.31 51.72 69.60 Country of birth (%) NA NA NS Belgium 6.80 3.90 Turkey/Morocco 93.20 96.10 Social support (scale range 0–100) NS NS Mean MOSS-score 76.62 73.71 71.61 SD MOSS-score 23.82 26.86 27.41 Belgian Health Interview Survey 2001 and 2004—own calculations NA not applicable, NS not significant # P < 0.05, ** P < 0.001; *** P < 0.0001 192 our model, namely income and labor market position, confirm the tendency of a positive association be- tween social adversity and common mental health complaints. This is in line with many other studies on ethnic variation in psychopathology [e.g. 5 , 20 ]. In our analysis, the positive association is most apparent for the income-indicator, a finding which should be seen within the context of very large poverty figures for both immigrant communities in Belgium. Poverty figures for 2001, for example, show 10.16% of Belgian natives to experience poverty, compared to 58.94 and 55.66% among the Turkish and Moroccan popula- tions respectively [ 69 ]. In both immigrant groups, processes of impoverishment are strongly related to ongoing discrimination and racism, especially on the labor market. These processes result in high levels of unemployment which might be experienced as stressful and health-damaging, especially by Turkish and Moroccan males since Turkish and Moroccan culture prescribe males to provide for their family’s financial needs [ 24 ]. This health-damaging effect of unemployment is however not suggested by the findings reported in Table 3 . When we compare our results with those of a Dutch study of Turkish male immigrants, we see a similar non-significance for depression, but higher levels of anxiety and psycho- logical distress (based on the GHQ) when unem- ployed [ 5 ]. We repeat that the lack of non-significance in our analysis is related to limited statistical power, but the possibility should not be ignored that addi- tional processes are operative, leading to a real lack of health differences in working and non-working Table 3 Risk factors for psychological distress, depression and anxiety in the Turkish and Moroccan immigrant population (aged 18–65) in Belgium, 2001 and 2004 (weighted odds ratios, 95% CI and v 2 ) Psychological distress (GHQ 2+) Depression (SCL-90-R 90% severity threshold) Anxiety(SCL-90-R 90% severity threshold) OR 95% CI P > v 2 OR 95% CI P > v 2 OR 95% CI P > v 2 Region of origin NS NS NS Morocco 1.00 1.00 1.00 Turkey 1.10 (0.59–2.06) 0.76 (0.32–1.84) 0.77 (0.33–1.81) Gender ** ** *** Male 1.00 1.00 1.00 Female 2.20 (1.14–4.23) 3.82 (1.54–9.49) 4.47 (1.84–10.84) Age NS NS NS 1.00 (0.96–1.01) 0.98 (0.93–1.02) 0.99 (0.95–1.03) Household type NS NS NS Single, no children 1.00 1.00 1.00 Single, with children 0.67 (0.13–2.54) 1.69 (0.24–11.82) 2.23 (0.32–15.52) Couple, no children 1.30 (0.43–3.98) 2.48 (0.55–11.12) 3.36 (0.75–15.03) Couple, with children 1.58 (0.52–4.84) 0.69 (0.13–3.66) 1.16 (0.24–5.70) Other household type 0.76 (0.30–1.95) 0.55 (0.14–2.12) 0.78 (0.21–2.94) Educational level NS NS NS None/low 1.00 1.00 1.00 Middle 1.09 (0.50–2.37) 1.35 (0.48–3.81) 1.29 (0.47–3.55) High 1.36 (0.66–2.80) 1.39 (0.90–3.90) 1.36 (0.58–4.08) Studying 0.84 (0.31–2.26) 0.72 (0.16–3.33) 0.65 (0.14–3.04) Labor market position NS NS NS Employed 1.00 1.00 1.00 Unemployed 1.17 (0.54–2.54) 1.51 (0.53–4.34) 0.80 (0.28–2.32) Sick/handicapped 1.98 (0.44–8.89) 4.06 (0.72–22.91) 4.28 (0.79–23.02) Other inactive 0.51 (0.21–1.20) 0.44 (0.13–1.48) 0.41 (0.13–1.26) Income NS NS NS <750 EURO 1.00 1.00 1.00 750–1,000 EURO 0.45 (0.11–1.87) 0.27 (0.04–1.95) 0.26 (0.04–1.78) 1,000–1,500 EURO 0.37 (0.09–1.59) 0.54 (0.08–3.83) 0.34 (0.05–2.33) 1,500–2,500 EURO 0.48 (0.10–2.27) 0.52 (0.06–4.29) 0.26 (0.03–2.14) >2,500 EURO 0.43 (0.07–2.79) 0.65 (0.06–7.55) 0.47 (0.05–4.93) Home ownership NS NS NS Owner 1.00 1.00 1.00 Renter 1.15 (0.59–2.24) 0.95 (0.38–2.37) 0.76 (0.32–1.82) Country of birth NS NS NS Belgium 1.00 1.00 1.00 Turkey/Morocco 3.34 (0.66–16.91) 2.15 (0.36–13.05) 1.99 (0.34–11.52) Social support *** 0.99 (0.97–0.99) 0.98 (0.97–0.99) 0.98 (0.97–0.99) : 11.85. Model fit severe depression: LR = 43.03, df = 20, P = 0.002, ) R 2 : 25.23. Model fit severe anxiety: LR = 44.27, df = 20, P < 0.001, ) R 2 : 25.11 NS not significant * P < 0.01; ** P < 0.001; *** P < 0.0001 193 Turkish and Moroccan males. One such process might be related to the fact that Turkish and Moroccan males are disproportionally employed in jobs and labor market segments that are more stressful. Another reason might be that irrespective of employment status, the Belgian welfare state secures direct and indirect money transfers to attain a certain living standard, and thus in some ways, ‘discharges’ males from the economic responsibility imposed upon them by their culture. A third possibility is related to processes of social comparison, which play a significant role in the development of mental health problems such as depression [ 71 ]. When total Moroccan communities, feelings of relative depriva- tion might be less sharp, and therefore unemployment might be less health-damaging compared to individuals in communities with high employment levels. Com- pared to their male counterparts, unemployment is not an issue for Turkish and Moroccan women, at least as far as traditional Turkish and Moroccan culture is concerned [ 24 ]. Women are mostly responsible for the affairs within their family and unemployment suits this role. In Table 3 , house-keeping is catego- rized as ‘non-active’ on the labor market. Results show low levels of psychological distress, depression and anxiety, when controlled for the other variables in the model. This lack of a significant employment ef- fect on the mental health status of Turkish and Moroccan women is consistent with findings for Turkish women in the Netherlands [ 5 ]. Finally, we want to stress that gender differences in depression and anxiety in the immigrant population are nearly double those found in the native Belgian population. This is remarkable because most of the abovementioned labor market related processes of immigrant men than immigrant women, leading us to expect a diminished, rather than an enlarged gen- der ratio in depression. This brings us to speculate about gender specific social processes influencing the mental health of both immigrant men and women not directly linked to their socio-economic position. First, one cannot rule out the influence of emigration as a selective process. The emigration of Turkish and Moroccan men is to a large amount based on eco- nomic motives, while the emigration of Turkish and Moroccan women is more function of family reunion [ 40 ]. Hence, these selection effects differentially affect men and women. One study found that emigration based on economic motives favors persons who are more work-oriented, who have higher achievement and power motivation, but lower affiliation motiva- tion and family centrality [ 6 ]. So, selection processes could be present favoring men who are less, and women who are more vulnerable for internalizing problem behavior. Second, the migration process it- self, as far as it concerns the disruption of family ties, could differentially affect women and men, as in tra- ditional strong male breadwinner systems the mental health of women as kin keepers is more strongly linked to the quality and strength of the relationships with kin. Finally, a post-migration acculturation process amplifying the imbalance of power among women and men should be considered as another possible reason. The lack of independent control over economic resources linked to the presence of male dominated kinship based ethnic ties and the sense of rupture women experience as a result of the feelings of disconnectedness linked with attempts to maintain membership in both their country of origin and their country of settlement [ 54 ], probably accounts for a substantial part of the enhanced prevalence of depression among Turkish and Moroccan immigrant women. Most of these post hoc explanations are mere speculations. Needless to say that, as concerns the nexus between emigration to Europe, gender and mental health, the adage ‘more research is needed’ is more than just loose saying. j Implications Our findings call for further research, both cross-sec- tional and cohort studies, as well as intervention studies in order to discover the complex network of influences of migration on common mental health problems. When focussing on the Turkish and Moroccan immigrant populations, gender-specific is- sues should be given special attention, since our analysis showed high gender-differences in psycho- pathology. Although additional analyses showed no significant gender-ethnicity interaction effect in addition to both main effects (results not shown), the high ORs reported for gender in Table 3 are remark- able especially when compared to the findings on depression in Turkish and Moroccan immigrants in the Netherlands based on data on first hospital admissions. In their Dutch study, Selten, van Os and Nolen [ 58 ] found significantly higher first admission rates for Turkish and Moroccan males as compared to Dutch natives, but significantly lower health services use in Turkish and Moroccan females. If this pattern of service use is also relevant for the Belgian context, then our findings may indicate a seriously under serving of Turkish and Moroccan female immigrants suffering common mental health problems. This possible un- derserving should be studied thoroughly, given special attention to ethnic and gender-related differentials in psychiatric diagnoses or treatment, and thresholds experienced in help-seeking processes. While some of these thresholds, such as fear for stigmatisation, arguably apply to all population groups, Turkish and Moroccan immigrants might in addition have to contend with culture-bound factors (e.g. language barriers) or aspects that are related to their socioeco- nomic position (e.g. financial thresholds). From a public health perspective, the higher rates of psychological distress, depression and anxiety in 194 Turkish and Moroccan immigrants underline the need for an answer to several urgent questions. One such question is whether special health or social inclusion- programmes are required, a question that is becoming more prominent with rising numbers of Turkish and Moroccan immigrants due to marriage migration and high fertility rates. Another question is how demo- graphic changes in the composition of the Turkish and Moroccan community, with rising numbers of elderly immigrants, will affect levels of psychopathology and health service use in the near future. j Strengths and limitations Our study has a number of strengths and limitations. The main strength is that it provides nationwide community-based evidence on the prevalence and determinants of psychological distress and severe complaints of depression and generalised anxiety in two immigrant populations in a European setting. Such evidence is scarce since most European studies on the link between migration and health concentrate on less common mental disorders, and more often than not, use data on patients which may influence the results due to ethnicity-related and country-spe- cific differences in treatment-seeking and admission practices [ 13 , 65 ]. Our study focuses on Turkish and Moroccan immigrants in the general population, two population groups that have not only formed large communities in Belgium, but also in several other European countries, including France, Germany, the Netherlands, Spain and Italy. Another important strength is that our study identifies one’s immigrant status based on informa- tion regarding nationality as well as country of birth [see also 38 ]. To consider country of birth only would limit the analysis to first-generation immigrants, thereby neglecting a growing number of subsequent- generation immigrants. On the other hand, to consider current nationality only would inadequately reflect the social reality of immigrants in Belgium, especially since recent legislative change has resulted in many people of foreign origin acquiring Belgian nationality. The combined information on nationality and country of birth enabled us to identify Belgians with foreign roots as immigrants. However, people with foreign roots who were born in Belgium and who hold Belgian nationality could not be identified as immigrants. It is unclear whether there are significant differences be- tween identified and non-identified second or third generation immigrants in terms of acculturation and other processes or characteristics that are relevant to depression and anxiety. If non-identified immigrants are worse off, then reported prevalence rates and ORs may be underestimations; if they are better off, actual risks may be smaller than those reported. The main limitation of our study is related to the fact that for the SCL-R scales, no established cut-offs are available [ 55 ]. We therefore opted for an indica- tion of severe depression and anxiety on the basis of a pragmatic 90% severity threshold. This strategy en- abled us to look at severe syndromes without claiming to assess psychiatric disorder, but has the potential drawback of miscategorising individuals, thereby compromising our study’s ability to identify valid risk factor patterns. However, additional analysis based on a 95 and 80% threshold shows the reported risk profile to be robust (analysis not shown). Another point to consider relates to the cross-cul- tural validity of the scales used and the culture-bound expression and subjective experience of the syndromes being studied. These may have introduced some bias in our analyses [see 2 ]. In research on Turks and Moroccans, a recurrent consideration is that they fre- quently use somatic complaints as a metaphor and as a pathway to medical care for mood disorders [ 11 , 19 ] and that they may show a tendency to exaggerate symptoms [ 67 ]. If somatisation is in order, this may have led to an underestimation of prevalence rates, while exaggeration of symptoms may have introduced overestimation of levels of experienced psychopathol- ogy. However, if both tendencies are equally present in both immigrant communities, the comparisons between and within both population groups were not affected by these forms of bias. The same holds for possible bias introduced by differential familiarity with European idioms of mental health in subsequent generations of immigrants, leading to differential re- sponse behaviour to the survey questions used to assess psychiatric problems. If such differential response behaviour exist, this may have biased reported levels of psychopathology for the different immigrant genera- tions, but since the proportion of first-generation mi- grants in our sample is not significantly different in both migrant communities, our comparisons between the Turkish and Moroccan communities remains unaffected. A third limitation of our study is that the written questionnaires used for gathering mental health information, were only available in Dutch, English, French or German. Although help with translation was allowed, this fact may have skewed our sample towards more acculturated immigrants. If the classic acculturation hypothesis of positive effects on mental health is correct, then our prevalence estimates may underestimate the levels of psychopathology experi- enced in first-generation immigrants and overesti- mate those in later generation Turks and Moroccans. However, recent studies on the positive or negative effect of the acculturation process have come to inconsistent conclusions [ 21 ]. A final limitation pertains to the overall response rate of 61.4% for the total Belgian Health Interview Survey, which falls well in the range of 52–95% ob- served in other European health interview surveys [ 3 ]. For the specific age groups considered in our study, the actual response rate was somewhat larger, varying from 63.0 to 70.6%. Analysis also showed non-EU citizens to 195 be more inclined to participate than Belgians or EU- immigrants, and less than 2% of non-response was due to language problems [ 61 ]. Although the link between participation and survey error is not straightforward and studies with low response rates may in fact be less biased than studies with high response rates [ 62 ], selection bias related to nationality could have been an issue in our study, but research by Lorant et al. [ 43 ] has shown it is not. What should be taken into account, is selection bias related to socioeconomic status: com- ... The only Belgian study [49] was performed on a national community sample. The study showed that the prevalence of high-severity depressive disorder (90% cut-off on the SCL-90 depression subscale) was higher among both Turkish (15.4%) and Moroccan immigrants (14.2%) than among native Belgian (9.1%). ... ... Turkish identity) or a low education level were more likely to report depressive symptoms. Among Dutch-and Belgian Moroccan mainly community samples, about half of the studies found female sex positively related to depressive symptoms [37,41, 49, 65]. On the other hand, also about the half of the studies examining large Moroccan-Dutch and Turkish community and patient populations of Germany, The Netherlands, and the UK found sex neither to be related to nor predictive of depressive symptoms [43,52,56,59,60,63,[70][71][72]. ... ... The vast majority of the studies examining age in Turkish or Moroccan groups found no relationship with depressive symptoms in Belgium [49] , the Netherlands [43,60,71], Germany [50,56,59,63,[72][73][74] and UK [75]. The remaining studies showed mixed results, stating older age as a predictor of higher depressive symptomatology in Turkish-German [51, 53, 57] -Dutch populations [37]. ... Depression among Turkish and Moroccan immigrant populations in Northwestern Europe: a systematic review of prevalence and correlates BMC PSYCHIATRY Gabriela Sempértegui Christos Baliatsas Jeroen W Knipscheer Marrie H J Bekker Background This systematic review aimed to synthesize the prevalence and correlates of depressive disorders and symptoms of Turkish and Moroccan immigrant populations in Northwestern Europe, formulating evidence-informed recommendations for clinical practice. Methods We conducted a systematic search in PsycINFO, MEDLINE, Science Direct, Web of Knowledge, and Cochrane databases for records up to March 2021. Peer-reviewed studies on adult populations that included instruments assessing prevalence and/or correlates of depression in Turkish and Moroccan immigrant populations met inclusion criteria and were assessed in terms of methodological quality. The review followed the relevant sections of the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting (PRISMA) guideline. Results We identified 51 relevant studies of observational design. Prevalence of depression was consistently higher among people who had an immigrant background, compared to those who did not. This difference seemed to be more pronounced for Turkish immigrants (especially older adults, women, and outpatients with psychosomatic complaints). Ethnicity and ethnic discrimination were identified as salient, positive, independent correlates of depressive psychopathology. Acculturation strategy (high maintenance) was related to higher depressive psychopathology in Turkish groups, while religiousness appeared protective in Moroccan groups. Current research gaps concern psychological correlates, second- and third-generation populations, and sexual and gender minorities. Conclusion Compared to native-born populations, Turkish immigrants consistently showed the highest prevalence of depressive disorder, while Moroccan immigrants showed similar to rather moderately elevated rates. Ethnic discrimination and acculturation were more often related to depressive symptomatology than socio-demographic correlates. Ethnicity seems to be a salient, independent correlate of depression among Turkish and Moroccan immigrant populations in Northwestern Europe. ... Migrant populations experience discrimination more frequently, which constitutes an additional mental health risk factor (Levecque et al., 2009; Missinne & Bracke, 2012). Although mental health problems are often identified by primary healthcare services, some studies, however, have shown that general practitioners' (GPs') therapeutic decisions regarding patients with a migration background are suboptimal: breakdowns in communication and in the relationship between a migrant patient and a GP can be a frequent source of misunderstanding, the time devoted to a consultation is often shorter for migrants, and GPs' diagnostic, treatment and referral decisions are sometimes biased by their behaviours and beliefs of migrant patients (Gaya-Sancho et al., 2021;Lepièce et al., 2014;Shannon et al., 2016). ... ... We chose to recruit Belgian GPs. Belgium is an interesting case study because firstly, it is a country with a long history of immigration and secondly, there is a higher prevalence of depression among migrants, especially those from Morocco, and this difference is more significant in Belgium than in other European countries (Levecque et al., 2009; Missinne & Bracke, 2012). The study was carried out with licensed and trainee GPs practising in two of the three Belgian regions: Brussels and Wallonia. ... Unintentional Discrimination Against Patients with a Migration Background by General Practitioners in Mental Health Management: An Experimental Study Katrijn Delaruelle Vincent Lorant Populations with a migration background have a higher prevalence of mental health problems than their native counterparts. They are also more likely to have unmet medical needs and are less frequently referred to mental health services. One potential explanation for this is that physicians, such as general practitioners (GPs), may unintentionally discriminate against migrant patients, particularly when they lack humanization. To date, no experimental study has investigated this hypothesis. This paper assesses the influence of humanization on GPs' discriminatory decisions regarding migrant patients with depression. A balanced 2 × 2 factorial experiment was carried out with Belgian GPs (N = 797) who received video-vignettes depicting either a native patient or a migrant patient with depression. Half of the respondents were exposed to a text that humanized the patient by providing more details about the patient's life story. Decisions related to diagnosis, treatment and referral were collected, as well as the time spent on each video and text, and were analysed using ANOVA. Migrant patients' symptoms were judged to be less severe than those of native patients (F = 7.71, p < 0.05). For almost all treatments, the decision was less favourable for the migrant patient. Humanization had little effect on medical decisions. We observed that GPs spent significantly more time on the vignette with the humanization intervention, especially for the migrant patients. The results indicate that ethnic differences in the management of depression persist in primary care. Humanization, however, does not mitigate those differences in medical decisions. ... This means that migrating can have a negative impact on individuals' health due to multiple physical and psychosocial tensions suffered during the migration process [10,11]. These tensions can lead to high levels of stress and an increase in risk-behaviors in immigrants, thus affecting their overall health [12][13] [14] [15] and potentially causing them to develop certain chronic diseases or worsening existing conditions. The long-term negative consequences of chronic diseases on health are widely known. ... ... The protective nature of social support networks has been seen in multiple studies, as it can also be seen in the recent revision by Garcini et al. (2016) [22]. These studies show the protective nature of social support networks in the development of diseases in immigrant populations [14, 27,28]. Social support can act as a coping agent and a mediating variable between stress due to acculturation suffered by immigrants and their health [15,29,30]. ... Psychosocial and Sociodemographic Determinants Related to Chronic Diseases in Immigrants Residing in Spain Mar 2022 Int J Environ Res Publ Health María José Martos-Méndez Luis Gómez Jacinto Isabel Hombrados-Mendieta Iván Ruiz-Rodríguez The aim of the study is to analyze the effect of the psychosocial determinants of satisfaction with social support, resilience and satisfaction with life, and the sociodemographic determinants of age, gender and length of residence on chronic diseases in immigrants living in Spain. The sample was composed of 1131 immigrants from Africa, Eastern Europe, Latin America and Asia. 47.1% were men and 52.9% were women. Most relevant results point to age as the sociodemographic variable with the highest predictive effect in the six chronic diseases analyzed. Gender, in this case female, predicts arthrosis, chronic back pain and migraine, whereas length of residence was only significant in the case of chronic allergies. Regarding psychosocial variables, resilience is a good predictor of hypertension, chronic allergies and arthrosis. However, satisfaction with social support appears to be the best predictor for chronic back pain in the regression equation, satisfaction with life being a significant variable in migraine, arthrosis, allergies and high cholesterol. Results are notably relevant for the design of preventive health programs in immigrants, as well as in ensuring their appropriate access to the health system so that their chronic diseases can be diagnosed. Given the relevance and incidence of the chronic diseases analyzed in immigrants, preventive strategies should be improved to tackle chronic diseases that can have a serious impact on immigrants’ health. ... There is a lack of data on unintentional ethnic and racial discrimination among general practitioners in Europe and too little attention has been paid to the North African population. This applies particularly to people of Moroccan descent, who constitute the largest and fastest-growing minority group in countries in the European Union (EU), including Belgium, where the Moroccan population doubled between 1991 and 2014. 1 This ethnic group is also disproportionately at risk of poor health outcomes, such as more depressive symptoms [18] and higher mortality caused by diabetes and infectious diseases [19]. ... Implicit and explicit ethnic biases in multicultural primary care: the case of trainee general practitioners Apr 2022 Duveau Camille Stéphanie Demoulin Marie Dauvrin Vincent Lorant Background General Practitioners (GPs) are the first point of contact for people from ethnic and migrant groups who have health problems. Discrimination can occur in this health care sector. Few studies, however, have investigated implicit and explicit biases in general practice against ethnic and migrant groups. This study, therefore, investigated the extent of implicit ethnic biases and willingness to adapt care to migrant patients among trainee GPs, and the factors involved therein, in order to measure explicit bias and explore a dimension of cultural competence. Methods In 2021, data were collected from 207 trainee GPs in the French-speaking part of Belgium. The respondents passed an Implicit Association Test (IAT), a validated tool used to measure implicit biases against ethnic groups. An explicit attitude of willingness to adapt care to diversity, one of the dimensions of cultural competence, was measured using the Hudelson scale. Results The overwhelming majority of trainee GPs (82.6%, 95% CI: 0.77 – 0.88) had implicit preferences for their ingroup to the detriment of ethnic and migrant groups. Overall, the majority of respondents considered it the responsibility of GPs to adapt their attitudes and practices to migrants’ needs. More than 50% of trainee GPs, however, considered it the responsibility of migrant patients to adapt to the values and habits of the host country. Conclusions This study found that the trainee GPs had high to very high levels of implicit ethnic bias and that they were not always willing to adapt care to the values of migrants. We therefore recommend that they are made aware of this bias and we recommend using the IAT and Hudelson scales as educational tools to address ethnic biases in primary care. ... Studies conducted in the USA and Europe related to immigration and mental health have indicated a relationship between maintaining social support networks for immigrants and improved mental health. The more migrants have and maintain social support networks, the fewer problems they have with their mental health (Levecque et al., 2009) . In Belgium, many formal and informal services are offered to immigrants, and they can benefit from health care services, whether registered or not, under the legal framework of eligibility. ... Social Support Effectiveness of the Mental Health of Immigrants Living in Belgium Belçika'da Yaşayan Göçmenlerin Ruh Sağlığının Sosyal Destek Etkinliği BRIT J SOC WORK Yaser Snoubar Oguzhan Zengin The increase in immigration has required social workers to focus more on this field and understand the social support systems of immigrants and the effects of their relationships with these systems to improve their effectiveness. Subsequently, this study examined the perceived social support, psychological resilience and coping strategies of immigrants living in Belgium, which has a significant immigrant population compared with its population. Using a cross-sectional design, data were collected from 289 participants living in Belgium. According to our findings, immigrants with a high perceived level of social support also have high psychological resilience. However, immigrants’ high levels of perceived social support lead to more intense use of problem-focused and emotion-focused coping styles. These findings emphasise the functionality of the social support system for immigrants and shed light on the issues that social workers should focus on when working with immigrants. ... In the study, the analyses were performed with Stata package software using the data set obtained from the questionnaires. Because logit and probit models were more useful in practice (Gujarati, 2004, p.582-583), the ordered Elif AKKAŞ, Mustafa AKKUŞ & Ömer Selçuk EMSEN [3964] probit model (Diette et al., 2018) was preferred due to its being easy in mathematical operations as the analysis method because the studies with similar subjects (Levecque et al., 2009; Doherty et al., 2008) offered differences due to frequently analyzing with logit model (Greene, 2002, p.667). ... INVESTIGATING THE RELATIONSHIP BETWEEN SOCIO-ECONOMIC CHARACTERISTICS AND DURATION OF DEPRESSION TREATMENT IN PATIENTS DIAGNOSED WITH DEPRESSION Jan 2021 Elif AKKAŞ Mustafa Akkuş ... As we found in a previous study (Toselli et al., 2018), one of the main reasons for the migration of the examined sample of women is family reunification, followed by the search for a job. It is also clear from the literature (Levecque et al., 2009) that the relationships between relatives have a significant impact in activating the migration process. In particular, an Italian demographic study, based on a recent survey conducted by the Italian Institute with the NA cultural values linked to the family (Toselli et al., 2018). ... Psychosocial health and quality of life among North African women Studies on relationships between psychosocial factors and health among North African (NA) women are scarce. This research investigated the self-perceived psychosocial well-being of NA women by a structured questionnaire and anthropometric survey examining the possible explanatory variables of their mental health in comparison to a sample of NA migrants. The association of endogenous stress, psychological well-being, discomfort, and quality of life with migrant/non-migrant status, demographic characteristics, and adiposity indices was examined. Moreover, the internal consistency of the questionnaire was tested using Cronbach's alpha. A sample of 228 women living in Tunis and Casablanca participated in a survey in Tunisia and Morocco. According to multiple regression models, migrant/non-migrant status was the best explanatory variable of well-being and quality of life, marital status, educational level and the number of children were explanatory variables of discomfort and endogenous stress. Among anthropometric variables, central adiposity was a significant explanatory variable of well-being. The comparison with women who migrated mainly from Morocco and Tunisia to Italy (NA migrants) exhibited higher weight status and central adiposity in NA migrants. The perceived stress and discomfort were the same in the two groups; the migrants, despite reporting lower psychological well-being, presented a higher quality of life than residents. Our findings emphasise the potential to promote monitoring of the psychosocial health of NA women, planning effective interventions. ... Studies in different European countries: Sweden, London, Belgium and Germany reported that migrants usually had poorer access to preventive health care offers compared to the respective native populations [104, 105] . Consequently due to infrequent use of prevention programmes they are overrepresented in emergency units [50,54]. Unfortunately at the same time many European countries still are not able to grant full equality in health care access for migrants [38] although the proportion of migrants living in Europe is quite high. ... Transcultural differences in suicide attempts among children and adolescents with and without migration background, a multicentre study: in Vienna, Berlin, Istanbul While suicide can occur throughout the lifespan, worldwide suicide is the second leading cause of death among young people aged between 15 and 29 years. The aim of this multicentre study, conducted in Austria, Germany and Turkey, is to investigate the transcultural differences of suicide attempts among children and adolescents with and without migration background. The present study is a retrospective analyses of the records of 247 young people, who were admitted after a suicide attempt to Emergency Outpatient Clinics of Departments of Child and Adolescent Psychiatry of the collaborating Universities including Medical University of Vienna, Charité University Medicine Berlin and Cerrahpaşa School of Medicine and Bakirkoy Training and Research Hospital for Mental Health in Istanbul over a 3-year period. The results of the present study show significant transcultural differences between minors with and without migration background in regard to triggering reasons, method of suicide attempts and psychiatric diagnosis. The trigger event “intra-familial conflicts” and the use of “low-risk methods” for their suicide attempt were more frequent among patients with migration background. Moreover among native parents living in Vienna and Berlin divorce of parents were more frequent compared to parents living in Istanbul and migrants in Vienna. These results can be partly explained by cultural differences between migrants and host society. Also disadvantages in socio-economic situations of migrants and their poorer access to the healthcare system can mostly lead to acute and delayed treatments. Larger longitudinal studies are needed to understand better the impact of migration on the suicidal behaviour of young people. Background Resilience has proved to be a versatile notion to explain why people are not defeated by hardship and adversity, yet so far, we know little of how it might apply to communities and cultures in low to middle income countries. Aim This paper aims to explore the notion of resilience in cross-cultural context through considering the lived experience of internal migration. Methods A sample of 30 participants with experience of migration was recruited from a low-income slum dwelling neighbourhood in the city of Pune, India. These individuals participated in biographical narrative interviews in which they were encouraged to talk about their experience of migration, their adaptation to life in their new environment and making new lives for themselves. Results Participants referred to a variety of intra-individual and external factors that sustained their resilience, including acceptance of their circumstances, the importance of memory, hope for their children’s futures as well as kindness from family friends and community members and aspects of the physical environment which were conducive to an improvement in their lives. Conclusions By analogy with the widely used term ‘idioms of distress’, we advocate attention to the locally nuanced and culturally inflected ‘idioms of resilience’ or ‘eudaemonic idioms’ which are of crucial importance as migration and movement become ever more prominent in discussions of human problems. The nature and extent of people’s coping abilities, their aspirations and strategies for tackling adversity, their idioms of resilience and eudaemonic repertoires merit attention so that services can genuinely support their adjustment and progress in their new-found circumstances. Using data from the 1991 census, the occupational outcomes of the entire Turkish and Moroccan labour force aged 18 to 29 are mapped relative to the occupational status of the Belgian labour force in the same age category. The analyses provide evidence of ethnic underachievement, taking the form of unemployment levels being disproportionately high among ethnic minorities and an overrepresentation in non-skilled labour categories. In accounting for ethnic underachievement, particular significance has been attached to the deficit-thesis, stating that the overrepresentation of ethnic minorities in unemployment is due to an ethnic labour force being underqualified and thus unable to compete with the indigenous labour force. The analyses of the census data clearly challenge the validity of the deficit argument, however, indicating that even in the case of equal qualifications the occupational outcomes of ethnic minorities fall short to those of the Belgian labour force. Additional analyses demonstrate that educational attainment and occupational outcomes of ethnic minorities are nevertheless sequentially linked. Both for the indigenous and the ethnic labour force, education thus turns out to be an important factor in gaining access to employment. In addition, the analyses suggest that characteristics such as age, educational attainment and settlement patterns are more relevant to the occupational outcomes of ethnic minorities than nationality or the age-at-immigration. Education and the transition to employment: young Turkish and Moroccan adults in Belgium Using data from two national surveys conducted in 1994-1996, the educational attainment is examined for both the second generation and the young first generation of immigrants. Different effects of migration on the educational outcomes emerge depending on the timing of the disruption in the educational career. Disruptions at more advanced stages generally result in an early ending of the educational career, especially in the case of the Turkish immigrants. The bilingual educational system in Morocco is an additional factor causing the educational careers of Moroccan immigrants to deviate from what is found for Turkish students. The unemployment spells of Turkish and Moroccan school-leavers entering the labour market are examined subsequently, expanding on the results of the previous analyses by explicitly introducing the educational trajectory of respondents as an explanatory variable. One year after leaving school, 23 percent of the Turkish and 31 percent of the Moroccan school-leavers have been unemployed without interruption. Consistent with the higher proportion of men having graduated from higher education and the stronger orientation on general subjects at the secondary level, Moroccans show a stronger inclination toward 'white collar' employment. The majority of Turkish and Moroccan school-leavers, however, are found taking up 'blue collar' occupations after leaving school. In addition, 'white collar' employment largely boils down to employment as 'clerks' or 'service workers'. A very limited number of Turkish and Moroccan school-leavers find their way to positions at the managerial level. This article examines the intensity and trends of marriages of Turks and Moroccans living in Belgium to partners from their countries of origin (‘imported partners’) and the motives for marrying such partners. Using data from the 1991 Belgian census, we show that large proportions of the migrant groups choose a partner from the country of origin and that marrying such a partner is certainly not dying out. Furthermore, the results of logit analyses reveal that marrying an imported partner is more than merely an act of traditional behavior: women may marry an imported partner in order to satisfy ‘modern’ goals.
https://www.researchgate.net/publication/23193250_Psychological_distress_depression_and_generalised_anxiety_in_Turkish_and_Moroccan_immigrants_in_Belgium
BCM-HGSC | Eric Boerwinkle, Ph.D. | page 11 Associate Director, Baylor College of Medicine Human Genome Sequencing Center Contact information [email protected] Other positions Dean, UTHealth School of Public Health M. David Low Chair in Public Health Kozmetsky Family Chair in Human Genetics Professor, Human Genetics Center and Dept. of Epidemiology Research interests The research interests of Dr. Boerwinkle encompass the Eric Boerwinkle, Ph.D. Associate Director, Baylor College of Medicine Human Genome Sequencing Center Contact information [email protected] (link sends e-mail) Other positions Dean, UTHealth School of Public Health M. David Low Chair in Public Health Kozmetsky Family Chair in Human Genetics Professor, Human Genetics Center and Dept. of Epidemiology Research interests The research interests of Dr. Boerwinkle encompass the genetic analysis of the common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes. Dr. Boerwinkle received his B.S. in Biology from the University of Cincinnati in 1980, an M.A. in Statistics (1984), and M.S. and Ph.D. in Human Genetics (1985) from the University of Michigan, Ann Arbor where he served as Senior Research Associate in the Department of Human Genetics from 1985-1986. He joined the University of Texas-Houston Center for Demographic/ Population Genetics in 1986 as a Research Assistant and became Assistant Professor in the same year. In 1991 he joined the Department of Human Genetics at the School of Public Health, University of Texas-Houston Health Science Center as Associate Professor, in 1996 was promoted to Professor, and in 1997, Director of the Human Genetics Center. He became a faculty member of the Institute of Molecular Medicine in 1996 and became Professor and Director of the Research Center for Human Genetics. Dr. Boerwinkle is a member of the American Diabetes Association and the American Society of Human Genetics. The research interests of Dr. Boerwinkle encompass the genetic analysis of common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes. This work includes localizing genes which contribute to disease risk, identification of potentially functional mutations within these genes, testing these candidate functional mutations in experimental systems, defining the impact of gene variation on the epidemiology of disease, and determining the extent to which these genes interact with environmental factors to contribute to disease risk. Activities include both statistical analysis and laboratory work. A large part of Dr. Boerwinkle's current research effort consist of localizing genes contributing to disease risk using modern genome-wide mapping methods. Success depends on keeping up with the latest genomic technical advances. The laboratory is set-up and operating as a high through-put sequencing and genotyping facility in which speed, accuracy and efficiency are monitored continuously. However, we are constantly seeking out more efficient methods to collect and manage genetic information. Dr. Boerwinkle and colleagues have completed the world's first genome-wide analyses for a variety of CAD risk factors, including diabetes and hypertension. These investigations have lead to the identification of novel susceptibility genes in both cases. Dr. Boerwinkle is particularly interested in methods for identifying potentially functional mutations within a gene region. This seemingly simple objective is made difficult because the functional mutations are expected to have small effects and are imbedded in a sea of silent genetic variation. Once nearly all of the variation is catalogued directly by DNA sequencing, individuals are genotyped for each variable site. Both novel and traditional statistical methods are applied to relate the array of genetic information to a wealth of phenotypic data. This algorithm generates "candidate functional mutations" that are then tested in an in vitro or mouse model system. Once a functional mutation has been identified, Dr. Boerwinkle's group evaluates the ability of the variable site to predict the onset of disease (e.g. myocardial infarction or stroke) above and beyond traditional risk factors. This work is carried out as part of multiple prospective studies of cardiovascular disease and its risk factors in tens of thousands of individuals representing the major American ethnic groups. Finally, he is working on experimental designs for studying genotype by environment interaction in humans. In particular, we are working on the extent to which interindividual variation in lipid lowering and anti-hypertensive medications are influenced by genetic factors. The practical objective of the research is to use genetic information to identify individuals at increase risk of disease and to design more efficacious interventions. Genetic studies are defining, at the molecular level, novel mechanisms of disease risk, onset and progression. Dr. Boerwinkle and collaborators address the localization of genes which contribute to disease risk in cardiovascular diseases, hypertension and diabetes. The methodology used involves screening of families having the disease and linking the presence of disease with known markers of the human genome. In this manner, the genomic region in which relevant mutations are located can be mapped and the relevant DNA sequenced. By assessing the structural change the mutation may have caused in the gene product (protein), it is possible to infer how it may affect biological function. In order to determine experimentally whether a mutation is functional, it is necessary to introduce the mutated gene into an animal, usually a mouse, and assess its biological effects on the animal's phenotype. Dr. Boerwinkle has participated in multiple notable discoveries since joining the Institute. Only two will be highlighted here. First, Dr. Boerwinkle's group has completed the first ever genome-wide search for genes contributing to inter-individual blood pressure levels. This initial effort has lead to the identification of an important gene (an adrenergic receptor) which influences blood pressure levels and the risk to hypertension. This is the first time that such a genome-wide approach has led to the identification of a susceptibility gene to a major cardiovascular disease risk factor. Second, Dr. Boerwinkle has participated in similar efforts to identify genes contributing to the risk of developing non-insulin dependent (type II) diabetes. In this case, however, there were no genes in the region that were suspects for the disease. A team of collaborating investigators have painstakingly characterized the genetic region and identified the mutated gene (in this case a protease). This is the first time that anyone has ever positionally cloned a gene contributing to any common chronic disease. This work is of obvious potential clinical importance. It may lead to improved prediction of those at increased risk of disease and the design of more efficacious intervention strategies. The technologies and information from the human genome project provide new tools for lessening the burden of ill-health. Dr. Boerwinkle's accomplishments in developing an internationally recognized team of investigators targeting the genetics of cardiovascular disease and its risk factors ensures a productive future and further discoveries. Publications 2017 Stray-Pedersen A,Sorte HSørmo,Samarakoon P,Gambin T,Chinn IK,Akdemir ZHCoban, et al..Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.J Allergy Clin Immunol. 2017;139(1):232-245. PubMed DOI Google Scholar Tagged Simino J,Wang Z,Bressler J,Chouraki V,Yang Q,Younkin SG, et al..Whole exome sequence-based association analyses of plasma amyloid-β in African and European Americans; the Atherosclerosis Risk in Communities-Neurocognitive Study.PLoS One. 2017;12(7):e0180046. PubMed DOI Google Scholar Tagged Nandakumar P,Tin A,Grove ML,Ma J,Boerwinkle E,Coresh J, et al..MicroRNAs in the miR-17 and miR-15 families are downregulated in chronic kidney disease with hypertension.PLoS One. 2017;12(8):e0176734. PubMed DOI Google Scholar Tagged 2016 Huang Z,Rustagi N,Veeraraghavan N,Carroll A,Gibbs RA,Boerwinkle E, et al..A hybrid computational strategy to address WGS variant analysis in >5000 samples.BMC Bioinformatics. 2016;17(1):361. PubMed DOI Google Scholar Tagged Guo D-chuan,Grove ML,Prakash SK,Eriksson P,Hostetler EM,LeMaire SA, et al..Genetic Variants in LRP1 and ULK4 Are Associated with Acute Aortic Dissections.Am J Hum Genet. 2016;99(3):762-9. PubMed DOI Google Scholar Tagged Lubitz SA,Brody JA,Bihlmeyer NA,Roselli C,Weng L-C,Christophersen IE, et al..Whole Exome Sequencing in Atrial Fibrillation.PLoS Genet. 2016;12(9):e1006284. PubMed DOI Google Scholar Tagged Yazdani A,Yazdani A,Liu X, Boerwinkle E.Identification of Rare Variants in Metabolites of the Carnitine Pathway by Whole Genome Sequencing Analysis.Genet Epidemiol. 2016;40(6):486-91. PubMed DOI Google Scholar Tagged Ogunwale AN,Morrison AC,Sun W,Dodge RC,Virani SS,Taylor A, et al..The impact of multiple single day blood pressure readings on cardiovascular risk estimation: The Atherosclerosis Risk in Communities study.Eur J Prev Cardiol. 2016;23(14):1529-36. PubMed DOI Google Scholar Tagged Harel T,Yoon WHee,Garone C,Gu S,Coban-Akdemir Z,Eldomery MK, et al..Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.Am J Hum Genet. 2016;99(4):831-845. PubMed DOI Google Scholar Tagged Jakobsdottir J,van der Lee SJ,Bis JC,Chouraki V,Li-Kroeger D,Yamamoto S, et al..Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.PLoS Genet. 2016;12(10):e1006327. PubMed DOI Google Scholar Tagged J Smith G,Felix JF,Morrison AC,Kalogeropoulos A,Trompet S,Wilk JB, et al..Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.PLoS Genet. 2016;12(5):e1006034. PubMed DOI Google Scholar Tagged Harel T,Yesil G,Bayram Y,Coban-Akdemir Z,Charng W-L,Karaca E, et al..Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.Am J Hum Genet. 2016;98(3):562-70. PubMed DOI Google Scholar Tagged Huang J,Wang K,Wei P,Liu X,Liu X,Tan K, et al..FLAGS: A Flexible and Adaptive Association Test for Gene Sets Using Summary Statistics.Genetics. 2016;202(3):919-29. PubMed DOI Google Scholar Tagged Liu X,Wu C,Li C, Boerwinkle E.dbNSFP v3.0: A One-Stop Database of Functional Predictions and Annotations for Human Nonsynonymous and Splice-Site SNVs.Hum Mutat. 2016;37(3):235-41. PubMed DOI Google Scholar Tagged Campbell IM,Gambin T,Jhangiani SN,Grove ML,Veeraraghavan N,Muzny DM, et al..Multiallelic Positions in the Human Genome: Challenges for Genetic Analyses.Hum Mutat. 2016;37(3):231-4. PubMed DOI Google Scholar Tagged Scott RA,Freitag DF,Li L,Chu AY,Surendran P,Young R, et al..A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.Sci Transl Med. 2016;8(341):341ra76. PubMed DOI Google Scholar Tagged Rhee EP,Yang Q,Yu B,Liu X,Cheng S,Deik A, et al..An exome array study of the plasma metabolome.Nat Commun. 2016;7:12360. PubMed DOI Google Scholar Tagged Charng W-L,Karaca E,Akdemir ZCoban,Gambin T,Atik MM,Gu S, et al..Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate.BMC Med Genomics. 2016;9(1):42. PubMed DOI Google Scholar Tagged Mirzaa GM,Campbell CD,Solovieff N,Goold CP,Jansen LA,Menon S, et al..Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism.JAMA Neurol. 2016;73(7):836-45. PubMed DOI Google Scholar Tagged Tajuddin SM,Schick UM,Eicher JD,Chami N,Giri A,Brody JA, et al..Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.Am J Hum Genet. 2016;99(1):22-39. PubMed DOI Google Scholar Tagged
https://www.hgsc.bcm.edu/people/boerwinkle-e?f%5Bauthor%5D=4691&page=10
Microorganisms | Free Full-Text | The Best of All Worlds: Streptococcus pneumoniae Conjunctivitis through the Lens of Community Ecology and Microbial Biogeography The study of the forces which govern the geographical distributions of life is known as biogeography, a subject which has fascinated zoologists, botanists and ecologists for centuries. Advances in our understanding of community ecology and biogeography—supported by rapid improvements in next generation sequencing technology—have now made it possible to identify and explain where and why life exists as it does, including within the microbial world. In this review, we highlight how a unified model of microbial biogeography, one which incorporates the classic ecological principles of selection, diversification, dispersion and ecological drift, can be used to explain community dynamics in the settings of both health and disease. These concepts operate on a multiplicity of temporal and spatial scales, and together form a powerful lens through which to study microbial population structures even at the finest anatomical resolutions. When applied specifically to curious strains of conjunctivitis-causing, nonencapsulated Streptococcus pneumoniae, we show how this conceptual framework can be used to explain the possible evolutionary and disease-causing mechanisms which allowed these lineages to colonize and invade a separate biogeography. An intimate knowledge of this radical bifurcation in phylogeny, still the only known niche subspecialization for S. pneumoniae to date, is critical to understanding the pathogenesis of ocular surface infections, nature of host-pathogen interactions, and developing strategies to curb disease transmission. Lawson Ung 1,2 , Paulo J. M. Bispo 1,2 , Noelle C. Bryan 2,3 , Camille Andre 1,2 , James Chodosh 1,2 and Michael S. Gilmore 1,2,* 1 Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA 2 Infectious Disease Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA 3 Massachusetts Institute of Technology, Department of Earth, Atmospheric and Planetary Sciences, Cambridge, MA 02139, USA * Author to whom correspondence should be addressed. Microorganisms 2020 , 8 (1), 46; https://doi.org/10.3390/microorganisms8010046 Received: 1 November 2019 / Revised: 16 December 2019 / Accepted: 21 December 2019 / Published: 25 December 2019 (This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections ) The study of the forces which govern the geographical distributions of life is known as biogeography, a subject which has fascinated zoologists, botanists and ecologists for centuries. Advances in our understanding of community ecology and biogeography—supported by rapid improvements in next generation sequencing technology—have now made it possible to identify and explain where and why life exists as it does, including within the microbial world. In this review, we highlight how a unified model of microbial biogeography, one which incorporates the classic ecological principles of selection, diversification, dispersion and ecological drift, can be used to explain community dynamics in the settings of both health and disease. These concepts operate on a multiplicity of temporal and spatial scales, and together form a powerful lens through which to study microbial population structures even at the finest anatomical resolutions. When applied specifically to curious strains of conjunctivitis-causing, nonencapsulated Streptococcus pneumoniae , we show how this conceptual framework can be used to explain the possible evolutionary and disease-causing mechanisms which allowed these lineages to colonize and invade a separate biogeography. An intimate knowledge of this radical bifurcation in phylogeny, still the only known niche subspecialization for S. pneumoniae to date, is critical to understanding the pathogenesis of ocular surface infections, nature of host-pathogen interactions, and developing strategies to curb disease transmission. Keywords: biogeography ; community ecology ; selection ; diversification ; drift ; dispersion ; Streptococcus pneumoniae ; epidemic conjunctivitis ; nonencapsulated 1. Introduction The study of biogeography is primarily concerned with understanding how ecological and geographical forces shape spatial distributions of life in our natural world [ 1 , 2 ]. While this concept may evoke images of Darwin and his legendary explorations of the Galapagos, the principles of biogeography have now transcended their epistemological roots in zoology and botany, and are beginning to guide our understanding of microbiology and microbial ecology. The notion of biogeography was touched on in the now-canonized words of Dutch scientist Lourens Baas-Becking, who in 1934 wrote, “everything is everywhere, but the environment selects” [ 3 ]. This statement includes two keys as to why microorganisms colonize in the patterns we observe: opportunity or access, and selection for fitness in that habitat. However, more contemporaneous renderings of microbial biogeography have used models of community ecology in an attempt to explain the processes underlying all microbial assemblage [ 1 , 2 , 4 ]. Such models now point to four fundamental and synergistic principles, which shape all patterns of life in the natural world: selection, diversification, dispersion and ecological (stochastic, i.e., random) drift, which operate on a multiplicity of spatial and temporal scales. Indeed, if life were to be considered a continuum, then it is intuitively obvious that the forces affecting macroorganisms might also influence the distribution of life in the microbial universe—including bacteria, viruses, archaea and fungi [ 5 ]. As data emerges from high-resolution, high-throughput, microbial sequencing at unprecedented levels of quantity and complexity, a unifying model of biogeography seems an appropriate starting point to explain where and why life exists as it does in a chosen environment, with special reference to sites of infection. The literature regarding microbial biogeography and community ecology has hitherto focused primarily on characterizing microbial populations on a “macro” scale—for instance, within non-spatially resolved environments such as soil and water [ 6 , 7 , 8 ]. Yet studies defining microbial consortia at various anatomical geographies now highlight the notion that microorganisms also display clear distribution patterns on this anatomical level, from site to site and tissue to tissue, varying in states of health and disease [ 9 ]. One of the best examples of the importance of biogeography for human pathogens comes from the evolution of a highly specialized clade of nonencapsulated Streptococcus pneumoniae —the epidemic conjunctivitis cluster (ECC)—which has a near exclusive predilection to infect the conjunctiva [ 10 ]. In this review, we explore this unique specialization through the lens of biogeography and community ecology, with a focus on new insights regarding the molecular epidemiology of this rogue S. pneumoniae clade which enabled it to become a leading cause of epidemic bacterial conjunctivitis. We explore the mechanisms that allowed this lineage to extend its range into a new biogeography, and the functional consequences of their genomic adaptations in the context of its unique tropism to the ocular surface. We offer critical and perhaps generalizable insight regarding fundamental questions of disease pathogenesis, acquisition of virulence factors and the nature of host–pathogen interactions, which are key to the study of all microbiology. 2. The Intersection of Community Ecology and Microbial Biogeography 2.1. Towards a Unified Model of Community Assembly Current conceptions of biogeography and ecology have become inextricably bound, and the observation of distinct biogeographical patterns in nature has proven to be a watershed moment in shaping the discourse surrounding the forces governing all community assembly. The most recent and widely cited of these ecological approaches have drawn on broader principles in evolutionary biology and population genetics, including neutral [ 11 , 12 , 13 , 14 ] and metacommunity theory [ 15 , 16 , 17 ]. Other models have examined the relative contributions of historical contingencies in explaining these spatial relationships [ 2 , 18 , 19 , 20 ]. However, recognizing that the literature had become replete with seemingly divergent frameworks which differed more in the emphases placed on ecological phenomena rather than the concepts themselves—a “mess”, as described by prominent British ecologist John Lawton [ 21 ]—Mark Vellend proposed an elegant framework to explain ecological (and by extension, biogeographical) patterns by considering the interplay between four factors: selection, drift, speciation and dispersal [ 22 ]. Importantly, Vellend does not contend that all four factors are equally important in determining the composition of any given ecosystem; on the contrary, it is the ecosystem and its inhabitants within this environment that determine the relative importance of any given factor. The model’s inherent simplicity, structure, and above all conciliation of the age-old niche (deterministic) vs. neutral (stochastic) debates has seen it become an attractive framework for studying both macrobial and microbial communities [ 1 , 23 , 24 ]. Vellend did not explicitly intend for his model to be applied to microbial ecology or biogeography per se; however, the pace at which sequencing data is now being acquired from metagenomic studies demands a sufficiently robust model to provide fundamental insights and hypotheses that may be used to inform current and future biological inquiry [ 25 ]. 2.2. The Four Tenets of Vellend’s Model Selection, in its broadest sense, refers to the patterns of community assembly which occur as a result of disparities in survival fitness among community inhabitants, usually conceived in terms of environmental factors [ 22 ]. These environmental factors can be further subdivided into biotic factors (microbe–microbe interactions including competition, commensalism, mutualism and parasitism [ 23 ]) and abiotic factors (nutrient availability, pH, climate, mechanisms of adherence, surface area, to name a few). These selective pressures lie at the core of the Baas–Becking hypothesis, though more recent conceptions of selection now take into account the effect of its pressures on whole communities, where adaptations acquired on a social level [ 26 ] confer a survival advantage for entire microbial communities (e.g., through the phenomenon of “quorum sensing” [ 27 , 28 ]). Ecological drift, or demographic stochasticity, introduces the role of chance in determining community composition. The effect of chance on community assembly is greatest when selective pressures are weakest [ 11 , 29 ]. This principle recognizes that processes such as birth, death and reproduction are inherently random events, and that low-abundance organisms are the most vulnerable to local extinction due to sampling effects [ 30 ]. Speciation refers to the evolutionary processes by which new species arise through genetic diversification [ 22 ], with classical driving forces including genomic recombination (e.g., with horizontal gene transfer [ 31 , 32 , 33 , 34 ], phage interactions [ 35 , 36 ] and highly mobile iterative and conjugative elements (ICEs) [ 37 , 38 ]), exposure of microorganisms to antibiotics [ 39 , 40 ], and physical isolation [ 41 , 42 ]. Finally, dispersal refers to the migration of organisms on both spatial and temporal scales. On a worldwide level, we might consider the effect of natural vehicles for dispersion (atmospheric currents and water; climate, weather and natural disasters; mass human migration and urbanization), while factors such as microbial motility, displacement and physical barriers between host compartments, are important on an individual level. However, the extent to which dispersal may explain community composition, or indeed be subject to empirical demonstration, remains a contentious issue [ 43 ]. Certain bacterial species, such as Staphylococcus aureus , S. pneumoniae , Haemophilus influenzae and Escherichia coli are widely distributed, but little agreement exists regarding the drivers of such cosmopolitanism. 2.3. Anatomical Biogeography In addition to the broad principles of biogeography outlined above, there is also increasing recognition that specific microbial distributions also exist on the finest of spatial scales: that of the individual anatomical level, from body compartment to compartment, from tissue to tissue and even from cell to cell [ 9 , 44 , 45 , 46 ]. In other words, the distribution of microbes in and on humans is not the result of stochastic (random) events alone. The clearest evidence for this is the observation of species endemism, or the lack thereof, within particular niches in human bodies, such as the exclusive residence of Helicobacter pylori within the pylorus of the stomach [ 47 , 48 ], or the sterile and immune-privileged nature of cerebrospinal fluid, which in healthy states is protected by the blood–brain barrier [ 49 ]. Utilizing the main pillars of Vellend’s model, it is likely that the residence of specific microbes at particular locations is therefore determined by numerous factors, including: (1) comparative fitness for the physical and chemical attributes of that habitat as described above; (2) prior occurrence and degree of establishment of other organisms that may be antagonistic or synergistic; and (3) opportunities for potential displacement by more fit microbes, as determined by the population size achievable and access to an open microbial-rich environment. The patterns of microbial populations evolve as the environment changes, whether it is a host environment evolving in response to a senescent immune system, or host surfaces or other environments evolving because of changing ambient temperatures. Therefore, we propose an extension of Vellend’s conceptual synthesis by adding a fourth spatial scale beyond the originally conceived global, regional and local dimensions, emphasizing the notion that the principles of community assembly also apply at the level of individual anatomical sites within hosts ( Figure 1 ). 2.4. Infection through the Lens of Community Microbial Ecology and Biogeography Observing microbial assemblages through community ecology theory at an anatomical scale lends itself particularly well to cases of infection for several reasons [ 50 , 51 , 52 ]. The first and most obvious reason is that these frameworks facilitate a practical conceptualization of the forces which underpin all infectious disease ecology, which can be considered a very specific biogeographical phenomenon involving distinct patterns of community organization. Secondly, such models steer us away from reductionist paradigms which reflect a historical tendency to study microorganisms in isolation [ 53 , 54 ], where little consideration was given to how ecological interactions may influence both health and disease. At its most basic level, successful pathogens must be able to establish infection by colonizing, and proliferating within a suitable niche, and these processes of dispersion must occur in sufficiently large numbers to overcome stochastic events that may lead to the organism’s local extinction. This may occur with immigration of the pathogen into this niche, or replacement colonization, where a resident microbe with invasive potential outcompetes and displaces other resident microbes by exploiting local opportunities and resources, often following disturbances to the local microbial community. In all cases, the resident diversity of the environment is important, because with greater diversity comes a greater likelihood that these residents will possess a competitive advantage over the invading species, thereby providing “colonization resistance” against infection [ 55 , 56 , 57 ]. Furthermore, the pathogen must possess traits or virulence factors which allow it to survive in the face of mounting and shifting selective pressures. This includes the ability to evade host immune responses; to resist human interventions such as the introduction of antimicrobials; diversify by acquiring locally advantageous adaptations which may suppress resident microbial reconstitution; to persist in a way that may not be solely dependent on a population abundance or density threshold [ 58 ]; and the ability to facilitate efficient transmission from host to host, particularly “dead-end” hosts. Finally, while the role of drift is difficult to quantify empirically, few would argue its importance particularly in low-abundance and/or highly isolated communities where microbes are most likely to experience “fadeout” [ 59 ]. Understanding whether infectious diseases are primarily driven by niche-based effects or stochastic events—or a combination of the two—may also offer critical insight to inform clinical decision making and public health interventions [ 4 ]. If dispersion is the primary force governing the spread of disease, as is the case in recent rapid Ebola and Zika virus outbreaks [ 60 ], then interventions geared towards quarantine, isolation, hospital cohorting and border control would appear most appropriate. Under dispersal-limited conditions, other mechanisms may be at play. For instance, local disturbances in intestinal flora induced by antibiotic use is now considered a major risk factor for Clostridium difficile colitis, increasingly treated with fecal transplantation [ 61 , 62 ]. Alternatively, where diversification is a major driver of disease dynamics, as is the case in multi-drug resistant tuberculosis [ 63 ], a multi-drug regimen combined with directly observed therapy (DOT) for pathogen eradication may stall the evolutionary acquisition of further genetic mutations conferring antimicrobial resistance. Importantly, modeling infectious diseases dynamics through a community ecology approach also sheds light on parasite interactions in the setting of coinfection within hosts, with some prominent examples including the increased risk of more severe Plasmodium infection in children coinfected by soil-based helminths [ 64 , 65 ], and the copathogenicity of S. pneumoniae and respiratory viruses in precipitating infectious pneumonia (the risk of which is ameliorated with pneumococcal vaccines) [ 66 ]. 3. The Curious Case of Streptococcus pneumoniae Conjunctivitis 3.1. Streptococcus pneumoniae: An Old Foe Streptococcus pneumoniae (the pneumococcus) is a Gram-positive, facultative, anaerobic bacterium which appears as lanceolate diplococci, single cocci and/or in short chains under microscopy. S. pneumoniae colonizes the human upper respiratory tract mucosa, including that of the nasopharynx, larynx and trachea [ 67 ], beginning in the first few months of life [ 68 ]. It has been estimated that over 60% of children will become asymptomatic nasopharyngeal carriers of S. pneumoniae by preschool age [ 69 , 70 , 71 ], with the highest prevalence documented in developing countries [ 72 , 73 ]. Following this childhood peak, an age-related decline into adulthood is observed, with an 8–20% carriage rate past the age of 18 [ 72 , 74 ]. In most cases under healthy conditions, S. pneumoniae forms a part of the normal respiratory flora. Following colonization, however, opportunistic infection may occur following local (e.g., ear, sinus) or systemic (e.g., lung, bloodstream) spread, which is more likely to occur in states of immune dysfunction or immaturity, such as that associated with extremes of age, asplenism and malignancy [ 75 ]. Historically, the clinical manifestations of pneumococcal infection have been divided into the potentially lethal “invasive pneumococcal diseases” [ 76 ] of pneumonia, meningitis and septicemia, and the non-systemic diseases of otitis media, sinusitis and conjunctivitis [ 77 ], which are collectively associated with significant morbidity, mortality and profound costs to human society [ 78 , 79 , 80 , 81 , 82 ]. To mitigate the burden of disease, pneumococcal conjugate vaccines have been in widespread use since 2000, albeit with limited coverage against the most common encapsulated strains and consequences to human pneumococcal population structures which continue to unfold [ 83 , 84 ]. 3.2. Nonencapsulated Strains of S. pneumoniae The virulence of S. pneumoniae has long been attributed to its anionic polysaccharide capsule, the basis on which its now over 100 serotypes have been described [ 85 , 86 ]. The presence of a capsule enables S. pneumoniae to evade the physical and chemical elements of the host immune response, and confers protection from clearance by respiratory mucosa, and from complement-mediated opsonophagocytosis [ 87 , 88 ]. Both factors therefore facilitate nasopharyngeal colonization [ 89 ]. However, reports of nonencapsulated strains of S. pneumoniae (NESp) surfaced in the early 1980s [ 90 ]. Early descriptions reported “atypical” and “non-typeable” lineages which did not react to capsule-specific antisera [ 91 , 92 ], but were nonetheless phenotypically consistent with S. pneumoniae on the basis of agar hemolysis patterns, sensitivity to optochin and bile solubility [ 93 ]. These strains were historically overlooked due to their small, “rough” and non-mucoid appearance on agar, but have likely been in intercontinental circulation for decades [ 90 , 94 , 95 , 96 ]. These nonencapsulated strains are now recognized as a significant cause of human disease, capable of causing both systemic and local infections, including “invasive” pneumococcal disease [ 97 , 98 , 99 ], bacterial conjunctivitis [ 91 , 100 , 101 , 102 ], and otitis media [ 103 , 104 ]. Recent comparative genomic analyses now allow us to characterize these NESp strains into two groups based on alterations in their capsular polysaccharide synthesis ( cps ) loci: group I NESp, which contains mutationally defunct or absent cps genes; and group II NESp, where these cps genes are replaced almost entirely by novel gene content [ 87 , 105 ]. The latter group contains a distinct phyletic cluster of mostly nonencapsulated S. pneumoniae with an almost exclusive proclivity for causing epidemic conjunctivitis [ 10 , 106 , 107 , 108 ]. If one basic assumption of all evolutionary biology is that genetic change is driven mostly by the underlying pursuit for survival, then the loss of encapsulation and the acquisition of virulence factors in this rogue clade must also confer a basic survival advantage within a new environmental niche. Using the principles of community ecology described earlier, we explore the driving forces and ecological relationships behind this radical divergence in phylogeny, which may have contributed to the establishment of this new disease phenotype within a new anatomical biogeography. 3.3. A New Biogeography: The Epidemic Conjunctivitis Cluster (ECC) of S. pneumoniae This deeply resolved classic lineage of NESp has now been described by a number of national and international studies [ 10 , 94 , 107 , 108 ], and is the only known example of niche subspecialization in S. pneumoniae . We investigated the molecular epidemiology of 271 epidemic conjunctivitis-causing isolates of S. pneumoniae , collected from 32 states in the US. Using multilocus sequence typing, these lineages localized to a distinct and closely-related group including ST448, ST344, ST1186, ST1270 and ST2315 [ 10 ]. These strains were labeled the epidemic conjunctivitis cluster (ECC) of S. pneumoniae , as they accounted for approximately 90% of conjunctivitis cases in our study ( Figure 2 and Figure 3 ). Conversely, less common causes of conjunctivitis, including the encapsulated strains ST632, ST667, ST180, ST199, ST42 and ST190, were dispersed among non-ocular reference strains. These results were consistent with another study conducted by Croucher and colleagues who described the Sequence Cluster 12 (SC12), a group of nonencapsulated strains including ST448 and ST344, which were the most phylogenetically distant group in 616 isolates of asymptomatically-carried pneumococci [ 109 ]. Assuming that the mutation rate of ECC lineages approximates that of non-ECC S. pneumoniae , the divergence of ECC and its non-ocular counterparts occurred approximately 8400 years ago [ 10 ], rather than as a response to the introduction of pneumococcal vaccines, as previously suggested. Curiously, this timeframe also corresponds with other instances of clade divergence in other bacteria, including Enterococcus faecium [ 110 ] and S. aureus [ 111 ], which have been hypothesized to have arisen around the time of accelerated human urbanization, animal domestication, agriculture and possibly improved hygiene practices [ 112 ]. The ECC lineages do not meet the standard threshold for speciation, as determined by the requirement for a shared average nucleotide identity (ANI) of <95% between the candidate organism and its nearest relatives [ 113 , 114 ]. However, a large proportion (>10%) of ECC genomes is occupied by novel gene content within a prolific accessory genome [ 10 ]. 3.4. Modes of Diversification in ECC Strains Differ from Encapsulated Strains It has been known for many decades that S. pneumoniae as a species displays remarkable genetic plasticity, with genetic diversification dominated by recombination [ 116 , 117 , 118 , 119 , 120 ]. Although S. pneumoniae population structures and recombination differ across different time scales [ 107 ], the observation that S. pneumoniae efficiently takes up and incorporates DNA [ 121 ] even in the absence of species-specific uptake sequences [ 122 , 123 , 124 ] suggests that diversification is fueled mostly by gene transfer from both pneumococcal and non-pneumococcal (e.g., oral streptococci) sources within its environmental niche [ 118 , 125 ]. The downstream consequences of such rapid transformation are demonstrated by recombination hotspots in the pneumococcal genome. In one example, the presence of highly conserved, non-capsular genes ( dexB and aliA ) which flank the cps gene locus allows remarkably rapid switching of capsular phenotype in response to selective challenges such as vaccination and the host immune response [ 83 , 126 , 127 , 128 ]. Horizontal gene transfer is augmented by “pneumococcal fratricide” [ 129 ], where competent (or highly transformable) clones destroy their poorly competent (and presumably less fit) neighbors, releasing their genomic material which can fuel downstream recombination events. In addition, transduction via bacteriophages [ 130 , 131 ] and conjugation with mobile elements such as ICEs [ 132 , 133 ] are also potent evolutionary drivers for S. pneumoniae diversification, although to a less appreciated degree [ 134 ]. The extent to which ECC population structure is driven by these forces, however, is unclear. Previously, it has been suggested that NESp, by virtue of lacking the barrier function of a capsule, may be more readily amenable to transformation and recombination than encapsulated strains [ 135 , 136 , 137 , 138 ]. However, inconsistencies in reported transformation efficiencies suggest that recombination alone is insufficient to explain this population structure [ 10 , 108 ]. For example, Hilty and colleagues found that the classical NESp types ST344 and ST488 were characterized by a lower rate of recombination when compared to a highly recombinogenic, non-typable strain (BC3-NT) retrieved from a refugee camp on the Thailand–Myanmar border [ 108 , 135 ]. This finding was recapitulated in our study, wherein distinct ECC phylogeny was preserved even after removing recombinogenic sequences from analysis [ 10 ]. This may suggest that ECC genomes are relatively stable, and that diversification is driven at least in part by other mechanisms, including endogenous mutation. Over millennia, they have become adapted to both nasopharyngeal and conjunctival colonization even in the absence of a capsule. Moving forward, it will be of primary importance to understand the mechanisms driving NESp genetic diversification, not least because instances of clade divergence may augur the future emergence of particularly virulent bacterial strains, as seen with vancomycin-resistant E. faecium and methicillin-resistant S. aureus (MRSA). 3.5. Extensive Cell Wall Remodeling Is Important for Conjunctival Colonization among ECC Lineages One of the most striking features of ECC strains of pneumococcus is their extensive cell surface remodeling. This reflects the influence of the capsule in defining the environment in which surface features occur on encapsulated strains, and novel selective pressures occur in its absence. Much of the novel genomic content in ECC strains appears to have been donated by unencapsulated oral streptococci [ 10 , 106 , 139 ]. Novel cell wall proteins, encoded by novel genes found at the cps locus, allow ECC strains to overcome or evade the robust suite of physical and chemical protections that characterize the conjunctival microenvironment. These include: the oligopeptide binding proteins AliC and AliD (encoded by AliC and AliD , respectively) [ 10 , 98 ], which may enhance mucosal colonization by conferring resistance to leukocyte cytotoxicity and complement deposition [ 98 ]; the choline binding protein A (CbpA) variants CbpAC1 and CbpAC2, which among other functions may be involved in binding to the secretory component of IgA [ 10 ] and also in preventing complement deposition [ 98 ]; surface exposed adhesins (SspBC1/SspBC2), which may be important in cell agglutination and conjunctival epithelial adhesion [ 10 , 106 ]; the neuraminidases (NanO1/NanO2) [ 10 ], which putatively cleave sialic acids on the surface of mucosal glycans and mucins [ 140 ]; and zinc metalloprotease C (zmpC1/zmpC2) [ 10 ], which reportedly cleaves the ectodomain portion of the membrane-bound mucin MUC16, thereby exposing the underlying epithelial cell to infection [ 10 , 141 ]. With a cell wall highly adapted for conjunctival colonization and invasion, it is tempting to speculate that NESp may have lost its capsule because it simply became an unnecessary metabolic burden [ 93 , 137 ]. An alternative hypothesis is that NESp strains are resistant to opsonization within complement-laden conjunctival tissues, where innate immune responses may preferentially target encapsulated organisms [ 142 ]. However, while the loss of capsule suggests that ECC strains have developed other specialized ways to overcome the unique defense mechanisms of the conjunctiva, this loss alone cannot be the sole reason for their peculiar ocular surface tropism. Many non-ECC unencapsulated strains are phylogenetically grouped with the majority of pneumococcal strains, and conversely, some encapsulated strains are capable of causing sporadic conjunctivitis. As a distinct cluster of NESp, ECC lineages are particularly well adapted specifically for conjunctival colonization and infection [ 10 , 106 ], most likely by virtue of their novel gene content. These adaptations do not appear to extend to isolates which invade other ocular sites: sequencing data from our laboratory (unpublished) and that of Antic and colleagues [ 106 ], suggest that clinical isolates of S. pneumoniae from keratitis and endophthalmitis (aqueous/vitreous) are clustered within the major phyletic group. 3.6. Dispersion and Transmission of ECC Having established that NESp follow cosmopolitan distributions worldwide, what can be made of colonization and dispersion dynamics within individual hosts? Comparative genomic analyses demonstrating the genomic equivalence of nasopharyngeal and conjunctival ECC isolates suggest that nasopharyngeal colonization is likely to precede conjunctival infection, favoring the hypothesis that ECC strains migrate freely between both host compartments [ 10 , 106 ]. This lack of evidence for a distance–decay relationship—which classically suggests that populations should become increasingly diversified with increasing physical displacement from its reservoir [ 143 , 144 ]—raises several questions regarding how these ECC strains have evolved to be able to physically straddle these two disparate biogeographies. It is feasible that a combination of factors govern the dispersion of ECC strains: the close physical proximity between the conjunctiva and the nasopharynx; the histological similarities between respiratory and conjunctival epithelia, which may be amenable to similar colonization mechanisms; and the paucimicrobial nature of the conjunctiva [ 145 ], which offers little colonization resistance from its resident commensals. Furthermore, we cannot discount the possibility of aerosolized dispersion of ECC strains, which may partly explain why conjunctivitis outbreaks are so common. The source–sink model of dispersion–evolution dynamics may be useful in understanding the spatial distribution and translocation of these ECC strains [ 146 , 147 , 148 , 149 ]. This model places organisms within distinct anatomical compartments: their source, referring to its reservoir habitat(s) which facilitates persistent colonization; and their sinks, referring to the environments which accommodate transient colonization. These source–sink dynamics confer differential rates of adaptation, depending on the nature of migration and the hostility of the sink habitat. Migration from a source to a “closed” sink is a one-way process, isolating the organism in its transient habitat, where it must adapt rapidly or face local extinction. A “black hole” sink supports continuous, one-way migration from a source, in a way which maintains population abundance within this new niche [ 150 ]. Finally, migration from a source to a “reciprocal” sink allows free physical exchange between the two compartments [ 146 ]. Over time, adaptation to these new sink environments (e.g., with the acquisition of novel surface proteins) results in colonization persistence, and the organism no longer relies on source migration to maintain viable populations [ 151 ]. Of all these possibilities, ecological drift is most likely to affect small populations within hostile, “closed” sink environments. With no current empirical data relating to the evolutionary consequences of S. pneumoniae migration between separate biogeographies, one fascinating line of inquiry would be to unearth genomic evidence of these source–sink relationships, and the extent to which physical isolation from a source habitat (e.g., the nasopharynx) drives adaptation in other niches (e.g., the conjunctiva), as famously articulated by Ernst Mayr (1904–2005) [ 42 ]. Elucidating such evidence may also provide critical insight regarding the mechanisms of genomic adaptation, because relative physical isolation may reduce opportunities for recombination and explain why the literature has been inconsistent with regard to the extent to which ECC population structures are driven by recombination events. What source–sink models do not explain, however, are the factors which govern asymptomatic colonization versus disease, and the relationships between pathogen load, host responses and other factors which influence these phenotypes. 3.7. Changes in Community Composition Following Human Intervention Earlier, we alluded to potential changes to community microbial composition that may occur as a response to human intervention. The most pertinent example of one such intervention is the population-wide use of the pneumococcal conjugate vaccine (PCV), which has resulted in sweeping reductions in the incidence of invasive pneumococcal diseases, particularly in young children and the elderly [ 152 , 153 , 154 , 155 , 156 ]. However, PCV has also had an effect on shaping the microbial social networks of which S. pneumoniae are part. A community ecology approach asks us to predict what may occur when a subgroup of a taxonomically diverse and heterogenous microbial consortium is removed from its natural source habitat. While a trend towards serotype replacement with less virulent clones has been observed following PCV [ 157 , 158 ], we are now witnessing a rise in the incidence of invasive pneumococcal disease associated with non-target serotypes (e.g., 19-A [ 159 , 160 ]). Furthermore, evidence of replacement colonization by the natural competitors of these target strains, including S. aureus and H. influenzae, has been reported [ 161 , 162 ]. The inverse relationship between encapsulated S. pneumoniae and MRSA carriage in particular has been an area of intensive debate [ 163 ], with some researchers observing a temporal rise in overall MRSA infection (particularly community-acquired strains) and the coincident fall in the human carriage of PCV-targeted encapsulated strains of pneumococcus [ 164 , 165 ]. Presumably, some of this vacant niche might also be filled by NESp [ 83 , 166 ], demonstrated by rising carriage among humans—now estimated to be in the order of 5–15% [ 100 , 135 ]. Disturbances such as vaccination are likely to have ripple effects through whole ecosystems, though the consequences are difficult to discern [ 167 ]. One possibility is that such effects may fundamentally alter the role of certain populations within their community. If NESp are a reservoir for antibiotic resistance genes as previously suggested [ 168 ], or a privileged intermediary between encapsulated pneumococcus and the related oral streptococci, what impact might this have on both carriage and disease transmission? Inevitably, human interventions entail collateral damage, and future hypothesis-driven testing may look at changes to the population structure of all pneumococcal strains, including the ECC, in the wake of the empty-niche turbulence induced by interventions including vaccination and antimicrobial use. 4. Conclusions A community ecology model which unites the core principles of selection, diversification, dispersion and ecological drift is a useful framework to study the microbial world, which continues to rapidly evolve in response to changing environmental stimuli. When applied to NESp, this hypothesis-generating model highlights the mechanistic underpinnings of how these atypical strains have been able to persist and evolve across temporal and multiple spatial scales, providing access to, colonization of, and adaptation to, disparate biogeographies in the absence of the famed pneumococcal capsule. Furthermore, biogeographical study highlights the large void in our understanding of host–bacteria relationships within anatomical niches, and how disturbances may lead to altered phenotypes, including infection. The current literature on this rogue pneumococcal clade provides more questions than answers at this early stage of our understanding, and many of our proposed lines of inquiry remain speculative. The evolutionary story of all microbiological communities—including those of which S. pneumoniae plays a prominent role—is still unfolding, and we have yet to fully understand the true impact of human interventions such as antimicrobial use and vaccination on its population structures. However, as with all biological endeavors, particularly as metagenomic and other “-omics” research become increasingly available, perhaps the answers will come by first asking better questions. A structured understanding of the biogeographical forces which govern community assortment on the smallest of anatomical levels may provide the calculus to help us understand the most basic elements of microbiology in states of both health and disease. Author Contributions Conceptualization, M.S.G., J.C., L.U., P.J.M.B.; literature search, L.U., P.J.M.B.; writing—original draft preparation, L.U.; writing—reviewing and editing—M.S.G., J.C., P.J.M.B., N.C.B., C.A., L.U. All authors have read and agreed to the published version of the manuscript. Funding This research was supported in part by EY024285 and AI083214 from the National Institutes of Health, and an unrestricted grant to the Department of Ophthalmology, Harvard Medical school, from Research to Prevent Blindness, NY, NY. L.U. was also supported by the Dozoretz Family Foundation. N.C.B. was supported by a NASA Space Biology Fellowship, award 80NSSC17K0688. Conflicts of Interest The authors declare no conflict of interest. References Stacy, A.; McNally, L.; Darch, S.E.; Brown, S.P.; Whiteley, M. The biogeography of polymicrobial infection. Nat. Rev. Microbiol. 2016 , 14 , 93–105. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Martiny, J.B.; Bohannan, B.J.; Brown, J.H.; Colwell, R.K.; Fuhrman, J.A.; Green, J.L.; Horner-Devine, M.C.; Kane, M.; Krumins, J.A.; Kuske, C.R.; et al. Microbial biogeography: Putting microorganisms on the map. Nat. Rev. Microbiol. 2006 , 4 , 102–112. [ Google Scholar ] [ CrossRef ] [ PubMed ] Becking, L.B. Geobiologie of Inleiding Tot de Milieukunde ; WP Van Stockum & Zoon: The Hague, The Netherlands, 1934. [ Google Scholar ] Costello, E.K.; Stagaman, K.; Dethlefsen, L.; Bohannan, B.J.; Relman, D.A. The application of ecological theory toward an understanding of the human microbiome. Science 2012 , 336 , 1255–1262. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] O’Malley, M.A. The nineteenth century roots of ‘everything is everywhere’. Nat. Rev. Microbiol. 2007 , 5 , 647–651. [ Google Scholar ] [ CrossRef ] [ PubMed ] Cho, J.C.; Tiedje, J.M. Biogeography and degree of endemicity of fluorescent Pseudomonas strains in soil. Appl. Environ. Microbiol. 2000 , 66 , 5448–5456. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] King, H.C.; Khera-Butler, T.; James, P.; Oakley, B.B.; Erenso, G.; Aseffa, A.; Knight, R.; Wellington, E.M.; Courtenay, O. Environmental reservoirs of pathogenic mycobacteria across the Ethiopian biogeographical landscape. PLoS ONE 2017 , 12 , e0173811. [ Google Scholar ] [ CrossRef ] Choudoir, M.J.; Doroghazi, J.R.; Buckley, D.H. Latitude delineates patterns of biogeography in terrestrial Streptomyces. Environ. Microbiol. 2016 , 18 , 4931–4945. [ Google Scholar ] [ CrossRef ] Costello, E.K.; Lauber, C.L.; Hamady, M.; Fierer, N.; Gordon, J.I.; Knight, R. Bacterial community variation in human body habitats across space and time. Science 2009 , 326 , 1694–1697. [ Google Scholar ] [ CrossRef ][ Green Version ] Valentino, M.D.; McGuire, A.M.; Rosch, J.W.; Bispo, P.J.; Burnham, C.; Sanfilippo, C.M.; Carter, R.A.; Zegans, M.E.; Beall, B.; Earl, A.M.; et al. Unencapsulated Streptococcus pneumoniae from conjunctivitis encode variant traits and belong to a distinct phylogenetic cluster. Nat. Commun. 2014 , 5 , 5411. [ Google Scholar ] [ CrossRef ][ Green Version ] Hubbell, S.P. The Unified Neutral Theory of Biodiversity and Biogeography (MPB-32) ; Princeton University Press: Princeton, NJ, USA, 2001. [ Google Scholar ] Volkov, I.; Banavar, J.R.; Hubbell, S.P.; Maritan, A. Neutral theory and relative species abundance in ecology. Nature 2003 , 424 , 1035–1037. [ Google Scholar ] [ CrossRef ][ Green Version ] Woodcock, S.; van der Gast, C.J.; Bell, T.; Lunn, M.; Curtis, T.P.; Head, I.M.; Sloan, W.T. Neutral assembly of bacterial communities. FEMS Microbiol. Ecol. 2007 , 62 , 171–180. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Kimura, M. The Neutral Theory of Molecular Evolution ; Cambridge University Press: New York, NY, USA, 1983. [ Google Scholar ] Leibold, M.A.; Holyoak, M.; Mouquet, N.; Amarasekare, P.; Chase, J.M.; Hoopes, M.F.; Holt, R.D.; Shurin, J.B.; Law, R.; Tilman, D.; et al. The metacommunity concept: A framework for multi-scale community ecology. Ecol. Lett. 2004 , 7 , 601–613. [ Google Scholar ] [ CrossRef ] Holyoak, M.; Leibold, M.A.; Holt, R.D. Metacommunities: Spatial Dynamics and Ecological Communities ; University of Chicago Press: Chicago, IL, USA, 2005. [ Google Scholar ] Leibold, M.A.; Chase, J.M. Metacommunity Ecology ; Princeton University Press: Princeton, NJ, USA, 2017. [ Google Scholar ] Chase, J.M. Community assembly: When should history matter? Oecologia 2003 , 136 , 489–498. [ Google Scholar ] [ CrossRef ] Hang-Kwang, L.; Pimm, S.L. The assembly of ecological communities: A minimalist approach. J. Anim. Ecol. 1993 , 62 , 749–765. [ Google Scholar ] [ CrossRef ] Brooks, D.R.; Ferrao, A.L. The historical biogeography of co-evolution: Emerging infectious diseases are evolutionary accidents waiting to happen. J. Biogeogr. 2005 , 32 , 1291–1299. [ Google Scholar ] [ CrossRef ] Lawton, J.H. Are there general laws in ecology? Oikos 1999 , 84 , 177–192. [ Google Scholar ] [ CrossRef ][ Green Version ] Vellend, M. Conceptual synthesis in community ecology. Q. Rev. Biol. 2010 , 85 , 183–206. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Nemergut, D.R.; Schmidt, S.K.; Fukami, T.; O’Neill, S.P.; Bilinski, T.M.; Stanish, L.F.; Knelman, J.E.; Darcy, J.L.; Lynch, R.C.; Wickey, P.; et al. Patterns and processes of microbial community assembly. Microbiol. Mol. Biol. Rev. 2013 , 77 , 342–356. [ Google Scholar ] [ CrossRef ][ Green Version ] Hanson, C.A.; Fuhrman, J.A.; Horner-Devine, M.C.; Martiny, J.B. Beyond biogeographic patterns: Processes shaping the microbial landscape. Nat. Rev. Microbiol. 2012 , 10 , 497–506. [ Google Scholar ] [ CrossRef ] Prosser, J.I.; Bohannan, B.J.; Curtis, T.P.; Ellis, R.J.; Firestone, M.K.; Freckleton, R.P.; Green, J.L.; Green, L.E.; Killham, K.; Lennon, J.J.; et al. The role of ecological theory in microbial ecology. Nat. Rev. Microbiol. 2007 , 5 , 384–392. [ Google Scholar ] [ CrossRef ] Eberl, G. A new vision of immunity: Homeostasis of the superorganism. Mucosal Immunol. 2010 , 3 , 450–460. [ Google Scholar ] [ CrossRef ] [ PubMed ] Williams, P.; Camara, M. Quorum sensing and environmental adaptation in Pseudomonas aeruginosa: A tale of regulatory networks and multifunctional signal molecules. Curr. Opin. Microbiol. 2009 , 12 , 182–191. [ Google Scholar ] [ CrossRef ] [ PubMed ] Williams, P. Quorum sensing, communication and cross-kingdom signalling in the bacterial world. Microbiology 2007 , 153 , 3923–3938. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Stegen, J.C.; Lin, X.; Fredrickson, J.K.; Konopka, A.E. Estimating and mapping ecological processes influencing microbial community assembly. Front. Microbiol. 2015 , 6 , 370. [ Google Scholar ] [ CrossRef ][ Green Version ] Gilbert, B.; Levine, J.M. Ecological drift and the distribution of species diversity. Proc. Biol. Sci. 2017 , 284 . [ Google Scholar ] [ CrossRef ] de la Cruz, F.; Davies, J. Horizontal gene transfer and the origin of species: Lessons from bacteria. Trends Microbiol. 2000 , 8 , 128–133. [ Google Scholar ] [ CrossRef ] Lawrence, J.G.; Retchless, A.C. The interplay of homologous recombination and horizontal gene transfer in bacterial speciation. Methods Mol. Biol. 2009 , 532 , 29–53. [ Google Scholar ] [ CrossRef ] Ochman, H.; Lawrence, J.G.; Groisman, E.A. Lateral gene transfer and the nature of bacterial innovation. Nature 2000 , 405 , 299–304. [ Google Scholar ] [ CrossRef ] Smith, J.M.; Dowson, C.G.; Spratt, B.G. Localized sex in bacteria. Nature 1991 , 349 , 29–31. [ Google Scholar ] [ CrossRef ] Williams, H.T. Phage-induced diversification improves host evolvability. BMC Evol. Biol. 2013 , 13 , 17. [ Google Scholar ] [ CrossRef ][ Green Version ] Brüssow, H.; Canchaya, C.; Hardt, W.-D. Phages and the evolution of bacterial pathogens: From genomic rearrangements to lysogenic conversion. Microbiol. Mol. Biol. Rev. 2004 , 68 , 560–602. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Guglielmini, J.; Quintais, L.; Garcillan-Barcia, M.P.; de la Cruz, F.; Rocha, E.P. The repertoire of ICE in prokaryotes underscores the unity, diversity, and ubiquity of conjugation. PLoS Genet. 2011 , 7 , e1002222. [ Google Scholar ] [ CrossRef ] [ PubMed ] Garcillán-Barcia, M.P.; Francia, M.V.; De La Cruz, F. The diversity of conjugative relaxases and its application in plasmid classification. FEMS Microbiol. Rev. 2009 , 33 , 657–687. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Palumbi, S.R. Humans as the world’s greatest evolutionary force. Science 2001 , 293 , 1786–1790. [ Google Scholar ] [ CrossRef ] Park, S.E.; Pham, D.T.; Boinett, C.; Wong, V.K.; Pak, G.D.; Panzner, U.; Espinoza, L.M.C.; von Kalckreuth, V.; Im, J.; Schutt-Gerowitt, H.; et al. The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa. Nat. Commun. 2018 , 9 , 5094. [ Google Scholar ] [ CrossRef ][ Green Version ] Mayr, E. Speciation and Macroevolution. Evolution 1982 , 36 , 1119–1132. [ Google Scholar ] [ CrossRef ] Mayr, E. Ecological factors in speciation. Evolution 1947 , 1 , 263–288. [ Google Scholar ] [ CrossRef ] Jenkins, D.G.; Brescacin, C.R.; Duxbury, C.V.; Elliott, J.A.; Evans, J.A.; Grablow, K.R.; Hillegass, M.; Lyon, B.N.; Metzger, G.A.; Olandese, M.L. Does size matter for dispersal distance? Glob. Ecol. Biogeogr. 2007 , 16 , 415–425. [ Google Scholar ] [ CrossRef ] Stearns, J.C.; Lynch, M.D.; Senadheera, D.B.; Tenenbaum, H.C.; Goldberg, M.B.; Cvitkovitch, D.G.; Croitoru, K.; Moreno-Hagelsieb, G.; Neufeld, J.D. Bacterial biogeography of the human digestive tract. Sci. Rep. 2011 , 1 , 170. [ Google Scholar ] [ CrossRef ][ Green Version ] Oh, J.; Byrd, A.L.; Deming, C.; Conlan, S.; Program, N.C.S.; Kong, H.H.; Segre, J.A. Biogeography and individuality shape function in the human skin metagenome. Nature 2014 , 514 , 59–64. [ Google Scholar ] [ CrossRef ][ Green Version ] Donaldson, G.P.; Lee, S.M.; Mazmanian, S.K. Gut biogeography of the bacterial microbiota. Nat. Rev. Microbiol. 2016 , 14 , 20–32. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Moodley, Y.; Linz, B.; Bond, R.P.; Nieuwoudt, M.; Soodyall, H.; Schlebusch, C.M.; Bernhöft, S.; Hale, J.; Suerbaum, S.; Mugisha, L. Age of the association between Helicobacter pylori and man. PLoS Pathog. 2012 , 8 , e1002693. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Perrin, P.; Herbreteau, V.; Hugot, J.-P.; Morand, S. Biogeography, Humans, and Their Parasites ; Oxford University Press: Oxford, UK, 2010; pp. 41–57. [ Google Scholar ] Abbott, N.J.; Patabendige, A.A.; Dolman, D.E.; Yusof, S.R.; Begley, D.J. Structure and function of the blood–brain barrier. Neurobiol. Dis. 2010 , 37 , 13–25. [ Google Scholar ] [ CrossRef ] [ PubMed ] Kinnunen, M.; Dechesne, A.; Proctor, C.; Hammes, F.; Johnson, D.; Quintela-Baluja, M.; Graham, D.; Daffonchio, D.; Fodelianakis, S.; Hahn, N.; et al. A conceptual framework for invasion in microbial communities. ISME J. 2016 , 10 , 2773–2775. [ Google Scholar ] [ CrossRef ] [ PubMed ] Johnson, P.T.; de Roode, J.C.; Fenton, A. Why infectious disease research needs community ecology. Science 2015 , 349 , 1259504. [ Google Scholar ] [ CrossRef ][ Green Version ] Seabloom, E.W.; Borer, E.T.; Gross, K.; Kendig, A.E.; Lacroix, C.; Mitchell, C.E.; Mordecai, E.A.; Power, A.G. The community ecology of pathogens: Coinfection, coexistence and community composition. Ecol. Lett. 2015 , 18 , 401–415. [ Google Scholar ] [ CrossRef ] Fuhrman, J.A. Microbial community structure and its functional implications. Nature 2009 , 459 , 193–199. [ Google Scholar ] [ CrossRef ] Buhnerkempe, M.G.; Roberts, M.G.; Dobson, A.P.; Heesterbeek, H.; Hudson, P.J.; Lloyd-Smith, J.O. Eight challenges in modelling disease ecology in multi-host, multi-agent systems. Epidemics 2015 , 10 , 26–30. [ Google Scholar ] [ CrossRef ][ Green Version ] Dunstan, P.K.; Johnson, C.R. Linking richness, community variability, and invasion resistance with patch size. Ecology 2006 , 87 , 2842–2850. [ Google Scholar ] [ CrossRef ] Crowe, C.C.; Sanders, W.E., Jr.; Longley, S. Bacterial interference. II. Role of the normal throat flora in prevention of colonization by group A Streptococcus. J. Infect. Dis. 1973 , 128 , 527–532. [ Google Scholar ] [ CrossRef ] Vollaard, E.J.; Clasener, H.A. Colonization resistance. Antimicrob. Agents Chemother. 1994 , 38 , 409–414. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Lloyd-Smith, J.O.; Cross, P.C.; Briggs, C.J.; Daugherty, M.; Getz, W.M.; Latto, J.; Sanchez, M.S.; Smith, A.B.; Swei, A. Should we expect population thresholds for wildlife disease? Trends Ecol. Evol. 2005 , 20 , 511–519. [ Google Scholar ] [ CrossRef ] [ PubMed ] McCallum, H.; Barlow, N.; Hone, J. How should pathogen transmission be modelled? Trends Ecol. Evol. 2001 , 16 , 295–300. [ Google Scholar ] [ CrossRef ] Murray, K.A.; Preston, N.; Allen, T.; Zambrana-Torrelio, C.; Hosseini, P.R.; Daszak, P. Global biogeography of human infectious diseases. Proc. Natl. Acad. Sci. USA 2015 , 112 , 12746–12751. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Antharam, V.C.; Li, E.C.; Ishmael, A.; Sharma, A.; Mai, V.; Rand, K.H.; Wang, G.P. Intestinal dysbiosis and depletion of butyrogenic bacteria in Clostridium difficile infection and nosocomial diarrhea. J. Clin. Microbiol. 2013 , 51 , 2884–2892. [ Google Scholar ] [ CrossRef ][ Green Version ] Khanna, S.; Pardi, D.S.; Kelly, C.R.; Kraft, C.S.; Dhere, T.; Henn, M.R.; Lombardo, M.J.; Vulic, M.; Ohsumi, T.; Winkler, J.; et al. A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection. J. Infect. Dis. 2016 , 214 , 173–181. [ Google Scholar ] [ CrossRef ][ Green Version ] Namouchi, A.; Didelot, X.; Schock, U.; Gicquel, B.; Rocha, E.P. After the bottleneck: Genome-wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection. Genome Res. 2012 , 22 , 721–734. [ Google Scholar ] [ CrossRef ][ Green Version ] Druilhe, P.; Tall, A.; Sokhna, C. Worms can worsen malaria: Towards a new means to roll back malaria? Trends Parasitol. 2005 , 21 , 359–362. [ Google Scholar ] [ CrossRef ] Spiegel, A.; Tall, A.; Raphenon, G.; Trape, J.F.; Druilhe, P. Increased frequency of malaria attacks in subjects co-infected by intestinal worms and Plasmodium falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 2003 , 97 , 198–199. [ Google Scholar ] [ CrossRef ] Madhi, S.A.; Klugman, K.P.; Vaccine Trialist Group. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat. Med. 2004 , 10 , 811–813. [ Google Scholar ] [ CrossRef ] Weiser, J.N.; Ferreira, D.M.; Paton, J.C. Streptococcus pneumoniae: Transmission, colonization and invasion. Nat. Rev. Microbiol. 2018 , 16 , 355–367. [ Google Scholar ] [ CrossRef ] [ PubMed ] Faden, H.; Duffy, L.; Wasielewski, R.; Wolf, J.; Krystofik, D.; Tung, Y. Relationship between nasopharyngeal colonization and the development of otitis media in children. J. Infect. Dis. 1997 , 175 , 1440–1445. [ Google Scholar ] [ CrossRef ] [ PubMed ] Regev-Yochay, G.; Dagan, R.; Raz, M.; Carmeli, Y.; Shainberg, B.; Derazne, E.; Rahav, G.; Rubinstein, E. Association between carriage of Streptococcus pneumoniae and Staphylococcus aureus in children. JAMA 2004 , 292 , 716–720. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Sá-Leão, R.; Nunes, S.; Brito-Avô, A.; Alves, C.R.; Carriço, J.A.; Saldanha, J.; Almeida, J.S.; Santos-Sanches, I.; de Lencastre, H. High rates of transmission of and colonization by Streptococcus pneumoniae and Haemophilus influenzae within a day care center revealed in a longitudinal study. J. Clin. Microbiol. 2008 , 46 , 225–234. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Gray, B.M.; Converse, G.M., 3rd; Dillon, H.C., Jr. Epidemiologic studies of Streptococcus pneumoniae in infants: Acquisition, carriage, and infection during the first 24 months of life. J. Infect. Dis. 1980 , 142 , 923–933. [ Google Scholar ] [ CrossRef ] [ PubMed ] Lloyd-Evans, N.; O’Dempsey, T.J.; Baldeh, I.; Secka, O.; Demba, E.; Todd, J.E.; McArdle, T.F.; Banya, W.S.; Greenwood, B.M. Nasopharyngeal carriage of pneumococci in Gambian children and in their families. Pediatr. Infect. Dis. J. 1996 , 15 , 866–871. [ Google Scholar ] [ CrossRef ] Usuf, E.; Bottomley, C.; Adegbola, R.A.; Hall, A. Pneumococcal carriage in sub-Saharan Africa—A systematic review. PLoS ONE 2014 , 9 , e85001. [ Google Scholar ] [ CrossRef ][ Green Version ] Goldblatt, D.; Hussain, M.; Andrews, N.; Ashton, L.; Virta, C.; Melegaro, A.; Pebody, R.; George, R.; Soininen, A.; Edmunds, J.; et al. Antibody responses to nasopharyngeal carriage of Streptococcus pneumoniae in adults: A longitudinal household study. J. Infect. Dis. 2005 , 192 , 387–393. [ Google Scholar ] [ CrossRef ][ Green Version ] Kulohoma, B.W.; Cornick, J.E.; Chaguza, C.; Yalcin, F.; Harris, S.R.; Gray, K.J.; Kiran, A.M.; Molyneux, E.; French, N.; Parkhill, J.; et al. Comparative genomic analysis of meningitis- and bacteremia-causing pneumococci identifies a common core genome. Infect. Immun. 2015 , 83 , 4165–4173. [ Google Scholar ] [ CrossRef ][ Green Version ] Whitney, C.G.; Farley, M.M.; Hadler, J.; Harrison, L.H.; Bennett, N.M.; Lynfield, R.; Reingold, A.; Cieslak, P.R.; Pilishvili, T.; Jackson, D. Decline in invasive pneumococcal disease after the introduction of protein–polysaccharide conjugate vaccine. N. Engl. J. Med. 2003 , 348 , 1737–1746. [ Google Scholar ] [ CrossRef ][ Green Version ] Bogaert, D.; De Groot, R.; Hermans, P.W. Streptococcus pneumoniae colonisation: The key to pneumococcal disease. Lancet Infect. Dis. 2004 , 4 , 144–154. [ Google Scholar ] [ CrossRef ] Smith, A.F.; Waycaster, C. Estimate of the direct and indirect annual cost of bacterial conjunctivitis in the United States. BMC Ophthalmol. 2009 , 9 , 13. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Alsarraf, R.; Jung, C.J.; Perkins, J.; Crowley, C.; Alsarraf, N.W.; Gates, G.A. Measuring the indirect and direct costs of acute otitis media. Arch. Otolaryngol. Head Neck Surg. 1999 , 125 , 12–18. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Drijkoningen, J.J.; Rohde, G.G. Pneumococcal infection in adults: Burden of disease. Clin. Microbiol. Infect. 2014 , 20 (Suppl. 5), 45–51. [ Google Scholar ] [ CrossRef ][ Green Version ] Said, M.A.; Johnson, H.L.; Nonyane, B.A.; Deloria-Knoll, M.; Katherine, L.; Team, A.A.P.B.S. Estimating the burden of pneumococcal pneumonia among adults: A systematic review and meta-analysis of diagnostic techniques. PLoS ONE 2013 , 8 , e60273. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Scott, J.A. The preventable burden of pneumococcal disease in the developing world. Vaccine 2007 , 25 , 2398–2405. [ Google Scholar ] [ CrossRef ] Brueggemann, A.B.; Pai, R.; Crook, D.W.; Beall, B. Vaccine escape recombinants emerge after pneumococcal vaccination in the United States. PLoS Pathog. 2007 , 3 , e168. [ Google Scholar ] [ CrossRef ][ Green Version ] Golubchik, T.; Brueggemann, A.B.; Street, T.; Gertz, R.E., Jr.; Spencer, C.C.; Ho, T.; Giannoulatou, E.; Link-Gelles, R.; Harding, R.M.; Beall, B. Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event. Nat. Genet. 2012 , 44 , 352. [ Google Scholar ] [ CrossRef ][ Green Version ] Geno, K.A.; Gilbert, G.L.; Song, J.Y.; Skovsted, I.C.; Klugman, K.P.; Jones, C.; Konradsen, H.B.; Nahm, M.H. Pneumococcal capsules and their types: Past, present, and future. Clin. Microbiol. Rev. 2015 , 28 , 871–899. [ Google Scholar ] [ CrossRef ][ Green Version ] Tettelin, H.; Nelson, K.E.; Paulsen, I.T.; Eisen, J.A.; Read, T.D.; Peterson, S.; Heidelberg, J.; DeBoy, R.T.; Haft, D.H.; Dodson, R.J.; et al. Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science 2001 , 293 , 498–506. [ Google Scholar ] [ CrossRef ][ Green Version ] Keller, L.E.; Robinson, D.A.; McDaniel, L.S. Nonencapsulated Streptococcus pneumoniae: Emergence and pathogenesis. MBio 2016 , 7 , e01792. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Nelson, A.L.; Roche, A.M.; Gould, J.M.; Chim, K.; Ratner, A.J.; Weiser, J.N. Capsule enhances pneumococcal colonization by limiting mucus-mediated clearance. Infect. Immun. 2007 , 75 , 83–90. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Shainheit, M.G.; Valentino, M.D.; Gilmore, M.S.; Camilli, A. Mutations in pneumococcal cpsE generated via in vitro serial passaging reveal a potential mechanism of reduced encapsulation utilized by a conjunctival isolate. J. Bacteriol. 2015 , 197 , 1781–1791. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Berrón, S.; Fenoll, A.; Ortega, M.; Arellano, N.; Casal, J. Analysis of the genetic structure of nontypeable pneumococcal strains isolated from conjunctiva. J. Clin. Microbiol. 2005 , 43 , 1694–1698. [ Google Scholar ] [ CrossRef ][ Green Version ] Carvalho, M.G.S.; Steigerwalt, A.G.; Thompson, T.; Jackson, D.; Facklam, R.R. Confirmation of nontypeable Streptococcus pneumoniae-like organisms isolated from outbreaks of epidemic conjunctivitis as Streptococcus pneumoniae. J. Clin. Microbiol. 2003 , 41 , 4415–4417. [ Google Scholar ] [ CrossRef ][ Green Version ] Whatmore, A.M.; Efstratiou, A.; Pickerill, A.P.; Broughton, K.; Woodard, G.; Sturgeon, D.; George, R.; Dowson, C.G. Genetic relationships between clinical isolates of streptococcus pneumoniae, streptococcus oralis, and streptococcus mitis: Characterization of “atypical” pneumococci and organisms allied to S. Mitis Harboring S. Pneumoniae virulence factor-encoding genes. Infect. Immun. 2000 , 68 , 1374–1382. [ Google Scholar ] [ CrossRef ][ Green Version ] Haas, W.; Hesje, C.K.; Sanfilippo, C.M.; Morris, T.W. High proportion of nontypeable Streptococcus pneumoniae isolates among sporadic, nonoutbreak cases of bacterial conjunctivitis. Curr. Eye Res. 2011 , 36 , 1078–1085. [ Google Scholar ] [ CrossRef ] Hanage, W.; Kaijalainen, T.; Saukkoriipi, A.; Rickcord, J.; Spratt, B. A successful, diverse disease-associated lineage of nontypeable pneumococci that has lost the capsular biosynthesis locus. J. Clin. Microbiol. 2006 , 44 , 743–749. [ Google Scholar ] [ CrossRef ][ Green Version ] Sá-Leão, R.; Simões, A.S.; Nunes, S.; Sousa, N.G.; Frazão, N.; De Lencastre, H. Identification, prevalence and population structure of non-typable Streptococcus pneumoniae in carriage samples isolated from preschoolers attending day-care centres. Microbiology 2006 , 152 , 367–376. [ Google Scholar ] [ CrossRef ][ Green Version ] Shayegani, M.; Parsons, L.M.; Gibbons, W.E., Jr.; Campbell, D. Characterization of nontypable Streptococcus pneumoniae-like organisms isolated from outbreaks of conjunctivitis. J. Clin. Microbiol. 1982 , 16 , 8–14. [ Google Scholar ] Lagos, R.; Muñoz, A.; Martin, O.S.; Maldonado, A.; Hormazabal, J.C.; Blackwelder, W.C.; Levine, M.M. Age-and serotype-specific pediatric invasive pneumococcal disease: Insights from systematic surveillance in Santiago, Chile, 1994–2007. J. Infect. Dis. 2008 , 198 , 1809–1817. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Bradshaw, J.L.; Pipkins, H.R.; Keller, L.E.; Pendarvis, J.K.; McDaniel, L.S. Mucosal infections and invasive potential of nonencapsulated Streptococcus pneumoniae are enhanced by oligopeptide binding proteins AliC and AliD. MBio 2018 , 9 . [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Martin, C.S.; Bradshaw, J.L.; Pipkins, H.R.; McDaniel, L.S. Pulmonary disease associated with nonencapsulated Streptococcus pneumoniae. Open Forum Infect. Dis. 2018 , 5 , ofy135. [ Google Scholar ] [ CrossRef ] [ PubMed ] Porat, N.; Greenberg, D.; Givon-Lavi, N.; Shuval, D.S.; Trefler, R.; Segev, O.; Hanage, W.P.; Dagan, R. The important role of nontypable Streptococcus pneumoniae international clones in acute conjunctivitis. J. Infect. Dis. 2006 , 194 , 689–696. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Martin, M.; Turco, J.H.; Zegans, M.E.; Facklam, R.R.; Sodha, S.; Elliott, J.A.; Pryor, J.H.; Beall, B.; Erdman, D.D.; Baumgartner, Y.Y. An outbreak of conjunctivitis due to atypical Streptococcus pneumoniae. N. Engl. J. Med. 2003 , 348 , 1112–1121. [ Google Scholar ] [ CrossRef ] [ PubMed ] Crum, N.F.; Barrozo, C.P.; Chapman, F.A.; Ryan, M.A.; Russell, K.L. An outbreak of conjunctivitis due to a novel unencapsulated Streptococcus pneumoniae among military trainees. Clin. Infect. Dis. 2004 , 39 , 1148–1154. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Xu, Q.; Kaur, R.; Casey, J.R.; Sabharwal, V.; Pelton, S.; Pichichero, M.E. Nontypeable Streptococcus pneumoniae as an otopathogen. Diagn. Microbiol. Infect. Dis. 2011 , 69 , 200–204. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Onwubiko, C.; Shires, C.; Quin, L.R.; Swiatlo, E.; McDaniel, L.S. Characterization of Streptococcus pneumoniae isolated from children with otitis media. FEMS Immunol. Med. Microbiol. 2007 , 50 , 119–125. [ Google Scholar ] [ CrossRef ][ Green Version ] Hathaway, L.J.; Meier, P.S.; Bättig, P.; Aebi, S.; Mühlemann, K. A homologue of aliB is found in the capsule region of nonencapsulated Streptococcus pneumoniae. J. Bacteriol. 2004 , 186 , 3721–3729. [ Google Scholar ] [ CrossRef ][ Green Version ] Antic, I.; Brothers, K.M.; Stolzer, M.; Lai, H.; Powell, E.; Eutsey, R.; Cuevas, R.A.; Miao, X.; Kowalski, R.P.; Shanks, R.M. Gene acquisition by a distinct phyletic group within Streptococcus pneumoniae promotes adhesion to the ocular epithelium. mSphere 2017 , 2 , e00213-17. [ Google Scholar ] [ CrossRef ][ Green Version ] Croucher, N.J.; Coupland, P.G.; Stevenson, A.E.; Callendrello, A.; Bentley, S.D.; Hanage, W.P. Diversification of bacterial genome content through distinct mechanisms over different timescales. Nat. Commun. 2014 , 5 , 5471. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Hilty, M.; Wüthrich, D.; Salter, S.J.; Engel, H.; Campbell, S.; Sá-Leão, R.; De Lencastre, H.; Hermans, P.; Sadowy, E.; Turner, P. Global phylogenomic analysis of nonencapsulated Streptococcus pneumoniae reveals a deep-branching classic lineage that is distinct from multiple sporadic lineages. Genome Biol. Evol. 2014 , 6 , 3281–3294. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Croucher, N.J.; Finkelstein, J.A.; Pelton, S.I.; Mitchell, P.K.; Lee, G.M.; Parkhill, J.; Bentley, S.D.; Hanage, W.P.; Lipsitch, M. Population genomics of post-vaccine changes in pneumococcal epidemiology. Nat. Genet. 2013 , 45 , 656–663. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Lebreton, F.; van Schaik, W.; McGuire, A.M.; Godfrey, P.; Griggs, A.; Mazumdar, V.; Corander, J.; Cheng, L.; Saif, S.; Young, S.; et al. Emergence of epidemic multidrug-resistant Enterococcus faecium from animal and commensal strains. MBio 2013 , 4 , e00534-13. [ Google Scholar ] [ CrossRef ][ Green Version ] Weinert, L.A.; Welch, J.J.; Suchard, M.A.; Lemey, P.; Rambaut, A.; Fitzgerald, J.R. Molecular dating of human-to-bovid host jumps by Staphylococcus aureus reveals an association with the spread of domestication. Biol. Lett. 2012 , 8 , 829–832. [ Google Scholar ] [ CrossRef ][ Green Version ] Wurster, J.I.; Saavedra, J.T.; Gilmore, M.S. Impact of antibiotic use on the evolution of Enterococcus faecium. J. Infect. Dis. 2016 , 213 , 1862–1865. [ Google Scholar ] [ CrossRef ][ Green Version ] Konstantinidis, K.T.; Tiedje, J.M. Genomic insights that advance the species definition for prokaryotes. Proc. Natl. Acad. Sci. USA 2005 , 102 , 2567–2572. [ Google Scholar ] [ CrossRef ][ Green Version ] Konstantinidis, K.T.; Ramette, A.; Tiedje, J.M. The bacterial species definition in the genomic era. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2006 , 361 , 1929–1940. [ Google Scholar ] [ CrossRef ] Guindon, S.; Dufayard, J.F.; Lefort, V.; Anisimova, M.; Hordijk, W.; Gascuel, O. New algorithms and methods to estimate maximum-likelihood phylogenies: Assessing the performance of PhyML 3.0. Syst. Biol. 2010 , 59 , 307–321. [ Google Scholar ] [ CrossRef ][ Green Version ] Feil, E.J.; Spratt, B.G. Recombination and the population structures of bacterial pathogens. Annu. Rev. Microbiol. 2001 , 55 , 561–590. [ Google Scholar ] [ CrossRef ] Donkor, E.S. Understanding the pneumococcus: Transmission and evolution. Front. Cell. Infect. Microbiol. 2013 , 3 , 7. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Hanage, W.P.; Fraser, C.; Tang, J.; Connor, T.R.; Corander, J. Hyper-recombination, diversity, and antibiotic resistance in pneumococcus. Science 2009 , 324 , 1454–1457. [ Google Scholar ] [ CrossRef ] [ PubMed ] Croucher, N.J.; Harris, S.R.; Fraser, C.; Quail, M.A.; Burton, J.; van der Linden, M.; McGee, L.; von Gottberg, A.; Song, J.H.; Ko, K.S.; et al. Rapid pneumococcal evolution in response to clinical interventions. Science 2011 , 331 , 430–434. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Mostowy, R.J.; Croucher, N.J.; De Maio, N.; Chewapreecha, C.; Salter, S.J.; Turner, P.; Aanensen, D.M.; Bentley, S.D.; Didelot, X.; Fraser, C. Pneumococcal capsule synthesis locus cps as evolutionary hotspot with potential to generate novel serotypes by recombination. Mol. Biol. Evol. 2017 , 34 , 2537–2554. [ Google Scholar ] [ CrossRef ] [ PubMed ] Avery, O.T.; Macleod, C.M.; McCarty, M. Studies on the chemical nature of the substance inducing transformation of pneumococcal types: Induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type iii. J. Exp. Med. 1944 , 79 , 137–158. [ Google Scholar ] [ CrossRef ] Claverys, J.P.; Prudhomme, M.; Mortier-Barriere, I.; Martin, B. Adaptation to the environment: Streptococcus pneumoniae, a paradigm for recombination-mediated genetic plasticity? Mol. Microbiol. 2000 , 35 , 251–259. [ Google Scholar ] [ CrossRef ] Lacks, S. Molecular fate of DNA in genetic transformation of Pneumococcus. J. Mol. Biol. 1962 , 5 , 119–131. [ Google Scholar ] [ CrossRef ] Bergé, M.; Moscoso, M.; Prudhomme, M.; Martin, B.; Claverys, J.P. Uptake of transforming DNA in Gram-positive bacteria: A view from Streptococcus pneumoniae. Mol. Microbiol. 2002 , 45 , 411–421. [ Google Scholar ] [ CrossRef ] Prudhomme, M.; Libante, V.; Claverys, J.P. Homologous recombination at the border: Insertion-deletions and the trapping of foreign DNA in Streptococcus pneumoniae. Proc. Natl. Acad. Sci. USA 2002 , 99 , 2100–2105. [ Google Scholar ] [ CrossRef ][ Green Version ] Bradshaw, J.L.; McDaniel, L.S. Selective pressure: Rise of the nonencapsulated pneumococcus. PLoS Pathog. 2019 , 15 , e1007911. [ Google Scholar ] [ CrossRef ] Bentley, S.D.; Aanensen, D.M.; Mavroidi, A.; Saunders, D.; Rabbinowitsch, E.; Collins, M.; Donohoe, K.; Harris, D.; Murphy, L.; Quail, M.A. Genetic analysis of the capsular biosynthetic locus from all 90 pneumococcal serotypes. PLoS Genet. 2006 , 2 , e31. [ Google Scholar ] [ CrossRef ][ Green Version ] Coffey, T.J.; Enright, M.C.; Daniels, M.; Morona, J.K.; Morona, R.; Hryniewicz, W.; Paton, J.C.; Spratt, B.G. Recombinational exchanges at the capsular polysaccharide biosynthetic locus lead to frequent serotype changes among natural isolates of Streptococcus pneumoniae. Mol. Microbiol. 1998 , 27 , 73–83. [ Google Scholar ] [ CrossRef ] [ PubMed ] Henriques-Normark, B.; Blomberg, C.; Dagerhamn, J.; Battig, P.; Normark, S. The rise and fall of bacterial clones: Streptococcus pneumoniae. Nat. Rev. Microbiol. 2008 , 6 , 827–837. [ Google Scholar ] [ CrossRef ] [ PubMed ] Brueggemann, A.B.; Harrold, C.L.; Rezaei Javan, R.; van Tonder, A.J.; McDonnell, A.J.; Edwards, B.A. Pneumococcal prophages are diverse, but not without structure or history. Sci. Rep. 2017 , 7 , 42976. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Romero, P.; Croucher, N.J.; Hiller, N.L.; Hu, F.Z.; Ehrlich, G.D.; Bentley, S.D.; Garcia, E.; Mitchell, T.J. Comparative genomic analysis of ten Streptococcus pneumoniae temperate bacteriophages. J. Bacteriol. 2009 , 191 , 4854–4862. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Croucher, N.J.; Walker, D.; Romero, P.; Lennard, N.; Paterson, G.K.; Bason, N.C.; Mitchell, A.M.; Quail, M.A.; Andrew, P.W.; Parkhill, J.; et al. Role of conjugative elements in the evolution of the multidrug-resistant pandemic clone Streptococcus pneumoniae Spain23F ST81. J. Bacteriol. 2009 , 191 , 1480–1489. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Chancey, S.T.; Agrawal, S.; Schroeder, M.R.; Farley, M.M.; Tettelin, H.; Stephens, D.S. Composite mobile genetic elements disseminating macrolide resistance in Streptococcus pneumoniae. Front. Microbiol. 2015 , 6 , 26. [ Google Scholar ] [ CrossRef ][ Green Version ] Croucher, N.J.; Chewapreecha, C.; Hanage, W.P.; Harris, S.R.; McGee, L.; van der Linden, M.; Song, J.H.; Ko, K.S.; de Lencastre, H.; Turner, C.; et al. Evidence for soft selective sweeps in the evolution of pneumococcal multidrug resistance and vaccine escape. Genome Biol. Evol. 2014 , 6 , 1589–1602. [ Google Scholar ] [ CrossRef ] Chewapreecha, C.; Harris, S.R.; Croucher, N.J.; Turner, C.; Marttinen, P.; Cheng, L.; Pessia, A.; Aanensen, D.M.; Mather, A.E.; Page, A.J.; et al. Dense genomic sampling identifies highways of pneumococcal recombination. Nat. Genet. 2014 , 46 , 305–309. [ Google Scholar ] [ CrossRef ][ Green Version ] Marks, L.R.; Reddinger, R.M.; Hakansson, A.P. High levels of genetic recombination during nasopharyngeal carriage and biofilm formation in Streptococcus pneumoniae. MBio 2012 , 3 , e00200-12. [ Google Scholar ] [ CrossRef ][ Green Version ] Pearce, B.J.; Iannelli, F.; Pozzi, G. Construction of new unencapsulated (rough) strains of Streptococcus pneumoniae. Res. Microbiol. 2002 , 153 , 243–247. [ Google Scholar ] [ CrossRef ] Chaguza, C.; Cornick, J.E.; Everett, D.B. Mechanisms and impact of genetic recombination in the evolution of Streptococcus pneumoniae. Comput. Struct. Biotechnol. J. 2015 , 13 , 241–247. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Kilian, M.; Riley, D.R.; Jensen, A.; Bruggemann, H.; Tettelin, H. Parallel evolution of Streptococcus pneumoniae and Streptococcus mitis to pathogenic and mutualistic lifestyles. MBio 2014 , 5 , e01490-14. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Norcross, E.W.; Tullos, N.A.; Taylor, S.D.; Sanders, M.E.; Marquart, M.E. Assessment of Streptococcus pneumoniae capsule in conjunctivitis and keratitis in vivo neuraminidase activity increases in nonencapsulated pneumococci following conjunctival infection. Curr. Eye Res. 2010 , 35 , 787–798. [ Google Scholar ] [ CrossRef ][ Green Version ] Menon, B.B.; Govindarajan, B. Identification of an atypical zinc metalloproteinase, ZmpC, from an epidemic conjunctivitis-causing strain of Streptococcus pneumoniae. Microb. Pathog. 2013 , 56 , 40–46. [ Google Scholar ] [ CrossRef ][ Green Version ] Nekola, J.C.; White, P.S. The distance decay of similarity in biogeography and ecology. J. Biogeogr. 1999 , 26 , 867–878. [ Google Scholar ] [ CrossRef ][ Green Version ] Bell, T. Experimental tests of the bacterial distance-decay relationship. ISME J. 2010 , 4 , 1357–1365. [ Google Scholar ] [ CrossRef ][ Green Version ] Doan, T.; Akileswaran, L.; Andersen, D.; Johnson, B.; Ko, N.; Shrestha, A.; Shestopalov, V.; Lee, C.S.; Lee, A.Y.; Van Gelder, R.N. Paucibacterial microbiome and resident DNA virome of the healthy conjunctiva. Invest. Ophthalmol. Vis. Sci. 2016 , 57 , 5116–5126. [ Google Scholar ] [ CrossRef ][ Green Version ] Sokurenko, E.V.; Gomulkiewicz, R.; Dykhuizen, D.E. Source–sink dynamics of virulence evolution. Nat. Rev. Microbiol. 2006 , 4 , 548–555. [ Google Scholar ] [ CrossRef ] Perron, G.G.; Gonzalez, A.; Buckling, A. Source–sink dynamics shape the evolution of antibiotic resistance and its pleiotropic fitness cost. Proc. Biol. Sci. 2007 , 274 , 2351–2356. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Holt, R.; Gomulkiewicz, R. Conservation implication of niche conservatism and evolution in heterogeneous environments. In Evolutionary Conservation Biology ; Ferriere, R., Dieckmann, U., Couvet, D., Eds.; Cambridge University Press: New York, NY, USA, 2004; pp. 244–264. [ Google Scholar ] Pulliam, H.R. Sources, sinks, and population regulation. Am. Nat. 1988 , 132 , 652–661. [ Google Scholar ] [ CrossRef ] Gomulkiewicz, R.; Holt, R.D.; Barfield, M. The effects of density dependence and immigration on local adaptation and niche evolution in a black-hole sink environment. Theor. Popul. Biol. 1999 , 55 , 283–296. [ Google Scholar ] [ CrossRef ] [ PubMed ] Holt, R.D. Adaptive evolution in source-sink environments: Direct and indirect effects of density-dependence on niche evolution. Oikos 1996 , 75 , 182–192. [ Google Scholar ] [ CrossRef ] Mehr, S.; Wood, N. Streptococcus pneumoniae—A review of carriage, infection, serotype replacement and vaccination. Paediatr. Respir. Rev. 2012 , 13 , 258–264. [ Google Scholar ] [ CrossRef ] [ PubMed ] Quintero, B.; Araque, M.; van der Gaast-de Jongh, C.; Escalona, F.; Correa, M.; Morillo-Puente, S.; Vielma, S.; Hermans, P.W. Epidemiology of Streptococcus pneumoniae and Staphylococcus aureus colonization in healthy Venezuelan children. Eur. J. Clin. Microbiol. 2011 , 30 , 7–19. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Miller, E.; Andrews, N.J.; Waight, P.A.; Slack, M.P.; George, R.C. Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: An observational cohort study. Lancet Infect. Dis. 2011 , 11 , 760–768. [ Google Scholar ] [ CrossRef ] Tan, T.Q. Pediatric invasive pneumococcal disease in the United States in the era of pneumococcal conjugate vaccines. Clin. Microbiol. Rev. 2012 , 25 , 409–419. [ Google Scholar ] [ CrossRef ][ Green Version ] Mackenzie, G.A.; Hill, P.C.; Jeffries, D.J.; Hossain, I.; Uchendu, U.; Ameh, D.; Ndiaye, M.; Adeyemi, O.; Pathirana, J.; Olatunji, Y.; et al. Effect of the introduction of pneumococcal conjugate vaccination on invasive pneumococcal disease in The Gambia: A population-based surveillance study. Lancet Infect. Dis. 2016 , 16 , 703–711. [ Google Scholar ] [ CrossRef ][ Green Version ] Olwagen, C.P.; Adrian, P.V.; Nunes, M.C.; Madhi, S.A. Evaluation of the association of pneumococcal conjugate vaccine immunization and density of nasopharyngeal bacterial colonization using a multiplex quantitative polymerase chain reaction assay. Vaccine 2018 , 36 , 3278–3285. [ Google Scholar ] [ CrossRef ] Hausdorff, W.P.; Hanage, W.P. Interim results of an ecological experiment—Conjugate vaccination against the pneumococcus and serotype replacement. Hum. Vaccines Immunother. 2016 , 12 , 358–374. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Pai, R.; Moore, M.R.; Pilishvili, T.; Gertz, R.E.; Whitney, C.G.; Beall, B.; Active Bacterial Core Surveillance Team. Postvaccine genetic structure of Streptococcus pneumoniae serotype 19A from children in the United States. J. Infect. Dis. 2005 , 192 , 1988–1995. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Dagan, R. Impact of pneumococcal conjugate vaccine on infections caused by antibiotic-resistant Streptococcus pneumoniae. Clin. Microbiol. Infect. 2009 , 15 (Suppl. 3), 16–20. [ Google Scholar ] [ CrossRef ][ Green Version ] van Gils, E.J.; Hak, E.; Veenhoven, R.H.; Rodenburg, G.D.; Bogaert, D.; Bruin, J.P.; van Alphen, L.; Sanders, E.A. Effect of seven-valent pneumococcal conjugate vaccine on Staphylococcus aureus colonisation in a randomised controlled trial. PLoS ONE 2011 , 6 , e20229. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Madhi, S.A.; Nunes, M.C. The potential impact of pneumococcal conjugate vaccine in Africa: Considerations and early lessons learned from the South African experience. Hum. Vaccines Immunother. 2016 , 12 , 314–325. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Reiss-Mandel, A.; Regev-Yochay, G. Staphylococcus aureus and Streptococcus pneumoniae interaction and response to pneumococcal vaccination: Myth or reality? Hum. Vaccines Immunother. 2016 , 12 , 351–357. [ Google Scholar ] [ CrossRef ][ Green Version ] David, M.Z.; Daum, R.S. Community-associated methicillin-resistant Staphylococcus aureus: Epidemiology and clinical consequences of an emerging epidemic. Clin. Microbiol. Rev. 2010 , 23 , 616–687. [ Google Scholar ] [ CrossRef ][ Green Version ] Creech, C.B., 2nd; Kernodle, D.S.; Alsentzer, A.; Wilson, C.; Edwards, K.M. Increasing rates of nasal carriage of methicillin-resistant Staphylococcus aureus in healthy children. Pediatr. Infect. Dis. J. 2005 , 24 , 617–621. [ Google Scholar ] [ CrossRef ] Sa-Leao, R.; Nunes, S.; Brito-Avo, A.; Frazao, N.; Simoes, A.; Crisostomo, M.; Paulo, A.; Saldanha, J.; Santos-Sanches, I.; De Lencastre, H. Changes in pneumococcal serotypes and antibiotypes carried by vaccinated and unvaccinated day-care centre attendees in Portugal, a country with widespread use of the seven-valent pneumococcal conjugate vaccine. Clin. Microbiol. Infect. 2009 , 15 , 1002–1007. [ Google Scholar ] [ CrossRef ][ Green Version ] McDaniel, L.S.; Swiatlo, E. Should pneumococcal vaccines eliminate nasopharyngeal colonization? MBio 2016 , 7 . [ Google Scholar ] [ CrossRef ][ Green Version ] Hauser, C.; Aebi, S.; Muhlemann, K. An internationally spread clone of Streptococcus pneumoniae evolves from low-level to higher-level penicillin resistance by uptake of penicillin-binding protein gene fragments from nonencapsulated pneumococci. Antimicrob. Agents Chemother. 2004 , 48 , 3563–3566. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ] Figure 1. Synthesis of interdependent ecological factors which explain patterns of microbial biogeography across a variety of spatial scales, as proposed by Vellend’s Conceptual Synthesis in Community Ecology (2010) [ 22 ]. We included a fourth dimension—that of individual anatomy, to demonstrate that specific biogeographical patterns occur even on a tissue and cellular level. Figure 1. Synthesis of interdependent ecological factors which explain patterns of microbial biogeography across a variety of spatial scales, as proposed by Vellend’s Conceptual Synthesis in Community Ecology (2010) [ 22 ]. We included a fourth dimension—that of individual anatomy, to demonstrate that specific biogeographical patterns occur even on a tissue and cellular level. Figure 2. Phylogenetic tree of conjunctivitis strains of S. pneumoniae based on multilocus sequence typing, constructed using the phylogeny software PhyML [ 115 ]. An associated bar graph demonstrates the percentage prevalence in 271 sequenced strains from the US. The analysis of single nucleotide polymorphisms within these strains demonstrated that the overwhelming majority of nonencapsulated conjunctivitis strains localized to a distinct phylogenetic cluster. Reprinted with author permission [ 10 ]. Figure 2. Phylogenetic tree of conjunctivitis strains of S. pneumoniae based on multilocus sequence typing, constructed using the phylogeny software PhyML [ 115 ]. An associated bar graph demonstrates the percentage prevalence in 271 sequenced strains from the US. The analysis of single nucleotide polymorphisms within these strains demonstrated that the overwhelming majority of nonencapsulated conjunctivitis strains localized to a distinct phylogenetic cluster. Reprinted with author permission [ 10 ]. Figure 3. The distinct epidemic conjunctivitis cluster (ECC) of S. pneumoniae , consisting of ST448, ST344, ST1186, ST1270 and ST2315 (printed in red). Like Figure 2 , this phylogenetic tree was constructed using PhyML, based on a concatenated set of 1160 core orthogroups, and which included S. mitis (strain B6) as a related group. Reprinted with author permission [ 10 ]. Figure 3. The distinct epidemic conjunctivitis cluster (ECC) of S. pneumoniae , consisting of ST448, ST344, ST1186, ST1270 and ST2315 (printed in red). Like Figure 2 , this phylogenetic tree was constructed using PhyML, based on a concatenated set of 1160 core orthogroups, and which included S. mitis (strain B6) as a related group. Reprinted with author permission [ 10 ]. Ung, L.; Bispo, P.J.M.; Bryan, N.C.; Andre, C.; Chodosh, J.; Gilmore, M.S. The Best of All Worlds: Streptococcus pneumoniaeConjunctivitis through the Lens of Community Ecology and Microbial Biogeography. Microorganisms 2020, 8, 46. https://doi.org/10.3390/microorganisms8010046 Ung L, Bispo PJM, Bryan NC, Andre C, Chodosh J, Gilmore MS. The Best of All Worlds: Streptococcus pneumoniaeConjunctivitis through the Lens of Community Ecology and Microbial Biogeography. Microorganisms. 2020; 8(1):46. https://doi.org/10.3390/microorganisms8010046 Ung, Lawson, Paulo J. M. Bispo, Noelle C. Bryan, Camille Andre, James Chodosh, and Michael S. Gilmore. 2020. "The Best of All Worlds: Streptococcus pneumoniaeConjunctivitis through the Lens of Community Ecology and Microbial Biogeography" Microorganisms8, no. 1: 46. https://doi.org/10.3390/microorganisms8010046
https://www.mdpi.com/2076-2607/8/1/46/xml
Towards safer risperidone prescribing in Alzheimer’s disease | medRxiv medRxiv - The Preprint Server for Health Sciences Towards safer risperidone prescribing in Alzheimer’s disease Suzanne Reeves , Julie Bertrand , Hiroyuki Uchida , Kazunari Yoshida , Yohei Otani , Mikail Ozer , Kathy Y Liu , Elvira Bramon , Robert Bies , Bruce Pollock , Robert Howard doi: https://doi.org/10.1101/2020.08.12.20173310 Now published in The British Journal of Psychiatry doi: 10.1192/bjp.2020.225 Abstract Full Text Abstract BackgroundIn the treatment of psychosis, agitation and aggression in Alzheimer’s disease (AD), guidelines emphasise the need to ‘use the lowest possible dose’ of antipsychotic drugs, but provide no information on optimal dosing. AimsThis analysis investigated the pharmacokinetic profiles of risperidone and active metabolite, 9-hydroxy (OH)-risperidone, and how this related to emergent extrapyramidal side effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness-AD study. MethodA statistical model, which described the concentration-time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and ‘active moiety’ (combined concentrations) (108 CATIE-AD participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model based predictions were used to simulate the dose adjustments needed to avoid EPS. ResultsThe model showed an age-related reduction in risperidone clearance (p<0.0001), and estimated that 22% of patients had slower active moiety clearance (concentration-to-dose ratio 20.2±7.2 versus 7.6±4.9 ng/mL per mg/day, Mann Whitney U, p<0.0001). Higher average and trough 9-OH-risperidone concentrations ( p<0.0001), and lower Mini-Mental State Examination (MMSE) scores (p<0.0001), were associated with EPS. Model based predictions suggest the optimum dose ranged from 0.25mg/day in those aged 85 years with MMSEs of 5, to 1mg/day in those aged 75 years with MMSEs of 15, with alternate day dosing required for those with slower drug clearance. ConclusionsOur findings argue for age- and MMSE -related dose adjustments and suggest that a single plasma sample could be used to identify those with slower drug clearance. Introduction Antipsychotic drug use in Alzheimer’s disease Alzheimer’s disease affects around 35 million people worldwide, fifty percent of whom will experience psychosis symptoms (delusions and hallucinations). (1) Psychosis symptoms are often distressing, increase the risk of aggression towards caregivers, predict faster cognitive and functional decline, and reduce ability to live independently (2). Although symptoms sometimes respond to psychosocial interventions, for those with severe persistent symptoms, antipsychotic medication is required to reduce distress and associated risks. (3) The best evidence of efficacy is for second generation antipsychotic drugs. (4) However, concerns about side-effects (sedation, falls, parkinsonism, and stroke) and increased mortality in people with dementia, (5,6) particularly in those aged over 80 years, (7) has led to a restriction in prescribing. In England, National Institute for Clinical Excellence (NICE) guidance emphasises the need to treat with ‘the lowest effective dose for the shortest possible time’ but provides little practical information on the optimal dose range for individual drugs. We have shown that amisulpride therapeutic plasma concentrations for the treatment of AD psychosis (40-100 ng/mL), are lower than those recommended for the treatment of schizophrenia (100-320 ng/mL), due to a leftwards shift in the dopamine D 2/3receptor concentration-occupancy curve. (8) These findings raise questions regarding the mechanisms of antipsychotic sensitivity in AD and suggest that, for amisulpride at least, 50 mg/day (compared to 400-800mg/day in young adults), may optimally balance the risks and benefits of treatment. (9) It is, however, not clear how far we can extrapolate this approach to other antipsychotic drugs. Pharmacokinetics and consensus guidance on risperidone prescribing Risperidone, an antipsychotic drug with high affinity for dopamine D 2/3and serotonin 5HT 2Areceptors, is the only drug licensed for short-term use in the treatment of aggression and psychosis in dementia in the European Union, and is typically prescribed across a 0.5-2 mg/day dose range in this indication. (5,10) Oral risperidone has high (70-85%) bioavailability and is extensively metabolized in the liver by cytochrome P450 2D6 (CYP2D6) to the active metabolite 9-hydroxy (OH)-risperidone. (11) Peak concentrations of risperidone and 9-OH-risperidone are reached after 1 and 3 hours respectively, and steady state concentrations of the active moiety (combined concentrations of risperidone and 9-OH-risperidone) are achieved after 4-5 days. The elimination half-life (t 1/2) of risperidone is dependent on multiple factors. Genetic variation in CYP2D6 genotype accounts for around 50% of the variability in risperidone concentrations (t 1/2for risperidone ranges from 4.7 hours in normal metabolisers to 22 hours in poor metabolisers); with age, hepatobiliary dysfunction, and use of CYP2D6 inhibitors (paroxetine) or inducers (carbamazepine) further contributing to variability (12,13). The metabolite is renally excreted, with a t 1/2of 20 hours; increased to 25 hours in the over-65s and in moderate renal failure. Consensus guidelines, based on therapeutic drug monitoring, (11,14) pharmacokinetic modelling, (15) and imaging of striatal D 2/3receptor occupancy (16) in risperidone treated patients with schizophrenia, recommend active moiety concentrations of 20–40 ng/mL (3-6 mg/day), (15) as higher concentrations increase occupancy beyond 80% and increase the risk of extrapyramidal side-effects (EPS). Recent guidance on personalised risperidone prescribing advocates dose reductions for those with slower clearance of the active moiety, indexed by concentration to dose (C/D) ratios of the active moiety over 14 ng/mL per mg/day. (17) There is a lack of empirical data from people with AD. Aims To investigate sources of variability in plasma concentration-time profiles of risperidone and 9-OH-risperidone, using an approach that allowed estimation of risperidone clearance (metabolism) in distinct subpopulations. To estimate pharmacokinetic indices (peak, trough and average concentrations of risperidone, 9-OH-risperidone and active moiety) for each individual, across the prescribed dose range. To investigate the relationship between the above pharmacokinetic indices with EPS. Method Data source CATIE-AD (6,18) was a randomized, double-blind, parallel group study comparing olanzapine, quetiapine, risperidone and placebo in the treatment of psychosis and aggression in AD (Clinicaltrials.gov identifier:NCT00015548). In phase 1, participants were randomized to receive risperidone, olanzapine, quetiapine, or placebo in a 1:1:1:1 allocation ratio, with study physicians having a choice of two capsule strengths (low or high). For risperidone, this corresponded to 0.5 mg or 1.0 mg. Doses were adjusted as clinically indicated by study physicians. If the physician judged that the patient’s response was not adequate at any time after the first 2 weeks, then treatment could be discontinued, with a further decision point being made at 12 weeks. Patients with an adequate response continued treatment for up to 36 weeks. Patients whose initial treatment was discontinued during phase 1 could be enrolled in phase 2 and randomly assigned under double-blind conditions to receive one of the antipsychotic drugs to which they were not initially assigned, or to receive citalopram. In phase 3, treatment was prescribed in an open manner. Within each phase, plasma drug concentration was measured at 2, 4 and 12 weeks, or when a medication switch was made (6,18).Clinical assessment (Baseline, every 2-4 weeks during dose titration) included the Simpson Angus Scale (SAS), (19) and Barnes Akathisia Scale (BAS). (20) Plasma concentrations of risperidone and the active metabolite 9-OH-risperidone were determined using a liquid chromatography-tandem mass spectrometry method with a detection limit of 0.1 ng/mL. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. Written informed consent was obtained from all patients. (6) A comprehensive plan was developed to ensure that all institutional, National Institute for Health, and federal regulations concerning informed consent were fulfilled. The plan included careful assessment of risks and benefits, review by the CATIE protocol and ethics committees, and re-view by the National Institute of Mental Health Data Safety and Monitoring Board. (18) Data Extraction Data available from risperidone treated participants included study identification number, phase, visit, dose (mg), timing of blood draw (hours post dose), number of days of treatment, dosage interval (daily), physiological characteristics (age, gender, height, weight, ethnicity (coded as white/other), and smoking (currently smoking or not), Mini-Mental State Examination (MMSE) scores, and plasma concentrations of risperidone and 9-OH-risperidone (ng/mL). Treatment emergent EPS were coded as present if SAS total scores were six or more, or BAS global scores were two or more at follow-up, in individuals with Baseline SAS ratings less than six and BAS scores less than two. Only participants without Baseline EPS were included in our analysis of outcome data. Information was cross-checked with adverse event data, to establish if the event was reported during the relevant phase of treatment; coded under Medical Dictionary for Regulatory Activities (MedDRA 4.0) (preferred terms ‘Parkinsonism’, ‘Parkinsonism aggravated’, ‘cogwheel rigidity’, ‘masked facies’, ‘bradykinesia’, ‘tremor’, ‘extrapy rami dal disorder’, ‘drooling’, ‘gait festinating’, akinesia, akathisia, or tardive dyskinesia); and rated as possibly or probably related to treatment. Data extracted on other adverse events included sedation (preferred terms ‘sedation’, ‘somnolence’, ‘hypersomnia’, ‘lethargy’), falls (preferred term ‘fall’), and postural hypotension (preferred term ‘hypotension or hypotension not otherwise specified’). Rating scales and recorded adverse events were checked for consistency with pharmacokinetic data, using phase, number of days treatment, and the timing of blood sampling. Statistical Analysis Demographics Demographic data were analysed using statistical package for social sciences version 22.0. Mann Whitney U tests were used to describe group comparisons. Chi-squared tests were used to compare frequencies between groups. Pharmacokinetic model development Plasma concentration-time profiles of risperidone and 9-OH-risperidone were evaluated using a statistical model (21) that linked parent risperidone and metabolite 9-OH-risperidone via a metabolism rate constant ( km), with the following parameters: i) Risperidone clearance ( CL RISP), ii) Risperidone volume of distribution ( V RISP), iii) Absorption rate constant (ka), iv) 9-OH risperidone volume of distribution ( V 9-OH-RISP), and v) 9-OH-risperidone clearance ( CL 9-OH-RISP). The analysis estimated fixed effects (parameters describing dose-concentration relationships), and random effects, comprised of inter-individual variability (difference between individual and predicted model parameter values for the sample), and residual variability (system noise, dosage history errors). (22) Model development was carried out using Monolix software (version 2018r;www.lixoft.eu). Parameters were estimated using an iterative approach which provided maximum likelihood estimates and standard errors. Plasma concentration was converted from ng/mL to mcg/L for use in model building. The model allowed estimation of the probability of there being more than one subpopulation in relation to risperidone clearance, by including a latent covariate. No assumption was made that latent categories corresponded solely to CYP2D6 genotype, as multiple factors contribute to hepatic metabolism in older people. Residual variability was estimated separately for risperidone and 9-OH-risperidone. Covariates (height, age, gender, smoking, ethnicity, weight) were incorporated in a stepwise manner, through visual inspection of covariate plots and regression analysis in R for categorical covariates. Models were evaluated using goodness-of-fit criteria, including diagnostic scatter plots, visual predictive checks, degree of shrinkage, change in inter-individual variability, model precision, and approximate likelihood ratio tests. A change in log likelihood estimate was considered significant if =>4 (equivalent to p<0.05, one degree of freedom), and accompanied by no change or a decrease in Bayesian Information Criteria. Pharmacokinetic biomarkers and clinical outcome Model based estimates were used to calculate peak, trough, and average concentrations of risperidone, 9-OH-risperidone and active moiety (their combined concentrations) for each individual, across the dosage interval. Concentration-to-dose ratio for the active moiety was calculated from trough estimates, to allow comparison with recommendations regarding personalised dosing of risperidone. (17) Each pharmacokinetic biomarker was individually considered as an independent variable (regressor) in a binary logistic model which described the probability of EPS.. The model accounted for random effects, and adjusted for potential confounders (age, sex, MMSE, height, weight). Best fit models were used to simulate and predict plasma concentrations and probability of response and EPS, accounting for factors that contributed to variability. Results Sample characteristics Of 110 risperidone treated patients, 65 (59.1%) were randomised to risperidone treatment in phase one, 31 (28.2%) in phase two, and 14 (12.7%) in phase three (188 plasma samples, collected 26.9±69.9 hours post dose). After excluding four samples, taken after 180 hours (above six half-lives post dose), data from 108 patients remained (52 (47.3%) men, aged 78.4±6.7 years, weight 68.9±14.7 kg, height 1.6±0.1m, MMSE 14.6 ±6.2); sampled 18.1±26.8 hours post dose, after 92.4±76.8 days treatment with 1.0±0.7 mg/day of risperidone (risperidone plasma concentrations 2.4±3.1ng/mL, 9-OH-risperidone plasma concentrations 10.0±8.4 ng/mL). Eight participants with Baseline SAS scores of six or more (indicating EPS prior to commencing risperidone), were excluded from the analysis of outcome data. Those with Baseline EPS had greater global cognitive impairment (MMSE 7.8±7.0 versus 15.2±5.8, Mann Whitney U, p<0.0001) but there were no differences in other characteristics (Table 1). Treatment emergent EPS occurred in 14 (14%), sedation in 13 (13%), falls in five (5%), postural hypotension in two (2%) and ECG abnormalities in three (3%) patients (Table 1). Those with EPS were prescribed a higher risperidone dose (1.7±0.9mg versus 0.9±0.5mg; Mann Whitney U, p<0.003), had lower MMSE scores (10.2±4.2 versus 16.0±5.6, Mann Whitney U, p<0.0001) and a greater proportion (5 (37.5%) versus 6 (7.0%) patients) were treated with concomitant anti-depressant medication (trazodone) (chi-squared p=0.007, odds ratio = 7.4, 95% CI 1.9-29.2). Table 1. Demographic and Clinical Characteristics of Risperidone-Treated CATIE-AD Participants Pharmacokinetic model The base model included a latent covariate with two categories (the model failed to converge using a covariate with three categories). Parameters were estimated with good precision, apart from V 9-OH-RISP(relative standard error 60.1%). Residual variability was 0.1 mcg/L (56.2%) for risperidone and 0.7 mcg/L (28.2%) for 9-OH-risperidone. Covariate testing identified a significant contribution of log transformed age (tAge) to the variability in risperidone clearance (β =-0.3, p=9.13e-04). Inclusion of an age effect on CL RISPincreased the precision of the model (Supplementary Table 1) and reduced the estimated probability of being in latent category 1 from 32% to 22%. Stepwise testing of other covariates on clearance parameters did not improve the precision or model fit. Model based predictions, based on the mean age (78.4 years) of the sample, suggested that for patients assigned to latent category one, risperidone clearance was 8.7L/hr (t 1/222 hours), compared to 34.2L/hr (t 1/25 hours) for those in latent category two. Patients in latent category one were thus considered to represent ‘functionally poor’ metabolisers (PM). Predictions based on the observed contribution of age to risperidone clearance estimated that, for those aged 88 years, risperidone clearance would be reduced by 22% (t 1/228.8 hours in PM and 6.5 hours in functionally normal metabolisers (NM). Based on V 9-OH-RISPand CL 9-OH-RISP, t 1/29-OH-risperidone was 27 hours. Visual predictive checks, (VPCs) shown as percentile plots, superimposed on observed data, are shown inSupplementary Fig 1. Pharmacokinetic biomarkers and functional metaboliser status Of the 100 participants included in the analysis of clinical outcome, 18 were categorised as PM. There were no differences in clinical or demographic or clinical variables in PM and NM. Cholinesterase inhibitors were prescribed in a higher proportion of PM (four (77.8%) versus 37 (45.1%), chi squared p=0.01, odds ratio 1.27, 95% confidence interval (CI) 1.04-1.53), and a higher proportion of PM were women (14 (77.8%) versus 39 (47.6%), chi squared p= 0.02, odds ratio 1.24, 95% CI 1.04-1.49). PM were prescribed a lower dose of risperidone (0.7±0.4 mg/day versus 1.1±0.7mg/day, Mann Whitney U, p=0.007), and had higher concentrations across all pharmacokinetic biomarkers (Supplementary Table 2). Trough active moiety concentration-to-dose ratio was markedly increased in PM (20.2±7.2 versus 7.6±4.9 ng/mL per mg/day, Mann Whitney U, p<0.0001), shown inFig 1. There were no differences in the proportion of participants with emergent EPS in PM and NM. Fig 1. Active moiety concentration to dose ratio Estimated concentration to dose (C/D) ratios for the active moiety (ng/mL per mg/day) are shown at trough in those categorised as functionally poor (PM) and functionally normal (NM) metabolisers, aged 75 and 85 years, prescribed 250, 500 and 1000mcg risperidone daily. The red line (7ng/mL per mg/day) represents typical estimates for C/D in a reference group, based on therapeutic drug monitoring studies of risperidone. Pharmacokinetic biomarkers and clinical outcome Associations between individual pharmacokinetic biomarkers and EPS are detailed inTable 2. Pharmacokinetic biomarkers showed a significant association with EPS, achieving greatest significance in relation to trough and average concentrations of 9-OH-risperidone and the active moiety (Wald test p<0.0001). MMSE and height also contributed to the best fit regression models ( p<0.0001). Table 2. Pharmacokinetic Biomarkers and Emergent EPS (n=100) Model-based simulations (seeFig 2) suggest that for NM aged 75 years with an MMSE of 15, 1mg/day risperidone would be associated with minimal risk of EPS. For those aged 75 years with an MMSE of 5, a dose reduction to 0.5mg/day would be required. For those aged 85 years, the dose would need to be reduced by 50% to achieve equivalent plasma concentrations, and PM would require very low alternate daily dosing (0.25-0.5mg/48 hours in those aged 75 years, and 0.125-0.25mg/48 hours in those aged 85 years). For completeness, the same analysis was carried out in relation to sedation, but there were no significant associations. The number of participants with other emergent side effects was too small to investigate through the use of logistic regression. Fig 2. Simulated trough 9-OH-risperidone concentrations and EPS Simulated trough 9-OH-risperidone concentrations and the probability of extrapyramidal side effects (EPS) are shown for a population of 100 people in each of the following categories: 75 or 85 years old; with an MMSE score of 5, 10 or 15; prescribed 250, 500 or 100mcg risperidone daily in A) Functionally normal metabolisers (NM) and B) Functionally poor metabolisers (PM). Discussion Age and functional metaboliser status contribute to pharmacokinetic variability The consensus, based on meta-analyses of placebo controlled trials of risperidone in people with psychosis in AD, is that 1 mg/day risperidone may optimally balance efficacy and adverse effects. (4-6,10) However, meta-analyses can only inform the ‘average’ dose requirements, but are less able to identify subgroups who are most susceptible to side-effects. In this analysis we have investigated the pharmacokinetic (dose-concentrations) and pharmacodynamic (concentration-outcome) contribution to EPS, to guide safer prescribing. We estimated that 22% of patients were functionally poor metabolisers and observed an independent effect of age on risperidone clearance. Pharmacokinetic biomarkers were robust predictors of EPS, with higher trough and average concentrations of 9-OH-risperidone providing the best fit for the data. Lower MMSE, a marker of more severe global cognitive impairment, was an independent predictor of EPS. Model based simulations suggest that, for NM aged 75 years with an MMSE of 15 (moderate AD severity), 1mg/day would be associated with minimal risk of EPS, but a dose reduction to 0.5mg/day would be required for those with an MMSE of 5. For those aged 85 years, a 50% dose reduction would be required and, for PM, alternate day dosing would be required to avoid excessive exposure. Drug metabolism is a major contributor to pharmacokinetic variability (23) and, in older adults, the relative importance of genotype is difficult to disentangle from physiological and clinical factors. (17) In the absence of information on CYP2D6genotype, the extent of any genetic contribution to functional metaboliser status is unclear, although estimates of risperidone clearance in PM and NM were broadly consistent with estimates for CYP2D6-predicted ‘poor’ and ‘extensive’ metabolisers. (13) Age was independently associated with risperidone clearance and, when incorporated into the model, led to the reassignment of six patients who were initially categorised as PM. Although previous research has not shown an effect of age specifically on risperidone clearance, (13) a 30% decrease in hepatic metabolism in those aged over 70 years has been observed for other CYP2D6 substrates (24) and it is thus likely that our findings are explained by the older age of CATIE-AD participants. Similarly the absence of an association between age and 9-OH-risperidone clearance reflects the older age of CATIE-AD participants compared to previous analyses. Mechanistic insights into emergent EPS Statistical modelling of the relationship between risperidone active moiety plasma concentrations and D 2/3receptor occupancy (25) in adults with schizophrenia, suggests that trough concentrations of 10.5-38.2 ng/mL are associated with 60-78% occupancy in the striatum, and 6.5 ng/mL (95% CI, 3-10 ng/mL) is associated with 50% occupancy. In CATIE-AD participants, EPS emerged from trough active moiety concentrations of 3.4 ng/mL (of which 3.2 ng/mL was 9-OH-risperidone), and concentrations exceeded 10ng/mL (60% occupancy) in eight of 14 patients with EPS. In the absence of occupancy data, it is unclear whether the emergence of EPS at such low concentrations signifies a leftwards shift in the concentration-occupancy curve, similar to that observed during amisulpride treatment. (8) This is possible, as risperidone and 9-OH-risperidone are substrates for P-glycoprotein, (26) a blood brain barrier efflux transporter that is marked reduced older people with AD. (27) However age or disease-specific changes in brain drug distribution, clearance, and competition with endogenous dopamine at receptor sites need to be considered. (8) Pharmacodynamic changes (reduced D 2/3receptor reserve, altered signal transduction) which lead to a greater functional outcome for a given occupancy are also important. We have previously observed EPS at low striatal D 2/3receptor occupancies (60% compared to 80% in young people), in risperidone-treated older people with schizophrenia, (28,29) and amisulpride-treated older people with psychosis in AD. (8) Given the error margin of occupancy predictions, we cannot rule out the possibility that occupancy was under-estimated in a proportion of those with active moiety concentrations less than 10ng/mL. (25) To our knowledge, this is the first demonstration of the contribution of MMSE score, a marker of increasing dementia severity, to the risk of antipsychotic related EPS. An association between agitation, antipsychotic use and death in those with more severe dementia has however been reported in a recently published cohort study (30). The mechanisms of antipsychotic-induced EPS are not fully understood, but D 2/3receptor antagonism of inhibitory dopaminergic inputs to striatal medium spiny neurones and cholinergic interneurones may play a key role. (3) It is unclear whether the risk of EPS in those with lower MMSE scores reflects greater in networks that modulate motor control, or is associated with as yet unidentified factors that potentiate EPS. Limitations Limitations to the analysis include sparse sampling, which meant it was not possible to estimate within-subject variability in clearance of risperidone or 9-OH-risperidone, or to investigate the contribution of concomitant medications to pharmacokinetic variability. Neither was it possible to investigate the contribution of comorbid medical conditions to variability in pharmacokinetics or emergent side effects. We cannot account for the fact that those with emergent EPS were more likely to have been prescribed concomitant trazodone, given the small sample size and uncertain exposure (dose, continuity of the prescribed drug) of individual participants to trazodone. However, we cannot rule out the possibility of potential drug-drug interactions, including an interaction with P-glycoprotein (trazodone is a substrate), or potentiated EPS through the inhibition of serotonin uptake. (3) Other limitations relate to the CATIE-AD study design, which may have reduced our ability to detect associations between pharmacokinetic indices and clinical outcome. This includes flexibility in starting dose (low or high), the option of making adjustments or of discontinuing a phase, based on clinician judgement. Dose adjustments needed to avoid treatment emergent EPS This analysis represents a step towards safer risperidone prescribing and argues strongly for age- and MMSE-related dose reductions. From a pragmatic perspective, clinicians should ‘start low go slow’ (0.5-1mg/day) in those aged 75 years with moderate stage AD, and ‘start low, stay low’ (maximum 0.5mg/day) in those aged 75 years with severe AD. For those aged 85 years, the dose should be halved, and alternate daily dosing considered if side effects emerge, as it is likely that the person has slower active moiety clearance. Personalised prescribing should ideally incorporate knowledge of genetic, environmental and personal variables to determine dosing. This is currently happening in clinical practice and there has been a lack of empirical data in older people to justify the use of routine therapeutic drug monitoring. Consistent with a recently proposed personalised prescribing algorithm, CATIE-AD participants categorised as PM had high active moiety concentration-to-dose ratios. (17) Therapeutic drug monitoring thus offers the opportunity to guide dose adjustments with greater precision, as this measure could be derived from a single plasma sample, to identify those with slower drug clearance. Future research should test our proposed dose predictions and could evaluate the clinical utility of therapeutic drug ‘screening’ (measurement from a single plasma sample). Contributors SR led the study design, carried out data extraction, carried out data analysis and led on the writing of the paper; JB, HU, RB, BP and RH gave input into the study design and analysis plan; KY, YO and KL extracted data on clinical outcome measures; MO extracted data on adverse events; JB supervised SR in the analysis of the data, carried out simulations, and led on data presentation; EB and RH gave input into the interpretation and presentation of pharmacokinetic data; all authors contributed to the interpretation of the clinical findings and the writing of the paper, and approved the submitted manuscript. Competing interests There are no competing interests Funding R.H. is supported by the NIHR University College London Hospital Biomedical Research Centre (UCLH BRC) Supplementary Material Supplementary Table 1. Pharmacokinetic Model for Risperidone and 9-hydroxy-risperidone (n=108) Supplementary Fig 1. Visual predictive checks Visual predictive checks (VPC): 95% prediction intervals around the 10th (lower blue shaded area), 50th (pink shaded area) and 90th (upper blue shaded area) percentiles are shown for the final model overlaid to observed data for risperidone in A) Functionally poor metabolisers and B) Functionally normal metabolisers. Each blue circle represents a single plasma sample. Blue lines represent the empirical predictions for each percentile and outliers are circled in red. Supplementary Table 2: Pharmacokinetic Biomarkers and Functional Metaboliser Status Acknowledgements Data used in the preparation of this article were obtained from the limited access datasets distributed from the NIH supported “Clinical Antipsychotic Trials of Intervention Effectiveness in AD” (CATIE-AD) (MH64173, MH90001). This is a multisite, clinical trial of people with psychosis and/or agitation in the content of AD, which compared the effectiveness of randomly assigned medication treatment. This manuscript reflects the views of the authors and may not reflect the opinions or views of the CATIE Study Investigators or the NIH. No funding was provided for this analysis. Suzanne Reeves had full access to the data included in this analysis, and had final responsibility for the decision to submit for publication. References 1. ↵ Ropacki SA , Jeste DV . Epidemiology of and risk factors for psychosis of Alzheimer’s disease: a review of 55 studies published from 1990 to 2003 . Am J Psychiatry . 2005 ; 162 ( 11 ): 2022 – 30 . 2. ↵ Connors MH , Ames D , Woodward M , Brodaty H . Psychosis and Clinical Outcomes in Alzheimer Disease: A Longitudinal Study . Am J Geriatr Psychiatry . 2018 ; 26 ( 3 ): 304 – 13 . 3. ↵ Ohno Y , Kunisawa N , Shimizu S . Antipsychotic Treatment of Behavioral and Psychological Symptoms of Dementia (BPSD): Management of Extrapyramidal Side Effects . Front Pharmacol . 2019 ; 10 : 1045 . 4. ↵ Tampi RR , Tampi DJ , Balachandran S , Srinivasan S . Antipsychotic use in dementia: a systematic review of benefits and risks from meta-analyses . Ther Adv Chronic Dis . 2016 ; 7 ( 5 ): 229 – 45 . 5. ↵ Ballard C , Howard R . Neuroleptic drugs in dementia: benefits and harm . Nat Rev Neurosci . 2006 ; 7 ( 6 ): 492 – 500 . 6. ↵ Schneider LS , Tariot PN , Dagerman KS , Davis SM , Hsiao JK , Ismail MS , et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease . N Engl J Med . 2006 ; 355 ( 15 ): 1525 – 38 . 7. ↵ Howard R , Costafreda SG , Karcher K , Coppola D , Berlin JA , Hough D . Baseline characteristics and treatment-emergent risk factors associated with cerebrovascular event and death with risperidone in dementia patients . Br J Psychiatry . 2016 ; 209 ( 5 ): 378 – 84 . 8. ↵ Reeves S , McLachlan E , Bertrand J , D’Antonio F , Brownings S , Nair A , et al. Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer’s disease . Brain . 2017 ; 140 ( 4 ): 1117 – 27 . 9. ↵ Reeves S , Bertrand J , McLachlan E , D’Antonio F , Brownings S , Nair A , et al. A Population Approach to Guide Amisulpride Dose Adjustments in Older Patients With Alzheimer’s Disease . J Clin Psychiatry . 2017 ; 78 ( 7 ): e844 - e51 . 10. ↵ Katz I , de Deyn PP , Mintzer J , Greenspan A , Zhu Y , Brodaty H . The efficacy and safety of risperidone in the treatment of psychosis of Alzheimer’s disease and mixed dementia: a meta-analysis of 4 placebo-controlled clinical trials . Int J Geriatr Psychiatry . 2007 ; 22 ( 5 ): 475 – 84 . 11. ↵ Mauri MC , Paletta S , Di Pace C , Reggiori A , Cirnigliaro G , Valli I , et al. Clinical Pharmacokinetics of Atypical Antipsychotics: An Update . Clin Pharmacokinet . 2018 ; 57 ( 12 ): 1493 – 528 . 12. ↵ de Leon J , Wynn G , Sandson NB . The pharmacokinetics of paliperidone versus risperidone . Psychosomatics . 2010 ; 51 ( 1 ): 80 – 8 . 13. ↵ Feng Y , Pollock BG , Coley K , Marder S , Miller D , Kirshner M , et al. Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study . Br J Clin Pharmacol . 2008 ; 66 ( 5 ): 629 – 39 . 14. ↵ Hiemke C , Bergemann N , Clement HW , Conca A , Deckert J , Domschke K , et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 . Pharmacopsychiatry . 2018 ; 51 ( 1-02 ): e1 . 15. ↵ Vandenberghe F , Guidi M , Choong E , von Gunten A , Conus P , Csajka C , et al. Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort . Clin Pharmacokinet . 2015 ; 54 ( 12 ): 1259 – 72 . 16. ↵ Uchida H , Takeuchi H , Graff-Guerrero A , Suzuki T , Watanabe K , Mamo DC . Dopamine D2 receptor occupancy and clinical effects: a systematic review and pooled analysis . J Clin Psychopharmacol . 2011 ; 31 ( 4 ): 497 – 502 . OpenUrl CrossRef PubMed Google Scholar 17. ↵ de Leon J . Personalizing dosing of risperidone, paliperidone and clozapine using therapeutic drug monitoring and pharmacogenetics . Neuropharmacology . 2019 : 107656 . 18. ↵ Schneider LS , Tariot PN , Lyketsos CG , Dagerman KS , Davis KL , Davis S , et al. National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer disease trial methodology . Am J Geriatr Psychiatry . 2001 ; 9 ( 4 ): 346 – 60 . 19. ↵ Simpson GM , Angus JW . A rating scale for extrapyramidal side effects . Acta Psychiatr Scand Suppl . 1970 ; 212 : 11 - 9 . 20. ↵ Barnes TR . A rating scale for drug-induced akathisia . Br J Psychiatry . 1989 ; 154 : 672 - 6 . 21. ↵ Panhard X , Goujard C , Legrand M , Taburet AM , Diquet B , Mentre F , et al. Population pharmacokinetic analysis for nelfinavir and its metabolite M8 in virologically controlled HIV-infected patients on HAART . Br J Clin Pharmacol . 2005 ; 60 ( 4 ): 390 – 403 . 22. ↵ Duffull SB , Wright DF , Winter HR . Interpreting population pharmacokinetic-pharmacodynamic analyses - a clinical viewpoint . Br J Clin Pharmacol . 2011 ; 71 ( 6 ): 807 – 14 . OpenUrl CrossRef PubMed Google Scholar 23. ↵ McLachlan AJ , Pont LG . Drug metabolism in older people--a key consideration in achieving optimal outcomes with medicines . J Gerontol A Biol Sci Med Sci . 2012 ; 67 ( 2 ): 175 – 80 . 24. ↵ Sotaniemi EA , Arranto AJ , Pelkonen O , Pasanen M . Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions . Clin Pharmacol Ther . 1997 ; 61 ( 3 ): 331 – 9 . 25. ↵ Uchida H , Takeuchi H , Graff-Guerrero A , Suzuki T , Watanabe K , Mamo DC . Predicting dopamine D(2) receptor occupancy from plasma levels of antipsychotic drugs: a systematic review and pooled analysis . J Clin Psychopharmacol . 2011 ; 31 ( 3 ): 318 – 25 . 26. ↵ Wang JS , Ruan Y , Taylor RM , Donovan JL , Markowitz JS , DeVane CL . The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein . Int J Neuropsychopharmacol . 2004 ; 7 ( 4 ): 415 – 9 . 27. van Assema DM , Lubberink M , Bauer M , van der Flier WM , Schuit RC , Windhorst AD , et al. Blood-brain barrier P-glycoprotein function in Alzheimer’s disease . Brain . 2012 ; 135 ( Pt 1 ): 181 - 9 . 28. ↵ 29. ↵ Graff-Guerrero A , Rajji TK , Mulsant BH , Nakajima S , Caravaggio F , Suzuki T , et al. Evaluation of Antipsychotic Dose Reduction in Late-Life Schizophrenia: A Prospective Dopamine D2/3 Receptor Occupancy Study . JAMA Psychiatry . 2015 ; 72 ( 9 ): 927 – 34 . 30. ↵ Aworinde J , Werbeloff N , Lewis G , Livingston G , Sommerlad A . Dementia severity at death: a register-based cohort study . BMC Psychiatry . 2018 ; 18 ( 1 ): 355 .
https://www.medrxiv.org/content/10.1101/2020.08.12.20173310v1.full
Use of Fertility Awareness-Based Methods for Pregnancy Prevention Among Ghanaian Women: A Nationally Representative Cross-Sectional Survey | Global Health: Science and Practice ORIGINAL ARTICLE Use of Fertility Awareness-Based Methods for Pregnancy Prevention Among Ghanaian Women: A Nationally Representative Cross-Sectional Survey Chelsea B. Polis , Easmon Otupiri , Suzanne O. Bell and Roderick Larsen-Reindorf Global Health: Science and Practice June 2021, 9(2):318-331; https://doi.org/10.9745/GHSP-D-20-00601 Article Key Findings Standard approaches underestimate fertility awareness-based method (FABM) use; we posit that at least 18% of contracepting Ghanaian women likely use an FABM. Economically and educationally advantaged women had higher odds of current FABM use (versus intrauterine device/hormonal method), which may suggest deliberateness of method selection (as opposed to limited access to alternatives). Most (92%) rhythm users wish to improve the effectiveness of their method, and many are willing to track additional biomarkers, but only 17% ever discussed their method with a health professional. Key Implications Researchers, programmers, and funders should better understand and address FABM users' needs, in commitment to reproductive autonomy and choice. ABSTRACT Few studies in low- and middle-income countries have examined the use of fertility awareness-based methods (FABMs) for pregnancy prevention. Understanding the prevalence of FABM use among Ghanaian contraceptors and the characteristics and practices of users is essential. Our 2018 nationally representative survey of Ghanaian women included detailed questions on the use of rhythm and Standard Days Method/Cycle Beads (SDM). After considering multimethod use patterns, we estimated likely FABM prevalence among contraceptors, identified characteristics associated with current use of an FABM (vs. current use of a hormonal method/intrauterine device [IUD]), and described how women report using FABMs. At least 18% of contracepting Ghanaian women likely use an FABM, though this may be underreported. Among FABM users, 57% reported current use of an FABM alone; the remainder reported concurrent use of other methods. Women who were older, richer, more educated, and had fewer children had higher odds of current FABM use versus IUD/hormonal method. Although FABM users were more likely than other contraceptors to correctly identify the approximate fertile time, only 50% of FABM users did so correctly. Most (92%) rhythm users were interested in making their method use more effective. While 72% had heard of SDM, less than 25% had heard of various other ways to make the rhythm method more effective. Only 17% of rhythm users had ever discussed the method with a health professional. Rhythm users indicated substantial willingness to track additional biomarkers (e.g., daily temperature or cervical mucus) or to use a phone to enhance the effectiveness of their method, and most indicated no substantial difficulty getting partners to abstain or withdraw on fertile days. A nontrivial proportion of reproductive age Ghanaian women are using an FABM, nearly all of whom are interested in learning how to improve its effectiveness. The family planning field should better address these women's contraceptive needs in commitment to reproductive autonomy and choice. INTRODUCTION Understanding the extent of people's reliance on fertility awareness-based contraceptive methods (FABMs) and the characteristics and practices of such users is essential to comprehensively meeting reproductive needs. A concise introduction to FABMs can be found elsewhere. 1In brief, FABMs aim to identify the span of days during each menstrual cycle when sexual intercourse is most likely to result in pregnancy (the “fertile window”). Depending on the requirements of the specific FABM, users track changes in 1 or more fertility biomarkers (e.g., menstrual start dates, basal body temperatures, cervical mucus or cervical position, and urinary hormone metabolites) in attempts to identify their fertile window during each menstrual cycle. Certain FABMs can be used to either plan or prevent pregnancy. If pregnancy prevention is desired, users can either avoid penile-vaginal intercourse or use other methods (e.g., barrier methods, withdrawal, etc.) on days the method identifies as fertile. Such FABM users are taking action to avoid conceiving but may be more vulnerable to unintended pregnancy compared with users of certain other contraceptive methods. For example, in low-income countries, an estimated 19% of those who report using the rhythm method (a type of FABM, described in greater detail below) will experience an unintended pregnancy in the first year of use, compared with 0.3% of implant users. 2Contraceptive effectiveness is a key attribute for many people choosing a method, but other method characteristics influence contraceptive decision making, such as safety, side effects, impact on bleeding patterns, cost, ease of use, protection from sexually transmitted infections, privacy, etc. 3 – 7Despite a common assumption that people resort to less effective contraceptive methods due to a lack of access to more effective options, these choices often reflect user preferences. 8 – 13For example, side effects and health concerns are the most common reasons for nonuse or discontinuation of hormonal contraception among women in low-income countries who do not desire pregnancy, 14 , 15whereas methods perceived as “natural” may appeal to people with these concerns. 12 Despite a common assumption that people resort to less effective contraceptive methods due to a lack of access to more effective options, these choices often reflect user preferences. FABMs have received relatively limited attention in the contraceptive literature. Rhythm is perhaps the most widely known FABM, although many who report using rhythm are not likely using its formal requirements. 16Relatively little is known about how those who identify as rhythm users actually use the method and the extent to which they rely on other contraceptive methods during the fertile window versus abstaining from sex during this period (i.e., practice periodic abstinence). Rhythm is typically classified as a traditional method. However, certain other FABMs (e.g., Standard Days Method [SDM], TwoDay Method, etc.) are often classified as modern—although these classifications are not universal (e.g., the United Nations Population Division does not classify these methods as modern)—and the nomenclature is imperfect. 17 – 21In addition to FABMs, some people use menstrual tracking smartphone apps or devices to time sexual intercourse for pregnancy prevention. Although 2 apps have received clearance from the United States Food and Drug Administration for use as a contraceptive method (Natural Cycles in 2018, 22which also received CE Marking in Europe, and Clue in 2021 23), most such apps or devices are not tested or indicated for this purpose and may offer predictions of unknown accuracy regarding the timing of fertile days. 24 , 25 Research focused specifically on FABM use in low- and middle-income countries (LMICs) has been particularly limited (with exceptions from the United States Agency for International Development and the Institute for Reproductive Health at Georgetown University 18 , 26 – 31). However, there are existing and emerging reasons for greater understanding around FABM use in LMICs. First, our understanding of contraceptive decision making is incomplete without understanding people who select contraceptive options that are not among the most highly effective. Understanding such choices can help to support client-centered approaches to contraceptive counseling, programming, and method development. Second, FABMs use is increasing in some contexts, 32and multiple researchers have identified substantial underestimation of methods (including rhythm) in nationally representative surveys. 12 , 13 , 33 – 35This suggests incomplete existing information on the prevalence of FABM use, which impacts our understanding of who chooses FABMs and impacts estimation of other key metrics (e.g., unmet need for contraception). Third, without understanding how people employ these methods, we have little ability to identify approaches that enhance the effectiveness of their contraceptive practices while respecting their contraceptive preferences. Our understanding of contraceptive decision making is incomplete without understanding people who select contraceptive options that are not among the most highly effective. Additional reasons for understanding FABM use in LMICs have emerged more recently. First, the coronavirus disease (COVID-19) pandemic has limited access to contraceptive services, prompting calls by some international organizations for counseling on FABMs, 36which are less vulnerable than other methods to commodity supply chain disruptions. 37Furthermore, there is an increasing understanding of the application of principles of self-care to sexual and reproductive health worldwide, 38as well as emerging literature on whether fertility knowledge (e.g., regarding the timing of ovulation or impacts of age on fertility) impacts reproductive outcomes. 39 , 40Although FABMs are not appropriate for all individuals, they can assist certain couples to avoid (or seek) pregnancy with limited or no clinical support after being trained in and correctly using the method. Finally, the increasing development of new technologies will continue to provide new tools that facilitate use of FABMs and may increase their prevalence. The contraceptive field can play a useful role in helping people who prefer a method they may perceive as “natural” in understanding if new technologies have reliable evidence on contraceptive effectiveness 41and to optimize the effectiveness of chosen methods. To expand understanding of FABM use in LMICs, we aimed to examine the use of 2 FABMs (rhythm method and SDM/CycleBeads) in a nationally representative sample of Ghanaian women. Our objectives were to estimate the prevalence of FABM use among Ghanaian contraceptors (including careful consideration of multimethod use patterns), understand characteristics associated with choosing an FABM (relative to choosing an intrauterine device [IUD] or hormonal method), and collect detailed information on various aspects of how Ghanaian women use FABMs. This article also aims to contribute to improvements in measuring FABM use across diverse contexts by detailing methodological considerations around terminology and definitions used for FABMs in large-scale surveys and how these might be improved. We aimed to estimate the prevalence of FABM use among Ghanaian contraceptors, understand characteristics associated with choosing an FABM, and collect information on how Ghanaian women use FABMs. METHODS Survey Design and Implementation Our survey design and sampling have been described in detail elsewhere. 42Briefly, data for this analysis were drawn from a nationally representative, community-based survey of reproductive-aged (15–49 years) women in Ghana (N=4,722), conducted in 2018 as part of a larger study on abortion incidence in Ghana. 43The survey was a collaborative effort between the Guttmacher Institute, the Kwame Nkrumah University of Science and Technology (KNUST), and the Performance Monitoring and Accountability 2020 team at the Johns Hopkins Bloomberg School of Public Health. We used a multistage stratified cluster sampling design and probability-proportional-to-size sampling to select 100 enumeration areas, each consisting of approximately 200 households. We then listed, mapped, and randomly selected 42 households in each selected enumeration area. In those households, we conducted a short household survey to collect socioeconomic information and to identify eligible female respondents. We invited all eligible women to give informed consent and participate in the full survey. Trained resident enumerators collected data for both surveys in a private area, using an Android smartphone enabled with Open Data Kit electronic data collection software. Households with one or more participating respondents who completed the full survey received a bar of soap. The Institutional Review Boards of the Guttmacher Institute, the KNUST Committee on Human Research, Publication and Ethics, and the Johns Hopkins Bloomberg School of Public Health provided ethical approval. Prior analyses of these data showed that among all respondents aged 15–49 years in our sample who had ever had sex (n=4,139), 33.7% currently reported using any contraceptive method. 44 Identifying Rhythm or SDM Users Traditional methods and modern FABMs are likely underreported in many surveys, including Demographic and Health Surveys (DHS). Studies suggest that some respondents interpret filtering questions (e.g., “are you or your partner currently doing something or using any method to delay or avoid getting pregnant?”) as pertaining only to modern or non-“natural” methods. 12 , 13 , 33 , 34Additionally, when asked to spontaneously name methods used, a qualitative study of 48 Ghanaian women found that “fertility awareness methods were rarely spontaneously mentioned as a way to prevent pregnancy…yet counting days was almost universally used at one time or another and participants described it as a taken-for-granted part of a woman's life.” 34Other studies suggest that women using multiple methods (e.g., an FABM with condoms during the fertile window) may potentially report only condom use, 12unless, for example, she is asked about the use of all potential methods. Our study did not address the first concern as we did use the filtering question, but it did address the second concern by asking about the use of each method among those who affirmed using a method. Specifically, survey respondents were asked, “Have you or a partner ever done something or used any method to delay or avoid getting pregnant?” We asked respondents who said “yes” to spontaneously list methods ever used, and then the interviewer asked about each of the possible methods to capture users who self-identified as using any of these methods (female and male sterilization, implants, IUDs, injectables (3 month and 1 month), pill, emergency contraception (EC), male and female condoms, diaphragm, foam or jelly, SDM/Cycle Beads, lactational amenorrhea method, N-tablet, rhythm method, withdrawal, washing, or “other traditional method”). The interviewer next followed a similar process for current method use by asking nonpregnant women, “Are you or your partner currently doing something or using any method to delay or avoid getting pregnant?” Again, we only asked respondents who said “yes” to list methods currently used, before being asked about each possible method, to self-identify as current users. Like DHS and other surveys, our survey may suffer from underreporting of traditional or “natural” methods, if respondents answered “no” to both filtering questions under the assumption that traditional or “natural” methods do not count. Therefore, we interpret our prevalence estimates as a lower bound. However, each respondent who acknowledged ever or currently doing something or using any method to delay or avoid pregnancy was probed on all possible contraceptive methods. Data Analysis Method-specific prevalence is typically calculated based upon the most effective method a person reports currently using. For example, each DHS survey contains a hierarchical list of methods, ordered by typical use contraceptive effectiveness estimates. If a DHS respondent reports currently using both SDM and condoms, she is considered a condom user in prevalence estimation. This approach may underestimate FABM prevalence, as some FABM users use barrier methods or EC during the fertile window 34 , 45and would thus be coded as a barrier or EC user, despite having sex with no contraception on days that the method (correctly or incorrectly) identifies as infertile. Method-specific prevalence is typically calculated based on the most effective method a person reports currently using, but this approach may underestimate FABM prevalence. To address this underestimation issue, we used an approach previously applied to data from the United States 46to estimate likely FABM prevalence among Ghanaian contraceptors. First, we calculated a standard prevalence estimate based on “most effective” method (using the ordering represented inTable 1); as already noted, this approach may underestimate FABM use. Next, we recalculated prevalence, incorporating information on multiple method use. That is, a person who reported currently using 2 or more methods would be included in all reported method categories for method-specific prevalence estimation. These are likely overestimates since some women use an FABM with a highly effective method (such as sterilization, an IUD, or hormonal contraception), which likely serves as their primary mode of contraception. Therefore, to identify the most likely FABM prevalence estimate, it is necessary to examine specific patterns of multiple method use among FABM users. We classified respondents who reported any current use of an FABM into 3 categories: Category A: Reported current use of an FABM alone or with current use of a less effective method (i.e., withdrawal, washing, etc.) Category B: Reported current use of an FABM in conjunction with current use of barrier methods and/or EC Category C: Reported current use of an FABM in conjunction with current use of a highly effective method (i.e., hormonal contraception, an IUD, or sterilization). TABLE 1. Percent Distribution of Contraceptors aAged 15–49, by Current Contraceptive Method(s) Used at Interview, Ghana, 2018 As in a prior study, 46we considered women in Category A as definite FABM users, women in Category B as likely FABM users, and women in Category C as relying primarily on a highly effective (non-FABM) method. Thus, we included women in Categories A or B in our FABM prevalence estimation. We calculated prevalence estimates among “contraceptors,”*excluding women who: did not report that they (or their partner) were “currently doing something or using any method to delay or avoid getting pregnant”; women who were currently trying for pregnancy, women who were currently pregnant, and women who reported never having had sexual intercourse. We considered the remaining 1,165 participants “contraceptors.” Next, we conducted bivariate and multivariable logistic regressions to identify characteristics we hypothesized to be associated with being a current (definite or likely) FABM user versus a current user of hormonal contraceptives or an IUD, and that were available in these data. Characteristics we examined included ecological zone (Northern, Middle, Central), residence (urban vs. rural), age (continuous), marital status (currently married/cohabiting, formerly married or cohabiting, never married or cohabiting), parity (continuous), education (none, primary or middle, secondary), religion (none, any Christian, Muslim, traditional/other), wealth (poorest 60% vs. richest 40%), importance of avoiding a pregnancy now (very important, somewhat important, not at all important), and correct knowledge of approximate fertility time (incorrect vs. correct). We present a multivariable model including all variables hypothesized to be relevant (a sensitivity analysis demonstrated similar results when including only those variables significant at P≤.05). Finally, we calculated descriptive statistics on a series of detailed questions asking FABM users about their knowledge of and ways in which they practice FABMs. We performed analysis in Stata version 16, accounting for the complex survey design using survey weights to adjust for the probability of selection and the Taylor Linearization method to calculate standard errors that correctly account for clustering. We also used the subpopoption to restrict to appropriate analytic populations. RESULTS FABM Prevalence Among Contraceptors Among contraceptors, 9.2% reported rhythm and 4.3% reported SDM as their most effective method (Table 1). As previously noted, these are likely underestimates. Calculating prevalence among contraceptors based on all methods reported increased rhythm prevalence to 13.6% and SDM prevalence to 6% (Table 1). As mentioned, these are likely overestimates, so we examined specific patterns of multimethod use among FABM users. Our data revealed a diverse range of FABM method use patterns. Among all women who reported currently using rhythm or SDM, over half (57.3%) reported using that FABM without any additional methods (Table 2). The next most common pattern of multimethod use among rhythm users involved either EC or withdrawal (among 5.9% and 5.6% of women who reported rhythm use, respectively), and among SDM users, involved either withdrawal or male condoms (among 11.9% and 8.6% of women who reported SDM, respectively). If classified by most effective method, 68% and 72% of women who reported currently using rhythm or SDM, respectively, would be classified as a user of the FABM they reported (Table 2, category A). Approximately 23% and 28% of women who reported using rhythm or SDM, respectively, would be classified as either a user of male condoms or EC using the standard prevalence estimation approach; though these women may rely primarily on an FABM and use condoms and/or EC episodically during their presumed fertile window (Table 2, category B). Finally, 9% of women who reported using rhythm (and 0% of women who reported using SDM), reported also currently using a permanent, long-acting reversible, or hormonal method, and would be classified as a user of that more highly effective method using the standard prevalence estimation approach (Table 2, category C). Our data revealed a diverse range of FABM method use patterns. TABLE 2. Use Patterns Among Women Reporting Current Use of Rhythm or SDM, With or Without Current Use of Other Methods We assumed that respondents in categories A and B (Table 2) should be counted as FABM users, suggesting that at least 18.1% of contraceptors in Ghana relied primarily on an FABM, whether modern (SDM: 6%) or traditional (rhythm: 12.4%) (Table 3). In other words, taking multiple method use (i.e., among women using an FABM plus (fe)male condoms and/or EC) into account increased the percentage of women who likely relied on an FABM from 13.5% (95% confidence interval [CI]=10.9, 16.7, and composed of 9.2% rhythm users and 4.3% SDM users) to 18.1% (95% CI=14.9, 21.8). TABLE 3. Prevalence of FABMs by Estimation Method and Population Subgroup Characteristics Associated With FABM Use vs. Hormonal Contraception/IUD Use In bivariate analyses, factors associated with approximately twice the odds of FABM use relative to hormonal contraception/IUD use included: living in the Middle or Central zone (vs. Northern zone), having never been (vs. currently being) married or cohabitating, feeling that avoiding pregnancy now was not at all (vs. very) important, identifying with any Christian religion (vs. no religion), and correctly identifying the approximate fertile time (vs. not knowing or correctly identifying it) (Table 4). Living in an urban (vs. rural) area and being in the richest 40% (vs. poorest 60%) of the population were associated with approximately 3 times the odds. Having attended secondary school (vs. no school) was associated with over 4 times the odds of FABM use (vs. hormonal contraception/IUD use). Each additional child born was associated with 20% lower odds of FABM use. Age was not significantly associated with FABM use. TABLE 4. Odds Ratio Associated With Use of an FABM Relative to Use of Hormonal Contraception or an IUD In multivariable analysis, factors significantly associated with FABM use (vs. hormonal contraception/IUD use) included: age (each year was associated with an increase in odds of FABM use by 10%), parity (each child was associated with a decrease in odds of FABM use by 30%), and being richer or having attended secondary school or higher, each of which was associated with approximately double the odds of FABM use (Table 4). Feeling that avoiding pregnancy was not at all important and correct knowledge of the approximate fertile time were associated with an elevated odds ratio in bivariate analysis but did not reach statistical significance at P≤.05 in multivariable analysis. Interestingly, among contraceptors, 34% of those not using an FABM and 50% of FABM users correctly identified the approximate fertile time (i.e., “halfway between 2 periods”) ( P-value for chi 2= 0.01,SupplementB). It is also worth noting that most (80%) FABM users felt it was “very important” for them to avoid pregnancy now (SupplementB). How Women Report Using the Rhythm Method The vast majority (85%) of rhythm users noted that they identify their fertile and nonfertile days by counting days of a menstrual cycle using a calendar (SupplementC) (participants could report more than 1 response). We did not obtain more detailed information on which rules, specifically, were used to determine fertile days using a calendar. About 1 in 6 rhythm users (17%) used an unspecified approach to determine her fertile window, and 9% did so by observing changes in cervical mucus. Alternative approaches were reported by 5% or less of rhythm users: using a mobile phone app (5%), observing the position or texture of their cervix (3%), recording daily temperature (1%), or using CycleBeads to determine her fertile days (0%). Among rhythm users, 12% believed there was no chance of getting pregnant over the course of a year while using the method, and 64% reported believing that there was a ≥50% chance. Nearly three-quarters (72%) of rhythm users had heard of the SDM. Less than one-quarter had heard of ways to make FABMs easier to use, such as CycleBeads (22%) or the CycleBeads mobile app (17%), other mobile FABM apps (23%), or other simple-to-use FABMs like TwoDay method (22%). Nearly all rhythm users (92%) expressed interest in learning how to make the rhythm method more effective at pregnancy prevention. Among women who wanted to make their rhythm use more effective (and were not already using the given approach mentioned), a majority would be willing to learn about approaches facilitated by a phone (82%) or to record their daily temperature (76%). Slightly over half (53%) expressed a willingness to collect their cervical mucus daily or to observe the texture of their cervix by inserting their fingers into their vagina daily. Only half of rhythm users knew where to go for advice on using rhythm effectively. Among those who knew, most (53%) would go to a family planning service provider. However, only 17% of rhythm users had ever discussed using the rhythm method with a health professional. How Women Report Using FABMs (Rhythm or SDM) Overall When FABM users were asked how they avoided pregnancy on days identified as fertile (and permitted to list as many responses as desired), 74% reported avoiding intercourse (SupplementD). The next most common answer (19%) was withdrawal, followed by using condoms or another barrier method (16% among rhythm users, and 13% among SDM users), and EC (12% among rhythm users and 11% among SDM users). The majority (64%) of FABM users who abstained from sex during the fertile window reported that it was “very easy” to get their partner to abstain on these days, with another 22% reporting that it was somewhat easy. Only 14% reporting that this was somewhat or very hard. Among FABM users who reported using withdrawal during fertile days, 68% said very easy, 10% somewhat easy, and 22% somewhat or very hard. We asked a similar question about condom use, but an ODK programming error precluded calculating estimates for this question. When FABM users were asked whether menstruation affects sexual activity with their partner, 76% said “yes, we generally avoid sex when I am menstruating,” but 20% stated, “no, because we don't have sex regularly.” Only 4% responded, “no, we generally have sex when I am menstruating.” DISCUSSION We posit that at least 18% of contracepting women in Ghana likely relied primarily on an FABM for pregnancy prevention. Had we relied on the most effective method reported, as is standard procedure, the estimate would be 13.5% (9.2% rhythm, 4.3% SDM). Our 18% estimate likely represents a lower bound, because, like the 2014 Ghana DHS 47and 2017 Ghana Maternal Health Survey, 48we used a filtering question. †However, unlike those surveys, among women who acknowledged ever or currently doing something or using a method to prevent pregnancy, our survey asked about all methods. Also, unlike those surveys, we assessed patterns of multiple method use to ascertain likely FABM users. We posit that at least 18% of contracepting women in Ghana likely relied primarily on an FABM for pregnancy prevention. Our rhythm prevalence estimates (based on most effective method) were slightly lower than those from the 2017 Ghana Maternal Health Survey for all women, currently married women, and sexually active unmarried women (SupplementA). This may be because SDM users may have reported themselves as rhythm users in that survey; combining our rhythm and SDM estimates results in estimates similar to estimates for rhythm in that survey. Overall, based on our estimate that 18% of contracepting Ghanaian women likely rely primarily on an FABM, we estimate that a minimum of 343,890 Ghanaian women (of an estimated 1,899,943 Ghanaian female contraceptors) currently rely primarily on an FABM 49; a larger number than those using oral contraceptive pills or using male condoms, and nearly as many as those using 3-monthly injectables. Among FABM users, more than half (57%) reported currently using only their FABM, while the remainder also reported current use of condoms, withdrawal, EC, and/or other methods. Prior studies in Ghana suggest that such contraceptive “mosaics” of methods that are viewed as natural are common. These methods are believed to help protect the regular flow of menses from bleeding changes induced by other methods 50as bleeding changes are perceived as linked with infertility. 7 , 51 – 53These contraceptive patterns have implications for how FABM prevalence is calculated in large-scale surveys and merits re-examination of the use of terms like “periodic abstinence” and the definition of “rhythm” currently used in DHS and other survey questions. For example, the Ghana 2017 Maternal Health Survey describes rhythm as “to avoid pregnancy, women do not have sexual intercourse on the days of the month they think they can get pregnant”; this definition inaccurately implies that rhythm is always practiced with abstinence. We elaborate upon this concern inSupplementE, where we advocate that the term “periodic abstinence” be replaced with a less assumption-laden term, such as “fertility awareness-based method.” Similarly, we describe how language used to describe FABMs to respondents should be revised to avoid the assumption of abstinence during the fertile time. Contraceptors who reported currently using FABMs (versus IUDs or hormonal methods) appeared to have several relatively advantaged characteristics: after controlling for multiple sociodemographic factors, they are more likely to be older, richer, more educated, and to have fewer children. This corroborates other findings from Ghana, in which contraceptors who were older, urban, more educated, and had fewer children were more likely to choose a traditional instead of modern method, 12though these patterns do not necessarily hold in other countries. 11Use of FABMs by relatively advantaged women may reflect distinct preferences for these methods, as identified in other Ghanaian studies 10 , 13and elsewhere 8 , 9or may reflect that aspects of FABMs may be less accessible to more disadvantaged women (e.g., power differentials negating an ability to negotiate the timing and circumstances of sexual activity with a partner, which women in our sample did not report particular difficulty in doing). Though only borderline statistically significant in our multivariable model, correct knowledge of the approximate fertile time did appear to be higher among likely FABM users, which has been observed previously in Ghana, 48yet only 50% of FABM users correctly identified the approximate fertile time, indicating substantial room for improvement among individuals relying upon this information to prevent pregnancy. The majority (85%) of rhythm users reported identifying fertile and nonfertile days using a calendar, though it remains unclear exactly what rules they used to determine fertile and infertile days. Many were likely not using the formal rules of the rhythm method and may have simply avoided unprotected sex on days when they believed—possibly inaccurately—that pregnancy was possible. 16InSupplementE, we elaborate upon impreciseness in current use of the term “rhythm,” which has come to be used as a generic word for a diverse array of nonformalized practices, 54perhaps better described as “informal rhythm.” Furthermore, less than a quarter of rhythm users had heard of ways to make FABM use easier, and few reported using tools like CycleBeads or apps indicated for pregnancy prevention. Yet, nearly all rhythm users expressed interest in learning how to make use of their method more effective, and a substantial proportion of rhythm users expressed willingness to collect additional biomarkers (i.e., temperature, cervical mucus, cervical position) or to use tools such as mobile phone apps. Given that only 17% of rhythm users had ever discussed use of the rhythm method with a health professional, there appears to be a substantial missed opportunity to assist rhythm users in identifying ways to improve the effectiveness of their chosen contraceptive method. Given that only 17% of rhythm users had ever discussed using the method with a health professional, there appears to be a substantial missed opportunity to assist users in identifying ways to improve the effectiveness of their chosen contraceptive method. This missed opportunity has also been reflected in prior work in Ghana. For example, in a small (n=85) survey in central Ghana conducted in 2010 on contraceptive self-care options, only 36% of respondents indicated interest in self-administered injections, but 75% indicated wanting to learn more about FABMs. 55In a monitoring study of a free FABM app, 60.8% of Ghanaian women who downloaded the app for the purpose of pregnancy prevention were not using a method of contraception in the prior 3 months, and 23% noted that it was the first method they had ever used, 26suggesting that FABMs may attract new users. Researchers have recommended that family planning programs in Ghana consider the promotion of modern FABMs along with other modern methods, 55 , 56which would require health professionals (particularly community health nurses and midwives who commonly offer and provide family planning methods in Ghana) to be trained to offer FABMs. Furthermore, certain FABMs (e.g., CycleBeads) require commodities, but to the best of our knowledge, nationally representative, facility-based, reproductive health commodities and service surveys in Ghana funded by United Nations Population Fund have not included FABM-related commodities when assessing the availability of modern methods at service delivery points. Strengths of this study include the use of a nationally representative sample of Ghanaian women and the incorporation of probing on the ever or current use of all methods of contraception. This builds upon an approach used by Rossier et al. in Burkina Faso, wherein investigators probed on all traditional methods. 33Finally, as far as we are aware, this is one of the first studies in a low- or middle-income country to ask detailed questions on FABM use, eliciting information that could be used to inform better outreach to and counseling for rhythm method users, who appear to be interested in understanding how to improve the effectiveness of their chosen contraceptive method. Limitations Our study has multiple limitations, key among them being that our prevalence estimates suffer from some of the same methodological flaws as other nationally representative studies in Ghana, given that we used a filtering question in asking about method use, which may lead to underreporting of FABMs and other methods. We believe this would have been more impactful in soliciting “ever” use (vs. current use). If a participant acknowledged having ever used anymethod, interviewers would eventually ask about all methods, priming the respondent (before answering the current method question), that rhythm and SDM “count” as contraceptive methods. In addition, we did not specifically ask about the use of FABMs other than rhythm or SDM in our survey, which could potentially mean that users of methods such as TwoDay, symptothermal, or others are undercounted; however, we expect this to be highly unlikely, particularly given the responses to questions on knowledge of other FABMs. One of our questions on rhythm suffered from the same definitional errors as seen in other large-scale survey questions on rhythm. Specifically, one of our questions asked, “You noted that you use the rhythm method, or avoiding sex on days when you are more likely to get pregnant. Can you please state all of the ways in which you identify your fertile and non-fertile days?” The implicit assumption that rhythm users abstain from sexual activity on days they believe they are more likely to get pregnant should be discontinued in survey research on FABMs, as described above and elaborated upon inSupplementE. We do not know whether Ghanaian women who refer to their practice as “counting days” (as identified in other studies 34) would label themselves as a rhythm user, an SDM user, a nonuser, or something else.SupplementE also highlights that the way in which users of specific FABMs (such as SDM, symptothermal method, etc.) are classified in DHS may depend upon whether the survey specifically asks about these methods or not; a point which researchers should be cognizant of when analyzing survey data. Future surveys might more deeply investigate the use of menstrual trackers and how they are perceived, as well as examine whether variables not available in our data (i.e., distance to health facility) may be associated with FABM use. Finally, as noted previously, 46our approach to FABM prevalence estimation assumes that women reporting multiple contraceptive methods use them in conjunction with one another (rather than that, for example, a user was switching permanently from an FABM to condom use during the month of interview). Another complexity of understanding patterns of multiple method use is that our labeling of individuals being “primarily” FABM users is somewhat subjective; such users may perceive their “primary” method to be condoms or EC, for example, even if the FABM is being “used” throughout the cycle and condoms or EC are being used episodically during periods believed to be infertile. CONCLUSION Our study indicates that a nontrivial proportion of reproductive age Ghanaian contracepting women (18%) are using a traditional or modern FABM (rhythm or SDM); more than those who report using oral contraceptive pills and nearly as many as report using 3-monthly injectables. Findings reiterate that standard approaches to measuring these methods underestimate their use, but additional survey methodological changes are required to further improve the accuracy of FABM use estimates. Results showed that more advantaged women were more likely to be using an FABM, suggesting that FABM use among this population may be a preference and not simply a lack of access to alternative options. Understanding these choices can help to support client-centered contraceptive counseling and programs for women and couples interested in using these methods. As side effects and health concerns are increasingly the main reasons for contraceptive nonuse in low- and middle-income countries, FABMs may offer an approach to pregnancy prevention to women whose contraceptive needs are not met by other options. 12Family planning programs should work to respectfully address these needs as part of a commitment to reproductive autonomy and choice. Acknowledgments We are grateful to our entire fielding team and all study participants. Funding This study was made possible by United Kingdom Aid from the United Kingdom Government and a grant from the Dutch Ministry of Foreign Affairs. Disclaimer The views expressed are those of the authors and do not necessarily reflect the positions and policies of the donors. Author contributions CBP led the conceptualization of the analysis, programmed the analytical code and conducted the analysis, and verified the overall reproducibility of the results. CBP and SOB managed and cleaned data. EO and RL-R led data collection efforts. CBP, EO, SOB, and RL-R provided resources in terms of study materials, contact with respondents, and computing resources. CBP wrote the original draft of the manuscript. CBP, EO, SOB, and RL-R participated in reviewing and editing the draft. Data availability De-identified versions of the Community-Based Survey collected by the authors and used in this analysis are available from the Guttmacher Institute upon reasonable request to researchers who wish to use the data for scholarly analysis. To discuss obtaining copies of these datasets, please contact [email protected] the detailed protocol for your proposed study, and information about the funding and resources you have to carry out the study. Competing interests None declared. Footnotes ↵ *For comparability to other existing estimates, we also calculated contraceptive prevalence among all women, married women, and sexually active unmarried women (SupplementA). ↵ †As described in the methods section, the filtering question excluded women who do not perceive themselves as “doing anything or using any method to delay or avoid getting pregnant.” Notes Peer Reviewed First published online:June 17, 2021. Cite this article as:Polis CB, Otupiri E, Bell SO, Larsen-Reindorf R. Use of fertility awareness-based methods for pregnancy prevention among Ghanaian women: a nationally representative cross-sectional survey. Glob Health Sci Pract. 2021;9(2):318-331.https://doi.org/10.9745/GHSP-D-20-00601 Received: October 16, 2020. Accepted: May 11, 2021. Published: June 30, 2021. © Polis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly cited. To view a copy of the license, visithttps://creativecommons.org/licenses/by/4.0/. When linking to this article, please use the following permanent link:https://doi.org/10.9745/GHSP-D-20-00601 REFERENCES 1. ↵ Urrutia RP , Polis CB . Fertility awareness based methods for pregnancy prevention . BMJ . 2019 ; 366 : l4245 . doi: 10.1136/bmj.l4245 . pmid: 31296535 2. ↵ Bradley SEK , Polis CB , Bankole A , Croft T . Global contraceptive failure rates: who is most at risk? Stud Fam Plann . 2019 ; 50 ( 1 ): 3 – 24 . doi: 10.1111/sifp.12085 . pmid: 30791104 OpenUrl CrossRef PubMed Google Scholar 3. ↵ Madden T , Secura GM , Nease RF , Politi MC , Peipert JF . The role of contraceptive attributes in women's contraceptive decision making . Am J Obstet Gynecol . 2015 ; 213 ( 1 ): 46.e1 – 46.e6 . doi: 10.1016/j.ajog.2015.01.051 . pmid: 25644443 OpenUrl CrossRef PubMed Google Scholar 4. Lessard LN , Karasek D , Ma S , et al . Contraceptive features preferred by women at high risk of unintended pregnancy . Perspect Sex Reprod Health . 2012 ; 44 ( 3 ): 194 – 200 . doi: 10.1363/4419412 . pmid: 22958664 5. Donnelly KZ , Foster TC , Thompson R . What matters most? The content and concordance of patients' and providers' information priorities for contraceptive decision making . Contraception . 2014 ; 90 ( 3 ): 280 – 287 . doi: 10.1016/j.contraception.2014.04.012 . pmid: 24863169 6. Peipert JF , Madden T , Allsworth JE , Secura GM . Preventing unintended pregnancies by providing no-cost contraception . Obstet Gynecol . 2012 ; 120 ( 6 ): 1291 – 1297 . doi: 10.1097/aog.0b013e318273eb56 . pmid: 23168752 7. ↵ Polis CB , Hussain R , Berry A . There might be blood: a scoping review on women's responses to contraceptive-induced menstrual bleeding changes . Reprod Health . 2018 ; 15 ( 1 ): 114 . doi: 10.1186/s12978-018-0561-0 . pmid: 29940996 8. ↵ Basu AM . Ultramodern contraception . Asian Popul Stud . 2005 ; 1 ( 3 ): 303 – 323 . doi: 10.1080/17441730500441178 9. ↵ Johnson-Hanks J . On the modernity of traditional contraception: time and the social context of fertility . Popul Dev Rev . 2002 ; 28 ( 2 ): 229 – 249 . doi: 10.1111/j.1728-4457.2002.00229.x 10. ↵ Machiyama K , Cleland J . Unmet need for family planning in Ghana: the shifting contributions of lack of access and attitudinal resistance . Stud Fam Plann . 2014 ; 45 ( 2 ): 203 – 226 . doi: 10.1111/j.1728-4465.2014.00385.x . pmid: 24931076 11. ↵ Rossier C , Corker J . Contemporary use of traditional contraception in sub-Saharan Africa . Popul Dev Rev . 2017 ; 43 ( Suppl 1 ): 192 – 215 . doi: 10.1111/padr.12008 . pmid: 29307923 OpenUrl CrossRef PubMed Google Scholar 12. ↵ Gebreselassie T , Bietsch K , Staveteig S , Pullum T . Trends, Determinants, and Dynamics of Traditional Contraceptive Method Use . ICF ; 2017 . Google Scholar 13. ↵ Staveteig S . Fear, opposition, ambivalence, and omission: results from a follow-up study on unmet need for family planning in Ghana . PLoS One . 2017 ; 12 ( 7 ): e0182076 . doi: 10.1371/journal.pone.0182076 . pmid: 28759624 OpenUrl CrossRef PubMed Google Scholar 14. ↵ Sedgh G , Ashoford LS , Hussain R . Unmet Need for Contraception in Developing Countries: Examine Women's Reasons for Not Using a Method . Guttmacher Institute ; 2016 . Accessed May 24, 2021 . https://www.guttmacher.org/sites/default/files/report_pdf/unmet-need-for-contraception-in-developing-countries-report.pdf Google Scholar 15. ↵ Bradley SE , Schwandt H , Khan S . Levels, Trends, and Reasons for Contraceptive Discontinuation . DHS Analytical Studies 20 . ICF Macro ; 2009 . Accessed May 24, 2021 . http://cedar.wwu.edu/fairhaven_facpubs/1/ Google Scholar 16. ↵ Che Y , Cleland JG , Ali MM . Periodic abstinence in developing countries: an assessment of failure rates and consequences . Contraception . 2004 ; 69 ( 1 ): 15 – 21 . doi: 10.1016/j.contraception.2003.08.006 . pmid: 14720614 OpenUrl CrossRef PubMed Google Scholar 17. ↵ Festin MPR , Kiarie J , Solo J , et al . Moving towards the goals of FP2020 — classifying contraceptives . Contraception . 2016 ; 94 ( 4 ): 289 – 294 . doi: 10.1016/j.contraception.2016.05.015 . pmid: 27287693 OpenUrl CrossRef PubMed Google Scholar 18. ↵ Malarcher S , Spieler J , Fabic MS , Jordan S , Starbird EH , Kenon C . Fertility awareness methods: distinctive modern contraceptives . Glob Health Sci Pract . 2016 ; 4 ( 1 ): 13 – 15 . doi: 10.9745/GHSP-D-15-00297 . pmid: 27016540 19. Austad K , Chary A , Colom A , et al . Fertility awareness methods are not modern contraceptives: defining contraception to reflect our priorities . Glob Health Sci Pract . 2016 ; 4 ( 2 ): 342 – 345 . doi: 10.9745/GHSP-D-16-00044 . pmid: 27353626 20. Marston C , Church K . Response to Letters to the Editor from Irit Sinai “Standard Days Method Effectiveness: opinion disguised as scientific review” and Kelsey Wright, Karen Hardee, and John Townsend “The pitfalls of using selective data to represent the effectiveness, relevance and utility of the Standard Days Method of contraception” . Contraception . 2016 ; 94 ( 4 ): 376 – 378 . doi: 10.1016/j.contraception.2016.06.003 . pmid: 27318005 21. ↵ Hubacher D , Trussell J . A definition of modern contraceptive methods . Contraception . 2015 ; 92 ( 5 ): 420 – 421 . doi: 10.1016/j.contraception.2015.08.008 . pmid: 26276245 OpenUrl CrossRef PubMed Google Scholar 22. ↵ U.S. Food & Drug Administration . FDA allows marketing of first direct-to-consumer app for contraceptive use to prevent pregnancy . Published August 10, 2018 . Accessed May 24, 2021 . https://www.fda.gov/news-events/press-announcements/fda-allows-marketing-first-direct-consumer-app-contraceptive-use-prevent-pregnancy Google Scholar 23. ↵ U.S. Food & Drug Administration . Clue birth control . In 510(k) Premarket Notification [database online]. Updated May 24, 2021 . Accessed May 24, 2021 . https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K193330 Google Scholar 24. ↵ Starling MS , Kandel Z , Haile L , Simmons RG . User profile and preferences in fertility apps for preventing pregnancy: an exploratory pilot study . mHealth . 2018 ; 4 : 21 – 21 . doi: 10.21037/mhealth.2018.06.02 . pmid: 30050917 OpenUrl CrossRef PubMed Google Scholar 25. ↵ Duane M , Contreras A , Jensen ET , White A . The performance of fertility awareness-based method apps marketed to avoid pregnancy . J Am Board Fam Med . 2016 ; 29 ( 4 ): 508 – 511 . doi: 10.3122/jabfm.2016.04.160022 . pmid: 27390383 26. ↵ Haile LT , Fultz HM , Simmons RG , Shelus V . Market-testing a smartphone application for family planning: assessing potential of the CycleBeads app in seven countries through digital monitoring . mHealth . 2018 ; 4 : 27 – 27 . doi: 10.21037/mhealth.2018.06.07 . pmid: 30148140 OpenUrl CrossRef PubMed Google Scholar 27. Weis J , Festin M . Implementation and scale-up of the Standard Days Method of family planning: a landscape analysis . Glob Health Sci Pract . 2020 ; 8 ( 1 ): 114 – 124 . doi: 10.9745/GHSP-D-19-00287 . pmid: 32033980 28. Shelus V , Ashcroft N , Burgess S , Giuffrida M , Jennings V . Preventing pregnancy in Kenya through distribution and use of the CycleBeads mobile application . Int Perspect Sex Reprod Health . 2017 ; 43 ( 3 ): 131 – 141 . doi: 10.1363/43e4617 . pmid: 29553474 OpenUrl CrossRef PubMed Google Scholar 29. Ashcroft N , Shelus V , Garg H , McLarnon-Silk C , Jennings VH . Implementation of CycleTel Family Advice: an SMS-based service to provide family planning and fertility awareness information in India . mHealth . 2017 ; 3 : 20 . doi: 10.21037/mhealth.2017.05.01 . pmid: 28607906 OpenUrl CrossRef PubMed Google Scholar 30. Igras S , Sinai I , Mukabatsinda M , Ngabo F , Jennings V , Lundgren R . Systems approach to monitoring and evaluation guides scale up of the Standard Days Method of family planning in Rwanda . Glob Health Sci Pract . 2014 ; 2 ( 2 ): 234 – 244 . doi: 10.9745/GHSP-D-13-00165 . pmid: 25276581 OpenUrl Abstract / FREE Full Text Google Scholar 31. ↵ Arévalo M , Jennings V , Nikula M , Sinai I . Efficacy of the new TwoDay Method of family planning . Fertil Steril . 2004 ; 82 ( 4 ): 885 – 892 . doi: 10.1016/j.fertnstert.2004.03.040 . pmid: 15482764 32. ↵ Kavanaugh ML , Jerman J . Contraceptive method use in the United States: trends and characteristics between 2008, 2012 and 2014 . Contraception . 2018 ; 97 ( 1 ): 14 – 21 . doi: 10.1016/j.contraception.2017.10.003 . pmid: 29038071 33. ↵ Rossier C , Senderowicz L , Soura A . Do natural methods count? Underreporting of natural contraception in urban Burkina Faso . Stud Fam Plann . 2014 ; 45 ( 2 ): 171 – 182 . doi: 10.1111/j.1728-4465.2014.00383.x . pmid: 24931074 34. ↵ Marston C , Renedo A , Nyaaba GN , Machiyama K , Tapsoba P , Cleland J . Improving the measurement of fertility regulation practices: findings from qualitative research in Ghana . Int Perspect Sex Reprod Health . 2017 ; 43 ( 3 ): 111 – 119 . doi: 10.1363/43e4517 . pmid: 29553472 35. ↵ Staveteig S . Understanding Unmet Need in Ghana: Results From a Follow-up Study to the 2014 Ghana Demographic and Health Survey . DHS Qualitative Research Studies No. 20 . ICF International ; 2016 . Accessed May 24, 2021 . https://www.dhsprogram.com/pubs/pdf/QRS20/QRS20.pdf Google Scholar 36. ↵ Nanda K , Lebetkin E , Steiner MJ , Yacobson I , Dorflinger LJ . Contraception in the era of COVID-19 . Glob Health Sci Pract . 2020 ; 8 ( 2 ): 166 – 168 . doi: 10.9745/ghsp-d-20-00119 . pmid: 32312738 37. ↵ Purdy C . Opinion: How will COVID-19 affect global access to contraceptives — and what can we do about it? Devex . Published March 11, 2020 . Accessed May 24, 2021 . https://www.devex.com/news/sponsored/opinion-how-will-covid-19-affect-global-access-to-contraceptives-and-what-can-we-do-about-it-96745 Google Scholar 38. ↵ Brady M , Drake JK , Namagembe A , Cover J . Self-care provision of contraception: evidence and insights from contraceptive injectable self-administration . Best Pract Res Clin Obstet Gynaecol . 2020 ; 66 : 95 – 106 . doi: 10.1016/j.bpobgyn.2020.01.003 . pmid: 32199705 39. ↵ Iyanda AE , Dinkins BJ , Osayomi T , Adeusi TJ , Lu Y , Oppong JR . Fertility knowledge, contraceptive use and unintentional pregnancy in 29 African countries: a cross-sectional study . Int J Public Health . 2020 ; 65 ( 4 ): 445 – 455 . doi: 10.1007/s00038-020-01356-9 . pmid: 32270234 40. ↵ Delbaere I , Verbiest S , Tydén T . Knowledge about the impact of age on fertility: a brief review . Ups J Med Sci . 2020 ; 125 ( 2 ): 167 – 174 . doi: 10.1080/03009734.2019.1707913 . pmid: 31964217 OpenUrl CrossRef PubMed Google Scholar 41. ↵ Polis CB . Published analysis of contraceptive effectiveness of Daysy and DaysyView app is fatally flawed . Reprod Health . 2018 ; 15 ( 1 ): 113 . doi: 10.1186/s12978-018-0560-1 . pmid: 29940983 42. ↵ Polis CB , Otupiri E , Hindin M , et al . Prevalence and correlates of perceived infertility in Ghana . Stud Fam Plann . 2020 ; 51 ( 3 ): 207 – 224 . doi: 10.1111/sifp.12136 . pmid: 32964426 43. ↵ Keogh SC , Otupiri E , Chiu DW , et al . Estimating the incidence of abortion: a comparison of five approaches in Ghana . BMJ Glob Health . 2020 ; 5 ( 4 ): e002129 . doi: 10.1136/bmjgh-2019-002129 . pmid: 32337086 OpenUrl Abstract / FREE Full Text Google Scholar 44. ↵ Keogh SC , Otupiri E , Castillo PW , et al . Hormonal contraceptive use in Ghana: the role of method attributes and side effects in method choice and continuation . Contraception . 2021 ; S0010-7824(21)0015107 . doi: 10.1016/j.contraception.2021.05.004 . pmid: 33992609 OpenUrl CrossRef PubMed Google Scholar 45. ↵ Sheon AR , Stanton C . Use of periodic abstinence and knowledge of the fertile period in 12 developing countries . Int Fam Plan Perspect . 1989 ; 15 ( 1 ): 29 – 34 . doi: 10.2307/2133276 OpenUrl CrossRef Google Scholar 46. ↵ Polis CB , Jones RK . Multiple contraceptive method use and prevalence of fertility awareness based method use in the United States, 2013–2015 . Contraception . 2018 ; 98 ( 3 ): 188 – 192 . doi: 10.1016/j.contraception.2018.04.013 . pmid: 29702082 OpenUrl CrossRef PubMed Google Scholar 47. ↵ Ghana Statistical Service (GSS), Ghana Health Service (GHS), ICF International . Ghana Demographic and Health Survey 2014 . GSS, GHS, ICF International ; 2015 . Accessed May 24, 2021 . https://www.dhsprogram.com/pubs/pdf/FR307/FR307.pdf Google Scholar 48. ↵ Ghana Statistical Service (GSS), Ghana Health Service (GHS), ICF . Ghana Maternal Health Survey 2017 . GSS, GHS, and ICF ; 2018 . Accessed May 24, 2021 . https://dhsprogram.com/pubs/pdf/FR340/FR340.pdf Google Scholar 49. ↵ Ghana Statistical Service (GSS) . Projected Population by Age and Sex, 260 Districts, 2020 . GSS ; 2020 . Accessed May 24, 2021 . https://www.statsghana.gov.gh/infobankdetails.php?infobank=NzM4OTU5NzcwLjU0Mg==/infodesk/5ss09qq33r Google Scholar 50. ↵ Marston C , Renedo A , Nyaaba GN . Fertility regulation as identity maintenance: Understanding the social aspects of birth control . J Health Psychol . 2018 ; 23 ( 2 ): 240 – 251 . doi: 10.1177/1359105317726367 . pmid: 28925281 OpenUrl CrossRef PubMed Google Scholar 51. ↵ Osei IF , Mayhew SH , Biekro L , Collumbien M ; ECAF Team . Fertility decisions and contraceptive use at different stages of relationships: windows of risk among men and women in Accra . Int Perspect Sex Reprod Health . 2014 ; 40 ( 03 ): 135 – 143 . doi: 10.1363/4013514 . pmid: 25271649 OpenUrl CrossRef PubMed Google Scholar 52. Hindin MJ , McGough LJ , Adanu RM . Misperceptions, misinformation and myths about modern contraceptive use in Ghana: Table 1 . J Fam Plann Reprod Health Care . 2014 ; 40 ( 1 ): 30 – 35 . doi: 10.1136/jfprhc-2012-100464 . pmid: 23771916 OpenUrl Abstract / FREE Full Text Google Scholar 53. ↵ Atijosan A , Adeyeye O , Ogungbayi O . Knowledge and perception regarding infertility among university students in Ile-Ife: a view through gender lens . Covenant J Bus Soc Sci . 2019 ; 10 ( 1 ): 14 . doi: 10.20370/0tcm-n551 OpenUrl CrossRef Google Scholar 54. ↵ Hatcher RA , Nelson AL , Trussell J , et al Jennings VH , Polis CB . Fertility awareness-based methods . In: Hatcher RA , Nelson AL , Trussell J , et al ., eds. Contraceptive Technology . 21st ed. Ayer Company Publishers, Inc. ; 2018 . Google Scholar 55. ↵ Krakowiak-Redd D , Ansong D , Otupiri E , et al . Family planning in a sub-district near Kumasi, Ghana: side effect fears, unintended pregnancies and misuse of a medication as emergency contraception . Afr J Reprod Health . 2011 ; 15 ( 3 ): 121 – 132 . pmid: 22574499 OpenUrl PubMed Google Scholar 56. ↵ Eliason S , Baiden F , Yankey BA , Awusabo-Asare K . Determinants of unintended pregnancies in rural Ghana . BMC Pregnancy Childbirth . 2014 ; 14 ( 1 ): 261 . doi: 10.1186/1471-2393-14-261 . pmid: 25104039 OpenUrl CrossRef PubMed Google Scholar , No. 2
https://www.ghspjournal.org/content/9/2/318?__hsfp=3465878509&__hssc=175320440.1.1683127251397&__hstc=175320440.17a0c1947c9cc892647352dc6a14f9b0.1683127251396.1683127251396.1683127251396.1
U.S. v. SCHLIFER | 403 F.3d 849 (2005) | f3d84911153 | Leagle.com WILLIAMS Circuit Judge. James Schlifer appeals his sentence of 120 months on the ground that the district court violated the Sixth...f3d84911153 U.S. v. SCHLIFER No. 04-3398. View Case Cited Cases Citing Case 403 F.3d 849 (2005) UNITED STATES of America, Plaintiff-Appellee, v. James T. SCHLIFER, Defendant-Appellant. United States Court of Appeals, Seventh Circuit. https://leagle.com/images/logo.png Argued March 1, 2005. Decided April 7, 2005. Attorney(s) appearing for the Case Paul W. Connell (argued), Office of the United States Attorney, Madison, WI, for Plaintiff-Appellee. T. Christopher Kelly (argued), Kelly & Habermehl, Madison, WI, for Defendant-Appellant. Before KANNE, EVANS and WILLIAMS, Circuit Judges. United States Court of Appeals, Seventh Circuit. WILLIAMS, Circuit Judge. James Schlifer appeals his sentence of 120 months on the ground that the district court violated the Sixth Amendment by sentencing him as a career offender without presenting the facts underlying his prior convictions to a jury. He also argues that in light of the Supreme Court's decision in United States v. Booker,___ U.S. ___, 125 S.Ct. 738, 160 L.Ed.2d 621 (2005), the district court erred in applying the guidelines under the prior mandatory sentencing scheme. Although Schlifer's Sixth Amendment argument lacks merit, we vacate his sentence and remand for resentencing because the district court erred under Bookerby sentencing Schlifer under a mandatory guidelines system, and the government has not demonstrated that the error was harmless. I. BACKGROUND In June 2004 Schlifer pleaded guilty to one count of conspiracy to manufacture methamphetamine, in violation of 21 U.S.C. §§ 846 and 841(a)(1). Under the November 2003 sentencing guidelines, Schlifer's crime ordinarily would have carried a base offense level of 30 based on evidence that the quantity of methamphetamine was at least 360 grams. U.S.S.G. § 2D1.1(c)(5). However, the probation officer who prepared the presentence investigation report (PSR) recommended that the court sentence Schlifer as a career offender because among his prior crimes were two unrelated convictions for aggravated assault. SeeU.S.S.G. § 4B1.1. Under the career offender guideline, Schlifer's base offense level increased to 32 and his criminal history category was VI regardless. U.S.S.G. § 4B1.1. The court then deducted three levels for acceptance of responsibility. SeeU.S.S.G. § 3E1.1. This resulted in a total offense level of 29, which, combined with Schlifer's criminal history category of VI, yielded a sentencing range of 151 to 188 months. In response to the PSR and again at his sentencing hearing, Schlifer objected to being sentenced as a career offender. He argued that in order to classify him as a career offender the district court was required to find facts beyond the mere existence of two prior convictions. Specifically, he argued that the district court had to determine whether his prior convictions were for crimes of violence and whether the two crimes were unrelated. SeeU.S.S.G. §§ 4B1.2(c), 4A1.2(a) & cmt. n. 3. These determinations, Schlifer argued, required the district court to go beyond the "fact of a prior conviction" and thus exceeded the judicial factfinding exception for recidivism recognized in Almendarez-Torres v. United States,523 U.S. 224, 118 S.Ct. 1219, 140 L.Ed.2d 350 (1998), and preserved in Apprendi v. New Jersey,530 U.S. 466, 120 S.Ct. 2348, 147 L.Ed.2d 435 (2000). Accordingly, Schlifer contended that under Blakely v. Washington,___ U.S. ___, 124 S.Ct. 2531, 159 L.Ed.2d 403 (2004), and United States v. Booker,375 F.3d 508(7th Cir.2004), these facts must be admitted or proven beyond a reasonable doubt before they could be used to increase his guideline range. The district court rejected Schlifer's argument, concluding that Blakelyand this court's opinion in Bookerdo not apply to prior convictions. The district court denied Schlifer's motion to depart under U.S.S.G. § 5K2.0, rejecting his argument that his offense primarily involved manufacturing methamphetamine for personal use and thus fell outside of the "heartland" of drug [403 F.3d 852] manufacturing and distribution cases contemplated by the guidelines. The court, however, granted the government's motion for a downward departure based on Schlifer's substantial assistance. See U.S.S.G. § 5K1.1. The court calculated a new effective range of 120 to 150 months by departing the equivalent of three levels, and sentenced Schlifer to 120 months' imprisonment. II. ANALYSIS Schlifer argues in his opening brief that the district court impermissibly sentenced him as a career offender without submitting the issue to a jury. After that brief was filed, and after his case had already been set for oral argument, the Supreme Court decided Booker.We granted Schlifer's motion to file a supplemental brief in light of Booker.Schlifer now argues in addition that his sentence is erroneous because the district court imposed it under the mandatory guidelines system that existed prior to Booker.He thus contends that his sentence should be vacated and his case remanded for resentencing in light of the Court's decision that the guidelines are advisory. A defendant is a career offender under U.S.S.G. § 4B1.1 if he commits a felony drug offense after the age of 18 and has at least two prior felony convictions for crimes of violence or drug trafficking offenses. The prior offenses must be unrelated. Schlifer argues in his opening brief that these determinations require a sentencing court to find facts outside the judgment of conviction and thus entail impermissible factfinding by the court. Prior to the Supreme Court's decision in Booker,Schlifer's appeal would have been frivolous. Neither the Supreme Court's decision in Blakelynor this court's opinion in Bookerdisturbed the principle that the "fact of a prior conviction" falls outside the Apprendirule that facts increasing a sentence beyond the otherwise applicable statutory maximum must be proved to a jury beyond a reasonable doubt. See United States v. Pittman,388 F.3d 1104, 1109 (7th Cir.2004). Thus in Pittmanthis court held that imposing a career offender sentence under § 4B1.1 without resort to a jury or proof beyond a reasonable doubt of the prior convictions did not violate Blakelyas interpreted by this court in Booker. Id. Pittmanhas not been affected by the Supreme Court's decision in Bookerbecause the Court again preserved the Almendarez-Torresexception for prior convictions. See Booker,___ U.S. at ___, 125 S.Ct. at 758. And, although the Supreme Court recently called its future into question, the Almendarez-Torresexception for prior convictions still stands. Shepard v. United States,___ U.S. ___, 125 S.Ct. 1254, ___ L.Ed.2d ___, 2005 WL 516494 (U.S. March 7, 2005). Schlifer attempts to distinguish his case by arguing that the district court's conclusion that he is a career offender entailed finding facts outside the "fact of a prior conviction," namely, whether his prior convictions are for crimes of violence and whether they are "related." But we have already rejected a similar argument in United States v. Morris, 293 F.3d 1010 (7th Cir.2002). In Morris, a defendant who was sentenced under the Armed Career Criminal Act, 18 U.S.C. § 924(e), argued that his sentence was unconstitutional under Apprendi because the government did not prove beyond a reasonable doubt that his prior convictions had been committed on separate occasions as required by the statute. We rejected the argument, noting that there was no precedent for "parsing out the recidivism inquiry." Id. at 1012. Likewise, Schlifer cites no authority in support of his argument that, although "the fact of a prior conviction" may be found by a judge by the preponderance [403 F.3d 853] of the evidence, the factors that bear on that determination must be proved beyond a reasonable doubt. In this case, the district court did not engage in impermissible factfinding with respect to its determination that Schlifer was a career offender, and Schlifer's sentence accordingly does not violate the Sixth Amendment. In his supplemental brief, however, Schlifer raises the nonfrivolous argument that the Supreme Court's remedial opinion in Bookerinvalidates his sentence even in the absence of a Sixth Amendment violation. In Justice Stevens's opinion in Booker,the Court extended its holding in Blakelyto the federal sentencing guidelines and held that the Sixth Amendment right to trial by jury is violated where a defendant's guidelines range is increased based on facts (other than a prior conviction) found by the judge without a jury or using a preponderance standard. Booker,___ U.S. at ___, 125 S.Ct. at 756. Second, the Court, in an opinion authored by Justice Breyer, severed from the authorizing statute the provision that called for the mandatory application of the Guidelines and the provision that established the appellate standard of review. Id.at 765. The Court thus crafted a system under which the district courts are obligated to consider the guidelines but are not bound by them. Id.at 767. The remedial portion of the Court's decision, which invalidates the mandatory application of the guidelines and instead requires the courts to consult them in an advisory fashion, must be applied to all cases pending on direct review, even in the absence of a Sixth Amendment violation. See id.at 765. Thus in every pending appeal where the district court sentenced a defendant under the now-defunct mandatory guidelines scheme, error will have been committed. See id.at 768, 1769 (holding that parties in respondent Fanfan's case "may seek resentencing under the system set forth in [ Booker]" though "Fanfan's sentence d[id] not violate the Sixth Amendment"); United States v. Paladino,Nos. 03-2296 et al.,401 F.3d 471, 2005 WL 435430, at *7 (7th Cir. Feb.25, 2005) (finding Bookererror where a portion of defendant Velleff's sentence "was based on mandatory provisions of the sentencing guidelines"); see also, United States v. Crosby,397 F.3d 103, 114-15 (2d Cir.2005); United States v. Hughes,401 F.3d 540, 2005 WL 628224, at *4 (4th Cir. Mar.16, 2005); United States v. Labastida-Segura,396 F.3d 1140, 1142-43 (10th Cir.2005). The existence of error, however, does not mean that every appeal must lead to resentencing. In Booker, the Court instructed that the "ordinary prudential doctrines" of plain error and harmless error should be applied in determining whether resentencing is necessary. ___ U.S. at ___, 125 S.Ct. at 769. Thus we must first determine whether Schlifer preserved his Booker claim and what standard of review applies to the claim. See United States v. McDaniel, 398 F.3d 540 (6th Cir.2005). The doctrine of plain error applies when a defendant forfeits a ground in the district court but raises it on appeal. [403 F.3d 854] United States v. Pawlinski, 374 F.3d 536 , 540 (7th Cir.2004). Otherwise, the appellant is entitled to plenary review of a sentencing error. This is not a plain error case, and our recent decision in Paladinois inapposite here. Schlifer was sentenced prior to the Supreme Court's opinion in Booker,but he objected to his sentence in the district court on Blakelygrounds. Schlifer also anticipated the possibility that the guidelines were severable. His objection was specific enough to preserve the argument he makes now about the mandatory character of his sentence because it was sufficient to alert "the court and opposing party to the specific grounds for the objection." United States v. Linwood,142 F.3d 418, 422 (7th Cir.1998). This is also the position recently taken by the Tenth Circuit, which held that an appellant who raised a Blakelyargument in the district court also preserved for appeal a Bookererror. See Labastida-Segura,396 F.3d at 1143. In contrast, the courts of appeal that have applied plain error analysis to a Bookerclaim have done so because no Sixth Amendment challenge was raised in the district court. E.g., Paladino,401 F.3d 471, 2005 WL 435430, at *7; Hughes,401 F.3d 540, 2005 WL 628224, at *5; United States v. Rodriguez,398 F.3d 1291, 1298 (11th Cir.2005). Because, in effect, the district court's error amounts to a misapplication of the guidelines, Schlifer's sentence must be vacated unless the error was harmless. See United States v. Hollis,230 F.3d 955, 958 (7th Cir.2000); United States v. Jackson,32 F.3d 1101, 1109-10 (7th Cir.1994). When an error relates to the validity of a defendant's sentence, it is harmless only if it did not affect the district court's choice of sentence. United States v. Smith,332 F.3d 455, 460 (7th Cir.2003); Jackson,32 F.3d at 1109. The government argues in its supplemental brief that any error in Schlifer's sentence was harmless because it did not affect the district court's choice of sentence. First, the government argues that the district court's decision to depart downward the equivalent of just three offense levels based on Schlifer's substantial assistance signals the court's unwillingness to exercise the discretion already available to it by further lowering Schlifer's sentence. This argument has some facial appeal, but it ignores the fact that a sentencing judge, prior to Booker,had the guidelines and the appellate standard of review in mind when fashioning a departure. A departure decision, even if "discretionary," was nevertheless informed by the guidelines and thus sheds little light on what a sentencing judge would have done knowing that the guidelines were advisory. Moreover, although the size of the departure was within the court's discretion, see U.S.S.G. § 5K1.1, the government cites no examples of past cases in which this argument has been accepted as basis for concluding that a guidelines misapplication was harmless. Typically, we require a higher degree of certainty for such a conclusion. For example, we have noted that when a sentencing judge must choose between two sentencing ranges that overlap, and expressly acknowledges that it would impose the same sentence under either range, this court can be certain that an error in choosing the wrong range was harmless. Jackson, 32 F.3d at 1110. But "there is no such certainty here." See id. Nor is this a case where the district court clearly stated that it wanted to impose the maximum available sentence, see United States v. Benitez, 92 F.3d 528 , 539 (7th Cir.1996), or where the district court "erred on the high side but the sentence could not have been any lower because of a statutory minimum," see United States v. Giacometti 28 F.3d 698 , 704 (7th Cir.1994). [403 F.3d 855] Ultimately, this court would have to speculate that the district court's error in thinking itself bound by the guidelines did not affect the sentence. The government next argues that the district court's rejection of Schlifer's motion for a downward departure under § 5K2.0 evinces its unwillingness to impose a lower sentence. This argument is unpersuasive because it appears that the district court simply did not agree that Schlifer had presented a permissible basis for departure under that guideline. In denying Schlifer's motion, the court determined that the circumstances of his case were not "outside the heartland." Given this determination, the district court did not have a solid basis to depart under § 5K2.0. Thus the court's denial of Schlifer's motion sheds no light on whether the court would have departed had Schlifer presented different grounds, or whether the court might have granted the very same motion had it known that Bookereffectively allows greater latitude in making departure decisions. Finally, the government makes the undeveloped argument that the district court's acknowledgment of Schlifer's extensive criminal history reveals a disinclination to impose a lesser sentence. The government provides no support for this argument, and although the district court characterized Schlifer's criminal history as "horrendous," it did so in the context of explaining its decision to sentence him as a career offender. Moreover, this court has acknowledged that such comments are common at sentencing, and are not necessarily evidence that an error was harmless. See Jackson,32 F.3d at 1110. Thus, the most that can be inferred from the district court's statement is that Schlifer's criminal history warranted sentencing under § 4B1.1. The government ultimately fails to meet its burden of demonstrating that, if the district court had known that the guidelines are advisory rather than mandatory, its choice of sentence would have been the same. While the result might be different under a plain error standard, where the defendant has the burden of demonstrating that his substantial rights were affected, in this case the error cannot fairly be deemed "harmless." III. CONCLUSION For the reasons stated above, we VACATE Schlifer's sentence and REMAND the case to the district court with instructions to resentence in light of Booker. This opinion was circulated to the entire court before issuance. No member of the court in active service voted to hear the case en banc. FootNotes 1. The Government would render the Guidelines advisory in "any case in which the Constitution prohibits" judicial factfinding. But it apparently would leave them as binding in all other cases. We agree with the first part of the Government's suggestion. However, we do not see how it is possible to leave the Guidelines as binding in other cases.... [W]e believe that Congress would not have authorized a mandatory system in some cases and a nonmandatory system in others, given the administrative complexities that such a system would create. Such a two-system proposal seems unlikely to further Congress' basic objective of promoting uniformity in sentencing. Id. at 768. Throughout our history we have sought to build and serve our community through offering our comprehensive library of over ten million published and unpublished decisions and orders for free. We have done this though the generosity of our wonderful team. But in recent years, the economic environment has proven fickle and tumultuous, and now such personal generosity is too-slender a reed upon which to hang our entire enterprise. That's why in April we are launching a paywall — a model that rewards our community of users with very reasonable terms of access and will help us keep Leagle the most reliable source of U.S. case law. Our community will continue to be able to find their parties or cases of choice through their favorite search engines. At the same time, we remain committed to the importance of an accurate understanding of the law in our national public discourse. Hence, we will continue to serve the public benefit by offering the most recent daily and breaking decisions and orders to all users for free. To our large community of users - thank you for your understanding and continued loyalty as we provide the highest quality legal reporting.
https://www.leagle.com/decision/20051252403f3d84911153
VIPM Updates Biweekly vegetable integrated pest management updates Avoiding Seed Corn Maggots in Spring Melons - 2019 I was driving through the Yuma Valley last week and noticed several fields that had recently been planted with spring melons.  I also noticed beds that had been listed for melon planting and saw a lot of broccoli residue in the beds.   This reminded me of the threat of seed corn maggots on early planted melons, particularly in a wet winter like we’re having this season.  Seed corn maggot is a pest that is best avoided.  Seed corn maggots are always a concern for melon crops planted from Jan-Mar, and are most prevalent under cool, wet weather; ideal conditions for infestations.    Seed corn maggots can cause significant stand reductions in melons and other large seeded crops (e.g., cotton, corn, safflower) due to the maggots feeding on germinating seed, roots and stems of young seedlings and transplants.  If larvae populations are high in the soil, replanting parts or all of an infested field is often necessary.  Not only is this an inconvenience to the grower, but replanting is expensive and can disrupt harvest schedules.  Unfortunately, once maggots have been found infesting the soil during stand establishment, there is usually nothing you can do.  Thus, avoidance of the problem is the most effective way of preventing stand reductions.  First, weather plays a major role in determining the damage potential for seed corn maggot. Melon stands are more susceptible to seed corn maggot during wet, cool spring weather in which seed germination is slowed or delayed.  These conditions give seed corn maggots a chance to develop in the soil and attack the seeds before they can emerge. However, I’ve also observed seed corn maggots take down direct seeded cantaloupe and transplanted watermelon stands established under warm, dry conditions when fly populations were high.  Secondly, our cropping system plays a key role.  Melon crops following produce are the most often attacked because seed corn maggot adults are attracted to freshly tilled soils with high levels of decomposing organic matter and will readily lay eggs in the soil. This includes heavy plant residue remaining after harvest of the previous lettuce or cole crop, as well as applications of composted manure prior to planting.  Growers would be encouraged to delay planting melons into fields under these conditions.  However, if growers decide to plant in these conditions, then it would be wise to use a preventative insecticide applied at planting to minimize the impact from seed corn maggot and give seedlings a fighting chance.   A few alternatives are available that have shown activity against seed corn maggot and may be practical for their management in spring melons. For more information, visitSeed Corn Maggot in Spring Melons 2019. To contact John Palumbo go to: [email protected] Water and Food Security in the Desert Southwest The difficulties we are experiencing with water in the west are the consequence of the worst megadrought in 1200 years, which is increasingly clear to be a process of aridification and climate change (Wheeler et al., 2022).  These conditions are bearing down on desert agriculture in a very significant way. In the next week, the U.S. Bureau of Reclamation (BoR) is expected to announce the 2023 operational plan for the Colorado River and it will definitely involve reductions in water allocations. On 14 June 2022 BoR Commissioner Camille C. Touton described the need to achieve additional reductions on Colorado River allocations.  The BoR has been engaging in discussions with the seven basin states that depend on the Colorado River to develop a plan for the reductions, and that decision will be announced in the next few days.  As Commissioner Touton described, the BoR has the authority to “act unilaterally to protect the system, and we will protect the system.” (Bureau of Reclamation, 28 June 2022).  Commissioner Touton stated that the seven basin states on the Colorado River must reduce allocations by 2 to 4 million acre-feet (MAF). The basic arithmetic on the Colorado River is as follows: 16.5 MAF is currently the allocated amount of water budgeted with 7.5 MAF allocated to both the upper and lower basins, plus 1.5 MAF allocated to Mexico: (7.5+7.5 MAF = 15 MAF U.S. + 1.5 MAF Mexico = 16.5 MAF total ) In the past two decades, the average annual flow of the Colorado River from 2000 - 2018 has been approximately 12.4 MAF , which is 16 % lower than the 1906-2017 average of 14.8 MAF/year .  Thus, we can see where the 4 MAF differential is determined. A reduction of Colorado River water allocations from 16.5 MAF to 12 MAF represents a 27% reduction.  That is in line with the climate and hydrological reality we are dealing with and a huge reduction for the Colorado River basin.  So, while the good news is that we do have approximately 12 MAF coming down the river, the bad news is that it is almost 1/3 less than what has been allocated on the existing Colorado River water budget.  To bring the Colorado River system into better balance will require some major changes. The valleys of the Colorado River watershed are tremendously valuable resources with alluvial soils that are young geologically, extremely fertile, and highly productive if sufficient water is provided.  These are some of the richest agricultural areas in the western United States.  For example, the lower Colorado River valley, particularly the valleys in the Yuma, Arizona and Imperial Valley, California areas, provide more than 90% of the leafy green vegetables (all types of lettuce, broccoli, cauliflower, etc.) for the U.S. and Canada every year from November through March.  These valleys produce an abundance of other crops including high quality durum wheat production that supports the pasta industry, including most Italian pastas, and a seed production industry that provides high quality seed stocks regionally, nationally, and internationally.  An extremely well developed and sophisticated infrastructure system is in place to direct and manage water to the fields for highly efficient and productive irrigation systems.  The management of these systems requires a high level of specialized and well-developed expertise which is in place and operating in the rich and productive valleys of the lower Colorado River.  Thus, the valleys of the Colorado River and the people on the ground in the field are managing some of the most productive farms in the U.S. and anywhere in the world.  These are resources that we should value and protect for both water and food security that is both regionally and nationally significant. Analysis of the desert Southwest’s paleoclimate have shown a distinct susceptibility of the region to experience extraordinary megadroughts that can last for decades or even centuries (Baum, 2015; Stahle et al., 2000; and Acuna-Soto et al., 2002).  For example, paleoclimate records show that a fifty-year drought struck the Southwest, Northern Mexico, and the Rocky Mountains between about AD 1540 and 1590.  Three hundred years earlier, records reveal the Great Drought of AD 1267-1299.  It is believed that this 32 year Great Drought period was at least partially responsible for the abandonment of concentrated Native American populations throughout the Southwest (Cook et al., 2007; Benson et al., 2007; and Cook et al., 2010).  Paleoclimate records indicate that droughts of more than a century in length have hit this region in the past (Stine, 1994). The result of this overall situation is that we are reaching a crossroads in the development of a strategy to deal with the changing conditions in the west and immediate action is needed.  All efforts that have been directed to deal with this issue in the past 20 years, although well-intended, have not been sufficient in addressing the problem, including the 2007 interim guidelines, the Intentionally Created Surplus program, the Drought Contingency Plan, and the 500+ Plan.  The climate is changing much faster than our system of governance.  Thus, we are facing an existential crisis for the desert Southwest that includes the interface between the agricultural and urban sectors of our society.  It seems to be one of the classic cases of “If you are not at the table, you are probably on the menu.”  In this case, it might be both. One of the difficulties with this overall situation is the past tendency to develop short-term responses to a situation that has long-term implications and needs.  In general, people have a tendency in strategic management at all levels, from international relations, to national, state, and local governance towards “Strategic Narcissism”, which is the tendency to define challenges as we would like them to be while ignoring the agency that other entities have over our results. This term of strategic narcissism was first presented by Hans J. Morgenthau and he expanded on this theme in his 1948 book Politics Among Nations where he introduced the concept of political realism, presenting a realist view of power politics.  He pointed out that strategic narcissism and the tendency to think idealistically and narrowly about the scope of the problem or challenge usually leads to narrow solutions and strategies, which commonly fail. In his 2020 book Battlegrounds: The Fight to Defend the Free World , H.R. McMaster reinforces Morgenthau’s point regarding the dangers of indulging in strategic narcissism and the corresponding tendency to artificially separate interconnected problem sets, which encourages short term and simplistic solutions to complex problems.  He describes the common tendency to define and address a problem in a manner that allows us to develop a response that we favor.  This is often based on wishful thinking and our own capacity for self-delusion with flawed assumptions rather than dealing with a realistic assessment of basic facts. While Morgenthau and McMaster are addressing strategic issues on the international scale, we are confronted with similar challenges of avoiding the indulgence in strategic narcissism in our efforts to develop effective strategies to manage our water resources in the desert Southwest, as exemplified in the Colorado River situation.  It is important for us to recognize the legitimacy and importance of all involved components, current and future, including both urban and agricultural interests and understand that the decisions made today will have an impact on residents of the desert Southwest in the decades to come in all sectors. Thus, we need to be considerate of more than ourselves and the immediate needs and include the prospects for our children, grandchildren, and the unborn generations yet to come.  Considering the basic facts associated with the current Southwestern megadrought and the realistic indications that we are dealing with increasing aridification of the climate through the process of climate change is a good example.  We have consistently held onto the hope that the drought will end, and we will soon return to the climate and hydrological patterns of the mid-20 th century.  Instead, it would be better to plan for the probable contingency that aridification is taking place and future generations in the desert Southwest will be forced to continue to deal with it.  As the paleoclimate records show us, this is within the range of possibilities. A case of strategic narcissism is the belief and conviction that some people hold that commercial agriculture in the desert Southwest should be eliminated with the food and fiber production being replaced by distant and perhaps international sources or small farm local crop production operations.  Placing future generations at the mercy of long-distance sources of food production is dangerous and it would be irresponsible to do at this time.  These are rather simplistic and idealistic visions.  For example, small scale local farming can serve as a nice food supplement to some communities, particularly in urban areas, but it is not going to replace the needs for large scale food and fiber production supporting 7.4 M Arizonans, 330 M people in the United States and nearly 8 B people on the planet today.  These ideas run counter to good and practical strategic planning for water and food security for the desert Southwest. Admittedly, it is exceedingly difficult for humans to have the necessary discipline to avoid strategic narcissism and develop a better sense of empathy for strategic planning.  As Jamil Zaki, a psychologist from Stanford University has pointed out, it is difficult for people to develop the necessary empathy because it runs counter to our basic nature and instincts (Zaki, 2019).  Both time and distance diminish our capacity for empathy because “humans caring instincts are short sighted.  Our ability to feel empathy about future development is limited because we tend not to feel for our future selves.  It goes against our instincts to tackle problems that we have not yet been forced to confront.” As we plan and develop a functional strategy for future water and food security in the desert Southwest, it is realistic to consider that large urban areas will exist and continue to grow.  Agriculture is essential to any society and that is certainly true for the large cities of the Southwest, present and future.  In 2022 we should be very alert to the dangers of depending on long supply chains and the single points of failure in supply chains that can be devastating to the dependent populations.  The current situation is an opportunity to strategically plan for the future of the desert Southwest in a manner that provides for both water and food security. Based on the agricultural capacities of the desert Southwest, Arizona could be self-sustaining, or very nearly so.  Considering Arizona, New Mexico, and California collectively, the possibility of long-term agricultural sustainability is entirely possible.  But sufficient water is required to support the agricultural systems necessary to support that population. I am confident that we can work through these challenges in a balanced and effective manner but “business as usual” will not be sufficient in addressing the demands of today.  This is a complex situation environmentally, geographically, politically, economically, and socially.  Compounding the current challenges is the fact that actions need to take place rather swiftly and here are many factors to consider simultaneously.  It is important that we develop a consideration of the broad and long-term impacts of our decisions for all parties with critical issues such as the management of our water resources for both water and food security in the desert Southwest.  This requires a conscious and concerted effort to do so and all parties taking Colorado River water should share in absorbing the changes that are coming, nobody should get a pass.  It is possible to develop a balance of coexistence with agriculture and urban development with the water resources available in this region but it will not be easy. As stated in the old Greek proverb: “ Society grows great when old men plant trees whose shade they know they shall never sit in .” We can see the value of that line of thought that was true 3,000 years ago and also with what we are dealing with today.  This is one of the great challenges of our time and I believe we can step up and deliver in a balanced and constructive manner. References: Acuna-Soto, R., D.W. Stahle, M.K. Cleaveland, and M.D. Therrell. 2002. Megadrought and Megadeath in16th Century Mexico.  Historical Review 8(4): 360-362. Baum, R. 2015.  Climate change and drought in the American Southwest.  The Climate Institute. https://climate.org/effects-of-21st-century-climate-change-on-drought-disk-in-the-american-southwest/#:~:text=Drought%20is%20a%20common%20occurrence%20in%20the%20American,completely%20unprecedented%20within%20the%20past%2010%2C000%20years.%208 Benson, LV., M.S. Berry, E.A. Jolie, J.D. Spangler, and D.W. Stahle. 2007. Possible impacts of early-11th-, middle-12th-, and late-13th-century droughts on western Native Americans and the Mississippian Cahokians. Quaternary Science Reviews 26(3): 336-350. Bureau of Reclamation, 28 June 2022 https://www.usbr.gov/ColoradoRiverBasin/ Cook, E.R., R. Seager, M.A. Cane MA, D.W. Stahle. 2007. North American drought: Reconstructions, causes, and consequences. Earth Science Reviews 81(1): 93-134. Cook, E.R., R. Seager, R.R. Heim Jr., R.S. Vose, C. Herweijer, and C. Woodhouse C. 2010.  Megadroughts in North America: placing IPCC projections of hydroclimatic change in a long-term paleoclimate context.  Journal of Quaternary Science 25(1): 48-61. McMaster, H.R., 2020. Battlegrounds: The Fight to Defend the Free World. Harper Collins Publishers, New York, NY. Morgenthau, H.J. and K. Thompson. 1948. Politics Among Nations. New York: McGraw-Hill. (1985, 6th ed.). Stahle, D.W., E.R. Cook, M.K. Cleaveland, M.D. Therrell, D.M. Meko, H.D. Grissino-Mayer, E. Watson, and B.H. Luckman. 2000. Tree-ring Data Document 16th Century Megadrought Over North America.  EOS 80(12): 121-125. Stine, S. 1994.  Extreme and persistent drought in California and Patagonia during mediaeval time.  Nature 369: 546-549. Wheeler, K.G, B. Udall, J. Wang, E. Kuhn, H. Salehabadi, and J.C. Schmidt. 2022. What will it take to stabilize the Colorado River?  Science, 377 (6604) p. 373-375. • DOI: 10.1126/science.abo4452 Zaki, J. 2019. The War for Kindness: Building Empathy in a Fractured World. Crown Publishing Group (NY). To contact Jeff Silvertooth go to: [email protected] Botrytis rot is not considered a major problem in lettuce  and we saw the disease in only couple of fields this growing season. However, it can cause significant damage/loss when the field conditions are favorable for the pathogen. Cool wet conditions are favorable for the pathogen. Symptoms include water-soaked, brownish-gray to brownish-orange, soft wet rot that occurs on the oldest leaves in contact with the soil. Old leaves are more susceptible than young leaves and the fungus can move into the healthy parts. Fuzzy gray growth can be observed in the disease area which is characteristic of the pathogen. In worse cases, the entire plant can collapse. Romaine cultivars, transplanted lettuce that are big and have leaves touching the soil are more susceptible.The pathogen: Botrytis cinereaBotrytis cinerea affects most vegetable and fruit crops, as well as a large number of shrubs, trees, flowers, and weeds. Outdoors Botrytis overwinters in the soil as mycelium on plant debris, and as black, hard, flat or irregular sclerotia in the soil and plant debris, or mixed with seed. The fungus is spread by anything that moves soil or plant debris, or transports sclerotia. The fungus requires free moisture (wet surfaces) for germination, and cool 60 to 77 F, damp weather with little wind for optimal infection, growth, sporulation, and spore release. Botrytis is also active at low temperatures, and can cause problems on vegetables stored for weeks or months at temperatures ranging from 32 to 50. Infection rarely occurs at temperatures above 77 F. Once infection occurs, the fungus grows over a range of 32 to 96 F.Masses of microscopic conidia (asexual spores) are produced on the surface of colonized tissues in tiny grape-like clusters (see picture). They are carried by humid air currents, splashing water, tools, and clothing, to healthy plants where they initiate new infections. Conidia usually do not penetrate living tissue directly, but rather infect through wounds, or by first colonizing dead tissues (old flower petals, dying foliage, etc.) then growing into the living parts of the plant.Disease management:1. Buy high-quality seed of recommended varieties. Treat the seed before planting.2. Practice clean cultivation. Plant in a light, well-drained, well-prepared, fertile seedbed at the time recommended for your area. If feasible, sterilize the seedbed soil before planting, preferably with heat. Steam all soil used for plantbeds at 180 F (81 C) for 30 minutes or 160 F (71 C) for one hour.3. Avoid heavy soils, heavy seeding, overcrowding, poor air circulation, planting too deep, over-fertilizing (especially with nitrogen), and wet mulches.4. Focus on healthy plant vigor. Do not over fertilize.5. Use drop or furrow irrigation instead of sprinklers. If sprinklers have to be used, irrigate morning or early afternoon giving enough time for foliage to dry.6. Apply recommended fungicides when conditions favor disease development. Make sure to rotate fungicide to avoid development of resistance. Prefar (bensulide) Prefar (bensulide) is an organophosphate herbicide that has been used for more than 50 years in Arizona for lettuce production. In fact, it is one of the standard herbicides used for this purpose.The University of Arizona Vegetable IPM Team conducted a Yuma County and Imperial Valley Survey evaluating a portion of the acres checked by Pest Control Advisors. The 2017 data indicated that in 58% of the lettuce acreage reported was treated with Prefar. Similarly, in the 2018 survey 52% received a Prefar application.This product performs well when incorporated with sprinkler irrigation at stand establishment. It also works best in course textured soil’s such as the ones found in Coachella Valley, California. One of the weeds controlled by Prefar is pigweed (Amaranthus palmeri), which was found to be resistant to glyphosate herbicide in Arizona by Dr. William B. McCloskey in 2012. Other weeds are purslane (Portulaca oleracea), goosefoot (Chenopodium murale),Lambquarter (Chenopodium album), and some species of grasses.The list of crops in which bensulide is used demonstrates the importance of this weed control tool for the agricultural industry.According to the 1080 Pesticide Use Reporting Database provided by the Arizona Pest Management Center the list of crops includes: Arugula, Bok choy, Broccoli, Brussel Sprouts, Cabbage, Cantaloupe, Cauliflower, Celery, Cilantro, Corn, Cress, Endive, Fennel, Mustard, Kale, Lettuce, Onion, Parsley, Squash, Swiss chard, and others.Please read the following contribution from Dr. Al Fournier on theEPA Notice- Petition to Revoke Organophosphate Tolerances: (includingBensulide). Petition to Revoke Tolerances and Cancel Certain OP Uses: Comment Deadline Extended Al Fournier, IPM Program Manager, Arizona Pest Management Center10 August 2022The EPA has extended its deadline for public comment on a Petition to Revoke Tolerances and Cancel Registrations for Certain Organophosphate Uses untilSeptember 25, 2022.The petitioners, including United Farm Workers, Earthjustice, and several other groups, request that the Agency revoke all tolerances and cancel all associated registrations for food uses of 15 listed OPs, and further requests that the Agency complete its registration review process for these chemicals no later than October 1, 2022. The pesticides are currently at various stages of review, and the proposed deadline does not align with EPA’s published schedule to complete scientific reviews.Among 15 Organophosphates named in the petition are 10 with reported uses in Arizona (bolded below). Those with known uses in lettuce and other produce include Bensulide (Prefar) and Acephate (Orthene).Acephate,Bensulide,Chlorethoxyfos, Chlorpyrifos-methyl,Diazinon,Dichlorvos,Dicrotophos, Dimethoate,Ethoprop,Malathion, Naled, Phorate,Phosmet,Terbufos, TribufosRead the full EPA Notice here:https://www.regulations.gov/document/EPA-HQ-OPP-2022-0490-0001To submit comments to the docket, use the following link:https://www.regulations.gov/commenton/EPA-HQ-OPP-2022-0490-0001To contribute to Arizona Pest Management Center comments, contact Al Fournier Area wide Insect Trapping Network (February 23, 2022) Results of pheromone and sticky trap catches can be viewed here. Area wide Insect Trapping Network VegIPM Update, Vol. 13, No. 4, Feb 23, 2022 Corn earworm : CEW moth counts remain low across all locations; average for this time of the season. Beet armyworm : Trap counts decreased in all locations, and below average for late-January. Cabbage looper: Cabbage looper trap counts remained low in all locations; below average for early February. Diamondback moth: Adult activity increased slightly in some locations, particularly fields where trap is adjacent to with nearby brassica seed crops. Overall, activity is below average for this time of year. Whitefly: Adult movement remained low in all locations consistent with previous seasons. Thrips: Thrips adult movement beginning to increase slightly in most locations. Activity a about average for mid-February. Aphids: Aphid movement increased in many locations, particularly in Yuma Valley. Trap captures about average for this time of year. Leafminers: Adult activity increased in most areas, below average for this time of season.
https://acis.cals.arizona.edu/agricultural-ipm/vegetables/vegetable-ipm-updates/19?Insectpage=89&Trappingpage=25
Carboplatin and Paclitaxel and Taladegib in Gastroesophageal Junction Adenocarcinoma and Stage IB Esophageal Adenocarcinoma AJCC v7 and Stage II Esophageal Adenocarcinoma AJCC v7 - Clinical Trials Registry - ICH GCP This phase IB/II trial studies the side effects of taladegib, paclitaxel, carboplatin, and external beam radiation therapy and to see how well they work in trea... Taladegib, Paclitaxel, Carboplatin, and Radiation Therapy in Treating Patients With Localized Esophageal or Gastroesophageal Junction Cancer A Phase 1B/2 Study of Taladegib in Combination With Weekly Paclitaxel, Carboplatin, and Radiation in Localized Adenocarcinoma of the Esophagus or Gastroesophageal Junction Study Overview Status Terminated Conditions Gastroesophageal Junction Adenocarcinoma Stage IB Esophageal Adenocarcinoma AJCC v7 Stage II Esophageal Adenocarcinoma AJCC v7 Stage IIA Esophageal Adenocarcinoma AJCC v7 Stage IIB Esophageal Adenocarcinoma AJCC v7 Stage IIIA Esophageal Adenocarcinoma AJCC v7 Stage IIIB Esophageal Adenocarcinoma AJCC v7 Intervention / Treatment Other: Laboratory Biomarker Analysis Drug: Carboplatin Drug: Paclitaxel Radiation: External Beam Radiation Therapy Drug: Taladegib Detailed Description PRIMARY OBJECTIVES: I. To evaluate the toxicity of taladegib administered orally daily concurrently with weekly paclitaxel, carboplatin and radiation therapy in patients with localized nuclear glioma-associated oncogene homolog (Gli-1) expressing adenocarcinoma of the esophagus or gastroesophageal junction. (Phase IB) II. To assess the rate of pathologic complete response (pathCR) when taladegib is administered orally daily concurrently with weekly paclitaxel, carboplatin, and radiation therapy in patients with localized nuclear Gli-1 expressing adenocarcinoma of the esophagus or gastroesophageal junction. (Phase II) SECONDARY OBJECTIVES: I. To evaluate the toxicity of biochemoradiation in the phase II study. II. To assess additional biomarkers (hedgehog [Hh] related and Hh unrelated) in sequentially procured tissues (biopsies and resected specimens). IV. Assess relapse-free survival and overall survival. OUTLINE: PHASE IB: Patients receive taladegib orally (PO) once daily (QD) on days 1-38, paclitaxel intravenously (IV) over 3 hours on the first radiation day of each week for 5 doses, carboplatin IV over 2 hours on the first radiation day of each week for 5 doses, and undergo external beam radiation therapy 5 days weekly on 28 consecutive weekdays for 5.5 weeks. PHASE II: Patients are assigned to 1 of 2 steps. STEP I: Patients receive taladegib PO for 7 days, followed by taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB. STEP II: Patients receive taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB. After completion of study treatment, patients are followed up at 3 months, every 3-6 months for 1 year, every 6 months for 2 years, and at years 4 and 5. Study Type Interventional Enrollment (Actual) 7 Phase Phase 2 Phase 1 Contacts and Locations This section provides the contact details for those conducting the study, and information on where this study is being conducted. Study Locations United States Texas Houston, Texas, United States, 77030 M D Anderson Cancer Center Participation Criteria Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments. Eligibility Criteria Ages Eligible for Study 18 years and older (Adult, Older Adult) Accepts Healthy Volunteers No Genders Eligible for Study All Description Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction (EAC) Localized EAC and its baseline clinical stage determined as: T2-T3N0 or T1-3N positive (+); imaging studies suspicious for metastases must be followed with a negative biopsy before a patient can enter the study Patients with malignant celiac nodes are eligible if the primary lesion is in the mid-thoracic or distal thoracic esophagus or it is involving the gastroesophageal junction Tumor must have labeling index of >= 5% of the nuclear Gli-1 (integral biomarker) performed in the MD Anderson Cancer Center Clinical Laboratory Improvement Amendment (CLIA) laboratory for patient to be eligible in this trial (if enough archival tissue is not available to determine labeling index, patient must agree to a biopsy to be eligible for the study) Tumor may not extend > 4 cm below the gastroesophageal junction Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 All patients must be willing to provide research tumor tissue for biomarker studies at baseline, from archival tumor tissue or through endoscopy if sufficient archival tissue is not available; all patients must also allow biomarker studies on the tissue obtained through surgery to remove the primary cancer Phase II only: patients volunteering for the Phase II part of the protocol must be willing to undergo a research endoscopy for tissue collection on day 8 (+/- 2 days) from the beginning of therapy Absolute neutrophil count >= 1500/mm^3 Platelets greater >= 100,000/mm^3 Hemoglobin >= 8 g/dL Serum creatinine =< 2 x upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN Serum bilirubin =< 1.5 x ULN Patient must be able to comprehend the approved consent document and have the willingness to sign it; the patient prior to enrollment and the administration of any protocol-specific therapy must sign the consent document Willingness and ability to comply with study procedures and follow-up examinations Must be considered medically fit for operation as determined by multidisciplinary evaluation Males and females with reproductive potential must agree to use 2 forms of medically approved contraceptive precautions and for at least 6 months following the last dose of biochemoradiation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Women of childbearing potential are defined as follows: having regular menstrual cycles; has amenorrhea, irregular menstrual cycles or using a contraceptive method that precludes withdrawal bleeding; have had a tubal ligation; women are considered not to be of childbearing potential for the following reasons: had hysterectomy and/or bilateral oophorectomy; post-menopausal defined by amenorrhea for at least 1 year in a woman > 45 years old Females with childbearing potential must have a negative serum pregnancy test within 14 days prior to treatment start Exclusion Criteria: Baseline clinical stage of T1N0 or inoperable T4 (unequivocal organ involvement) are to be excluded Unequivocal metastatic tumor at baseline Tracheo-esophageal (TE) fistula or direct invasion into the tracheo-bronchial mucosa; a bronchoscopy (biopsy and cytology should be performed) is required to exclude TE fistula or tracheo-bronchial involvement in patients with a tumor located at < 26 cm from the incisors Cervical esophageal cancer will not be entered in this study Any prior chemotherapy, surgery, or radiotherapy for EAC Prior mediastinal irradiation (for any reason) Clinically significant ulcerative colitis, inflammatory bowel disease, or partial or complete small bowel obstruction are to be excluded Malabsorption syndrome or other condition that would interfere with intestinal absorption are excluded Pregnant or nursing females are to be excluded; breastfeeding should be discontinued if the mother is treated with taladegib Presence of other significant cancer(s) or history of other significant cancer(s) within the last 3 years (patients who have been cancer-free for 3 years, or have a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma of the cervix are eligible) Known active viral or other chronic types hepatitides (hepatitis B, C) or cirrhosis Uncontrolled concurrent illness including, but not limited to: serious uncontrolled infection, symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia that interfere with blood pressure, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with the study requirements Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation Patients who are receiving concurrent non-protocol anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, targeted therapy, biologic therapy, or tumor embolization) are to be excluded Patients may not be receiving any other investigational agents Patients with known hypersensitivity to taxanes or platinums are to be excluded Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin) are ineligible; patients on strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors will also be excluded Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy Any other conditions or circumstances that would, in the opinion of the investigator, make the patient unsuitable for participation in the study Study Plan This section provides details of the study plan, including how the study is designed and what the study is measuring. How is the study designed? Design Details Primary Purpose : Treatment Allocation : Non-Randomized Interventional Model : Parallel Assignment Masking : None (Open Label) 2 Arms and Interventions Participant Group / Arm Intervention / Treatment Experimental: Step I (taladegib, paclitaxel, carboplatin, and radiation) Patients receive taladegib PO for 7 days, followed by taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB. Other: Laboratory Biomarker Analysis Correlative studies Drug: Carboplatin Given IV Other Names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo Drug: Paclitaxel Given IV Other Names: Taxol Anzatax Asotax Bristaxol Praxel Taxol Konzentrat Radiation: External Beam Radiation Therapy Undergo external beam radiation therapy Other Names: EBRT Definitive Radiation Therapy External Beam Radiation External Beam Radiotherapy External Beam RT external radiation External Radiation Therapy external-beam radiation Radiation, External Beam Drug: Taladegib Given PO Other Names: Benzamide, 4-Fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)-1-phthalazinyl)-4-piperidinyl)-2-(trifluoromethyl)- LY-2940680 LY2940680 Experimental: Step II (taladegib, paclitaxel, carboplatin, and radiation) Patients receive taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB. Other: Laboratory Biomarker Analysis Correlative studies Drug: Carboplatin Given IV Other Names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo Drug: Paclitaxel Given IV Other Names: Taxol Anzatax Asotax Bristaxol Praxel Taxol Konzentrat Radiation: External Beam Radiation Therapy Undergo external beam radiation therapy Other Names: EBRT Definitive Radiation Therapy External Beam Radiation External Beam Radiotherapy External Beam RT external radiation External Radiation Therapy external-beam radiation Radiation, External Beam Drug: Taladegib Given PO Other Names: Benzamide, 4-Fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)-1-phthalazinyl)-4-piperidinyl)-2-(trifluoromethyl)- LY-2940680 LY2940680 What is the study measuring? Primary Outcome Measures Outcome Measure Measure Description Time Frame Safety of taladegib when given in combination with paclitaxel, carboplatin, and radiation therapy defined by dose-limiting toxicities (Phase IB) Time Frame: Up to 5 weeks The safety data will be summarized using frequencies and percentages by adverse event category, grade and attributions. Up to 5 weeks Pathologic complete response rate (Phase II) Time Frame: Up to 5 years A pathologic complete response (pathCR) rate of at least 35% (>= 40% is desirable) will be of interest. The pathCR rate in each of the treatment step will be estimated, along with the 95% confidence interval. Up to 5 years Secondary Outcome Measures Outcome Measure Measure Description Time Frame Change in biomarker expression levels of primary and secondary resistance Time Frame: Baseline to the time of surgery A linear mixed effect model will be used to assess the change of biomarkers over time. The outcome variable will be biomarker expression level and the covariates will include time, treatment step and time by treatment interaction. The biomarker expression may be log-transformed prior to fit the model in order to satisfy the normality assumption. Also, a logistic regression model will be used for the binary outcome of pathCR, using treatment step, baseline biomarker and the change of biomarker between baseline and at surgery as covariates. Baseline to the time of surgery Relapse-free survival Time Frame: Up to 5 years Kaplan-Meier method will be used to estimate the probabilities of relapse-free survival. Up to 5 years Overall survival Time Frame: Up to 5 years Kaplan-Meier method will be used to estimate the probabilities of overall survival. Up to 5 years Collaborators and Investigators This is where you will find people and organizations involved with this study. Sponsor M.D. Anderson Cancer Center Collaborators National Cancer Institute (NCI) Investigators Principal Investigator: Jaffer A Ajani, M.D. Anderson Cancer Center Publications and helpful links The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study. Helpful Links MD Anderson Cancer Center Website Study record dates These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website. Study Major Dates Study Start (Actual) March 7, 2017 Primary Completion (Actual) January 7, 2022 Study Completion (Actual) January 7, 2022 Study Registration Dates First Submitted August 19, 2015 First Submitted That Met QC Criteria August 19, 2015 First Posted (Estimate) August 21, 2015 Study Record Updates Last Update Posted (Estimate) January 16, 2023 Last Update Submitted That Met QC Criteria January 13, 2023 Last Verified January 1, 2023 Esophageal Diseases Adenocarcinoma Esophageal Neoplasms Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Antineoplastic Agents, Phytogenic Carboplatin Paclitaxel Albumin-Bound Paclitaxel Other Study ID Numbers 2014-0966 (M D Anderson Cancer Center) NCI-2015-01554 (Registry Identifier: CTRP (Clinical Trial Reporting Program)) Drug and device information, study documents Studies a U.S. FDA-regulated drug product Yes Studies a U.S. FDA-regulated device product No This information was retrieved directly from the websiteclinicaltrials.govwithout any changes. If you have any requests to change, remove or update your study details, please [email protected]. As soon as a change is implemented onclinicaltrials.gov, this will be updated automatically on our website as well. Clinical Trials on Gastroesophageal Junction Adenocarcinoma NCT05836584 Not yet recruiting NCT05802056 NCT05753306 NCT05733000 NCT05709574 NCT05705635 NCT05677490
https://ichgcp.net/clinical-trials-registry/NCT02530437
Whirlpool W11427474A 30 Inch Freestanding Gas Range User Guide Learn how to safely operate your Whirlpool W11427474A 30 Inch Freestanding Gas Range with these easy-to-follow instructions. Discover how to use the oven and range functions, including setting the temperature and adjusting the flame. Avoid common mistakes, such as using aluminum foil on the oven bottom, with our helpful tips. Whirlpool W11427474A 30 Inch Freestanding Gas Range User Guide Contents hide 1 Whirlpool W11427474A 30 Inch Freestanding Gas Range 2 OPERATING INSTRUCTIONS 3 Using Your Oven 4 POSITIONING RACKS AND BAKEWARE 5 BAKING COOKIES AND LAYER CAKES ON TWO RACKS 6 BURNER SIZE 7 OVEN VENT 8 OVEN LIGHT 9 Online Ordering Information 10 Documents / Resources 10.1 References Whirlpool W11427474A 30 Inch Freestanding Gas Range OPERATING INSTRUCTIONS WARNING: To reduce the risk of fire, electric shock, or injury to persons, read the IMPORTANT SAFETY INSTRUCTIONS, located in your appliance’s Owner’s Manual, before operating this appliance. Using Your Oven Step 1 . Select oven function Step 2. Set the temperature Step 3. Press Start Step 4. Place food inside the oven once the set temperature is reached. Close the oven door. Step 5. (Optional) Enter time to cook Step 6. The Cancel button can be used to cancel the function during or after cook time. NOTE: For more detailed instructions on specific functions, see the online Control Guide. Using Your Range Before setting a control knob, place filled cookware on the grate. Do not operate a burner using empty cookware or without cookware on the grate. The flame should be adjusted so it does not extend beyond the edge of the pan. NOTE: Visually check that the burner has lit. If the burner does not ignite, listen for a clicking sound. If you do not hear the igniter click, turn the burner off. Check for a tripped circuit breaker or blown household fuse. Check that the control knob is pressed completely down on the valve shaft. If the spark igniter still does not operate, call a trained repair specialist. To Set: WARNING Fire Hazard Do not let the burner flame extend beyond the edge of the pan. Turn off all controls when not cooking. Failure to follow these instructions can result in death or fire. Electric igniters automatically light the surface burners when the control knobs are turned to Ignite. POWER FAILURE In case of prolonged power failure, the surface burners can be lit manually. Hold a lit match near a burner and turn the knob counterclockwise to IGNITE. After the burner lights, turn the knob to set. ALUMINUM FOIL IMPORTANT: To avoid permanent damage to the oven bottom finish, do not line the oven bottom with any type of foil or liner. For best cooking results, do not cover entire oven rack with foil because air must be able to move freely. POSITIONING RACKS AND BAKEWARE IMPORTANT: To avoid permanent damage to the porcelain finish, do not place food or bakeware directly on the oven door or bottom. Racks Position racks before turning on the oven. Do not position racks with bakeware on them. Make sure racks are level. To move a rack, pull it out to the stop position, raise the front edge, and then lift out. Use the following illustrations as a guide. For hamburger patties to have a well-seared exterior and a rare interior, use a flat rack in rack position 7. Preheat the oven for 5 minutes. Side 1 should cook for approximately 4 to 5 minutes. Side 2 should cook for approximately 41/2 to 51/2 minutes. Expect a moderate degree of smoke when broiling. BAKING COOKIES AND LAYER CAKES ON TWO RACKS Baking Layer Cakes For best results when baking cakes on two racks, use the Bake function, a flat rack in rack position 5, and a flat rack in rack position 2. If you do not have two flat racks, use a Max Capacity Oven Rack in rack position 6. Place the cakes on the racks, as shown. Keep at least 3″ (7.6 cm) of space between the front of the racks and the front cakes. Baking Cookies For best results when baking cookies on two racks, use the Convection Bake function, a flat rack in rack position 5, and a flat rack in rack position 2. If you do not have two flat racks, use a flat rack in rack position 2 and a Max Capacity Oven Rack in rack position 6. If you do not have Convection Bake, use the standard Bake function. BURNER SIZE Select a burner that best fits your cookware. See the following illustration and chart. OVEN VENT The oven vent releases hot air and moisture from the oven, and should not be blocked or covered. Blocking or covering the oven vent will cause poor air circulation, affecting cooking and cleaning results. Do not set plastics, paper or other items that could melt or burn near the oven vent. OVEN LIGHT The oven light is a 40 W halogen bulb. Before replacing, make sure the oven and cooktop are cool and the control knobs are in the Off position. To Replace Disconnect power. Turn the glass bulb cover in the back of the oven counterclockwise to remove. Remove bulb from socket. Replace bulb, using tissue or wearing cotton gloves to handle bulb. To avoid damage to or decreasing the life of the new bulb, do not touch bulb with bare fingers. Replace bulb cover by turning clockwise. Reconnect power. IMPORTANT: Do not use lamps rated higher than 40 W. SABBATH MODE: The Sabbath Mode sets the oven to remain on in a bake setting until disabled. For guidance on usage and a complete list of models with Sabbath Mode, visit www.star-k.org or contact us as per the information given below. Online Ordering Information For detailed installation instructions and maintenance information, winter storage, and transportation tips, please see the Owner’s Manual included with your machine. For information on any of the following items, a full cycle guide, detailed product dimensions, or for complete instructions for use and installation, please visit https://www.whirlpool.com/owners , or in Canada https://www.whirlpool.ca/owners . This may save you the cost of a service call. However, if you need to contact us, use the information listed below for the appropriate region. United States: 1–800–253–1301 Whirlpool Brand Home Appliances Customer eXperience Center 553 Benson Road Benton Harbor, MI 49022–2692 Canada: 1–800–807–6777 Whirlpool Brand Home Appliances Customer eXperience Centre 200–6750 Century Ave. Mississauga, Ontario L5N 0B7 IMPORTANT:Retain this guide for future use. 2020 Whirlpool. All rights reserved. Used under license in Canada. Documents / Resources Whirlpool W11427474A 30 Inch Freestanding Gas Range [pdf] User Guide W11427474A 30 Inch Freestanding Gas Range, W11427474A, 30 Inch Freestanding Gas Range, Freestanding Gas Range, Gas Range References Kosher Certificates | Kosher Certification | Star-K Welcome to Whirlpool® Customer Care | Whirlpool Welcome to Whirlpool® Customer Care | Whirlpool
https://manuals.plus/whirlpool/w11427474a-30-inch-freestanding-gas-range-manual
Paul Nash’s Geological Enigma | Article index | Articles | British Art Studies An online, open-access and peer-reviewed academic journal for research on all aspects of British art, architecture and visual culture. Paul Nash’s Geological Enigma ArticlebyAnna Reid Paul Nash, The coast at Kimmeridge, Dorset, circa 1935-1936, black and white negative, 8.9 × 12 cm. Tate Archive Collection (TGA 7050PH/947). Digital image courtesy of Tate (CC-BY-NC-ND 3.0 Unported). Abstract This essay explores the attunement of Nash’s work to pioneering geophysical research in England, connections which have not yet been fully recognized. In a context of the early-to-mid twentieth century, when geophysicists read the startling radioactivity of the land and worked mathematical equations to put a vastly ancient and sensational new age on the rocks of the earth, Nash’s landscape works, fraught with mathematical problems, equations, stones and bones, resonated afresh, beyond the confines of the Modern. Through these interests, I argue, Nash channelled and revitalized a British tradition of engagement with the aesthetics of the geological. Fig. 1 ). 1 This essay describes how, when read in the context of geological knowledge, the landscape work of Paul Nash exhibits a prescient realism and evinces experimentation amidst a new era of empirical research. 2 <here is a image db8e4e0a6c898061-89a60eef4506096b> DOI Figure 1. Paul Nash, Equivalents for the Megaliths, 1935, oil on canvas, 45.7 × 66 cm. Collection of Tate (T01251).Digital image courtesy of Tate (CC-BY-NC-ND 3.0 Unported). Nash worked in a context of astounding geological discovery: that of a radioactive earth legible by mathematics—a new geological real. The attunement of Nash’s work to this discovery is under-recognized. This is partly owing to the concurrence of his work with the emergence of modernist critical thought in Britain, which exactly rejected the possibility of ontological description and its history in art. Critical thought of modernist origins has now been decentred by the engagement of artists with pressing matters of the geological real. Nash’s work, read as intense realism, offers a rich precedent to realisms of the twenty-first century. It guides the eye towards dynamic geological problems and curiosity. An English Landscape Artist Nash’s work tends to be described first as “English”. 3 I propose that the English concept of the land at play in the work has to do with universal new insight gained through geological discovery. From the perspective of a modernist critic in England, driven by the imperative to break with the immanent in pursuit of international critical dialogue, Nash’s refusal to relinquish the landscape appeared at best insular. 4 Yet the “English” adjective is invested in a way that does not contradict the modern reverence for the virtuosity of human perception above and beyond the immanent land. The Age of the Earth ( Fig. 2 ) . It detailed mesmerizing earth processes: uranium halos, atoms sparking and bursting like rockets, flashing zinc sulphide, Beta and Gamma Rays, pitchblende glowing with light in the darkness, “Man putteth an end to the darkness and exploreth to the utmost limit the stones of darkness.” 5 Figure 2. The Age of The Earth: An Introduction to Geological Ideas, Arthur Holmes (ed.) (London: Ernest Benn, 1927[1913]), pp. 92–93. Digital image courtesy of Arthur Holmes / Ernst Benn. Figure 3. The Age of The Earth: An Introduction to Geological Ideas, Arthur Holmes (ed.) (London: Ernest Benn, 1927[1913]), pp. 59. Digital image courtesy of Arthur Holmes / Ernst Benn. Holmes proceeded to work with the physicist Frederick Soddy, who had discovered that elements exist in diverse isotopes. They worked together using mathematics to read complex sequences of radioactive decay from one isotope to another, occurring in diverse rock samples. From these legible sequences arose new “radio-metric” dating ( Fig. 3 ). Holmes worked complex and elegant equations to put an age of 370 million years on a mineral in a Devonian Norwegian rock, astoundingly older than the extant estimated age of the earth at 100 million years. 6 Three editions of Holmes’s book gave vivid and accessible accounts of this new vision of an abundant land, vast in time. The 1927 edition was part of the Benn Sixpenny Library , which was aimed at a general audience. The new research was well known in the public domain. From 1929, the BBC published The Listener as a weekly magazine and it covered the new geological breakthroughs (Nash wrote art criticism and reviews for The Listener on a regular basis). The science section of the very first edition featured “Revolutionary Discoveries”, a text describing spontaneous radioactivity: 7 The artist’s own book collection includes a copy of The Mysterious Universe 8 During the inter-war period, the science community was receptive to the concept of the land as being more complex, intricate, and legible than ever imagined—a land replete with new avenues for research. Amidst increasingly precise radiometric estimates at this time arose another equation which was solved: putting an age on the earth of 3 billion years. 9 A historian of geology, Martin Rudwick, has noted the universal implications, not only for the earth itself but also for the earth in relation to the sun, the solar system, and the cosmos. 10 He cites the geologist William Sollas, who remarked in 1921 that the geologist who before had been “bankrupt” in time, now finds himself suddenly transformed into “a capitalist with more millions in the bank than he knew how to dispose of.” 11 Modern Painters (1843–1860), Ruskin urged artists to study geology. His interest in Turner was as a painter of vital new geological truth, and of The Fall of the Tees , he said: “With this drawing before him the geologist could give a lecture upon the whole system of aqueous erosion” ( Fig. 4 ). 12 <here is a image 979d59466beee1f4-97d3051dc11d6991> DOI Figure 4. Joseph Mallord William Turner, Fall of the Tees, Yorkshire, 1825–26, watercolour over pencil on wove paper, 27.9 × 38 cm. Collection of Indianapolis Museum of Art at Newfields (1997.141).Digital image courtesy of Indianapolis Museum of Art at Newfields. 13 Going back further, to the seventeenth century, the footwork between poetic and scientific work on the geological landscape in the British context has been explored by the historian Stephen Gould, who foregrounds the role of Thomas Burnet’s 1681 Sacred Theory of the Earth in instigating geological thought, to contradict “whiggish” accounts of geological history, which pit rational empiricism against the theological and poetic. 14 Unseen Landscapes Throughout the British landscape tradition, there is an impetus to devise new strategies to visualize previously unknown or unseen dimensions of the land. This could be described as the geological impetus. Nash certainly took an active interest in mysterious physical phenomena. 15 In his contribution to the book Unit One: The Modern Movement in English Architecture, Painting and Sculpture , which presented the work of the artists’ group founded by Nash, he refers to his imaginative research in the “hidden” land. 16 He recalls the hidden land that is gleaned in the work of Turner, Blake’s ancient Britain, Albion, and the renewed task of the landscape artist. Nash’s endeavours have often been read as Blakean, as seeking the spirit of the land or place, the genius loci. In this, and in a recent neo-romantic reading, Nash’s hidden land is envisaged as a spiritual sphere and realm of the mind, theological, and connected to Christian Science’s “soaring rhetoric of spirit over the material world”. 17 A reading with geological context can pull Nash’s unseen land back to a material dimension, less emanating spirit of place and more as land that is literally emanating radioactivity. In 1927, Holmes described a magnificent unseen earth, veined with radioactive minerals from Ceylon to St Ives, Katanga to the Mourne Mountains. He detailed the high-velocity ejections of electrically charged helium atoms that are Alpha “rays”, long and intricate patterns of transformations that can be traced, “each accompanied by an explosive liberation of energy”. 18 These revolutionary discoveries were described as “the processes going on in a garden”. 19 Nash’s Unseen Landscape too, as he describes in his May 1938 article of the same name for Country Life magazine, is a land of “stones, bones, empty fields … back gardens” alive with new intrigue and offering “endless possibilities of fresh adventure” . His is a view of land seething with processes of decay and transformation: petrified forests, bleached objects, blanched springs and branches, “mutilated by shafts of light”. It is not a residual landscape, but one with the “terrific animation” of the landscape of the white horse , flickering as the eye moves across it, traversed by the radiance of the sun and the moon, “beating down on glinting white” 20 ( Fig. 5 , Fig. 6 , Fig. 7 ). Figure 5. Paul Nash, Unseen Landscapes, in Country Life, 21st May 1938, pp. 526–527. Digital image courtesy of TI Media Limited. Figure 6. Paul Nash, Stone Forest, 1937, pencil, black chalk, and watercolour on paper, 58.7 × 40 cm. Collection of The Whitworth, University of Manchester (D.1950.10). Digital image courtesy of University of Manchester. Figure 7. Paul Nash, Study for Landscape of Bleached Objects, 1934, watercolour and pencil on paper, 28.4 × 39.4 cm. Collection of The Daniel Katz Gallery, London. Digital image courtesy of The Daniel Katz Gallery. 21 Nash’s hidden lands are “unseen merely because they are not perceived; only in that way can they be regarded as ‘invisible’.” 22 They are a materiality that is not visible to the unaided eye. In 1926, Holmes described his research, citing Swinburne: “man can see through the years flowing round him, the law lying under the years” 23 ( Fig. 8 ). A crucial observation of the new geological discovery was that radioactive decay takes place in minerals at rates that are constant throughout deep time. The discovery of an Earth emitting radioactivity was also a discovery of intricate and legible sequences and patterns. Holmes describes radium: 24 Nash’s interest in pattern has recently been described by Inga Fraser as a search for order, and in line with a mediumistic conception of the land as offering “a glimpse of another metaphysical reality” . 25 Yet Nash’s work can also be read as dealing with the literal and immanent geological appearance of order and pattern. It appears to see, for the first time, a land infused with design of an intricacy quite beyond belief—an unseen material land, that in its immanent self radiates transcendence. <here is a image efb29e5303a6660f-1bd5b46ed5b84611> DOI Figure 8. Arthur Holmes, Radium Uncovers New Clues to Earth’s Age, published in The New York Times, 6 June 1926, Sect IX, pp. 4f. One of Nash’s natural science books, The Worship of Nature by James George Frazer, is a volume which from its opening pages contemplates atoms and electrons, “the imperceptible particles of matter”, with reference to works by Soddy and by the physicist William Bragg, whose 1912 Studies in Radioactivity 26 Nash made streams of photographs observing and visualizing sequences and patterns made “by design” and otherwise: the ploughed earth , a cobbled road, the rhythms of a dry stonewall, the surface of the sea ( Fig. 9 . Fig. 10 , Fig. 11 , Fig. 12 ). The photographs bestow these overlooked forms of the earth with new intrigue, signalling the discovery of long “invisible” processes. Nash’s preferred medium to capture these patterns is apposite: a chapter in Holmes’ The Age of the Earth addressing radioactivity opens by describing the photographic plate and Henri Becquerel’s discovery of emanation. Holmes writes that, “uranium salts and minerals give out invisible rays which are capable of penetrating black paper and of revealing their existence by their effect on a photographic plate wrapped within it.” 27 Figure 9. Paul Nash, The coast at Kimmeridge, Dorset, circa 1935-1936, black and white negative, 8.9 × 12 cm. Tate Archive Collection (TGA 7050PH/947). Digital image courtesy of Tate (CC-BY-NC-ND 3.0 Unported). Figure 10. Paul Nash, Kimmeridge Bay (double exposure), unknown date, black and white negative, 8.2 × 12.1 cm. Tate Archive Collection (TGA 7050PH/950). Digital image courtesy of Tate (CC-BY-NC-ND 3.0 Unported). Figure 11. Paul Nash, A stone wall, Worth Matravers, unknown date, black and white negative, 8.6 × 12.4 cm. Tate Archive Collection (TGA 7050PH/1234). Digital image courtesy of Tate (CC-BY-NC-ND 3.0 Unported). Figure 12. Paul Nash, Wave breaking on Chesil Beach, Dorset, 1935, black and white negative, 8 × 12.5 cm. Tate Archive Collection (TGA 7050PH/369). Digital image courtesy of Tate (CC-BY-NC-ND 3.0 Unported). There is a darker aspect here too: in 1938, German scientists split the nucleus of a Uranium atom freeing enormous explosions of energy. The British and American collaboration, The Manhattan Project , worked to develop an atomic bomb and the spectre of this invention loomed in the public imagination. A 1939 letter to The Times speculated on the threat of “a death ray; some super-atomic bomb”. 28 One journalist described how the weapon, used by the enemy, “might destroy the whole world—even Germany!” 29 The very same discoveries that had animated the earth were pointing towards a “dreadful miracle” (Nash’s words) to which Nash alludes in his 1945 Flight of the Magnolia . 30 On 7 August 1945, The Times described how scientists were harnessing the “basic power of the universe”, or to use Truman’s phrase, “the force from which the sun draws its power”. Viewed with this contemporary understanding of ubiquitous radiation in mind, a set of Nash’s 1940s landscapes—saturated as they are in colour and viscous rays—seem to evoke the legion processes of the radiating sun and land ( Fig. 13 , Fig. 14 , Fig. 15 ). <here is a image 43cd9390e6c0738c-82174e31c7db9e6f> DOI <here is a image 8101cb4d140dd51e-ce89e512af1fd1c8> DOI <here is a image 8def8438fd78192e-589f12e8391ae0e4> DOI The Real Object The artist’s engagement with the rediscovered land and earth can be traced in his work with found objects. In 1936, Nash cited and reflected on a review of his sculpture Found Object Interpreted , exhibited that year as part of the International Surrealist Exhibition in London, which it described as, “an awkward object to have knocking around in the unconscious”. “From that little remark,” Nash retorted in The Architectural Review , “anyone might say to himself, oh, so that is what Mr Nash finds in his unconscious; whereas, actually, I found it on the Romney Marsh.” 31 Nash’s prosaic response is not only a joke, and I propose that it should be heard in its fullest geological sense: Nash’s found object and unconscious thoughts derive not from the individual psyche, but from the geological land. André Breton described the surrealist object as deriving from dreams or the waking unconscious. He celebrated the capacity of such objects to unleash and vitalize powers of invention, and to “depreciate those objects of ‘usefulness’ which clutter the so called real world”. 32 In his 1937 essay, “The Crisis of the Object”, Breton describes the disruptive, perturbing potential of surreal objects in the problematic context of modern rationality and its “unprecedented desire to objectify” . He alludes to the “marvellous” quality of such disruption, derived from dream and the unconscious, as distinct from the marvellous impulse of romanticism, which he calls “the urge to coalesce the mind and the tangible world, which led to the inauguration of the rationalist era.” 33 Breton was interested in an experience of the marvellous that is not romantic, theological, and ontological, but rather one that is epistemological, deriving from the psyche and its irrational dimension as described by Freud. The subjective mind is the source of potential, transformation, and revolution as embodied in Breton’s object. By contrast, Nash’s marvellous objects, his animate bleached stones, illuminated monoliths and minerals, his nests of the phoenix rising, derive from far beyond the limits of the subject and psyche ( Fig. 16 , Fig. 17 ). In the mid-1930s, Nash resided in Dorset, on the Jurassic coast of England, over an extended period and his experimental work with objects was exuberant. He collected stone, flint, driftwood, objects foremost derived from the processes of the land, which he handled, studied, posed, and documented. Dorset was a revelation for Nash, as presented in the artist’s 1936 Dorset: Shell Guide , one of a series produced for motorists, which closely articulates his sense of the landscape as a geological and surrealist object. In it, he describes seeing “Charlbury at twilight—cut against the afterglow, as to experience an almost unnerving feeling of the latent force of the past.” 34 <here is a image 11d9e1202172a07c-c62f8c22dad28e7e> DOI <here is a image 3b9fc5ae705f1a4e-e76250dd35f34e3d> DOI Fig. 18 , Fig. 19 , Fig. 20 , Fig. 21 , Fig. 22 , Fig. 23 ). The Dorset: Shell Guide is replete with the fantastic natural forms of the Jurassic coast: the folded limestone strata of Stair Hole, the implausible land formations of Lulworth Cove, Durdle Door, and Chesil bank, which were in his words, “the result of a mystical judgement called the law of compensation”. 35 Figure 18. Paul Nash, Dorset: Shell Guide, front cover, 1936. Tate Archive Collection (TGA/964/1/16). Figure 19. Paul Nash, Dorset: Shell Guide, p. 8, 1936. Tate Archive Collection (TGA/964/1/16). Figure 20. Paul Nash, Dorset: Shell Guide, p. 20, 1936. Tate Archive Collection (TGA/964/1/16). Figure 21. Paul Nash, Dorset: Shell Guide, p. 37, 1936. Tate Archive Collection (TGA/964/1/16). Figure 22. Paul Nash, Dorset: Shell Guide, p. 39, 1936. Tate Archive Collection (TGA/964/1/16). Figure 23. Paul Nash, Dorset: Shell Guide, back cover, 1936. Tate Archive Collection (TGA/964/1/16). A new link, articulated by Sarah Fill, between the Dorset: Shell Guide and the materialism of Georges Bataille aids the task of interpreting it in a geological context. 36 Bataille, the “debaser” of Surrealism, produced the journal Documents from 1929–1930, and pursued an alternate trajectory to Bretonian Surrealism. In his view, Breton’s notion of human irrationality was idealizing and sublimated the base, perverse, and violent—a material irrationality into which he ventured. 37 Nash too was interested in this “underside”, a corrective to the bias of Bretonian Surrealism, and he was engaged with Documents. 38 Documents and the Dorset: Shell Guide have been described as sharing an anti-humanist sentiment. In the words of Sarah Fill, Nash’s guide made “the nation’s ancestors appear as primitive monsters”. 39 40 Dorset: Shell Guide derives from the accident of encountering a scintillating geological real. The new land was also understood as an active chronometer with regular and even rhythm—its minerals “timekeepers of the earth’. Nash opens his guide to the animate “face of Dorset” in metre, with an excerpt from Thomas Hardy’s An August Midnight : A shaded lamp and a waving blind And the beat of a clock from a distant floor: On this scene enter—winged, horned and spined— A longlegs, a moth, and a Dumbledore: While ‘mid my page there idly stands A Sleepy fly, that runs its hands … Thus meet we five in this still place At this point of time, at this point in space … Nash’s May 1937 article for Country Life , titled “The Life of the Inanimate Object”, channels a history of perceiving the pulse of the land, citing the Psalms of David: “The mountains skipped like rams and the little hills like lambs”. 41 Mary Ann Doane describes the increasing reification and standardization of time during the early twentieth century, the “temporal demand” of modernity. 42 As this abstracted demand looms large and the contingency of the surrealist object is but an ephemeral release from it, Nash’s found object, alive with the beat of real time, derives from far beyond any such duality. 43 It is a vision that does not accord with the anthropocentric time of modernity, and exceeds the chance encounter. Nash’s marvellous is not ephemeral, conditioned by the subjective unconscious—it is infinite. In grappling with this marvellous, Nash’s work is ontological enquiry and description, hand in hand with the geologist whose concerns and queries are shared. Nash’s Equivalents for the Megaliths Fig. 1 , Fig. 24 ). <here is a image 92cfa48e2eae6f07-d5f22a97d3c77172> DOI Figure 24. Paul Nash, Poised Objects, 1932, pencil, chalk, and watercolour on paper, 55.9 × 37.5 cm. Collection of St Anne’s College, Oxford.Digital image courtesy of The Principal and Fellows of St Anne’s College, Oxford | Photo: Keith Barnes. The work indicates a vertiginous shift of dimensions, such that time and space are stretched, enlarged, flattened, transformed. The solid modern monoliths appear here from a high and scaled-back perspective as two-dimensional remains in the land, equivalent to the megaliths amidst a vast new timescale. The scene appears as if from some distant time or space, wherein modern art objects, human remains of mysterious ritual value, stud the land. Herein, the work not only poses as archaeological and geological material, it also hints at its own status being actual geological material; the abstraction of the work of art is construed as part of material geological reality. What is the position of the human in this encounter? Does the archaeological nature of these megaliths imply a potential future without a human vantage point? The work is a captivating geological problem and mathematical hieroglyph. As does Nash’s oeuvre more broadly, it makes a virtue of the curiosity that sustains the adventure of the guessing mind: 44 The Flightless Bird To conclude, I aim to solve one rich geological curiosity among many posed by Nash’s oeuvre. Nash’s Nest of Wild Stones and his 1937 written piece of the same name are characteristically evocative of the connections between stones, mathematical harmony, and deep time ( Fig. 25 ). Nash says of the stones in question: 45 Another passage, in Nash’s “Unseen Landscapes”, illuminates the title of the work: he refers to “the nests of giant birds … scattered groups of fantastic nests … a sanctuary for Moas.” 46 The Moa is a giant flightless bird, extinct, that once roamed and dominated the forests of New Zealand. Figure 25. Paul Nash, The Nest of Wild Stones, 1937, watercolour and pencil on paper, 37.1 × 55 cm. Collection of Arts Council Collection, Southbank Centre (AC 30). Digital image courtesy of Arts Council Collection. Figure 26. Moa Gizzard Stones, Collection of Thames Mineralogical Museum, Coromandel, New Zealand. Elsewhere, in William Corliss’ Unknown Earth: A Handbook of Geological Enigmas , a striking discovery of stones is described, with words from Professor Lee, of the Geological Survey, first published in Science , in 1924: Fig. 26 ). The extraordinary discovery of the precious stones of the Moa captivated Lee, who remarks on: the good judgment of these extinct birds in choosing jewel stones for use in their lapidary mills. By judicious selection of material, these first families among diamond cutters handed down lasting memorials to admiring posterity. 47 Nash’s “Nest of Wild Stones” too is marvellous geological enigma, legible stones, deciphered in the field, alive with mathematics and the turn of a conjuror’s hand. In a context where geophysicists read the startling radioactivity of the land and worked mathematical equations to put a vastly ancient and sensational new age on the rocks of the earth, Nash’s landscape works, fraught with mathematical problems, equations, stones and bones, resonate afresh, beyond the confines of the Modern. Nash’s work poses as a geological problem, implicating the art works as vital geological remains and training the eye of the beholder to marvellous geological mystery. In describing and adventuring in a new geological consciousness, alongside empirical geology, Nash engages with an effable geological reality, channelling and revitalizing a British tradition. Nash’s landscapes are prescient of and suggestive to new modes of engagement in the current context of geological discovery, of a geological age of man, and the landscape now. Acknowledgements Footnotes Paul Nash, “Contribution to Unit One”, in Andrew Causey (ed.), Paul Nash: Writings on Art(Oxford: Oxford University Press, 2000), 107–110. 1 I make this argument at greater length in Anna Reid, “The Nest of Wild Stones: Paul Nash’s Geological Realism”, Visual Culture in Britain19, no. 2 (2018): 189–215. 2 Emma Chambers, “Introduction”, in Emma Chambers (ed.), Paul Nash(London: Tate, 2016), 11. 3 Charles Harrison, “England’s Climate”, in Brian Allen (ed.), Studies in British Art: Towards a Modern Art World(London: Yale University Press, 1995), 207–223. 4 The Book of Job cited in Arthur Holmes, “The Radioactive Timekeepers of the Rocks”, in Arthur Holmes (ed.), The Age of The Earth: An Introduction to Geological Ideas(London: Ernest Benn, 1927 [1913]), 55–75. 5 Martin Rudwick, Earth’s Deep History: How It was Discovered and Why It Matters(Chicago, IL: University of Chicago Press, 2014), 235–241. 6 Oliver Lodge, “Revolutionary Discoveries”, The Listener, 16 January 1929, Science section, 11. 7 James Jeans, The Mysterious Universe(Cambridge: Cambridge University Press, 1930). 8 The American geochemist, Clair Patterson arrived at 4.5 billion years in 1953—this radiometric date still stands as the most accurate. 9 Rudwick, Earth’s Deep History, 235–241. 10 Words spoken by Sollas and recorded in: J.W.S. Rayleigh, William Sollas, J.W. Gregory, and Harold Jeffreys “The Age of the Earth”, Nature108, 13 October 1921, 217–218. 11 Rebecca Bedell, “The History of The Earth: Darwin, Geology and Landscape Art”, in Diana Donald and Jane Munro (eds), Endless Forms: Charles Darwin, Natural Science and the Visual Arts(London: Yale University Press, 2009), 49–77. 12 Noah Heringman, Romantic Rocks, Aesthetic Geology(Ithaca, NY: Cornell University Press, 2004), 94–137. 13 Stephen Jay Gould, Time’s Arrow Time’s Cycle: Myth and Metaphor in the Discovery of Geological Time(London: Harvard University Press, 1987), 4–15. 14 For example, of the books collected by Nash, The Universeby Félix Archimède Pouchet is an in depth guide to the principles of geology; The Atmosphereby Camille Flammarion is an illustrated exploration of such phenomena as sun halos, snow crystals, the refraction of light through raindrops or emanations of phosphoretted hydrogen gas, and an in-depth description of the geomorphic processes of the wind, atmospheric temperature, “water-clouds-rain” and thunderstorms; The Heavensby Amédée Guillemin details processes of tides, eclipses, gravity, and meteoric form; Nash arranged, illustrated, and retained a “Sun Calendar” for the year 1920. 15 Nash, “Contribution to Unit One”. 16 David Mellor, “A Spectral Modernity”, in Emma Chambers (ed.), Paul Nash(London: Tate, 2016), 23–33. 17 Holmes, “The Radioactive Timekeepers of the Rocks”. 18 Lodge, “Revolutionary Discoveries”. 19 Paul Nash, “Unseen Landscapes”, in Herbert Read (ed.), Outline, an Autobiography and Other Writings(London: Faber & Faber, 1949), 229–231. 20 Félix Archimède Pouchet, The Universe (or the Infinitely Great and the Infinitely Little)(London: Blackie and Son, 1885), see, for example, 3–38, 502–510, and 537. 21 Nash, “Unseen Landscapes”. 22 Arthur Holmes, “Radium Uncovers New Clues to Earth’s Age”, The New York Times, 6 June 1926. 23 Holmes, “The Radioactive Timekeepers of the Rocks”. 24 Inga Fraser, “‘From a Sheet of Paper to the Sky’: Pattern in the Work of Paul Nash”, in Emma Chambers (ed.), Paul Nash(London: Tate, 2016), 59–67. 25 James George Frazer, The Worship of Nature, Vol. 1 (London: Macmillan and Co, 1926). 26 Holmes, “The Radioactive Timekeepers of the Rocks”. 27 Anonymous (civilian), “The New Weapon”, The Times, 28 September 1939. 28 “That Dreadful Atom Bomb”, Press and Journal, 20 August 1943. 29 Paul Nash, “Aerial Flowers,” in Herbert Read (ed.), Outline, an Autobiography and Other Writings(London: Faber & Faber, 1949), 258–265. 30 Paul Nash, “The Object”, The Architectural Review(November 1936): 207–208. 31 André Breton, “The Crisis of the Object”, in Myfanwy Evans (ed.), The Painter’s Object(London: Gerald Howe, 1937), 275–280. 32 Breton, “The Crisis of the Object”. 33 Paul Nash, Dorset: Shell Guide(London: Architectural Press, 1936). 34 Nash, Dorset. 35 Sarah Fill, “Paul Nash Surrealism and Prehistoric Dorset”, in Emma Chambers (ed.), Paul Nash(London: Tate, 2016), 49–57. 36 Dawn Ades and Simon Baker (eds), Undercover Surrealism Georges Bataille and Documents(London: Haywood Gallery, 2006). 37 Sarah Fill describes how Bataille’s thought reached Nash via Edward Burra, in Sarah Fill, “Paul Nash Surrealism and Prehistoric Dorset”, 51. 38 Fill, “Paul Nash Surrealism and Prehistoric Dorset”. 39 Gould, Time’s Arrow, Time’s Cycle, 1–3. 40 Paul Nash, “The Life of the Inanimate Object”, in Andrew Causey (ed.), Paul Nash: Writings on Art(Oxford: Oxford University Press, 2000), 137–139. 41 Symptomatic is Frederick W. Taylor’s subjecting of the human body to temporal management, see Mary Anne Doane, The Emergence of Cinematic Time, Modernity, Contingency, the Archive(London: Harvard University Press, 2002), 2–11. 42 Nash, “Unseen Landscapes”. 43 Paul Nash, “The Nest of Wild Stones”, in Myfanwy Evans (ed.), The Painter’s Object(London: Gerald Howe, 1937), 38–40. 44 Nash, “The Nest of Wild Stones”. 45 Nash, “Unseen Landscapes”. 46 William R. Corliss, Unknown Earth: A Handbook of Geological Enigmas,(Glen Arm, MD: The Sourcebook Project, 1980), 474. 47 Bibliography Ades, D. and Baker, S. (2006) Undercover Surrealism Georges Bataille and Documents. London: Haywood Gallery. Anon. (1939) “The New Weapon”. The Times, 28 September. Bedell, R. (2009) “The History of the Earth: Darwin, Geology and Landscape Art”. In Diana Donald and Jane Munro (eds), Endless Forms: Charles Darwin, Natural Science and the Visual Arts. London: Yale University Press, 49–77. Breton, A. (1937) “The Crisis of the Object”. In Myfanwy Evans (ed.), The Painter’s Object. London: Gerald Howe, 275–280. Causey, A. (ed.) (2000) Paul Nash: Writings on Art. Oxford: Oxford University Press. Chambers, E. (ed.) (2016) Paul Nash. London: Tate Publishing. Corliss, W.R. (1980) Unknown Earth: A Handbook of Geological Enigmas.Glen Arm, MD: The Sourcebook Project. Doane, M.A. (2002) The Emergence of Cinematic Time, Modernity, Contingency, the Archive. London: Harvard University Press. Evans, M. (ed.) (1937) The Painter’s Object. London: Gerald Howe. Fill, S. (2016) “Paul Nash Surrealism and Prehistoric Dorset”. In Emma Chambers (ed.), Paul Nash.London: Tate, 49–57. Fraser, I. (2016) “‘From a Sheet of Paper to the Sky’: Pattern in the Work of Paul Nash”. In Emma Chambers (ed.), Paul Nash. London: Tate, 59–67. Gould, S.J. (1987) Time’s Arrow, Time’s Cycle: Myth and Metaphor in the Discovery of Geological Time. London: Harvard University Press. Harrison, C. (1995) “England’s Climate”. In Brian Allen (ed.), Studies in British Art: Towards a Modern Art World. London: Yale University Press, 207–223. Heringman, N. (2004) Romantic Rocks, Aesthetic Geology. Ithaca, NY: Cornell University Press. Holmes, A. (1926) “Radium Uncovers New Clues to Earth’s Age”. The New York Times, 6 June. Holmes, A. (1927 [1913]) The Age of the Earth: An Introduction to Geological Ideas. London: Ernest Benn. Holmes, A. (1927 [1913]) “The Radioactive Timekeepers of the Rocks”. In Arthur Holmes (ed.), The Age of The Earth: An Introduction to Geological Ideas. London: Ernest Benn, 55–75. Lodge, O. (1929) “Revolutionary Discoveries”. The Listener, 16 January. Mellor, D. (2016) “A Spectral Modernity”. In Emma Chambers (ed.), Paul Nash. London: Tate, 23–33. Nash, P. (1936) Dorset: Shell Guide. London: Architectural Press. Nash, P. (1936) “The Object”. The Architectural Review(November): 207–208. Nash, P. (1937) “The Nest of Wild Stones”. In Myfanwy Evans (ed.), The Painter’s Object. London: Gerald Howe, 38–40. Nash, P. (1949) “Aerial Flowers”. In Herbert Read (ed.), Outline, an Autobiography and Other Writings. London: Faber & Faber, 258–265. Nash, P. (1949) “Unseen Landscapes”. In Herbert Read (ed.), Outline, an Autobiography and Other Writings. London: Faber & Faber, 229–231. Nash, P. (2000) “Contribution to Unit One”. In Andrew Causey (ed.), Paul Nash: Writings on Art. Oxford: Oxford University Press, 107–110. Nash, P. (2000) “The Life of the Inanimate Object”. In Andrew Causey (ed.), Paul Nash: Writings on Art. Oxford: Oxford University Press, 137–139. Press and Journal(1943) “That Dreadful Atom Bomb”, 20 August. Rayleigh, J.W.S., Sollas, W., Gregory, J.W., and Jeffreys, H. (1921) “The Age of the Earth”. Nature108, 13 October. Read, H. (ed.) (1949) Outline, an Autobiography and Other Writings. London: Faber & Faber. Reid, A. (2018) “The Nest of Wild Stones: Paul Nash’s Geological Realism”. Visual Culture in Britain19, no. 2: 189–215. Rudwick, M. (2014) Earth’s Deep History: How It was Discovered and Why It Matters. Chicago, IL: University of Chicago Press. Shand, P.M. (1939) “Object and Landscape”. CountryLife, 3 June. Selected books and items from the Paul Nash Collection Flammarion, C. (1873) The Atmosphere.London: Sampson Low. Frazer, J.G. (1926) The Worship of Nature, Vol. 1. London: Macmillan and Co. Guillemin, A. (1883) The Heavens (an illustrated Handbook of Popular Astronomy).London: Richard Bentley & Son. Jeans, J. (1930) The Mysterious Universe.Cambridge: Cambridge University Press. Nash, P. (1920) The Sun Calendar For The Year 1920.London: The Sun Engraving Company. Pouchet, F.A. (1885) The Universe (or the Infinitely Great and the Infinitely Little).London: Blackie and Son. Imprint Author Anna Reid Date 29 November 2018 Category Article Review status Peer Reviewed (Double Blind) Licence CC BY-NC International 4.0 Downloads PDF format Article DOI https://doi.org/10.17658/issn.2058-5462/issue-10/areid Cite as Anna Reid, "Paul Nash’s Geological Enigma", British Art Studies, Issue 10, https://doi.org/10.17658/issn.2058-5462/issue-10/areid
https://www.britishartstudies.ac.uk/index/article-index/nash-geological-enigma/search/www.artspace.com/year/2015/article-category/cover-collaboration
[A case of multiple sulfatase deficiency with fiber type disproportion] Download Citation | [A case of multiple sulfatase deficiency with fiber type disproportion] | We describe a case of multiple sulfatase deficiency with fiber type disproportion. An 8-year-old girl had slow motor and mental deterioration... | Find, read and cite all the research you need on ResearchGate [A case of multiple sulfatase deficiency with fiber type disproportion] February 1984 No to hattatsu. Brain and development 16(3):205-9 Authors: S Fujibayashi K Wagatsuma R Minami Abstract We describe a case of multiple sulfatase deficiency with fiber type disproportion. An 8-year-old girl had slow motor and mental deterioration since the age of 17 months. She had main clinical features characterized by contractures in all extremities, gargoyle face, ichthyosis, retinitis pigmentosa, and enlarged liver. Laboratory examinations showed elevated CSF protein and delayed nerve conduction velocity. Radiologic bone survey disclosed deformities similar to those of mucopolysaccharidosis. The activities of arylsulfatase A, B and C were markedly reduced in culture in skin fibroblastosis. The findings of biopsied sural nerve showed metachromatic granules in Schwann cell cytoplasma and segmental demyelination without onion-bulb formations. Electron microscopy showed tuff-stone bodies. Those findings coincided with those of the infantile form of metachromatic leukodystrophy. Muscle biopsy showed that type I fibers were predominant and the diameter of type I fibers was relatively smaller than that of type II fibers without other obvious histological findings. These findings coincided with the histopathology of congenital fiber type disproportion. The finding of fiber type disproportion is observed in various conditions such as experimental tenotomy and joint fixation. Our case had bilateral fixed knee joints. This condition might introduce fiber type disproportion. However, demyelination of peripheral nerves in multiple sulfatase deficiency might be a factor associated with fiber type disproportion. We suggest that the pathogenesis of fiber type disproportion in our case with multiple sulfatase deficiency is associated with various complex factors. ... Mutations in ACTA1 (Laing et al. 2004), SEPN1 (Clarke et al. 2006), TPM3 (Clarke et al. 2008), RYR1 (Wilmshurst et al. 2010), and more recently MYH7 (Ortolano et al. 2011) have also been identified in patients with FTD. To add to its nonspecific nature, this morphological finding has been reported in association with several inherited metabolic disorders including Pompe disease (Martin et al. 1976), multiple sulfatase deficiency (Tachi et al. 1984) , congenital lactic acidosis (Iso et al. 1993), metachromatic leukodystrophy (Krendel et al. 1994), carnitine palmitoyltransferase deficiency (Shintani et al. 1995), and Krabbe disease (Marjanovic et al. 1996). To our knowledge, FTD has never been described in patients with CDG. ... Further Delineation of the Phenotype of Congenital Disorder of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping Jan 2012 Faiqa Imtiaz Abeer Al-Mostafa Zuhair Al-Hassnan Congenital disorders of glycosylation (CDG) are an expanding group of genetic diseases affecting protein and lipid glycosylation. These disorders have a variable presentation and are individually rare. DPAGT1-CDG is a protein N-glycosylation disorder with epilepsy, development delay, severe hypotonia, and dysmorphy, reported in a single patient. Here we present the second family with DPAGT1-CDG identified through homozygosity mapping in a large consanguineous family with 18 affected infants. The patients had severe hypotonia, global developmental delay, seizures, and microcephaly but no dysmorphy. In the index case, the brain MRI revealed delayed myelination, and there was fiber type disproportion on muscle biopsy. Homozygosity mapping identified a large block of homozygosity on chromosome 11p15.5-q25 where two known CDG-I causing genes, ALG9 and DPAGT1, are located. Sequencing ALG9 did not reveal any mutations while analysis of DPAGT1 identified a novel homozygous mutation c.902G>A (p.R301H) in two affected infants. The disorder was fatal in all affected cases and mostly in early infancy. A serial muscle biopsy study in a case of congenital fiber-type disproportion associated with progressive respiratory failure Feb 1990 BRAIN DEV-JPN Yoshihiko Mizuno Kazuhiko Komiya The muscle fiber diameter and distribution were studied in serial muscle biopsy specimens taken at the ages of 21 months and 8 years in a girl with congenital fiber type disproportion. The patient was floppy from birth and showed delayed motor development. Progressive respiratory failure developed from the age of 8, which required artificial respiration during the night. The mean diameters of type 1 fibers at the ages of 21 m and 8 y were 10 mu and 21 mu, and those of type 2 fibers 32 mu and 61 mu, respectively. Whereas most type 1 fibers were hypotrophic in both biopsy specimens, a small number of type 1 fibers (approximately 15%) were normal-sized or hypertrophic, measuring 50 to 90 mu, in the second biopsy specimen, which were thought to have arisen on the maturation of normal-sized or hypertrophic type 1 fibers measuring 15 to 35 mu in the first biopsy specimen. Excessive hypotrophy of type 1 fibers was considered to be responsible for the progressive respiratory failure due to weakness of the diaphragm. The pattern of type 1 fiber evolution from the first to the second biopsy specimen suggested that dysmaturation of spinal motoneurons innervating type 1 muscle fibers would be involved in the pathophysiology of the fiber type disproportion in this case. Congenital fiber type disproportion myopathy in Lowe syndrome Nov 1989 PEDIATR NEUROL Jun Kohyama Fumio Niimura Koichiro Kawashima Ikuya Nonaka Two brothers with the typical clinical features of oculocerebro-renal syndrome of Lowe exhibited delays in developmental milestones, muscular weakness and hypotonia, and high serum creatine kinase activity. The biopsied muscle revealed selective type 1 fiber atrophy and mild type 1 fiber predominance, similar to that observed in congenital fiber type disproportion myopathy. The abnormal fiber type distribution may be responsible for the common finding of muscle hypotonia in this syndrome. Association of Krabbe leukodystrophy and congenital fiber type disproportion Aug 1996 PEDIATR NEUROL B Marjanović Dubravka Cvetković S Dozić Milena Djuric Hypotonia and weakness developed in a 12-month-old boy whose psychomotor development had previously been normal. The muscle biopsy demonstrated a disparity in the mean diameters of type 1 and type 2 fibers and satisfied major histologic criteria for diagnosis of congenital fiber type disproportion (CFTD). However, deterioration of motor and mental function, which developed subsequently, strongly suggested progressive encephalopathy. Examination of leukocyte cerebral enzymes at 15 months of age revealed a complete lack of galactosylceramide-beta-galactosidase. Selective type 1 fiber atrophy with type 1 fiber predominance has been observed in various conditions, including Krabbe disease. We report an additional case of Krabbe leukodystrophy associated with CFTD. The finding on the molecular level will resolve the dilemma of whether CFTD is a congenital myopathy or whether these patterns of disproportion may result from a number of different processes that interfere with the maturation of the developing motor unit. Congenital fiber type disproportion - 30 Years on Nov 2003 Nigel F Clarke Kathryn N North Thirty years ago, M. H. Brooke coined the term "congenital fiber type disproportion" (CFTD) to describe 12 children who had clinical features of a congenital myopathy and relative type 1 fiber hypotrophy on muscle biopsy. It is now clear that this histological pattern can accompany a wide range of neurological disorders, leading to disillusionment with CFTD as a distinct nosological entity. To determine whether the CFTD has clinical utility as a diagnostic entity, we have reviewed the literature for cases of type 1 fiber hypotrophy and have used strict exclusion criteria to identify 67 cases of CFTD. Most patients presented at birth with weakness and hypotonia, had normal intelligence, and followed a static or improving clinical course. In 43% of families, more than 1 individual was affected. Failure to thrive was common and 25% of patients had contractures or spinal deformities. Bulbar weakness and ophthalmoplegia were less common and cardiac involvement was rare. Twenty-five percent followed a severe course and 10% had died at the time of reporting, all from respiratory failure. Ophthalmoplegia and facial and bulbar weakness were significantly associated with a poorer prognosis. The relatively homogeneous phenotype supports the retention of CFTD as a distinct diagnostic entity and familial occurrence suggests a genetic basis. Regarding the diagnosis of CFTD, we found no strong evidence that the minimum difference between type 1 and type 2 fiber sizes should be increased from 12% to 25%. We also list the other reported causes of relative type 1 fiber hypotrophy to aid their exclusion from CFTD.
https://www.researchgate.net/publication/16728801_A_case_of_multiple_sulfatase_deficiency_with_fiber_type_disproportion
The Oxford Oratory A sanctuary in the midst of the city The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman. Two relics of his are displayed this month in our relic chapel, including a letter bearing his signature. #oxfordoratory Flos paradisi Today we celebrate the great solemnity of the patron of our church: St Aloysius Gonzaga of the Society of Jesus. St Aloysius is, together with St Gabriel Possenti, patron of young people, students, and seminarians and thus was a natural choice as patron for our church in this university city. He is also the patron of our parish school and we entrust to his loving intercession all our children who are able to learn the love of God from his example. We have his shrine in the chapel of Our Lady of Oxford, his statue is there on the reredos, and his initials guide our eyes towards his heavenly home as we look up at the sanctuary ceiling. Our patrons are important — St Aloysius has been given to us in this parish by God, through his Church, to watch over us in a particular manner, to intercede for all those who live and worship here, and to encourage us in our own quest for holiness. Born the eldest son of the Marquis of Castiglione, St Aloysius seemed destined for a life of political intrigue and secular affairs, but, as with St Ignatius before him, it was the lives of the saints that really captivated him and placed in his heart the desire to strive for something better. This was not some childish caprice; he had seen the reality of life at court with its violence, frivolity, and degradation of human dignity, and desired not only to turn his back on it, but to embrace with all his heart a life given wholly to God. He began in earnest, adopting severe penances and teaching the local children their catechism. Hearing about the missions of St Francis Xavier, he set his heart on becoming a Jesuit — much to the horror of his family. Eventually, having not overcome family opposition but at least its concrete obstacles, and having renounced his rights of inheritance, he entered the Jesuit novitiate in Rome in 1585. He had much to learn and much to which to adapt himself, but whatever he had to do he simply did it with all his heart — trusting in the sure knowledge that God was at work. Would he have met St Philip in Rome? Concrete evidence is hard to find, though these two saints of Rome are often depicted in art. We know they had mutual friends and these no doubt would have told them of Rome’s Third Apostle and of the holy Jesuit novice. One can imagine St Aloysius on a novitiate walk popping in to the Chiesa Nuovato see Mister Father Philip whom all Rome spoke of and revered or of St Philip blessing a crowd of passing Jesuit novices and knowing the heart of one of them that would see them both in glory. St Aloysius’ real work in Rome was that which St Philip had embarked upon at the beginning — the care of the sick and the destitute. When plague broke out he volunteered to go with the other novices to pick people off the streets, to wash them, to prepare them for the sacraments and care for their souls. At first, he admitted to his director St Robert Bellarmine, this revolted him, but he soon learnt to see the image of Christ in these people, and to love them, not only in caring for them, but in seeing Christ in them. Never one to enjoy good health, Aloysius himself fell ill of plague, and died at the age of 23 on 21 June 1591, just a few years before St Philip’s death. When we look at images of St Aloysius we normally see a rather pale young man who looks like so many other sickly young saints, distinguished perhaps only by the great ruff that he wears about his neck. But he was more than that. He was a young man who bothered about God and thus about other people. He was not yet in his mid-twenties, when he had discovered that real freedom comes from serving God with all ones heart; that Christian love has to be lived in the real, strength-sapping, heart-breaking, service of others; that there is joy in taking people off the streets, washing them, bandaging their wounds and restoring them to the dignity that is theirs as children of God. The image attached to these words is a depiction of St Aloysius in Milan in the Chiesa di Santa Maria presso San Satiro. The saint looks rather weak and malnourished, but what strength he has is used to hold up a man who is either dying or dead, with St Aloysius pressing the Cross to him and holding the man’s head up with his hands. The look on St Aloysius’ face is one, simply, of love — of love for God and neighbour, and of joy found in bringing the love of God to others. How much this young man, St Aloysius, still has left to teach us… Heart of Jesus, all-holy! Fountain of all blessings, I adore thee, I love thee, and with a lively sorrow for my sins, I offer thee this poor heart of mine. Make me humble, patient, pure, and wholly obedient to thy will. Good Jesus, grant that I may live in thee and for thee. Protect me in the midst of danger; comfort me in my afflictions; give me health of body, assistance in my temporal needs, thy blessing on all that I do, and the grace of a holy death. Amen. #oxfordoratory A photo from Sunday’s Solemn Mass for Corpus Christi. June Music Sunday 4 JuneSolemn Mass 11:00The Most Holy TrinityKyrie MundyMissa Euge bone TyeLibera nos SheppardHonor, virtus et potestas Tallis Sunday 11 JuneSolemn Mass 11:00Corpus ChristiMissa Pange lingua JosquinLauda Sion PalestrinaOculi omnium Byrd Friday 16 JuneSolemn Mass 18:00The Most Sacred Heart of JesusMissa Dormendo un giorno GuerreroImproperium PalestrinaSancte Deus Tallis Sunday 18 JuneSolemn Mass 11:0011th Sunday of the YearMissa Brevis in F Op.117 RheinbergerBenedicam Dominum VictoriaSalve Regina Poulenc Wednesday 21 JuneSolemn Mass 18:00St Aloysius GonzagaMissa O quam gloriosum VictoriaJustitiae Domini A ScarlattiO bone Jesu Anchieta Sunday 25 JuneSolemn Mass 11:0012th Sunday of the YearMissa Repleatur os meum PalestrinaPerfice gressus meos LassusHomo quidam fecit coenam magnam Mouton Thursday 29 JuneSolemn Mass 18:00St Peter and St PaulMissa Petre ego pro te rogavi LoboPetre ego pro te rogavi GuerreroJanitor caeli Ortiz The Sacred Heart Love is a funny thing. Materialists will tell us that it is purely the result of a series of electro-chemical responses in the brain, and yet others will tell us that it is the result of fate, the conspiracy of the alignment of the planets or the times we find ourselves in. The heart has long been understood as the centre of a person, a place of knowledge as much as will. It makes us do unreasonable things like acts of unwarranted kindness and altruism and by the edge of its blade we can be hurt in ways that we just can’t speak about. And yet none of these express what love is in itself — only God does that. On Friday we venerate the Heart of our Lord as the symbol of his human love in which God’s divine love is revealed to us. In most of the prayers to or the meditations on the Sacred Heart, even those very ancient prayers, the woundedness of our Lord’s heart comes to the fore. That heart pierced with a lance and bruised with outrages and blasphemies is a stark and realistic image of the extent to which Christ loves us. Christ, who is the image of the unseen God, the Icon of the Father, shows us precisely what God’s love for us looks like. And it looks like a heart pierced and bruised on account of our sins, yet burning with ardent love for you and for me. This divine love is not for softies. The time when we celebrate this feast is very fitting. We have come to the end of the Church’s celebration of the mysteries of our redemption: the Passion, the Cross, the Resurrection, the Ascension, Pentecost, the Feast of the Blessed Trinity and Corpus Christi. But today we commemorate the divine-human love which motivated them all. In adoring the Sacred Heart, we adore the totality of Christ’s saving work — it represents the way in which God holds nothing back from us. And in order to share his divine life with us, he reaches down into the very depths of our life, even — and especially — where it is painful, difficult to speak of, hidden. By taking it all and joining it to himself, he scoops us up, he enables us to become like him. By sharing our life, and by sharing our pains, he heals us, he sanctifies us, and he strengthens us. It is also true that his heart welcomes us precisely so that we might become like it. The whole thrust of our Christian life is that we might be conformed to our Saviour, that we might resemble him, and in this sense, in the life of faith, we should ask ourselves continually whether our heart resembles his. His Sacred Heart is both the example and the cause of our becoming like him. His love is attractive. The more we consider the love with which Jesus acted, and spoke and gave of himself for us, the more we can begin, by his grace, to imitate him — it is truly the school of Christian perfection. And we begin in that school by prayer. When St John Henry Newman, our Cardinal, chose his motto, he looked to St Francis de Sales’ Treatise on the Love of God. The phrase he chose and paraphrased, Cor ad Cor loquiturrepresents for us the central mystery of the prayer that can begin to transform us. St Francis de Sales wrote: Truly the chief exercise in mystical theology is to speak to God and to hear God speak in the bottom of the heart; and because this discourse passes in most secret aspirations and inspirations, we term it a silent conversing. Eyes speak to eyes, and heart to heart, and none understand what passes save those who speak. We may be no great shakes at the spiritual life, or prayer, or we may feel that excelling in virtue is beyond us, but if we can in the simplest of ways open our poor heart to his Sacred Heart, and speak to him as to a friend, if we can entrust our lives to him and ask him devoutly and sincerely to shape us after the model of his Heart, then our Christian life will be all the more graced. The Corpus Christi procession concluded with Benediction at the University Chaplaincy. #oxfordoratory The procession finished at the University’s Catholic Chaplaincy. #oxfordoratory The numbers caught the attention of the local media: https://www.oxfordmail.co.uk/news/23582016.oxfords-catholic-congregations-take-part-corpus-christi-procession/ #oxfordoratory Children scattered flower petals before the Blessed Sacrament all the way. #oxfordoratory Our route now passes through the city in a straight line, taking us directly through the busiest shopping areas. #oxfordoratory The canopy was carried by members of the University of Oxford wearing their academic dress. #oxfordoratory Fr Robert Ombres OP preached a sermon. #oxfordoratory We paused at Blackfriars. #oxfordoratory We were joined by local clergy and religious orders as we processed through the streets to the Dominican Priory at Blackfriars. #oxfordoratory The processions sets off… #oxfordoratory We had record numbers for the procession this year. There wasn’t space in church for everyone at the beginning! There were more people outside too. #oxfordoratory The beginning of our Corpus Christi procession last Sunday.#oxfordoratory View on Instagram The Oratory Prayer Book is now shipping internationally! We’ve made it even easier to buy the Oratory Prayer Book from anywhere in the world. And we’ve made it easier to order multiple copies too — in the UK and worldwide. Order your copy here:https://tinyurl.com/opb-buy If you have one, we’d love to hear what you think about it. Let us know in the comments, or tag a photo of your prayer book in the wild with #oratoryprayerbook Thanks to @acatholicinoxford for the photo. #oxfordoratory Worship What does it actually mean to worship God? In the New Testament, the word we most often translate as ‘worship’ doesn’t mean to reverence another in some abstract sense. It always involves some kind of bodily action. When we think about the magi visiting the Holy Family, we sometimes convey this motion by describing them — after they fall to their knees — as ‘doing homage’. But it’s actually that same word here we might translate elsewhere as ‘worship’. It’s just that we recognise the need to describe the bodily sign of their submission and adoration of the new born King with something that sounds a bit more physical. The word we usually translate as ‘worship’ ( proskuneo) comes literally from a root meaning ‘to make yourself like a dog before the other person’. It originally meant prostrating yourself on the floor to show your humble submission before another. By the time of the New Testament, people wouldn’t necessarily have had the root of this word in mind whenever they used it,* but the word still carries with it the idea of doing something with your body to express your worship. The feast of Corpus Christi is all about this kind of bodily worship. It’s tied to the fact that we are not pure spirits, but that we are human beings, body and soul. To worship God is not just a spiritual act. The right worship of God does not consist in simply having the right kinds of thoughts towards him. But the worship of God involves the humble submission of our entire human being, body and soul, before the God who is greater than all of us. And ever since the Incarnation, we do this not just before an abstract spirit. Because, from the moment of the Incarnation, God really does have a human body, that we can worship, that we fall down on our knees before, like the magi and the Canaanite woman, and so many others in the Gospel who kneel down and worship Christ. When we worship God, we kneel before God who is present in the flesh, under the appearances of bread and wine, in our churches all over the world. Corpus Christi is a joyful celebration of Christ’s presence among us, and it gives us an opportunity to think about how we respond to that gift. All this talk of kneeling and worship might not sound so joyful, but one of the great paradoxes of Christianity is that we find our greatest freedom in the humble service of God. Our greatest joy really should be found in finding ways to express this loving worship. So at least once a year, it is no bad thing to think about how we express with our own bodies that worship of God’s body, and what ways we can find to worship him even more perfectly. This Sunday, we will carry Christ’s Body through the streets of our city. We have a chance to demonstrate to the world our love, our joyful service, our worship of him, through our presence. The procession leaves our church at 2:30pm. Make sure you are there. But we should also think about the more ordinary things, like making sure we show that worship whenever we are in his presence. We should show through our behaviour in church that we believe him to be there: by genuflecting before him in the tabernacle of the church, and by keeping the church quiet and prayerful. We show our worship above all by kneeling down before him — like all those people in the Gospel — for the moment of Holy Communion. And we allow the priest to place the Host on our tongues, so that we don’t handle unnecessarily what is holy and precious, and no particles of Our Lord’s Body are ever dropped or lost through carelessness. We continue that worship in our prayers of thanksgiving after Communion and once the Mass has ended. We certainly never leave church during Communion. And we might think of ways of extending the time we spend with Christ present in the Blessed Sacrament: by attending Mass during the week sometimes, or visiting him during the times each week when his Body is exposed solemnly on the altar for Adoration, or even just by visiting an empty church, where he is waiting for us to show him our worship. Our Lord is hidden there, waiting for us to come and visit him, and make our request to him. See how good he is! He is there in the Sacrament of his love, sighing and interceding incessantly with his Father for sinners. To what outrages does he not expose himself, that he may remain in the midst of us! He is there to console us; and therefore we ought often to visit him. How pleasing to him is the short quarter of an hour that we steal from our occupations, from something of no use, to come and pray to him, to visit him, to console him for all the outrages he receives! When he sees pure souls coming eagerly to him, he smiles upon them. They come with that simplicity which pleases him so much, to ask his pardon for all sinners, for the outrages of so many ungrateful men. What happiness do we not feel in the presence of God, when we find ourselves alone at his feet before the holy tabernacles! ‘Come, my soul, redouble thy fervour; thou art alone adoring thy God. His eyes rest upon thee alone.’ — St John Mary Vianney * One exception is that I do think Christ had this root meaning in mind when he spoke to the Canaanite woman in Matthew 15:21–28. He wasn’t randomly insulting her by comparing her to a dog, but drawing attention to the fact that she was making herself like a dog before him — i.e. worshipping him — because she recognised him to be God. In other words, he was acknowledging her worship as proof of her faith and humility. These reflections are sent out each Wednesday to all those on our mailing list. Click here to sign up to our mailing list , and receive our Sunday E-newsletter and these reflections straight to your inbox. © 2023 Oxford Oratory. All rights reserved. The Oxford Oratory of St Philip Neri is a Registered Charity number 1018455
https://www.oxfordoratory.org.uk/publications/blog/post/9857-9857/blog/post/10021-10021/friends.php
Town Of Springfield v. Newton, 1205. - Vermont - Case Law - VLEX 889135547 0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object] Town Of Springfield v. Newton, 1205. Docket Nº No. 1205. Citation 50 A.2d 605 Case Date January 07, 1947 Court United States State Supreme Court of Vermont 50 A.2d 605 TOWN OF SPRINGFIELD v. NEWTON et al. No. 1205. Supreme Court of Vermont. Jan. 7, 1947. 50 A.2d 606 Original prohibition proceeding by the Town of Springfield against Maurice A. Newton and others, County Road Commissioners for the County of Windsor, respondents, to restrain the respondents from enforcing an order made by them requiring the petitioner to make certain designated repairs on a bridge situated within limits of the petitioner, wherein Harry P. Fitch and others, citizens and taxpayers of the petitioner, intervened and filed an answer. Issuance of writ of prohibition ordered. 50 A.2d 607 H. H. Blanchard, of Springfield, and Lawrence and O'Brien, of Rutland, for petitioner. Clifton G. Parker, of Morrisville, for respondents. Ernest F. Berry and Barber & Barber, all of Brattleboro, for intervenors. Before MOULTON, C. J., and BUTTLES, STURTEVANT and JEFFORDS, JJ. MOULTON, Chief Justice. This is a petition for a writ of prohibition, by which it is sought to restrain the County Road Commissioners for the County of Windsor (hereinafter called the respondents) from enforcing an order made by them requiring the Town of Springfield, in that County, (hereinafter called the petitioner) to make certain designated repairs upon a bridge situated within the limits of the Town. The writ is sought upon the ground that the bridge is not a public highway or a part of a public highway, never having been laid out under authority of law, or dedicated or accepted as such, and that therefore the respondents were without jurisdiction or authority to entertain or hear any complaint, or to make any legal or binding order upon the petitioner in connection therewith, or to take any steps for the enforcement of such order if the petitioner should fail to comply with it. Upon presentation of the petition to a Justice of this Court a stay of all proceedings respecting the matters alleged was granted pending that final disposition of the controversy. 50 A.2d 608 The respondents have filed an answer. Harry P. Fitch, Nora S. Fitch, Ervin C. Balch and Hugh H. Balch, all citizens and taxpayers of Springfield (hereinafter called the intervenors) who were the complainants to the respondents, have, upon their motion, been permitted to enter as parties respondent, and have filed an answer. The cause is before us upon the report a Commissioner, who has been appointed to find and report the facts in issue. The proceedings which resulted in the order made by the respondents were those prescribed by statute. As provided by P.L. 4945 the intervenors gave notice of the insufficiency of the bridge and the nature of such insufficiency to the selectmen of the petitioner; and after a neglect by the petitioner to commence work upon the bridge for 36 hours, filed a complaint with the respondents, signed and sworn to, with security for costs. In accordance with P.L. 4946, 4947 and 4948 the respondents, after giving the required notice, heard the parties, examined the bridge, and filed their report that the public good required that certain specified repairs should be made thereon, allocating the sum of $500.00 for the purpose, with an order that the petitioner commence work upon them within a designated time. The hearing was held over the protest and objection by the petitioner that the respondents were without authority or jurisdiction in the matter, for the same reason as that set forth in the petition. The petition alleges that unless prohibited by an order of this Court the respondents, in the event that the repairs shall not be made, will continue to exercise jurisdiction, will appoint an agent to expend the amount allocated by them, will file a certificate in the office of the County clerk of Windsor County, and cause a judgment for this sum to be entered against the petitioner and execution issued thereon, as provided by P.L. 4949 and 4950. The function of a writ of prohibition is to prevent the unlawful assumption of jurisdiction by a tribunal either of the entire subject matter or of something collateral or incidental thereto, contrary to common law or statutory provisions. Leonard v. Willcox, 101 Vt. 195, 203, 142 A. 762 and cas.cit. The writ lies not only to courts eo nomine but also to inferior ministerial bodies possessing incidentally judicial powers, such as are known as quasi judicial functions. In re First Congressional District Election, 295 Pa. 1 , 144 A. 735 , 739, 43 Am.Jur.Tit. ‘Prohibition,’ p. 153, para. 14, and cas.cit. In the proceedings to order repairs upon defective highways and bridges under the sections of our Statutes above referred to the County Road Commissioners constitute such an inferior tribunal having certain quasi judicial power, and therefore the writ may issue against them to prevent an assumption of jurisdiction not conferred by law. Town of Shrewsbury v. Davis, 101 Vt. 181, 187, 142 A. 91 . In this case the status of the bridge in question as a public highway is the essential jurisdictional element. Town of Shrewsbury v. Davis, supra. A highway, which term includes a bridge and its approaches (P.L. 13; Cook v. Town of Barton, 63 Vt. 566 , 568, 22 A. 663 ), is established either by regular statutory proceedings, or by dedication and acceptance. Hyde, Adm'r, v. Town of Jamaica, 27 Vt. 443, 454. In the case just cited it is intimated that the establishment may also be by prescription, but it is said in Gore v. Blanchard, 96 Vt. 234, 241, 118 A. 888 , 891, that: ‘Inasmuch as the public cannot take by grant, prescription, which presupposes a grant, in its strict sense, seems to have no application to highways.’ In the present case there is nothing to show that the bridge was ever laid out as a highway by the authority of statute; in fact, it appears that all the available surveys and records are silent upon the subject. But the legality of its establishment is not disproved by the absence of a record, for it may have acquired its status by dedication and acceptance, as the defendants and the intervenors claim to be the case in this instance. Judd v. Challoux, 114 Vt. 1, 3, 39 A.2d 357 ; Brown v. Town of Swanton, 69 Vt. 53 , 56, 37 A. 280 ; Page v. Town of Weathersfield, 13 Vt. 424, 429. A dedication of a road as a highway is the setting apart of the land for public use, and may be either express or implied from the acts of the owner. It need not be evidenced by any writing or by any form of words, but may be shown by evidence of the 50 A.2d 609 owners' conduct, provided his intention, which is the essential element, clearly appears. Gore v. Blanchard, 96 Vt. 234, 239, 118 A. 888 ; Littlefield v. Hubbard, 124 Me. 299, 128 A. 285 , 287, 38 A.L.R. 1306. It is not, like a grant, to be presumed from length of time alone, but may, if the act of dedication be unequivocal, take place immediately. State v. Wilkinson, 2 Vt. 480, 486, 21 Am.Dec.560... 20 practice notes Concerned Loved Ones and Lot Owners Ass'n of Beverly Hills Memorial Gardens v. Pence, CC993 United States Supreme Court of West Virginia July 21, 1989 ...S.W.2d 528, 528 (1953); Priolo v. City of Dallas, 257 S.W.2d 947, 952 (Tex.Civ.App.1953); Town of Springfield v. Newton, 115 Vt. 39, 44, 50 A.2d 605 , 609 (1947); Humphrey v. Krutz, 77 Wash. 152, 155, 137 P. 806, 807 (1913). See 11 E. McQuillin, The Law of Page 838 Municipal Corporations § 3...... Thompson v. Smith, 311 United States Vermont United States State Supreme Court of Vermont February 7, 1957 ...law and fact. Smith v. Vermont Marble Co., 99 Vt. 384, 395-396, 133 [119 Vt. 498] A. 355; Town of Springfield v. Newton, 115 Vt. 39, 47, 50 A.2d 605 . See also Rothfarb v. Camp Awanee, Inc., 116 Vt. 172, 176, 71 A.2d 569; Merchants Mutual Casualty Co. v. Izor, supra, 118 Vt. at page 443, 111...... Kirkland v. Kolodziej, 14–339. United States Vermont United States State Supreme Court of Vermont July 17, 2015 ...Town of Bethel v. Wellford, 2009 VT 100, ¶ 14, 186 Vt. 612, 987 A.2d 956 (mem.) (quoting Town of Springfield v. Newton, 115 Vt. 39, 47, 50 A.2d 605 , 610 (1947) ). We defer to the trial court's findings of fact if, viewed in a light most favorable to the prevailing party, they are not clearl...... Watson v. City of Albuquerque, 7774 United States New Mexico Supreme Court of New Mexico July 18, 1966 ...485; Board of Comm'rs of Jefferson County v. Warneke, 1929, 85 Colo. 388, 276 P. 671; Town of Springfield v. Newton, 1947, 115 Vt. 39, 50 A.2d 605 ; compare City of Carlsbad v. Neal, 1952, 56 N.M. 465, 245 P.2d 384; State ex rel. Shelton v. Board of Com'rs of Bernalillo County, 1945, 49 N.M....... 20 cases Concerned Loved Ones and Lot Owners Ass'n of Beverly Hills Memorial Gardens v. Pence, No. CC993 United States Supreme Court of West Virginia July 21, 1989 ...S.W.2d 528, 528 (1953); Priolo v. City of Dallas, 257 S.W.2d 947, 952 (Tex.Civ.App.1953); Town of Springfield v. Newton, 115 Vt. 39, 44, 50 A.2d 605 , 609 (1947); Humphrey v. Krutz, 77 Wash. 152, 155, 137 P. 806, 807 (1913). See 11 E. McQuillin, The Law of Page 838 Municipal Corporations § 3...... Thompson v. Smith, No. 311 United States Vermont United States State Supreme Court of Vermont February 7, 1957 ...law and fact. Smith v. Vermont Marble Co., 99 Vt. 384, 395-396, 133 [119 Vt. 498] A. 355; Town of Springfield v. Newton, 115 Vt. 39, 47, 50 A.2d 605 . See also Rothfarb v. Camp Awanee, Inc., 116 Vt. 172, 176, 71 A.2d 569; Merchants Mutual Casualty Co. v. Izor, supra, 118 Vt. at page 443, 111...... Kirkland v. Kolodziej, No. 14–339. United States Vermont United States State Supreme Court of Vermont July 17, 2015 ...Town of Bethel v. Wellford, 2009 VT 100, ¶ 14, 186 Vt. 612, 987 A.2d 956 (mem.) (quoting Town of Springfield v. Newton, 115 Vt. 39, 47, 50 A.2d 605 , 610 (1947) ). We defer to the trial court's findings of fact if, viewed in a light most favorable to the prevailing party, they are not clearl...... Watson v. City of Albuquerque, No. 7774 United States New Mexico Supreme Court of New Mexico July 18, 1966 ...485; Board of Comm'rs of Jefferson County v. Warneke, 1929, 85 Colo. 388, 276 P. 671; Town of Springfield v. Newton, 1947, 115 Vt. 39, 50 A.2d 605 ; compare City of Carlsbad v. Neal, 1952, 56 N.M. 465, 245 P.2d 384; State ex rel. Shelton v. Board of Com'rs of Bernalillo County, 1945, 49 N.M.......
https://case-law.vlex.com/vid/town-of-springfield-v-889135547
Wavefront-guided LASIK and Wavefront-optimized LASIK in Astigmatism and Myopia - Clinical Trials Registry - ICH GCP The purpose of the study is to compare the results of LASIK surgery when using wavefront-guided excimer laser treatment compared to wavefront optimized excimer... Wavefront-guided Versus Wavefront-optimized LASIK for Nearsightedness The purpose of the study is to compare the results of LASIK surgery when using wavefront-guided excimer laser treatment compared to wavefront optimized excimer laser treatment in patients with nearsightedness with and without astigmatism Study Overview Status Completed Conditions Astigmatism Myopia Intervention / Treatment Procedure: Wavefront-guided LASIK Procedure: Wavefront-optimized LASIK Detailed Description This is a research study comparing the outcomes of LASIK surgery for nearsightedness when using the two different excimer laser technologies. Patients will have both eyes treated with the Alcon WaveLight Allegretto excimer laser. You will be one of 150 sighted patients at Stanford to undergo treatment in this clinical research trial. This will be a prospective, randomized, research study in which up to 300 consecutive eyes scheduled to undergo excimer laser in situ keratomileusis (LASIK) using one laser technology in the first eye and the second laser technology in the fellow eye for the correction of myopia (nearsightedness) with or without astigmatism will be enrolled. The choice of which eye receives the wavefront guided technology and which eye receives the wavefront-optimized technology will be randomized prior to enrollment. Randomization will be done according to a randomization schedule. You will know which eye is being treated with which each technology. The randomization will determine only whether your right or left eye is treated with the wavefront guided technology. The other eye will be treated with wavefront-optimized laser technology. You have a fifty percent chance of having your left eye treated with custom wavefront guided technology as your right eye. Subjects will undergo bilateral (both eyes at once) LASIK treatments using the Alcon WaveLight Allegretto excimer laser. All subjects will be followed for one year after the vision correction procedure. Subjects scheduled to undergo LASIK for the correction of myopia (nearsightedness) with or without astigmatism will be screened for eligibility. Eligible subjects will be examined preoperatively to establish a baseline for ocular condition (the general health and glasses prescription of the eyes). Postoperatively, subjects will undergo an ophthalmic evaluation (complete eye examination) at regular intervals as specified in this protocol. Retreatments (a second operation on the same eye for residual nearsightedness) will not be allowed during the first twelve months of this study. If you elect to undergo a retreatment of your LASIK surgery prior to the 12-month post-operative visit, the retreated eye will be exited from the study as of the retreatment date. Any significant new finding developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject or subject's representative in a timely manner. Study Type Observational Enrollment (Actual) 36 Contacts and Locations This section provides the contact details for those conducting the study, and information on where this study is being conducted. Study Locations United States California Stanford University School of Medicine Participation Criteria Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments. Eligibility Criteria Ages Eligible for Study 21 years and older (Adult, Older Adult) Accepts Healthy Volunteers No Genders Eligible for Study All Sampling Method Non-Probability Sample Study Population Subjects age 21 and older with healthy eyes. Nearsightedness between -7.50 diopters and -7.00 diopters with or without astigmatism of up to 3.50 diopters. Description Inclusion Criteria: Subjects age 21 and older with healthy eyes. Nearsightedness between -7.50 diopters and -7.00 diopters with or without astigmatism of up to 3.50 diopters. Exclusion Criteria: Subjects under the age of 21. Patients with excessively thin corneas. Patients with topographic evidence of keratoconus. Patients with autoimmune diseases. Patients who are pregnant or nursing. Patients must have similar levels of nearsightedness in each eye. They can not be more than 3.0 diopter of difference between eyes. Patients must have similar levels of astigmatism in each eye. They can not have more than 4.0 diopters of difference in nearsightedness or astigmatism between their two eyes. Study Plan This section provides details of the study plan, including how the study is designed and what the study is measuring. How is the study designed? Design Details Observational Models : Case-Control Time Perspectives : Prospective What is the study measuring? Primary Outcome Measures Outcome Measure Time Frame Changes in best corrected visual acuity Time Frame: 12 months 12 months Changes in 5 and 25% contrast visual acuity Time Frame: 12 months 12 months Refractive predictability Time Frame: 12 months 12 months Uncorrected visual acuity Time Frame: 12 months 12 months Secondary Outcome Measures Outcome Measure Time Frame Changes in higher order aberrations Time Frame: 1 yr 1 yr Quality of vision measurement Time Frame: 1 yr 1 yr Topographic analysis Time Frame: 1 yr 1 yr Collaborators and Investigators This is where you will find people and organizations involved with this study. Sponsor Edward E. Manche Publications and helpful links The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study. General Publications Sales CS, Manche EE. One-year outcomes from a prospective, randomized, eye-to-eye comparison of wavefront-guided and wavefront-optimized LASIK in myopes. Ophthalmology. 2013 Dec;120(12):2396-2402. doi: 10.1016/j.ophtha.2013.05.010. Epub 2013 Jun 15. Study record dates These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website. Study Major Dates Study Start (Actual) April 6, 2010 Primary Completion (Actual) April 30, 2012 Study Completion (Actual) April 30, 2012 Study Registration Dates First Submitted June 3, 2010 First Submitted That Met QC Criteria June 4, 2010 First Posted (Estimate) June 7, 2010 Study Record Updates Last Update Posted (Actual) December 8, 2021 Last Update Submitted That Met QC Criteria November 24, 2021 Last Verified November 1, 2021 More Information Terms related to this study Keywords Wavefront-guided LASIK. Wavefront-optimized LASIK. Custom LASIK Additional Relevant MeSH Terms Eye Diseases Refractive Errors Astigmatism Other Study ID Numbers SU-05272010-6188 Stanford Protocol # 18692 This information was retrieved directly from the websiteclinicaltrials.govwithout any changes. If you have any requests to change, remove or update your study details, please [email protected]. As soon as a change is implemented onclinicaltrials.gov, this will be updated automatically on our website as well. Clinical Trials on Astigmatism NCT05844397 Not yet recruiting SMILE vs. LASIK Using Contoura With Phorcides Astigmatism Myopia NCT05829980 Not yet recruiting Contoura vs Wavefront Optimized Ablation Astigmatism NCT05796674 Not yet recruiting Clareon IOL Retrospective Data Collection Astigmatism Aphakia NCT05796453 Not yet recruiting Post Market Clinical Follow-up (PMCF) Study of Clareon Vivity & Clareon PanOptix Presbyopia Astigmatism Aphakia NCT05750862 Recruiting Accuracy of Topography Guided Automatic Marking of the Intraocular Lens (IOL) -Axis Cataract Senile Astigmatism NCT05740293 Recruiting Post-approval Study of New Enrolment Patients Undergoing Bilateral Treatment With the VisuMax SMILE Procedure Astigmatism Myopia NCT05713253 Recruiting A PHASED, PROSPECTIVE, MULTI-CENTER STUDY OF THE ELITA SYSTEM Refractive Error NCT05684237 Not yet recruiting Using the VisuMax Femtosecond Laser System to Perform SMILE Optimized for Presbyopia by Modulation of Postoperative Spherical Aberration NCT05670626 Recruiting Correlation Between Preoperative Refraction and Anterior Segment Parameters With ICL Vault Refractive Errors Myopia Myopic Astigmatism NCT05629078 Not yet recruiting Vision and Balance Changes After Bilateral Implantation of Toric IOLs Cataract Bilateral Astigmatism Bilateral Clinical Trials on Wavefront-guided LASIK NCT05588882 Active, not recruiting Wavefront-guided vs. Topography-guided LASIK Myopia NCT01135719 Completed A Comparison of Fellow Eyes Undergoing LASIK or PRK With a Wavefront-guided Excimer Laser Versus a Wavefront-optimized Excimer Laser Astigmatism Myopia Hyperopia NCT01454843 Completed LASIK Using the Alcon Allegretto Wavefront-Guided Excimer Laser vs AMO Visx Wavefront-Guided Excimer Laser (LASIK) Astigmatism Myopia Wavefront-guided Photorefractive Keratectomy (PRK) Versus Wavefront-guided Lasik for Myopia Astigmatism Myopia NCT00366743 Completed Evaluation of Visual Outcomes After Myopic LASIK Astigmatism Myopia Myopic Astigmatism NCT00366769 Completed Evaluation of Outcomes Following LASIK Surgery Using CustomVue Astigmatism Myopia Myopic Astigmatism
https://ichgcp.net/clinical-trials-registry/NCT01138189
The 33-bus network results with load factor µ = 0.75. | Download Table Download Table | The 33-bus network results with load factor µ = 0.75. from publication: A New Method for Distribution Network Reconfiguration Analysis under Different Load Demands | The strategies of distribution network reconfiguration are applicable for minimizing power loss and saving electrical energy in the distribution system. Network reconfiguration is usually represented by constant load demand so ignoring the variability of load demand causes... | Distributed Systems, Patterns and Switches | ResearchGate, the professional network for scientists. The 33-bus network results with load factor µ = 0.75. A New Method for Distribution Network Reconfiguration Analysis under Different Load Demands The strategies of distribution network reconfiguration are applicable for minimizing power loss and saving electrical energy in the distribution system. Network reconfiguration is usually represented by constant load demand so ignoring the variability of load demand causes uncertainty and misleading results in the minimization of power loss. This p... Context in source publication Context 1 ... are four levels of load demand starting from µ = 0.75 to µ = 1.25 with step changes of 12.5%. Tables 4-7 show the switch set (s07, s09, s14, s32, s37) had minimum active power loss compared with other methods at different load levels. Table 3 shows the results of Case 1 at µ = 1. ... Optimal Allocation of Renewable Distributed Generation and Capacitor Banks in Distribution Systems using Salp Swarm Algorithm Recent advances in power generation technologies using renewable energy resources, changes in utility infrastructure and government policies tend to increase the interest in a renewable-based distributed generation units (DGs) in a distribution system. To obtain reduced power loss, voltage deviation and improved bus voltage stability in distributio... Citations ... On the other hand, a meta-heuristic methodology for network reconfiguration with demand variation is presented in [20, 21], aiming to minimize network losses while observing the operating constraints of system voltages, currents, and the final topology. This methodology includes, among other things, particle swarm optimization and an improved coyote optimization algorithm. ... Optimal Load Redistribution in Distribution Systems Using a Mixed-Integer Convex Model Based on Electrical Momentum This paper addresses the problem concerning the efficient minimization of power losses in asymmetric distribution grids from the perspective of convex optimization. This research’s main objective is to propose an approximation optimization model to reduce the total power losses in a three-phase network using the concept of electrical momentum. To obtain a mixed-integer convex formulation, the voltage variables at each node are relaxed by assuming them to be equal to those at the substation bus. With this assumption, the power balance constraints are reduced to flow restrictions, allowing us to formulate a set of linear rules. The objective function is formulated as a strictly convex objective function by applying the concept of average electrical momentum, by representing the current flows in distribution lines as the active and reactive power variables. To solve the relaxed MIQC model, the GAMS software (Version 28.1.2) and its CPLEX, SBB, and XPRESS solvers are used. In order to validate the effectiveness of load redistribution in power loss minimization, the initial and final grid configurations are tested with the triangular-based power flow method for asymmetric distribution networks. Numerical results show that the proposed mixed-integer model allows for reductions of 24.34%, 18.64%, and 4.14% for the 8-, 15-, and 25-node test feeders, respectively, in comparison with the benchmark case. The sine–cosine algorithm and the black hole optimization method are also used for comparison, demonstrating the efficiency of the MIQC approach in minimizing the expected grid power losses for three-phase unbalanced networks. ... The network reconfiguration problem can be formulated as a mixed-integer nonlinear programming (MINLP), which addresses the nonlinear nature of power losses. Some linearization strategies have been proposed in the literature, such as the linearization of the power flow [7], the power losses [4], [8], or the demand [9] . This paper uses a linearization of the power flow based on a load model approximating the power-voltage relationship to propose a dynamic reconfiguration method for application in an active distribution system. ... A Dynamic Reconfiguration Method based on a Deterministic Optimization Approach in Active Distribution Systems This article proposes a method for dynamic distribution network reconfiguration (DDNR) with distributed generation for loss reduction. Advantages and conceptual principles of a deterministic optimization method are exposed, which allows the minimization of technical power losses in distribution systems based on a linear approximation of the loads. In this work is proposed the application of this approach for the modelling of distributed generation sources, obtaining a mathematical formulation that exploits mixed-integer nonlinear programming in solving the optimal reconfiguration problem. The DDNR method is implemented in an automatic tool integrating OpenDSS and GAMS software. IEEE69-Bus test system is considered to demonstrate the effectiveness of the technique. Dynamic results are obtained by implementing the optimal reconfiguration strategy, making the dynamic adjustments of the mathematical modelling in the face of variations in distributed generation and demand profiles. The results reveal schemes that range from one to twenty-four daily control actions. ... For this case, the whole Q loss increases from 302.26 kVAR to 428.9 kVAR, while the percentage increase of total Q loss is 41.90%. Optimal DG sizes are found as [71] 0.9706 0.9450 ITS [72] 0.9686 0.9420 SLR [73] 0.9684 0.9420 PSO [68] 0.9556 0.9254 MPSO [68] 0.9684 0.9453 Proposed HHO 0.9843 0.9417 Figure 9(a) illustrates the bus voltage magnitude of 33-bus RDN with and without considering the deployment of two DGs for the autumn load. e bus voltage magnitude is upgraded from 0.87025 (per unit) to 0.89229 (per unit). ... ... For this case, the whole Q loss increases from 302.26 kVAR to 428.9 kVAR, while the percentage increase of total Q loss is 41.90%. Optimal DG sizes are found as [71] 0.9706 0.9450 ITS [72] 0.9686 0.9420 SLR [73] 0.9684 0.9420 PSO [68] 0.9556 0.9254 MPSO [68] 0.9684 0.9453 Proposed HHO 0.9843 0.9417 Figure 9(a) illustrates the bus voltage magnitude of 33-bus RDN with and without considering the deployment of two DGs for the autumn load. e bus voltage magnitude is upgraded from 0.87025 (per unit) to 0.89229 (per unit). ... ... International Transactions on Electrical Energy Systems Loss Reduction (%) ACO-ABC [35] BA [36] HA [37] HGWO [38] EMA [29] SPEA2 [40] SSA [42] GSA-GAMS [31] GA [47] CSCA [78] QOCSOS [44] IHSA [51] PPA [72] Proposed HHO Algorithm vmin (per unit) PLOSS Reduction (%) Proposed HHO PPA [72] GA [77] PSO [77] GA/PSO [77] HSA [68] BFOA [79] ABC [68] SSA [42] WCA [82] HGWO [84] 1. Proposed HHO PPA [72] GA [77] PSO [77] GA/PSO [77] HSA [68] HSA [33] BFOA [79] BFOA [34] ABC [68] SSA [42] FWA [43] SFLA [43] SSA [42] WCA [82] WCA [82] HGWO [38] HGWO [84] 1. RDN, the ANOVA test has been carried out between fourteen (14) algorithms, while for IEEE 69-bus RDN, the test has been performed between twenty (20) algorithms. e value of F for both RDNs is less than the critical level. ... 8640423 (2) ... For this case, the whole Q loss increases from 302.26 kVAR to 428.9 kVAR, while the percentage increase of total Q loss is 41.90%. Optimal DG sizes are found as [71] 0.9706 0.9450 ITS [72] 0.9686 0.9420 SLR [73] 0.9684 0.9420 PSO [68] 0.9556 0.9254 MPSO [68] 0.9684 0.9453 Proposed HHO 0.9843 0.9417 Figure 9(a) illustrates the bus voltage magnitude of 33-bus RDN with and without considering the deployment of two DGs for the autumn load. e bus voltage magnitude is upgraded from 0.87025 (per unit) to 0.89229 (per unit). ... ... For this case, the whole Q loss increases from 302.26 kVAR to 428.9 kVAR, while the percentage increase of total Q loss is 41.90%. Optimal DG sizes are found as [71] 0.9706 0.9450 ITS [72] 0.9686 0.9420 SLR [73] 0.9684 0.9420 PSO [68] 0.9556 0.9254 MPSO [68] 0.9684 0.9453 Proposed HHO 0.9843 0.9417 Figure 9(a) illustrates the bus voltage magnitude of 33-bus RDN with and without considering the deployment of two DGs for the autumn load. e bus voltage magnitude is upgraded from 0.87025 (per unit) to 0.89229 (per unit). ... ... International Transactions on Electrical Energy Systems Loss Reduction (%) ACO-ABC [35] BA [36] HA [37] HGWO [38] EMA [29] SPEA2 [40] SSA [42] GSA-GAMS [31] GA [47] CSCA [78] QOCSOS [44] IHSA [51] PPA [72] Proposed HHO Algorithm vmin (per unit) PLOSS Reduction (%) Proposed HHO PPA [72] GA [77] PSO [77] GA/PSO [77] HSA [68] BFOA [79] ABC [68] SSA [42] WCA [82] HGWO [84] 1. Proposed HHO PPA [72] GA [77] PSO [77] GA/PSO [77] HSA [68] HSA [33] BFOA [79] BFOA [34] ABC [68] SSA [42] FWA [43] SFLA [43] SSA [42] WCA [82] WCA [82] HGWO [38] HGWO [84] 1. RDN, the ANOVA test has been carried out between fourteen (14) algorithms, while for IEEE 69-bus RDN, the test has been performed between twenty (20) algorithms. e value of F for both RDNs is less than the critical level. ... Optimal Placement and Sizing Problem for Power Loss Minimization and Voltage Profile Improvement of Distribution Networks under Seasonal Loads Using Harris Hawks Optimizer Abdul Khalique Junejo Improving efficiency with sustainable radial distribution networks (RDNs) is challenging for larger systems and small grid-connected RDNs. In this paper, the optimal placement of DGs with the Harris hawks optimizer (HHO) under seasonal load demands is proposed to simultaneously reduce total active and reactive power losses and minimize bus voltage drops with the consideration of operational constraints of RDNs. HHO is a newly inspired metaheuristic optimization algorithm primarily based on the Harris hawks’ intelligent behaviors during the chasing of the prey. Furthermore, the authors have investigated four stages of DGs. The first stage involves the optimal allocation of one DG. The second stage includes an investigation with two DGs, the third stage considers three DGs, and the fourth stage investigates the integration of four DGs. The effectiveness of the applied HHO is validated on IEEE 33 and 69 bus RDNs, and results are analyzed by comparing with the standard optimization methods. The Big-O test is also executed for statistical analysis with standard algorithms. The simulation results reveal the better performance of the applied HHO under different circumstances than other algorithms. Furthermore, the total active and reactive power losses and bus voltage drops are improved by adding more DGs into IEEE 33 and 69 bus RDNs. ... The method included constraints on node voltages, feeder currents and radiality of the network. 8 The PSO was applied in solving the NWR problem with a goal of lowering the APL. The method adapted a tree algorithm controlling the solution improvisation process with a view of enhancing the exploration during search with reduced computations. ... Modified rainfall optimization based method for solving distributed generation placement and reconfiguration problems in distribution networks This article formulates the distribution generation placement and the network reconfiguration problems of distribution networks (DNs) as a composite multi-objective optimization problem by normalizing and combining the objective functions, and suggests a new rainfall optimization (RFO) based method for solving the developed problem. The RFO, a metaheuristic optimization algorithm that models the behavior of raindrops falling down from a hill towards sea, has certain drawbacks such as removal of inactive raindrops that weakens the search process, and the possibility of choosing the same raindrop as inactive throughout the iterative process. This article also introduces modifications in the RFO for overcoming its drawbacks before adopting it in the proposed method. It considers two scenarios with seven test cases for simulation study, and compares the results of two standard DNs with existing methods for exhibiting the superior performances in respect of final solution, robustness, voltage profile, and average execution time of the proposed method. ... A method combining small population PSO and dynamic neighborhood PSO with Pareto optimization was proposed to improve the performance of ship power system fault reconfiguration in Wang et al. [25]. A modified PSO was proposed with a gradually decreasing inertia factor, and a learning factor consisting of a normalized random number [26] . Results show that the algorithm improves the performance of the distribution network reconfiguration. ... A fault reconfiguration strategy based on adjustable space operator discrete state transition algorithm for ship microgrid system Tengfei Zhang Saifeng Huang As an independent power supply network, when the ship ring microgrid system (SRMS) fails or is damaged, the power-loss load can be reasonably distributed to other power sources through the control switch, thereby improving the reliability of the power grid. We consider the maximum power load, minimum switching action and generator efficiency as the reconfiguration goals. In order to complete the reconfiguration quickly, we present an optimization strategy based on an adjustable space operator (ASO) and the discrete state transition algorithm (DSTA), the ASODSTA. The main idea of DSTA is to use four spatial geometric operators to find the optimal solution. The optimization is completed by combining the operators with the sigmoid function, and an ASO is proposed as the variable of the sigmoid function. The spatial distribution of the candidate solutions is more widespread through the unification of the four operators. The introduction of the sigmoid function and the ASO improves the quality of the global optimal solution and shortens the running time of the algorithm. The simulation results show that the proposed method can solve the SRMS reconfiguration problem faster and more effectively by comparing with the algorithms EO, WOA, GWO and BPSO in the references. ... [117]. In this context, SGs analysis and optimization was extended to consider time-dependent loads in a wide energy-based assessment [118] . Furthermore, the growth of EDN electronic automation is performing for the DNO the possibility of switching from one to another configuration more easily than in the past. ... Pitch Angle Control of the PMSG Wind Turbine The applications of wind generation progress are faster than any other renewable energy. During this rapid development of the wind power, the majority of the wind turbines has been operated with diverse generators. One way to generate an efficient power is to control the pitch angle of the wind turbine. This paper aims at studying the pith angle and turbine management control strategy with Permanent Magnet Synchronous Generator-based different conditions. This research has investigated a model of the PMSG Wind Turbine Pitch Angle Control technique. Three different controllers namely: no controller, PI and PID control techniques are compared. On the other hand, the PID parameters have been adjusted. A PI/ PID pitch angle controller is studied in this paper to ensure the stability of mechanical torque and response of wind power. The model is implemented in MATLAB/SIMULINK software to investigate the outlined concept and control strategy. The simulation with PID controller shows good result when comparing with the others cases of study, in terms of the advanced stability of the parameters. ... The DN distributes the power from the substation to various consumers using distribution lines and distribution transformers (DTRs). In designing a DN of a power grid, the line length should be short because a long line means more technical power losses due to the high current at a low voltage level [7] . However, in some rural areas, the three-phase DTRs supply the consumers through long distribution lines due to the long distances between consumers. ... [7, 20]. The line reconfiguration method improves the voltage profile at both the LV and MV sides of the DN. ... ... The discussed technologies presented in the literature and their technical/economic gaps are also clarified in Table 1. [17,18] Line reconfiguration The need for an active network and real-time communications [7, 20] Injecting the reactive power via FACTS High initial cost [22,23] Using solid-state transformers Low efficiency, more harmonics [24,26] Restructuring the cross-section area of LV conductors Low voltage improvement at the tail end [9] Converting LV system to MV system The presented studies did not consider the economic feasibility [27,28] ... Voltage Profile Enhancement and Power Loss Reduction with Economic Feasibility Using Small Capacity Distribution Transformers Firas M. F. Flaih ... These research goals that can be satisfied by network reconfiguration are the decrease of power loss and enhancing the voltage profile, taking into account limitations and dissimilar scenarios of load variations. The objective function used to calculate the smallest value of the overall active power losses is illustrated in Eq. (6) [13] . (6) Where : control variable vector; : tie switch state; switch. ... ... A constant load model may be defined as a polynomial load representing the power relationship to voltage magnitude and frequency [19]. As shown in Eq. (12) and (13) , the general structure of a load model comprising of actual and reactive power reliance on voltage and frequency is: ... Analysis of Distribution System Reconfiguration under Different Load Demand in AL-KUT City by using PSO Algorithm ... Al-Mahroqi, 2012).The network reconfiguration method is one such method that is proven to be effective and reliable (Napis, Khatib, Hassan, & Sulaima, 2018). The distribution network reconfiguration and re-settlement is a complex combinational work that contains the optimization process; aimed at finding a radial operating structure and minimizes the system power loss while satisfying operating constraints (Flaih et al., 2017; Rao, Ravindra, Satish, & Narasimham, 2012). With the advent of highly capable computers,a requirement of high computing power and complex decision-making process (Shilpa Kalambe, 2013) for network reconfiguration can now be easily fulfilled. ... Performance Enhancement of Radial Distribution System via Network Reconfiguration: A Case Study of Urban City in Nepal Increasing unplanned energy demand has led to network congestion, increased power losses and poor voltage profile. To decrease these adverse effects of an unmanaged power system, distribution network reconfiguration provides an effective solution. This paper deals with improving the power losses and poor voltage profile of the Phulchowk Distribution and Consumer Services (DCS) via the implementation of an optimum reconfiguration approach using Genetic Algorithm (GA). The developed algorithm is firstly put into work on the IEEE 33 bus system to improve its voltage profile and the poor power losses. The effectiveness of the developed system is validated as it reduced the voltage drop by 5.66% and the power loss by 25.96%. The algorithm is further implemented on Pulchowk DCS. Without overhauling the entire network, a better reconfiguration of the present network is provided which can be realized with the reconfiguration or allocation of tie-switches and sectionalizing switches within the network.After reconfiguring the system in different individual cases, optimum network reconfiguration is selected that improved the voltage profile and the active and reactive power losses when compared to the base case scenario.
https://www.researchgate.net/figure/The-33-bus-network-results-with-load-factor-075_tbl2_315934493
Remarks at a Meeting on Women in Health Care | The American Presidency Project Remarks at a Meeting on Women in Health Care The President.Well, thank you very much. I appreciate you being here. It's a great honor, very great honor. I want to thank Vice President Pence, Secretary Tom Price, and Administrator Seema Verma—who's done an incredible job, by the way—for all of the time and energy they've put into repairing and replacing Obamacare ahead of tomorrow's crucial vote. Big vote tomorrow in the House. I want to especially thank Seema, the Administrator of the Centers for Medicare and Medicaid Services—a wonderful job she's doing and definitely a complex job, but you have it under control, right—[ laughter]—for hosting this very important meeting to discuss the vital role women play in health care and the hardships inflicted on them by the Obamacare catastrophe. It's been bad. Administrator Seema Verma is playing the leading role for us in helping us to repeal and replace Obamacare. The doctors, nurses, and health care professionals here today represent the millions of women—millions and millions—who play a vital and indispensable role in Americans' health care. Unfortunately, Obamacare is making their lives so much more difficult, as we all know, and putting enormous barriers in the way of helping patients who we are going to help. We're going to get this thing done. We're going to get it figured out. It's a tough situation our country has been put in. It's not easy. Women doctors and health care leaders have changed the face of health care in America, saving and improving countless American lives. In 1965, only 9 percent of accepted medical school applicants were women—9 percent. Last year, nearly 50 percent of newly accepted applicants were women. Congratulations. Good job. It's a good job. Thirty-eight percent of physicians and surgeons are women, and that number will continue to grow. That's a big victory for our society, big victory for America. I want to also thank all of the women nurses and health care aides for their incredible service and dedication to our country. What you do is remarkable. Unfortunately, Obamacare is making it much harder for all of the doctors, nurses, and health care professionals—men and women alike—to do their job. As insurers flee Obamacare's broken marketplace—and it is broken, it's broken badly; the insurance companies are fleeing—millions of patients can no longer access the health care professionals the know and trust. That was "keep your doctor, keep your plan"—didn't work out that way. You don't get your doctor; you don't get your plan. So that is one of the more vital reasons why we must repeal Obamacare. It's one of the reasons why we're here today. So with that, I want to turn it over to Administrator Verma, and we'll start a meeting. Centers for Medicare and Medicaid Services Administrator Seema Verma.Thank you. The President.Thank you very much. You could probably do it and stay for this little while, and then, we'll clear out the room and talk, okay? Administrator Verma.Sounds great. The President.Go ahead. Administrator Verma.Well, thank you, Mr. President. The President.Thank you. Administrator Verma.Appreciate it. This gentleman has been very supportive as I started my position at CMS, and I am very appreciative to be a part of this great health care team. The President.Thank you. Administrator Verma.And thanks to all the women that came today. It's great to see so many strong, professional women that are on the frontlines of healthcare. So thanks again for coming today. Obamacare has just been a broken promise. Instead of meaningful health care, we have higher costs, less choices, and more mandates. Right now we have the Government that's making decisions about our health care, not patients and not doctors. As a mother and as a woman, the most important thing about my health care is being able to pick out the doctor that I feel comfortable with, but unfortunately, with Obamacare, we have less choices. And I think the other thing that concerns me is hearing from providers. Many providers are faced with dealing with regulations and mandates instead of focusing on high-quality care and spending time with their patients. They are forced to deal with regulations. And I came to DC because I was so concerned about the direction our health care was going in because of Obamacare. I want to be a part of the solution. I'm very excited about the American Health Care Act, if there's a vote on that tomorrow. I think this is an opportunity for us to finally get rid of Obamacare and move towards a system that's going to drive costs down, give Americans more choices, and put patients and doctors in control of their health care. So once again, thank you for coming today. And I look forward to hearing all the stories. Thank you. The President.Thank you very much. NOTE: The President spoke at 11:24 a.m. in the Roosevelt Room at the White House. In his remarks, he referred to Secretary of Health and Human Services Thomas E. Price. Also participating in the meeting were National Economic Council Director Gary D. Cohn; State Sens. Donna Campbell and Dawn Buckingham of Texas; Steffany Williams, chairwoman, Novant Health Professional Nurses Council; Lina Varela-Gonzalez, director of nursing, Novant Health Presbyterian Medical Center Emergency Department; and Parmis Khatibi, anticoagulation/antithrombotic and tobacco treatment specialist, University of California—Irvine Medical Center. Donald J. Trump, Remarks at a Meeting on Women in Health Care Online by Gerhard Peters and John T. Woolley, The American Presidency Project https://www.presidency.ucsb.edu/node/326450 Filed Under Categories Presidential Spoken Addresses and Remarks Location Washington, DC
https://www.presidency.ucsb.edu/documents/remarks-meeting-women-health-care
(PDF) UNIVERSITAS CATHOLICA RU MBEROK Ž O PDF | This article discusses the importance of ethical aspects in the work of social services/personal assistants with regard to the applicability of... | Find, read and cite all the research you need on ResearchGate September 2020 Authors: Lukáš Stárek Univerzita Jana Amose Komenského Praha Download full-text PDF Read full-text Download citation Copy link Link copied Read full-text Download citation Copy link Link copied References (54) Abstract This article discusses the importance of ethical aspects in the work of social services/personal assistants with regard to the applicability of the Ethical model for decision making. Main purpose of the text is research of the influence of social service workers, especially personal assistents with ethical code. How is ethical code useable while dealing with ethical dilemmas in relation to the performance of this profession. Further we search for familliarity with Ethical model for decision making between those assistents. In their almost daily routine, personal assistents are facing particular ethical questions. Their realization, searching for answers and wondering about the questions in general requires neccesary care and time. It leads to the importance and influence of the Ethics that might be possibly flouted. Reflection of ethical aspects may contribute to improvment of provided social services, more precisely to professionalism of the profession or strengthening professional competencies. Discover the world's research 25+ million members 160+ million publication pages 2.3+ billion citations Join for free Public Full-text 1 Content uploaded by Lukáš Stárek Author content All content in this area was uploaded by Lukáš Stárek on Jun 28, 2022 Content may be subject to copyright. S T U D I A S C I E N T I F I C A F A C U L T A T I S P A E D A G O G I C A E / / 3 2020 U N IV E R S I TA S C A TH O L I C A R U M B ER O K Ž O S T U D I A S C I E N T I F I C A F A C U L T A T I S P A E D A G O G I C A E / / r 3 2020 oční k XIX. / / r 3 2020 oč ní k XIX. ISSN 1336-2232 9 7 7 1 3 3 6 2 2 3 0 0 5 6 0 KATOLÍCKA UNIVERZITA V RUŽOMBERKU STUDIA SCIENTIFICA FACULTATIS PAEDAGOGICAE UNIVERSITAS CATHOLICA RUŽOMBEROK Ružomberok 2020 STUDIA SCIENTIFICA FACULTATIS PAED AGOGIC AE UNIVERSITAS CATHOLIC A RUŽOMBEROK Vedecký recenzovaný časopis Číslo 3, jún 2020, ročník 19. Vychádza 5 - krát do roka. Šéfredaktor: doc. PaedDr. Tomáš Jablonský , PhD. – Catholic University in Ružomberok (Slovakia) Medzinárodná redakčná rada: prof. PaedDr. Pavel Doulík , PhD. – J. E. Purkyně University in Ústí nad Labem (Czech Republic) prof. PhDr. Ingrid Emmerová , PhD. – Catholic University in Ružomberok (Slovakia) doc. PaedDr. PhDr. Miroslav Gejdoš , PhD. – Catholic University in Ružomberok (Slovakia) doc. PhDr. Ladislav Horňák , PhD . – The University of Prešov (Slovakia) prof. PhDr. Jolana Hroncová , CSc. – Matej Bel University in Banská Bystrica (Slovakia) prof. PaedDr. Anna Hudecová , PhD. – Catholic University in Ružomberok (Slovakia) prof. dr hab. Stanislaw Juszczyk , PhD. – Catholic University in Ružomberok (Slovakia) doc. PaedDr. Barbora Kováčová , PhD. – Catholic University in Ružomberok (Slovakia) doc. PhDr. Vladimír Klein , PhD. – Catholic Universi ty in Ružomberok (Slovakia) prof. PaedDr. Milan Ligoš , CSc. – Catholic University in Ružomberok (Slovakia) dr hab. Piotr Mazur – Pa ństwowa Wyższa Szkoła Zawodowa in Chełmie (Poland) prof. Pradeep Kumar Misra , PhD. – Chaudhary Charan Singh University (India) prof. Bart McGettrick – Liverpool Hope University (United Kingdom) prof. dr hab. Marian Nowak – Catholic University of Lublin (Poland) prof. PhDr. Erich Petlák , CSc. – Catholic University in Ružomberok (Slovakia) prof. PhDr. Mária Pisoňová , PhD. – Constantine the Philosopher University in Nitra (Slovakia) prof. PhDr. Mária Potočárová , PhD. – Comenius University in Bratislava (Slovakia) prof. dr. Gabriella Pusztai – University of Debrecen (Hungary) prof. PhDr. Karel Rýdl , CSc. – University of Pardubice (Czech Republic) doc. PhDr. Albín Škoviera , PhD. – University of Pardubice (Czech Republic) prof. Juan Carlos Torre Puente – Universidad Pontificia Comillas Madrid (Spain) prof. PaedDr. Milan Valenta , PhD. – Palacký University Olomouc (Czech Republic) prof. PhDr. Miron Zelina , DrSc. – DTI University in Dubnica nad Váhom (Slovakia) Za jazykovú a štylistickú úroveň príspevkov zodpovedajú ich autori. Výkonný redaktor : PaedDr. Ján Gera, PhD. Obálka: doc. akad. mal. Pavol Rusko, ArtD. EV 4416/11 Katolícka univerzita v Ružomberku © VERBUM – vydavateľstvo Katolíckej univerzity v Ružomberku Hrabovská cesta 5512/1A, 034 01 Ružomberok IČO: 37 -801-279 ISSN 1336-2232 Obsah Predhovor Ján Gera ........................................................................................................ 5 Motivace frekventantů celoživotního vzděláván í pro výkon učitelské profese Kamil Janiš ml., Kamil Janiš st. ................................................................... 7 Oblasť environmentálnej výchovy u det í školského veku Mária Šoltésová, Lucia Dimunová ............................................................. 18 Míra významnosti pastorace mládeže v postupu jící sekularizaci české společnosti René Strouhal ............................................................................................. 23 Príčiny školského podvádzania Gabriela Gabrhelová, Dáša Porubčanová ................................................... 34 Etický model rozhodování se jako pro fesní nástroj Lukáš Stárek ............................................................................................... 42 Tri piliere kvalitatívnej transformácie výučby materinského jazyka I. (Rámcové východiská) Milan Ligoš ................................................................................................ 58 Fröbelova teória hry a jej relevancia pre súč asné vzdelávanie detí mladšieho školského veku Miroslav Gejdoš, Ivana Prachárová ........................................................... 73 Inštitucionálna príprava a vzdelávanie učit eliek v Košiciach do roku 1938 Miroslava Gallová ...................................................................................... 83 Zmeny a reformy slovinského vzdelávaci eho systému od roku 1991 po súčasnosť Alexandra Punčová .................................................................................. 102 Kooperatívne učenie ako prostriedok napĺňania filozofie inkluzívnej edukácie Zdenka Zastková ...................................................................................... 108 Recenzie ........................................................................................................ 114 Contents Preface Ján Gera ........................................................................................................ 6 Motivation of Lifelong Learning Trainees for the Teaching Profession Kamil Janiš ml., Kamil Janiš st. ................................................................... 7 The Area of Environmental Education o f Children of School Age Mária Šoltésová, Lucia Dimunová ............................................................. 18 The Importance of Youth Pastoral Work in the Progressive Secularization of Czech Society René Strouhal ............................................................................................. 23 Causes of School Cheating Gabriela Gabrhelová, Dáša Porubčanová ................................................... 34 Ethical Model for Decision Making as a Professional Tool Lukáš Stárek ............................................................................................... 42 Three Pillars of Qualitative Transformat ion of Teaching of Mother Tongue I. (Framework Starting Points) Milan Ligoš ................................................................................................ 58 Froebel's Theory of Play and its Relevance for the Teaching of Children of Younger School Age Mirosla v Gejdoš, Ivana Prachárová ........................................................... 73 Institutional Training and Education of Wo men Teachers in Košice by 1938 Miroslava Gallová ...................................................................................... 83 Changes and Reforms of the Slovenian Education S ystem from 1991 to the Present Alexandra Punčová .................................................................................. 102 Cooperative Learning as a Means of Achieving the Philosophy of Inclusive Education Zdenka Zastková ...................................................................................... 108 Critiques ....................................................................................................... 114 STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 5 Pr edhovor Tret ie tohtor očné čís lo vedec kého čas opisu „S tudia Sci entific a Facult atis Paedagogicae Universitas Catholica Ružomberok“ ponúka pestrú paletu štúdií na relevantné pedagogické témy. Kam il Janiš ml. a Kam il Janiš st. sa zaobera jú motivá ciou frek venta ntov celoživotného vzdelávania pre výkon učiteľskej profesie. Mária Šoltésová a Lucia Dimunová približujú výsledky prieskumu, ktorý realizovali v rámci environmentálnej výchovy u žiakov druhého stupňa základnej šk oly. René Strouhal sa venuje miere v ýznamnosti pastorácie mládeže v postupujúcej sekularizácii českej spoločnosti . O príčinách školského podvádzania píšu Gabriela Gabrhelov á a Dáša Porubč anová. Luk áš Stárek pojed náva o dôlež itosti etických aspektov v práci pracovníkov v sociálnych službách s ohľadom na využiteľnosť Etického modelu rozhodovania sa. Milan Ligoš približuje rámcové východiská kvalitatívnej transform ácie výučby materinského jazyka v európskom v zdelávacom priestore. Miroslav Gejdoš a I vana Prachárová prezentujú analýzu teórie hry proponovanú významným nemeckým klasickým pedagógom Friedrichom Fröbelom a dokumentujú jej prínos pre súčasné primárne vzdelávanie. Miroslav a Gallová predstavuje vzdelávanie dievčat a žien a ich prípravu na povolanie učiteľky na viacerých učiteľských ústavoch v K ošicia ch do rok u 1938. A lexan dra Pun čová sa sú streďu je na zm eny a ref ormy slovinského vzdelávacieho systému za posledných 30 rokov, respektíve od osam ostat nenia k rajiny po s účasno sť. Zd enka Z astkov á spája inkl uzívnu eduká ciu s kooperatívnym učením. PaedDr. Ján Gera , PhD. Gera, J .: Preface 6 Pr eface Th e t hird issue of th e sci entifi c jou rnal “ Studia Scie ntific a Fac ultati s Paedagogicae Universitas Catholica Ružomberok” of this year brings a varied palette of studies on relevant pedagogical topics. Kam il Ja niš Jr. a nd K amil Janiš Sr. deal with motivat ion of l ifelong lear ning at tendan ts for th e teachi ng prof ession . Mária Šoltésová and Lucia Dimunová introduce the results of the research they implemented within environmental education of second ary school pupils. René Strouhal deals with the impor tance of pastoral care of youth in the time of advanc ing secularizati on of the Czech society. T he causes of school cheating are discussed by Gabriela Gabrhelová and Dáša Porubčanová. Lukáš Stá rek writes about the importance of ethical aspects in the work of social services workers with regard to usability of the Ethical model for decision making. Milan Ligoš describes the framework starting points of the q ualitative transformation of teaching the mother t ongue in European educational b ackground. Miroslav Gejdoš and Ivana Prachárová present the analyses of the game theory proposed by the disting uished classical Germ an pedagogue Friedrich Fröbe l and they do cument its contribut ion to the curre nt pri mary educa tion. Mirosla va Gallová introduces education of girls and w omen and their trai ning for teaching profession at several teaching institutions in Košice since 1938. Alexandra Punčová focus es on the changes and reform s of Slovenian educational system in the last 30 years, or in other wo rds – since country independence up to present day. Zdenka Zastková conjoins inclusive education w ith cooperative learning. PaedDr. Ján Gera , PhD. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 7 Motivace frekventan tů celoživotního vzděláván í pro výkon učitelské profese Motivation of Lifelong Learning Traine es for the Teaching Profession Kamil Janiš ml., Kamil Janiš st. Abstract The lack of teachers is one of the factors t hat threatens t he functioning of education. The paper deals w ith the presentation of data obtained from the trainees of the lifelong learning course, which will enable them to meet the qualification requirements for the teaching profession. The aim of our paper is to describe and d iscuss the data that describes the motives of respondents leading to the subject. Keywords: Teacher. Qualification. Study. Mo tivation. Úvod Česká republ ika se v současné době potýk á a v blízké budoucnosti stále potýkat bude, a to mnohem závažněji, s nedost atkem učitelů obecně a učitelů s konkrétními předm ětovými aprobacemi. Chybějící počet učitelů se pohybuje v řádech jednotek tisíc. Významným faktorem, který umožňuje velmi negativní predikci daného stavu je relativně vy soký věkový průměr učitelů, kdy více než polovina učitelů je starších 45 let ( Statistická ročenka MŠMT [online]; Hlavní výstupy z Mimořádného šetření ke stavu zajištění výuky učiteli v MŠ, ZŠ, SŠ a VOŠ [online]). Ministerstvo školství, mládeže a tělovýchovy (dále j en „MŠMT“) se tuto situaci s naží změnit tím, že uv olňuje nebo uvolníme podmínky pro uznání kvalifikace pro učitele, po siluje výuku na pedagogických fakultách jistými bonifikacemi (navýšením rozpočtu), zvyšováním platu učitelů. Tyto všechny podmínk y jsou tedy někter ými považová ny jako motivač ní pro to, aby vstoupi li do školského systému. V našem příspěvku jsme se zam ěřili na zjišťování důvodů, které vedli vybranou skupinu jedinců k tomu, aby si doplnili pedagogické vzdělání a splnili tak kvalifikační podmínky dané z ákonem. Domníváme se, že důvody, které k takovému kroku jedince vedou se následně projevu jí v praxi a v jeho kvalitě výuky. Cílem našeho příspěvku je popsat a diskutovat zjištěná data popisující motivy respondentů vedoucí k vý konu učitelské profese. Janiš ml., K., Janiš st., K.: Motivace frekventantů celoživotního vzdělávání pro výkon učitelské profese 8 Metodologie výzkumu a její limity Výzkumný vzorek byl tvořen frekventanty kurzu celoživotního vzděláv ání, jehož úspěšn é dokončení vede ke spln ění zákonných kva lifikačních předpok ladů pro v ýkon učitelské profese na střední škole. Celk em se výz kumu zúčastnilo 268 respondentů, z nic hž 254 bylo žen a 14 mužů. Z tohot o genderového nepoměru (který sice odpov ídá r ozložení ve školách základních) nebyly odpovědi porovnávány mezi jednotlivým i pohlavím i, ale na základě věkových skupin. Všichni respondenti měli magisterské vysokoškolské (neučitelské) vzdělávání, popř. jej dokončovali společně s daným kurzem celoživotního vzdělávání (dále jen CŽV) . V dotaz níku bylo vy užito škály Lik ertova typu . Respondenti odpovídali na 5 stupňové škále (6. možnost byla „neuvažoval/a jsem o tom“), zda je dané t vrzení motivovalo k tomu, aby se stali učitelem /učitelkami. K vy hodno cení a interp retaci dat by lo využit o tzv. znamén kové schém a. V tabulkách č. 3 až 14 je v jednotlivých polích tabulky vždy nej výše uvedena pozo rovan á č etnost , v z ávorc e po d ní vý sledek z- skóre a pod výsl edkem z - sk óre jsou uvedena znaménka z něj vyplývající. Tabulky č. 1 a 2 jsou interpretační pro vypočtené hodnoty z - skóre. Z konstrukce jednotlivých otázek a jejich znění vyplývá, že jsme nevyužili celkovou „šíři“ různorodých motivů, které mohou vést jednotlivce k tomu, aby se stal učitelem. Záměrně jsme vynechali otázky, které směřují na smysluplnost učitelské profese, jejího významu ve spol ečnosti, touhu člověka pozitivně působit na mladé lidi apod. Důvodem nebylo, že bychom takové „motivy“ nepovažovali za významné, v některých případech naopak“, ale chtěli jsme se zaměřit na „motivy“ nižší. Tato skutečnost vyplynulo z aktuální situace v České republice (viz výše), kdy j e učitelů všeobecně nedostatek, zvyšuje se jejich věkový průměr (srov. Skopalová, Janiš ml., 2017) a snahou ústředních orgánů (MŠMT) je přilákat do škol (všech stupňů) právě jedince, kte ří nevyst udoval i u čitelsk é studijn í program y a v s oučasn é d obě tedy nes plňují zákonné podmínky pro výkon dané profese. Předpokládáme tedy, ž e motivace těchto jedinců z počátku vychází či vy cházela z nižších pohnutek. Dalším limitem je skutečnost, že volbu povolání mohou ovlivnit i faktory, které jsme v rámci našich proměnných nezachytili. Dále pak j sou naše výsledky limitovány celkovou četností respondentů, kte rou rozhodně nelze pov ažovat za nízkou, ale u více t abulek a ve více polích tabulky je četnost příliš nízká na to, abychom mohli, sice platný, výsledek významněji generalizovat. Analýza výsledky Jednotlivé výsledky je vždy nutné posuzo vat a hodnotit v kontextu charakteristiky cílové skupiny. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 9 Tab. č. 1: Hodnota z - skóre s přiřazením znaménk a ZNAMÉNKO INTERVAL 0 -1,96 < z < 1,96 + 1,96 ≤ z < 2,58 + + 2,58 ≤ z < 3,30 + + + 3,30 ≤ z - -2,58 < z ≤ -1,96 - - -3,30 < z ≤ -2,58 - - - -3,30 > z (Chráska, 2007, s. 75) Tab. č. 2: I nterpretace znaménkového schématu ZNAMÉNKO INTERPRETACE 0 Mezi pozorovanou a očekávanou četností není statisticky významný rozdíl. + Pozorovaná četnost je významně větší než četnost očekávaná na hladině významnosti 0,05. + + Pozorovaná četnost je významně větší než četnost očekávaná na hladině významnosti 0,01. + + + Pozorovaná četnost je významně větší než četnost očekávaná na hladině významnosti 0,001. - Pozorovaná četnost je významně menší než četnost očekávaná na hladině významnosti 0,05. - - Pozorovaná četnost je významně menší než četnost očekávaná na hladině významnosti 0,01. - - - Pozorovaná četnost je významně menší než četnost očekávaná na hladině významnosti 0,001. (Chráska, 2007, s. 76) Janiš ml., K., Janiš st., K.: Motivace frekventantů celoživotního vzdělávání pro výkon učitelské profese 10 Tab. č. 3: Chtěl/a jsem být vždy učitelem/uč itelkou věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvažoval/a jsem o tom CELKEM do 24 0 (-1,781) 0 1 (-1,808) 0 14 (5,092) + + + 4 (-0,345) 0 2 (-1,321) 0 2 (-0,397) 0 23 25 - 30 9 (1,061) 0 13 (0,770) 0 15 (1,063) 0 12 (-0,033) 0 11 (-0,156) 0 0 (-3,122) - - 60 31 - 45 11 (-0,862) 0 25 (1,090) 0 17 (-2,079) - 22 (-0,545) 0 23 (0,171) 0 17 (1,480) 0 118 46 - 65 10 (1,119) 0 10 (-0,821) 0 8 (-1,934) 0 16 (0,879) 0 12 (-0,270) 0 11 (1,566) 0 67 CELKEM 30 49 54 54 51 30 268 S vědomím, že nikdo z dotazovaných nemá vystudovaný studijní program učitelství, tak není překvapující, že v tab. č. 3 převažuje jakási nerozhodnost a odpovědi, které signalizují, že dotazovaní nechtěl i bý t v ždy učiteli a učitelkam i. Z ajímavé jsou rozdíly v jednotliv ých věkových skupinách, kdy skupiny mladší jsou spíše nerozhodnější. Signifikantní je to zejména u nejmladší věkové skupiny. Tab. č. 4: Bylo to velké přání mých rodičů věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvažoval jsem o tom CELKEM do 24 0 (-0,935) 0 1 (-0,907) 0 3 (0,495) 0 7 (0,968) 0 9 (-0,346) 0 3 (0,171) 0 23 25 - 30 4 (1,615) 0 7 (0,584) 0 7 (0,465) 0 18 (1,606) 0 17 (-2,526) - 7 (-0,074) 0 60 31 - 45 3 (-0,658) 0 10 (-0,602) 0 11 (-0,363) 0 23 (-1,009) 0 54 (0,947) 0 17 (1,104) 0 118 46 - 65 2 (-0,196) 0 8 (0,715) 0 6 (-0,352) 0 12 (-1,015) 0 34 (1,569) 0 5 (-1,305) 0 67 CELKEM 9 26 27 60 114 32 268 Vliv rodičů na budoucí povolání dětí je nepopiratelný, a to vliv přímý i nepřímý. Není výjimkou, že v rodinách existuje i určitá učitelská tradice. Z výsledků z - skóre je zřejmé, že v celé tabulce (až na jednu výjimku) neexistují žádné statisticky významné rozdíly v rámci jednotlivých skupin. Z celkových četností ve sloupcích vyplývá, že rodina, resp. ze strany rodičů nebylo žádné velké přán í, aby se respondenti stali také učiteli. Opět tuto skutečnost lze přisoudit tomu, že mají vystudované jiné obory a dál e nebylo zjišťováno, jakou profesi vykonávají jejich rodiče. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 11 Tab. č. 5 : Studovat učitelství mi připadalo jednodu ché věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvažoval jsem o tom CELKEM do 24 0 (-1,221) 0 3 (-0,410) 0 4 (0,775) 0 7 (1,701) 0 5 (-1,038) 0 4 (0,030) 0 23 25 - 30 5 (1,047) 0 16 (2,545) + 9 (0,719) 0 12 (0,569) 0 14 (-1,518) 0 4 (-2,448) - 60 31 - 45 10 (1,818) 0 14 (-1,654) 0 15 (0,176) 0 17 (-1,195) 0 28 (-2,383) - 34 (4,486) + + + 118 46 - 65 0 (-2,301) 0 10 (-0,288) 0 5 (-1,395) 0 11 (-0,278) 0 37 (4,866) + + + 4 (-2,806) - - 67 CELKEM 15 43 33 47 84 46 268 U této otázky jejichž výsledky jsou uvedeny v tab. č. 5 musíme uznat, že m ohla vzbuzovat tzv. sociální žádoucnost odpovědi. Učitelstvím je v dané otázce myšlen předmětný kurz C ŽV. Za zajímavá považujeme u vybrané tabulky dat ve dvou polích, a to že nestarší věková skupina rozhodně nepovažuje studium za jednoduché. To lze vysvětlit nejen tí m , že získávané informace a celkový průběh studia považuje za obtížný, ale i tím, že jakékoliv studium považuje za obtížné, a to na z ákladě proměny kognitivních funkcí, i když docilita je celoživotní. Druhým zajímavým výsledkem je, že významná část druhé nejstarší věková skupiny nad daný m nepřemýšlela. Konstat ujeme, že je po zitivní, že respondenti spíš e nep ovažují studium za jednoduché. V opačn ém případě by to vedlo k devalvaci samotné učitelské profese. Uvedené konstatování je nut né konfrontovat s první větou našeho komentáře k dané tabulce. Tab. č. 6 : Být učitelem/učitelkou mi připadalo jednoduché věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvažoval jsem o tom CELKEM do 24 0 (-1,221) 0 3 (0,294) 0 3 (0,566) 0 6 (1,013) 0 7 (-0,018) 0 4 (-0,842) 0 23 25 - 30 5 (1,047) 0 9 (1,061) 0 5 (-0,406) 0 18 (2,665) + + 18 (-0,114) 0 5 (-3,325) - - - 60 31 - 45 8 (0,747) 0 11 (-0,862) 0 13 (0,645) 0 15 (-2,093) - 38 (0,506) 0 33 (1,125) 0 118 46 - 65 2 (-1,074) 0 7 (-0,224) 0 5 (-0,715) 0 10 (-0,821) 0 19 (-0,459) 0 24 (2,456) + 67 CELKEM 15 30 26 49 82 66 268 Janiš ml., K., Janiš st., K.: Motivace frekventantů celoživotního vzdělávání pro výkon učitelské profese 12 Výsledky v tab. č. 6 do jisté míry kopírují výsledky v t abulce předchozí. Otázka však neměla a nemá plnit funkci zjišťování tzv. lži - skóre. Byla zařazena z důvodu, že „představu“ o náročnosti studia si zpravidla každý nedokáže představit, popř. má danou „představu“ zprostředk ovanou. Avšak s rolí učitele, jeho chováním, přístupem se setká (až na naprosté výjimky způsobené ně jakým zdravotním postižením) každý z nás. V průběhu školní docházky se setkáváme s různými ty py učitelů. Z celkových výsledků je potěšující, že většině nepřipadá být učitelem jako jednoduché. Tento závěr však musíme opět konfrontovat s posledně uvedeným odstavcem u tab. č. 5. Tab. č. 7 : Tak trochu z „nouze cnost“ (naskytla se šance) věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvaž oval jsem o tom CELKEM do 24 0 (-0,988) 0 5 (1,364) 0 5 (0,959) 0 4 (2,013) + 7 (-2,228) - 2 (-0,046) 0 23 25 - 30 0 (-1,731) 0 6 (-0,710) 0 10 (0,430) 0 7 (1,568) 0 36 (1,301) 0 1 (-2,244) - 60 31 - 45 9 (2,985) + + 10 (-1,838) 0 11 (-2,283) - 6 (-1,134) 0 65 (0,719) 0 17 (2,772) + + 118 46 - 65 1 (-1,116) 0 13 (1,907) 0 14 (1,584) 0 2 (-1,512) 0 33 (-0,636) 0 4 (-0,988) 0 67 CELKEM 10 34 40 19 141 24 268 U učitelské prof ese je při výkonu pro fese relativně poznat nezájem o práci a její vykonávání jen z nutnosti obživy. Kraus (2014) mj. uvádí negativní typy pedagogů a zmiňuje typ tzv. lhostejného, který vykonává svou profesi jen z důvodu, že nějakou práci m ít musí. Z tab. č. 7 vyplývá , ž e sice v ětšina učitelů svou práci vyk onává nikoliv z nouze cnosti, ale z jiného důvodu, ale v ýznamná část naopak. Statis ticky významné rozdíly v jednotlivých polích j sou u četností, kde se setkáváme spíše s rozdílem v řádu jednotek. Zajímavá je zejména kategorie nejmladších učitelů, jejichž četnost i jsou relativně pra videlně rozlož eny. To nelze považ ovat za pozitivní signál do jejich budoucího pedag ogického působení. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 13 Tab. č. 8 : O učitele je všude zájem věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvažoval jsem o tom CELKEM do 24 2 (-1,922) 0 8 (0,289) 0 5 (0,151) 0 3 (1,625) 0 2 (0,089) 0 3 (0,883) 0 23 25 - 30 11 (-1,422) 0 22 (0,862) 0 21 (3,152) + + 3 (-0,228) 0 3 (-1,028) 0 0 (-2,629) - - 60 31 - 45 39 (2,562) + 29 (-2,337) - 22 (-0,675) 0 7 (0,212) 0 13 (1,485) 0 8 (-0,756) 0 118 46 - 65 16 (-0,324) 0 27 (1,662) 0 7 (-2,358) - 2 (-1,074) 0 4 (-0,771) 0 11 (2,827) + + 67 CELKEM 68 86 55 15 22 22 268 Otázka u tab. č. 8 byla do jisté míry podobná otázce p ředešlé, ale přesto z jejího znění cítíme, že takový motiv je pozitivnější, než výše uvedená z nouze cnost. Není, zde však dominance v k ategorické odpovědi rozhodně ano nebo rozhodně ne. V jednotlivých polích tabulky byly zazna m enány statisticky významné rozdíly mezi pozorovanou a očekávanou četností. Z výsledků si můžeme klást otázku, proč j e druhá nejmladší kategorie „nerozhodná“. Jednoznačnou odpověď jsme nenalezli. Tab. č. 9 : Učitelé mají velkou prestiž ve spol ečnosti věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvažoval jsem o tom CELKEM do 24 1 (-0,706) 0 4 (0,521) 0 6 (-0,333) 0 6 (-0,046) 0 5 (0,296) 0 1 (0,402) 0 23 25 - 30 5 (0,040) 0 13 (2,004) + 15 (-0,794) 0 20 (1,363) 0 6 (-2,091) - 1 (-0,681) 0 60 31 - 45 8 (-0,756) 0 9 (-2,601) - - 34 (-0,093) 0 33 (0,485) 0 28 (1,588) 0 6 (1,792) 0 118 46 - 65 8 (1,285) 0 11 (0,716) 0 23 (1,087) 0 12 (-1,838) 0 13 (0) 0 0 (-1,658) 0 67 CELKEM 22 37 78 71 52 8 268 Každý z nás chce vykonávat ve svém životě zaměstnání, které je společno stí uznávané . Domníváme se, že toto by mě lo být i jedním z určujících motivů pro to, když se někdo rozhodně stát se učitele m. Z tab. č. 9 vyplývá, že sami respondenti se nedomnívají, že by učitelská profese byla vnímána jako prestiž ní. St atisticky význam né roz díly se opě t v té to tabu lce objevují v polích, kde jsou rozdíly mezi pozorovanou a oček ávanou četností v rámci jednotek. Janiš ml., K., Janiš st., K.: Motivace frekventantů celoživotního vzdělávání pro výkon učitelské profese 14 Tab. č. 10 : Učitelům se neustále zvyšují platy věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvažoval jsem o tom CELKEM do 24 2 (-1,166) 0 4 (-0,683) 0 6 (0,039) 0 7 (1,517) 0 2 (-0,046) 0 2 (0,577) 0 23 25 - 30 9 (-0,587) 0 15 (0,389) 0 16 (0,185) 0 12 (0,303) 0 4 (-0,705) 0 4 (0,258) 0 60 31 - 45 25 (1,393) 0 30 (0,788) 0 30 (-0,107) 0 16 (-1,900) 0 10 (-0,244) 0 7 (-0,023) 0 118 46 - 65 11 (-1,762) 0 13 (-0,836) 0 17 (-0,081) 0 15 (0,905) 0 8 (0,988) 0 3 (-0,595) 0 67 CELKEM 47 62 69 50 24 16 268 Výběr profese je přirozeně ovlivněn i určitými benefity , které přináší. Jedním z nich je určitá jistota v růstu platu, která j e dána nejenom dle platných tabulek založených na započítaných letech, ale i tím, že platy jsou pravidelně zvyšovány. Z tab. č. 10 vyplývá, že tato skutečnost je pro respondenty motivační či alespoň částečně. V tabulce nebyly zaznamenány žádné statisticky významné rozdíly. Tab. č. 11 : Poměrně krátká denní pracovní doba věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvaž oval jsem o tom CELKEM do 24 4 (-0,803) 0 5 (-0,659) 0 6 (0,445) 0 5 (1,439) 0 2 (-0,397) 0 1 (0,715) 0 23 25 - 30 14 (-0,189) 0 13 (-1,169) 0 18 (1,606) 0 10 (1,165) 0 4 (-1,263) 0 1 (-0,340) 0 60 31 - 45 37 (2,406) + 38 (1,491) 0 21 (-1,599) 0 8 (-2,445) - 11 (-0,862) 0 3 (0,298) 0 118 46 - 65 10 (-2,057) - 18 (-0,158) 0 15 (0) 0 10 (0,751) 0 13 (2,461) + 1 (-0,477) 0 67 CELKEM 65 74 60 33 30 6 268 Dalším benefitem , který spíše vnímán laickou veřejností, je relativně krátká denní pracovní doba. Tato představa však může být zkreslující a nereflektující přípravu učitelů, tvorbu didaktických materiálů a dalších pomůcek (tedy nepřímou pedagogickou činnost), které pravidelně aktualizují. Záleží tedy na přístupu pedagoga. Z tab. č. 11 plyne, že se jedná o m otiv, který v íce než polov ina dotazovaných považovala za významný pro volnu jejich profes e. Z ajímavá skutečnost je ta, že těch, kteří nad daným neuvažoval i je nejméně (společně s tab. č. 12). STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 15 Tab. č. 12 : Dva měsíce prázdnin a samé vo lno věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvažoval jsem o tom CELKEM do 24 5 (-1,001) 0 4 (-0,763) 0 7 (0,723) 0 4 (1,061) 0 2 (0,089) 0 1 (0,920) 0 23 25 - 30 16 (-0,818) 0 14 (-0,113) 0 16 (0,495) 0 4 (-1,176) 0 9 (2,175) + 1 (-0,129) 0 60 31 - 45 44 (1,984) + 32 (1,103) 0 28 (-0,177) 0 12 (-0,304) 0 0 (-4,342) - - - 2 (0,183) 0 118 46 - 65 18 (-0,839) 0 14 (-0,662) 0 14 (-0,741) 0 9 (0,795) 0 11 (2,827) + + 1 (-0,261) 0 67 CELKEM 83 64 65 29 22 5 268 V tab. č. 12 jsou uvedeny výsledky odpovědí na otázku, který laická veřejnost vnímá jako ten ne jvětší benefit učitelsk é profese, a který je často prezentován v kontextu požadavků učitelů. Na zvýšení platů. Ve smyslu: „Co by ještě ch těli, vždyť ma jí furt prázdn iny.“ Z výs ledků vidíme, že opět převaž ují možnosti odpovědí, ze kterých lz e určit, že daná skutečnost je významným faktorem. U věkové skupiny 31 až 45 let se jedná o dominantní faktor, což potvrzuje nulová četnost a výsledek z - skóre u m ožnosti rozhodně ne . Tab. č. 13 : Konečně mne bude někdo poslouchat věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvažoval jsem o tom CELKEM do 24 0 (-0,435) 0 3 (1,763) 0 3 (-0,363) 0 6 (0,957) 0 6 (-2,665) - - 5 (2,863) + + 23 25 - 30 0 (-0,762) 0 3 (-0,088) 0 6 (-1,372) 0 16 (1,808) 0 33 (0,421) 0 2 (-1,287) 0 60 31 - 45 2 (1,600) 0 5 (-0,644) 0 15 (-1,182) 0 24 (0,627) 0 67 (1,212) 0 4 (-2,093) - 118 46 - 65 0 (-0,820) 0 3 (-0,317) 0 17 (2,522) + 4 (-3,078) - - 35 (-0,071) 0 8 (1,786) 0 67 CELKEM 2 14 42 50 141 19 268 Danou otázku v tab. č. 13 jsme nezařadili z důvodu, že bychom chtěli respondenty nějak pobavit, ale z v lastní praxe víme, že existuje určitá část učitelů, kteří svou profesi vykonávají z důvodu, že mají publikum (žáky), kteří je poslouchají. Tímto si však kompenzují určitý nedostatek ve svém občanském životě. Potěšující je, že většina dotazovaných tuto skutečnost nevnímala jako motiv. Ale zanedbatelná není ani skupina nerozhodných respondentů. Statisticky významné rozdíly jsou o pět v polích, kde se jedná o rozdíly v řádech jednotek. Janiš ml., K., Janiš st., K.: Motivace frekventantů celoživotního vzdělávání pro výkon učitelské profese 16 Tab. č. 14 : Přesvědčil mne můj učitel/ka věk Rozhodně ano Spíše ano Tak napůl Spíše ne Rozhodně ne Neuvažoval jsem o tom CELKEM do 24 0 (-1,038) 0 2 (1,161) 0 2 (-0,109) 0 5 (2,595) + + 12 (-1,383) 0 2 (-0,109) 0 23 25 - 30 5 (1,874) 0 2 (-0,342) 0 12 (3,226) + + 4 (-0,383) 0 35 (-1,287) 0 2 (-1,812) 0 60 31 - 45 6 (0,717) 0 7 (1,338) 0 7 (-1,696) 0 7 (-1,029) 0 76 (-0,272) 0 15 (1,689) 0 118 46 - 65 0 (-1,955) 0 0 (-1,955) 0 4 (-1,091) 0 5 (-0,131) 0 52 (2,445) + 6 (-0,121) 0 67 CELKEM 11 11 25 21 175 25 268 Na úplný závěr našeho dotazníku jsme zařadili otázku, která přinesla nejjednoznačnější odpověď a vyjádření respondentů. Uvedené vý sledky v tab. č. 14. je nutné interpretovat v kontextu charakteristik cílové skupiny. Z dat vyplývá, že čím starší věková skupina, tím jsou méně ovlivněny svým učitelem. Vzhledem k tomu, že ani jeden dotazovaný nemá vystudovaný magisterský učitelský obor, je zjevné, že se původně jeho myšlenky na budoucí profesi ubíraly jiným směrem. Mladší respondenti tak mají více v paměti svého učitele. Závěr Z výsledků vyplývá, že jedněmi z nejsilnějších motivů pro výkon učitelsk é profese jsou jisté benefity , které přináší. Mezi jednot livými věkovým i skupinami a ani uvnitř nich nebyly zaznamenány přílišné a časté statisticky významné rozdíly. V našem výzkumu jsme se nezaměřili na celé spektrum různých motivů, ale jak jsme již předznam enali v první části příspěvk u, tak na motivy nižší úrovně. Z námi zjištěných dat pro praxi plyne následující:  Zvyšovat prestiž učitelské profese tak, aby možnost ji vykonávat byla sama o sobě motivující. Tuto skutečnost lze zajistit efektivnější komunikací mezi rodinou a školou. Zaváděním inovativních metod a prvků učení aj. Nesmíme zapom ínat, že učitele hodnotí rodiče.  Prezentovat široké veřejnosti sk utečnou náplň učitelské profese tak, aby byla vnímána každá její součást tedy nejen přímá, ale i nepřímá pedagogická či nnost. K tomuto lze opět využít široké spektrum komunikačních kanálů (sociální sítě, webové s tránky apod.).  Na základě četnosti zastoupení věkových skupin, tak motivovat mladé lidi k tomu, aby se vydali na učitelskou kariéru, a to systémem podpory z ačínajících učit elů, uvádějícím i učiteli, metodic kou podporou v praxi apod. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 17 Z několik výše uvedený ch bodů vyplývá, že se do jisté míry j edná o marketing a o činnosti, které je relativně jednoduché naplňovat, alespoň to tak lze vnímat. Z výzkumu Janiše ml. a Skopalové (2017) mj. vyplývá, že jedny z nejčastějších problematických situací ve škole jsou problémy s rodiči žáků nikoliv se žáky samotnými. Je tedy důležité neustále hledat cesty, jak naplňovat nám i uvedený bod první, i když chápeme, že se mnohdy j edná o Sisyfovskou práci. Bibliografie Hlavní výstupy z Mimořádného šetření ke s tavu zajištění výuky učiteli v MŠ, ZŠ, SŠ a VOŠ . [online][cit. 20. 3. 2020] . Dostupné z : <http://www.msmt.cz/file/50371/> CHRÁ SKA , Mirosl av. Me tody p edago gického výzk umu: zá klady kvant itativ ního výzkumu . Praha: Grada, 2007. ISBN 978-80-247-1369-4. KRAUS, Blahoslav. Základy sociální pedagogiky . Vyd. 2. Praha: Portál, 2014. ISBN 978-80-262-0643-9. SKOPALOVÁ , Jitka a JANIŠ , Kamil. Profesní připravenos t učitelů základních škol v oblasti řešení rizikového cho vání a možnosti jeho prevence v Moravskoslezském kraji. I, Pedagog ické aspekty . Opava: Slezská univerzita v Opavě, Fakulta veřejný ch politik, 2017. ISBN 978-80-7510-235-5. Statistická ročenka MŠMT. [online][cit. 21. 3. 2020 ]. Dostupné z: <http://toiler.uiv.cz/rocenka/rocenka.as p> Mgr. Kamil Janiš, Ph.D. Katedra tělesné výchovy a sportu Univerzita Hradec Králové , Pedagogická fakulta U Pivovarské Flošny 296/3, Hradec Králové, Česká re publika [email protected] D oc. PhDr. et PaedDr. Kamil Janiš, CSc. Ústav pedagogických a psychologických v ěd Slezská univerzita v Opavě , Fakulta veřejných po litik v Opavě Bezručovo nám. 14, 746 01 Opava, Česká repub lika [email protected] Šoltésová, M., Dimunová, L.: Oblasť environmentálnej výchovy u detí školského veku 18 Oblasť environmentálnej výchovy u detí šk olského veku The Area of Environmental Education of Chi ldren of School Age Mária Šoltésová, Lucia Dimunová Abstract The aim of the paper is to present the results of the research we have carried out within the e nvironmental education of p upils of the seco nd stage of primary school. We focused on information in the field of wast e so rting, ele ctrosmo g an d th e u se of in formati on and communic ation equi pment. The f indings of the survey sh ow that pup ils are kept u p- to -date on topics related to environmental education. Keywords: Enviromenal education. Electrosmog . Gender. Waste separation. Úvod Problematika env ironmentálnej výc hovy v súvislosti s čoraz v äčším vply vom člove ka na jeho životn é prostre die predst avuje jedn u z najak tuálne jších tém súčasnosti. Jej význam podči ark uje aj fakt, že environmentálna vý chova je prierezovou témou v rámci štátneho vzdelávacieho programu (Fryková, 2012). O životnom prostredí môžeme rozprávať ako o komplexnom mnoho- zložkovom systéme, ktorý je vytv orený a určený fyzikálnym, chemickým, biologi ckým a sociálnym prostre dím, v ktorom človek žije a realizuje kultúr ne, soci álne, mater iálne a biolo gické potre by (Urm inská , 2010 ). V ži votnom pros tredí sa stretáv ame s veľkým množstvom fyz ikálnych fak torov, ktoré môž u pozitívne no v ko nečnom dôsled ku aj negatív ne ovplyvňov ať kvalitu ž ivota. Envir onmen - tálna výchova na druhom stupni základných škôl je prierezová téma, ktorá sa prelína najmä s biológiou, chémiou a geografiou. Na formovaní environmen - tálneho poved omia žiakov sa po dieľajú aj spoločensko - v edné predmety, najmä občianska a etická výchova, slovenský jazyk a literatúra. Cieľom environmen - táln ej vých ovy je pr ispieť k rozvo ju osobn osti žia ka tak, ab y v obl asti ved omostí , zručností a schopností nadobudol schopnosť chápať, analyzovať a hodnotiť vzťahy medzi čl ovek om a jeho životným prostredím. Tieto zručnosti získa na základe poznania zákonov, ktorými sa riadi život na Zemi, pochopením súvislosti medzi vývojom ľudskej populácie a vzťahom k prostrediu. Taktiež chápaním súvislostí medzi globálnymi a lokálnymi problémami a najmä vlastnej zodpovednosti vo vzťahu k prostrediu (MŽP SR, 2015). Cieľom STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 19 environmentálnej výchovy j e aj komplexný prístup k environmentálnym problémom s prihliadnutím na Listinu základných práv a slobôd, v ktorej sa okrem iného píše, že každý človek má právo na priaznivé životné prostredie, má pr ávo na vč asné a úpl né inform ácie o stave živ otného prostr edia a p rírodn ých zdr ojov, pričom nikto nesmie pri v ýkone svojic h práv ohroz ovať a ni poš kodzov ať životné prostredie, prírodné zdroje, druhové bohatstvo prírody a kultúrne pamiatky nad mieru ustanovenú zákonom. Tieto základné e tické a morálne pri ncípy je potrebné systematicky rozv íjať aj u žiakov na základnej škole. Rezortná koncepcia environmentálnej výchovy, vzdelávania a osvety do rok u 2025 (M ŽP SR) up riamuj e pozor nosť na t ri pilier e určen é na zvyš ovanie environmentálneho povedomia: environmentálnu výchovu, environmentálne vzdelávanie a osvetu. V rámci stanovených priorít sa zameriava na environ - mentálne rizikové faktory v jednotlivých odvetviach. Eliminácia environmen - tálnych rizikových faktorov je jedn ou z nosnýc h tém environm entálnej výc hovy u žiakov základných škôl. V duchu tejto myšlienky sme sa rozhodli realizovať prieskum. Jeho hlavným cieľom bolo z istiť, ak é ma jú deti školského veku informácie o možných environmentálnych rizikových faktoroch. Zamerali sme sa na informácie z oblasti trie denia odpadu, elektrosmogu a využívania informačno - komunikačných zariadení (m obilov, počítačov, smartfónov). Metodika Súbor tvorili deti navštevujúce druhý stupeň základnej školy. Celkovo sa do prieskumu zapojilo 146 žiakov – 69 (47 %) chlapcov a 77 (53 %) dievčat vo veku 12 - 15 rok ov. Metódou zberu údajo v bol dotazník vlas tnej konštrukcie. Zber dát sa realizoval v januári a februári 2020 v košickom kraji. Na spracovanie údajov sme využili deskriptívnu a i ndukt ívnu štatistiku (Pearsonov chí - kvadrát test na hladine výz namnosti α = 0.05). Výsledky Triedením odpadov šetríme primárne zdroje surovín a vytvárame predpoklad pre zabezpečenie proce su recyklácie odpadov. V oblasti t riedeni a odpadu sme sa zamerali na informovanosť o správnej separácií plastov, skla a papiera do farebne označených kontajnerov. Z počtu 146 opýtaných žiakov priradilo správne plastový odpad k farbe kontajneru n = 113 (77,4 %) detí, sklo n = 100 (68,5 %) detí a papier n = 116 (79,5 %) detí. V tabuľke č. 1 sú uveden é od povede na základe pohlavia. Zisťov ali sme a j, či existu je štatisticky významný rozdiel medzi i nformov anosťou a pohlav ím. Chí - kvadrát testom neboli zistene signifikantné rozdiely. Šoltésová, M., Dimunová, L.: Oblasť environmentálnej výchovy u detí školského veku 20 Tabuľka č. 1 : Informovanosť žiakov o separácii odpadov (n = 146) Separácia materiálu chlapci dievčatá správna odpoveď n (%) nesprávna odpoveď n (%) správna odpoveď n (%) nesprávna odpoveď n (%) χ 2 p plast 51 (73,9) 18 (26,1) 62 (80,5) 15 (19,5) 0,429 0,225 sklo 44 (63,8) 25 (36,2) 56 (72,7) 21 (27,3) 0,286 0,162 papier 54 (78,3) 15 (21,7) 62 (80,5) 15(19,5) 0,838 0,447 χ 2 - Chí - kvadrát test (p < 0.05) Elektrosmog alebo „znečistenie elektrinou“ predstavuje elektro - magnetické vlnenie, ktoré je um elo vyrobené človek om. Možno ho merať a vyhodnocovať prostredníctvom špeciálnych meracích zariadení. Zvýšená hladina elektrosmo gu má dopad na naše z dravie. Info rmovanosť detí o význam e slova elektrosmog sm e zisťovali v ďalšej otázk e. Medzi elektromagnetické vlnenie, ktoré sa stáva súčasťou každodenného života u deti školského veku môžeme zaradiť okrem iného aj tablety, notebooky, mobilné telefóny a počítače. Pojem elektros mog je pre viaceré deti nez námy, o čom svedčí odpoveď „neviem“ od 49 (33,6 %) žiakov . Správnu odpoveď, že sa j edn á o znečisťovanie pro stredia elektrinou uviedlo len 78 (5 3,3 %) žiakov. Fenoménom súčasne doby je využívanie technológii vo zvýšenom množstve najmä u detí. Ďalšou otázkou sme zisťovali koľko času de nne venujú žiaci práci s telefónom a počítačom . Podrobné údaje sú uvedené v tabuľke č. 2. Údaje poukazujú, že na počítači trávia viac času chlapci ako dievčatá. Zaujímavým zistením bolo, že pri používaní mobilného telefónu to bolo naopak. Pri mobilno m tele fóne, a to viac ako 60 minút, trávia viac času dievčatá n = 45 (58,4 %) ako chlapci n = 35 (50,7 %). Sledovali sme aj signifikantnú závislosť medzi pohlaviami. Zistili sme signifikantný rozdiel v dĺžke trávenia času s počítačom, a to v neprospech chlapcov (p < 0,05). V dĺžke používania mobilu počas dňa sme signifikantné interpohlavné rozdiely nezistili (p ˃ 0,05). Tabuľka č. 2 : Čas žiakov strávený na počítač i a telefóne počas dňa (n = 146) Čas denne/ počítač 0 minút n (%) > 30 min n (%) 30 -60 min n (%) > 60 min n (%) neviem n (%) χ 2 p Chlapci 11 (15,9) 10 (14,5) 19 (27,5) 23 (33,3) 6 (8,8) 20,748 ,000 Dievčatá 30 (38,9) 21 (27,3) 14 (18,2) 8 (10,4) 4 (5,2) Spolu 41 (28,1) 31 (21,2) 33 (22,6) 31 (21,2) 10 (6,9) Čas denne/ mobil Chlapci 3 (4,3) 9 (13) 19 (27,5) 35 (50,7) 3 (4,3) 2,662 ,616 Dievčatá 1 (1,3) 6 (7,8) 21 (27,3) 45 (58,4) 4 (5,2) Spolu 4 (2,7) 15 (10,3) 40 (27,4) 80 (54,8) 7 (4,8) χ 2 - Chí - kvadrát test (p < 0.05) STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 21 Problematike mobilných telefónov sme sa venovali hlbšie, nakoľko sú známe negatívne účinky najmä na psychické zdravie. Našim záujmom bolo zistiť, či žiaci používajú telefón, aby som sa cítili lepšie , keď im je nanič. Podľa nášho prieskum u až 64 (43,8 %) ži akov sa nevie vyjadriť, či využíva telefón na zlepšenie psychického stavu, čo považujeme za vysoké číslo. V rámci rodových rozdielov sme zistili signifikantný rozdiel v neprospech chla pcov, vy počíta ná hodno ta chí = 10,7 84; p = 0,013 (p < 0, 05). Naš e v ýsled ky sa odlišujú od výsledkov štúdie HBSC (2019) realizovanej na Slovensku, kde chlapci a dievčatá uvádzali v rovnakej miere, že používajú svoj telefón, aby sa cítili lepšie, keď im je na nič. Tento rozdiel je možné vysvetliť lokálnym rozdielom ale súčasne aj naznačuje, že je po trebnú tento fenomén naďalej sledovať. Na základe výsledkov považujeme využívanie mobilných telefónov za rizikový faktor, ktorému je potrebné venov ať pozornosť. Záver Enviromentálna výchova vedie žiakov ku komplexnému pochopeniu vzájomného vzťahu človeka k životném u prostrediu. Dôležitosť environmen - tálnej výchovy na základných školách je bezpochybne opodstatnená. Náš prieskum poukazuje na nie veľmi dostatočnú i nfo rmovanosť u detí v proble- matike triedenia odpadu. Znepokojujúcim je aj čas, ktorý trávia deti na mobile a po čítači . Výsledk y ďalej pou kazujú , že je veľmi dôl ežité ži akom inte nzívne jšie priblíži ť prob lematiku elektros mogu a poukázať na jeho dôs ledky. Máme zato, že environmentálna výchova vytvára tento priestor a prijatie informácií deťmi môže pozitívne ovplyvniť aj rodičov. Bibliografia HBSC. Sociálne determinanty zdrav ia školákov. vyd. Úrad verejného zdravotníctva SR, 2019. 203 s. ISBN 978 -80- 7159-242-6. FRYKOVÁ, E. Environmentálna výchov a v edukačnom procese. Bratislava: Metodick o- pedagog ické centrum , 2012. 6 4 s. ISBN 9 78 - 80 - 8052 - 441 - 8. MŽP SR – Ministerstvo životného prostredia S lovenskej republiky a jeho rezortné organizácie. Rezortná koncepci a environmentálnej výchovy, vzdelávania a osvety do roku 2025. vyd. MŽ P SR, 2015. 35 s. URMINS KÁ, J. 2010. Potenciáln y vplyv vy braného g eochemickéh o prostredia na zdravotný stav detskej populácie v oblasti žiarsk ej kotliny. 1. vyd. Nitra: Slovenská poľnohospodárska univerzita Ni tra. 69 s. ISBN 978-80-552-0399-7. Šoltésová, M., Dimunová, L.: Oblasť environmentálnej výchovy u detí školského veku 22 Ing. Bc. Mária Šoltésová Vysoká škola zdravotníctva a sociálnej práce sv . Alžbety Detašované pracovisko bl. Sáry Salkaháziov ej Rožňava Kósu Schoppera 22, 048 01 Rožňava [email protected] Doc. PhDr. Lucia Dimunová, PhD . Ústav ošetrovateľstva Univerzita Pavla Jozefa Šafárika v Košiciach, Lek árska fakulta Tr. SNP č. 1, 040 22 Košice [email protected] STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 23 Míra významnosti pastorace mládeže v postupující sekularizaci česk é společnosti The Importance of Youth Pastoral Wor k in the Progressive Secularization of Czech Soc iety René Strouhal Abstract The younger generations are classified as a hope for the future in many fields. In the pastoral work of the Church, the formation of young Christians is borne by its relevance. Both the solid statistical data of soci ologists of religion and our resear ch have contri buted to the dis cussion of such an accent by the auth ority of the Chu rch. Shifting the experience of faith from quantity to inner quality and an adequate offer of pastoral activiti es for young p eople are becomin g new starting points. Keywords: Youth. Pastoral care. Privatizat ion of faith. Secularization. Specialized surveys. A ntropologické konsekvence a otázky relevantnos ti pastorace mládeže Každá nová mladá ge nerace je nadějí pro budoucnost 1 nejen z hlediska biologického či z hlediska kulturní antropologie nebo evoluční psy chologie, ale i z pozic etických a spirituálních, vede se i nezřídka manipuluje k různým budoucím hodnotám a je akcentována její edukace a vůbec formace. Z antropologického hlediska subkultury mládeže percipujeme jako velk é skupin y mladý ch (dosp ívajíc ích) lidí , kteří m ají spol ečného něco (pr oblém, zájem, zvyk), co je odlišuje od členů ostatních sociálních skupin, vztahují ke specifickým způsobům chování, vykazují silný sklon k určitým hodnotovým preferencím, akceptování či zavrhování určitých nor em a životních stylů. 2 1 Srov. BENEDIKT XVI . Spe salvi , článek 25. 2 Srov. THORNTON, S., s. 1 – 7. Strouhal, R.: Míra významnosti pastorace mládeže v postupující sekularizaci české společnosti 24 Konkrétněji je charakterizuje styl jako hudba, tanec, oblečení, úprava těla apod., čemuž členové subkultur přikládají specifický význam a který současně tímto vyhraněním determinuje hranice vůči jiným subkulturám a uskupením vně subkultury 3 . Jejich styl je vyjádřen následujícími prv ky: 1) image – vzhled, tj. oblečení, účes, různé doplňky, tetování; 2) vystupo vání – tvoř ené výrazem tváře, sty lem chůze a postojem t ěla; 3) argot – speciální slovní zásoba a způsob, jakým je pronášena. 4 V rámci specifické péče o věřící , která se nazývá pojmem past orace 5 , je na formaci mládeže rovněž kladen velký důraz, a to dokonce au toritou církve. Je však otázkou, zda je vůbec relevantní. Všeobecně a v jisté nezávislosti na aktivity církve ji lze hodnotit z pozice sociologie náboženství na základě pevných statistických dat kvantitativního výzkumu vyjadřující zájem mládeže o spiritualitu: ‒ Extrémně malá identifikace české populace a zejména české mládeže s církvem i vyvolává zdán í, jako by se otázka spirit uality české m ládeže vůbec netýkala. Tento dojem je ještě umocněn společenským pově - domím, v němž člověk, který se veřejně zajímá o duchovní život, vybočuje z většinově žitých norem. ‒ Pochybnost o relevanci tématu spi rituality je v současném českém prostředí způsobena zejména trojím zjednodušením , které je v naší společnosti velmi rozšířené: 1) nereflektované automatické ztotožnění spirituality s křesťan - stvím, 2) ztotožnění víry v Boha s příslušností k něk teré církvi, zejména k církvi katolické, 3) ztotož nění obsahu křesťansk é ví ry se zjedn odušenou formu lací některých dogmat. ‒ Podle výzkumu spirituality mládeže:  33% se deklarovalo jako ateisté (nevěří v žádného Boha), 3 Srov. KOLÁ ŘOVÁ , M., Hudební subkultury mládeže v současné ČR – postsubkulturní či postsocialistické? , s. 233. 4 Srov. BRAKE , M., Comparative Youth Culture, s. 224. 5 V iEncyklopedii.cz se uvádí, že slovo pastýř pochází z latinského slova pastor. V Bibli se tak obrazně nazývají králové a představení, přičem ž nejvyšším pastýřem je Bůh a Ježíš je dobrý pastýř, jen ž dává život za své stádo. Rozšířením pak byl tento výraz vztažen na biskupy jako před staven é k řesťan ských společen ství. Srov. htt p://ww w.ienc ykloped ie.cz/ pastyr /. V Teo logick ém slovníku Karla Rahnera se dočteme, že pastýř a stádo jsou v Izraeli a v No vém zákoně běžné a důležité obrazy , jež popisují vztah Boha k jeho lidu jako osobní, star ostlivý a záchranný. Dnes je tento obraz těžko použitelný, pro tože výrazem „stádo“ bývá označována tupá, shora řízená masa. V katolické církvi se pod pojmem pastorace rozumí péče a doprovázení lidí ve víře a v prožívání celého života. Srov. RAHNER, K., Teologický slovník , s. 236. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 25  29% se zařadilo do sk upiny „je nerozhodný, agnostik, neví, zda je Bůh, nepatří k žádné náboženské skupině“,  26% se označilo jako věřící (8% jako praktikující, 18% jako nepraktikující). ‒ Nábože nství tedy před stavuje kladno u hodnotu minim álně pro ¼ mladé populace v ČR, téměř každý třetí nemá v této otázce jasno a zbytek se k této otá zce staví buď lhostejně nebo odm ítavě. Jednoznačn é je pouze to, že většina mládeže se k žádné círk vi přímo nehlásí. ‒ Důležitým j evem j e takzvaná sekulární religiozita, tedy hledání transcendentního rozměru v běžném životě: ‒ K duchovním skutečnostem evidovaným ve výzkumné popul aci mládeže se řadí hledání přátelství, lásky a sounáležitosti. 6 Církev proklamuje, že je důl ežité věnovat se mládeži ze všech sociálních oblastí, to znamená středoškolákům, vysokoškolákům, učňům, pracujícím i nezaměstnaným. Je důležité, aby kněží a další zodpovědní za pastoraci mládeže měli čas na osobní setkání s mladými lidmi. J ejí pastorace mládeže má být záležitostí celé církve a jejím úkolem je pomáhat mladému člověku klást si otázky a napomáhat m u nacházet na ně správné odpovědi. 7 Církev m á být pro mladé lidi domovem, kde se m ladý člověk cítí přijat i přes svou odlišnost a často i kritičnost a kde cítí být m ezi svými. 8 S tím kolerují její snahy o budování i nterní sociální struktury: mladí potřebují zázemí, ve kterém se budou cítit pochopeni a př ijati, a kde se ve svých postojích budou navzájem povzbuzovat. 9 Nabízí zázemí a zároveň hájí formační axiom, že sami mladí lidé musí být z apojeni jako aktivní činitelé života církve. 10 Afirmace Plenárního sněmu Čeští a moravští biskupové 5. č ervence 1997 na Velehradě vyhlásili Plenární sněm katolické církve v České republice 11 . Dle jeho reflexe se situace mládeže v české společnosti rapidně změnila, a to zejména v oblasti demografické, sociální, kulturní a náboženské. Známé sociální ten dence, 6 Srov. EUROPEAN COMMISSION. Eu robarometer public opinion in the Eu ropean union , s. 101 – 255. 7 Srov. S EKCE PRO MLÁDEŽ ČESKÉ BISKUPSKÉ KONFERE NCE , Pastorační plán sekce pro mládež ČBK , s. 14 – 15. 8 Srov. tamtéž, s. 16. 9 Srov. Závěry 17. konferenc e o mláde ži Sekce pro mládež České biskupské konf erence , dostupné z: https://cbk.blob.core.windows.net/cms/CirkevOld/015696.pdf 10 Srov. JAN PAVEL II., Christifideles laici , článek 46. 11 Sněm se chronologicky členil na několik fá zí a vytvořil osm sněmovních komisí, které po dva roky zpracovávaly stanovená témata ze života a poslání křesťanů v církvi v naší zemi i ve světě a byly v trvalém kontaktu mezi sebou i s vedením sněmu. Strouhal, R.: Míra významnosti pastorace mládeže v postupující sekularizaci české společnosti 26 jakými jsou nárůst násilných trestných činů pác haný ch dětmi a dospívajícími, jsou pro církev velkou pastorační výzvou. Jen malá část mladých lidí je oslovena pastoračními aktivitami církv e. Tvoří ji: 1) mladí lidé v církvi plně socializovaní a k ní loajální, 2) ti, kdo své místo v církvi teprve začínají n acházet, 3) i ti, kdo využívají služeb církve bez ohledu na vlastní náboženské přesvědčení. Z povahy svého věku mladí křesťané mají mnohdy spoustu výhrad vůči praxi nebo nauce církve. Tuto kritičnost, ačkoli je někdy podána provokativní formou, nelze pouze odmítat, je ji potřeba rovněž chápat jako příležitost k dialogu a k zamýšlení se nad naší past orační praxí. To klade nároky na schopnost kněží, jáhnů i dalších pastorační ch pra covníků partnersk y doprovázet a moudře poradit, lidsky a pravdivě přiblížit evangelium. Církev tak s otevřeností může nabídnout dom ov, aniž by uspíšila proces konverze. Prot o mají být mlad í l idé akcept ováni ve far ních spol ečenstv ích s porozu měním , podporováni ve svý ch dobrých snahách, k j ejichž realizac i nejsou dost silní, a přitom konfrontováni s jednoznačnými postoji v oblasti víry i m orálky, které nejsou podávány moralizujícím nebo odsuz ujícím způsobem. Faktor náboženských specifik České repub liky Relaci mezi náboženstvím a společností ozřejmuje již Durkheim ve své teorii, podle níž je náboženství klíčovým faktorem pro pochopení základn ích sociologický ch otázek: jak se vytváří a udržuje integrita společ nosti nebo jaký je vztah jedince k ní ( „náboženství je jednotný systém víry a praktik vztahujících se k posvátným věcem“ ). 12 N áboženské chování je efektivní zjišťovat nejen skrze návštěvnost bohoslužeb 13 , kladením otázek o víře v B oha, ale i dotazováním se např. na člověka převyšující skutečnosti či informace o religiozitě z celorepublikov ého sčítání lidu, domů a bytů. 14 A konečně využít je možné také data z příle - žitostných či opakovaných sociologických průzkumů státních či soukromých institucí (Institut pro výzkum veřejného mínění IVVM, Středisko empirických výzkumů STEM, aj. ). 12 Srov. VÁCLAVÍK, D., Náboženství a moderní česká společnost, s. 10 – 11. 13 Ve všech dosavadních výzkumech návštěvnosti bohoslužeb v různých evropských zemích je v zásadě zachováno následující pořadí zemí: země s vysokou účastí (Irsko, Polsko, Portugalsko, Slov ensko) a na opačné m k onci země s ní zkou účast í. Srov. VÁVRA M., Jak zji š ťovat návš těvnos t bohoslužeb? Problémy s měřením náboženského fenoménu . 14 Nábo ženské vy znání bylo v rám ci SLDB zjišťo váno od vz niku Českos lovensk a/Česk é republik y v letech 1921, 1930, 1950, 1991, 2001 a 2011. Údaje o náboženském vyznání obyvatel ze SLDB j sou využívá ny zejména pro formulování dlouhodobé koncepce uspořádání vztahu mezi státem a církv emi a náboženskými spol ečnostmi i pro vyhodno cování nábožensk é svobody v ČR. Využívají je také jednotlivé církve a náboženské sp olečnostii nevládní organizace, sociologická a vědecká pracoviště apod. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 27 Religiozita může být studována na pozadí obe cných společenských hodnoto vých orientací (např. výz nam duchovních strán ek života v hodnotovém žebříčk u jedin ců). Da lším možným výzkumem je zjišťování místa náboženst ví v osobním životě jednotlivců. 15 Religioz ita měřená otázkou na víru v Boha vykazovala v počátku druhého tisíciletí vcelku stabilní výsledky (zhruba jedna třetina populace ČR je věřící, 50 % je ateistů a jedna p ětina nemá v této otázce jasno). K víře v Boha se hlásí tém ěř polovina osob starších 60 let, v ostatních věkových skupinách se podíl věřících pohybu je mezi jednou pětinou a j ednou čtvrtinou věřících. 16 Naše společnost je tvořena zhruba půl na půl bezvěrci a religiózními lidmi (pevnou víru v Boha a silné náboženské přesvědčení v šak deklaruje pouze necelá pětina z nich). Do náboženského života se řadí i mnoho dalších činností kultovního i mimokultovního charakteru (modlení, svěcení nábo - ženských svátků, vyznávání nábožensk ých symbolů, přednášková, výchovná i propagandistická činnost – úča st na náboženské výchově, di skuse o nábo - ženství, studium náboženské literatury aj.). Součástí náboženského chování je rovněž znalost a vyznávání náboženské etik y a hodnot. Důležitou součást náboženského přesvědčení a vz tahu k náboženství představuje vědomí o k onečnosti lidského ž ivota, a to i v případě necírkevních forem. 17 Vědomí vlastní smrtelnosti má vliv na náboženské i nenáboženské postoje většiny lidí, obojí se odráží v jejich konkrétním „zacházení se smrtí“, pohřebních obřadech (či j ejich absenci). P ostoj e české společnosti jsou v tomto ohledu světovým unikátem. V našem národě je výskyt církevních pohřbů i kremací velmi nízký . 18 Při interpretaci výsledků výzkumů r eligiozity se musí postupovat obezřetně, neboť individuální víru člověka je nesnadné jednoznačně převést do forma lizovaného jazy ka empirický ch výzkumů, ne ní možné vždy posti hnout rozdílná osobní pojetí víry a pro zjišťování religiozity má velký význam 15 Generační přenos vztahu k náboženství (přenos rodinnou tradicí) je dle výzkumů STEM velmi silný. Podle některýc h výzkumů až 75 % nábožensky založených lidí pochází z rodin, kde nábož enství bylo důle žitou součástí hodnotové orie ntace. Srov. HABERL OVÁ, V., Problé my empirického zkoumání religiozity v české společnosti, [2011: online]. 16 Srov. HA BERLOVÁ, V., Problémy empirického zkoumání religiozity v české společnosti, [2011: online]. 17 Někteří autoři se domnívají, že právě smrt je jednou z hlavních příčin vzniku náboženství, res p. jednou z je ho hlavníc h fu nkcí je právě „vy rovnáv ání se smrtí“ . Na př. dle brits kého sociá lního antropolo ga Bronislawa Mal inowského je smrt nejdůl ežitějším prame nem náboženství. Am erický sociolog ná boženství Thomas O´De a vy mezil mezi svými šesti základní mi funkcemi náboženst ví také „ú těchu a podpo ru při akcepta ci smrti a přísl ib posmrtn é ex istenc e“. Srov. NEŠ POROVÁ, O. , Existenciální dimenze současné církevní zbožnosti, s. 39-40. 18 V ČR je podíl kre mací (tedy pohřbů žehem v krematoriích) na všech uskutečně ných pohřbech 75,9 % (rok 2000), což je zdaleka nejvy šší podíl v Evropě. Srov. NEŠPOR , Z. , VÁCLAVÍK , D., Příručka sociologie náboženství, s. 180. Strouhal, R.: Míra významnosti pastorace mládeže v postupující sekularizaci české společnosti 28 odlišení víry v „osobního“ Boha od pojetí boha jako universální síly, která řídí a organizuje svět. 19 Mají - li lidé odpovědět na otázku, ke kterém u vyznání se hlásí, jejich odpo věď na výzku mnou otáz ku může být moti vována ce lou řadou s ubjekti vních faktorů a ateistická sebedeklarace ještě nemusí znamenat odmítání transcen - dentna (např. může jít o demonstrat ivní odpor vůči církvím). Počet lidí, kteří se nepovažují za členy církví, ale v „něco“ věří, daleko převyšuje počet oficiálních věřících i ateistů u nás (v některých případech může jít o polovinu až dvě t řetiny české populace). 20 Můžeme se v ní setkat s ji stou formou religioz ity zejména pros třednictvím alte rnativní, detr adicionaliz ované a privátní podoby náboženství. 21 S ociologové náboženství se dom nívají, že historický vývoj národa s v elkou pravd ěpodo bností vytv ořil skrytý po tenciá l k je ho výrazn é sek ulariz aci, která s e významně projevila až v obdob í státního ate ismu v le tech 1948- 1989. 22 V evropských zemích včetně té české přetrvává navzdory j ejich sekularizovanému charakteru vcelku vysoká v íra v nadpřirozeno č i alespoň podmínk y pr o ni, ale jedná se spíše o k vazinábože nské představy, názory nebo činnosti, které stojí mimo oficiální církevní věrouku, proto je označujeme generálně termínem alternativní religioz ita. 23 Většina výzkumů religiozity v ČR byla dosud zam ěřena na její menší, tj. institucionalizovaný segment (příslušnost k cír kv i, návštěvnost bohoslužeb aj.). Analyzováním religiózních jevů v českém národě v celé jejich šíři (tedy i mimocírkevních) se v ČR (kromě několika výzkumů z 90. let 20. stol.) v prvn ím desetiletí tohoto tisíc iletí zabýv al zejména vý zkum Detradi cionalizace a i ndividual izace náboženství v České republice (DI N 2006), jehož výsledky, doplněné o informace z obdobných výzkumů, např. Mezinárodní program 19 Např . z výzkumu ST EM, prová děného tímto způs obem, vyš el podíl ne věřícíc h v naší spo lečnos ti na zhruba jednu pětinu populace a 43 % lidí uvedlo víru v nějakou duchovní či životní sílu. 20 Údaje o „klasické“ (oficiál ní, institucionalizo vané) religiozitě tedy stále méně a mé ně odrážejí náboženskou situaci současné moderní společnosti. 21 Individualizovaná a detradicionalizované religiozita v ČR je často omezena na úzké rodinné či přátelskékruhy, na nejrůznější spirituální společenství nebo na „náboženský konzum“ jednotlivců (ten se projevuje např.velkým zájmem o duchovní a terapeutickou literaturu, různé formy spirituálního rozvoje osobnosti či magickénebo okultní praktiky a horoskopy). Z to hoto pohledu je česká společnost daleko méně nenábo ženská, než se naprvní pohled jeví či než sama sebe nazírá (spirituální zájmy přitom často ovlivňují i sociální jednání, spotřebu i celou řadu dalších oblastí lidského života a jednání). 22 Jak je patrné z údajů SLDB z let 1921, 1930 a 1950, byl v této dob ě stabilní p očet věřících (92,82 %, 92,19 % a 93,90 %) a (z dnešního pohledu) re lativně nízký podíl lidí bez vyz nání (7,16 %, 7,8 % a 5,84 %). S LDB z roku 1991 však již generuje pouze 43,9 % věřících a 39,9 % lidí bez vyznání a SLDB z roku 2001 dokonce pouze 32,2 % věřících a 59 % lidí bez vyznání. Srov. LUŽNÝ, D., NAVRÁTILO VÁ , J., Náboženství a sekularizace v České republice [2011: online]. 23 Současná hnutí tohoto typu navaz ují na v Evropě bohatou historickou tradici alternativní religiozity (od gnosticismu, přes hermetismus, neoplatonismus až k okultismu). STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 29 sociální ho výzk umu (I SSP – In ternational Social Survey Program , 1992- 2005) či Evropská studie hodnot (EVS – European Value Survey , 1999), nabízí konkrétnější obraz o alternativních formách r eligioz ity v ČR. V roce 2007 se také opakoval výzkum Religio zita v reformovaný ch zemích východo(stře - do)evropských z roku 1997 (AUFBR 2007) . Ze závěrů těchto šetření vyplývá, že ačkoliv Češi neprojevují velký zájem o tradiční církevní religiozitu, je mez i nimi značně rozšířena víra v nadpřirozené jevy. Výzkumy potvrdily, že trendy na poli religiozity z 90. let 20. stole tí, které potvrdil také cenzus z roku 2001 a 2011 (SLDB), v české společnosti pokračují a současně je pokračujícím jevem intenzita odcírkevnění. Česká společnost více než za sekulární b y se dala označit za necírkevní . 24 Zpětná vazba výzkumného šetření K optim álnímu monitorování a analyzování co nejpravdivější míry a formy religiozity v České republice není možné pracovat jen na základě SLDB, sociologických výzkumů či údajů jednotlivých náboženských sdružení a církví, ale je nutné využít také specializované průzk umy, jež poskytují dle závěrů soci olog ů náboženství nejbohatší materiál ke studiu současného stavu religiozity. Tvrzení o relevantnosti zaměření se na pastorační péči o mládež jsme se snažili konfirm ovat alespoň nějakým výzkumným šetřen ím. Byly sta noveny výzkumné metody s ohledem na zmíněnou intenci předmětu zkoumání a formulování cílů, kterých mělo být dosaženo. Náš výzkum je charakte - rizován užitím techniky dotazníku a následný m použitím matematicko -statis- tické procedury. Bylo užito dotazník ového šetření, komparační metody a Likertovy škály, přičemž u posledně uvedené m etody škálování (vytváření škál) byl o významné, že pomocí této metody lze zachytit určité náboženské kvalitativní jevy v kvantitativní podobě a dobře inform uje o míře stupně souhlasu či. Jako zkoumaná populace byli vybráni respondenti, kteří praktiku jí křesťanskou víru, a to z řad laiků a duchovních z různých druhů farností: tradičních většinových (většina obyvatel obce se cítí být součástí farnosti), menšinových ( kostel je plný, farnost živá, ale zasahuje to jen menšinu obyvatel obce) a vymírajících nebo již prakticky neexistujících (nemůžeme reálně očekávat její vnitřní regeneraci). Výběr byl zamýšlen a realizován lokálně ze všech regiónů naší vlasti, věkově od nejmladších s plnol etostí po seniory, muži i ženy . C elkem se do výzkumu zapojilo 72 respondentů. 24 K alternativní religiozitě inklinují na základě zjištěných údajů lidé mladší a také ti, kteří dříve dle vlastního tvrzení sice navštěvovali bohoslužby, ale ne příliš často. Srov. HAMPLOVÁ, D., Čemu Češi věří: dimenze soudobé české religiozity, s. 709-711. Strouhal, R.: Míra významnosti pastorace mládeže v postupující sekularizaci české společnosti 30 Tabulka 1: Respondenti dle pohlaví v pro centech Muži Ženy Věřící laici 50 50 Kněží 100 - Celkem 69 31 Tabulka 2: Respondenti dle vzdělání v p rocentech Základní Vyučen/a Maturita Vysokoškolské Věřící laici - - 18 82 Kněží - - - 100 Celkem 0 0 11 89 Tabulka 3: Respondenti dle typu farnosti v proc entech Farnost tradiční Farnost menšinová Farnost vymírající Věřící laici 18 82 - Kněží 3,6 78,6 17,8 Celkem 12,5 80,6 6,9 Graf 1: Akcentace oblastí evangelizace a pastorace Na sedmi st upňov é škále významnosti pastorační péče o m ládež u věříc ích laiků zaujímá prv ní místo s hod notou 6,8 Liker tovy stupnice, u kněží se nachází na třetím místě s hodnotou 5,5 Likertovy škály po pastoraci rodin a pastoraci nemocných. Její vysoké hodnocení v míře významnosti svědčí o relevantnosti akcenta ce shora uved eného typu p astorační péče církve a rov něž z pozic e kněží, kteří jsou primárním i činiteli komplexní pastorace, lze vnímat nutnost jejího zakotvení v širším prostoru rodiny jako z ákladní buňky církve a společnosti. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 31 Zralá reflexe víry jako východiska Fokusu jeme – li směrem k pastorac i mládeže, lz e konstatov at, že v Česk é republic e je celkov ě zaz namenán pokles zájmu o náboženské skupi ny. Nejvíce je tomu u skupiny v r ozm ezí 15 – 18 let, jež se výrazně posunuje k prioritám konzumní společnosti, a to jak svou hodnotovou stupnicí, tak způsobem života. Na oblast náboženství se v současné době nejvíce orientují mladí lidé ve v ěku kolem 20 let. Jako iniciující fak tor zde může být potřeba hledán í smyslu života a bytí i osobní existencionální krize. I zde byl však diagnosti - ková n posun z ájmu k vn itřní a ne organiz ované spiritu alitě. Tím se rov něž otev írá nový a netradiční prostor pro oslovení mladý ch lidí z hlediska duchovního rozměru člověka. 25 Za tohoto předpokladu by pastorace mládeže měla pokračovat nikoliv množe ním akcí, ale přede vším jejich zkvalitněn ím a hledán ím nových přístupů ve stávající ch aktivitách. 26 Může doko nce recipročně pomáha t vy tvářet v církvi pros tor k věd oměji pro žívan é spiritu alitě, která ze své podst aty nab ídne odp ovědi hledajícím , aby i pastorace ostatních skupin byla více expanzivní a otev řená . 27 Vždyť fo rmovaný mladý věřící v dnešní m světě veřejné diskuze a při používání moderních forem sdělovacích prostředků přispívá k utváření veřejného mínění ve společnosti i církvi a osvojuje si schopnost rozeznávat různé podoby manipulací a propagandy a formovat si svá stanov iska a hodnotové soudy. Pastorační možnosti formace mladých jsou pak různé: duchovní prog ramy a boh osluž by, život v mo dliteb ních skupi nách, syste matick é p rogram y rozhovorů nad Biblí a o víře, duchovní poradenství a doprovázení pro české i zahraniční studenty, duchovní cvičení a obnovy, pomoc při duchovním r ozlišování, přípravy k přijetí svátostí, kulturní, hudební a umělecké tvůrč í aktivi ty, poutě a sportovní č innosti, vz dělávací a diskusní poř ady a před nášky. 28 Plodem a stěžejním měřítkem kvality pastorace mládež e se takto stává předávání konkrétní odpovědno sti za živé slavení liturgie, solidní vzdělávání ve víře, misijní nasazení, moudrost v rozlišování povolání, diakonický rozměr i schopnost spolupodílet se na fungování nutného zázemí farností a podobně. I proto je akcenta ce formace mládež e v pastoračním ús ilí církve a nejen v jejím konání relevantní. 25 Srov. SAK, P., Proměny české mládeže , s. 131 – 145. 26 Česká biskupská konference schválila pod číslem ČBK 45 - XVII – 5 - c „Pastorační plán Sekce pro mládež ČBK“ : h ttps://cbk.blob.core.windows.net/cm s/ContentItems/297_00297/21 - pastoracni-plan.pdf 27 Srov. FRANTIŠEK , Evangelii gaudium , článek 31. 28 Srov. ČESKÁ BISKUPSKÁ KONF ERENCE , Koncep ce vysoko školské pastorace v České republice , článek 13. Strouhal, R.: Míra významnosti pastorace mládeže v postupující sekularizaci české společnosti 32 Bibliografie BENEDIKT XVI. Spe salvi, O křesťanské nadě ji . Encyklika. Přeložil Prokop Brož. 1. vyd. Praha: Paulínky, 2008. 63 s. I SBN 978 -80-86949-41-3. BRAKE, Mike. Comparative Youth Culture . 1. vy d. Londýn: Routledge, 1990. 238 s. ISBN 13-978-0415051088. ČESKÁ BISKUPSKÁ KONF ERENCE. Koncepce v ysokoškolské pastorace v České republice . Praha: ČBK, 2017. Pro vnitřní po třebu. ISBN neuvedeno. FRANTIŠEK. Evangelii gaudium . Apoštolská e xhort ace o hlásání evangelia v současném světě. Přeložil Milan Glaser. 1. v yd. Praha: Paulínky, 2014. 83 s. ISBN 978-80-7450-118-0. EUROPEAN COMMISSION. Eurobarometer pub lic opinion in the European union . 1. vyd. Brusel: Directorate-General Press and Communication, 2002. ISBN neuvedeno. HABERLOVÁ, Věra. Problémy empirického z koumání religiozity v české společnosti. In: <http://www.stem.cz/clanek /406> [2011: online] HAMPLOVÁ, D ana. Čemu Češi věří: dimenze so udobé české religiozity. In: Sociologický časopis, 4/2008: 703-723. iEncyklopedie.cz [online]. Praha: 2007 [cit. 2012- 03- 31]. Dostupné z: http://www.iencyklopedie.cz/pastyr/. JAN PAVEL II., Christifideles laici . O povolání a pos lání laiků v církvi a ve světě. Posynodní list. Překladatel neuveden. 1. vy d. Praha: Zvon, 1990. 69 s. ISBN 80-7113-162-8. KOLÁŘOVÁ , Marta. Hudební subkultury mlá deže v současné ČR – postsubkulturní či postsocialistické? In DA NIEL , Ondřej, KAVKA, Tomáš, MACHEK , Jakub. Populární kultura v čes kém prostoru , s. 323 – 248. 1. vyd. Praha: Karolinum, 2013. 328 s. ISBN 978-80-246-2192-0. LUŽNÝ, Dušan, NAVRÁTILOVÁ , Jolana. Nábo ženství a sekularizace v České republice. In: <http://snem.cirkev.cz/downlo ad/Luzny.htm> [online] NEŠPOR, Zdeněk. Ústřední vývojové trendy so učasné české religiozity. In: Jaká víra? Současná česká religiozita/spir itualita z pohledu kvalitativní sociologie náboženství. Sociologické studie 5/2004. Praha: 21 -37. NEŠPOROVÁ, Olga. Existenciální dimenze souč asné církevní zbožnosti. In: Jaká víra? Současná česká religiozita/spiritua lita z pohledu kvalitativní sociologie náboženství . Sociolog ické studie 5/2004. Praha: 38-55. NEŠPOR, Zdeněk, VÁCLAVÍK , David. Příručka soc iologie náboženství. 1. vyd. Praha: SLON, 2008. 449 s. ISBN 978-80- 86429-92-2. SAK, Petr. Proměny české mládeže . 1. vyd. Praha : Petrklíč, 2000. 300 s. ISBN 80-7229-042-8. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 33 SEKCE PRO MLÁDEŽ ČBK., Pastorační plán sekce pro mládež ČBK [online]. Praha: 2002 [cit. 2012-03-31], s. 14- 15. Dostupné z: https://cbk.blob.core.windows.net/cms/ContentI tems/297_00297/21- pastoracni-plan.pdf. THORNTON, Sarah. General Introduction . I n GELDER, Ken, THORNTON, Sarah. The subcultures reader , s. 1 – 7. 1. vyd. London: Routledge, 1997. 599 s. ISBN 0415127270. VÁCLAVÍK, David. Náboženství a moderní čes ká společnost. 1. vyd. Praha: Grada, 2010. 243 s. ISBN 978-80-247-2468-3. VÁVRA, Martin. Jak zjišťovat návštěvnost bohos lužeb? Problémy s měřením náboženského fenoménu . In Naše společnost 7/ 1, s. 32 – 39. Praha : Centrum pro výzkum veřejného mínění, S ociologický ústav AV ČR, 2009. ISSN 1214-438X. PhDr. Mgr. René Strouhal Římskokatolická farnost Moutnice Moutnice 248, 664 55 Moutnice [email protected] Gabrhelová, G., Porubčanová, D.: Príčiny školského podvádzania 34 Príčiny školského podvádzania Causes of School Cheating Gabriela Gabrhelová, Dáša Porubčanová Abstract The article analyzes the theoretical basis of the issue of school cheating. It clarifies the phenomenon of school cheating in connection with scientif ic know ledge and result s of renowned experts on an int ernational scale with an emphasis on ethical-moral, socio-psychological and peda - gogi cal-did actic as pects in the educa tional c ondition s of seco ndary sch ools. The co ntribution was process ed within the solution of the grant project KEGA no. 001DTI-4/2018 Cheating in the schools as a problematic aspect of evaluating the results of the educational process in secondary sc hools. Keywords: Cheating. Education. School. Teach er. Teen-student. Úvod Pri analýze domácich i zahraničných zdrojov vo vzťahu k skúmaniu príčin, (dô vodov, motív ov) školského podv ádzania žiakov , nachádzame viac eré spolupôsobiace aspekty negatívnych tendencii správania žiakov. Vrbová, Stuchlíková, (2012) uvádzajú, že podvádzanie sa st alo všade prítomným problémom školského vzdelávania na všetkých jeho úrovniach. Na vedeckej úrovni sa danej problematike venujú mnohí slovenskí i zahraniční odborníci (Ciz ek, 2 003 ; Panákov á, 2011; D avis, Dri nan, Gal lant, 200 9; Bajtoš , Honzík ová, 2019) a ďalší. Pri vym edzení pojmu školské podvádzanie sa stretávame s viacerými neja snosťa mi. Pr esne p ojem ch arakt erizov ať je p roblem atick é. Pod ľa odbo rníkov , podvádzanie v škole identifikujú tri znaky. Je to porušovanie stanovených školských pravidiel, prinášanie výhody voči ostatným spolužiakom a zníženie spoľahlivosti a presnosti pedagogického hodnotenia ( Cizek , 2003; Mareš, 2005, s. 312). Detekc ia príčin škols kého podvádz ania je v odbor nej literatúre a výsku - moch najčastejšie charakterizovaná v dvoch rovinách. Prvá rovina sa prepája s osobnostnými predispozíciami žiakov . Druhú rovinu tvoria situačné a kon- textuálné faktory, ako prediktory podvádzania. V týchto súvislostiach budeme analyzovať príčiny školského podvádzania. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 35 Osobnostné predispozície žiaka a ko príčina školského podvádzania Axiolog ickým prístupom k problé mu podvádzania sa zaobe ral Kolberg (1976). Skúmal väzby medzi podvádzaním a autonómnym morálnym rozho - dovaním, ktoré sa, v súvislosti s rozvojom abstraktného myslenia, formuje až po jeden astom rok u života. Vek ová skupi na pätnásťro čných sa p otom nachádz a, podľa autora, niekde medzi druhým a tretím štádiom morálneho usudzovania. Heidbrink, (1997) uvádza, že je to na rozhraní m edzi predkonvenčný m a kon- venčným stupňom. Druhé štádium je prepojené s účelovým myslením (konám tak, a by sa mi vrát ilo, čo som poskytol), n azývané aj, ako orientáci a na odmen u. Tretie š tádium, zho da s ostatným i – je skôr vý počtom určit ých cností, o rientácia na normy jednej alebo niek oľkých referenčných skupín. Správne je to, čo za sprá vne považ ujú ostatn í. Štúdie o vplyv e ro vesník ov na početno sť podvádz ania pritom preukázali silnú pozitívnu koreláciu medzi pozorovaným podvádzaním u spolu žiakov a v lastným podvádzaním (McCabe, Trevio, 1993). Výskum nie je ale možné obmedzovať len na väzbu medzi podvádzaním a morálnym výv inom ž iakov, aj ke ď ide nespor ne o dôleži tú imp likáciu neče stného správ ania. Říčan, (2010) opisuje výskum detskej poctivosti, ktorý v roku 1928 uskuto čnili Hartshon a May. Deti boli v laboratórny ch podmienka ch podrobené niekoľkým skúškam, kde im bolo nenápadne umožnené podvádzať. Všetko bolo dôsledne sledované, avšak deti o tom nevedeli. Výskum nepotvrdil pôvodn é očak ávania, ktoré m ali potv rdiť exi stenciu poctivosti, ako všeobecne j vla stnost i. Bola tu len m alá prav depodo bnosť od hadu, či die ťa, ktor é podvád zalo v jednej situácii, bude podvádzať aj v situácii inej. Z toho vychádza, že existujú ľudia poctiví a nečestní, ale nedá sa presne odpovedať, či je správanie viac ovplyvnené osobnosťou, alebo danou situác iou Lind, 2009). Vývinové r ozdie ly medzi žiakmi sú dôsledkom ich rozdielnych kognitívnych schopností a odlišných sociálnych štruktúr, s ktorými žiaci v edukačnom kontexte interagujú. Pozornosť analýzy prí čin školského podvádzania primárne zacieľujeme na obdobie ado lescencie. Psychologický prístup odhaľovania príčin, objasňuje nazeranie na štruktúru osobnos ti. Stredoškolák, adolescen t bio -psycho- sociálne vyzriev a. Dochádza k výraznému vývinu intelektu. Vytvárajú sa optimálne podmienky pre efektívne učenie sa, rozvíja sa preferovaný učebný štýl. Význam nadobúda sociálne učenie všetkých stupňov. Rôzne vý skumy zamerané na osobnostné rysy adolescentov potvrdzujú, že dnešná mladá generácia sa podstatn e odlišuje o d svojich pr edchodcov. Osobnostné charakterist iky súčasne j mládeže podľa Slavíka (2012) definujú: otvorenosť, kritickosť, prílišné seba - vedomie, asertívnosť, dobrá znalosť cudzích jazykov, zručnosť v práci s infor- mač no - kom unikač nými t echnol ógiami , slob oda, n esamost atnosť a zod povedn osť. Veľk ý v ýznam v obd obí dospie vania má vzť ah k s poluži akom, vrstovník om. Silný vzťah k jedincom i k skupinám, veľká potreba kontak tu s vrstovníkmi, snah a neo dlišov ať sa, byť v skupi ne obľ úbený a uzn ávaný, je úst redným motív om dospiev ania stredoš kolskej m ládeže. Pri v zdelávaní m ládeže sa v enuje špeciá lna Gabrhelová, G., Porubčanová, D.: Príčiny školského podvádzania 36 pozornosť psychickým predpokladom, predovšetkým schopnostiam a nadaniu pre určitú činnosť. Z hľadiska budúceho smerovania edukácie sa v pedagogike čoraz viac pozo rnosť up riamuje na budovan ie kompe tencii žia ka pre živo t. Nezane dbateľ né sú tiež emočné determin anty a soc ializačné aspekt y, k toré prispievajú k poch o- peniu často kladených otázok. Čo, alebo čomu, a ako sa m á stredoš kolák učiť, aby z ískal uvedené kompetencie? Príčiny podvádzania z hľadiska osobnostných faktorov, sú podľa Zelinu (2018) spájané so schopnosťou sociálne j a psychickej regulácie. Člov eka a jeho pôsobe nie v so ciálne j sk upine , v spo ločnost i ov plyvň uje široká šk ála parametrov ľudského života, životných podm ienok (Balogová, 2018). Sociáln a reg ulácia osobnosti je utváraná soci álnymi normami, zákonm i, zvyklo sťami, ku ltúrou, form ovaná j e výchovou, spoločensk o - kultúrnym systé - mom a médiami. Psychická regulácia je spojená s vedomím, svedomím vedomosťami a inteligenciou, schopnosťami, citmi, hodnotam i a skúsenosťami. Školsk é podvádzanie môže mať súvi s so sociálnym učením. Výsk umný tím Millera (2007) prezentoval významné výsledky skúmania príčin správania osobnosti, s označením ako „vnímaná osobná účinnosť“, alebo tiež vedomie vlastnej účinnosti. Z pohľadu autorov ide o presvedčenie jedinca o jeho schopnosti realizovať aktivity k dosiahnutiu požadovaných výsledkov v škole. Žiaci so schopnosťou sebariadenia viac veria svojim schopnostiam dosiahnuť ciele. Vo väčš ej miere dokážu čeliť nárokom na učenie a preverovanie ich vedomostí v škole. Z výskumu tiež vzišli zistenia, že žiaci, ktorí pochybovali o zvládnutí zadanej úlohy , pravdepodobnejšie zvolili podvádzanie (Miller at al., 2007). Tieto závery pot vrdil aj výskumný tím Murdocka, Haleho a Webera (2001). V ich výskumnej štúdii sa rovnako pot vrd ilo, že príčinou vyššej pravdepodobnosti podvádz ania bola nižšia osobná účinnosť. Autori vyslov ili názor, že prí činou nižšej osobnej účinnosti, je strac h z neúspechu. Ten pravde podobnosť podvádz ania zvyšuje. Strach z neúspechu je zároveň viazaný na úroveň sebavedomia žiaka a tá sa odví ja od výchovných vplyvov v rodine. Z uvedenéh o vyplýva, že pri hľadan í príčin školskéh o podvádzania ide o mu lti- faktoriá lny jav. Vplyvy rodiny ako príčina podvádzania žiaka v škole Primárnym prostredím, ktoré zásadným spôsobom ovplyvňuje rozvoj psychiky a hodnotovú orientáciu dieťaťa je rodina. Poskytuje základné skúsenosti, ktoré dieťaťu sprostredkujú pohľad na s vet určitým spôsobom. Významne sa podieľa na rozvoji pocitov sebaistoty a sebadôvery, na ktorých záleží ďalš ie uplatnenie dieťať a v živ ote. Potreba pozitív neho prijatia je silným prvkom formovania charak teru jedinca a výrazne ovplyvňuje interpretáciu STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 37 správania rodičov. Má dosah na ďalšie konanie jedinca v budúcnosti (Pasternáková, Krásna, 2015). Okrem biologických dispozícií, úroveň kognitívnych schopností, ktoré sú geneticky už v organizme žiaka definované, na rozvo j jeho poznávacích schopnosti a ich výkon v škole vplýva postoj rodičov k škole, k vzdelaniu k hodnotám všeobecne. Rodinné prostredie for m uje kompetencie a uvažovanie dieťaťa v jeho smerovaní pre budúcnosť. Význam určitých kompetencií rodičia z dôrazňujú viacerými spôsobmi:  verbálnou proklamáciou,  svojim vl astným správaním,  hodnotením dieťaťa,  odmenami a t restam i, ktorými si formuje svoj morálny charakter a buduje si sebavedomie (Vágnerová, 2001). Práve rodičia môžu byť príčinou, prečo ich dieťa volí stratégie podvádzania pred stratégiami efektívneho učenia. Voľba k podvádz aniu m á dve podoby: 1. Únik žiaka pred záťažovou situáciou a stresom, z reakcii rodičov na nedostatočné výsledky v škole: Vplyv prísn ej vý chovy, trestan ie rodičov za zlý prospech, vzbudí u dieťaťa už v období mladšieho školského veku, potrebu hľadať možnosti, ako tejto situácii predísť. Nakoľko dosahovanie dobrých vý sledkov si vyžaduje viac času k plneniu úloh a osvojovaniu s i nového učiva, dieťa – žiak sa snaží si vypom ôcť inou než legálnou cestou. Štýl výchovy ovp lyvňuje rozhodov acie procesy mladého človek a, ich vply vom si vy tvára sv oj morál ny kódex . Rodič ia pred stavujú význam ný prvok formov ania osobnosti žiaka aj v uvedenej oblasti. 2. Následok nenaplnených očakávaní rodičov, učiteľov na výkon žiaka: Slavík, (1999) zistil, že u školopovinných jedincov vzniká úzkostný strach z toho, aby neurobili chybu, ktorá by viedla k výčitkám učiteľov, príp adne k smút ku rodičo v. Nejde o podv ádzan ie z dôvodu pos tihu ale z d ôvodu obáv nenaplnenia očakávaní. Aby žiak predišiel nenaplneniu očakávaní, volí stratégiu podvádzania. S uvedeným javom sa prepája následne schopnosť (ne) zvládať záťažové situ ácie v živote, čo vedie u adolescentov k ča stém u zlyhaniu, nezáujem o život, plány a ciele do budúcnosti (Barnová, Tamášová, Krásna, 2019). Súčasný nelichotivý postoj spoločnosti ku škole, k profesii učiteľa je jedn ou z ď alších príčin podvá dzani a. Krit ickos ť adol escento v ku šk ole a učite ľom je následok vývinových zmien jedincov, a zároveň jej podmienenosť prepája so sociáln ymi vplyvm i. Kritika a nerešpe ktovanie prav idiel v škole často svedčí o nedostatočnej identifikácii so školou. Vzťah ku škole, s ktorou sa jedinec nestotožňuje, môže mať charakter povrchnej akceptácie, úplnej ľahostajnosti alebo dokonca odporu (Vágnerová, 2005). Ďalej autorka vo svojom výskume zistila, že existujú zásadné rozdiely medzi žiakmi odborného vzdelávania (3 - ročný ch uče bných odborov ) a žiak mi štu dijných odborov (4 - roč. odborný ch Gabrhelová, G., Porubčanová, D.: Príčiny školského podvádzania 38 škôl a žiakov gymnázií ). Postavenie žiakov („ učňov“) bolo výsledkami z výskumu spojené s nižšou sociálnou prestížou. Žiaci učebných odborov, preto zväčša bývajú menej konformní, odmietajú alebo ignoru jú autoritatívne pôso benia ško ly a ve ľmi často nie sú so svojo u profesi jnou rolou id entifi kovan í. Naproti tom u žiaci 4 - ročných študi jných odborov býv ajú so svojím postaven ím identifikovaní vo väčšej miere, a preto tiež bývajú sociálne konform nejší. K tejto konformi te žiakov môže prispievať jednak tlak zo strany rodiny a vedom ie, že strata roly stredošk oláka, by viedla k znížen iu ich spoločenskéh o statusu a bolo by ohrozené ich budúce postavenie. V súvislosti so vzťahom ku škole, Vágnerová (2005) výsledkami skúmania potvrdila, že motivácia stredo - školákov (prevažne žiakov učebných odborov) je veľmi nízka. Výnimk ou sú iba žiaci, ktorí majú v úmysle pokračovať v štúdiu na vysokej škole. Ostatní žiaci po príchode na strednú školu motiváciu strácajú. Vedia, že na v ýkon zv olenej profesie im postačí školu absolvovať a na výsledkoch im až tak nezáleží. Väčšine žiakov stačí udržať si iba taký prospech, aby boli sami s výsledkami spokojní a nevyvolávali konflik tné situácie s rodičmi a učiteľmi. Výv inové hľadisk o, je spoje né s hľadis kom m otivač ným a výučbo vým. Stredoškolák podvádza buď preto, že nevie, ako sa efek tívne učiť, alebo preto, že nechce do učenia investovať čas. Žiaci, ktorí si plánujú svoj čas na učenie, menej často vol ia podvádzanie ako tí, ktorí si nechávajú učenie na poslednú chvíľu (Miller et al., 2007). Adolescenti formujú svoju identitu, nachádzajú v zložitom období, už nie sú deťmi, ale t iež stále nie sú dospelými. Sú medzi nimi veľké individuálne aj typologick é rozdiely. Školské podvádzanie ako pedagog icko-dida ktický aspekt Z kontextuálnej roviny, predstavuje šk olské podvádzanie nežiaduci zásah do vyučovac ieho procesu , pričom sk resľuje reáln u úroveň nadobudnutý ch vedomostí, zručností a kompetencií žiakov. Žiaci, ktorí si uvedom ujú, že môžu dosiahnuť dobrý prospech aj použitím nedovolených metód, strácajú motivá ciu osvojiť si uči vo. Jednou z príč in, prečo žiac i podvádzajú je negatívne vnímanie alebo uberanie významnosti j ednotlivým predmetom. Inak sa pripravujú na predmet, ktorý považujú za dôležitý z hľadiska ďalšieho vzdelávania, alebo neskoršieho uplatnenia, a inak sa pripravu jú na nedôležitý učebný predmet. Predmety, ktoré považujú za menej dôležité odsúvajú. Ex istuje predpoklad, že žiaci sa v prípade predmetov s menšou náročnosťou, uchýlia k podvádzaniu. Žiaci, ktorí sa učia pre známky , nie kvôli vedomostiam, pociťujú silnejšiu motiváciu podvádzať, najm ä ak nie sú schopní učivo si osvojiť. Niekedy aj náročnosť učiva a obsah učiva rôznych predmetov môže byť spúšťačom podvádzania v škole. Zo spom enutých motívov, rôznych zahra - ničnýc h výskumov, kt oré identifik ovali príčiny školského pod vádzania, exis tuje jeden zásadný. Je ním dôvod byť čo najlepšie k lasifikovaný (Ci zka, 2003). STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 39 Výchovná funkcia hodnotenia v škole nielenže neprisp ieva k nado- budnutiu správnych hodnôt žiaka, naopak dáva mu dôvod myslieť si, že podvádzanie je regulárny spôsob ako sa dopracovať k cieľu. Žiaci často hľadajú cesty najmenšieho odporu, snažia sa dosiahnuť maximum pri minimálnom množstve času a úsilia. Preto nevnímajú školské podvádzanie ako problém, ale skôr ako odôvodnenú stratég iu pre zisk lepších známok. Uveden á príčina je často spojená s benevolen tným prístupom zo strany učiteľa. Jeho nevšímavosť, či jednoduchosť podvádzať je pre žiakov tichým súhlasom k podvádzaniu. Záver Mladá gener ácia nepripisuje v ážnosť školském u po dvádzaniu. Ign oruje autorské práva rôznych prác vedome, či nevedome. Nie len s tredoškolská mládež si myslí, že všetko, čo je na internete patrí všetkým, pričom si neuv edomu jú, že kradnú , podvádza jú, klamú . Sm e svedkam i nárastu nef érové ho dosahovania výsledkov v škole, pokles spoločenského vnímania hodnoty vzdelania, a tiež pokles kvality vyučov ania. Z uvedeného kontextu riešenej problematiky si dovoľujeme tvrdiť, že školsk é po dvádzanie nie je len záležitosťo u a pochy bením žiaka. Vnímam e ho, ako súhrn mnohých činiteľov. Viac eré nami realizované pilotné či priebežné skúmania v rámci projektu odhalili kor elácie medzi problémovými aspektami edukácie a školským podvádz aním. K významným problémovým aspektom zaraďujeme klímu šk oly, klímu triedy a nerešpektovanie prav idiel v škole (Hanuliaková, Porubčanová, 2018), spôsob výučby a vnímanie procesu hodnotenia žiakom (Bajtoš, Honzíkov á, 2019; Bajtoš, Hanu liaková, 2019), význam nosť predmetov vo vzde lávaní (Gabrhelo vá, Hasajová, 2019 ; Hasajová, 2019), ale i nuda v škole je jednou z príčin kedy žiaci podvádzajú, len tak pre zábavu, našepkávajú, opisujú a skúšajú či si ich konanie učiteľ všimn e. Potreba byť uznávaným, byť „niekto“ devalvuje potrebu byť múdry m a dobrým človekom. Chceme veriť, že v zanietených učiteľoch je stále veľa pozitívnych stimulov, viesť žiaka k rozvoju potencialít pre život. Odporúčame v edukácii žiakov na všetkých stupňoch vzdelávania viac pozornosti smerov ať k rozvíjaniu ľudských kvalít, tvorivému, prirodz enému a spontánnemu učeniu. V pr íprave učiteľov dôraz klásť na m orálny status a v prípade hodnotenia využívať formatívne hodnotenie a rešpektov ať osobnosť žiaka. Bibliografia BAJTOŠ, J., HANULI AKOVÁ, J. 2 019. Zisťo vanie názor ov žiakov na školské podvádz anie. In: Súčasnosť a perspektív y edukácie I II. národný program rozvoja výchovy a vzdelávania 1. vyd. Ružomberok: Katolícka u n iverzita v Ružomberku. VERBUM 2019. s. 32 -38. Gabrhelová, G., Porubčanová, D.: Príčiny školského podvádzania 40 BAJTOŠ, J., HONZÍKOVÁ, J. 2019. Školsk é podvádzanie z pohľadu učiteľov – pilotné výskumné šetrenie. I n: Arnica: acta rerum naturalium didactica = časopis pro rozvoj přírodovědnéh o vzdělávání. 2019, 9 (2) s. 51-58. BALOGOVÁ, B. 2018. Sociálne kontexty hodnôt. 1. v yd. Prešov: Prešovská univerzita v Prešove. Filozofická faku lta, 2018. 82 s. Opera Socialia ; 6/2018. CIZEK, G. J. 2003. Detecting and preventing classroom cheating: Promoting integrity in schools. Thousand Oaks, CA : Corwin, 2003. 168 s. DAVIS, S. F., DRINAN, P. F., GALLANT, T. B. 200 9. Cheating in school: what we know and what we can do. Malden: Wi ley-Blackwell. 256 s. GABRHELOVÁ, G., HASAJOVÁ, L. 2019. I nterakčné a komunikačné stratégie riadenia vyučovacieho procesu v súv islosti s podvádzaním . In: Didaktická konference. 13. mezinárodní vědeck á konference: Sborník příspěvků 1. vyd. Brno: Masarykov a univerzita, 2019. s. 45 -50 [online]. HANULIAKOVÁ, J., PORUBČANO VÁ, D. 2018. Školské podvádzanie a porušovanie pravidiel In: Jazykovedné, literárnov edné a didaktické kolokvium. Bratislava: Z-F LINGUA, 2018, s. 133- 139. HASAJOVÁ, L. 2019. Školské podvádz anie v matematike ako problémový aspe kt ho dnoten ia kur ikulár nej tra nsform ácie. In: S účasn osť a p erspek tívy edukácie III. Národný program rozvoja vý chovy a vzdelávania . 1. vyd. Ružomberok: Katolícka univerzita v Ruž omberku. VERBUM 2019. s. 107-113. HEIDBRINK, H. 1997. Psychológie m orálního vývoje. Praha, Portál, 1997. 175 s. KOLÁŘ, Z.,VALIŠOVÁ, A. 2009. Analýz a vyučování. Vyd. 1. Praha: Grada, 2009. 230 s. MAREŠ, J. 2005. Tradiční a netradiční podvádě ní ve škole. In: Pedagogika 55 (2), s. 310-334. MILLER, A.D., et al. 2007. Who are all th ese cheaters? Characteristics of academically dishonest students. In: Anderman, E.M.; Murdock, T.B. Psychology of academic cheating. London: Academ ic, 2007. s. 9-32. McCA BE, D . L., TREVIÑ O, L. K. 199 3. Ac ademic disho nesty : Hono r code and other contextual influences. Journal od Higher Ed ucation, 1993, 64 (5), s. 522-538. MURDO CK, T. B.,HA LE, N. M.,W EBER, J. M. 2001. Pre dictors of C heating among Early Adolescents: Academ ic and Social Motivations. Contemporary Educational Psychology , 2001, 26, s. 96-115. KOHLBERG, L. 1976. Moral stages and m oralisation. In: Lickona, T. Moral development and bahavior. New York , Holt-Rinehart, Sauders, Wilson, 1976. LIND, G. 2009. Moral ist lehrbar. München: O ldenbourg Schulbuchverlag, 2009. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 41 PANÁKOVÁ, M. 2011. Fenomén podv ádění ve školách. Faktory ovlivňující podvádění studentů na středních školách v Pa rdubickém kraji [online], 2011. PASTERNÁKOVÁ. L., KRÁSNA, S. 2015. Psy chológia výchovy. 1. vyd. Brno: Tribun EU, 2015. 89 s. ŘÍČAN, P. 2010. Psychologie osobnosti: obor v pohybu. Vyd. 6. Praha: Grada, 2010. 208 s. SLAVÍK, J. 1999. Hodnocení v současné šk ole: východiska nové a metody pro praxi. Vyd. 1. Praha: Portál, 1999. 192 s. VÁGNEROVÁ, M. 2001. Kognitivní a soc iální psychologie žáka základní školy. Karlova univerzita v Prahe, Karolinum : Praha, 2001. s. 304. VRBOVÁ, J., STUCHLÍKOVÁ, I. 2012. Šk olní podvádění starších žáků – pilotní studie. Pedagog ika 62 (3): 317 – 331. ZELINA, M. 2018. Psychoedukácia. Aplikov aná pedagogická psychológia. VŠ DTI. Dubnica nad Váhom, 2018. 271 s. Príspevok bol spracovaný v rámci riešenia grantového projektu KEGA č. 001DTI- 4/2018 Školské podvádzanie ako prob lémový aspekt hodnotenia výsledkov výchovno - vzdelávacieho procesu na stredných školách. D oc. PaedDr. PhDr. Gabriela Gabrhelová, PhD. Katedra didak tiky odborných predm etov Vysoká škola DTI Sládkovičova 533/20 , 018 41 Dubnica nad Vá hom gabrhelova@d ti.sk PaedDr. Dáša Porubčanová, PhD. Katedra školsk ej didaktiky Vysoká škola DTI Sládkovičova 533/20 , 018 41 Dubnica nad Vá hom porubcanova@ dti.sk Stárek, L.: Etický model rozhodování se jako profesní nástroj 42 Etický model rozhodování se jak o profesní nástroj Ethical Model for Decision Making as a Profe ssional T ool Lukáš Stárek Abstract This article discusses the importance of ethical aspects in the work of social services/personal assistants with regar d to the applicability of the Ethical model for decision making. Main purpose of the text is research of the influence of social service workers, especially personal assistents with ethical c ode. How is ethic al co de useable while dealing with ethical dilemmas in relatio n to the performance of this profession. Further w e search for familliarity with Ethical model for decision making between th ose assistents. In their almost daily routine, personal assistents are facing particular ethical questions. Their realization, searching for answers and wondering about the questions in general requires n eccesar y care and time. It leads to the importance and influence of the Ethics that might be possibly flouted. Reflection of et hical aspects may contribute to improvment of provided social s ervices, more precisely to professionalism of the profession or strengthening professional competencies. Keywords: Ethical dilemma. Ethical model for d ecision making. Ethical code. Personal assistance. Vymezení a vhled do problematiky Co j e a co není etické pro pracovníka v sociálních službách j e v několika případech možné osvětlit i v rámci společenského úkolu sociáln í práce. Společenský úkol sociální práce vytváří rámec poskytující smysl p rofesního jednání. Tím je dáno pochopení sociální práce a zároveň i to, co po ní už ivatelé sociálních služeb a jiní mohou vyžadovat. Pracovník dosahuje toho, že se lidé ve vzájemném působení se svým okolím lépe rozvíjejí, podle vlastní přirozenosti, potřeb a názorů. Ilustrací vztahu m ezi etikou a úkolem sociální práce se můž e týkat důvěrností a utajení informací, které pracovník v sociálních službách získává od uživ atelů. Sociální práce sama sebe chápe jako profesi poskytování pomoci, ke které patří vztah založený na důvěře. Pro to není náhoda, že v profesním kodexu zaujímá důležité místo důvěrnost a utajení. Aby bylo možno morálně STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 43 přijatelně působit, j e potřebné rozlišovat následující aspekty, které jsou určující pro zmapování etiky a její přijatelno st:  hodnoty, normy, morálka;  rozhodnutí se – řešení problému;  profesní etika;  osobnost a postoje. (Haterd van de et. al, 2000) Etický kodex jako nástroj pro výkon pracovn íků v sociálních službách Správný a kvalitní výkon profese v sociálních službách, to j e zásada, která vymezuje pros tor ve vztahu uživatele služby a pracovníka v sociálních službách. Zásady vycházejí z etického kodexu dané org anizace, primárně však z Et ickéh o kodexu so ciální ho pracov níka Čes ké repub liky, pr ameníc í z Všeob ec - né dekl arace lid ských prá v, z Listiny z ákladn ích práv a svobo d České repu bliky , ze zákona č. 108/2006 Sb., o soci álních službách a navazuje na zásady etiky sociální práce definované Mezinárodní federací sociá lní práce. Etický kodex je jedním z prvků charakteru dané profese a určuje tak profesní hodnoty a normy. Kodexem se udává směr chování pracovníka a kladou se tak nároky na jeho chování a jednání. Kodex určuje prostor i způsob jednání, které zároveň ukotvuje a usm ěrňuje. „Etický kodex vyjadř uje poslání pr ofese, zabe zpečuje vede ní a inspirac i členům, vytváří a udržuje profesní i dentitu , zdůrazňuje status profese, slouží jako měřítko pro hodnoce ní aktuální praxe, chrání klienty před zneužitím úřední moci a zanedbá ním péče, poskytuje souhr nná poučení v oblasti et ických dilema t a chrání pr ofesi před vnějším u směrňováním .“ (Nečasov á, 2010, s . 93) Etika není jen kodex, dispozice a záměr, ale jsou to lidé, které můžeme oslovit prostřednictvím jejich činnosti nebo nečinnosti. Nejenom pracovníci v sociálních službách jsou zatížení morálním úkolem péče, za který nesou odpovědnost. Toto zdůrazňování odpovědnosti probíhá nejen v rámci toho, co organizace nebo instituce po pracovníkovi požaduje, ale i ve v ztahu k hodnotám a normám, které lidé dodržují. Tak má také každý představu o tom, co je dobré, správné a proto hodné následování. Kodex nemívá závaznost právního charakteru, ovšem některé organizace mohou mít možnost výkon profese konkrétního pracovníka n ebo instituce komentovat a ovlivnit. Smyslem kodexu je ochrana uživatele služby a pracovníka v sociálních službách tím, že se určí hranice. Důsledné osvojení si profesního éto su a ho dnot má svůj praktický význam i pro osob u pracovníka v sociálních službách, jelikož napomůže k občasnému zamyšlení se nad tím, jak člověk sám pohlíží na hodnoty, bez který ch se daná profese neobejde. Kodex je platný pro dané členy profesní skupiny. Je důležité, aby profesní skupina učinila své profesní hodnoty a normy transparen tními a vysvětlila je. K tomu slouží kodex. Kodex t ím určuje směr profesního Stárek, L.: Etický model rozhodování se jako profesní nástroj 44 jednání. Aby pracovník mohl v praxi řešit nejen etická dilemata, měl by tedy znát svůj vlastní kodex a umět jej aplik ovat. Uživatelé služeb i společnost by si měli nárokovat, aby pracovníci jednali profesionálně. Hodnoty a normy, které jsou obsaženy v kodexu, jsou proměnné a závisí na socio - kulturním postavení dané spo lečnosti. Vytvoření kodexu je cílevědomý proces, jehož hlavním obecným cílem je předcházení nebo minimalizování projevů neetického chování. Hlavní důvody, proč dochází k podporování etických kodexů jsou následující (Levy, 1992):  kod ex zabez pečuj e vede ní a ins piraci svým č lenům a stává se prův odcem etické praxe;  kodex podporuje profesní chování a chrání uživatele služby před nekvalitní péčí;  kodex pracuje s hodno tovými kritérii dané profese v návaznosti na společenský rámec;  kodex podporuje a utváří identitu profes e. Etický kodex má čtyři důležité obecné funkce, které znázorňuje následující obrázek. Zdroj: Rolný, 1998, s. 30. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 45 Etické problémy – etická dilemata Člověk se někdy dostává do si tuace, a to nejen v profesním životě, kdy s tojí př ed vol bou mez i dvěma řešení mi. Něk teré p roblémy nás nu tí, aby chom zvážili situaci a rozhodli se, hovoříme o tzv. di lematech. U těc hto dilemat je často zapojeno více osob (skupin). Základem je vědomí vlastních hodnot, norem a zájmů, na kterých je založeno etické jednání. V rámci výzkumného šetření je etické jednání vnímáno jako jednání, které je v souladu s Etickým kodexem Společnosti sociálních pracovník ů České republiky (2006). „Řecké slov o problema označuje diskutabilní, složité situace, které vyžadují řešení. Etické problémy mají alespoň jedno správné řešení nebo jednu možnost správného řešení. Rozhodování v některých situacích může být těžké, složité nebo pro blematické, ale pokud existu je správné řeš ení, nemůžem e hovo řit o dil ematu. Naproti tomu řeck ý výraz dilema oz načuje dvojak ý argum ent (dyo – dvě) v konfliktních složitých situacích. Všeobecně potom dilematem rozumím e vý běr m ezi dvěma nebo více nechtěným i možn ostmi.“ (Mátel et al., 2010, s. 110) Každodenní praxe se zabývá etickými otázkami, kdy dilemata často nabý vají for my konf liktů, otázek lo ajality nebo uč inění vol by. V rá mci zac házení s těmito dilematy j e důležité sledovat ja k společenský úkol sociální práce , tak způsob vztahu mez i pracovník em v sociáln ích službác h a uživate lem služby. Diskuse, která se vede o etických problémech či dilematech (Banks, Janoušková, Nedělníkov á, Úlehla) je p ro pracovníky v sociálních služ bách důležitá, a to zejména v oblasti orientace v nejednoznačných kauzách. Na jejich rozhodnu tí jsou uživatelé služby závislí. Pro některé pracovníky řešení etických dilemat může být jen otázkou dodržování pevně stanovených pravide l. Jiní pracovníc i mohou situaci vní mat jako etický problém – pracovn ík ví, jak by měl rozhodnout, ale je to pro ně j složité. Etický kodex Společnosti sociálních pracovníků České republiky (2006) se mimo jiné zaměřuje na takzvané etické problémové okruhy, které nastiňují specifika sociální práce v různých oblastech. Je dná se o práci s jednotlivcem, rodinou, skupinou či organizací, kde působí jak sociální pracovník, tak pracovník v sociálních službá ch. Etické problém ové okruhy nastiňují problematiku, s níž se pracovník může setkat, a nabádá ho k využití všech zákonných možností, které m á. Především k využití informací a m etod práce, které může využívat v rámci profese. Jedná se o víceméně ucelený postup při řešení etický ch problém ů, kde je zřejmé, že důležité jsou konz ultace s odborníky a ko legy. Základ ní etické problém ové okruhy, které vy cházejí z Etického kodexu sociálních pracovníků České republiky (2006), jsme upravili a specifikovali přímo na pracovníky v sociálních služ bách. Konkrétně jde o tyto zák ladní okruhy:  V jakých případech by měl pracovník vstoupit či zasáhnout do života občana, potencionálního uživatele služby . Stárek, L.: Etický model rozhodování se jako profesní nástroj 46  Správné vyhodnocení míry pomoci, k terá by vedla uživatele služ by k lepší kvalitě živ ota či změn ě jeho posto jů. Míra pom oci je každ odenní otázkou.  Kdy nastane správný čas pro ukončení/přerušen í služby. Další problémové okruhy:  střet zájmu uživatele služby a pracovník a;  konflikt mezi uživatelem služby a dalším spoluobčanem;  konflikt mezi institucí, organizací a už ivatelem služby;  střet zájmu uživatele služby a majoritní společnost i;  konflikt mezi zaměstnavatelem a osobn ím asistentem. Pracovník v sociálních službách nabízí pomoc a kontrolu zároveň. V návaznosti na tyto dvě funkce sociální práce si má pracovník vy jasnit etické důsledk y své role vůči uživatelům sociálních služe b. (Etický kodex Spo lečnosti sociálních pracovníků České republiky , 2006) „Etické problémy mohou vznikat v situacích, když pracovník má přijmout rozhodnutí, se kterým není osobně ztotožněný. Nemůže uživateli služby poskytnout pomoc, službu z důvodu nesplnění stanovených kritérií státem anebo organizací poskytujících sociální pomoc. Pokud ani jedno z možných způsobů řešení nelze označit za “dobré“, výběr je rozporuplný a konečné rozhodnutí má být “menším zlem“ anebo “menším utrpením“. Riziko se zvyšuje tím, že rozhodnutí můž e být vnímané i jako (negativní) precedens. Jakékoliv rozhodnut í může přinést kromě nežádoucích důsledků i pocity viny, lítost a výčitky s vědom í, se kterými se ten, kdo dělá rozhodnutí, musí vyrovnat.“ (Janigová, 2008, s. 48) Oblastí v so ciální práci, kde mohou vznikat etická dilemata, střety zájm ů, je nespo čet. Můž eme sem zař adit kon flikty m ezi zaměs tnanc i organiz ace, ale také kon flikty mez i s amotným i už ivate li s lužby. Dále pa k st řet osobno stních hodn ot s hodnot ami organ izace. Nem alý vliv na pro blema tiku etiky rozhodov ání mají ho dnoty a z ájmy skupin o byvatelstv a v rámci k omunity neb o společnost i. Etické problémy a dilemata mohou být následkem konfliktních situací v práci pracovníků v sociálních službách. Podle podnětů z praxe autorky Ba nks (2010), uvádíme časté příčiny těchto p roblémů:  nedostatek zkušeností a znalostí pracovníka, který se může projevit v řešení náročnějších situací;  nejasné informace o roli osobního asistenta;  nedůvěryhodnost ve vztahu mezi koleg y;  přehlížení komplexnosti celé situace, kdy je pracovník zaměřen pouze na jednotlivosti. Nejspor nější oblast í etiky u pom áhajících prof esí je podle B anks (2010) konflikt mezi etickými hodnotami a prin cipy. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 47 Postupy při řešení etických problémů Etic ký kodex Spo lečnos ti sociáln ích pracov níků Česk é republi ky (2006) nabádá, jak řešit etické problémy. Jedná se o tato doporučení:  Hlavním právem pracovníka je diskuse, nejen se svým i kolegy, ale i s uživateli, kterých se problém týk á.  Závažné etické problémy jsou řešeny v rámci Společnosti sociálních pracovníků České republiky.  Společnost sociálních pracovníků České republiky může kodex přizpůsobit pro oblast terénní sociální práce, kde jsou etické problémy komplikované i závažné. Etický model rozhodování se se skládá z několika otáz ek. Jejich zodpovězení by nakonec mělo vytvořit eticky odpovědné rozhodnutí. Pomocí tohoto modelu se pracovníci v sociálních službách naučí pracovat s etickým i dilematy a kromě toho mohou zpětně hodnotit svá rozhodnutí. Pak lze hovořit o péči - službě, která je smysluplně posky tována. V praxi se stává, že jsou etické otázky opomíjeny. Pracovníci bývají stále častěji vyzýváni k tomu, aby se k nim stavěli věcně a efektivně. Hov oří se o vz růstajícím “taylorismu péče“ = běž ící pás v zem i blaha. To by znamena lo rychlejší dosahování výsledků, méně rozhovorů a na výkon péče průměrně méně minut. Standardizace a práce s protoko ly mají zvýšit účinnost práce a mno ho zá ležitostí je pečlivě zapiso váno pomocí vyvinutý ch systémů. (Haterd van de et al., 2000) Ani pom ocí Etického modelu rozhodování se není reálné vytvoření určitého v zorce, plného údajů, které nás zavedou k jednoznačném u řešení. Jestliže vycházíme z principu, že etika je proces, nikoliv řešení samo o sobě, stávají se východiskem otázky, které se snaží identifikovat podstatu daného etického problému. Samostatným bodem eti ckého rozhodování je logická analýza problému v návaznosti na řešení ce lé situace. Etický model rozhodování se je spíše nástrojem, který nám usnadní řešení dilemat bez přímého návodu ke k onkrétnímu rozhodnutí. Je potřebné si uvědomit, že potenciální uživatel služby se obrací na instituci za j istým účelem, potřebou pomoci či podpory, a přichází tedy s problémem nebos břemenem. Nestačí pouze potenciálního uživatele služby vy slechnout a nechat vypovídat. Pracovník se vyjadřuje k tomu, o čem potenciální uživatel služby hovoří. Při k aždé činnosti, kterou osobní asistent provádí, se bude zabývat (ne)vědomou otázkou: „Je to možné, nebo ne?“ Dalším autorem, který se kromě Haterd van de (2000) snaží o zdůraz - nění system atického přístu pu v procesu řešení dilema tických situací, je Ream er (2006). Stárek, L.: Etický model rozhodování se jako profesní nástroj 48 Navrhl systematický postup pomoci pracovníkům, kteří se dostanou do dilematické či eticky problematické situace, ve které je potřebné se rozhodnout. Tento přístup je tvořen sedmi následujícím i body: 1) identifikace etického problému, dilematu vyskytujícího se v konfliktu, včetně hodnot a povinností sociální prác e; 2) identif ikace jednotli vců, skupin neb o organizací, kterých se bude etic ké rozhodnutí pravděpodobně týkat; 3) zamyšlení se nad potencionálními přínosy a riziky konání pro všechny zúčastněné; zároveň můžeme určit více v ariant řešení; 4) důkladné prozkoumání výhod a nevýhod k aždé z variant řešení s ohle- dem na:  etický kodex a platnou le gislativu,  etické teorie, principy a směry,  praktické teorie a principy sociální práce,  osobní hodnoty v četně kultu ry, nábožen ství a etick ých hodnot; 5) konzultace s kolegy a příslušným i odborníky; 6) zajištění dokumentace k celému procesu rozhodování; 7) monitorov ání, zhodnocování a dokumentace rozhodnutí. Z výše uvedených modelů tedy plyne, že jedním z úkolů profesionála je umět řešit a rozhodnou t se v situacích, které můžeme vyhodnotit jako problem atické či eticky dilematick é. Et ický model rozhodování se (viz kapitola níž e) nebo Sy stemat ický pos tup řeš ení etic kých di lemat nen í zaruč eným náv odem ke správnému výsledku rozhodnutí, ale spíše by nám měl pomoci a tím ulehčit práci, jež s sebou přináší nemálo náročných situací. Podíl má také osobnost pracovníka, jeho zkušenosti a vědomosti. Zkušení pracovníci by měli předávat své poznatk y nově začínajícím a pokusit se eliminovat chyby, kterých se tito nezkušení pracovníci mohou dopustit na už ivatelích služeb. Význam etické ot ázk y pak narůstá společně s profesionalizací. Etické přístupy jsou součástí etických principů a hodnot celé společnosti a každý odborník stojí před volbou a měl by nést za tuto volbu odpovědnost. Etický model rozhodování se – Rob Sentse Model je sestaven ze čtyř základních pilířů, které mají napomoci při řešení ne jen etických dilemat. Prvním bodem je v ytyčení samotných faktů a stanovení osob, které na nich mají zájem. Navazujícím, druhým bode m, je popsání regulace chování a následků s tím spojených. První dvě otázky uvedeného m odelu jsou určeny zejména k tomu, aby mohla být situace nebo dilema co nejobjektivněji popsáno. Následu jící body (to jest III. a IV.) jsou propojené, a jelikož mají za úkol vybrat správné řešení a následně vést STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 49 k rozhodnutí, vybízejí osobního asistenta, aby chován í kvalifikoval za použití několika kritérií. I. Jaká jsou fakta a kdo jsou ti, kteří na nich ma jí zájem? (cui bono) Je důležité, aby osobní asistent inventarizoval veškerá relevantní fakta týkající se problémové situace, která má být vyřešena. Snaha o co nej - objektivnější pop is situace - dilematu a využít pro to vý stižných vět a slov. Nesmí dojít k převládání emocí, jelikož b y umožnily přijmutí jen určité představy nebo pohledu člověka. J e důležité si všimnout lidí (skupin) neb o institucí, které jsou účastné a mají zájem na dané problémové situaci. V případě, že se nám podaří splnit tato požadovaná kritéria, můžeme přistoupit k dalšímu kroku. II. Jaké jsou možné regulace chování a jaké j sou jejich následky? Pohled pracovníka má být realistický, ale zároveň kreativní. Využív at vědomého přístupu k uživateli služby a vytvořit si tak co nejvíce úhlů pohledu na j eho chování a vyhodnocování následků, kdyby dané chování bylo vykonáno. Přitom se vžívat do argumentů, úvah a zájmů lidí, kteří jsou účastni problému. Přemýšlet navíc o tom, jaké by to mohlo mít dopady na lidi nebo na organizaci. Nakonec bude nutné zjistit, do jaké míry osobní asistent může splnit původní otázku služby osobní as istence. III. Vyzkoušení různých možností řešení a je jich následky Vyzkoušení různých možností řešen í a jejich následky na základě těchto otázek:  Je to legální?  Jsou zváženy všechny zájmy?  Je to možné uskutečnit? Každé řešení a jeho následky je nutné posoudit v rámci morální správnosti, zodpovězení výše zmíněných otázek. Tyto otázky zde více rozvedeme: Je to legální? Zde je nutné posoudit legalitu různých možností řešení a jejich následků. Jsou volbou určitého řešení ohrož eny stávající zákony nebo pravidla platná buď v rámci společnosti, nebo vlastní organizace? Hranice, v rámci kterých bude možné rozhodnutí odůvodnit, udáv ají tak referenční rámec či kontrolní bod. Překročení těchto hranic je v rá mci platné kultury společnosti a organizace dovoleno pouze imaginárně. Tento referenční rámec je hlavně vytvářen zákony či zákonodárstvím . Stárek, L.: Etický model rozhodování se jako profesní nástroj 50 Jsou zváženy veškeré zájmy? Jsou- li zváženy veškeré zájmy, použ ijeme následujících pomocných otázek:  Je rozhodnutí mezi osobními záj m y a zájmy organizace ospravedlni - telné?  Je to ospravedlni telné pro všechny zúčastněné, jak z krátkodobého, tak z dlouhodobého hlediska?  Jsou vol bou určitého řeš ení rovnom ěrně rozdělen y pozitivní a neg ativní následky mezi různými zainteresovaným i stranami? Je možné uskutečnění? U této otázky osobní asistent posuzuje každou formu péče podle svých osobních hodnot a norem. Posouzení může proběhnout na základě následujících otázek:  Byl bych hrdý na zvolené řešení?  Jak bych se cítil, kdyby moje rodina by la informovaná o této volbě?  Kdyby ch byl nejd ůležitějším účastníkem (nikoliv os obním asistentem), jak bych se pak cítil, kdyby bylo zv oleno toto řešení? IV. Možnost rozhodnutí se Pokud je zvoleno řešení, mělo by být přijato. Člověk si klade různé druhy ot ázek v návazno sti na informac e, prohlášení nebo pomoc. Jed na z těchto otázek by se měla týkat smyslu a vý znamu existence , jedná se tedy o ex istenční otázky. Zde st ojí centrálně vztah mezi JÁ a TY ve vztahu ke zvážení dobra a zla. (Sentse, 2010) Výzkum V rámci výzkumného cíle jsme zjišťovali využitelnosti Etického modelu rozhodování se v každodenní praxi pracovníků v sociálních službách, konkrétně osobních asistentů, j enž jsou konfrontováni s konk rétními etickým i otázkami. Jejich uvědomění si, hledání odpovědí na tyto otázky a přemýšlení o nich, však vyžaduje potřebnou péči a čas. V rámci výzkumu jsme se též zaměřili na obeznámenost s etickým kodexem, který by měl určovat směr profesního jednání. Aby pracovník mohl v praxi řešit nejen etická dilemata, měl by tedy znát svůj vlastní kodex a umět je j aplikovat. Součástí výzkum u byla realizace pracovního setkání – workshopu , kde byl pracovníkům osobní asistenc e představen Etický model rozhodování se, včetně detailního prakticistního postupu, jak jej využít v rámci své každodenní práce, včetně konkrétních situací/okamžiků s kterými se mohou set kat p ři výkonu svého povolání. Se tkání trvalo cca 180 m inut, za účasti všech respondentů, kteří byli zapojeni do výzkumu. Od realizace workshopu STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 51 a prvního rozhovoru uplynula doba 4 měsíců. Důvodem byla možnost aplikovatelnosti získaných poznatků do praxe, s možností využití odborné konzultace. Příprava a průběh rozhovoru Jako pomocný scénář pro vedení rozhovorů jsme využili připravenou strukturu vztahující se k tématu, jenž pramenila z obecných t em atických okruhů. Témata rozhovorů vycházela ze z aměření celého výzkumu. Jak využív ají osobní asistenti mohou pracovat s Etickým modelem rozhodování se? Jak uplatňují etický kodex při řešení etických dilemat? Na některé okolnosti (konkrétní postupy, e tická dilemata, popis krizové nebo náročné situace při výkonu povolání) j sm e se více vybavili dalšími, podrobnějšími otázkami. Uvědomovali jsme si riziko, skryté v tom, že rozhovor s pevně danou a připravenou strukturou otázek by mohl být poněkud zkreslující. Tudíž byly použity okruhové otázky, které jsme dále modifikovali dle průběhu rozhovoru s jednotlivými respondenty. Pro některé respondenty bylo však potřebné dotazy přizpůsobit, tak aby jim osobní asistenti byli schopni porozumět a orientovat se v tématu a jeho závažnosti. Celkem proběhlo pět polo strukturovaných rozhovorů , respondenti vyslovili souhlas s provedením rozhovoru a s následným využitím pro interpretaci získaných údajů. Nikdo z oslovených osobních asistentů neodmítl prosbu o rozhovor pro výzkumné účely. Pro zaznamenávání celého interview jsme využili diktafon. Každý z respondentů byl obez námen s využitím této technik y a nikdo proti tomu nic nenamítal. V případě, že by některý z respondentů nesouhlasil s využitím diktafonu, byla připravena varianta zaznamenávání odpovědí respondentů písemně během rozhovoru. Interview probíhalo v prostorách kanceláře, kterou pracovníci znají. Byla jim nabídnuta možnost provedení interview v kavárně či na místě, kde by se oni sami cítili příjemně. Nikdo z dotazovaný c h takové nabídky nevy užil. Setkání vždy probíhala bez přítomn osti tř etích osob, kterých se to ne týkalo. Vytvoře ní ot evřených kontak tů byl o zp rvu u všech respo ndentů navozeno obecnými otázkami k tématu, clem bylo získání důvěry. Vytvoření přátelské atmosféry, být taktní a projevit přiměřený zájem o výpovědi respond enta pom ohlo k d osažení uvolněného rozhovoru. V průběhu rozhovor u jsme dbali na to, aby nebyla použita slova, kterým by respondent nerozuměl. Otázky byly formul ovány neutrálně tak, aby ned ošlo k naznačová ní oček ávané odpovědi. Měli jsme snahu klást stručné otázky, pokud možno v holých větách. Byla volena strategická metoda, kdy otázky začínaly u obecn ějších problémů/okruhů t ém at a následně se zaměřovaly na zcela konkrétní témata. Úkolem tazatele b ylo, aby při všech interview byly kladeny otázky standardi - zovaně, se stejný m akcentem. Nebyla opomenuta analýza reakcí respondentů , Stárek, L.: Etický model rozhodování se jako profesní nástroj 52 jejich chování a také neverbálního vyjadřování během rozhovoru – pohyby těla, gesta, pohyby obličeje, mimika, úsměv, smích, pohledy očí. Všech pět rozhovorů proběhlo bez žádné nenadálé č i trapné situace, k terá by mohla narušit důvěru mezi respondentem a tazatelem. Všech pět vybraných osobních asistentů projev ilo maximální v střícnost, ale tak é zájem o téma. Průměrná časová dotace každého rozhovoru trvala cca 45 m inut. Charakteristika respondentů , cílová skupina respondentů nebyla nikterak omez ena pohlavím, věkem, barvou ple ti, náboženským vyznáním, dosaže ným vzděláním nebo délko u působení v pracovní poz ici osobní asis tent – prac ovník v sociálních službách. Abych om mohl i zodp ovědět výzkumné otázky, získali jsme informace od určité skupiny lidí. Jedná se o pracovníky, kteří jsou zařazeni do pracovní pozice “pracovník v sociálních službách – osobní asistent“ a vyk onávají tak terénní službu osobní asistence. Výzkumný vzorek je tedy tvořen pracovníky ze služeb osobní asistence, a to dvou neziskových organizací, k teré p rimárně nabízejí služby osobní asistence. Organizace jsou rozdílné. Především v tom, že jedna z nich nabízí služby nejen v Praze, ale také v dalších krajích České republiky. Posláním této organiza ce je snaha o maxim ální možné zapoje ní svých uživa telů do jejich přirozené sociální sítě a společnosti. Druhá organizace je jiná, pokud jde o působnost. Své služby nabízí v Praze a občas také ve Středočeském kraji a má omezenou kapacitu na 40 uživatelů sl užby . Posláním této organizace je podpořit sociální začlenění dětí se zdravotním postižením. Tabulka 1: Přehled osobních asistentů, s nimiž byl proveden rozhovor STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 53 Výzkumné zjištění Etický model rozhodování byl prezentován jako další z možných nástrojů, v součinnosti s etickým kodexem, tak aby bylo patrné, že záměrem není tvrzení , že by osobní asistenti vykonávali svou práci dobře nebo špatně. Primárním cílem je v yužitelnost nástroje, který může upozornit a podpořit vazbu mezi etikou a každodenní činností pracovníků. Primárně z workshopu, který se zaměřoval na prezentaci Etického modelu rozhodování se, je patrné, že pracovní ci př ijímají nové informac i s ak tivním zapojením . Jejich zpracová ní a aplikovatelnost v praxi je pak náročnější. Celkem 4 respondenti, za zmiňovaný časový úsek – tj. nejméně 4 měsíců, se snažili v praxi uplatnit Etický model rozhodování se. Stěžejní oblastí, která byla pro všechny responden ty, kteří využili Modelu, náročná a ne vž dy naplněna, po dstata nabídk y „všech“ mož ných variant ře šení. Primár ní situace, kdy pracovníci využili Modelu, byly ve vztahu pracovník a klient. Další problémovou oblastí byla podstata možnosti rozhodnou se, a to ze st rany uživatele služby. Tendence pracovník ů by la založena na komunikaci s uživ atelem služby , na společné diskusi, ale t endence k r ozhodnutí či f inálnímu výsledku přicházela ze strany pracovník a. Z rozhovorů vyplynula skutečnost, že obeznám ení s etickým kod exem dané organizace proběhlo, ale bylo spíše na formální bázi. Respondentka R1 poukazuje na skutečnost, že prioritou pro pracovníka je vždy pracovní smlouva. Přílohám , které jsou přikládány k e smlouvě, kde je právě etický kodex dané organizace, dále pak c íle a poslání organizace atd., není věnována taková míra pozornosti, jaká by měla být. Z rozhovoru s respondentkou R1 vyplývá, že teoretická a praktická znalost etického ko dexu je minimální. Tato skutečnost je způsobena především přístupem zaměstnavatelů v otázkách seznámení nově nastoupeného osobního a sistenta se samotnou smlouvou a etickým kodexem a dalšími dokumenty, které jsou „pouze“ přílohou. Rozhovor s respondentkou R1 poukázal na skutečnost, jak jsou křehké hranice mezi uživatelem služby a osobním asistentem, které mohou být narušeny jakoukoliv „maličkostí“, která se pak následně stává etickým dilematem. Dilematem nejen pro osobního asistenta, ale i pro uživatele služby. Důležitost znalosti a praktick ého využití kodexu se tedy jeví jako potřebná, aby bylo možné některým etickým dilematům př edcházet. Morální rozpor se může objevovat v každodenních činnostech a situacích, které tvoří pracovní náplň osobního as istenta. Prvek výskytu morálního rozporu je patrný, ale osobní nastavení aktérů – osobních as istentů již tak zřetelný není. Z rozhovoru bylo zjištěno, že převážná část respondentů (4 osobní asistenti) přistupují k oblasti předávání informací o uživateli služby vůči někomu dalšímu zodpovědně. Můžeme se jen domnívat, jaké faktory tuto skutečnost tvoří, zda jde o osobní nastavení as istenta, který si na základě vlastní zkušenosti uvědomuje důležitost a citlivost získaných údajů, nebo o znalost práv uživatele služby a osobního asistenta, kdy citlivost s osobními Stárek, L.: Etický model rozhodování se jako profesní nástroj 54 údaji je prioritou. Roli má zajisté i etický kodex a jeho znalost. Z rozhovorů vyplynula skutečnost, že citlivost ve vztahu k osobním údajům není pro prac ovník a pouhý m práz dným po jmem. Z rozho vorů, předev ším s re spond entkou číslo 1, bylo patrné pozastaven í se u smý šlení výkonu práce a etick ého jednání. V praxi se setkáv áme se situacemi, které nazý váme nebo je řadíme do etický ch dilemat. Je patrné, že respondenti mají povědomí o existenci etického kodexu. Problematickou oblastí zůstává efektivní použite lnost etického kodexu a jeho propojení na každodenní výkon povolání. Analýzy roz hovorů poukazuj í, ž e oso bní asistenti jsou žádá ni o služ by, které nejsou vym ezeny ve smlouvě s uživatelem služby. Hlavním faktorem je měnící se zdrav otní stav uživatelů služby . Služby – úkony, které uživatel služby požaduje, jsou různé a někdy mohou být pro osobního asistenta překvapující. Tato skutečnost se následně může projevit i vznikem etického dilematu: ač osobní asistent zná náplň své práce, na druhé straně je uživatel služby, který se obrací s prosbou o pomoc. Z rozh ovoru s respondentem R3 je patrné, že osobní asistence je někdy úzce propojena se vznikem přátelství s uživatelem služby. Vymezení se v rámci nead ekvátních požadavků je v takto nastavených vztazích složitější. Otázkou může být, zda právě přátelské vztahy m ezi osobními asistenty a uživateli služby mohou minimalizovat etická dilemata. Etické jednání je potřebné vnímat nejen ze strany pracovníků, ale také ze strany uživatelů služby. Přibývá více situací, kdy se uživatelé služby nechovají adekvátně a jejich ataky směřují právě na osobní asistenty. Osobní asistent je člověk, který by v rámci své profesionality měl zvládat takto náročné situace, ač se jedná o okamž iky psychicky náročné. Z rozh ovorů je patrn é, ž e se u uživatelů služby setkávám e s či nnostmi, které jim šk odí. Okolnosti, které to způsobují, jsou různé – ať už se jedná o alkohol, nedodržování pitného režimu nebo nezdravé stravování. Osobní asistenti by měli být připraveni na takové si tuace/ okamžiky a vědět, jak postupovat. Nejen vedoucí pracovník, ale p rá vě i etický kodex je jednou z možných variant, jak se nad věcí zamyslet a začít hledat řešení a správný postup. Pestrost etických dilemat v každodenní praxi osobních asistentů se potvrdila. Znalost a podstata etického kodexu není úplně nulová, ale zvolen í řešení nebo posto je k dané situaci s vazbou na etický kod ex se zde nepotvrdila. Jedná se o subjektivní pohled pracovníků, kteří jsou v přímém kontaktu s uživatelem. Nutno podotknout, že uživatelé sociálních služeb mají plné právo rozhodovat o svém životě a nesou zodpov ědnost za tato rozhodnutí. Jednou z hlavních myšlenek, která vychází z Etického kodexu Společnosti sociálních pracovníků České republiky (2006), je vzájemná podpora a možnost pomoci, kter ou můžeme očekávat od kolegů. Prvotním krokem j sou právě kladné vztahy na pracovišti, kterým napomáháme především tím, že respektujeme znalosti a zkušenosti nej en svých kolegů, al e i ostatn ích odborník ů. Respondent i, s kterými byl proveden rozhov or, potvrzují, že sdílení informací je pro kvalitní péči o uživatele služby nezbytné a v tomto STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 55 ohledu nezáleží na délce praxe a ani na úrovni vzdělání. Z uvedených informací lze vyvodit, že osobní asistenti užívají pro přenos informací nejvíce telefon nebo e- mail. Tato skutečnost je dán a rychlostí přenosu informací v návaznosti na nutnost rychlého reagování v rámci služby osobní asistence. Respondenti v oblasti přenosu informací nepoukázali na možnost etických dilemat. Přínosem je však skutečnost, že dochází k setkáním mimo pracovní dobu, což může pozitivně ovlivňovat vztahy na pracovišti a vypovídá to i o atmosféře v organizaci a také o kultuře organizace. Organizace, které nabízejí služby osobní asistence, jsou tvořeny týmem spolupracovníků, a to klade velký důraz na spolupráci. Jedním z úskalí, k terá by měla týmová spolupráce překonat, je právě špatná komunikace a nesdílen í informací nebo jejich špatný přenos. Proto je nezbytné, aby zaměstnanci uměli komunikovat a sdílet informace nejen s uživateli služby , ale také vzájemně mezi sebou. Při rozhov orech byla většin a (4 respondenti) ve vnímání společen ského uznání na stupních leh ce nadprům ěrného společ enské uznán í; vyšší spole čenské uznání a vysoké společen ské uznání. Respondent R3 výstižně popsal, jak uznání vnímá nejen on sá m, ale i jeho okolí. Důležitým prvkem je, jak je povolání osobního asistenta prezentováno a jak jej prezentuje především samotný pracovník vůči okolí. Závěrem V kaž dém pov olání s e prolín á osobn ost jedi nce a jeh o post oj k mor álním hodnotám a k morálce. Z toho plyne, že morální povinností osobního asistenta je zůstat stále se učícím profesionálem, účastnit se vzdělávání a školení v uznaných školicích střed iscích, s ledovat odbornou literaturu, k onzultovat s kolegy, učit se z minulých případů, sdílet znalosti a pracovat na schopnosti tvoření morálního úsudku. Přemýšlení a diskutování o etických otázkách v osob ní asi stenci, nepřichá zí sam o o sobě. Krom ě času je předev ším nez bytná vstřícnost, empatie, ale také jistá míra discip líny. Ač nechceme hodnotit etický kodex organizace či Etický model rozhodování se, tak je patrná positivní reakce ze strany pracovníků. Otázkou dále zůstává jejich odborné vedení, a zjišťování refl exe na okolnosti v kterých chtěli či se snažili uplatňovat dva stěžejní nástroje, kterým byl věnován výše uvedený t ext. Problematickou oblastí zůstává tedy efektivní použitelnost etického kodexu a Etického modelu rozhodování se ve vztahu k propojení na každodenní výkon povolání dané profese. Morální orientace osobních asistentů – pracov níků v sociálních službách je v klíčové pozici v oblasti vzniku a násled ného zpracován í eti ckého dilematu. Po ukazujeme na potřebn ost hlubší orientace v samotné profesi za stá l ého podporování zájmu o vztah k uživateli služby i k organizaci. Zjištěn í plynoucí pro prax i jsou patrná v sam otném základu pr ofesiona - lity sociální pedagogiky či so ciální práce. Jestliže podporujeme myšlenku profesionalizace, tak je nedílnou součástí tohoto procesu etika a profesní Stárek, L.: Etický model rozhodování se jako profesní nástroj 56 etika. Výzkum poukazuje na realistické využívání zejména etických kodexů. Otázka se tedy vztahuje k formě, nastavení a obsahu těchto dokumentů, které jsou v současné době nedílnou součástí profese, ale jsou velice povrchně poja ty. Plynoucím dopo ručením je tedy zohledňovat pro fesní profil daných pracovníků, k dy nejsou jen sociálními pracovníky , sociálními pedagog y či pracovníky v sociálních službách, ale stávají se z nich odborníci na danou oblast s ohledem na zaměření pomoci a podpory určité cílové skupiny (děti, seni oři, oso by s post ižením at d.) či urči té oblast i (sociá lní práce v e zdravot nictv í, školství atd.). Je tedy nutná modifikace a specifikace oblasti etiky s ohledem na profesní zaměření pracovníka či specializace na cílovou skupinu. Následně pak může daný pracovník lépe identifikovat možná úskalí nejen ve vztahu k práci jako takové, ale i k sobě samotnému. Etika profe sního života by měla korespondovat s etikou celkového života. Je nezby tné vážit si osobní kvality a morálního stanoviska každého spolupracovníka. Kromě kodifikovaných pravidel a e tických z ásad, které je nutno dodrž ovat, je pro profesi sociální práce důležité a nepostradatelné, aby pracovník měl vysokou úroveň mravních a osobních hodnot. Etika je nedílnou součástí osobní asistence. Bibliografie BANKS, S., 2010. Interprofessional ethics: A dev eloping field? Notes from the Ethics & Social Welfare Conference, Shef field, UK, May 2010. Ethics and Social Welfare , 4(3), 280-94. HATERD van de, J. et al., 2000. Beroepsprofiel van h elpenden en verzorgenden. Utrecht: Elsevier Gezondheidszorg /LCVV. ISBN 90-352-2332-2. JANIGOVÁ, E., 2008. O manažmente v sociálnej prác i. Ružomberok: Pedagogická fakulta, Katolícka univerzita v Ruž omberku, s. 48. ISBN 978-80-84-301-4. JANOUŠKOVÁ, K., NEDĚLNÍKOVÁ, D ., 2008. Profesní dovednosti terénních pracovníků. Ostrava: Grafico. I SBN 978-80-7368-503-4. LEVY, S. Ch., 1992. Social Work Ethics on the L ine. London: The Hawort Press. ISBN 1-56024-283- 3. MÁTEL, A. et al. 2010. Aplikovaná etika v sociální práci. Brno: Institut mezioborových studií Brno, s. 110. ISB N 978 -80-87182-13-0. NEČASOVÁ, M., 2010. Profesionalismus a et ické kodexy v sociální práci. In: FISCHER, O., MILFAIT, R. et al. Etika pro soc iální práci. Praha, JABOK, s. 93. ISBN 978- 80 - 904137-7-1. POLUTTA , A., RETKO WSKI, A., 2020. Soziale Arb eit als Beru f – Proffes ion und Ethik . Stuttgart, Barbara Budrich, UTB. ISB N 978-3-8252-4577-1. REAMER, G. F., 2013. Social Work Values and Et hics. New York: Columbia University Press. ISBN 978-0-231-53534-2. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 57 ROLNÝ, I., 1998. Etika v podnikové strategii. Boskov ice: Albert, s. 30, 74. ISBN 80-7261-122-4. SENTSE, R.. Levensbeschouwing & Ethiek. Eindhoven. [cit. 12. 02. 2019]. Dostupné z: http://pt.slideshare.net/RobSents eBc/ethisch- besluitvormingsmodel SPOLEČ NOST SOCIÁL NÍCH PRACO VNÍKŮ ČR. Etický kodex S polečnost i sociálních pracovníků ČR [online]. [cit. 20. 04. 2019 ]. Dostupné z: http://s ocialniprac ovnici.cz/ public/uploa d/image/et icky_kodex _sspcr.pdf STÁREK, L., 2015. Etika v práci osobních asis tentů . Praha. Disertační práce, Pedagogická fakulta, obor studia: Speciální p edagogika. ID práce 100098. ÚLEHLA, I., 2005. Umění pomáhat: učebnice me tod sociální praxe. Praha: Sociologické nakladatelství. ISBN 978 -80-86429- 36-6. Zákon č. 108/2006 Sb., o sociálních službách. I n : Sbírka zákonů České republiky . 14. 03. 2018. ISSN 1211- 1244. Dostupné z : https://www.zakonyprolidi.cz/cs/2006-108 Mgr. Lukáš Stárek, Ph.D., MBA Katedra speciální pedagogiky Univerzita Jana Amose Komensk ého Praha Roháčova 1148/63, 130 00 Praha 3 [email protected] Ligoš, M.: Tri piliere kvalitatívnej transformácie výučby materinského jazyka I. (Rámcové východiská) 58 Tri piliere kvalitatívnej transformáci e výučby materinského jazyka I. (Rámcové východisk á) Three Pillars of Qualitative Transform ation of Teaching of Mother Tongue I. (Framework Starting Points) Milan Ligoš Abstract The article explains the framework starting points of the qualitative trans format ion of teachi ng of the mot her ton gue in Europe an edu cationa l background. Based on the opening of wider context of the dynamics of socio-cul tural conditions, the author points to the area of new challenges and dimensions of teaching o f the mother tongue on the level o f general starting points in the intentions of integrated profiling of graduates for the 21 st century. He moves from general to specific, targe ted teaching of the mother tongue, acknowledging the creation of curricular documents as well as highlig hting the progr essive tendencies of the most successful school system in the w orld. General principles and target attributes of the European education policy lead to s pec ification of the expected competences of school graduates, which are specifically reflected in the area of the educational programme for teaching of the mother tongue. Keywords: Education. Teaching. Mother tong ue. Competence. Curriculum. Project of the teaching subject. Úvod Aktu álnos ť kval itatív nej tr ansfo rmácie vyuč ovania mater inské ho jaz yka v stredoeurópskom geopo litickom priestore po r. 1989 vidím v kontexte histo rických spoločensko - kultúrnych zmien v integrácii postsocialistických krajín do vyspelého európsk eho sveta. V syntetick ej podobe som sa tým to otázkam venoval v štúdii Współczesność i przyszłość nauczania języka ojczy stego w środkowoeu ropejskiej przestrzen i kszta łcenia (z uwzględn ieniem języ ka słow ackieg o, czesk iego, niem ieckie go i p olskieg o), ktorá ak tuálne (2 020) vyšla v Poľsku 1 . Z nej vyberám niektoré relevantné myšlienky do úvodu pred - kladan ého príspevku. Ak o už naznačuje jeho názov , ťažiskovo potom pr iblížim 1 Odkazy na zdroje vo východiskách k predkladanému príspevku sa nachádzajú v tejto štúdii. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 59 tri základné piliere alebo nosníky kvalitatívnej zmeny výučby materinského jazyka z pozície súčasnosti s roztvorením problematiky do budúcnosti. V uv edene j štúdii som sa z aobera l najm ä pohľa dom na is tú kom patibi litu školstv a stredoeuróp skych postso cialistick ých krajín so v zdelávacím pr iestorom Európy i vy spelým školstv om sveta s konkretiz áciou a aktualizácio u na vý učbu materinského (vyučovacieho) jazyka v kontinuu súčasnosti a budúcnosti. Na najvšeobecnejšej úrovni je súčasná európska vzdelávacia koncepcia postavená na štyroch strategických c ieľový ch pilieroch, a to: učiť sa žiť, učiť, konať a spolupracovať. Z nich sa odvíjajú cieľové zámery druhej úrovne v podobe 8 nosnýc h kom petencií, ktoré Európ sky parlament a Rada Európ y (2006/962/ES) stanovili ako rozhodujúce a strategické pre v zdel ávanie občanov Európy v 21. storočí. Ide o tieto ťažisk ové kompetencie: komunikácia v materinskom jazyku (ďalej aj MJ ) a komunikácia v cudzích jazykoch, matematická a príro - dovedná kompetencia, kompetencia v oblasti informačno - komunikačných technológií, kultúrna kompetencia, kompetencia učiť sa ako sa učiť, kompe - tencia riešiť problémy , osobnostná, sociálna a občianska kompetencia. Tieto kompetencie tvoria podlož ie pre stanovenie cieľov tretej úrovne, a to jednak v obla sti kľúčový ch nadpredm etových kompetenc ií a jednak základných osobnostných kompetencií. Pre výučbu materinských jazykov nadpredmetové kľú čové kompet encie sú orient ované prim árne na oblasť získ avania kog nitívn ej, komunikačnej, personálnej, sociálnej a kultúrnej kompetencie. So zreteľom na osobn ostné dimenzie je pre vzdelávanie nosný tvorivo - humanistický model, ktorý zohľadňuje rozvíjanie hlavných sfér osobnosti žiaka kognitívneho a nonkognitívneho charakteru, ktoré sa vzťahujú na: kognitívnu, emocion álnu, motiva čnú, sociálnu, axioolog ickú, kreatívnu a spirituálno - duchovnú dimenz iu. Tento model poznáme pod akronymom KEMSAKS (pozri bližšie Zelina, 2011; Ligoš, 2003; Lig oš et al. 2011). Na báze týchto cieľov ých úrov ní sa potom odvíjajú v národných vzdelávacích programoch základné vzdelávacie oblasti a kurikulá jednotlivých vzdelávacích odborov a učebných predmetov. V rámci kurikúl sú stanovené špecifické predmetové kompetencie v postupnej konkretizácii k čiastkovým predmetovým kompetenciám až po jednotlivé deskrip tory, t. j. elementárne jednotky c ieľ ovo- obsa hového zam erania učebn ého predmetu ako náplň al ebo k onkrétne učivo. Tento strategický postup vidím ako presýp acie ho diny č i spoje né nád oby, k eď v pr ojektov aní uč ebného predm etu pracujeme s otázkou „presýpania“, t. j. postupného zužovania a konkreti zácie zámerov vzdelávace j politiky ku elementárny m jednotkám vzdelávania (t émam, deskriptorom, cieľom, obsahu, metódam a pod.), realizáciou ktorých m áme v ka ždode nnej a neop akova teľnej pedag ogick ej praxi mať na z reteli rev erzibi lný postup „presýpania“, t. j. dosahovanie č oraz širších cieľov vzdelávania c ez jednotlivé stupne zámerov až po štyri základné méty, resp. strategické piliere moderného európskeho vzdelávania. Vo výučbe jazykov bol EK najskôr v r. 1996 prijatý Spoločný európsky referenčný rámec pre jazyky (SERR) a následne aj Európsky indikátor jazyk ových kompetencií, podľa ktorého si štáty na národnej úrovni Ligoš, M.: Tri piliere kvalitatívnej transformácie výučby materinského jazyka I. (Rámcové východiská) 60 rozpracovali istý štandard ovládania cudzích jazykov na šiestich referenčných úrovniach. V praxi sa potvrdili špecifiká osvojovania si materinského j azy ka v kont exte socio- ku ltúrnej komu nikácie, preto v EÚ do popredia vy stúpil zámer pripraviť aj SERR pre vyučovanie materinských jazykov. V tejto súvislost i sa v roko ch 2005- 2006 kon ali reprezentatív ne konferenc ie v Štrasburg u a Krakove k vypra covaniu štandardizácie úrovní ovládania MJ, avšak tento projekt zatiaľ zostal v rámci EÚ ne dokončený. 2 V r. 201 6 vyšla v anglickej mu tácii publik ácia Teaching of Nati onal Languag es in the V4 Countrie s (Vyučovanie národných jazykov v krajinách Vyšehrádskej štvorky), v ktorej sa celkove potvrdila istá podobnosť v spoloč enskom vývoji i v teórii a praxi vyučov ania materinského jazy ka. V tý chto post social istický ch štáto ch stredn ej Európy je p ríznač ný príklo n ku integrovanej koncepcii jazykovo- komunikačnej a lite rárne j komunikácie so záž itkovým , konštr uktivi stickým a holist ickým prí stupom k rozvíja niu osob nosti. žiaka. Avšak analy zujúc silné a slabé stránky národný ch edu kačných systémov autori publikácie zhodne konštatujú istú diskrepanciu medzi požiadavkami didak tickej teórie a deklarovanými zámermi v pedagogických dokum entoch a reálnou štátnou vzdelávacou politikou s markantným negatívnym dopadom na š kolskú prax. Je to v zhode s moji mi skú senosť ami a zisteni ami, p odľa k torýc h na viacerých miestach publikačných výstupov konštatujem túto tendenciu vo vyuč ovaní sloven činy vý razne od Februá ra 1948 v Česko sloven sku. I šlo o z námy rozpor medzi deklarovanými cieľmi, často i propagandisticky pr edkladaným i zámermi ústredných orgánov v programových vyhláseniach, zákonoch a i . dokumentov na j ednej strane a koncepciou i obsahovou náplňou spracovania východiskových podkladov, najmä však v kolízii s reálnou praxou na strane druhej. Podľa cit. príspevku (Ligoš, 2020) súčasnú koncepciu vy učovania slov enčiny ch arakte rizujem e ak o vy ústen ie p rogres ívnych hist orický ch tendenc ií v kontexte nových výziev moderného európskeho vzdelávania, ktoré v genéze post upne sme rovali k vyv ažovan iu jazyko vo - sys témove j (aj slohov o - syst émovej , literárn o - systém ovej) a kognitív no - komunik ačnej (aj kultú rn o- literárne j) výcho - vy, a to v integrácii smerom ku holistickému poňatiu v intenciách rozvíjania istých kompetencií a scho pností žiaka. V tomto zmysle súčasnú koncepciu vyučovania slovenčiny chápem e predovšetkým ako integračnú komunikačno - - kognit ívnu a zá žitkovú (poz ri najmä Liptákov á et al., 2015, s. 12; Ligoš, 2019 , s. 170). V pod state to znamená, že vy chádzajúc z na jnovších pozna tkov lingvo - didaktiky a pedagogicko-psychologicke j i odborovo-didaktickej vednej oblasti modernú koncepciu vyučovania materinského jazyka vidíme na podloží ťažisk ových všeobecn odidaktický ch a lingvistic ko- literárno vedných princ ípov, vrátane princípov rečovo - komunikačnej ontogenézy žiaka, smerujúce od 2 Na Slo vensku bol dokončený projekt KEGA (č, 3/2245/04) Štandardizácia úrovní ovládania slovensk ého jazyka s výst upom v r. 2008, ktorý koordinovala FF UCM v T rnave so zodpoved nou riešiteľkou E. Nemcovou. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 61 kognitívneho (konceptuálneho) kurikula cez transform áciu ku didaktickému projekt u uče bného predmetu (didaktickému systému, modelu) a na tejto báze sa približujeme k projektovaniu edukačnej praxe či jej realizácii, t. j. ku realizovanému a dosiahnutému kurikulu (porov. Lipták ová et al., 2015, s. 33 – 35). Hlavný problém pri aplikácii u vedene j koncepci e v praxi vyvstáva v tom, že v centrálnych pedagogických dokumentoch v intenciách jej postupnej konkre tizácie, t. j. na úrovni Štátneho vzd elávacieho prog ramu (ŠVP) a vzdelá - vacích štandardov na vyučovanie slovenského jazyka a literatúry (VŠ na SJL) ich spracovanie „sklzáva“ do podoby tradičného teoreticko - akademického programu, v ktorom reálne do po predia vystupuje sy stém, štruk túra, po jmy, faktuálne, prípadne i k onceptuálne znalosti a absentuje kontext v reláciá ch s očak ávaným zvládnutím jazykovo - k omunikačný ch kom petencií, s rozvíjaním vyšších k ognitívnych funkcii, kritického my slenia, riešenia komunikačných situácií a pod. s métou profilácie integráln ej osobnosti žiaka. Do východísk a úv odu zaradím ešte niekoľko vybraných m yšlienok z medzinárodných meraní najlepších škôl vo svete z ostatného obdobia (pozri podrobnejšie Ligoš, 2020, 3. časť). Metriky v medzinárodný ch kontextoch a komparáciách sa výraznejšie dostávali do popre dia v 2. polovici minulého storočia najmä v rámci UNESCO a OCED, ktoré boli zamerané primárne na meranie dosahovania funkčnej gramotnosti s preferovaním čitateľskej gramotnosti a vôbec čitateľskej kultúrnej gramotnosti žiakov primárneho a nižšieho sekundárneho vzdelávania, u 15- ročných sa testovanie orientovalo i na matematickú a prírodovednú gramotnosť, pri čom postupne pribúdajú i pa ramet re sociál no - kul túrnej ko mpete ncie, tím ovej prác e či kritic kého mys lenia a hodnotenia (testovanie PIRLS, TIMSS, PISA a i. ). Inou oblasťou je metrika Prog ramu medz ináro dného hod noten ia kompete ncie dosp elých (PI AAC) OEC D. V ostatnom období sú aktuálne i otázky zvládnutia cudzích jazykov (podľa SERR EÚ jazyk ový pas, jazykov é portfólio, v US A štandardizov ané testy ACT zamera né n a predpoklady v o blasti angličti ny, matematik y, čítania a prírod ných vied, nehovoriac o problematike merania rankingov VŠ) alebo úrovne telesnej kultúry a zdatnosti. Do tohto okruhu by sme mohli zaradiť i tradičné talentov é a iné pre dpoklady u chádzačov o štúdium, r esp. o isté fu nkčné miest a a pracovné pozície, ale to je už oblasť mim o záujmu tohto príspevku. Vráťme sa teda k rezortu školstva. Sloven sko s os tatnými stredoeurópsk ymi po stsocialistic kými kr ajinami sa po r. 2000 na úrovni regionálneho školstva z apája v etablovanej metrike PISA v rámci OCED a r elevantnú výpovednú hodnotu má i zostavovanie rebríčka najvyspelejšieho školstva vo sv ete, napr. známe výstupy Top 40 krajín s najlepšími školami, zverejnené na portáloch britskej vysielacej stanice BBC. Pr i tomto probléme sa bližšie pristavím nižšie v prvom tematickom okruhu tohto textu. Na úvod tu len spomeniem, že podľa posledného merania v r. 2018 (pozri zverejnené výsledky PISA, 9.12.2019, dostupné online na: https://www.nucem.sk/dl/4628/Priloha_vysledky _kra-jin_PISA_2018.pdf) SR sa zo 79 krajín v čitateľskej gramotnosti umiestnila pod priemerným výkonom Ligoš, M.: Tri piliere kvalitatívnej transformácie výučby materinského jazyka I. (Rámcové východiská) 62 (skóre 458), v tejto kategórii aj Maďarsk o (sk óre 476), s priemerný m výkonom ČR, avšak v prvej desiatke bolo Poľsko (na 10. mieste so skóre 512 za takým i krajinami, ako B-S-J- Z (Čína), Singapur, M akao (Čína), Honk ong, Kanada, Fínsko, Írsko a Južná Kórea. Pod priemernými výsledkami sa Slovensko umiestnilo i v prírodovednej gramotnosti, pričom v matematickej kompetencii malo lepšie výsledky o jednu kategóriu (na priemernej úrovni), pričom ČR si udržala v matematic kej i prírodov ednej oblasti nadprieme rné výsledky a Poľsku patr ilo 10 . mies to nie len v č itateľs kej, a le aj m atemat ickej g ramot nosti, 11. m iesto obsadilo v obla sti pr írodovedný ch komp etencií. Podľa m erania PISA v r . 2018 je ešte relevantný prinajmenšom údaj, že rizikovú skupinu tvorí 31, 4 % našich žiakov. Ide najmä o žiakov, ktorí navštevujú nematuritné odbory stredných škôl a základné školy. S uvedeným i výsledkami evidentne koreluje takisto spomenut ý rebríček či ranking najvyspelejšieho školstva sveta (v ostatných rokoch najmä obľúbený Top 40 krajín). V tomto kontexte je prinajmenšom zaujímavý a inšpiratívny príklad školstva Poľska po r. 1989. Totiž, k ým do r. 2006 v medzinárodných meraniach výraz ne zaostávalo i za k rajinami ako ČR, Maďarsko a Slovensko, testovania PISA v r. 2014 alebo 2018 preukázali, že poľské školstvo sa zaradilo ako 4. najlepšie v Európe a 10. na svete. Podľa výsledkov v komparácii 40 vybraných krajín „vyšiel ako najlepší systém n a svete v Južnej Kórei, za ktorou nasledujú Japonsko, Singapur a Honkong. Až za nimi sa umiestnil viacročný líder Fínsko a po ňom na 6. mieste, ako druhý najlepší systém vzdelávania v Európe V B. 10. miesto opäť patrilo Poľsku, za ním na 11. pozícii Dánsku, 11. Nem ecku, 13. Rusku a 14. boli USA. Medzi najlepšími sa ocitlo aj Česko (20. miesto) a Maďarsko (22. m iesto). Slovensko skončilo na 27. pozícií. Okrem Fínska a VB sa teda do prvej desiatky dostali aj Poliaci, ktorí predbehli krajiny ako Nemeck o, Rakúsko, Dánsko a USA (pozri Ligo š, 2020). I keď k nadužívan iu m etrík môžeme zaujať kritick ý postoj (pozri nižšie, ad 1), ako vidieť z uvedených výsledkov, hodno sa zamyslieť, na čom je založený dlhodobejší úspech školstva niektorých krajín, resp. pre náš stredoeurópsky vzdelávací priestor postsocialistických štátov je určite relevantná otázka, preč o sa stalo Poľsko po r. 2010 takým svetovým lídrom v školstve. Opierajúc sa o moju najnovšiu monografiu (Ligoš, 2019) a štúdiu (Ligoš , 20 20) v predkladan ých dvoch štúdiách ťažis kovo načrtnem tri zákla dné piliere kvalitatív nej transfor mácie slo venského regionálneho školstva s ilustra- tívnou konkretizáciou vyučovania materinského jazyka, osobitne slovenčiny so zreteľom na isté výhľady do budúcnosti. 1. p ilier. Rámc ov é ko ntexty vyučo vania vyuč ov acieho (mate rinské ho) j azyka Do rám cových k ontext ov zaraďu jem spolo čensk o - polit ické, ek onomick é a kultúrno - vzdelávacie prostredie širšieho, t. j. v našom prípade najmä európ - skeho, slovenského i lokálneho charakteru. Patrí tu problematika vzdelávacej STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 63 politiky, jazykovej kultúry a komunikácie na rôznej úrovni, ktorá vytvára podl ožie pr e konkr étnu rea lizác iu výcho vno - vz deláva cieho pô soben ia v uče bnom predmete MJL (SJL) prostredníctvom každodennej náplne učiteľa slovenčiny. Ako som naznačil vyššie v úvode, pre jazykovo - komunikačné vzdelávanie máme v súčasnosti vytvorené základné piliere a rámcové cieľové atribúty prof ilácie občana E Ú s očaká vaným i kľúčov ými komp etenci ami pre 21 . storoč ie. Kým pre cudzie jazyky ciele a náplň sú jasne vymedzené východiskovým dokumentom SERR, vo vyučovacích, resp. materinských jazykov bude treba dopracovať analogický strategický materiál v podobe Spoločného európ skeho referenčného rámca pre vy učovanie (osvojovanie si) materinských jazyk ov (SERR/MJ). Určité kroky v tomto smere boli už vykonané (pozri vyššie v úvod e), avšak užit očné by bolo vy pracovať is té stupne ovlá dania a použ ívania materinských jazykov v podobe rámcových štandardov, čo je špecifické pre rodn é, resp. materinské jazyky v úzkom prepojení na komunikačnú a kultúrnu kompetenciu človeka v reláciách s komplexným integrovaným rozvojom jeho osobnosti. V prvej etape by postačilo okrem istých štandardizácií úrovní ovládania MJ uvažovať o dosiahnutí portfólia (podobne ako v CJ). V tomto zmysle by išlo o iné východiskové úrovne, súvisiace s prirodzeným osvojením si MJ a komunikácie, na čo by sa vzťahovali aj ďalšie úrovne až po štandardizácie z hľadiska vykonávania rôznych spoločenských a pracovných pozícií, napr. špecifikácie pri povolaní učiteľa, herc a, politika, lekára, kňaza, obchodníka, manažéra a pod., na čo by sa vzťahovali isté predpoklady, požiadavky a očakávania pri z vládnutí šta ndardných rečovo - k omunikačných situácií z hľadiska dynamiky života. V kontexte vzdelávacích rámcov vyučovania sl ove nčiny problém vidím v spoločensko - politickej klíme a v reálnom nastav ení vzdelávania v SR. Dlhodobo som totiž svedkom síce moderných, progresív nych a kultúrno - humanistických zámerov v programových dokumentoch centrálnych štátnych orgánov , t. j. vý konnej moci i parlamen tnej demokracie, avš ak na báz e vlast nej empírie sa presvie dčam o tom, že zväč ša ide iba o deklará cie alebo pr opagáciu nových cieľ ov v ro zpore so sk utočnosťou v každo dennej praxi. Dá sa p ovedať, že vzdelávanie (aj celoživotné) sa má st ať relevantnou, resp. ťažiskovou záležitosťou celej spoločnosti. Vzájomné prepojenie sa potom participačným subsidiárnym efektom prejaví na priaznivej spoločens kej klím e a v dôstojnom živote pre všetký ch občanov. V tomt o zmysle vystupuje do popredia problém absencie kľúčových legislatívnych a pedagogických dokumentov po r. 1989, ktoré by kontinuálne a strategicky nasmerovali slovenské školstvo dopredu v kompatibilite s vyspelými krajinami sveta, resp. i v našom stredoeurópskom vzdelávacom priestore. Tu totiž zaostávam e aj za štátmi V4. Ako som vyššie naznačil, v súlade s novým školským zákonom č. 245/2008 Z.z. a posledným Národným programom výchovy a vzdelávania na r. 2018 – 2027 (dostupné na: https://www.slov-lex.sk/pravne- predpisy/SK/ZZ/ 2008/245/, https://www. mine du.sk /data/ att/13 285.pd f) do teraz platn é dok umenty centr álneho cha rakter u, najmä ŠVP a VŠ predmetov, konk rétne pre SJL všetký ch stupňov regio nálneho Ligoš, M.: Tri piliere kvalitatívnej transformácie výučby materinského jazyka I. (Rámcové východiská) 64 vzdelávania sú neadekvátne, ťažkopádne, neprehľadne a neinštruktívne konci - pované a bude treba ich nanovo prepracovať v konfrontácii s dokumentm i vyspelých krajín (pozri nižšie, ad 2). Problém začína už tým, že v ŠVP pre jednotl ivé stupn e vzde lávania prí liš zlož ito, širok o a kom plikovane vymedzuje základný cieľ výc hovy a vzdelávania. Takto sú všeobecné ciele a profil abso lventa predl ožené n a pribli žne jed nej str ane tex tu (poz ri napr . ŠVP IS CED 2, dostupn é na: http://ww w.statpedu.s k/files/art icles/doku menty/inov ovany-statny - vzdelav aci-program /svp_nsv_ 6_2_2015.p df, s. 4 – 5). Na porovnani e v kra jine top školstva Singapur hlavný cieľ majú jednoducho a výstižne stanovený takto: Spolo čnosť chce, aby absolvent školy bol angažovaný občan, dobrý pracov ník a sebavedomá osoba, ktorá sa vie učiť. Vo všet kých najúspešnejš ích vzd elávac ích p rogram och sveta sa v p odstat e najč astejš ie pr ezent uje po žiadav ka sebavedomia a sebaobrazu, sebariadenia, tvorivosti, angažovanosti a informo- vanosti (porov. Feřtek, 2015, s. 32). Ako vidieť, tieto ci eľové atribúty sa približujú k základným pilierom vzdelávacieho priestoru Európy (pozri vyššie v úvode). Okrem rámcov ých spoločensko - kultúrnych kontex tov a celkovej klímy v krajin e sa mi ponú ka otázka, v čom spočív a tendenčný alebo dlhodo bý úspech niektorých vzdelávacích systémov vo svete. V porovnan í so Slovenskom je totiž profit príznačný i pre také blízke krajiny ako Poľsko alebo ČR, príkladné však m ôžu byť i Fíns ko, Nemeck o alebo Dánsk o a Estónsk o (pozri Lig oš, 2020, s. 103 – 105). V Poľsku pre kvalitatívnu zmenu určite výpovedne hovoria ambiciózne radikálne reformy po roku 1989, z ktorých sa ako najvýraznejšie vnímajú reformy v rokoch 1999 a 2007. 3 Podobne ako v našej tradícii od čias 1. štátneho školského zákona Ratio edukationis (1777, 1806) z obdobia vládnutia Márie T erézie (pozri podrobnejšie Ligoš, 2019, 1. kap.) o 6- ročne j základnej škole a najúspešnejšie vzdelávacie systém y sveta (najmä východo - ázijské krajiny, ale i Poľsko a i.) sa vyznačujú prevažujúcim modelom štruktúry regionálnych škôl 6 -3-3/4, t. j. po 6- ročnej základnej škole nasleduj e prechod ný j ed notný 3 - ročný typ nižšej školy, ktorý zvyčajne končí závere čnou skú škou s funk ciou istej pote nciáln ej di ferenc iácie v ďa lšom štúdi u. V Nemeck u (alebo v Rakúsku) majú tradične 4 - ročnú základnú školu, po ktorej už podľa dosiahnutých výsledkov žiaci môžu pokračovať na 3 - 4 typoch nižšieho sekundárneho vzdelávania v otvorenom zmysle, t. j. ide o skoršiu vzdelávaciu diferenciáciu, pričom je tu špecifi cky rozvin utý duálny systém vzdelávania v podmienkach stavovských organizácii a firiem v úzkej previazanosti s dôstojným statusom remeselníka v krajine. 3 Treba však poznamenať, že aktuálne podľa ustanovenia Zákona o vzdelávaní z r. 2016 a tzv. deklara tívneho uznesenia vlády sa od septembr a 2019 končí v Poľsku reformný model štruktúry národného školstva. V podstate sa sp iatočnícky vracia do centralistických kontúr pred rok 1989 a jeho ďalší vývoj je otázny a neistý. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 65 Porovnávajúc najvyspelejšie školy sveta sa ako zaujímavý ukázal fakt o t om , že na výsledkoch relevantným spôsobom naparticipujú také premenné ako j e dĺžka povinnej školskej dochádzky či rozsah denného/ročného pobytu žiaka v ško le (známe najmä vo východo ázijských krajin ách), takisto frekv encia testovania, zdroje financovania alebo oblasť jednotného vs. diverzifikovaného kurikula. V súvislosti s metrikami a testovaním sa potvrdzuje Colemanova správa z r. 1966, dobovo objednaná admin istratívnou pr ezidenta USA Joh nsona v rámci projektu „Rovné vzdělávací příležitosti“, v ktorej konštatoval, že „vý stupy ško l závise jí na vstupe ch: výko ny stude ntů kore lují těsn ě se sociál ními, ekonomickými a vzdělávacími výsledky jejich rodičů“ (Muller, 2020, s. 88). Tieto závery v zhode s mojou empíriou i vlastným bádaním jednoznačne v ostatnom období potvrdzujú viaceré medzinárodné merania (pozri vyššie). Podľa správy PISA z r. 2019 sa dokonca ukazuje, že zo všetkých porovná - vaných krajín má rodinný pôvod (a rodinné zázemie) na výsledky žiakov najväčší vplyv na Slovensku, na čo sa ešte príz načne vzť ahuje zistenie, že žiaci z najchu dobnejších slovenských rodín majú v značnej miere horšie výsledky ako ich relatívne podobne chudobní vrs tovníci v zahraničí. Prakticky to znamená záver, že rozd iely vo výsledkoch vzdelávania nemožno celkom „ve skutečnosti lepším vzděláním odstranit – a že důvody přesahují rámec škol“ (ibid., s. 88). V tejto súvislosti je už inou o tázkou problematika chápania pojm u „me ranie“ a ďal ších oblastí , ako testo vanie, evalv ácia a diag nostik ovanie v komplexnom zmysle (pozri ďalej, ad 2). Okrem spomenutého soc iálno - -e konomického a kultúrneho zázemia rodiny žiaka v danom prostredí medzi najzávažnejšími faktormi úspešnosti školských výstupov sa ukázali tieto: „zainteresovanosť (záležitosť) celej spoločnosti, kvalitní učitelia a ich spoločenský status, štruktúra vzdelávacieho systému, progresívna koncepcia a adekvátne pedagogické dokumenty (v ostatných rokoch sa presadzuje viacúrovňové kurikulum, prinajmenšom určené štátom a školou, povinné a nepov inné a pod.), kvalita výchovy a výučby, komple xný a holistický prístup k žiakovi“ (Ligoš, 2020, s. 105). V ďalšej č asti upriamim pozornosť na dva z tý chto rozhod ujúcich deter minan toch ak o o pi lieroc h kval itatív nej tra nsform ácie výchovno - vzdelávacieho procesu v MJ. 2. pilier. Projekt učebného predmetu (kur ikulum) a problematika modelovania, plánovania, riadenia, realiz ácie a diagnostikovania výchovno - vzdelávacieho procesu. 4 S rámcovým kontextom je v prieniku prepojená prob lematika projektu učebného predmetu a realizácie procesu ako komplexnej tvorivej ľudskej činnosti v intenciách holistického rozvíjania integrovanej osobnosti žiaka. 4 Doko nčenie 2. piliera a 3. pilie r priblí žim v ďal šej štúd ii s pred poklado m publik ovania v period iku Studia scientifica fakultatis pedagogicae r. 2021. Ligoš, M.: Tri piliere kvalitatívnej transformácie výučby materinského jazyka I. (Rámcové východiská) 66 Do projektu zaraďujem všetky podklady, resp. dokumenty kurikula v podobe konc epcie , mo delova nia, plánov ania, ria denia a pr ípravy na konk rétnu real izáciu výchov no - vzdeláva cieho pro cesu. V na šich vý skumoch som tomut o fenomén u prisúdil status základného objektívneho a relatívne statického motiv ačného činiteľa (porov. v prácach Ligoš, 1999, 2003, Ligoš et al., 2011 a i.). Projekt učebného predmetu vnímam na horizontálnej i vertikálnej úrovni, a to j ednak n a centrálnej v rámci štátu a jednak na lokálnej (školskej) úrovni i úrovni učiteľa slovenčiny, na dru hej strane v istom hierarchickom rozvrstvení od najširších rám cov až po konkrétnu p rípravu na vyučovanie učiteľa aj jeho realizáciu, vrátane diagnostikovan ia, hodnotenia, sebareflexie a modelovania ďalšej činnosti. Aspoň stručne priblížim jednotlivé polohy tohto faktora. Na úrovni širších kontextov by sa projekt mal koncipovať v rámci zámerov medzinárodného spoločenstva, čo pre nás znamená, ako som vyššie p oukáz al, na báze vzdelávacej poli tiky EÚ a SR. Na úrovni štátu ide o národný program výchovy a vzdelávania (najnovší z r. 2018) a ŠVP (inovovaný v r. 2015), vrátane vzdelávacích štandardov učebný ch predmetov a ostatných centrálnych pedagogický ch dokumentov, ku ktorým patria najmä rámcový učebný plán, metodické pokyny na hodnotenie a klasifikáciu, štandardné testy, ako nepovinné aj uč ebnice, metodické prí ručky, cvičebnice, pracovné zošity a pod. V kontexte školy projekt učebného predmetu je koncipovaný na po dloží školského vzdelávacieho programu (ŠkVP), tem atických vý chovno - - vzdelávacích plánov učiteľa a jeho prípravy na vyučovania, pričom do tohto okruhu implic itne a p rierezovo patrí i odborná pedag ogicko - didak tická kompe - tencia učiteľa, materiálno -technick á vybavenosť školy, zariadenie, učebné pomôck y, vých ovno - vzdelá vacia sila ped agogického kolekt ívu i socio- kultúrn e prostredie školy, jej riadenie a osobitne rodinné zázemie žiakov. Ako sa uvedené rozmery prejavujú vo vertikálny ch priezoroch? Na prvom mies te kurikulum, resp. projekt učebného predmetu musí zohľadňovať východiská, piliere a princípy vzdelávania medzinárodného vzdelávacieho priestoru v intenciách očakávanej profilácie občana daného spoločenstva v istom zoskupení (EÚ). Na tieto širšie kontexty nadväzuje kurikulum prinajmenšom v trojstupňovom rozlíšení, a to najskôr konceptuálne kurikulum, ktoré predstavuje kognitívny model učebného pr edm etu v podobe odborného podložia z hľadiska didaktickej komunikácie (pozri pod robnejšie Liptáková et al., 2015, s. 33 – 35, Ligoš, 2014, 2015, 2016). V zhode s Liptákovou (op. cit., s. 35) uvádzam, že pre teóriu a prax vyučovania materinského jazyka sú pri koncipovaní konceptuálneho kurikula relevan tné jednak princípy z hľadiska jazykovedno - literárnovednej oblasti (princípy súvisiace so stavbou, vývinom a fungovaním jazyka, s recepciou, analýzou a interpretáciou literárneho textu a s proces om rečovej ontogenézy žiakov) a pedagogicko- psychologickej oblasti (zo všeobecnodidaktických princípov najmä princípy korelujúce s vytváraním optimálnych podmienok vyučovania a zohľadňujúce reálne uč ebné m ožnosti ž iakov). Z konceptuálneho kurik ula sa odvíja didaktický systém v podobe ďalšej konkretizácie projektu učebného STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 67 predmetu. Na tejto úrovni na základe špecifických princípov vyučovania MJL (pozri Svobodová 2000, Ligoš, 2005, 2009a, 2009b, 2009c, Obert, 1992, 2003, Liptáková et al., 2015 a i.) sú stanovené ciele, obsah, organizácia a riaden ie, proces a hodnote nie v učebnom predme te. V podstate ide o rámco vé centráln e kurikulum pre SJ L, t. j. o ŠVP, VŠ, učebné plá ny, vstupné a vý stupné štandardné testy, metodické pokyny na klasifikáciu, v ktorých sa implicitne a prierezovo majú uplatniť špecifické princípy koncepcie učebného predmetu. Tretiu úroveň kurikula predstavuje edukačný systém, „t. j. konkretizácia projektovaných kurikulárnych vstupov a výstupov a plánovaného procesu vyučov ania v školských dokume ntoch, v učebných materiálo v a v o vyuč ovacej praxi“ (L iptáková et al., 2015, s. 33). Ide teda o modelovanie, plánovanie, realizác iu a zavŕš enie výchovn o - vzdelávac ieho procesu v škole s hod noteným, dosiahnutým výstupom. Ako vidieť, táto úroveň z ahŕňa zložitú komplexnú a reálnu oblasť výchovno - vzdelávacieho pôsobenia učiteľa slovenčiny v konkrétnej praxi, v rámci ktorej sa ukáže jeho erudícia, pripravenosť, kompetencia a špecifická participácie na integrovane j profilácii absolventa školy. A v tejto súvislosti môžu vyvstávať do popredia viaceré problémy, na ktoré výberovo ďalej poukážem z hľadisk a zámeru tohto príspevku. Jeden z hlavných problémov vidí m v spracovaní konceptuálneho a didak tického kuriku la na ce ntrálnej úrovni . Na ten to problém som v ostat nom období poukázal v niektorých publikačných výstupoch (poz ri Ligoš, 2015, 2016) na báze komparácie vzdelávacích programov v blí zk om zahraničí. Dôležité je, aby ŠVP a VŠ boli pre riadenie učebného predmetu v škole rámcové, stručné, prehľadné, zrozumiteľné a inštrukt ívne na jednej strane, na strane druhej, aby zahŕňa li nielen ciele a obsah (pričom je vhodné spájať cieľovo - obsahovú kategór iu v podobe vzdelávacieho štandardu), ale i proces, riadenie a najmä diagnostikovanie. Na úrovni cieľovo - obsahového zamerania je nevyhnutné prejsť od teoreticko - akademického chápania ku kompetenčno - pojmovému, r esp. vhodnejšie ku kompetenčno - zážitkovému prístupu vzdelá - vacieho štandardu, v ktorom teor etick é poznatky (pojmy, fakty, pri ncípy, štruktúry a pod.) majú status odborného podložia (opory) pre získavanie očakávaných kompetencií žiaka v učebnom predmete. V tejto súvislosti sa mi žiada zdôrazniť, že do učiva, res p. učebného obsahu nepatria iba vedomosti alebo zručnosti, ale i metódy, postupy, stratégie, procesy, návyky, hodnoty, postoje, záujmy, schopnosti a požadov ané kom petencie. V novom poňatí sú východiskovou didaktickou kategóriou ciele ako zámery a lebo výstupy, z ktorých sa odvíja obsah učebného predmetu, lebo ciele sú o niečom, t. j. organicky ukazujú i na učebný obsah (učivo), ktorý sa nemôže tradične orientovať iba na vedomosti a zručnosti, ale i na vyššie úrovne rozvoja osobnosti žiaka. Preto v nových pedagogický ch dokumentoch sa uvádzajú nielen faktuálne a k onceptuálne znalosti, ale i procesuálne a metakognitívne s dimenziami prinajmenšom 6 úrovní kognitívneho procesu: zapamätať si, rozumieť, aplikov ať, analyzovať, hodnotiť a tvoriť (pozri Liptáková, 2012, s. 24 a i.). Podľa mojich analýz a zistení ŠVP a VŠ na vyučovanie SJL treba Ligoš, M.: Tri piliere kvalitatívnej transformácie výučby materinského jazyka I. (Rámcové východiská) 68 nanovo spracovať z hľadiska koncepcie, formátu, štruktúry, takisto a j rozsahu, zrozumiteľnosti a inštruktívnosti pre tvorbu učebných textov a edukačné kurikulum. Napr. v týchto platných dokumentoch úplne absentuje oblasť modelových úloh, konkretizácie cieľových zámerov smerom ku čiastkov ým cieľom v podobe deskriptorov, nehovoriac už o procese, hodnotení a diagnos- tikovaní. Pristavím sa pri závaž nej a v teórii, ale najmä v praxi podceňovanej, zna čne reduk ovane j oblast i diagno stikov ania. To tiž je roz diel med zi hodn otením , klasifikáciou, evalváciou, metrikami a diagnostikovaním. Rozdiel treba vidieť i medzi diagnostikovaním a diagnostikou. Podľa P. Gavoru (Kožuchová et al., 2011, s. 10, 11, 12): „Pedagogická diagnostik a je vedná disciplína zaoberajúca sa t eóriou diagnostického procesu... Od diagnostiky musíme odlišovať pedagogickú evalváciu (resp. jej činnosť – pedagogické evalvovanie)... Diagnostikovanie (diagnostická činnosť) na rozdiel od diagnostiky... je zisťovanie, analyzovanie a hodnotenie úrovne rozvoja žiaka (žiakov, triedy) ako objektu a subjektu výchovného a vzdelávacieho pôsobenia“. V zhode s m ojím názoro m te nto autor uvádz a (op. cit., s. 12 – 19 ), ž e sú časné konc epcie diag nostik ovani a smerujú ku zí skania kom plexn ejšej a kon zisten tnejše j diagnóz y žiaka, učiteľa, šk oly, kontextu či rodinné ho prostredia, pričom vyz dvihuje skutočnosť medzinárodného merania (metrík), ako PIRLS, PISA alebo TIMSS, ktoré predstavujú skôr evalváciu ako diagnostik ovanie. V tejto relácii je dôležité, že diagnostikovanie sa vzťahuje na permanentný proces pôsobenia učiteľa, t. j. ako princíp a neoddeliteľnú, organickú súčasť výchovno - vzdelá - vac ieho proces u, a to od vs tupnéh o d iagnost ikova nia cez p riebež né (format ívne) až po výstupné, záverečné alebo sumatívne di agnos tikovanie žiakov. T akist o nejde iba o diag nostikovanie ale i o sebadiagnostikovanie (učiteľa, žiaka, žiakov) a t iež o diagnostikovanie rodinného prostredia. Treba brať do úvahy, že učiteľ nemôž e plánovať, organizovať, riadiť výchovno - vzdelávací proces, ak by nepoznával žiaka a nediagnostikoval ho a celý proces svojho pôsobenia, pričom hodnotenie je istou výstupnou zložkou tejto činnosti. A následne i vstupnou kategóriou. V uvedenej súvislosti si načim položiť otázku, čo by učiteľ mal diagnostikovať v intenciách posilňovania komplexnosti. Podľa cit. Gavoru (op. cit., s. 14) ide širokú škálu vlastností, prejavov a sfér žiaka, a to: kognitívnu oblasť (pozornosť, pamäť, vedomosti, zručnost i a schopnosti), tvorivosť, afektívne vlastnosti (postoje, motívy, hodnoty, záujmy), osobnostné vlastnosti (sebapoňatie a sebaoceňovanie ), behaviorálne vlastnosti (správanie, usilovnosť, vytrvalosť, svedomitosť), klímu triedy (sociálne vzťahy v triede), ta kisto psychosomatickú k ondíciu žiaka (zdravotný stav, práceschopnosť či únavu). Na tomto mieste vyzdvihujem, že tejto problem atike zo všeobecno - didaktického hľadiska sa P. Gavora venoval podrobne v monografii Akí sú moji žiaci? Pedagogická diagnostika žiak a (1999). Prirodzene, na podloží týchto rámcov sa nám ďalej otvára oblasť špecifík diagnostik ovania v jaz ykovo- komu nikačnom, slo hovo - komu nikačnom a literárno - komunikačnom vzdelávaní v materinskom jazyku. Ako vieme, STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 69 tradične sa tu hodnotia najmä kognitívne rozmery , a to primárne zam erané na vedomosti a zručnosti, čiastočne i na ústny a písomný prejav (orientovaný skôr na pro dukt ako na proces) , analyticko - interpretačn ú činnosť, tiež intuitívne klímu triedy, tvorivosť, motiváciu, postoje alebo hodnoty a pod. Dôležité je podčiarknuť, že táto problematika je z načne podcenená a málo prebádaná. Táto oblasť bude určite aj jednou z výziev a vízií kvalitatívnej transformácie jednak pedagogicko- didaktickej teórie, jednak, a to v dlhodobom horizonte, v r eálnej výc hovno - vzdel ávacej pra xi. Prikl áňam sa k náz oru, že treba zo hľadni ť špecifiká pri novom kompetentnom prístupe diagnostikovania žiakov vo vyučovaní slovenčiny ako materinského jazyka. V tejto relácii odporúčam prijať aspo ň v rámcovom zmysle akceptácie špecifík diagnostikovania, ako ich predstavila Z. Hirschnerová v cit. pub likácii Kožuchovej et al. (2011, s. 2 6 – 51). Totiž z ohľad ňuje no vú kog nitívn o - komu nikačn ú zážit kovú k oncepc iu vyučovania slovenčiny v intenciách in tegrovaného rozvoja osobnosti žiaka (pozri Ligoš v štúdii, 2021). Záver V príspevku som rámco vo načrtol všeobecné východiská kvalitatívnej transformácie vyučovania materinského jazyka v širšom kontexte európskeho vzdelávacieho priestoru. V rozsiahlejšej úvodnej časti som predstavil hlavné tendenci e v ývoja školstva vo vybraný ch krajinách stredne j Euró py so z reteľom na parametre na jlepších škôl vo svete v ostatnom období jednak z pozície postavenia tohto rezortu v spoločnosti a jednak na podloží medzinárodných mera ní zis ťovani a výsl edkov v ýchov no - vzde lávac ieho p rocesu. Na tom to zák lade štúdia ponú ka pohľad do dvoch pilier ov kvalitatív nej transformác ie vyučovania materinského jazyka v postupnej konkretizácii a hierarchii od rámcových cieľových zámerov moderného e urópskeho vzdelávania pre 21. storočie v post upnej k onkretizáci i cez kognitív ne a o sobnostné dimenzie až po kľú čové a z ákladn é predm etové kompet encie v yučov ania m aterins kého ja zyka. V 2. pil ieri otváram problematiku projektu a riade nia výchovno - vzdelávacieho procesu vo výučbe materinského jazyka na v šeobecnej úrovni v komplexnom zmysle. Bibliografia FEŘTEK, T. 2015. Co je nového ve vzdělávání. P raha: Nová beseda, 2015. ISBN 978-80-906089-2-4. GAVORA, P. 1999. Akí sú moji žiaci? Pedagogická diagnos tika žiaka. Bratislava: Práca, 1999. ISBN 80 -7094- 335-1. GAVORA, P. 2011. Základné otázky pedag ogickej diagnostiky v aplikácii na primárne vzdelávanie. In: KOŽUCH OVÁ, M. et al. 2011. Pedagogická diagnostika v primárnom vzdelávaní. Bratislava: SPN, 2011, s. 9 – 25. ISBN 978-80-10-02053-9. Ligoš, M.: Tri piliere kvalitatívnej transformácie výučby materinského jazyka I. (Rámcové východiská) 70 HIRSCH NEROVÁ, Z. 2011. Diag nostikovani e žiaka v jaz ykovom vz delávaní. In: KOŽUCHOVÁ, M. et al. Pedagogická diagn ostika v primárnom vzdeláva ní. Bratis lava: SPN, 2011, s. 26 – 51. ISBN 978- 80 - 10 - 02053 - 9. KOŽUCHOVÁ, M. et al. 2011. Pedagogická diagnost ika v primárnom vzdelávaní. Bratislava: SPN, 2011. ISB N 978-80-10-02053-9. LIPTÁKOVÁ, Ľ. et al. 2015. Integrovaná didaktika slovenského jazyka a literatúry pre primárne vzdelávanie. Prešov: Pedag ogická fakulta PU, 2015. ISBN 978-80-555-1252-5. LIGOŠ, M. 1999. Možnosti rozvíjania vnútorný ch dynamických síl osobnosti žiaka vo vyučovaní slovenského jazyka. Ružom berok: KPF sv. Ondreja ŽU, 1999. ISBN 80 -7100-579-7. LIGOŠ, M. 2003. Motivačné a duchovné rozme ry vyučovania slovenského jazyka. Ružomberok: FF KU, 2003. ISB N 80 -89039- 16 -2. LIGOŠ, M. 2005. Princípy v teórii a praxi vy učovania slovenského jazyka. In: Slovo o slove. Zborník Katedry komunik ačnej a literárnej výchovy PdF PU. Ed. Ľ . Sičák ová – Ľ. Li ptákov á. Pre šov: P U, 200 5. Roč . 11, s. 84 – 90. ISBN 80-8068-362-X. LIGOŠ, M. 2009a. Základy jazykového a literárne ho vzdelávania I. Ružomberok: FF KU, 2009a. ISB N 978 -80-8084-429-5. LIGOŠ, M. 2009b. Základy jazykového a literárne ho vzdelávania II. Ružomberok: FF KU, 2009b. ISBN 978 - 80-8084-430-1. LIGOŠ, M. et al. 2 011. Rozvíja nie motivác ie u žiakov vo vyučov aní slovenč iny. Ružomberok: Verbum KU, 2011. I SBN 978 -80-8084-785-2. LIGOŠ, M. 2014. K transformácii učiva z o slovenčiny v kontexte nových odb orovo- didaktickýc h a slovak istických p odnetov. In Jazyk a lite ratúra [online]. 1, 2014, č. 4, s. 31 – 52. Dost upné na: ht tp://www.statpedu.sk / files/articles/nove_dokumenty/jazyk- a-literatura/cislo4.pdf. LIGOŠ, M. 2015. K transformácii učiva z o slovenčiny v kontexte nových odborov o- didaktick ých a slov akistickýc h podnetov. In Jazyk a l iteratúra . [online]. 2, 2015, č. 1, s. 3 – 23. Dostupné na: ht tp://www.statpedu.sk/ files/articles/dokumenty/jazyk-a-literatura/1_ci slo 2015.pdf. LIGOŠ, M. 2016 a. Nad inovovaným štátnym vzdelávacím programom zo slovenského jazyka a literatúry pre sekundárne vzdelávanie. In Slovenčinár . [online]. 3, 2016, č. 1, s. 73 – 83. Dos tupné na: http ://sau sba.sk /pdf_ casopi s/web/ casopi sy/slo venci nar7_c asopis SAUS.p df. LIGOŠ, M. 2016b. Vyučovanie s lovenčiny ako materin ského jazy ka v kontex te nových výzev a perspektív (Z teórie a praxe v yučovania slovenského jazyka a literatúry). In Jazyk a literatúra . [online]. 3 , 2016, č. 3 – 4, s. 2 – 33. Dostupné na: http://www.statpedu.sk /files/sk/publik acna- cinnost/jazyk-literatura-casopis/jazyk-literatura/ja l-3. LIGOŠ, M. 2017. Ešte k novým výzv am a perspektívam vyučovania slovenčiny ako materinského jazyk a (K návrhu štátneho a školského kurikula zo slovenského jazyka a literatúry ). In Jazyk a literatúr a . [online]. 4, 2017, č. 1 – 2, s. 2 – 36. Dostupné na : http://www.statpedu.sk/files/sk/aktuality/1- 2-jal-2017_doplnenie.pdf. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 71 LIGOŠ, M. 2018. Old new dimensions of teaching mother tongue and literature (in the context of new challeng es and perspectives). In L1 Educational Studies in Language and Literatu r e. [online]. L1Research Archives Online, 2018, pp. 1- 15, Dostupné na: https: //l1.publication- archive.com/publication/2/1749. LIGOŠ, M. 2019. V yučovanie slo venčiny ako materinsk ého jazyka v minulosti , prítomnosti a budúcnosti. Bratislava : Veda SAV, 20 19. ISBN 978-80-224-1770-9. LIGOŠ, M. 2020. Súčasnosť a budúcnosť vyučov ania materinského jazyka v stredoeurópskom vzdelávacom priestore ( so zreteľom na slovenčinu, češtinu, nemčinu a polštinu). Współczesność i p rzyszłość nauczania języka ojczystego w środkowoeuropejskiej przestrz eni kształcenia (z uwzględnieniem języka słowack iego, czesk iego, niemieckiego i polskiego). In: Beskydské dědictví. Svazek č. VI . Ed. L. Hampl. Łodygowi ce : Beskidzki Instyytut Nauk o Cz lowieku, 2020, s. 93 – 114. ISBN 978-83-62092-76-5. MULLER, J. Z. 2020. Tyranie metrik. Praha : Aca demia, 2020. ISBN 978-80-200-3074-0. Národný program výchovy a vzdelávania na r. 2018 – 2027. Národný program rozvoja výchovy a vzdelávania. Kvalitn é a dostupné vzdelanie pre Slovensko. [online]. Bratislava: MŠVVaŠ SR, 20 18. Dostupné na: https://www.minedu.sk/data/att/13285.pdf [cit. 2019- 10-06]. OBERT, Viliam – SULÍK, Ivan. 1992. Nové pohľad y na vyučovanie slovenskej literatúry v súčasnej škole. Bratislav a : ÚÚVU, 1992. OBERT, Viliam. 2003. Rozvíjanie literárnej kultúry žiakov. Bratislava : Poľana, 2003. PIENIᾼŽEK, M. – ŠTĚPÁNEK , S. (Eds.) 2016. Teac hing of National Languages in the V 4 Countries. Praha: PdF UK, 2016. ISBN 978-80-7290-913-1. SVOBODOVÁ, J. 2000. Jazyk ová specifika školské komunikace a výuka mateřstiny. Spisy Ostravské univerzity , 2000, 133. Ostrava: OU, 2000. ISBN 80-7042-175-4. Štátny vzdelávací program. [online]. Bratislava, MŠ VVaŠ, SR, 2008, 2011, 2015. [online]. Dostupné na: http://www.m inedu.sk/8387-sk/statne- vzdelavacie-programy/; http://www.statpedu.sk /sk/svp/inovovany- statny-vzdelavaci-program/. Štátny vzdelávací program ŠVP ISCED 2, dostupné na : http://www.statpedu.sk/files/articles/dokum enty/inovovany-statny- vzdelavaci-program/svp_nsv_6_2_2015.pdf. Vzdelávací štandard zo slovenského jazyka a literatúry – nižšie sekundárne vzdelávanie . [online]. Dostupn é na: http://www.statpedu.sk/files/articles/dokum enty/inovovany-statny- vzdelavaci-program/sjl_nsv_2014.pdf. Ligoš, M.: Tri piliere kvalitatívnej transformácie výučby materinského jazyka I. (Rámcové východiská) 72 Vzdeláv ací štandard Slovenský jazyk a lit eratúra – g ymnázium s o štvorročný m a päťročným vzdelávacím programom . [online]. D ostupné na: http://www.statpedu.sk/sk/svp/inovovany- statny-vzdelavaci- program/inovovany-svp-gymnazia- so - stvorrocnym-patrocnym- vzdelavacim-programom/jazyk-komunik acia/slovensky_jazyk_ a_literatura_g_4_5_r_novy.pdf. PISA 20 18 na Slove nsku. Čita teľská, mat ematická a p rírodovedn á gramotnos ť. [online]. Dostupné na: https://www.nucem.sk /dl/4628/ Priloha_vysledky_krajin_PISA_2018.pdf. Zákon o výchove a vzdelávaní (školský zák on) a o zm ene a dopln ení niektor ých zákonov. [online]. Dostupné na: https://www.v edatechnika.sk/SK/ VedaATechnikaVSR/Legislatva/245_2008_sk olsky_zakon.pdf. ZELINA, M.2011. Stratégie a metódy rozvoja osobno sti dieťaťa. 3. doplnené vydanie. Bratislava: Iris, 2011. ISB N 978-80-89256-60-0. P rof. PaedDr. Milan Ligoš, CSc. Katedra slovenského jazyka a literatúry Katolícka univerzita v Ružomberku , Filozofická f akulta Hrabovská cesta 1, 034 01 Ružomberok [email protected] STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 73 Fröbelova teória hry a jej relevancia p re súčasné vzdelávanie detí mladšieho školsk ého veku Froebel's Theory of Play and i ts Relevance for the Teaching of Children of Younger School A ge Miroslav Gejdoš, Ivana Prachárová Abstract The study presents an analysis of the theory of play promoted by famous German classical teacher Friedrich Froebel an d documents its contribution to contemporary primary educat ion. It deals with the description of the quintessence of Froebel's theory of e ducation of children of younger school age and interprets current, inspiratio nal ideas, their impulsiveness and relevance for the development of cognition of children. It points to an analogy between the ped agogical writings Ed ucation of Ma n, representing the methodology of education of children and constructivis t theo ry of learning and educati on, opposing trans missiv e, m echanic al, memory learn ing. It provides prim ary educati on teachers with a perspective on how to plan a learning process to meet the needs of each child by u sing a game of stimulating self-expression and subse quent learning , empowering the world and fin ding a place in it. Keywords: Primary Education. Friedrich F roebel. Theory of the play. Play as a method. Úvod Avantg ardné, dnešný svet spr evádzajúce inovácie zaprí činené rýchlym rozv ojom ved y a tech niky zasa hujú aj do oblasti šk olstva . Parale lne s pro speri tou sa prakticky neustále hľadajú aj nové spôsoby výučby, ktoré by mali dôkladne zabezpečiť kvalitný rozvoj poznávacích procesov detí mladšieho školského veku. Moderný spôsob výučby vyž aduje aj od dnešných učiteľov primárneho vzdelávania, aby rozvíjali komplexne žiakovu osobnosť, jeho osobnostné, kognitívne, psychomotorické i afektívne črty najmä takými vyučovacími stratégiami či metódami, ktoré sú prínosné primárne pre žiakov a podporujú trvácnosť vedomostí. Samotná relevantnosť tohto stupňa vzdelávania spočí va v jeho zameraní na objavovanie základov každej vednej oblasti, kreujúce konštitutívne poznatky ako platf ormu pre nadväzujúce vzdelávanie i budúci život v spoločnosti. Gejdoš, M., Prachárová, I.: Fröbelova teória hry a jej relevancia pre súčasné vzdelávanie detí mladšieho školského veku 74 V pedagogickej literatúre sa však stretávame s konštatovaniami, že dnešná edukačná prax veľmi sporo akceptuje progresívne formy vzdelávania. V tejto kontinuite tak vyzdvihujeme dejiny šk olstva a pedagogiky, ktoré sú a stále budú podnetne inšpiratívnym odkazom i cestou vedúcou k pochopeniu vých odísk účinne j výchov y a vzd elávan ia. Tém ou štúd ie nie je le n retro spekt ívny návrat do minulosti, kedy prekvitala Fröbelova pedagogická činnosť, ale poskytuje vo vzťahu k jeho fundamentálnym zásadám vzdelávania vý hľadovú perspektívu. Zatiaľ čo je nemecký klasický pedagóg celosvetovo známy ako autor konc epcie predškolsk ej výchovy , jeho gnómická teória vzdelávania detí mladšieho školského veku prostredníctvom hry je veľmi málo inšpiratívna pre jej aplikáciu pre súčasné prim árne vzdelávanie. Témou štúdie je tak polemizovať tradičnému vzdelávaniu obnovením výzvy hry ako účinného strategického prostr iedku edukácie, ktorý je zrkadlom budúceho života detí i jedinečným prostriedkom intelektuálneho, sociálneho, emocionálneho a fyzického r ozv oja sebadisciplíny i sociálneho správania 1 . Východiskovým a primárnym prameňom pre spracovanie štúdie bolo pre nás Fröbelove dielo „O výcho ve človek a“, ktoré ako spomína Cipro 2 si dodn es zachováva nemalú pedagogickú hodnotu pr e svoj rešpekt k prirodzenej aktivite dieťaťa a cenné psycholog ické rady vzchádzajúce zo starostlivého pozorov ania die ťaťa. Ako lapi dárne konštatuje Quick 3 „všetky najlepš ie smer y novodobého myslenia v pedagogike ako vede vrcholia v tom, čo povedal a urobil Fröbel“ , pre to i zámerom štúdie je vyzdvihnúť atemporálnu platnosť Fröbelovho pedagogického odkazu zachovaného v podobe hry pre inovačné vyučovacie stratégie orientované na hodnotné rozvíjanie poznávania detí mladšieho školského veku a poskytnúť tak súčasným učiteľom možný východiskový bod pre modifikáciu prvk ov v prístupe k vzdelávaniu. Formulácia cieľa štúdie, charakteristika metód a teoretické východiská Korporatívne s vyššie ilustrovanou intenciou sme si determinovali hlavný cieľ štúdie, ktorým je „analyzovať a zhodnotiť prínos myšlienok Friedricha Fröbela pre primárne vzdelávanie“ . Vychádzajúc z hlavného zamerania štúdie sme indikovali aj čias tkové ciele:  Interp retovať Fr öbelove ide y o hre v k ontexte prim árneho vz delávania.  Zdôvodniť relevantnosť jeho pedagog ickej teórie hry pre súčasnosť. Eminentnou metódou v našej historicko - vedeck ej štúdii bola metóda priama, prostredníctvom ktorej sm e získavali fakty z pôvodného prameňa. 1 FRÖBEL, F.: Education of Man. New York : A. Lovell & Company, 1885. p. 30 – 31. 2 CIPRO, M.: Průvodce dějinami výchovy . Praha : Panorama, 1984. s. 297. 3 QUICK, R. H.: Vychovávatelští reformátoři. P raha : Ján Laichter na Král. Vinohradech, 1897. s. 315. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 75 K získavaniu i spracovaniu údajov sme ďalej využili literárno - historickú metódu a opierali sa aj o ďalšie. Explikáciu starších j avov pomocou nových nám umožnilo využitie progresívnej metódy, v neposlednom rade didakticko- - metodická metóda nám umožnila transformovať Fröbelove pedagogické náhľady pre súčasné vzd elávanie. K sp racovaniu úda jov, dôklad nej interpretác ii a zver ejneniu výsledkov z bádania sme využili kvalitatívnu metódu, metódu analýzy. Pri spracovaní štúdie nám teoretické východiská poskytli literárne zdroje pu blikované u nás i v zahraničí. Primárnym prameňom pre nás bolo Fröbelo ve dielo O vých ove človeka . Se ku ndárne zdr oje súvisiace s Fröbelovým i pedagogicko- filozofickými náhľadmi i teóriou hry pre nás boli diela od autorov E. Opravilová, V. Štverák, O. Chlup, M. Cipro. J. L. Hughes, S. S. Ravi, E. Provenzo, P. Bowlby. Záverom podotýkame, že získané inform ácie boli korektne rozobrané, podrobne a kriticky analyzované k interpretácii a vyvodeniu záverov. Pedagogicko- filozofické náhľady Friedricha Fröbe la Friedrich Fröbel založil v roku 1817 svoj prvý ústav pre výchovu a vzdelávanie detí v meste K eilhau, v ktorom z úročil vo svojej vlastnej pedagogickej praxi imanentné skúsenosti z detstva, poz orovania prírody či okolitého sveta, poznatky i vedomosti zo štúdií, výchovnej činnosti i pobytu v Pestalozziho ústave v Yverdone. Prečo to spomíname je skutočnosť, že svoju filozoficko- pedagogickú prezentác iu prístupu a metód uplatňovaných vo Všeobecnom nemeckom výchovnom ústave stelesnil do diela s titulom O výcho ve človeka. V obdo bí klasicko - idealisticke j epochy v Nemeck u zastával Fröbel významnú úlohu práve tým, že vydal svoj hlavný spis, v ktorom predstavuje svoje myšlienky o výchov e vychádzajúce z jeho idealistického náz oru a komp lexnéh o pr ístupu , ke dy z Boha, ako pod staty všet kého stvor eného odôvodňuje kvintesenciu výchovy, sprevádzajúcu dieťa cez štádiá vývinu k cieľu, t. j. zhode ako u J. A. Komenského k životu v Bohu. Vzťah Fröbela ku Komenskému vyjadrujú predovšetkým i ch jednotné názory na ponímanie človek a, dôležitosť strategicke j výchovy i nu tnosť rodinne j výchovy. Na rozdiel od neho sa však Fröbel zamýšľal nad tým, ak o v praxi posky tnúť rodine možnosť i vzdelávacie prostriedky pre výchovu na podklade názornosti a sústavy detských hier a disparátne sa zameral na reform u celého vzdelávania ľudskej bytosti 4 . Neodmysliteľnou pre zaujatie miesta človeka v spoločnosti a svete je v kongruencii s Komenského „autopraxiou“ i u neho „samočinnosť“ dieťaťa 4 OPRAVILOVÁ, E. – ŠTVERÁK, V. : Friedrich Fröbel. O výchově člověka. Praha : Státn í pedagogické nakladatelství, n. p., 1982. s. 26 Gejdoš, M., Prachárová, I.: Fröbelova teória hry a jej relevancia pre súčasné vzdelávanie detí mladšieho školského veku 76 využívajúce hru, ktorá je jedinou zárukou dosiahnutia svojho sebaurčenia. Zdôraznenie i m anentnej aktivity dieťaťa či považovanie hry za najdôleži tejší výchovný i vzdelávací princíp Chlup 5 osobitne vyzdvihuje a vyslovuje sa, že práve vo Fröbelovej koncepcii je plne rozvinutý Komenského princíp poznávania – ratio – or atio – operatio, v novom poradí operatio – ratio – oratio. V metodike školy vychádza tak od činnosti a každé poznanie vzchádza z činnosti, v aktivite, t. j. hre, z ktorej sa buduje predstava a názor a na obe plynule nadväzuje rozvoj myslenia a reči. A práve z tejto premisy sa odvíjajú následné segmenty predkladanej štúdie, ktoré ď alej podrobne explikujeme. Hra a te ória hry v ponímaní Fröbela O výchove človeka ak o repreze ntujúce dielo filozofickej prezentácie princípov a metód uplatňovaných vo Fröbelovom ústave zachytáva, že v edukačnej praxi sa metodicky orientoval na rozvoj síl dieťaťa mladšieho školského veku v tr och rovinách: sily, vním ania, myslenia. Z didaktického hľadiska práve hrou a činnostným zameraním vzdelávania prechádzal vo vyuč ovaní kontin uálne o d jedno duché ho k zlo žitému , od zná meho k neznám emu, v neposlednom r ade od názoru k pojmu. Svojím prístupom k podstate hry sa v spise vyslovoval ak o o najčistejše j tvorbe človek a a súčasne ak o o prostriedk u spodobňujúcom celý budúci život 6 . Ako je ďalej známe z odbornej literatúry, hra sprevádza a je súčasťou ontogenézy človeka, r esp. zo života sa nevytráca, ale m odifikuje svoj charakter. Túto jedinečnú a zároveň špecifickú vlastnosť hry spozoroval Fröbel a preto hlavnou funkciu hry detí mladšieho školského veku prestáva byť exetri orizá cia – vy jadren ie vn útra vo n, ale prech ádza sa k úče lu inte rioriz ácie, t. j. hra v tom to období napomáha deťom zmocňovať sa sveta. Ako sa ďalej expertízne vyjadruje Hughes 7 , Fröbel zasvätil svoj život práci a štúd iu dieťaťa, pričom kládol dôraz na jeho vlastné sily, poskytol mu priestor a pomáhal v sebavz delávaní a jeho prirodzený ch sc hopnostiam a mož nostiam boli prispôsobené všetky vzdelávacie metódy. Radikálne sa snažil zm eniť rolu a postav enie učiteľa a n a vlastné, dieťa ťom konštruo vané poznávan ie v zmyslu- plnej hre. Práve na činnost né hľadisko kládol dôraz viac, ako ktorýkoľvek iný významný pedagóg v dejinách pedagog iky a školstva. Hra, predovšetkým ako edukačný činiteľ a najvyšší stupeň rozvoja a poznávania dieťaťa mladšieho školského veku okrem rozvoja myslenia 5 CHLUP, O.: Mateřská škola. Sborník přednášek o ško le ma teřské. Svazek 2. Praha : Nákla dem Svazu učitelek škol mateřských, 1928. s. 29. 6 FRÖBEL, F.: Education of Man. New York : A. Lovell & Company, 1885. p. 30 – 38. 7 HUGHES, J. L.: Froebel´ s Educational Laws for all Teachers. New York : D. Appleton and Company, 1897. p. 1 – 7. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 77 spája dieťa so širším svetom a ako nám sám Fröbel 8 podčiarkuje, dieťa hrou a v hre zisťuje, čo môže urobiť, odhaľuje svoje možnosti, schopnosti, resp. dôkladne poznáva seba samé. Príťažlivou a starostlivo vyberanou zacielenou hrou, ktorá je prispôsobená záujmom detí sa naučia ovládať svoje telo, ako dosahovať vlastné ciele, používať jazyk, učiť sa žiť v sociálnej skupine, spoznávať svet, objavovať, rozv íjať svoje vedomosti, schopnosti a zručnosti z každej vednej oblasti. Fröbelom konštruovaná didaktická metóda vyučovania je založená na 4 kľúčových princípoch – zásadách, ktoré Ravi 9 charakterizuje nasledovne:  zásada samosta tnej činnosti reprezentujúca tie aktivity, ktoré dieťa mlad šieho šk olské ho veku vyk onáva v kon gruenc ii so svoji mi vlast nými potrebami, záujmom bez násilného vnúteni a;  zásada učenia sa hrou vychádza z veľkého detského interesu o hry a aktivity, pričom ako zásada je založená z presvedč enia, že stanovené výchovno - vzdelávacie ciele sa majú napĺňať form ou hry a v hre;  zásada spoločenstva poukazuje na dobré spoločenské prostredie, kolek tív, ktorý podporu jú skupinové hry pre rozvoj empati e, so lidarity, tolerancie a priateľstva;  v neposlednom rade zásada a princíp slobody požaduje ponechať úplnú slob odu vo vyjadr ovaní, precí tení, stvárne ní hier vo vzd elávacom procese, resp. požaduje zosúladiť spontánnosť s kont rolou. Fröbel zastával kritický postoj k odovzdávaniu hotových poznatkov, veril a požadoval od učiteľov, že budú deti viesť k tomu, aby sa stali schopnými, nezávislými mysliteľmi, t. j. mysliace a inteligentné bytosti 10 . Jedn ou z mno hých pozo ruhodný ch Fröbe lových ď alších zm ienok fuz ionova ných s prínosom k pedagogickej teórii vo vzťahu k hre je i to, že vzdelávanie by malo vzchádzať z aktuálneho individuálneho stavu poznania za rešpektov ania štádií psychického vývinu 11 . Jedine a výlučne s plnou vážnosťou i akceptáciou plynulosti psychického vývinu a prebiehajúc ich zmien v období mladšieho školského veku je vytvorený predpoklad celostne dokončeného každého nasledujúceho vývinového obdobia 12 . 8 FRÖBEL, F.: Education of Man. New York : A. Lovell & Company, 1885. p. 34. 9 RAVI, S. S.: Philosophical and Sociological Bases of Education. Delhi : PHI Learning Pvt. Ltd., 2015. p. 186. 10 FRÖBEL, F.: Education of Man. New York : A. Lovell & Company, 1885. p. 67. 11 LILLEY, I.: Friedrich Froebel: A Selection from His Writings Cambridge Texts and Studies in the History of Education. Cambridge : Cambridge UniversityPress, 1967. p. 59. 12 OPRAVILOVÁ, E. – Š TVERÁK, V. : Fr iedrich Fr öbel. O výc hově člověka. Praha : Státní pedagogické nakladatelství, n. p., 1982. s. 28. Gejdoš, M., Prachárová, I.: Fröbelova teória hry a jej relevancia pre súčasné vzdelávanie detí mladšieho školského veku 78 Prínos Fröbelových myšlienok pre primárn e vzdelávanie Fröbelova teória hry , ako fundamentálneho edukačného komponentu vzd elávan ia detí a žiak ov primá rneho vzde lávani a, vkompo novaná do s tarostl ivo sformulovaných vývinových štádi í ontogenézy človeka, tzv. životných fáz bez podmie nečne ov plyvn ila rozv oj mod erného pedagog ickéh o i psyc hologi ckého myslenia. V kontinuite proponovaného Fröbelovho systému vzdelávania zabezpečujúcom pl ynulé nadobúdanie vedomostí, zručností i schopností Provenzo 13 zdokumentoval ich usúvzťažnenosť s tým, čo neskôr vo svojej teórii častí kognitívneho konštruktivizmu vyslovil prominentný psychológ J. Piaget. Priam tak ak o Fröbelova teória i jeho sa zaoberá vekom dieťaťa a štádiami rozvoja s desk ripciou zmien v psychike dieťaťa i súhlasne študuje teóriu rozvoja poznávania schopností dieťaťa. Vzhľadom na to, že poznávaci a sústava detí mladšieho školského veku j e podľa jeho teórie viazaná na skutočné, hmatateľné i poznateľné skúsenosti, podmienené procesom konkrétnych operácií, súhlasne postuluje, aby učenie bolo u žiakov a ktívne, konštruovali s i svoje vedomosti a poznanie v agilnej činnosti, pretvárajúc doterajšie vedom osti na nové poznatky, schémy a modely asimilačne, t. j. prijatím rozšírením starej alebo ak omodačne, modifikáciou starej 14 . Piaget zopakoval Fröbelov pohľad v tom, keď lapidárne n apísal, že hra je prvoradou asimiláciou pred akomodáciou 15 . Pred stavi teľ teórie so ciáln eho konštr uktiv izmu L. S. Vygo tsky tiež ve ril, že hra bol a a je dôležitým procesom i komponentom vzdelávania. Tvrdil, že hra je eminentný faktor pre rozvoj osobnosti dieťaťa, pretože najväčšie úspechy zažíva a dosahuje výlučne len pri hraní sa hier, ktoré sa v nasledujúci deň pre menia vo ved omosť. Ved omosť al ebo súbor ved omostí ta k reprez entoval Kilpatrickom 16 delimitovaný, aktívny výsledok multilaterálnych činností realizo vaných v podnetnom prostredí, v yberaných učiteľom po dôkladnom, systematickom pozorovaní detí v ich samostatných činnostiach v zmysle vlastného bádania a učenia sa hrou. Táto minuciózne ilustrovaná Fröbelov a idea výchovy a vzdelávania detí mladšieho školského vek u si zachováva svoju aktuálnosť do dnes a okrem J. Piageta i L. S. Vygotského ovplyvnila i iné osobnosti vrátane B. Blooma, J. Deweya, M. Montessori a i., ktorí vo svo jej teórii vychádzajú z predpokladu, že dieťa nie je len pasívnym prijímateľom 13 PROVENZO, E.: Friedrich Froebel´s Gifts. Connecting the Spiritual and Aesthetic o the Real World of Play and Learning. In American Journal of play. 2009. p. 93. 14 TUREK, I. : Inovácie v didaktike : Príspevok k realizácii projektu Milénium vo vyučovacom procese na str edných a základných škol ách. 2. vyd. Bratislava : Metodic ko- pedagogi cké centrum, 2005. s. 201 – 202. 15 PIAGET, J. In JOHNSON, J. E. – EBERLE, S. G. – HENRICKS, T. S. – KUSCHNER, D.: The Handbook of the Study of Play 2. Lanham : Rowman & Littlefield, 2015. p. 290. 16 KILPATRIC, W. H. In BOWLBY, P.: A Case Study of froebel Education in Ptractice. 2016, p. 9. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 79 inf ormácií a objektom vzdelávania, ale naopak aktívny subjekt, ktorý si svoje poznan ie konštruuje sám , vlastnou sna hou, bádaním , skúsenosťou v priaznivom prostredí pod starost livým vedením učiteľa v spoločne kreujúcej a priaznivej atmosfére v triede. Sing ular it ou cieľav edomý ch, relevan tných hie r vy chádza júcich z okruhu záujmov žiakov , všeteč nosťou v ťahovaní do vých ovno - vzdeláv acieho systému sa stávajú priamym centrom diania a zažívajú v hre nové, nepoznané, v neposlednom rade vidia v učení význam a má pre nich osobný rozmer. Preniká do každej čiastočky ich bytia. „Silné a hodnoverné zážitky z vlastnej hry či činnosti, precítenie toho, čo učiteľ chce, aby si dieťa osvojilo, preskúmanie a ohmatan ie všetkými zmyslami“ sa podľa Cejpekovej 17 a iných autorov zaoberajúcich sa zm ieňovanou problematikou pokladá za apodiktickú cestu skutočného a efektívneho učenia. Ako sa zmieňuje Petty 18 , žiaci sú radi, ak môžu tvoriť, konať činnostne, komunikovať, hľadať spôsoby riešenia, hrou spoznávať a objavovať vedomosť. K problematik e aktivity žiakov sa konzekventne vyjadruje Petlák 19 , ktorý náležite zdôrazňuje, aby každá činnosť žiaka v kongruencii s cieľom vyučovania a obsahom vzdelávania prispievala k rozvoju trvácnosti, tvorivosti, sam ostatnosti a v zásade, aby nebol aktívny učiteľ, ale umožní priamu zainteresovanosť ž iakovi. Rezultu júc zo zistení z historic kého bádania z áverom poznamenávam e štyri fundamentálne princípy prístupu Fröbela k vzdelávaniu detí mladšieho ško lského vek u, ktorýc h gn ómicko sť a aktuá lnosť na zákl ade vyššie pr ezentov a- ného je nespo chybniteľn á a mali by byť int egrálnym kom ponentom prim árneho vzdelávania a mal by ich mať na zreteli k aždý učiteľ:  Hra pre svoju didaktickú tvárnos ť i fu nkčnosť vedie k učeniu a nema la by sa z výchovno - vzdelávacieho procesu v ytrácať.  Dieťa mladšieho školského veku je schopné učiť sa len to, na čo je vývinom pripravené.  Učiteľ by mal sprevádzať žiakove poz návanie a kategorickým pozoro - vaním jeho progresu, schopností i možností prispôs obovať metódy vyučovania.  Proces učenia, poznávania, objavovania nového by mal prebiehať výlučne v podnetnom prostredí a v priaznive j atmosfére. 17 CEJP EKOVÁ, J .: Peda gogika predškols kého vek u . Banská Bystric a : Pedagog ická fak ulta UMB, 2001, p. 43. 18 PETTY, G.: Moderní vyučování . Praha : Portál, s. r. o., 1996, s. 196. 19 PETLÁK, E.: Inovácie v edukačnom procese . Dubnica nad Váhom : Dubnický technologický inštitút, 2012, s. 71 – 78. Gejdoš, M., Prachárová, I.: Fröbelova teória hry a jej relevancia pre súčasné vzdelávanie detí mladšieho školského veku 80 Záver Vo Fröbe lovej filozoficko- pedagogickej teórii nachádzame dodnes veľa hodnotného, čo n epatrí len minulosti, ale s určitosťou i súčasnosti či budúcnosti. Bol to práve Fröbel, kto zmenil spôsob uv ažovania o hre a povýšil ju na fundamentálny prostriedok vzdelávania detí mladšieho školského veku, rešpektujúc ich schopnosti, možnosti, vek i interes. Jeho pedagogický odkaz v podobe diela reprezen tujúceho kontinui tu pedagogickej teórie a vývinovej psy chológ ie je trvale inšpira tívnym spisom p re učiteľ ov primá rneho vzd eláva nia, ktorí chcú rozvíjať komplexne žiakovu osobnosť vyučovacími stratégiami či metódami, ktoré sú prínosné primárne pre žiakov a podporujú trvácnosť v edomostí. V štúdii sme našu pozornosť zameriavali na možnosti zlepšenia a skvalitnenia primárneho vzdelávania jednou z možných Fröbelom determ i - novaných progresívnych metód, ktorých platformou sú inherentné skúsenosti pre konštrukciu vlastnej vedomostnej základne. Hlavným cieľom štúdie bolo analyzovať a zhodnotiť prínos myšlienok Friedricha Fröbela pre primárne vzdelávanie. Súhrnne konštatujeme, že nami stanovený cieľ sme v plnej miere dosiahli. Eminentný zámer sa naplnil podrobnou deskripciou kvintesencie Fröbelovej teórie vzdelávania. Interpretovali sme Fröbelove idey o hre nielen v intenciách histórie, ale i v k ontexte súčasného primárneho vzdelávania a z dôvodn ili jej relev antno sť pre rozv íjanie po znávan ia detí mla dšieho školskéh o veku . Impleme ntácio u hry do vých ovno - v zdeláv acieho pro cesu s cieľav edomý m pôsobením na priaz nivý, primeraný, individuálny rozvoj osobnosti ž iaka sa doceňuje rešpekt k prirodzenej aktivite die ťaťa a jej vkom ponovaním odmení učiteľa hneď dvakrát. Raz v podobe žiackeho záujm u o hru, prejavom radosti, agilnosti i všetečnosti o dozvedanie sa nového a druhý krát v podobe súboru trvalo osvojených vedomostí, zručností, schop ností. Bibliografia BOWLBY, P.: A Case Study of froebel Education i n Practice. [online]. Montreal : Concordia University, 2016. 90 p. [cit. 2020.03.31.] Dostupné na internete: <https://spectrum .library.concordia.ca/ 981703/14/Bowlby_MAed_F2016.pdf>. CEJPEKOVÁ, J.: Pedagogika predškolského ve ku. Banská Bystrica : Pedagogická fakulta UMB, 2001. 102 s. I SBN 80 -8055-491-9. CIPRO, M.: Průvodce dějinami výchovy . Praha : Panorama, 1984. 579 s. ISBN 11-088-84. FRÖEBEL, F.: The Education of Man . [online]. New Y ork : A. Lovell & Company, 1885. 273 p. [cit. 2020.03.28.] Dost upné na internete: <https://archive.org/details/educationofman00froe/pag e/n285>. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 81 HUGHES, J. L.: Froebel´s Educational Laws for all Teachers. [online]. New York : D. Appleton and Company, 1897. 296 p. [cit. 2020.03.28.] Dostupné na internete: <https://www.que stia.com/read/85862625/ froebel-s-educational-laws-for-all-teachers>. CHLUP, O.: Mateřská škola. Sborník přednášek o škol e mateřské. Svazek 2. Praha : Nákladem Svazu učitelek škol m ateřských, 1928. 381 s. JOHNSON, J. E. – EBERLE, S. G. – HENRIC KS, T. S. – KUSCHNER, D.: The Handbook of the Study of Play 2. [online]. La nham : Rowman & Littlefield, 2015. 600 p. [cit. 2020.03.31.] D ostupné na internete: <https://books.google.sk/books?id=vA WTBgAAQBAJ&pg=PA287&lp g=PA287&dq=gutek+froebel&source=bl&ots=P4 61XR1Lnv&sig=ACf U3U0Afr055g3QG_nGQnLBTb7Vt0N5h=sk&sa= X&ved=2ahUKEwj Hl_j58foAhXPyaQKHWgkCWUQ6A EwAHoECAsQLA#v=onepage& q=assimilation&f=false>. ISBN 978- 1475-580-796-7. LILLEY, I.: Friedrich Froebel: A Selection f rom His Writings Cambridge Texts and Studies in the History of Educa tion. Cambridge : Cambridge University Press, 1967. 188 p. OPRAVILOVÁ, E. – ŠTVERÁK, V.: Friedrich Fröb el. O výchově člověka. Praha : Státní pedagogické nakladatelství, n. p., 1982. 178 s. ISBN 14-354-82. PETLÁK, E.: Inováci e v eduka čnom proces e. Dubnica nad Váhom : Dubnický technologický inštitút, 2012. 158 s. ISB N 978 -80-89400-39-3. PETTY, G.: Moderní vyučování. Praha : Portál, s. r . o., 1996. 380 s. ISBN 80-7478-681-0. PROVENZO, E.: Friedrich Froebel´s Gifts. C onnecting the Spiritual and Aesthetic of the Real World of Play and Learn ing. In American Journal of play. [online]. 2009. vol. 2, no. 1, p. 85-99. [ci t. 2020.03.31.] Dostupné na internete: <https://www. journalofplay.org/sites/ www.journalofplay.org/files/pdf-articles/2-1- article-friedrich-froebels- gifts.pdf>. ISSN 1938-0402. QUICK, R. H.: Vychovávatelští reformátoři. Praha : Ján Laichter na Král. Vinohradech, 1897. 415 s. RAVI, S. S.: Philosophical and Sociological B ases of Education. [online]. Delhi : PHI Learning Pvt. Ltd., 2015. 488 p. [cit. 2020.03.31. ] Dostupné na internete: < https://books.goog le.sk/books?id=PjgJCgAA QBAJ&printsec=frontcover&hl=sk&source=gbs_g e_summary_r&cad= 0#v=onepage&q&f=false>. ISBN 978-81-203- 5113-4. TUREK, I.: Inovácie v didaktike : Príspevok k realizácii projektu Milénium vo vyučovacom procese na stredných a základných školách. 2. vyd. Bratislava : Metodicko- pedagogické centrum , 2005. 358 s. ISBN 80-8052-230-8. Gejdoš, M., Prachárová, I.: Fröbelova teória hry a jej relevancia pre súčasné vzdelávanie detí mladšieho školského veku 82 Doc. PaedDr. PhDr. Miroslav Gejdoš, PhD. Katedra pedagogiky a špeciálnej pedagog iky Katolícka univerzita v Ružomberku, Pedag ogická fakulta Hrabo vská cesta 1, 034 01 Ružomberok [email protected] Mgr. Ivana Prachárová Katedra predškolskej a elementárnej pedag ogiky (interná doktorandka) Katolícka univerzita v Ružomberk u, Pedagogická fakulta Hrabo vská cesta 1, 034 01 Ružomberok [email protected] STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 83 Inštitucionálna príprava a vzdelávanie u čiteliek v Košiciach do roku 1938 Institutional Training and Education of Wom en Teachers in Košice by 1938 Miroslava Gallová Abstract The article deals with the education of girls at normal schools in Košice by 1938. The first part discusses the education and training of women teachers of national (elem entary) and burgher's (civic) schools. Until 1919, there were two Ro man Catholic normal schools (boys' and girls') in Košice. In the 1920 s there was a state normal school in Košice whe re girls and boys w ere educated together. Since the school y ear 1937/38, a Roman Catholic normal school of Ursulines was re-opened in the city to educate girls. In the second part, the stud y is devoted to the education and training of kindergarten teachers and female handicra fts teachers at Košice vocational nor mal schools established in t he 1930s', which were administered by the Dominican Order. The study points to legislation that governed the functioning of individual types of normal schools and the study of girls there. It brings information on the conditions o f admission of pupils and, it also provides an overvie w o f the structure of pupils from a gender, nation al and religious pe rspective for som e schools. It also deals with the subjects of mentioned schoo ls. Keywords: Girls. Education. Teachers. Normal sc hools. Košice. Interwar period. Úvod Učiteľské ústavy pred stavovali v druhej polovici 19. storočia pre dievčatá jednu z mála možností získania vyššieho vzdelania. 1 Absolvovanie štúdia a nadobudnutie kvalifikácie na výk on pov olania učiteľky im zároveň umožnilo zabezpečiť si vhodné živobytie a uplatniť sa aj mimo domácej sféry. 2 Učiteľské ústavy boli obľúbeným typom š kôl pre dievčatá nielen 1 V zmysle dnešného stredoškolského vzdelania. 2 Domáca sféra bola v minulosti tradične určená ženám, keďže ich p rvoradou úlohou bolo byť dobrou manželkou, matkou a gazdinou. Gallová, M.: Inštitucionálna príprava a vzdelávanie učiteliek v Košiciach do roku 1938 84 v období dualizmu, ale aj v nasledujúcich rokoch. Cieľom predloženej práce je predstaviť vzdelávanie dievčat a žien a ich prípravu na povolanie učiteľky na viacerých uč iteľských ústavoch v Košiciach s dôrazom na medzivojnové obdobie. 3 Dôvodom výberu tejto témy je najmä jej doterajšie nedostatočné spracovanie v slovenskej historiografii. 4 Učiteľské ústavy Zákonným článkom č. 38/1868, 5 ktorý upravoval ľudové školstvo v Uhorsku, boli medzi ľudové školy zaradené aj učiteľské ústavy (tzv. preparandie), ktoré mali byť zakladané osobitne pre diev čatá a osobitne pre chlapcov. 6 Podmienkou prijat ia chlapcov bolo dovŕšenie minimálne 15. roku veku a absolv ovani e prijímac ej skúšk y z učiva v rozsah u št yroch tr ied gymná zia. U dievčat bola veková hranica 14 rokov a znížené boli i nároky na rozsah učiva, ktoré mali ovládať – učivo vyššej národnej školy. Rozdiely boli aj pri záverečných skúškach absolventov a absolventiek prípraviek. Žiaci museli po skúška ch z jedn otlivých predmetov absolvov ať skú šku z uči va vyšš ej národn ej i občianskej školy a metodiky vyučovania. Dievčatá mali vykonať skúšku len z tých predmetov, ktoré sa vyučovali v prípravke. Po ukončení štúdia v učiteľskom ústave mohli dievčatá vyučovať v dievčenských triedach na vyšších národných (ľudových) a občianskych (m eštianskych) školách. 7 3 Koši ce ako adm inistra tívne, hospodár ske, kul túrne a vz delanos tné centr um vých odného Sl ovenska disponovali vhodnými podmienkami a predpokladmi na vznik viacerých typov škôl vrátane učiteľských ústavov. 4 Vzdelávaním dievčat na ženskom učiteľskom ústave v Košiciach do roku 1918 sa zaoberala Mária Mihóko vá v rámci spracovania bibli ografie článkov k tém e stredného školstva v Koš iciach v období 1848 – 1918. MIHÓKO VÁ, Mária (ed.). Stredné školstvo v Košiciach v roko ch 1848 – 1918. Tematická bibliografia I. Košice : Štátna vedecká knižnica, 1981. 411s. MIHÓKOVÁ , Mária (ed. ). Stredné školstvo v Košiciach v rokoch 1848 – 1918. Tematická bibliografia II. Košice : Štátna vedecká knižnica, 1981. 439 s. Koedukačnému učiteľskému ústavu, ktorý v Košiciach existoval v 20. rokoch 20. storočia, sa venovala Alžbeta Bojková. Autorka vo svojej práci prináša inf ormácie o vzniku daného ústavu, jeho fungovaní a s tým súvisiacimi problémami. Neposk y tuje však pohľad na zloženie žiactva či profesorského zboru z rodového (genderového) hľadiska, ani porovnanie výučby na mužských a koedukačných učiteľských ústavoch na jednej strane a ženských učiteľských ústavoch na strane druhej. BOJKOVÁ, Alžbeta . Primárn e problé my transfor mácie sl ovenských stredných a odborných škôl v Košiciach v medzivojnovom období. Košice : UPJŠ v Košiciach, 2018. 205 s. 5 186 8. évi XXXVIII. törvénycikk a népiskolai közoktatás tárgyában [online]. 6 Podľa zákona existovali 4 typy škôl: elementárne (ľudové), vyššie národné (vyššie ľudové), občiansk e (meštia nske) a u čiteľské prípravne (učiteľské ústavy). Vyučovanie dievčat a c hlapcov na vyšších národných a občianskych školách muselo p rebiehať oddelene, teda v samostatných triedac h. BIL ČÍK, Jozef. Vývoj školstva na Slovensku do roku 1960 a s pracovávanie písom ností škôl. In Slovenská archivistika, 1973, roč. 8, č. 1, s. 31 - 33. 7 BILČÍK, J. Vývoj školstva na Slovensku ..., s. 34. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 85 V druhej p olovici 19. st oročia pôsobili v Košiciach dva učiteľské ústavy. V roku 1856 bol do Košíc presťahovaný rím skokatolícky učiteľský ústav z Miškovca, avšak riadne štúdium bolo na tejto škole až do jej zániku v roku 1919 sprístupne né len chlapcom. Dievčatá a ženy tam napriek tomu mohli skladať súkromné skúšky a nadobudnúť tak učiteľský diplom. 8 Druhý rímskokatolícky učiteľský ústav, ktorý v K ošiciach založili uršulínky, bol dievčenský. 9 Vyučovať sa na ňom začalo od roku 1860 v maďarskom a nemeckom jazyku . Ústav mal spočiatku dva ročníky. Medzi predmety, v ktorý ch sa žiačky vzdelávali, patrili: z emepis, deje pis, prírod opis, matem atika, fyzika, náboženstvo, maďarský jazyk a literatúra, pedagogika, spev, krasop is a ručné prá ce. Keďže podľa § 109 zák ona č. 38/1868 bolo nariad ené predĺženi e štúdia na učiteľských ústavoch na tri roky, musel sa tomuto predpisu prispôsobiť aj košický učiteľský ústav ur šulínok . 10 Štúdium sa tu predĺžilo na tri r oky v ro ku 1870 . 11 Od šk olskéh o roku 1 884/85 bol ústa v postu pne pre tváran ý na 4- ročný podľa ďalšieho nariadenia o rozšírení š túdia z roku 1881. 12 Vo všetkých 4 ročníkoch súčasne však vyučovanie prebiehalo až od školského roka 1903/04. V tomto období mal ústav ročne okolo 40 – 45 absolventiek. 13 Napriek tomu, že ústav bol v správe Rádu sv. Uršule, štúdium bolo umožnené aj dievčatám iného ako rímskokatolíckeho vierovyznania. Značnú časť budúcich učiteliek tvorili dcéry zo židovských rodín. V rokoch 1860 – 1896 bolo v ústav e zapísaných dokopy 711 riadnych žiačok, z ktorých 521 bolo r ímskokatolíckeho, 127 židovského a necelý ch 10 % dievčat bolo iného vierovyznania. Počas prvý ch 36 rokov existencie ústavu absolvovalo štúdium úspešne 574 riadnych žiačok a 64 externých. 14 Ženské učiteľské ústavy sa stali obľúbeným typom školy pre dievčatá a ich počet, ako aj počet žiačok postupne narastal v rámci celého Uhorska. Počet mužských učiteľských ústavov na prelome 19. a 20. storočia klesal. V ro ku 1913 doko nca počet štu dentie k na učiteľs kých ústav och (471 8) presia hol počet študentov (4503). 15 P odob ná si tuácia bola aj v mes te Košice, kde počet absolventiek učiteľského ústavu tiež začal postupne prevyšovať počet absolventov. Na mužskom učiteľskom ústave bolo v školskom roku 1910/11 8 MIHÓKOVÁ, M. Stredné školstvo ..., s. 143, 161. 9 II. výročná zpráva rádového čsl. dievč. reálneho gymnázia sv. Uršule v Košiciach a I. výročná zpráva rádového čsl. ženského učit. ústa vu uršuliniek v Košiciach za školský rok 1937 – 38 . Košice : Nákladom ústavu, 1938, s. 31. 10 MIHÓKOVÁ, M. Stredné školstvo ..., s. 167. 11 Felvidéki Tanügy , 15. október, 1881, č. 1 -2, s. 44- 45. 12 Počas prvých 24 rokov existencie ústavu ho z 340 prihlásených dievčat absolvovalo 320, z ktorých sa 65 zam estnalo na pozícii učiteľky a 150 – 160 absolventiek sa uplatnilo vo funkcii vychovávateľky. MIHÓKOVÁ, M. Stredné školstvo ..., s. 169-170. 13 II. výročná zpráv a rá dového čsl. dievč. reálneho gymnáz ia sv. Ur šule v Košiciach a I. výročná zprá va rád ového č sl. že nského učit. ústavu uršul iniek v Košic iach z a škols ký rok 1937 – 38 ..., s. 31. 14 MIHÓKOVÁ, M. Stredné školstvo ..., s. 174. 15 PUKÁNSZKY, B. Bevezetés a nőnevelés történetébe . Gallová, M.: Inštitucionálna príprava a vzdelávanie učiteliek v Košiciach do roku 1938 86 zapísaných 74 žiakov. Na ženskom učiteľskom ústave študovalo v Košicia ch v tom istom školskom roku 127 riadnych ž iačok a 5 privatistiek. 16 Ako už bolo vyššie uvedené, učiteľské ústavy, ktoré okrem štátu zakladali aj cirkvi, a to predovšetkým rímskokatolícka, boli pôvodne zaradené do systému z ákladného školstv a. Stredným i škol ami boli do roku 1918 len gymnáz iá. Zákon č. 293/1 919 Sb. z. a n. zo dň a 27. mája 1919 zara dil učiteľské ústavy v rátane odborný ch učiteľský ch ústavov medzi stre dné školy. 17 Na územ í Slovenska (aj Podkarpatskej Rusi) boli učiteľské ústavy zakladané podľa zák onného článku č. 38/1868 a zákon a č. 293/1 919 Sb. z. a n. Orga nizačný štatút bol v ydaný dňa 18 . decem bra 190 0 pod čí slom 4 5.781. 18 V rá mci ČS R exist ovalo niekoľko mužských alebo ženských učiteľských ústavov, ale viac bolo koeduk ačných, ktoré bo li vytvorené na zák lade výnosu č. 17 .714 zo dňa 6. júna 1919: „Aby se vyhovělo přáním s mnoha stran projeveným, povoluje se pro ta města, kde jest pouze jeden ústav učite lský, spoluvýchov a (koedukace) druhé ho pohl aví až do jedn é třetiny m aximál ního poč tu chovan ců.“ 19 Výn osom č. 40.0 25 zo dňa 12. apríla 1929 bolo navyše povolené prijať do prv ého ročníka 20 chlapcov a 20 dievčat. Dovtedy mohli dievčatá tvoriť maximálne 1/3 zo 40 prijatých žiakov. Celkovo však v 30. rokoch 20. storočia prevažov al na učiteľ - ských ústavoch počet dievčat nad počtom chlapcov . 20 Československý štátny učiteľský ústav v Koš iciach Obidva vyššie uvedené košické cirkevné učiteľské ústavy, na ktorých prebiehalo vyučovanie v maďarčine, boli v roku 1919 zrušené bez toho, aby sa uvažovalo o založení nového slovenského učiteľského ústavu. Vzhľadom k tomu, že v neďalekom Prešove existovali v tom čase tri učiteľské ústavy, prev ládal názor , že Ko šice uč iteľsk ý ústa v nepo trebu jú. Kvô li pot rebe p ritiah nutia študentov zo vzdialenejších oblastí východného Sloven ska k učiteľskému povolaniu, šírenia osvety a posilnenia národného povedomia došlo predsa len k založ eniu Česk oslovenskéh o štátneho učiteľské ho ústav u v Košiciac h v roku 1921 . V šk olskom roku 1 921/22 bol otv orený prvý r očník . Ústav bol do budova ný až v školskom r oku 1924/25, kedy boli otvorené všetky štyri r očník y. Kvôli neustálym problémom s umiestnením ústavu a neustálem u sťahovaniu jeho tried, ako aj nedostatk u učebných pomôcok, čo ovplyvňovalo kvalitu výučby i rozvoj samotného ústavu, b olo v roku 19 27 ro zhodnuté o jeho zru šení, resp. zlúčení so Štátnym československým koedukačným učiteľským ústavom 16 Magyar statisztikai évkönyv 1911 [online]. Budape st : Magyar Királyi Központi Statisztikai Hivatal, 1912, s. 370-371. 17 Zákon č. 293/1919 Sb. z. a n. ze dne 27. května 1919 o změně plat nosti ustanovení o středn ích školách na Slovensku [online]. 18 PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 567. 19 Citované podľa PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 816. 20 PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 816. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 87 v Prešove. 21 Od školského roku 1927/28 už neboli prij ímaní žiaci do prvého ročníka. 22 V školskom roku 1929/3 0 bol posledný štvrtý ročník učiteľského ústavu pričlenený ako pobočka k Československej štátnej vyššej reálke v Košiciach. 23 Podmienkami na prijatie do ústavu bola okrem telesne j vyspelosti a mravnej zachovalosti aj adekvátna príprava, čiže predchádzajúce dosiahnuté vzdelanie, kto ré malo z ahŕňať napríklad i hudobné vzdelanie. Z áujemcovia o štúdium museli absolvovať pr ijímaciu skúšku, pričom museli spĺňať i vekovú hranicu, ktorá bola stanovená na m inimálne 15 rokov veku života. K žiado sti o prijatie mali dievčatá a chlapci pripojiť krstný, resp. rodný list, posledné získané vysvedčenie, lekárske potvrdenie o telesnej spôsobilosti, ukážky z krasopisu a výkresy, ktoré museli byť overené školou, ktorú uchádzač napos ledy navštevoval. Od dievčat sa vyžadovali tiež ženské ručné práce. V prípade, ak záujemcovia ukončili predchádzajúce štúdium už skôr, mali predložiť i vysv edčenie o mravnosti, ktoré im mal vystaviť obecný úrad. Písomná a ústna prijímacia skúška sa skladala z vyučovacieho j azyk a a matematiky. Okrem toho sa preverovala i telesná zdatnosť a hudobný sluch záujem cov o štúdium. Učiteľsk ý ús tav bol poč as sv ojej existencie koeduk ačný. Každoročne mohlo byť prijatých 40 žiakov do jedného ročníka, pričom dievčatá mali tvoriť najviac 1/3 z c elkového počtu žiactva. 24 S tým súvisí aj prevaha v počte chlapcov nad počtom dievčat študujúcich na učiteľskom ústave, čo zobrazuje nasledujúca tabuľk a. Tabuľka č. 1: Počet riadnych žiakov a žiačok Československého štátneho učiteľského ústavu v Košiciach 25 Školský rok 1921/22 1922/23 1923/24 1924/25 1925/26 1926/27 1927/28 1928/29 1929/30 Žiaci 13 45 55 80 83 84 59 36 19 Žiačky 10 23 34 40 36 40 30 23 14 21 Viac o organizácii ústavu a problémoch s tým spojených BOJKOVÁ, Alžbeta. Primárne problémy ..., s. 168-174. 22 Výročná zpráva českoslov. št . učit. ústavu v Košiciach za roky 1921/22 – 1927/28 . Košice, 1928, s. 10-12, 25. 23 Čsl. štátna reálka v Košiciach a pobočka býv. št. učiteľského ústavu v Košiciach. XI. (za uč. pobočku: V.). Výročná zpráva za š kolský rok 19 29 - 30 . Košice : Nákladom v lastným, 1930, s. 10. 24 Výročná zpráva českoslov. št. učit. ústavu v Košiciach za roky 1921/22 – 1922/23 . Košice, 1923, s. 21-22. 25 Čsl. štátna reálka v Košiciach a pobočka býv. št. učiteľského ústavu v Košiciach. XI. (za uč. pobočku: V. ). výročná zpráva za škol ský rok 1929 - 30 ..., s. 19. Čsl. št. učiteľský úst av v Košiciach. Štvrtá výročná zpráva za školský rok 1928 - 29 . Košice, 1929, s. 13. Výročná zpráva českoslov. št. učit. ústavu v Košiciach za ro k y 1921/22 – 1922/23 ..., s. 6, 18. Výročná zpráva českoslov. št. učit. ústavu v Košiciach za roky 1921/22 – 1927/28 ..., s. 18, 34. Gallová, M.: Inštitucionálna príprava a vzdelávanie učiteliek v Košiciach do roku 1938 88 Pre por ovnan ie uvádzam e, že na začiatk u 20. storo čia, kedy v Ko šiciac h pôsobili dva uč iteľské ústav y – ženský a mužský, prevažoval počet dievčat nad počtom chlapcov. Napr. v školskom roku 1913/ 14, teda pred pr vou svetovou vojnou, mal mužský učiteľský ústav 70 žiakov a na ženskom uči teľ - skom ústave študovalo v tom čase 164 žiačok. 26 Spomed zi ži ačok navštevovali učiteľsk ý ústa v na jmä koši cké dievčatá. Tie tvorili viac ako polovicu žiačok ( 52,18 %) učiteľského ústavu v školskom roku 1 922/23. U ži akov však ko šickí chlapc i predstavo vali len 13 ,3 %. Dievča tá sa hlásili k slovenske j (82,61 %) alebo českej národno sti (17,39 %). U chlapcov bol podobný stav. K slov enskej národnosti sa prihlásilo 75,56 % chlapcov, k českej 22,22 %. 27 Neprítomnosť žiakov a žiačok ďalších národností na učiteľskom ústave súvisela s poprevratovým budovaním slovenského školstva a s tým spojenou potrebou vychovať a vzdelať dostatok slovenských učiteľov a učiteliek, ktorých bolo v povojnových rokoch veľ m i málo. Vzhľadom k tomu, že po vzniku Československa prichádzali nielen do Košíc, ale aj na ostatné územie Slovenska českí učitelia ale i úradníci a odborníci z rôznych sfér, ktorí zapĺňali prázdne pracovné miesta, je sam ozrejmé, že na košických ško lách, v rátane učite ľského ústav u, štud ovali ich ro dinní p rísluš níci. Nábože nské zložen ie žiactva ústavu bolo pes trejšie. Najvia c bolo zastúpené rím skokatolícke vierovyznanie, ku ktorému sa hlásilo 86,9 6 % dievčat a 77 ,78 % chlapcov. V prípad e dievčat na sledovalo g réckokatolí cke, evanjel ické a. v. a českobrat ské, ktoré mali zhodné zastúpenie po 4,35 %. U chlapcov nasledoval o za rímsko - katolíckym vierovyznaním evanjelické a. v. (11,11 %) a gréckokatolícke (4,44 %). K československ ému, helvétskemu a židovskému vierovyznaniu sa prihlásil len jeden žiak. 26 ASZTALOS, József. Kassa közoktatási és közművelődési intézmenyei. In Statisztikai Szemle [online], 1939, roč. 17, č. 5, s. 587. 27 K židovskej národnosti sa prihlásil len jeden ži ak. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 89 Tabuľka č. 2: Štatistické ukazovatele žiakov a žiačok v školskom roku 1922/23 (1. a 2. ročník) 28 Chlapci Dievčatá Spolu Rodisko Počet % Počet % Počet % Košice 5 11,11 2 8,70 7 10,29 Slovensko okrem Košíc 30 66,67 13 56,52 43 63,24 Ostatné časti ČSR 9 20,00 3 13,04 12 17,65 Zahraničie 1 2,22 5 21,74 6 8,82 Spolu 45 100 23 100 68 100 Bydlisko Košice (u rodičov) 6 13,33 12 52,18 18 26,47 Košice (u zodpoved. dozorcov) 11 24,44 3 13,04 14 20,59 V internáte 25 55,56 8 34,78 33 48,53 Dochádzajú 3 6,67 - - 3 4,41 Národnosť Slovenská 34 75,56 19 82,61 53 77,94 Česká 10 22,22 4 17,39 14 20,59 Židovská 1 2,22 - - 1 1,47 Náboženstvo Rímskokatolícke 35 77,78 20 86,96 55 80,88 Gréckokatolícke 2 4,44 1 4,35 3 4,41 Československé 1 2,22 - - 1 1,47 Evanjelické a. v. 5 11,11 1 4,35 6 8,82 Evanjelické českobratské - - 1 4,35 1 1,47 Evanjelické helv. v. 1 2,22 - - 1 1,47 Židovské 1 2,22 - - 1 1,47 Na základe výnosu č. 38.985 z 29. augusta 1919 a výnosu č. 21.788 z 27. júla 1922 sa mali žiaci a žiačky učiteľských ústavov vzdelávať v nasle- dujúcich predmetoch: náboženstvo, pedagogika a prax, vyučovací j azy k, nemecký jazyk, zemepis, dejepis a vlastiveda, matem atika, prírodopis, fyzika a chémia, poľné hospodárstvo, krasopis, kreslenie, spev a všeobecná náuk a o hudbe, hra na husliach, hra na klavíri, hra na organe, ženské ručné práce, telocvik, výchovné ručné práce (nepovinné). Rozdiely vo vyučovacích predmetoch na mužských a koedukačných učiteľských ústavoch na jednej 28 Výročná zpráva českoslov. št. učit. ústavu v Košiciach za roky 1921/22 - 1922/23 ..., s. 18-19. Gallová, M.: Inštitucionálna príprava a vzdelávanie učiteliek v Košiciach do roku 1938 90 strane a ženských učiteľských ústavoch na strane druhej boli minimálne. Mužské a koed ukačné ústavy mali v poslednom štvrtom ročníku o jednu hodinu vyučov acieho jazyka viac a o jednu hodinu kreslenia menej ako to bolo n a ž enskýc h ú stavoc h. V treťom ročníku sa vy učoval o poľné hosp odárstv o, pričom na ženských ústavoch takýto predmet dievčatá neabsolvovali. Pokým predmet hra na huslia ch bol povinný pre všetky typy učiteľských ústavov, hra na klavíri a hra na organe boli predmety, k toré sa mali vyučovať len na mužských a koedukačných učiteľských ústavoch a pre dievčatá študujúce na koedukačných ústavoch bolo ich absolvovanie nepovinné. Na ženských učit eľský ch ústav och moh ol byť pr edmet h ra na klav íri zav edený ak o nepov inný. Žiačky ženských učiteľských ústavov absolvovali počas prvých troch rokov štúd ia pred met žen ské ruč né prác e. Žiač ky a žia ci koe dukačn ých ale bo mužsk ých učit eľský ch ústavov m ohli v posl ednýc h dv och ročn íkoch abs olvova ť n epovin ný predmet výchovné ručné práce. 29 Výučba vy ššie uvedenýc h predmetov prebi ehala i na Česko slovenskom štátnom učiteľskom ústave v Košiciach. Hoci i šlo o koedu kačný ústav, pre kto rý nebol i predp ísané ž enské ru čné prá ce, ale l en nepov inný pr edmet výchov né ručné prá ce (v dobov ej terminológ ii vo výročn ých správach „rukodelné p ráce“), vyučovali sa tam oba spomínané predmety. 30 Okrem toho absolvovali ž iaci a žiačky i predmet zdravoveda a metodika elementárnej triedy. Na danom ústave vyučovali v prevažnej miere profesori – muži. Ženy sa tam uplatnili len ako výpomocné profesorky pri vyučov aní predmetu ženské ručné práce a telocvik pre dievčatá. Výnimkou bol školský rok 1927/28, kedy jedna z výpomocných profesoriek dočasne prevzala počas zastupovania profesora výučbu predmetov spev, hra na husliach, hra na k lavíri a hra na organe. 31 Rádový československý ženský učiteľský ústav s v. Uršule v Košiciach V roku 1937 bol po 18- ročnej prestávke znovuotvorený Rádový českos lovenský žen ský učiteľský ústav sv. Urš ule v Košiciach . 32 Rád sv. U ršule v Košiciach uvádzal ako hlavný dôvod j eho otvorenia nedostatok česko - slovenských a profesorsk ých síl. 33 Keďže išlo o rá dový ženský učiteľský ústav, jeho žiačkami sa mohli stať len dievčatá, pričom pri ich prijímaní platili 29 PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 617. 30 Na niek torých koeduka čných učiteľ ských ústavoc h bol predmet ž enské ručné práce považova ný za povinný. PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 592. 31 Výročná zpráva českoslov. št. učit. ústavu v Košiciach za roky 1921/22 – 1927/28 ..., s. 24-25. 32 II. výročná zpráv a rá dového čsl. dievč. reálneho gymnáz ia sv. Ur šule v Košiciach a I. výročná zpráva rádovéh o čsl. že nského uč it. ústav u uršul iniek v K ošiciach za školsk ý rok 19 37 – 38 ..., s. 31. 33 Arcibiskupský archív v Košiciach (ďalej AACass), fond (ďalej f.) Košické biskupstvo (ďalej KB), oddelenie (ďalej odd.) Košický biskupský ordinariát 1883 – 1946 (ďalej KBO), číslo spisu (ďalej č. sp.) 2447, 1936. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 91 predpisy, ktoré boli ustanovené pre štátne ženské učiteľské ústavy. Rovnako aj učebná osnova bola taká istá, ako v prípade štátny ch učiteľských ústavov. 34 Prvý školský rok 1937/38 absolvov alo 38 žiačok. Z Košíc pochádzalo 9 dievčat a z územia Slovenska (mimo Košíc) zvy šných 29, z ktorých bolo 28 ubytovaných v internáte rádu sv. Uršule a jedna v súkromnom byte. Všetky žiačky uviedli za svoju materinskú reč „československú“, ktorá označovala slovenský aj český jazyk. Vzhľadom k tomu, že všetky ž iačky pochádzali z územia Slovenska, môžeme predpokladať, že išlo len o slovenský jazyk. Z hľad iska vierovyznan ia bolo najv iac zastúpené rímsko katolícke nábože nstvo, ku ktorému sa hlásilo 35 dievčat a okrem neho i gréckokatolícke náboženstvo, ku kto rému sa hlás ili 3 dievč atá. Uveden é údaje zob razuje nasle dujúca tabu ľka. Tabuľka č. 3: Štatistické ukazovatele žiačok v školskom roku 1937/38 35 Školský rok Počet žiačok Rodisko Materinská reč Náboženstvo Košice Slovensko (okrem Košíc) Zvyšok ČSR Zahraničie Československá Nemecká Maďarská Rímskokatolícke Gréckokatolícke 1937/38 38 9 29 - - 38 - - 35 3 Profesorský zbor ženského učiteľského ústavu uršulínok tvorili okrem správkyne ďalšie 4 profesork y (vyučov ali slovenský jazyk, nemecký jazyk, dejepis, zemepis, prírodopis, spev, hru na husliach, telocvik a ženské ručné práce) a 6 profesori (vy učovali nábož enstvo, chém iu, fyziku, kreslenie, kra sopis a m atemat iku). 36 Pred mety, k toré ab solvov ali žia čky prv ého roč níka, z odpove dali pred pisom týk ajúcim sa štátn ych učiteľ ských ústa vov. Žiačky si svoje vz delani e doplnili i abso lvovaním 10 - hodinov ého kur zu výcho v nej rytm iky. Okrem toho sa 15 žiačok zúčas tnilo ošetrovat eľského kurzu, kt orý od 19. marca do 18. júna 1938 organizoval Československý Červený kríž v Košiciach. 37 Obnovený Rádový československý ženský učiteľský ústav sv. Uršule v Košiciach však 34 AACass, f. KB, odd. KBO, č. sp. 1354, 1937. 35 II. výročná zpráv a rá dového čsl. dievč. reálneho gymnáz ia sv. Ur šule v Košiciach a I. výročná zpráva rádového čsl. ženského učit. ústavu uršulin iek v Košiciach za školský rok 1937 – 38 ..., s. 37-38. 36 II. výročná zpráv a rá dového čsl. dievč. reálneho gymnáz ia sv. Ur šule v Košiciach a I. výročná zpráva rádovéh o čsl. že nského uč it. ústav u uršul iniek v K ošiciach za školsk ý rok 19 37 – 38 ..., s. 33. 37 II. výročná zpráv a rá dového čsl. dievč. reálneho gymnáz ia sv. Ur šule v Košiciach a I. výročná zpráva rádovéh o čsl. že nského uč it. ústav u uršul iniek v K ošiciach za školsk ý rok 19 37 – 38 ..., s. 36. Gallová, M.: Inštitucionálna príprava a vzdelávanie učiteliek v Košiciach do roku 1938 92 fungoval v tomto meste le n jeden školský rok. V novembri nasledu júceho školského roka, teda po viedenskej arbitráži, bol ústav presťahovaný do Bratislavy. 38 Odborné učiteľské ústavy Okrem učiteľských ústavov existovali i „odborné uč iteľské ústavy“. Toto pomenovanie ne bolo úradne stanovené, ale použ ívalo sa z organizačných dôvo dov v praxi M iniste rstva školstv a a ná rodne j osvety v Pra he (ďa lej MŠa NO). Označovalo zariadenia, ktoré slúžili na vz delávanie učiteliek domácich náuk a učiteliek materských škôl. Štúdium na odborných učiteľských ústavoch trvalo dva roky, pričom sa každý rok ot váral len jeden z dvoch ročníkov tak, ako to určoval organizačný štatút MŠaNO č. 29 387 zo dňa 14. novembra 1919. 39 Podľa n eho mali ústav y domácich ná uk poskytnúť dievčatám vz delanie, ktoré potrebovali pri vedení domácnosti, výchove v rodine a uspôsobovalo ich vyučovať domáce náuky, teda žensk é ručné práce. Ústavy pre vzdelávanie učitelie k materský ch škôl umož ňovali absolv entkám zam estnať sa v m aterských školách alebo detských opatrovniach ako vychovávateľky. Obidva druhy inšt itúcií ma li byť zakla dané pri štátn ych učite ľských ús tavoch . Iní zriaďov atelia ich mohli udržiavať i samosta tne, čo využívali najmä cirkvi. Do roku 1918 na území Slovenska odborné učiteľské ústavy neexistovali. 40 Učiteľské ústavy pre vzdelanie pestúnok (opat rovateliek) Okrem dvoch vyššie spomenutých r ímsk okatolíckych učiteľských ústavo v bola v roku 1918 v Košiciac h založená i škola pre vz delávanie uči teliek materských škôl (opatrovní), ktorá patrila pod správu dom inikánok. Pr edmety, v k torých sa mali d ievčat á počas š tvorro čného štúdia v zdeláv ať, bol i nábož enstvo a morálka, vyučovanie o duševnom a telesnom živote, pedagogik a a didaktika na ľudových školách, štruktúra uhorského ľudového škols tva, história pedago - giky, pedagogická prax, maďarský j azy k a literatúra, nemecký jazyk, druhý domáci jazyk (voliteľný), história, poznatky o uhorskej ústave, zemepis, mate matik a, pr írodop is, chémia , fyz ika, zdravo veda, hospo dárst vo (d omácn osť), 38 Esti újság , 1938, 10. november, roč. 3, č. 256, s. 9. Slov ák , 1938, 6. novem ber, roč. 20, č. 253, Nový učiteľský ústav v Bratislave, s. 7. 39 Predtým boli ústavy pre vzdelávanie učiteliek materských škôl zriaďované na základe naria - denia uhorského Ministerstva kultu a vý učby č. 3632, ktoré bolo prijaté 3. júla 1914 a neskôr zase na základe orga nizačného štatútu č. 167 279/ 36- II prijatého 15. marca 1937 . PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 572. 40 Jozef Bilčík uvádza, že prvý odborný učiteľský ústav vznikol v Prešove v roku 1922. Avšak už v roku 1918 bola v Košiciach založená škola pre vzdelávanie učiteliek opatrovní. BILČÍK, J. Vývoj školstva na Slovensku (III) ..., s. 154. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 93 spev, hudba, kreslenie, krasopis, ru čná práca, gymnastika a hry. 41 Škola fungov ala prav depodobne len jeden školský rok (1 918/19). V štatistike žiactv a v jedno tlivých školsk ých zariadenia ch dominikán ok v Košiciach za prvý polrok školského roka 1919/20 sa ústav pre vz delanie pestúnok už nespomí na. 42 Pre územie Slovenska platil ohľadom ústavov pre vzdelanie opatro - vateliek až do roku 1919 zákonný článok č. 15/1891. 43 Zákonom č. 293/1919 Sb. z. a n. boli tieto predpisy nahradené predpismi, ktoré dovtedy platili v ostatných častiach ČSR. 44 Ústavy pre vzdelanie pestúnok (opatrovateliek) sa teda aj na Slovensku mali od roku 1919 riadiť organiza čným štatútom č. 3.632 zo dňa 3. júla 1914. Založené mohli by ť buď pri učiteľsk om ústave alebo samost atne. Ich úlohou bolo poskytnúť žia čkam vzdelanie , ktoré: „[...] je nutn é pro zdárnou práci v mateřských školách (opatrovně), zvláště pochopení pro dětskou povahu, přesné obeznámení s cíli, prostředky a rázem výchovy v mateřských školách (opatrovnách), zručnost a jistotu v provádění všech povinností pěstounky (opatrovatelky).“ 45 Uchádzačky o štúdium na tomto type ústavu museli mať minimálne 16 rokov, byť mravne bezúhonné a telesne spôsobilé na zastávanie postu vych ováva teľky, byť zr učné v žen ských ru čných prác ach (mali pred ložiť vl astné ručné práce), mať hudobný sluch a dobrý spevácky hlas a mať predchádza júce vzdelanie, ktoré bolo podmienkou aj pre prijatie do učiteľských ústavov (overovalo sa prijímacou skúškou). Počas dvojročného štúdia boli žiačky vzdeláv ané v nasled ujúcich predm etoch: nábožen stvo, vychováv ateľstvo, náuka o mater skej škole (opatrovn i), praktické cvičenie v m aterskej škole (opatro vni), vyučovací jazyk, vecné vyučovanie (prírodopis a občianska náuka), kreslenie a modelovanie, výtvarné ručné práce, ženské ručné práce, sp ev a telocvik. Medzi nepovinné predmety patril cudzí jazyk, hra na husliach a hra na klavíri. Po úspešnom ukončení štúdia získali absolventky vysvedčenie spôsobilost i na výkon pov olania pestúnk y (opatrovateľ ky). Absolve ntky 4 - ročného učit eľského ústavu po najmenej t ro jmesačnom hospitovaní v materskej škole a dodatočnej skúške mohli túto spôsobilosť získať v o forme dodatku k vysvedčeniu. 46 Československý rádový ústav pre vzdelanie u čiteliek materských škôl Kongregácie sestier dominikánok v Košiciach V roku 19 29 zaslala Kongregácia sestier dominikánok v Košiciach žiadosť MŠaNO o povolenie na zriadeni e ústavu pre vzdelan ie učiteliek detský ch opatrovní v Ko šiciach. Do začia tku roka 1934 však ostala táto žiadosť 41 AACass, f. KB, odd. KBO, č. sp. 3264, 1930. 42 AA Cass, f. KB, odd. KBO, č. sp. 328, 1920. 43 1891. évi XV. törvénycikk a kisdedóvásról [online]. 44 PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 581. 45 PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 574. 46 PLACHT, O. – HAVELKA, F. Příručka školské ..., s . 574. Gallová, M.: Inštitucionálna príprava a vzdelávanie učiteliek v Košiciach do roku 1938 94 nevybav ená. 47 Českos lovenský rádov ý ústav pre vzd elanie učiteliek materských škôl Kongr egácie sestier domin ikánok v Košiciach bol založ ený až v ško lskom roku 1934/35. 48 Ústav bol dvojročný, pričom prv ý ročník sa otv áral každý druhý ro k, takže v škols kom roku 1935 /36 prebiehala v ýučba v druhom ročníku a v školskom roku 1936/37 bol otvorený znova prvý ročník. Okrem predmetu nábože nstvo, ktorý bo l vyučovaný pr iorom dominik ánskeho klášto ra, vyučoval i všetky ostatné predmety sestry dom inikánky. 49 Praktický výcvik žiačok prebiehal trikrát týždenne v materskej škole ústavu. Na praxi sa dievčat á striedali a každé z nich ju počas školského roka absolvovalo minimálne šesťk rát. Okrem povinných predmetov sa diev čatá súkromne vz delávali v cudzích jazykoch (francúzskom a ruskom), v hre n a klav íri ale bo v spev e. Ich šk olské vz delan ie bolo do pĺňané účasťou na premi etaní filmov, exkurziách či vý stavách. Žiačky sa zapájali tiež do mimoškolský ch aktivít. V decem bri 1935 posky tli svoje ručné a výtvarné práce v prospec h vianočného trhu, ktorý v meste usporiadali dobročinné organizácie na pomoc chudobným. 50 Charitatívnou činnosťou sa zaoberali aj v decembri 1937, kedy v predvianočnom obdob í darovali chudobným deťom bielizeň a šaty, ktoré vlastnoručne ušili. 51 V máji a júni 1936 sa 26 žiačok úst avu zúčastnilo samaritánskeho kurzu v rozsahu 30 hodín, k torý usporiadal Česk oslovenský Červený kríž. Po vykonaní skúšky z ískali diplom o spôsobilosti na výkon funkcie samaritánky. 52 Podobný kurz absolvovali žiačky aj v máji a júni 1938, kedy sa zúčastnili prednášok o anatómii, hygiene a prvej pomoci ako aj praktického výcviku prvej pom oci. Kurz bol ukončený vykonaním v erejnej skúšky. 53 47 V roku 1932 bol takýt o ústav založený v Ružom berku. AACass, f. KB, odd. KBO , č. sp. 2256, 1934. 48 I. výročná z práva rádového čsl. diev čen. reálneho gymnázia k ongr. sestier dominikánok v Košiciach za školský rok 1936 - 37 . Košice : Nákladom ústavu, 1 937, s. 4. 49 Hlavná výročná zpráva čsl. rádového ústavu pre vzdelávanie učiteliek materských škôl v Košiciach. Školský rok 1935 – 1936. Košice, 1936, b. s. 50 Hlavná výročná zpráva čsl. rádového ústavu pre vzdelávanie učiteliek materských škôl v Košiciach. Školský rok 1935 – 1936. .., b. s. 51 Výročná zpráva čsl. rádového ústavu pre vzdelanie u čiteliek domácich náuk a čsl. rádového ústavu pre vzdelanie učiteliek materských škôl. Školský rok 1937 – 1938 . Košice, 1938, s. 12. 52 Hlavná výročná zpráva čsl. rádového ústavu pre vzdelávanie učiteliek materských škôl v Košiciach. Školský rok 1935 – 1936 ..., b. s. 53 Výročná zpráva čsl. rádového ústavu pre vzdelanie u čiteliek domácich náuk a čsl. rádového ústavu pre vzdelanie učiteliek materských škôl. Školský rok 1937 – 1938 ..., s. 11. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 95 Učiteľské ústavy pre vzdelanie učiteliek do mácich náuk (ženských ručných prác) Výnosom MŠaNO č. 29.387 zo dňa 14. novembra 1919 bol vydaný organiz ačný štatút ústavov pre vzdelania uči teliek domácich náuk. 54 Dvojroč né ústavy pre vzdelanie učiteliek domácich náuk sa mali zakladať pr i š tátnych učiteľských ústavoch. Podľa organizačného štatútu bolo ich úlohou poskytnúť žiačkam také vzdelanie: „[...] aby dovedly vésti dívky ku pochopení úkolu ženy v domácnosti a vychovávati je k vytrvalé a uvědomělé práci pro sebe, rodinu a sv é bližní.“ 55 Počas dvo jročného štúdia sa diev čatá vzdeláv ali v týc hto predmetoch: pedag ogika s praktickými cvičeniami, vyučovací jazyk, počty, občiansk a náuk a a výchov a, organ izácia sociálnej sta rostlivost i, náuka o tkani- nách, telesná výchova, zdravotníctvo, spev a hudobná výchova, kreslenie, ženské ručné práce a výtvarné ručné práce, náuka o vedení domácnosti s praktickými cvičeniami vo varení. V jednom ročníku mohlo byť najviac 30 žiačok, od školského roku 1933/34 len 25, pričom neplatili žiadne šk olné. Medz i podm ienky, ktoré mu seli sp lniť zá ujemky ne o št údium, patril o dosia hnutie minim álne 17. roku v eku, ďalej mr avná bezúho nnosť, telesné a duševné z dravie a absolvovanie meštianskej školy alebo nižšej strednej školy a dvoch ročníkov priemyselnej školy. Prednosť mali absolventky gazdinskej školy. Okrem toho museli uchá dzačky vykonať prijí maciu skúšku, ktorá sa sklada la z m atematiky, vyučovacieho jazyka a základných techník ženských ručných prác (pletenia a háčkovania). Žiačky, ktoré úspešne absolvovali celé štúdium, získali na konci druhého ročníka vysvedčenie učiteľskej spôsobilosti vyučovať ženské ručné prá ce (domáce n áuky) na obecn ých (ľudový ch) školách. 56 Po absolv ovaní minimálne dvojročnej praxe na obecnej škole sa mohli učiteľky prihlásiť na skúšku, po vykonaní ktorej mohli vyučovať domáce náuky (ženské ručné práce) na meštianskej škole. 57 Československý rádový ústav pre vzdelanie u čiteliek domácich náuk Kongregácie sestier dominikánok v Košiciach Na základe výnosu MŠaNO č. 86.468/37 - II/2 zo dňa 13. júla 1937 bol na začiatku školského roka 1937/38 otvorený Č eskoslovenský rádový ústav pre vzdelanie učiteliek domácich náuk Kongregácie sestier dominikánok v Košic iach. Okrem vy ššie uvedenýc h predmetov mali žiačky košick ého ústavu v rámci vyučovania i náboženstvo. Každý týždeň absolvovali jednu ho spitáciu 54 PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 572. 55 PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 573. 56 MÁTEJ, J. et al. Dejiny českej a slovenskej pedagogiky . Bratislava : S lovenské pedagogické nakladateľstvo, 1976. 501 s. 347. 57 PLACHT, O. – HAVELKA, F. Příručka školské ..., s. 574. Gallová, M.: Inštitucionálna príprava a vzdelávanie učiteliek v Košiciach do roku 1938 96 na cvičnej ľudov ej šk ole, za k torou nasledovala pora da s d ôkladným rozborom vzo rového vy učovan ia. V pos lednom š tvrťrok u školsk ého roka im k ho spitác iám pribudla prax na danej ľudovej škole. Rovnako, ako to bolo v prípade ústavu pre vzdelávanie učiteliek materských škôl, aj na ústave pre vzdelávanie učiteliek ženských ručných prác vyučovali okrem náboženstva všetky ost atné predmety sestry dominikánky. 58 Výročné správy košický ch odbo rných učiteľských ústavov neobsahu jú štatistické údaje o žiačkach, ktoré na nich študovali. Nezachovali sa ani úradné knihy alebo spisový materiál z činnosti t ýchto ústav, preto nie je možné zistiť náboženské, národnostné alebo sociálne zloženie žiactva. Zakladanie odborných učiteľských ústavov na území Slovenska prebiehalo pomaly. V školskom roku 1937/38 existov ali na Slovensku len štyri ústavy, ktoré vzdelávali učiteľk y domácich náuk (v Košiciach, Levoči, Nových Zámkoch a Prešove ) a dva ústavy, ktoré pr ipravov ali učiteľky mate rskýc h škôl (v Košic iach a Ru žomber ku). 59 V dôsl edku uda lostí z n ovembr a 1938 obidva odborné učiteľské ústavy v Košiciach zanikli. Záver V Košici ach bolo od 6 0. rokov 19. storočia až do roku 1938 zalo žených ni ekoľko škôl, ktoré posky tovali dievčatám vzdelanie a prípravu na povolanie učiteľky. Do roku 1919 pôsobili v Košiciach dva rímskokatolícke učiteľské ústavy – osobitn e pre d ievčatá a osobitne pre chlapcov. Po vzniku Česko - slovenskej republiky tieto ústavy z anikli a v roku 1921 bol založený š tátny učiteľský ústav (zanikol koncom 20. rokov). Ten bo l síce koedukačný, ale počet prijatých dievčat nemal presiahnuť 1/ 3 z celkového počtu prijatých žiakov. Uršulínkam sa podarilo v roku 1937 obnov iť ich žensk ý učiteľský ústav, na ktorom začalo znova prebiehať vzdelávanie učiteliek (avš ak len do novembra 1938). V 30. rokoch vznikli v Košiciach dva odborné učiteľské ústavy, ktoré slúžili na vzdelávanie učiteliek materských škôl a učiteliek ženských ručných prác. Ústavy fungovali pod správou dominikánok. Prvú školu na vzdelávanie učiteliek detský ch opatrovní (materských škôl) založili dominikánky v Košiciach ešte v roku 1918, fungovala však len počas jedného školského roka. 58 Výročná zpráva čsl. rádového ústavu pre vzdelanie u čiteliek domácich náuk a čsl. rádového ústavu pre vzdelanie učiteliek materských škôl. Školský rok 1937 – 1938 ..., s. 1-2, 14. 59 BILČÍK, J. Vývoj š kolstva na Slovensku (III) ..., s. 154-155. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 97 Bibliografia Archívne pramene Arcibiskupský archív v Košiciach , Fond Košick é biskupstvo, oddeleni e Košický biskupský ordinariát 1883 – 1946. Výročné správy I. výročná zpráva rádového čsl. dievčen. reá lneho gymnázia kongr. sestier dominikánok v Košiciach za školský rok 1936 -37 . Košice : Nákladom ústa vu, 1937. 15 s. II. výročná zpráva rádového čsl. dievč. reá lneho gymnázia sv. Uršule v Košiciach a I. výročná zpráva rádového čsl. žens kého učit. ústavu uršuliniek v Košiciach za školský rok 1937 – 38 . Koši ce : Nákladom ústavu, 1938. 40 s. Čsl. štátna reálka v Košiciach a pobočka býv. št. u čiteľského ústavu v Košiciach. XI. (za uč. pobočku: V.). výro čná zpráva za školský rok 1929-30 . Košice : Nákladom vlastným , 1930. 30 s. Čsl. št. učiteľský ústav v Košiciach. Štvrtá výročná zpr áva za školský rok 1928-29 . Košice, 1929. 17 s. Hlavná výročná zpráva čsl. rádového ústavu pre vzdelávanie učiteliek mate rských škôl v Koš iciach . Škol ský ro k 193 5 – 1936. Ko šice, 1936. B. s. Výro čná z práva českos lov. š t. uči t. úst avu v Košici ach za roky 1921/ 22 – 1 922/23 . Košice, 1923. 22 s. Výro čná z práva českos lov. š t. uči t. úst avu v Košici ach za roky 1921/ 22 – 1 927/28 . Košice, 1928. 38 s. Výročná zpráva čsl. rádového ústavu pre vzde lanie učiteliek domácich náuk a čsl. rádového ústavu pre vzdelanie učiteliek ma terských škôl. Školský rok 1937 – 1938 . Košice, 1938. 14 s. Dobová periodická tlač Felvidéki Tanügy, 1881 . Esti újság, 1938 . Slovák, 1938 . Právne normy 1868. évi XXXVIII. törvénycikk a népiskola i közoktatás tárgyában [online]. [cit. 2. 11. 2019]. Dostupné na internete: <h ttp s://net.jogtar.hu/getpdf? docid=86800038.TV&targetdate=&printTitle=186 8.+%C3%A9vi+XX XVIII.+t%C3%B6rv%C3%A9nycik k&referer=1000ev> 1891. évi XV. törvénycikk a kisdedóvásról [online]. [ cit. 19.3.2020]. Dostupné na internete: <https://net.jogtar.hu/getpdf ?docid=89100015.TV &targetdate=&printTitle=1891.+%C3%A9v i+XV.+t%C3%B6rv%C3% A9nycikk&referer=1000ev> Gallová, M.: Inštitucionálna príprava a vzdelávanie učiteliek v Košiciach do roku 1938 98 Zákon č. 293/1919 Sb. z. a n. ze dne 27. května 1919 o změně platnosti usta novení o středních školách na Slovensku [online]. [cit. 5.3.2020]. Dostupné na internete: <http://ftp.aspi.cz /opispdf/1919/061 -1919.pdf> Literatúra ASZTALOS, József. Kassa közoktatási és k özművelődési intézmenyei. In Statisztikai Szemle [online], 1939, ro č. 17, č. 5, s. 585 - 595. [cit. 28. 10. 2019]. Dostupné na internete : <https://www.ksh.hu/statszemle_archivum #year=1939/issue=05.> BILČÍK, Jozef. Vývoj školstva na Slovensk u do roku 1960 a spracovávanie písomností škôl. In Slovenská archivistika, 1973, r o č. 8, č. 1, s. 26 -58. BILČÍK, Jozef. Vývoj školstva na Slovensk u do roku 1960 a spracovávanie písomností škôl (III). In Slovenská archivistik a, 1974, roč. 9, č. 1, s. 115-156. BOJKOVÁ, Alžbeta. Primárne problémy transformá cie slovenských stredných a odbor ných škôl v Košiciach v medzivojnov om období. Košice : UPJŠ v Košiciach, 2018. 205 s. Magyar statisztikai évkönyv 1911 [ online]. Bud apest : Ma gyar Király i Központi Stat isztik ai Hiv atal, 1912. 550 s . [cit . 28. 10. 20 19]. D ostupn é na intern ete: <htt p://ko nyvta r.ksh. hu/inc /kb_st atiszt ika/Ma nda/MS E2/MSE 2_191 1.pdf> MÁTEJ, Jozef et al. Dejiny českej a slovenskej pe dagogiky . Bratislava : Slovenské pedagogické nakladateľstvo, 1976. 50 1 s. MIHÓKO VÁ, Mária (e d.). Stredn é školstvo v Košiciac h v rokoch 1 848 – 1918. Tematic ká bibliogra fia I. Koš ice : Štátna vedecká k nižnica, 19 81. 411 s. MIHÓKO VÁ, Mária (e d.). Stredn é školstvo v Košiciac h v rokoch 1 848 – 1918. Tematic ká bibliogra fia II. Ko šice : Štát na vedecká knižnica, 1 981. 439 s . PLACHT, Otto – HAVELKA, František ( eds.). Příručka š kolské a osvětové správy. Praha : Státní nakladatelství v Prahe, 1934. 19 30 s. PUKÁNSZKY, Béla. Bevezetés a nőnevelés történe tébe [online]. [cit. 29. 10. 2019]. Dostupné na internete : <http://www.jgypk.hu/mentorhalo/tananyag /noneveles/index.html> STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 99 Prílohy Tabuľka č. 4: Učebný rozvrh pre učiteľské ústav y na Slovensku 60 Vyučovací predmet Počet vyučovacích hodín v jednotlivých ročníkoch Mužský alebo koedukačný ústav Ženský ústav I. II. III. IV. Spolu I. II. III. IV. Spolu Náboženstvo 2 2 2 2 8 2 2 2 2 8 Pedagogika a prax - 3 5 9 17 - 3 5 9 17 Vyučovací jazyk 7 7 5 6 25 7 7 5 5 24 Nemecký jazyk 2 2 2 2 8 2 2 2 2 8 Zemepis 2 2 2 2 8 2 2 2 2 8 Dejepis a vlastiveda 3 3 2 2 10 3 3 2 2 10 Matematika 4 3 3 2 12 4 3 3 2 12 Prírodopis 2 2 2 1 7 2 2 2 1 7 Fyzika a chémia 2 2 2 2 8 2 2 2 2 8 Poľné hospodárstvo - - 1 - 1 - - - - - Krasopis 1 - - - 1 1 - - - 1 Kreslenie 2 2 2 1 7 2 2 2 2 8 Spev a všeobecná náuka o hudbe 2 2 2 2 8 2 2 2 2 8 Hra na husliach 2 2 1 1 6 2 2 1 1 6 Hra na klavíri 2 2 - - 4 - - - - - Hra na organe - - 2 1 3 - - - - - Ženské ručné práce - - - - - 2 2 2 - 6 Telocvik 2 2 2 2 8 2 2 2 2 8 Výchovné ručné práce (nepovinné) - - 2 2 4 - - - - - Spolu 35 36 37 37 145 35 36 34 34 139 60 PLACHT, O. – HAVELKA, F. (eds.). Příručka školské ..., s. 617. Gallová, M.: Inštitucionálna príprava a vzdelávanie učiteliek v Košiciach do roku 1938 100 Tabuľka č. 5: Prehľad vyučovacích predmetov a počtu hodín na učiteľských ústavoch pre vzdelanie opatrovateliek (učitel iek materských škôl) 61 Predmet Počet hodín 1. ročník 2. ročník Povinné predmety: Náboženstvo 1 1 Vychovávateľstvo 2 2 Náuka o materskej škole (opatrovni) 1 1 Praktické cvičenie v materskej škole (opatrovni) 6 6 Vyučovací jazyk 3 23 Vecné vyučovanie 2 2 Kreslenie a modelovanie 2 2 Výtvarné ručné práce 2 2 Ženské ručné práce 2 2 Spev 2 2 Telocvik 2 2 Spolu 25 25 Nepovinné predmety: Cudzí jazyk 3 3 Hra na husliach 2 2 Hra na klavíri 2 2 Spolu 32 32 Tabuľka č. 6: Prehľad vyučovacích predmetov a počtu hodín na učiteľských ústavoch pre vzdelanie učiteliek domácich náuk 62 Predmet Počet hodín 1. ročník 2. ročník Pedagogik a s hospitác iami a praktick ými cvičeniam i 3 4 Vyučovací jazyk 2 2 Počty 2 2 Občianska náuka a výchova 2 - Zdravotníctvo 2 - Sociálna starostlivosť - 2 Náuka o tkaninách 2 - Telesná výchova 2 2 Spev a hudobná výchova 1 1 Kreslenie 5 4 Výtvarné práce - 1 Ženské ručné práce 7 10 Náuka o vedení domácnosti a praktické cvičenia 2 - Varenie 4 6 Spolu 34 34 61 PLACHT, O. – HAVELKA, F. (eds.). Příručka školské ..., s. 574. 62 PLACHT, O. – HAVELKA, F. (eds.). Příručka školské ..., s. 573. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 101 Mgr. Miroslava Gallová Katedra histórie (interná doktorandka) Univerzita Mateja Bela, Filozofická fakulta Tajovského 40, 974 01 Banská Bystrica Spoločenskovedný ústav (interná doktorandka) Centrum spoločenských a psychologických v ied SAV Karpatská 5, 040 01 Košice [email protected] Punčová, A.: Zmeny a reformy slovinského vzdelávacieho systému od roku 1991 po súčasnosť 102 Zmeny a reformy slovins kého vzdelávacieh o systému od roku 1991 po súčasnosť Changes and Reforms of the Slovenian Education System from 1991 to the Present Alexandra Punčová Abstract The Republic of Slov enia is currently gaining public attention due to the excellent results of its students in international testing. The paper focuses o n the changes and reforms of the Slovenia n education system over the last 30 years, respectively from its independence to the present. Ke ywords: Slovenia. Education system. Reform s. Úvod Slovin ská republika si mom entálne získ ava pozornosť verejnosti vďak a výborný m vý sledkom jej ž iakov v medzinárod ných testovaniach . Väčši nu čas u svojej existencie bolo Slovi nsko l en slovinsky hovoriacou skupinou tvoriacou súčasť v äčšieho celku . Slovinské vzd elávanie sa až do osa mostatnenia (25. júna 1991) rozvíjalo v rámci iných – väčších vzdelávacích sy stémov: tvorilo súčasť rakúskej m onarchie, vďaka vplyvu ktorej v roku 1918 predstavovalo jeden z najlepších a najmoderne jších vzdelávacích systémov vtedajšej Juhoslávie. Prís pevok sa sú streďu je na zmeny a r eformy s lovinsk ého vzd elávac ieho systé mu za posledných 30 rokov, resp. od osam ostatnenia krajiny po súčasnosť. Deväťdesiate roky 20. storočia Deväťdesiate roky boli pre viaceré európske krajiny obdobím veľkých zmien a obratov v ich histórii. V roku 1990 prvý slovinský minister školstva, kresťanský demokrat Peter Vencelj, zdôraznil, že napriek požiadavkám na radikálne zmeny vo vzdelávacom systéme, by sa tento proces nemal uskutočňovať unáhlene. Obhajoval postupnú zm enu z aloženú na odborných znalostiach, ktorá by priblížila slovinský vzdelávací systém k s ystém om rozvinutých krajín západu. Rok 1991 bol prelom om vo vývoji súčasného vzdelávacieho systému. Po získaní nezávislosti a demokratizácii Slovin skej republiky nastali v krajine zásadné štrukturá lne zmeny vo všetkých oblastiach spoločnosti (Plut - Pregelj, 2001). Vo svojom úsilí o vy tvorenie kvalitného STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 103 školského systému, ktorý by maxim álnemu počtu občanov umožnil nielen uplatniť svoje práva na vzdelanie, ale aj získať požadované z amestnanie, Slovinsko zaviedlo nové právne predpisy na reguláciu celého vzdelávacieho sys tému od p redško lskej vý chovy až po vyso koško lské vzd eláva nie (199 3 -1996) . Od r oku 199 3 je pre dškol ské vzd eláva nie neo ddelite ľnou s účasťo u vzdel ávacie ho systému a pa trí do právomoci ministerstva školstva, vedy a športu. V roku 1995 m inister školstva prijal príslušné usmernenia a bola uverejnená b iela kni ha „Vzde lávani e v Slovi nskej re publik e.“ Nov é vzdelá vacie z ákony sc hválen é v roku 1996 n a základe Bielej knihy sú založené na zásadách demokracie, slobody výberu, autonómie, prof esionality, kvality, excelentnosti, blízkosti k občanom, rovnakých príležitostí pre všetkých, ako aj práva na vzdelanie pre všetkých, bezplatné základné vzdelávanie, právo rodičov na zvolenie formy vzdelávania svojich detí, povinnosť štátu sponzorovať súkromné školy a posky tovať im rovnak ý práv ny ráme c. Teoret ickým základom vzdelávaci eho systému musia byť ľudské práva a štát dodržiavajúci právne predpisy. Všeobecnými c ieľmi vzdelávania sú: p oskytovanie rovnaký ch vzdelávacích príležitostí pre optimálny rozvoj všetkých jednotlivc ov; podpora vzájomnej tolerancie; rozvoj životných zručností demokratickej spoločnosti v rámci celoživotného vzdelávania; podpora rovnakých príležitostí pre obe pohlavia; rešpektovanie a spolupráca s tými, ktorí sú odlišní; dodržiavanie práv detí a ľudských práv. Právo na výber m edzi verejnými a súkrom nými školami alebo vzdelávaním v domácom prostredí je súčasťou práv a povinností žiakov, ktoré sú zdôraznené aj v Zákone o základných školách (1996), ktorý usmerňuje základné vzdelávanie, definuje ciele základného vzdelávania a zahŕň a: m edzinárodnú poro vnateľnosť výk onnostných štandard ov; získavanie vedomostí pre ďalšie vzdelávanie; spoznávanie cudzíc h kultúr; učenie cudzích jazykov; výučbu všeobecných kultúrnych hodnôt a civilizácie vyplývajúcich z európskej t radície; vzdelávanie zamerané na podporu vzájomnej tolerancie, rešpektovania odlišností, spolupráce s ostatnými, dodržiavania ľudských práv a základných slobôd; a následne rozvoj schopnosti žiť v demokratickej spoločnosti. Spolu so Zákonom o organizácii a financovaní vzdelávania upravuje Zákon o základných školách základné zásady riadenia a organizácie a r ozdeľu je zodpovednosť a autonómiu medzi štát, obce a školy. Zákon o gymnáziu uvádza, ž e jednou zo základných úloh gymnázií je posk ytovať medzinárodne porovnateľnú úroveň vedomostí, ktorá j e potrebná na pokračovanie vo vyššom vzdelávaní. Toto obdobie možno považovať za začiatok slovinskej politiky suverénneho vzdelávania (Štremfel, Lajh, 2012; Mlakar, 2015; UNESCO, 2012). Jedným z najdôležitejších cieľov reformného obdobia 1996- 2001 bolo dosiahnutie porov nateľnosti a väčšej kompatibility odborného vzdelávania, prípravy a kvalifikácií s ostatnými európskymi systémami. Zákon o odbornom a technickom vzdelávaní poskytuje základ pre system atickú podporu medzinárodne j činnos ti v odbornom vzdelá vaní, pretože definuje internacionalizáciu ako základné kritérium riadenia kvality a úspešne konk urenč ných sy stémov vzde lávan ia a o dborne j príp ravy ( Štremf el, L ajh, 2 012). Punčová, A.: Zmeny a reformy slovinského vzdelávacieho systému od roku 1991 po súčasnosť 104 Prvá dekáda 21. storočia Po systémových zmenách nasledovali podsta tné zmeny v kurikule (1999/2000), ktoré pripravila Kurikulárna komisia pre predškolské inštitúcie. Na prelome tisícročí sa na všetkých základných školách v Slovinsku začala vyučovať počítačová g ramotnosť. Bol vyvinutý tzv. Koncept celoživ otného učenia a vzdelávania – to sa prejavilo v jeho väčšej systematickej propagácii, zavádzaní systémov kontinuálneho vzdelávania, podpore rozvoja efektív neho prenosu vedomostí a dôrazu na interdisciplina ritu vedomostí. Tento proces sa začal väčším dôrazom na vzdelávanie dospelých a zamestnancov a neustále sa rozširoval medzi žiakmi a mladými ľuďmi, ktorí čoraz viac vnímajú význam celoživotného učenia (O koliš, 2008). Sociálne zmeny v Slovinsku a rozvoj celoživotného vzdelávania viedli k novým reformám a zmenám v oblasti vzdelávania detí, mládeže a dospelých. Začali sa objavovať nové typy vzdelávania okrem formálneho (bežného školského systému) aj neformálneho vzdelávania (v rámci jednotlivých inštitúcií, sam ovzdelávania, e - vzdelávania atď.) (Šverc a kol. 2007). Zákon o postsekundárnom odbornom vz delávaní a zmeny a doplnenia zákona o vysokých školách za viedli všetky prvky Bolonských reforiem terciárneho vzdelávania: terciárnu štruktúru, do datok k diplomu, eur ópsky systém prenosu a akumulácie kreditov (ECTS) a zabez- pečenie kvality (Štremfel, Lajh, 2012). V roku 2006 bol prijatý zákon upravujúci národné odborné kvalifikácie, ktorý vytvoril základ pre vytváranie sietí formálneho a neformálneho vzdeláv ania. Okrem toho zákon vytvoril základ na prenos výsledkov a poznatkov získaných v rôznych oblastiach a úrov niach vzdelávacie ho pro cesu. Najdôležite jšie politiky a ciele v zdelávania v Sl ovinsk u uverejn ilo mini sterstv o školstv a a športu v dokum ente „Vzd eláva nie v Slovinsku: včera, dnes, zajtra“ (2007). Zásadný význam má implementácia troch hlavných cieľov zameraných na oblasti zručností: zručnosti na kreatív ne ri ešenie problém ov, zručnosti na spoluprácu a komunik áciu s ostatn ými ľuďmi a zručno sti na celoživotné vzdelávanie. Celoživotné v zdelávanie nie je iba podstatnou vzdeláv acou politikou z hľadiska spoločenského vývoja, ale je to aj postoj k životu, ktorý ovplyvňuje k aždého jednotlivca. Začiatkom roku 2007 Slovinsko začalo s k oncepciou celoživotného v zdelávania, v k torej sa prenos poznatkov a skúseností medzi g eneráciami stal kľúčovým prvkom. Okrem toho Slovinsko zaviedlo osobitné stratégie a opatrenia, ktoré čerpajú zo skúseností v rámci Európskej únie s cieľom zlepšiť form álne, neformálne a informálne vzdelávanie (Mlakar, 2015). Zákon o základnej škole (zmenený a doplnený v rok u 2007) na riešenie problému ne dostatočného prospechu v ranom štádiu stanovu je, že základné školy musia poskytov ať doplnkové hodiny, individuálnu a skupinovú pomoc žiakom so slabými výsledkami a s poruchami učenia. Slovinsko tiež zaviedlo opatre nia na podporu z nevý - hodnených žiakov. V zmenenom a doplnenom zákone sa tiež stanovuje, že predškolské zariadenia a školy si každý rok prehodnocujú kvalitu programov, ktoré poskytu jú. Podľa zákona o základných školách (článok 60 písm. D) STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 105 z roku 2008 musí každá škol a pripraviť školský vzdelávací plán založený na cieľoch školy s cieľom vytvoriť bezpečné a zlepšujúce sa prostredie na dosahovanie cieľov základného vzdelávania (OECD, 2016; UNESCO, 2012). Druhá dekáda 21. storočia Nový prístup založený na kompetenciách v kurikule odborného vzdelávania (2008 - 2011) zaviedol modulovú štruktúru vo výučbe a učení, ako aj zvýšený podi el praktického výcviku. Učebné osnovy predmetov boli aktualizované vo všeobecnom vyššom sekundárnom vzdelávaní (gimnazija) (200 8/200 9) a zákla dnom vzd eláva ní (201 1/2012 ), pričom základ né kompe tencie boli zavede né do vš eobecn ého vzde lávani a. Nove la zákon a o zákla dných školách (2012) zav iedla povinné národn é ho dnotenie na konci VI. ročn íka pre všetkých žiak ov. Okr em toho boli zave dené čí selné z námky, ktoré na hrádza jú desk riptív ne hodnotenia pre žiakov, počnúc III. ročníkom. Národný program pre m ládež (2013- 2022) sa zameriava na zabezpečenie lepších príležitostí pre mladých ľudí (form álne aj n eformálne vzdelávanie). Tento prog ram je strategickým dokumentom, ktorý definuje ciele, základné op atrenia a ukazov atele, ktoré sa použijú pri hodnotení jeho vplyvu (OECD, 2016). Iniciatíva Otvorenie Slov inska – Opening Up Slove nia (201 4) sa zame riava na doplnen ie exist ujúcic h vzd elávac ích postu pov o inova tívne, dy namick é a otvore né vzdelá vacie pr ístupy . Cieľom je usk utočniť zmeny vo vzdelávaní v siedmich kľúčových oblastiach: 1) prem eniť exi stujúce v zdeláv acie met ódy na inova tívne, dy namick é a otvoren é vzdelávacie nástroje; 2) obnoviť prostredie spolupráce medzi verejným, súkromným a dobrovoľným sektorom výskumu; 3) rozvíjať a zavádzať otvoren ejšie vzdelávanie ; 4) budovať právn e mech anizmy na po dporu vykoná - vania otvor eného vzdelávania; 5) vyb udovať otvorenú platform u informačnýc h technoló gií, obsahu, služieb, ped agogických konce ptov a prís tupov; 6) obnoviť mechanizmy na z abezpečenie vysokej úrovn e k vality a hodnotenia služieb; 7) rozvíjať digitálne kompetencie v rámci celého vzdelávacieho systému a vykonávať konkrétne, medzidimenzionálne otvorené v zdelávacie pro jekty. Táto iniciatíva je podporovaná širokou škálou zainteresovaných strán a zahŕňa vý skum a vývoj nových konce ptov, modelov a metód v otvorenom vz delávaní. Nepretržitý rozvoj systému vzdelávania v Slovinskej republike je špecifiko - vaný v národných prog ramoch a iných dokumentoch týkajúcich sa jednej alebo viacerých úrovní alebo oblastí vzdelávania. Modernizáciou základného vzdelávania opísanou v reformách v roku 2017 tretina všetkých škôl (144) začala v školskom roku 2018/2019 rôzne implementačné modely modernizo - vaného konceptu rozšíreného programu. Žiaci budú mať možnosť vykonávať ďalšie aktivity v oblasti športu a zdravia. Devätnásť z týchto škôl realizuje skú šobné hod iny povin ného prv ého cudzi eho jazyk a už v I. ročník u a povinné ho druhého cudzieho j azy ka v VII. ročníku. Koncom roka 2018 a v januári 2019 bol uverejnený zmenený a doplnený vzdelávací program pre základné školy. Punčová, A.: Zmeny a reformy slovinského vzdelávacieho systému od roku 1991 po súčasnosť 106 Nasledovalo rozhodnutie Rady expertov Slovinskej republiky pre všeobecné vzdelávanie o rozšírení predmetového kurikula pre slov inčinu a včelárstvo na povi nne volit eľné predm ety a definov anie kurik ula predm etov film ovej výc hovy a slovinskej znakovej reči. Ich uplatňovanie sa začína školským rokom 2019 /2020 . V dece mbri 20 19 vlá da Slov inskej r epubl iky pri jala ná rodnú s tratég iu rozvoja čitateľskej gramotnosti 2019 - 2030. Nová stratégia sa zam eriava na čitateľskú gramotnosť ako základný kameň iných gramotností. Dôležitou súčasťou je kultúra čítania, ktorá zahŕňa čít anie ako hodnotu samu o sebe, a zdôrazňuje význam motivácie na čítanie. Cieľom tejto stratégie je, aby každý v Slovinsku rozv íjal úroveň gram otnosti potrebnú na to, aby sa mohol kvalifikovať v a ktív nom živote a práci. Vo februári 2020 schválili rady expe rtov Slovi nskej repub liky pre všeob ecné vzdelá vanie a odborné a techn ické vzdelávanie zmenené a doplnené programy vyššieho stredného vzdelávania. Prog ramy z ahŕňajú novú zlo žku ale bo iné formy vz deláv acích ak tivít: povinn ý súbor obsahu o aktívnom obči anstve, ako aj nepovinný obsah pre gymnáziá a záujmové činnosti v odbornom a technickom vzdelávaní. Rada expertov Slovinskej r epublik y pre všeobecné vzdelávanie okrem toho vo februári schválila predmetové študijné programy a k atalógy vedom ostí pre uvedený obsa h. Rev idova né prog ramy n adobud nú úči nnosť v škols kom ro ku 202 0/2021 (European Comission, EACEA, EURY DICE). Záver Od roku 1990 p rechádza slovinský vzdelávací systém nepretržitou reformou a zm enami. Krajina sa stala nezávislou len nedávno. Zo začiatku sa pozornosť v oblasti vzdelávania sústredila na zmenu organizačnej štruktúry, stanovenie nových vzdelávacích cieľov, zásad... Dnes krajina disponuje vzdelávacím systémom, ktorý zahŕňa všetky úrovne vzdelávania – od pred- primárneho po univerzitné. Podľa Európskej komisie (2017, 2019) Slov insko investuje do vzdelávania a odbornej prípravy viac ako je priemer EÚ. Účasť na vzdelá vaní a starostliv osti v ranom detstve sa zvyšu je a predčasné ukon čenie školsk ej doch ádzky je zrie dkavé (väčšinou mužská časť populácie ). Dô ležitým posunom je úplné zavedenie výučby cudzích jazykov v skorších ročníkoch základn ého vzdeláv ania. Zákla dné zručnost i slovinský ch pätnásťro čných žiak ov sú na celkovo vysokej úrovni a zlepšujú sa – dosahujú dobré výsledky v o všetký ch troch oblastiach tes tovaných v priesk ume OECD (PISA) z roku 2015: prír odné vedy , matemat ika a číta nie. Slov insko usi lovne pra cuje na mode rnizá cii odborné ho vzdelávania a prípr avy, a na pod pore vzdelávania dospe lých. Podiel dospelých s nízkou kvalifikáciou je malý, účasť na vzdelávaní dospelých je tesne nad priemerom EÚ. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 107 Bibliografia MINISTR Y OF EDUCA TION, SCIEN CE AND SPO RT OF THE R EPUBLIC OF SLOVENIA. 2017. The EDUCATION SYSTEM in the Republic of Slovenia 2016/2017. Ljubljana: Ministry of Educa tion, Science and Sport of the Republic of Slovenia, 2017. 72 s. ISSN 2536-3352. MLAKAR, J. 2015. Slovenia. (pp. 743-757). I n Hörner, W. – Döbert, D. – Reuter, R. R. – Kopp, B. The Education System s of Europe. Switzerland: Springer, 2015. 908 s. ISBN 978-3-319-07472-6. OECD. 2016. Education Policy Outlook: Slov enia. [Online]. [Cit. 5.6.2020]. Dostupné z: www.oecd.org/education/policyout look.htm. OKOLIŠ, S. 2008. Zgodovina šolstva na Slove ns kem. Ljubljana: Slovenski šolski muzej, 2008. 144 s. SBN 978 -961-6764- 00-1. OUSlovenia. Opening Up Slovenia. [Online]. [C it. 6.6.2020] Dostupné z: https://www.ouslovenia.net/. PLUT-PREGELJ, L. 2001. Educational Reform in the First Decade of Slovenian Political Pluralism. Wilson Center Ea st European Studies Meeting report 229. [Online]. [Cit. 4.6.2020]. Do stupné z: https://www.wilsoncenter.org/publicati on/229-educational-reform-the- first-decade-slovenian-political-pluralism. ŠTREMFE L, U. – L AJH, D. 2012 . Development of Slovenia n education policy in the e uropean con text and b eyond. (pp. 130-154). In Bulgaria n Journal of Science and Education Policy (BJSEP). Volume 6, Number 1, 2012. ŠVERC, A. – MEŽAN , J . – ŠKRIN JAR, M. A KO L. 2007. Sl ovene Educa tion System Yesterday, Today, Tomorrow. Ljubjana: M inistry of Education and Sport, 2007. 152 s. UNESCO, 2012. World Data on Education . 7th edit ion, 2010/11. [Online]. [Cit. 5.6.2020]. Dostupné z: http://www.ibe.unesco.org/sites/default/files/S lovenia.pdf. Mgr. Alexandra Punčová Katedra predškolskej a elementárnej pedag ogiky (interná doktorandka) Katolícka univerzita v Ružomberku, Pedag ogická fakulta Hrabovská cesta 1, 034 01 Ružomberok [email protected] Zastkov á, Z.: Kooperatívne učenie ako prostriedok napĺňania filozofie inkluzívnej edukácie 108 Kooperatívne učenie ako prostriedok napĺňania filozofie inkluzívnej edukácie Cooperative Learning as a Means of Ac hieving the Philosophy of Inclusive Education Zdenka Zastková Abstract In the article we present the reasons for strengthening inclusive education in the condit ions of Sl ovak schools, while perceiving inclus ive education in a broader context, meaning, as an approach that applies to all students with various educational needs. In accordance with the support and development of the individual potential o f each student, we clarify the inclusive approach in education and define it as the unco ndition al accept ance of the speci al needs of all chi ldren. By specify ing the main features o f cooperative learning, we emphasize this particular organizat ional form of teaching as one of the relev ant means for creating an inclusive environment. Keywords: Inclusive education. Coopera tive learning. Principles of cooperative learning. Úvod Jednou z aktuálnych t ém , ktoré v oblasti školstva rezonujú, je problematika inkluzívnej edukácie, ktorej saturácia sa okrem iného stala hlavnou doménou zadefinovanou v Národnom programe rozvoja výchovy a vzdelávania pre roky 2018 - 2027. Podľa tohto dokumentu sa javí podpora inkluzívneho prístupu v eduk ácií ako najvhodnejšia stratégia pre z lepšenie stavu kritických ukazovateľov v školstve, ktoré súv isia s nízkou mierou participácie detí na predprimárnom vzdelávaní, v nízkej miere účasti na ďalšom vzdelávaní dospelých, ale najmä sú prepojené s dosiah nutím nízkych zručností v testovaní PISA, a to predovšetkým v súvislosti s výsledkami žiakov zo sociál n e slabšieho prostredia (NPRVV, s. 14). Hoci je stratégia inkluzívnej edukácie obsiahnutá v základných legislatívnych dokumentoch a má oporu aj v m nožstve projektov, publikácií a metodík konkretizujúcich možnosti realizácie tohto princípu v slovenských školách, je otázne, ako sa uvedenú filozofiu vzdelávania darí v praxi reálne pr esadzovať. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 109 Podstata inkluzívnej edukácie Povinnosťou školy je poskytnúť všetkým žiakom bez rozdielu (etnika, jazyka, náboženskej príslušnosti, špecifických vzdelávacích potr ieb a po d.) kvalitn ú vý chovu a vzdelávan ie. Na jmä žiaci so špec iálnymi výchov no - vzdelá - vacími potrebami a rôznym znevýhodnením boli donedávna do škôl prevažne integro vaní. Podľ a V. Kleina a V. Šilonov ej (2016) spo číva rozd ielnosť inkl úzie a integrácie n ajmä v tom, že pokiaľ pri integrácií ide fyzické začleňovanie žiakov do bežnej školy, pri inklúzií ide o naplneni e základného práva na prístup všetkých ku vzdelaniu čo najvyššej kvality, ktoré vo svojej obsahovej zložke zahŕňa aj hod notový aspekt a v prístupe ku skupinám a osobám so špec iálnym i výc hovno - vzdelá vacím i potre bami rešpek tuje p rincípy sprav odliv osti a rovnosti šancí. Z hľadiska výchovy inklúzia znamená vytvorenie t akého edukačného pro stredia, aby bol každý žiak ochotný a schopný rešpektovať osobnosť ostatný ch. Z množstva prístupov r ôzny ch autorov sa nám javí najvhodnejšie vystihnutie podstaty inkluzívnej edukácie podľa Š. Porubského a kol. (2014, s. 3), k torí chápu inklúziu ako „ spôsob uskutočňovania výchovno - vzdelá - vacieho procesu , v ktorom učiteľ neustále uvažuje nad tým, ako vyhovieť rozvojovým potrebám jeho žiakov tak, aby predchádzal zlyhaniu žiakov a aby zároveň zabezpečil ich plnohodnotný rozvoj v rámci ich individuálnych možností, k toré sú u každého žiaka odlišné.“ Môžeme tak konštatovať, že inkluz ívne vzdelávanie sa neorientuje iba na individuáln e potr eby špecifického jedn otlivc a, ale týka sa všetk ých žiak ov, ktorí sú proc esu výchov y a vzdel ávania účastní. V rámci inkluzívnej edukácie potom nie je dôležité to, akí žiaci školu či triedu navštevujú, al e to, ako sa s nimi pedagogicky zaobchádza, teda ako sa k nim pristupuje. Inkluzívny prístup vhodne zadefinoval V. Klein a R. Rosinský (2013, s. 185) ako „bezpodmie nečné akceptovani e šp eciálnych potrieb všet kých detí.“ Ak hovoríme o triede, ktorá má vyhovieť potrebám všetký ch žiakov, máme na mysli vytvorenie takého prostredia, ktoré prijíma heterogenitu, podporuje sociálnu koherenciu a dokáže refl ektov ať potreby všetkých jej členov, pričom je založená na hodnotách tolerancie, akcep tácie, spolupráce a empat ie. Z mnohý ch k omponentov determ inujúcich kvalitu vytvor enia inkluzív - neho prostredia (odborné, personálne, materiálne, finančné komponenty) sa ďalej budeme venovať konkrétnemu spôsobu vyučovania, ktorý má potenciál podieľať sa na budovaní inkluzívnej kultúry triedy. Implementácia princípov kooperatívneho uč enia v intenciách inkluzívnej edukácie Vytvoriť prostredie, ktoré bude zodpovedať zásadám inklúzie, predpokladá etablovanie takej edukačnej bázy, ktorá sa musí uskutočňovať v celkovom kontexte spolupráce a vzájomnej podpory. Máme na mysli nielen Zastkov á, Z.: Kooperatívne učenie ako prostriedok napĺňania filozofie inkluzívnej edukácie 110 súlad edukačných a odborných postupov jednotlivý ch členov inkluzívneho tímu, ale najmä spoluprácu a vzájomnú podporu konkrétnych žiakov v kon- kré tnych so ciálny ch sku pinách . Práve s tratég ia koo peratív neho u čenia z dôrazň uje nenahraditeľnosť sociálnych interakcií pre rozvoj oso bnosti z aspektu kogni- tívneho, ale najmä socio - emocionálneho. M. Adams a M. Hamm (1994, In Tsay , M. – Bran dy, M. 2010, s. 78) vníma jú koo peratí vne uč enie ako org aniza čnú formu založenú na presvedčení, že žiaci sa v nej učia využitím sociálneho kontextu. V atmosfére rov noprávnosti a spolupráce si žiaci podľa I. Tureka (2008, s. 371) majú príležitosť navyknúť a osvojiť si také zručnosti a postoje, akými sú plánovanie a organizácia práce, vzájomná pomoc, spolupráca, komun ikácia, koordinácia úsilia, povinnosť, zodpov ednosť, tolerancia, váženie si cudzej pomoci, nenásilné riešenie konf liktov a pod. Kľúčovým bodom pre vytvorenie inkluzívneho prostredi a v triede je idea vytvorenia kooperatívneho učebného spoločenstva – prostredníctvom uplatnenia nasledovných princípov:  Vytvoriť pozitívnu vzájomnú závislosť , kedy sa žiaci v rôznych učeb ných sit uáciác h snažia do siahnu ť svoj cieľ a uspejú za predpok ladu, ak aj ostatní žiaci, kto rí sú s nimi pri riešení úlohy spojení, svoj cieľ dosiahnu. Vytvorenie vzájomnej závislosti medzi žiakmi teda závisí od cieľa a cha rakteru učebne j úlohy, pričom vzdelávacia činnosť je uskutočňovaná prostredníctvom interakcie jednotlivcov bez ohľadu na ich sociálny, kultúrny, etnický, zdravotný, či ekonomický pôvod. Uplatnenie uvedeného princípu v praxi tak má potenciál „narušiť“ vytvorenie hierarchie a „nálepkovania“ žiakov a umožňuje všetkým žiakom zapojiť sa do práce v skupine, spolupracov ať a profitovať. Podľ a T. Ja blons kého (I n Lech ta, V. 2010, s . 137) vo väčš ine ko operat ív - nych skupín sp olupra cujú žia ci s rôzn ou úrovň ou schop ností a s rôzny mi životnými skúsenosťami. Uvedené východisko považujeme v súlade so zásadam i inkluzívne j edukácie ako kľúč ové, keďže odlišno sť žiakov tu nie je vnímaná ako negatívny, či rušivý faktor pre vzdelávanie, ale má pozitívnu hodnotu (Janoško, P. – Neslušanová, S. 2014, s. 9).  Posi lniť indi viduá lnu zodpov ednosť , ktor á sa tý ka úsilia o d osiah nutie skup inové ho cieľ a a náp omoci d ruhým v tomt o úsilí. H. Kasí ková ( 2004, s. 85) bližšie konkretizuje uvedený princíp pričom tvrdí, že činnosť a výkon každého člena je zhodnotený a využitý pre celú skupinu a všetci členovia skupiny majú z kooperatívneho u čenia úžitok.  Umožniť vzájomný kontakt a komunikáciu tvárou v tvár , aby došlo k zdieľaniu učebných zdrojov, k pomoci, povzbudeniu medzi členmi skupiny a podpore dôležitej pre vytvorenie poci tu spolupa - tričnosti v triede. Interakcia v kooperatívnych situáciách vedie podľa H. Ka síkove j (2004, s. 70) k č astejše j, presn ejšej, otvor enej kom uniká cií, k jasnejšiemu porozumeniu perspektívy druhého, k diferencovaným, dynamickým a realistickým pohľadom medz i žiak mi, k zdravej seba- dôvere, k očakávaniu budúcej pozitívnej a produktívn ej interakcie. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 111 Vzh ľadom k tomut o princ ípu V. Battis tich (I n Gilli es, R. M., 200 3, s. 37 ) dokázal, že efektívnosť kooper atívneho učenia nezávisí od frekvencie apli kovan ia koo peratív nych a ktiví t, ale od kv ality skupi novej i nterak cie.  Viesť ži akov k formovan iu požadova ných interper sonálnych a sk u- pi nových z ručností. S cie ľom koordi novať úsilie o d osiahnutie sp oloč - ných cieľov sa žiaci musia: spoznávať sa a vzájomne si dôv erovať; presne, zrozumiteľne a jednoznačne komunik ovať; počúvať sa navzá - jom; vzájomne sa prijímať a podporov ať a v neposlednom rade kon- štruktívne riešiť konflikty (J ohnson, D. W. – Johnso n, R. T. 1990, s. 30). Uvedeným zručnostiam je potrebné ži akov postupne naučiť.  Ref lektovať skupinové činnosti prostredníctvom diskusie o tom, ako efektívne skupina dosahuje ciele a ktoré činnosti a správanie členov je pre skupinu užitočné alebo neužitočné. Reflexia skupinov ej činnosti podmieňuje rozhodnutie o ďalšom správaní jej č lenov . Spojenie princ ípov, resp. char akteristických znakov kooperatívneho prístupu vo vyučovaní (Johnson, D. W. – Johnson, R. T. 2009, 366-369) spolu so zásadami inklúzie, zodpovedá požiadavkám podčiarknutým v úvode príspevku, pričom môžeme hovoriť o spôsobe uskutočňovania výchovno - - vzdelávacieho pro cesu tak, aby bol v súlade s humanistickými a dem okra- tickými hodnotami spoločnosti . V. Lechta (2016, s. 166) v závislosti od špeciálnych potrieb žiakov uvádza podporné podmienky, ktoré sa vzťahujú na oblasť edu kácie, a ktoré je možné cháp ať ako „debarieriz áciu“ činnosti v ško le. Odporúča: ‒ koncipovať činnosti tak, aby sa do nich mohli v maximálne j možnej miere zaangažovať všetci žiaci, teda aj žiaci so špeciálnymi vzdelá - vacími potrebami, ‒ stanoviť ciele, ktoré sú dosiahnuteľné pre všetk ých žiakov, ‒ nevyčleňovať špecifické deti zo skupiny, ale prijímať ich ako plno - hodnotných členov skupiny, ‒ netolerovať neadekvátne správanie žiakov, ‒ podp orovať súťaž ivosť výhrad ne pri dosah ovaní takých cieľov , v kto rých si môžu deti spravodlivo konkurov ať. Môžeme si všimnúť, že prostredníctvom kooperatívneho učenia je vo vyučovaní možnosť dosiahnuť všetky uvedené odporúčania, t. j. pristupovať k plánovaniu, realizovaniu a hodnoteniu vyučovania tak, aby každý žiak uspel na vl astnej úrovni, tým plne rozvíjal a využíval svoj potenciál a zároveň, aby sa nauč il efektív ne komunik ovať a spo lupra covať s os tatným i. Sme toho názor u, že uvedený spôsob vyučovania pre inklúziu ponúka vytvoriť bezpečnú klímu založenú na pocite spolupráce, participácie, vzájomnosti a podpory, ktorá by mala byť súčasťou všetkého, čo sa v triede deje. Schopnosť škôl reagovať na rôznorodosť potrieb žiakov a efektívne s nimi pracovať nemá vplyv len na výs ledky žiako v s o šp eciáln ymi potreb ami, ale v súla de s uv edeným ovp lyvňuj e Zastkov á, Z.: Kooperatívne učenie ako prostriedok napĺňania filozofie inkluzívnej edukácie 112 vzd elávac ie možnos ti „bežný ch“ ži akov. Na záve r spomeni eme niek oľko výho d, ktoré prináša inkluzívne vzdelávanie z pohľadu žiaka (bliž šie Bagalová, Ľ. a kol., 2015, s. 14): ‒ rozma nitosť tr iedy pos kytuje ž iakovi r eálny ob raz o spo ločnosti, v ktore j bude žiť, pracovať a tým sa pripravuje na budúcno sť, ‒ žiaci sa prirodzene učia vnímať rozdielnosti medzi ľuďmi, chápu ich ako prirodzenú súčasť života, ‒ v he terog énnom kolek tíve (prost redníc tvom inter akcie medzi osta tnými ) si žiaci ľahšie rozv íjajú sociálne a občianske cítenie, umenie komu - nikovať a schopnosť riešiť problémy , ktoré zovšeobecnia a prenesú ich do iných oblastí spoločenského živ ota, ‒ v ko opera tívnyc h úlo hách majú žiaci možno sť zaž iť úspech, čo zvyšuje ich pozit ívnu hodnotu a sebavedomie. Záver Škola, ako jedna z n ajdôležitejš ích inšt itúcií zasahujúcich do utvárania osobnosti človeka sa v súčasnosti zaoberá aj otázkami, ako sa postaviť k rozdielom žiakov, vysporiadať sa s nimi a ako ich využ ívať vo vzdelávaní. P oprednú ú lohu pritom zohráva postoj školy, ktorá je schopná postaviť sa k rozmanitosti ako k neoc eniteľném u potenciálu pri prehlbovaní humánnych hodnôt. Úlohou učiteľa j e v tomto zmysle štruktúrovať vzdelávacie a sociálne prostredie tak, aby si žiaci rozvíjali zručnosti a postoje potrebné na interakciu medzi rôznorodým i žiakmi. V príspevku sme sa preto zamerali na konkrétny spôsob vyučovania, ktorý (podobne ako inklúzia) stavia na heterogenite a pomáha nám nielen pozitívne vnímať rozdielnosti (vy rovnávať ro zdiely, učiť žiakov vnímať rozdielnosti cez hranice etnicity, schopnost í, sociálno - - ekonomického statusu, záujmov, fyzický ch obmedzení a pod.), ale najmä kreovať kooperatívne inkluz ívne edukačné prostredie. Sme toho názoru, že prác a v hete rogénny ch skupin ách posky tuje žiak om viac prílež itost í na vn ímani e a oceňovanie rozmanitosti, ktorá existu je v triede aj v spoločnosti. Bibliografia BAGALOVÁ, Ľ. – BIZÍKOVÁ, Ľ. – FATULOVÁ, Z . 2015. Metodika podporujúca inkluzívne vzdelávanie v školách. Brat islava: ŠPU. 154 s. ISBN 978-80-8118-143-6. GILLIES, M. R. 2003. Structuring coopera tive group work in classrooms. In International Journal of Educational Resear ch. Vol. 39, p. 35-49. JANOŠKO, P. – NESLUŠANOVÁ, S. 2014. Škola s i nkluzívnou klímou. Ružomberok: Ver bum. 98 s. ISBN 978-80- 561-0193-3. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 113 JOHNSO N, D. W. – JOHNSON, R . T. 1990. S ocial skills for succes sful group work. In Educational leadership. Dec/Jan. p. 29- 33. [cit. 29.06.2020]. [online]. Dostupné na: https://www.researchgate. net/publication/ 234590538_Social_Skills_for_Successful_Group_Wo rk JOHNSON, D. W. – JOHNSON, R. T. 2009. An Educ ational Psychology Success Story: Social Interdependence Theo ry and Cooperative Learning. In Educational Researcher. Vol. 38, p. 36 5 – 379. eISSN 1935-102X. KASÍKO VÁ, H. 2 004. Ko operativní uč ení a vyučo vání. Teor etické a pra ktické problémy. Praha: Karolinum. 179 s. ISB N 978-80-246-0192-2. KLEIN, V. – ROSINSKÝ, R. 2013. Sociálna pedagog ika pre pomáhajúce profesie. Nitra: UKF. 168 s. ISBN 978-80- 8094-835-1. KLEIN, V. – ŠILONOVÁ, V. 2016. Inkluzívna edukác ia – výzva k pozitívnym zmen ám sú časnej školy . [onl ine]. [cit. 29.06. 2020]. Dostu pné na inte rnete: https://www.academia.edu/37601824/I NKLUZÍVNA_EDUKÁCIA_ VÝZVA_K_POZITÍVNYM_ZMENÁM_SÚČ ASNEJ_ŠKOLY_ INCLUSIVE_EDUCATION_A_CHA LLENGE_FOR_POSITIVE_ CHANGES_IN_PRESENT_DAY_SCHO OL LECH TA, V . 2010 . Zákl ady in kluziv ní ped agogi ky; dí tě s p ostižen ím, n arušen ím a ohrožením ve škole. Praha: Portál. 440 s. I SBN 978 -80-7367-679-7. LECHTA, V. 2016. Inkluzivní pedagog ika. Praha: P ortál. 463 s. ISBN 978-80-262-1123-5. Národný program r ozvoja výc hovy a vzdel ávan ia 2018- 2027. [cit. 29.06.2020 ]. [online]. Dostupné na: https://www.m inedu.sk/data/att/13285.pdf PORUBS KÝ, Š. – S TRÁŽIK, P. – VANČÍKOVÁ , K. – ROSI NSKÝ, R. 20 14. Pedagogický model inkluzívneho vzdelávania na základných školách. Prešov: MPC. 68 s. ISBN 978 -80-565- 0373-7. TSAY, M. – BRANDY, M. 2010. A case study of ccop erative learning and communication pedagogy: Does working in teams make difference? In Journal of the Scholarship of Teaching and L earning. Vol. 10, No. 2, p. 78-89. TUREK, I. 2008. Didaktika. Bratislava: I ura Edition. 598 s. ISBN 978-80-8078-198-9. Mgr. Zdenka Zastková Katedra predškolskej a elementárnej pedag ogiky (interná doktorandka) Katolícka univerzita v Ružomberku, Pedag ogická fakulta Hrabovská cesta 1, 034 01 Ružomberok [email protected] Recenz ie 114 Recenzie Critiques Ligoš, M.: Vyučovanie slovenčiny ako materinského jazyk a v minulosti, prítomnosti a bu dúcno sti (K apitol y z de jín vyu čovan ia slo venčin y s vý zvami d o bud úcnos ti) . Bratislava: VEDA, 2019, 240 s. ISBN 978-80- 224-1770-9. Súčasný proces vyučovania slovenského jazyka má svoj základ už v dávnej minulosti. História je teda podstatným pilierom pri vytváraní niečoho nového. Práve historické hľadisko v r ámci vyučovania slovenského jazyk a sa stalo východiskom pre vznik novej publikácie autora M. Ligoša. Publikácia zobrazuje pohľad na najstaršie časy vyučovania slovenčiny, ktoré autor rozdelil do štyroch rámcových etáp. Prvá etapa sa začína opisom obdobia Veľkej Moravy po vy danie 1. školského zákona Ratio educationis (1777, 1806). Druhá etapa pokračuje obdobím od Ratio educationis po r. 1918. Tretia etapa približuje obdobie od r. 1918 do začiatku 60. rokov 20. storočia. Štvrtá etapa zobrazuje obdobie od začiatk u 60. rokov 20. storočia po súčasnosť, ko nkrétne po r. 2008/2009. V publik ácii sa sp omínajú význam né m edzníky formovania slov enčiny ako spisovného jazyka. Autor vychádza z byzantskej misie solúnskych bratov a s ňou spojenou inštitucionálnou výučbou spisovnej staroslovienč iny, pričom upozorňuje zároveň aj na v tomto období už existujúcu formu domáceho jazyka – starej slovenčiny. Spomína predspisovné obdobie, ktoré bolo charak - teristické používaním latinčiny ako diplom atického jazyka. Pokračuje berno - lák ovskou a štúrov skou kod ifikác iou, na kto rú nadvia zala hodž ovsko - hatta lovsk á refo rma. Jedn otliv é obdobia sú do plnen é o releva ntné kodi fikač né a jazyk ovedn é publikácie a periodiká orientujúce sa na rozvoj spisovného jazyka a j azyk ovej kultúry. Nechýba ani zmienka o významných inštitúciách, ako je vznik a pôsobenie Matice slovenskej (1863 – 1875), prvé oficiálne zavedenie slovenčiny ako vyučovacieho jazyka na Gym náziu A. Sládkoviča v Banskej Bystric i (18 50) ako aj vzn ik prvého učiteľskéh o ústa vu v Uhorsku – v Spišskej Kapi tule (1 819), k de bo la zave dená spo lu so s lovenč inou aj m etod ika vyu čovan ia materinského jazyka v rámci sam ostatného učebného predmetu. Významným dielom, ktoré autor spomína vo svojej publikácii, je Pedagogia slovenská pre triwiálske školi (1820) od Juraja Pál eša – prvého riaditeľa Pedagogického inštitútu v Spišskej Kapitule. Bola to prvá metodik a vyučovania slovenského jazyk a, napísa ná v bernolákovč ine. Ob dobie vyučovania slovenčin y do r. 1918 autor analyzuje z pohľadu jednotlivých protichodných tendencií. Obdobie od r. 1918 je predstave né ako obdobie ideológie čechoslovakizmu. Ľudové školy STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 115 boli zamerané na zvládnutie elementárneho čítania a písania, osvojenia si pravopisu a základov jazyka, pričom v slohovej oblasti išlo zväčša o zručnosti spájajúce sa s reprodukciou. Autor vo svojej mo nografii predstavuje učebné osnovy pre školy spišskej diecézy, významné gymnáziá ako aj spoločensko - politické a kultúrne pomery v rámci vyučovania slovenčiny. Podáva charakteristiku metodickej príručk y Listár z 2. polovice 19. storočia , op isuje učebné osnovy pre slov enské ľudové školy (1930), učebné osnovy pre stredné školy a učiteľské ústavy, ako aj metodiku československého jazyka pre národné školy a vyberá kľúčové práce učiteľov slovenčiny z obdobia pred rok om 1989. Záverečná kapitola publikácie je venovaná súčasnej koncepcii vyučo - vania slovenčiny ak o materinského jazyka s víziami do bu dúcnosti. Autor v nej vyzdvihuje elementárnu znalosť slovenčiny, ktor á tak ako v minulosti, aj v dnešnej dobe je vnímaná ako základ zvládnutia vlastnej reči slovom a písmom. Predstavuje rôzne prístupy a koncepcie vyučovania slovenčiny od minulosti po súčasnosť. Zau jímavá je časť, v ktorej sa autor venu je novým podnetom a výzvam v rámci vyučovania slovenčiny ako materinského jazyka. Približ uje tu trilater álny koncept výrazových prostri edkov, silu jazyka a komu- nikácie ako aj výrazovo - komunikačnú kategóriu zrozumiteľnosti a komplexnú štylistiku. Monografia M. Ligoša je významným dielom, ktoré komplexne podáva prehľad o dôležitých medzníkoch, ktoré ovplyvnili úroveň vyučovania sloven ského jazyka ak o vyučovacieho predmetu. Prí nosnou je aj charak teristika pedagogických dokumentov a diel vý znamných osobností. PaedDr. Beáta Murinová, PhD. Code of Ethics for Publishing Articles in the Scientific Journal: STUDIA SCIENTIFICA FACULTATIS PAEDAGOGICAE 116 Manuscript Submission Guidelines for: STUDIA SCIENTIFICA FACULTATIS PAEDA GOGICAE UNIVERSITAS CATHOLIC A RUŽOMBEROK Accepted contributions will be published after recommendation of at least two reviewers and after an evaluation of journal’s Editorial Board. Formatting your article: Size B5 (18,2x25,7 cm) Margins top 3 cm bottom 3 cm left (outer edge) 3 cm right (inner edg e) 3 cm Font Times New Roman Font Size: 11: Line spacing – 1.0 (simple) Scope of a contribution: Maximum of 10-15 standard pages in A4 format i s recommended An article must contain the following items in their respective order: title, subtitle (if there is any) in the languag e of a contribution and in English, contributor’s n ame (names), email address, author’s workplace, abstract in English (up to 200 words), key words (up to 6 words in English), text, list of bibliographical references, picture descriptions (if there are any), picture and graph references. Besides original scientific and professional studies, every issue of the journal may contain essay s of renowned academics, book reviews and information about international conferences as well as brief research outcomes from recently completed empirical explorations. Citations and Lists of Bibliographical Re ferences: Citations should take the following form : STN ISO 690 – Documentation . Bibliographical References: References to these standard works should be consistent: the method of the first indication and the date. Dates for submissions: 1.2., 1.4., 1.6., 1.9., 1.11. Contact: [email protected] STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 117 Code of Ethics for Publishing Articles in the Scientific Journal: STUDIA SCIENTIFICA FACULTATIS PAEDAGOGICAE The publication process in the journal STUDI A SCIENTIFICA FACULTATIS PAEDAGOGICAE is governed by the standards for publication ethics of the scientific board of EU companies Elsevier and COPE/Committee on Publication Ethics. Duties of Authors According to the Code of Ethics The autho rs submitting articles to STUDIA SCIENTIFI CA FACULTATIS PAEDAGOGICAE declare that their manuscripts are entirely original works. The following duties listed for authors, editors, reviewers and the publisher are binding for them and they must adhere to the principles of the journal STUDIA SCIENTIFICA FACULTATI S PAEDAGOGICAE. Standard for Manuscripts, Access to Data and The ir Retention The authors of articles are obliged to use objective reasoning and objective results of scientific researc h. The data base of a scientific research should be explicitly presented. Scientific s tudies must be sufficiently detailed and the references used must enable readers to reprod uce their work objectively. The authors of the articles may be asked to provide source data used in the studies and articles for ed itorial control purposes, and if it is possible, the author should retain th e used data for a reasonably long period after the publication. Misleading or intentionally incorrect statem ents are considered unethical. Originality and Plagiarism The authors should ensure that they have written entirely original works, and if the authors have used the work and/or words of others, that this has been appropriately cited or quoted. Plagiarism in all its forms cons titutes unethical behaviour and is unacceptable. Plagiarism takes many forms, from ‘passing off’ another’s paper as the author’s own paper, to copying or paraphrasing substantial parts of another’s paper (without attribution), to claiming res ults from research conducted by others. Multiple, Redundant and Concurrent Publica tion An author should not in general publish manuscripts describing essentially the same research in more than one journal of primary publication. Subm itting the Code of Ethics for Publishing Articles in the Scientific Journal: STUDIA SCIENTIFICA FACULTATIS PAEDAGOGICAE 1 18 same manuscript to more than one journal concurrently constitutes unethical behaviour and is unacceptable Citing sources Authors should cite publications that have significantly influenced the reported article. The article should always contain correct and full qu otation of another’s paper. Information obtained privately must not be used or reported without explicit, written permission from the source, or from the owner of the property rights. Authorship of the Article Authorship should be limited to those who have made a significant contribution to the fi nal conception, design, execution, or interpretation of the reported study, article or paper. All t hose who have made substantial contributions should be listed as co-authors. Where there are others who have participated in certain substantive aspects of the paper, they should be recognised i n the article. The corresponding (responsible) author should ensure that all appropriate co-authors and no inappropriate co-authors are included on the paper, and that all co-authors have seen and approved the final version of the paper and have agreed to it s submission for publication. Fundamental Errors in the Published Works When an author discovers a significant error or inaccuracy in their own published work, it is the aut hor’s obligation to promptly notify the journal editor or publisher and cooperate with the editor to retract or correct the paper if deemed necessary by the editor. If the editor or the publisher learns from a third party that a published work contains an error, it is the obligation of the author to cooperate with the editor, including providing evidence of accuracy of the original results to the editor when reque sted. Duties of Editors According to the Code of Eth ics Publication decision: Editor in Chief of STUDIA SCIENTIFICA FACULTATIS PAEDAGOGICA E m ay accept, reject or request corrections of the articles reported to the journal for pub lication. In case both reviews are positive, the text is accepted to be published with the approval of editorial board. If both reviews are negative, the text is rejected. If one of the reviews is positive and the other negative, the author is invited by STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 119 the editor in chief to edit the article. Subsequently, the article will be reconsidered. Unpublished materials disclosed in a submitted article must not be used in anyone's own research without the express written consent of the author. Publication Decision Accepting articles into individual issues of the scientific journal STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE is in the competence of editorial board of the journal which takes into accou nt the reviews and other material acquired from the managing editor. T he vali dation of the article in question and its importance t o researchers and r eaders must be r ealized in accordance with the editorial rules. The managing editor is thus subject to legal requ irements in case of libel, copyright infringement and plagiarism. The managing editor may confer with other editors or reviewers in m aking these decisions. T he managing editor works with the manuscripts solely from the perspective of their content and qual ity Confidentiality The editor in chief or anyone i n the editorial office of the scientific journal STUDIA SCIENTIFICA FACULTATIS PAEDAGOGICAE must not provide any info rmation about submitted manuscripts to a ny subjects other than the corresponding author, reviewers, potential reviewers, members of the editorial board and publisher. Participation and Cooperation on Handling Comp laints The editorial o ffice shall take specific measures in case of complaints of ethical character regarding the submitted or published manuscript. These measures will generally include contacting the autho r of the m anuscript or paper and giving due consideration to the respective com plaint or claims made. The measures further include communications to the relevant institutions and research bodies and if the complaint proves to be justified, correction will be published, or the article wi ll be retracted, or other correction will be implem ented. Each reported case of unethical behaviour in publishing in the journal must be investigated, even in the case that the article has been published long time ago. Code of Ethics for Publishing Articles in the Scientific Journal: STUDIA SCIENTIFICA FACULTATIS PAEDAGOGICAE 120 Duties of Reviewers According to the Code o f Ethics Promptness: The accepted texts will be provided to two reviewers who are professionals in the given area and come from other workplaces than the author of the text. If the reviewer is not able to finish the review of the manuscript w ithin the agreed deadline, h e/she must communicate with the editor so that the manuscript will be provid ed to another reviewer. Contribution to Editorial Decisions Reviewer helps the editor and editorial board of the scientific journal STUDIA SCIENTIFICA FACULTATIS PAEDAGOGICAE with editorial decisions about publishing/rejecting articles. Reviewer’s comments assist t he author in improving the paper. Peer review is an essential com ponent of formal scholarly communication. Further Aspects/Time Perspective of Review P rocedure Each suggested reviewer who doe s not feel qualified to review a certain manuscript, or who knows tha t he/she will not be able to m ake the review within the agreed deadline, should notify the redaction office and excuse him/herself from the review process. Confidentiality Any manuscripts received for review must be treated as confidential documents. Reviewers must not show the manuscript or discuss t he manuscript with anyone unless the redactor in chief of the journal STUDIA SCIENTIFICA FACULTATIS PAED AGOGICAE permits it. Objectivity Reviews shoul d be conducted objectively. Personal criticism of the author is inappropriate. Referees should express their views clearly with supporting arguments. Citation of Sources Reviewers should point out the data and information that are wrongly cited or not cited at all by the author. Any proclamation that the data or information were already publ ished in the past must be supported by relevant documentation. A reviewer should bring to the attention of the editor any substantial similarity or overlap between the manuscript under consideration and any other published paper of which the rev iewer has personal knowledge. STUDIA SCIENTIFICA FACULTATIS PAEDAGOGI CAE UNIVERSITAS CATHOLICA RUŽOMBEROK 2020, č. 3 121 Publishing and Competing Interests Unpublished m aterials disclosed in a submitted manuscript must not be used in a reviewer’s own research without the express written consent of the author. Substantial in formation or ideas obtained th rough peer review are considered confidential and must not be used for personal advantage of the reviewer. Reviewers should not review articles in which a conflict of interests resulting from competitive or other relations wi th the author may arise. DUTIES OF THE PUBLISHER The publisher defines the relationship between the publisher, editors and other contracting parties, respects the confidentiality (e.g. towards the participants of a research, authors, professional reviewers), protects intellectu al property and copyright, and also supports editorial ind ependence. S T U D I A S C I E N T I F I C A F A C U L T A T I S P A E D A G O G I C A E / / 3 2020 U N I V E R S I T A S C A T H O L I C A R U M B E R O K Ž O S T U D I A S C I E N T I F I C A F A C U L T A T I S P A E D A G O G I C A E / / r 3 2020 oč ní k XIX. / / r 3 2020 oční k XIX. ISSN 1336-2232 9 7 7 1 3 3 6 2 2 3 0 0 5 6 0 Citations (0) References (54) ResearchGate has not been able to resolve any citations for this publication. Development of Slovenian education policy in the European context and beyond. Article Full-text available Apr 2012 Urška Štremfel Damjan Lajh Nowadays lifelong learning is widely recognized as a solu-tion in facing the intense new challenges of an increasingly globalized world. In facing these challenges and in order to achieve common educational goals, the nation states are included in different forms of international cooperation. It is very interesting to see how these different forms of international coopera-tion have impact on different aspects of national education policy and how the idea of lifelong learning has helped countries to increasingly perceive them-selves as similar with respect to necessary educational changes.Taking into consideration both inherent perspective (international cooperation influence and national responses to it), first of all it is essential to understand nation state’s historical legacies, the history of its policy paradigms and the history of its policy-making in the education field. From that point of view, on the one hand, the article explores the development of Slovenian education policy from its early beginning (the Reformation) till today. On the other hand, it focuses on the impact of different forms of international cooperation on the national education policy. On the basis of analysis of formal and informal documents and conducted semi-structured interviews, the article concludes that although Slovenia is included in various different forms of international cooperation, their influence on Slovenian education policy is limited. However, this cannot be solely attributed to education as a sensitive policy area with a low level of implementation imperative, where cooperation is in most cases voluntary, but also to the trends in Slovenian history. View Show abstract Social Skills for Successful Group Work Article Full-text available Jan 1990 EDUC LEADERSHIP David W Johnson Roger T. Johnson People do not know instinctively how to interact effectively with others. For cooperation to succeed, students must get to know and trust one another, communicate accurately and unambiguously, accept and support one another, and resolve conflicts constructively. A seven-step recommended procedure is outlined. Includes nine references. (MLH) View Show abstract A Case Study of Cooperative Learning and Communication Pedagogy: Does Working in Teams Make a Difference? Article Full-text available Jul 2010 Mina Tsay-Vogel Miranda Brady Cooperative learning has increasingly become a popular form of active pedagogy employed in academic institutions. This case study explores the relationship between cooperative learning and academic performance in higher education, specifically in the field of communication. Findings from a questionnaire administered to undergraduate students in a communication research course indicate that involvement in cooperative learning is a strong predictor of a student's academic performance. A significant positive relationship was found between the degree to which grades are important to a student and his or her active participation in cooperative learning. Further, the importance of grades and sense of achievement are strong predictors of performance on readiness assessment tests. View Show abstract An Educational Psychology Success Story: Social Interdependence Theory and Cooperative Learning Article Full-text available Jun 2009 David W Johnson Roger T Johnson The widespread and increasing use of cooperative learning is one of the great success stories of social and educational psychology. Its success largely rests on the relationships among theory, research, and practice. Social interdependence theory provides a foundation on which cooperative learning is built. More than 1,200 research studies have been conducted in the past 11 decades on cooperative, competitive, and individualistic efforts. Findings from these studies have validated, modified, refined, and extended the theory. From the theory, procedures for the teacher’s role in using formal and informal cooperative learning and cooperative base groups have been operationalized. Those procedures are widely used by educators throughout the world. The applications have resulted in revisions of the theory and the generation of new research. View Show abstract The education systems of Europe, second edition Book Jan 2015 W. Hörner H. Döbert L.R. Reuter Botho von Kopp This updated second edition presents an analytical description of the education systems of all European countries, following common guidelines. These conceptual guidelines consider various criteria concerning presumptions as to the quality of a good education system. One of the book central aims is to explore the paradoxical character of education, i.e. the relationship between universal values and the search for a national identity. The common structure of the different country analyses oriented by crucial problems of education worldwide guides to discover common patterns of European education compared to that of education systems outside Europe, making its reading relevant to educators around the world. The handbook provides many suggestions for further study. © Springer Science+Business Media B.V. 2007 and Springer International Publishing Switzerland 2015. View Show abstract Kooperativní učení a vyučování : teoretické a praktické problémy / Article Jan 2004 Hana Kasíková Univerzita Karlova. Filozofická fakulta 1. vyd. View Show abstract Jazyková specifikace školské komunikace a výuka mateřštiny / Article Jana Svobodová Ostravská univerzita. Pedagogická fakulta Vyd. 1. Anglický souhrn View Show abstract Structuring cooperative group work in classrooms Article R. M. Gillies Cooperative, small-group learning is widely recognised as a pedagogical practice that promotes learning and socialisation across a range of curriculum areas from primary school through to high school and college. When children work cooperatively together, they learn to give and receive help, share their ideas and listen to other students’ perspectives, seek new ways of clarifying differences, resolving problems, and constructing new understandings and knowledge. The result is that students attain higher academic outcomes and are more motivated to achieve than they would be if they worked alone. This paper provides an overview of five different studies that the author has conducted that demonstrate clearly the importance of explicitly structuring cooperative small-group work in classrooms if children are to derive the benefits widely attributed to this pedagogical practice. View Show abstract Pedagogická diagnostika v primárnom vzdelávaní. Bratislava: SPN, 2011, s. 26 -51 Jan 2011 Z Hirschnerová M Kožuchová HIRSCHNEROVÁ, Z. 2011. Diagnostikovanie žiaka v jazykovom vzdelávaní. In: KOŽUCHOVÁ, M. et al. Pedagogická diagnostika v primárnom vzdelávaní. Bratislava: SPN, 2011, s. 26 -51. ISBN 978-80-10-02053-9. Pedagogická diagnostika v primárnom vzdelávaní. Bratislava: SPN Jan 2011 M Kožuchová KOŽUCHOVÁ, M. et al. 2011. Pedagogická diagnostika v primárnom vzdelávaní. Bratislava: SPN, 2011. ISBN 978-80-10-02053-9. Show more Recommendations Discover more about: Social Services Article Observing the lighthouse September 1999 · European Journal of Social Work Chris Clark This paper discusses the nature of codes of ethics in social work. The desirability of defining rights and obligations in social services is widely accepted, but formal ethical codes often seem both excessively ambitious and insufficiently precise. Their usefulness is thus cast into doubt. The paper considers the influence of major traditions of moral theory and examines the nature of ... [Show full abstract] professional codes. It is argued that the precepts embodied in codes of ethics are of limited value unless supported by practical social institutions which attend to the proper implementation of ethical principles. The profession's code of ethics is likened to the function of the lighthouse: to serve as a point of reference and warning of danger, but not to work out one's course or one's destination. Read more Article Full-text available Ethical Aspects at Work of Personal Assistents September 2020 Lukáš Stárek Mgr Lukáš Stárek OBJECTIVES: Main purpose of the text is research of the influence of social service workers, especially personal assistents with ethical code. How is ethic code useable while dealing with ethical dilemmas in relation to the performance of this profession. Further we search for familliarity with ethical code between those assistents. THEORETICAL BASE: In their almost each daily routine are ... [Show full abstract] personal assistents facing particular ethical questions. Their realization, searching for answers and wondering about the questions in general, it requires neccesary care and time. METHODS: To answer above mentioned questions was used quantitative research strategy-through questionnaire. Data were processed from 105 questionnaires which were filled by workers at social services. OUTCOMES: We found out that moral orientation of workers at social services is appropriate key for ethical dilemma processing. The research proved that there is a need of deeper orientation in this profession meanwhile still keeping the focus on relation with the customer of the service and organization itself. This interest is linked with practical use and the knowledge of ethical code but also value of the social service. SOCIAL WORK IMPLICATIONS: Reflection of ethical aspects may contribute to improvment of provided social services, more precisely to professionalism of the profession or strengthening professional competencies. View full-text Article Observing the lighthouse. From theory to institutions in social work ethics November 1999 · European Journal of Social Work C. Clark This paper discusses the nature of codes of ethics in social work. The desirability of defining rights and obligations in social services is widely accepted, but formal ethical codes often seem both excessively ambitious and insufficiently precise. Their usefulness is thus cast into doubt. The paper considers the influence of major traditions of moral theory and examines the nature of ... [Show full abstract] professional codes. It is argued that the precepts embodied in codes of ethics are of limited value unless supported by practical social institutions which attend to the proper implementation of ethical principles. The profession's code of ethics is likened to the function of the lighthouse: to serve as a point of reference and warning of danger, but not to work out one's course or one's destination. Read more Article Full-text available A Czech Story about the Social and Legal Protection of Children October 2020 · World Journal of Social Science Research Lukáš Stárek In the Czech Republic, aid to and protection of children in various life situations have a longstanding tradition. In identifying children who are growing up in situations of risk, as well as providing them with full support and assistance in gaining their rights, all who work them professionally in some aspects of their lives are obliged to participate. Along with social workers, these are ... [Show full abstract] mostly paediatricians and other doctor specialists, midwives, pre-school teachers, teachers, pedagogues, psychologists… When applying work, social workers need to possess many layers of knowledge and skills on the one hand, and practice thoughtful ethical behaviour on the other hand. The text brings information about the system in the Czech Republic and the view of the social workers themselves helping children. View full-text Article Full-text available Code of ethics and the ethical decision-making model as a support in teachers' professional practice January 2020 Lukáš Stárek Educators are confronted by specific ethical issues in their everyday work. However, awareness of these issues, the search for answers to them and their consideration, demand due diligence and time. Thus, the importance of ethics and its impact may be downplayed. An educator aims to pay attention to the development of a child/student, especially with respect to the environment or social setting ... [Show full abstract] itself, and the responsibility toward society itself is evident from this. The educator's responsibility should also be related to the profession itself and the social perception of the teaching profession. The aim of the research was to examine whether a school's code of ethics and the training to use an Ethical Decision-making Model could be used to support teachers in solving ethical dilemmas. The research sample consisted of teaching staff working at a primary school in Prague. The teachers work in the first stage of primary school. The selected primary school has a code of ethics as an internal regulation. In total, five interviews with teachers were conducted. Respondents agreed that the Code of Ethics and Ethical Decision-making Model are good support for their professional practice. They are primarily useful in the communication process, especially when talking to children, colleagues and parents. View full-text Interested in research on Social Services? Join ResearchGate to discover and stay up-to-date with the latest research from leading experts in Social Services and many other scientific topics. Join for free ResearchGate iOS App Get it from the App Store now. Install Keep up with your stats and more Access scientific knowledge from anywhere or Discover by subject area Recruit researchers Join for free Login Email Tip: Most researchers use their institutional email address as their ResearchGate login Password Forgot password? Keep me logged in Log in or Continue with Google Welcome back! Please log in. Email · Hint Tip: Most researchers use their institutional email address as their ResearchGate login Password Forgot password? Keep me logged in Log in or Continue with Google No account? Sign up Company About us News Careers Support Help Center Business solutions Advertising Recruiting
https://www.researchgate.net/publication/361586838_UNIVERSITAS_CATHOLICA_RU_MBEROK_Z_O
Molecules | Free Full-Text | Co-Adsorption of H2O, OH, and Cl on Aluminum and Intermetallic Surfaces and Its Effects on the Work Function Studied by DFT Calculations The energetics of adsorption of H2O layers and H2O layers partially replaced with OH or Cl on an Al(111) surface and on selected surfaces of intermetallic phases, Mg2Si and Al2Cu, was studied by first-principle calculations using the density function theory (DFT). The results show that H2O molecules tended to bind to all investigated surfaces with an adsorption energy in a relatively narrow range, between & ndash;0.8 eV and & ndash;0.5 eV, at increased water coverage. This can be explained by the dominant role of networks of hydrogen bonds at higher H2O coverage. On the basis of the work function, the calculated Volta potential data suggest that both intermetallic phases became less noble than Al(111); also, the Volta potential difference was larger than 1 V when the coverage of the Cl-containing ad-layer reached one monolayer. The energetics of H2O dissociation and substitution by Cl as well as the corresponding work function of each surface were also calculated. The increase in the work function of the Al(111) surface was attributed to the oxidation effect during H2O adsorption, whereas the decrease of the work function for the Mg2Si(111)& ndash;Si surface upon H2O adsorption was explained by atomic and electronic rearrangements in the presence of H2O and Cl. Co-Adsorption of H 2 O, OH, and Cl on Aluminum and Intermetallic Surfaces and Its Effects on the Work Function Studied by DFT Calculations by Min Liu 1,2 , Ying Jin 1,* , Jinshan Pan 2 and Christofer Leygraf 2,* 1 National Center for Materials Service Safety, University of Science and Technology Beijing, Beijing 100083, China 2 Division of Surface and Corrosion Science, School of Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden Authors to whom correspondence should be addressed. Molecules 2019 , 24 (23), 4284; https://doi.org/10.3390/molecules24234284 Received: 6 September 2019 / Revised: 29 October 2019 / Accepted: 30 October 2019 / Published: 25 November 2019 Abstract The energetics of adsorption of H 2 O layers and H 2 O layers partially replaced with OH or Cl on an Al(111) surface and on selected surfaces of intermetallic phases, Mg 2 Si and Al 2 Cu, was studied by first-principle calculations using the density function theory (DFT). The results show that H 2 O molecules tended to bind to all investigated surfaces with an adsorption energy in a relatively narrow range, between –0.8 eV and –0.5 eV, at increased water coverage. This can be explained by the dominant role of networks of hydrogen bonds at higher H 2 O coverage. On the basis of the work function, the calculated Volta potential data suggest that both intermetallic phases became less noble than Al(111); also, the Volta potential difference was larger than 1 V when the coverage of the Cl-containing ad-layer reached one monolayer. The energetics of H 2 O dissociation and substitution by Cl as well as the corresponding work function of each surface were also calculated. The increase in the work function of the Al(111) surface was attributed to the oxidation effect during H 2 O adsorption, whereas the decrease of the work function for the Mg 2 Si(111)–Si surface upon H 2 O adsorption was explained by atomic and electronic rearrangements in the presence of H 2 O and Cl. Keywords: aqueous ad-layer ; work function ; micro-galvanic effect ; DFT ; aluminum ; intermetallics Graphical Abstract 1. Introduction Al alloys are widely used in many applications because of their mechanical properties, easy fabrication, and good resistance to corrosion in various environments. While improving strength, intermetallic particles (IMPs) commonly increase the susceptibility of Al alloys to localized corrosion. Mg 2 Si and Al 2 Cu are among the most common phases in 2xxx and 7xxx aluminum alloys [ 1 ]. The coupling of these IMPs to an Al matrix results in the so-called micro-galvanic effects induced by their potential difference, which may trigger localized corrosion [ 2 ]. On one hand, Cl − ions are believed to damage metal surfaces and hinder the re-passivation of localized corrosion of metals [ 3 , 4 , 5 , 6 ]. In a previous work, we studied co-adsorption of Cl and O 2 molecules on an Al(111) surface by density functional theory (DFT) and found that the interaction of Cl and Al weakened the O–Al bond when the Cl/O ratio increased [ 5 ]. Moreover, co-adsorption of H 2 O and Cl − ions on two of the common IMPs in Al, i.e., Al 2 Cu and Al 2 CuMg, was recently studied by DFT, and the results suggested that Cl − ions can distort the structure within Al–Cu layers and lead to the formation of corrosion products [ 7 ]. On the other hand, surface adsorption was also frequently reported to alter the measured work function [ 8 , 9 ], which can consequently change the micro-galvanic effect. This issue was also addressed in a previous paper by the authors, suggesting that the adsorption of pure water had a significant effect on the relative nobility of different IMPs [ 10 ]. Thus, in order to further study the impact of a more corrosive environment on the micro-galvanic effect, Cl-containing aqueous ad-layers were explored in this work to possibly reveal their effect on micro-galvanic corrosion. The work function is the minimum energy needed to emit an electron from the surface to vacuum, implying that a higher work function corresponds to a higher resistance against losing electrons, and vice versa. This means that the work function can be regarded as an indicator of corrosion tendency [ 11 , 12 ]. Scanning Kelvin probe force microscopy (SKPFM) is usually applied to measure the Volta potential difference of two phases, which directly responds to the work function of the probe and the phases [ 13 ]. Hence, it is expected that factors that can affect the work function can also have an impact on the Volta potential difference. Halogen adsorption was reported by DFT to decrease the metal work function. Examples include Cl on the (001) surface of Pt, Pd, and Rh [ 14 ], in which the polarization of halogen atoms overcompensates the charge transfer. Other studies have reported that Cl tends to increase the work function of Cu(111) [ 15 ] and Al(111) [ 16 ], while Br would raise the work function of Mg(0001) [ 17 ]. This can be explained by the strong electronegative character of halogen atoms, particularly Cl, which facilitates the formation of a dipole moment pointing from the halogen species to the metal surface [ 15 ]. A recent paper by Marks [ 18 ] reported that the galvanic effect between different sites on the oxide might be caused by a Cl adsorption-induced work function increase on several oxide surfaces, including Al 2 O 3 . Computational studies have shown that the adsorption of H 2 O decreases the work function of metal surfaces, such as Pt [ 19 , 20 , 21 ], Pd [ 22 ], and Cu [ 23 ]. This was attributed to electron transfer from H 2 O molecules to the interfacial region between the water layer and the metal surface because of the large polarizability of H 2 O [ 21 ], and different H 2 O adsorption orientations were believed to be the main reason for different directions of work function change [ 22 ]. A work function decrease caused by H 2 O adsorption was also observed in experimental studies [ 24 , 25 , 26 ]. Moreover, a correlation between the adsorption energy of H 2 O and the work function of the H 2 O-adsorbed Pt(111) surface could be discerned [ 20 ]. It should be mentioned that Cl atoms, rather than Cl − ions, are used in many DFT studies because of the lack of a clear description for ions in the calculation model, and some efforts have been made conceptually from an energetic point of view [ 27 , 28 ], in which the free energy of Cl − was replaced with that of gaseous Cl 2 . On the other hand, DFT calculations can reveal whether charge transfer occurs or not, so the use of Cl atoms in the DFT study can still provide valuable insights in the adsorption process. In an experimental work, the addition of pure Br 2 molecules was found to increase the work function of Cu(110). Subsequent introduction of H 2 O, on the other hand, substantially decreased the work function, mainly because of the H 2 O dipole orientation [ 29 ]. With the development of computational capacity, theoretical efforts have been accomplished to approach more realistic solvation environments at the electrochemical liquid/solid interface by including explicit H 2 O molecules. For example, Wasileski et al. [ 30 ] concluded that a mild aqueous environment containing O 2 , Na, and H 2 O can reduce the work function fluctuations of Pt(111). The theoretical studies mentioned above mainly focused either on single adsorbing species or on non-aggressive aqueous ad-layers. To better understand the localized corrosion mechanism of Al alloys, efforts are needed to study a more corrosive aqueous environment (e.g., with both Cl and H 2 O) on both pure and hydroxylated Al and on relevant IMPs, which can mimic more realistic electrochemical corrosion conditions. The objective of this theoretical work is to study several aqueous environments relevant to corrosion scenarios by DFT calculations of the energetics of adsorption of H 2 O molecules and of Cl on Al(111) and on two IMPs, Mg 2 Si and Al 2 Cu, and also the subsequent H 2 O dissociation and substitution by Cl. The corresponding work function changes will be discussed from a galvanic corrosion perspective, aiming at shedding some light on the localized corrosion mechanism. This work is a continuation of our previous study [ 10 ], in which micro-galvanic corrosion between an Al matrix and Mg 2 Si or Al 2 Cu was explored both computationally and experimentally in the presence of a pure H 2 O ad-layers without co-adsorption of other species. 2. Computational Details 2.1. Model Construction In this work, Al, Mg 2 Si, and Al 2 Cu crystals were considered. Aluminum has a cubic structure with a = 4.05 Å [ 31 ], and Mg 2 Si is cubic with a = 6.35 Å, while Al 2 Cu is tetragonal with a = 6.06 Å, c = 4.87 Å [ 32 ]. For Al, its (111) surface was studied. The Mg 2 Si(111) surface with Si and Mg terminations was selected, as these two terminations show rather different work function values. In addition, the Al 2 Cu(110)–Cu was selected for comparison. Note that vacuum was set to be at least as high as the thickness of the slab layers, and all atom positions were allowed to be optimized (details of the model construction can be found in [ 10 , 33 ]). In the following, Al(111), Mg 2 Si(111)–Si, Mg 2 Si(111)–Mg, and Al 2 Cu(110)–Cu will be simply written as Al, Mg 2 Si–Si, Mg 2 Si–Mg and Al 2 Cu–Cu, respectively. To begin with, intact H 2 O adsorption (this configuration is shortened INT herein) on each metallic surface with different coverages was constructed. Firstly, one H 2 O molecule was placed on the top site of each surface with flat or vertical orientation. After optimization, the configuration with the lowest total energy was selected and duplicated on another top site. Since there were a few top sites on each surface, non-equivalent adsorption configurations were constructed and optimized, and only that with the lowest total energy was used for further analysis. In this work, only the top site was considered, focusing on ad-layer coverage. On the basis of the final H 2 O adsorption configurations on each metallic surface, aqueous ad-layers including one hydroxyl group (OH) or one Cl atom, were subsequently constructed by one dissociated H 2 O (shortened DIS) and one substitution (SUB) of the dissociated OH by one Cl. To build the dissociation system, one H 2 O molecule was torn apart in the calculations, with the OH group remaining, and the H atom relocated to another top site. Hence, a few different dissociation ways were possible, and only those with the lowest total energy were selected and discussed. Figure 1 schematically depicts how the OH- and Cl-containing ad-layers were constructed. Figure 1. Top view depicting the different calculated configurations of adsorbed aqueous ad-layers: intact H 2 O (INT), water with one OH (DIS), and water with one Cl (SUB). The metallic surface for H 2 O adsorption is only a representative substrate. Note that in the SUB case, a surface bond is formed between the Cl and a surface atom. In this work, all results were discussed with the same coverage. The coverage of adsorbate, θ, is defined as the ratio of the number of adsorbates (e.g., water molecules, n W ) to the number of atoms in the first layer. Here, coverages with 0.25 monolayers (ML), 0.5 ML, 1 ML, and 2 ML were considered. Note that the dissociation and substitution systems consist of a mixture of adsorbates, 1OH + 1H + (n W -1) H 2 O (DIS models) or 1Cl + 1H + (n W -1) H 2 O (SUB models). In the following, INT-θ, DIS-θ, and SUB-θ were used when needed. H 2 O orientations were not considered, as the focus was to create Cl-containing aqueous ad-layers. Periodic DFT calculations together with the exchange–correlation functional, GGA-PW91, were performed using the Dmol3 code [ 34 , 35 ] implemented in MaterialsStudio. Core electrons were treated with DFT semi-core pseudopotentials (DSPP) with double numeric basis sets and polarization functions (DNP) [ 34 ]. A 6 × 6 × 1 k-point was used in all surface structures except for Al(111), for which a 3 × 3 × 1 k-point was used. Dipole correction was introduced vertically to each metallic surface to avoid dipole interactions. All atoms were relaxed until the energy, residual force, and displacement of each atom were less than 10 −5 Ha (Hartree), 0.002 Ha/Å (Ångström), and 0.005 Å, respectively. 2.2. Description of Energetics The work function of any surface configuration can be obtained by the energy difference between the vacuum level and the Fermi level, which is straightforward in DMol3 [ 33 ]. As proposed before, the Volta potential between different IMPs and the Al matrix is equal to their work function difference divided by e [ 33 ]. The adsorption energy per H 2 O, E ad , was calculated by Equation (1): E ad = ( E ( Surface + nH 2 O ) − E ( Bare surface ) − n · E ( H 2 O ) ) / n (1) where E ( Surface + nH 2 O ) , E ( Bare surface ) , and E ( H 2 O ) are the total energy of the H 2 O-adsorbed surface, bare surface, and H 2 O molecule, and n is the number of adsorbates. E ad ˂ 0 means that the adsorption is exothermic (favorable), and vice versa. The energy needed for the dissociation ( E d ) of one H 2 O molecule into OH and H and for substitution ( E s ) of one OH by one Cl was calculated by Equations (2) and (3) [ 36 ], respectively: E d = E DIS − E INT (2) E s = E SUB + E OH − E DIS − 1 / 2 E Cl 2 (3) where E INT , E DIS , and E SUB are the total energy for the INT, DIS, and SUB adsorption systems, while E OH and E Cl 2 are the energy for free OH and Cl 2 , respectively. 3. Results and Discussion 3.1. Adsorption of Pure H 2 O Ad-Layers As proposed in our previous work, water may adsorb in different configurations on different surfaces depending on their intrinsic properties. Nobility inversion was observed by DFT as well as by SKPFM when considering the work function change against coverage of water ad-layers [ 10 ]. In that previous study, the effect of H 2 O with different coverages on the work function was considered. It was concluded that the derived Volta potential difference between IMPs and the Al matrix agreed well with the experimental observations. In this work, however, the adsorption energy per H 2 O molecule with increasing H 2 O coverage, θ H 2 O , on each surface was further calculated by equation (1) and plotted in Figure 2 . The results show that H 2 O adsorption on the Mg 2 Si–Si surface was unfavorable at low coverage, but became increasingly favorable with increasing θ H 2 O , as indicated by a drastic drop in E ad from positive values to −0.4 eV with 1 ML of H 2 O. This can be explained by a change of balance between H 2 O–surface interaction and H 2 O-H 2 O interaction [ 37 ]. A similar trend was seen for H 2 O adsorption on Al 2 Cu–Cu, whereas H 2 O adsorption on Al and Mg 2 Si–Mg was favorable at all coverages, with only a slight change in E ad with H 2 O coverage ( Figure 2 ). This could indicate that the interaction between H 2 O and these two surfaces is a dominant factor, irrespective of H 2 O coverage. However, as will be shown in a later section, the hydrogen bonding between H 2 O molecules is a dominant factor, making the interaction between H 2 O and the substrate surface of minor importance. Besides, it can be seen in Figure 2 that E ad of all surfaces fell into a rather narrow range, −0.8 eV to −0.5 eV, with increasing coverage. Figure 2. Adsorption energy of H 2 O on Al, Mg 2 Si–Si, Mg 2 Si–Mg, and Al 2 Cu–Cu surfaces versus H 2 O coverage. To understand the trend in adsorption energy shown in Figure 2 , the energy difference between two hydrogen-bonded H 2 O molecules, E H 2 O – H 2 O , and two free H 2 O molecules was calculated to evaluate hydrogen bond strength ( E H – bond ). The molecules were not adsorbed on any surface during the calculation. Note that the van der Waals (VdW) force between H 2 O molecules was not considered, as it is not implemented in the DMol3 package: E H – bond = E H 2 O – H 2 O − 2 × E H 2 O (4) The initial distance between the two H 2 O molecules ( d 0 ) bonded by hydrogen bonding was allowed to decrease from 2.45 Å to 1.65 Å. After optimization, a nearly constant distance, d 1 = 1.91 Å, and a corresponding E H – bond = −0.25 eV, were obtained, agreeing well with the experimental and theoretical values found in the literature [ 20 , 38 ]. The calculated E H – bond suggests an explanation for the converging trend of the adsorption energy of H 2 O at higher H 2 O coverage (see Figure 2 ). Assuming that each H 2 O molecule has saturated hydrogen bonds, i.e., four H-bonds, then each H 2 O possesses two H-bonds and contributes −0.50 eV to the adsorption of H 2 O. The strength of H-bonds can be enhanced [ 20 ] or weakened [ 39 ] after the interaction with the substrate. With possible surface interactions neglected, we can conclude that hydrogen bonding is predominant when relatively large amounts of H 2 O molecules are present. On Mg 2 Si–Si, one of the four water molecules was found to spontaneously dissociate into OH and H ( Figure 3 ) when H 2 O adsorption reached 1ML. Looking back at the adsorption energy curve on the Mg 2 Si–Si surface ( Figure 2 ), it is evident that the dissociated OH can promote water adsorption at 1ML. Besides, the dissociated H atom binds to surface Si, as shown in Figure 3 b. Water dissociation on this surface may happen as the Si–H bond is stronger than the O–H bond in H 2 O [ 40 ]. Spontaneous dissociation was not observed on the other surfaces investigated. DFT calculations revealed a large energy barrier for H 2 O dissociation on Al(111) [ 41 ]. Figure 3. Optimized structure of H 2 O dissociation into OH and H (binding to surface Si) on Mg 2 Si–Si with 1ML H 2 O adsorption: ( a ) top view, ( b ) side view. Surface Si (Si s ) and bulk Si (Si b ) are indicated by dark and light orange color. Mg is in green, O in red, and H in white. By plotting the work function at different H 2 O coverages of Al, Mg 2 Si–Si, Mg 2 Si–Mg, and Al 2 Cu–Cu (published previously [ 10 ]) against the corresponding adsorption energy, some special features were found ( Figure 4 ). For Mg 2 Si–Mg and Al 2 Cu–Cu, the work function and adsorption energy were linearly correlated with one deviating value at 2 ML for Al 2 Cu–Cu. A favorable adsorption at 2 ML may be attributed to the formation of a water network on the Al 2 Cu–Cu surface. The deviating work function of this adsorption system may be due to the large dipole of H 2 O adsorbed far from the surface. A positive relationship was also observed for Mg 2 Si–Si. This correlation indicates that the more stable the adsorption (more negative E ad ), the lower the work function of the adsorption system, in accordance with other studies [ 20 , 21 ]. The Mulliken charge analysis in our work implies that electron transfer from Mg 2 Si–Mg to H 2 O increased from 0.64 e to 0.77 e with increasing H 2 O coverage. It seems that electron transfer fails to explain the work function decrease, in comparison with the bare surface (blue dashed bar in Figure 4 ). We noticed that water molecules adsorbed on Mg 2 Si–Mg in an upward direction on average ( Figure S1 ), which could compensate the effect of electron transfer. Therefore, water orientation is regarded as the predominant factor affecting the work function of Mg 2 Si–Mg. Figure 4. Plots of H 2 O adsorption energy on different surfaces versus work function under different H 2 O coverage (see the values without unit for each surface shown in the figure). The work function for each bare surface is highlighted by a dashed bar. Work function values for intact H 2 O adsorption were reported in our previous work [ 10 ]. For Al, the work function was nearly independent of the adsorption energy ( Figure 4 ). Water molecules were ~ 4 Å away from the Al surface when the coverage was beyond 1 ML. As a result, a large dipole was built between water and Al, determining the work function change. On the other hand, hydrogen bond formation denoted a strong interaction among water molecules, as more water molecules were present on Al. Previous calculations confirm that the H 2 O adsorption energy is mainly determined by the hydrogen bond strength. Therefore, it is reasonable to conclude that the work function is independent of the adsorption energy on Al. The optimized structures of pure H 2 O on the four metallic surfaces are listed in Figure S1 for comparison. We noticed that intact water adsorption caused a large surface relaxation on the Mg 2 Si–Si surface, even when only one H 2 O molecule was present. On the other hand, only a slight relaxation occurred on the Al 2 Cu–Cu surface with the formation of a Cu–H 2 O bond, and nearly no relaxation was seen on the other two surfaces (see Figure S1 ). It should be stressed, however, that there are many parameters that may influence the work function, such as surface relaxation, charge relaxation, and orientation of adsorbed H 2 O molecules. It is beyond the scope of this paper to be able to explain the relation between work function and adsorption energy for every investigated surface. The above correlation between adsorption energy and work function provides complementary information about the reactivity of adsorbates towards the investigated surfaces ( Figure 4 ). Though there may be several key factors which determine both work function and adsorption energy, carefully designed simulations or experiments may further reveal their influence on these interfacial properties, as reported previously [ 21 , 42 ]. The possibility of H 2 O dissociation on each investigated surface is discussed next. Since OH and Cl were reported experimentally to compete on metal surfaces [ 4 ], the substitution of OH by Cl is also discussed with respect to the mechanism of initiation of localized corrosion. 3.2. H 2 O Dissociation and Cl Substitution of OH Hydrolysis is common on aluminum surfaces exposed to a damp atmosphere or aqueous solution. The resulting hydroxyl species can generate a protective film on the aluminum surface as it may oxidize the aluminum surface, similar to oxygen species [ 43 ]. Therefore, the “dynamics” of the aqueous environment at the metal surface is of great interest for the metal performance in damp and aqueous environments. The dissociation energy ( E d ) is a measure of the tendency of H 2 O dissociation. On the basis of the INT-aqueous ad-layer, the E d of H 2 O on the four surfaces was calculated by equation (2) with increasing θ H 2 O from 0.25 ML to 1 ML. Four or five dissociation paths were calculated at each H 2 O coverage, with several different top sites present on each investigated surface. To reduce the computing time, only up to 1 ML coverage was considered in each case, which is sufficient to represent the system. The minimum H 2 O dissociation energy, E d min , versus H 2 O coverage is shown in Figure 5 . More information about the dissociation energy for different paths is provided in the supplementary materials (Figure S2 ). Figure 5. The minimum dissociation energy, E d min , as a function of H 2 O coverage for the four investigated surfaces. The dissociation energy of H 2 O on Al and on Al 2 Cu–Cu was close to zero, nearly independent of H 2 O coverage, suggesting that water was unlikely to dissociate under the current calculation conditions. In contrast, the tendency for H 2 O dissociation on Mg 2 Si–Si was strong, although it became less favorable as the H 2 O coverage increased, indicating that the formed OH might inhibit further water dissociation. This was possibly due to limited surface sites available for the dissociated species. E d min on Mg 2 Si–Mg decreased monotonically with water coverage, and H 2 O dissociation became favorable when θ H 2 O was larger than 0.5 ML. This can be explained by electron transfer from Mg 2 Si–Mg to the water layer, as mentioned in the previous section. That is to say, the surface Mg atoms were oxidized, indicating that reaction (5) proceeded in the right direction. Then, reaction (6) was promoted by the electrons from (5), increasing the tendency of H 2 O dissociation. Mg → Mg 2+ + 2e − (5) H 2 O + e − → H + OH − (6) On the basis of the dissociated ad-layers obtained above, ad-layers containing Cl were constructed by replacing the dissociated OH with one Cl on each investigated surface. The substitution energy ( E s ) values with increasing H 2 O are is listed in Table S1 . The substitution of OH by Cl in most cases is endothermic ( E s > 0), except for Al and Mg 2 Si–Si at θ H 2 O = 0.5 ML, which suggests that Cl can barely replace OH. One reason could be that Cl, upon substitution, disrupts the hydrogen bond networks between OH and H 2 O, which is energetically expensive [ 44 ]. Another possible reason is that Cl has a larger ionic radius than the OH group, making the substitution process unfavorable [ 45 ]. Cl substitution of OH was also found to be endothermic on NiO(111) when over 70% of OH species were replaced [ 6 ]. However, real metal surfaces possess different kinds of defects, and it is well known that Cl − ions can induce localized corrosion of many metallic materials. It is believed that defects or an applied electrode potential may drive the substitution process, as verified by other DFT studies [ 6 , 46 ]. Moreover, competitive adsorption has been observed experimentally [ 4 ]. Obviously, more complicated models relevant for real metal surfaces are needed for further calculations. Though the substitution process seems to be energetically favorable in only selected cases based on the current models and calculating parameters, the effect of Cl-containing ad-layers on the work function of Al(111) and Mg 2 Si–Si surfaces is discussed below for all coverages. 3.3. Effect on Work Function of Cl in the Aqueous Ad-Layer On the basis of the above optimized structures within the three aqueous environments (INT, DIS, and SUB configurations), the work function of the four metallic surfaces upon adsorption of each ad-layer was calculated as a function of H 2 O coverage from 0.25 ML to 1 ML, see Figure 6 . Figure 6. Work function change with adsorbed INT, DIS, SUB aqueous ad-layers on ( a ) Al and ( b ) Mg 2 Si–Si. Data for bare surfaces and INT aqueous ad-layer systems are from our earlier work [ 10 , 33 ]. The adsorption of pure intact water reduced the work function, compared to the value 4.16 eV for bare Al, as indicated by the dashed line in Figure 6 a. This was due to the slightly upward pointing of the water molecules ( Figure S1 ), which formed an upward dipole. In comparison with intact water adsorption, dissociation most likely increased the work function, except at coverage of 1 ML. This has been observed also on other metal surfaces, with OH being an electron acceptor [ 24 , 38 , 47 ]. Introduction of Cl raised the Al work function even further, as a result of a significant change of water molecules’ orientation upon adsorption of 1 ML of aqueous ad-layer, as seen in Figure S1 and Figure 7 a. Figure 7. Optimized structure of Cl-containing aqueous ad-layer on Al ( a ) and Mg 2 Si–Si ( b ). Deformation electron density (DED) maps on Al sliced through ( c ) one H 2 O plane, ( d ) the Cl atom, ( e ) both the Cl atom and H 2 O. DED maps on Mg 2 Si–Si ( f ) and schematic charge distribution in the surface layers ( g ) based on Figure 7 f. In Figure 7 c–f, the blue and red colors indicate electron deficiency and accumulation, respectively. Another important point depicted in Figure 7 a is that Cl stayed above the water layer. Thus, a direct interaction between Cl and the Al surface was largely screened by the water molecules. In agreement with experimental data, Cl − ions were observed to stay in the outer sphere of an Al 3+ ion when surrounded by Cl − and H 2 O molecules [ 48 ]. Intact water also decreased the work function of Mg 2 Si–Si at all coverages ( Figure 6 b). Different from the Al surface mentioned above, H 2 O dissociation or Cl substitution did not increase the work function. Cl adsorbed instead below the water layer, enabling Cl to interact directly with the surface at 1 ML of aqueous ad-layer adsorption ( Figure 7 b). On the other hand, the adsorption of Cl too close to the surface may be insufficient to create a surface dipole [ 14 , 49 ]. For comparison, the optimized structures for Mg 2 Si–Mg and Al 2 Cu–Cu upon adsorption of aqueous ad-layers containing Cl are also shown in Figure S4 in the Supplementary materials . When focusing only on the Cl-containing aqueous ad-layer, we found that it increased the work function of Al but decreased that of Mg 2 Si–Si with respect to their bare surfaces (see Figure 6 ). To illustrate this phenomenon, deformation electron density (DED) maps on both surfaces are displayed in Figure 7 c–g, by taking SUB-1 ML as an example. On the Al surface, there was electron transfer from the outmost Al surface to the aqueous layer ( Figure 7 c). As a result, a dipole pointing from the water layer to the Al surface was built, which explains the work function increase. Meanwhile, this electron transfer also implied that the Al surface was oxidized by the water ad-layer. In qualitative agreement with this, experimental data have shown that the surface potential of an Al matrix increased after immersion in NaCl solutions [ 50 ]. Similarly, the work function increased in an Al–Mg alloy was attributed to surface oxidation by the water ad-layer [ 51 ], whereas the work function increase of Cu(110) with subsequent introduction of Br 2 and H 2 O was attributed to the water dipole formed according to other experimental observations [ 29 From Figure 7 d it is seen, however, that slight electron density rearrangements occurred within surface Al, which could partly compensate for the work function change caused by the oxidation effect mentioned above [ 52 ]. Comparing the scale bars of Figure 7 c,d, the work function increase by oxidation was dominant over that caused by rearrangements within the Al surface. Due to its strong electron affinity, Cl gained a concentrated electron density atop of it, while it created an electron depletion area around it, indicated by the color contrast in Figure 7 d. However, direct electron transfer from Cl to Al was absent. By slicing another atomic plane ( Figure 7 e), Cl was demonstrated to gain electrons from an adjacent H 2 O, indicating a possible electronic interaction between these two species. The DED map of the Mg 2 Si–Si, sliced through Si–H and the metallic plane ( Figure 7 f), revealed strong atomic as well as electron rearrangements in the surface layer. The relaxation of the metallic surface may also contribute to the change in work function [ 49 ]. Electron transfer between Mg 2 Si–Si and the aqueous layer was missing, which was expected since a bare surface with large work function is more resistant to losing electrons [ 53 ]. For visualization, we marked the electron-depleted area with “+” (white), and the electron-rich area with “−” (grey). Then a net dipole pointing upwards was seen in the first metallic layer and the aqueous ad-layer ( Figure 7 g), resulting in a decreased work function. To demonstrate the impact of the Cl-containing aqueous ad-layer on the relative nobility of IMP and Al under the current conditions, we calculated Volta potential differences between the IMPs and Al, i.e., V IMP − V Al , covered by a SUB aqueous ad-layer, as shown in Figure 8 . The data in Figure 8 show how the galvanic effect between the IMP and Al surfaces may vary depending on the Cl/H 2 O ratio in the ad-layer. Note that in the SUB aqueous ad-layer cases, since the concept of H 2 O coverage was also used here, the real ad-layer contained 1Cl + 1H + (n W -1) H 2 O. At 1 ML coverage, Cl occupied one of the surface sites of the calculation system, corresponding to a Cl/H 2 O ratio of 1:3. Figure 8. Volta potential difference of Mg 2 Si–Si, Mg 2 Si–Mg, and Al 2 Cu–Cu relative to Al, with the adsorption of a Cl-containing aqueous ad-layer at different coverage levels. The Volta potential difference data in Figure 8 indicate that upon ad-layer adsorption at 0.25 ML, with actually the adsorption of Cl + H on the Mg 2 Si–Si surface and of Cl + H + H 2 O on the Al 2 Cu–Cu surface, the two IMPs transformed from cathode (bare) to anode relative to Al, while Mg 2 Si–Mg remained anodic. As the coverage increased to 0.5 ML, the Volta potential difference of all the three IMPs relative to Al increased in comparison with a decrease in coverage, and the two Mg 2 Si surfaces terminated by Mg and Si remained anodic relative to Al, while Al 2 Cu–Cu changed back to cathode at 0.5 ML. Furthermore, as the coverage of the Cl-containing ad-layer reached 1 ML, all three IMP surfaces became less noble than the Al surface, with a rather large Volta potential difference (>1 V). As can be seen from the work function at SUB-1 ML in Figure 6 and Figure S3 , the Al work function was the highest among those of all the studied surfaces, mainly due to the strong oxidation phenomenon, as described in Figure 7 c. Meanwhile, the initial galvanic couples Mg 2 Si–Si (cathode)/Al (anode) as well as Al 2 Cu–Cu (cathode)/Al (anode) were reversed with the adsorption of the SUB aqueous ad-layer, indicating a possible mechanism for the previously observed, so-called “nobility inversion” [ 54 ]. In all, this implies that different interactions (e.g., electron transfer and dipole formation) between the metallic surface and the aqueous ad-layer can result in changes of the galvanic effect. As has been recently calculated by L. Marks [ 18 ], Cl adsorption can increase the work function of Al 2 O 3 , which promotes heterogeneous oxidation in areas where Cl adsorbs, compared to areas where there is no Cl adsorption. 3.4. Short Summary and Implications In this theoretical work, we studied the effect of Cl-containing aqueous ad-layers on the Volta potential difference between three intermetallic surfaces and Al. This was accomplished by DFT calculations of the energetics of adsorption and dissociation of H 2 O as well as by substitution of OH with Cl within the ad-layers, followed by calculations of the work function of the surfaces covered by the aqueous ad-layers. To begin with, explicit H 2 O molecules up to 2 ML adsorbed on Al, Mg 2 Si–Si, Mg 2 Si–Mg, and Al 2 Cu–Cu surfaces were studied. Then, one OH was introduced by dissociation of one adsorbed H 2 O molecule, and afterward one Cl was introduced into the aqueous ad-layer by substitution of the OH. In this way, a more realistic corrosive environment was constructed for the assessment of the effect of the Cl-containing ad-layer on the galvanic corrosion due to the coupling between the IMPs and the Al matrix. These three model scenarios correspond to molecular H 2 O adsorption, subsequent H 2 O dissociation, and competitive adsorption between Cl and OH on an Al alloy surface containing Mg 2 Si or Al 2 Cu particles. The results showed that intact H 2 O adsorption on all four surfaces was exothermic when the H 2 O coverage increased to 1 ML ( Figure 3 ), and an enhanced H-bonding within the H 2 O ad-layer was observed. The introduction of one OH in the intact H 2 O ad-layer showed that H 2 O dissociation was not favorable on Al and Al 2 Cu–Cu under the examined calculation conditions, whereas H 2 O had a strong tendency to dissociate on Mg 2 Si–Si and Mg 2 Si–Mg ( Figure 5 ). By calculating the reaction free energy of H 2 O dissociation on the Al surface based on the methodology proposed by J.K. Nørskov [ 55 ], we found that H 2 O dissociation was favorable at a positive electrode potential (to be published elsewhere) [ 56 ]. In the future, the VdW corrections should also be taken into account because of the moderate modification of the adsorption energy produced by the VdW force, especially for energies around 0.1 eV [ 57 ]. When introducing one Cl into the aqueous ad-layer in replace of the OH, the present calculation indicated that the substitution process was endothermic in most of the calculation conditions ( Table S1 ). Since it is well known that chloride ions usually promote the corrosion of metals, further considerations are needed in the interpretation of the calculation results. Real metal surfaces contain different kinds of defects and are much more complicated than the calculation models used herein, which only represent single-crystal surfaces. On the other hand, DFT calculations, though only for simple systems, provide a fundamental understanding of the surface processes and interactions at the atomic scale. For example, when one Cl atom is added to the surface, DFT calculations can tell where electrons go and thus provide information about charge transfer or dipole formation, which can be viewed by the DED maps sliced at different atomic planes of the surface layer. Such information is helpful for understanding the effect of surface adsorbates on the work function of metal surfaces. The calculation of low-H 2 O-coverage models yielded some theoretical insights, while the model with one full monolayer (1 ML) of aqueous adsorbates was more relevant for corrosive environments. The work function of the metallic surfaces with Cl together with H 2 O molecules under varying H 2 O coverages ( Figure 6 a,b) agrees with both theoretical and experimental studies [ 15 , 16 , 29 ]. On Al, the adsorbed H 2 O layer attracted electrons from Al surface atoms ( Figure 7 c), forming a dipole at the surface and causing an increase in the work function [ 29 ]. The effect of Cl, positioned nearly 5 Å above the surface, seemed to be screened by the H 2 O molecules. The DED map evidenced electronic interactions between Cl and adjacent H 2 O ( Figure 7 e). In contrast, the adsorption of SUB-1 ML aqueous ad-layer on Mg 2 Si–Si led to a serious rearrangement both structurally and electronically ( Figure 7 f). The upward dipole formed at the surface layer was the main reason for the work function decrease ( Figure 7 f,g). Derived from the work function data, the Volta potential difference between the three IMP surfaces and Al covered by the adsorbates suggests that co-adsorption of Cl and H 2 O molecules makes the IMPs significantly less noble compared to Al at 1 ML coverage of the aqueous ad-layer ( Figure 8 ). This may provide an explanation for the effect of chloride ions in promoting localized corrosion of Al alloys. In this case, the dissolution of the IMPs is driven by micro-galvanic coupling with the Al matrix. 4. Conclusions In this study, we constructed a series of aqueous ad-layers containing H 2 O molecules up to two monolayers and aqueous ad-layers with one OH group or Cl atom on Al(111), Mg 2 Si(111)–Si, Mg 2 Si(111)–Mg, and Al 2 Cu(110)–Cu surfaces, seeking to mimic a simplified but, yet, realistic system relevant for micro-galvanic corrosion of Al alloys containing Mg 2 Si or Al 2 Cu particles. DFT calculations were performed to obtain the energetics of adsorption of H 2 O ad-layers, during dissociation of H 2 O and subsequent substitution of OH by Cl, the work function of the surfaces covered by the different aqueous ad-layers, and Volta potential differences between the intermetallic surfaces and Al with a Cl-containing aqueous ad-layer. The following conclusions can be drawn: For adsorption of pure H 2 O, there was an enhancement of H bonding under higher H 2 O coverage, which promoted stable adsorption on the surfaces and adsorption energies in a relatively narrow range between −0.8 and −0.5 eV for all surfaces investigated. Spontaneous H 2 O dissociation was only observed on Mg 2 Si(111)–Si, where H was bound to surface Si atoms. A large dissociation tendency was seen on Mg 2 Si(111)–Si and also on Mg 2 Si(111)–Mg at higher H 2 O coverage. However, subsequent substitution of OH with Cl was largely prevented within explicit H 2 O ad-layers, especially at higher H 2 O coverage. Electron transfer from surface Al atoms to the H 2 O ad-layer can explain the work function increase of Al(111) covered by the Cl-containing aqueous ad-layer, whereas atomic and electronic rearrangements on Mg 2 Si(111)-Si are the main reason for the work function decrease caused by the Cl-containing aqueous ad-layer. The Volta potential difference between the intermetallic surfaces and Al(111) suggests that co-adsorption of Cl and H 2 O molecules makes the IMPs significantly less noble compared to Al(111) at 1ML coverage of the aqueous ad-layer. Supplementary Materials The supplementary materials are available online. Author Contributions Conceptualization, M.L.; Data curation, M.L., Y.J., J.P., C.L.; Formal analysis, M.L., Writing-original draft, M.L.; Review & Editing, Y.J., J.P., C.L. Funding We acknowledge the partial support by the Swedish Foundation for Strategic Research (SSF project RMA11-0090) and the National Natural Science Foundation of China (U1837602) and we also thank the support from the Overseas Expertise Introduction Project for Discipline Innovation (B12012) in China for promoting the international collaboration. Acknowledgments The constructive discussions from Henrik Grönbeck from Chalmers University of Technology are greatly appreciated. The scholarship from the Chinese Scholarship Council to Min Liu for her PhD study at KTH is acknowledged. We are also grateful to the Swedish National Infrastructure for Computing (SNIC) for the use of Swedish super-computing resource in the DFT calculations. Conflicts of Interest The authors declare no conflict of interest. References and Note Birbilis, N.; Buchheit, R.G. Electrochemical characteristics of intermetallic phases in aluminum alloys-an experimental survey and discussion. J. Electrochem. Soc. 2005 , 152 , B140–B151. [ Google Scholar ] [ CrossRef ] Lebouil, S.; Tardelli, J.; Rocca, E.; Volovitch, P.; Ogle, K. Dealloying of Al 2 Cu, Al 7 Cu 2 Fe, and Al 2 CuMg intermetallic phases to form nanoparticulate copper films. Mater. Corros. 2014 , 65 , 416–424. [ Google Scholar ] [ CrossRef ] Marcus, P.; Maurice, V.; Strehblow, H.H. Localized corrosion (pitting): A model of passivity breakdown including the role of the oxide layer nanostructure. Corros. Sci. 2008 , 50 , 2698–2704. [ Google Scholar ] [ CrossRef ] Gründer, Y.; Drünkler, A.; Golks, F.; Wijts, G.; Stettner, J.; Zegenhagen, J.; Magnussen, O.M. Cu (111) in chloride containing acidic electrolytes: Coadsorption of an oxygenated species. J. Electroanal. Chem. 2014 , 712 , 74–81. [ Google Scholar ] [ CrossRef ] Liu, M.; Jin, Y.; Zhang, C.H.; Leygraf, C.; Wen, L. Density-functional theory investigation of Al pitting corrosion in electrolyte containing chloride ions. Appl. Surf. Sci. 2015 , 357 , 2028–2038. [ Google Scholar ] [ CrossRef ] Bouzoubaa, A.; Diawara, B.; Maurice, M.; Minot, C.; Marcus, P. Ab initio study of the interaction of chlorides with defect-free hydroxylated NiO surfaces. Corros. Sci. 2009 , 51 , 941–948. [ Google Scholar ] [ CrossRef ] da Silva, T.H.; Nelson, E.B.; Williamson, I.; Efaw, C.M.; Sapper, E.; Hurley, M.F.; Li, L. First-principles surface interaction studies of aluminum-copper and aluminum-copper-magnesium secondary phases in aluminum alloys. Appl. Surf. Sci. 2018 , 439 , 910–918. [ Google Scholar ] [ CrossRef ] Guo, L.Q.; Zhao, X.M.; Bai, Y.; Qiao, L.J. Water adsorption behavior on metal surfaces and its influence on surface potential studied by in situ SPM. Appl. Surf. Sci. 2012 , 258 , 9087–9091. [ Google Scholar ] [ CrossRef ] Gossenberger, F.; Roman, T.; Forster-Tonigold, K.; Groß, A. Change of the work function of platinum electrodes induced by halide adsorption. Beilstein J. Nanotech. 2014 , 5 , 152–161. [ Google Scholar ] [ CrossRef ] Örnek, C.; Liu, M.; Pan, J.; Jin, Y.; Leygraf, C. Volta potential evolution of intermetallics in aluminum alloy microstructure under thin aqueous adlayers: A combined DFT and experimental study. Top. Catal. 2018 , 61 , 1169–1182. [ Google Scholar ] [ CrossRef ] Sarvghad-Moghaddam, M.; Parvizi, R.; Davoodi, A.; Haddad-Sabzevar, M.; Imani, A. Establishing a correlation between interfacial microstructures and corrosion initiation sites in Al/Cu joints by SEM–EDS and AFM–SKPFM. Corros. Sci. 2014 , 79 , 148–158. [ Google Scholar ] [ CrossRef ] Schmutz, P.; Frankel, G.S. Characterization of AA2024-T3 by scanning Kelvin probe force microscopy. J. Electrochem. Soc. 1998 , 145 , 2285–2295. [ Google Scholar ] [ CrossRef ] Rohwerder, M.; Turcu, F. High-resolution Kelvin probe microscopy in corrosion science: Scanning Kelvin probe force microscopy (SKPFM) versus classical scanning Kelvin probe (SKP). Electrochim. Acta 2007 , 53 , 290–299. [ Google Scholar ] [ CrossRef ] Migani, A.; Sousa, C.; Illas, F. Chemisorption of atomic chlorine on metal surfaces and the interpretation of the induced work function changes. Surf. Sci. 2005 , 574 , 297–305. [ Google Scholar ] [ CrossRef ] Roman, T.; Gross, A. Periodic density-functional calculations on work-function change induced by adsorption of halogens on Cu (111). Phys. Rev. Lett. 2013 , 110 , 156804. [ Google Scholar ] [ CrossRef ] Zhu, Q.; Wang, S.Q. Trends and regularities for halogen adsorption on various metal surfaces. J. Electrochem. Soc. 2016 , 163 , H796–H808. [ Google Scholar ] [ CrossRef ] Zhou, W.L.; Liu, T.; Li, M.C.; Zhao, T.; Duan, Y.H. Adsorption of bromine on Mg (0001) surface from first-principles calculations. Comput. Mater. Sci. 2016 , 111 , 47–53. [ Google Scholar ] [ CrossRef ] Marks, L. Competitive Chloride chemisorption disrupts hydrogen bonding networks: DFT, crystallography, thermodynamics, and morphological consequences. Corros. 2017 , 74 , 295–311. [ Google Scholar ] [ CrossRef ] Duan, S.; Xu, X.; Tian, Z.Q.; Luo, Y. Hybrid molecular dynamics and first-principles study on the work function of a Pt (111) electrode immersed in aqueous solution at room temperature. Phys. Rev. B 2012 , 86 , 045450. [ Google Scholar ] [ CrossRef ] Meng, S.; Wang, E.G.; Gao, S. Water adsorption on metal surfaces: A general picture from density functional theory studies. Phys. Rev. B 2004 , 69 , 195404. [ Google Scholar ] [ CrossRef ] Schnur, S.; Groß, A. Properties of metal–water interfaces studied from first principles. New J. Phys. 2009 , 11 , 125003. [ Google Scholar ] [ CrossRef ] Pedroza, L.S.; Poissier, A.; Fernández-Serra, M.V. Local order of liquid water at metallic electrode surfaces. J. Chem. Phys. 2015 , 142 , 034706. [ Google Scholar ] [ CrossRef ] [ PubMed ] Tang, Q.L.; Chen, Z.X. Density functional slab model studies of water adsorption on flat and stepped Cu surfaces. Surf. Sci. 2007 , 601 , 954–964. [ Google Scholar ] [ CrossRef ] Tzvetkov, G.; Zubavichus, Y.; Koller, G.; Schmidt, T.; Heske, C.; Umbach, E.; Grunze, M.; Ramsey, M.G.; Netzer, F.P. Growth of H 2 O layers on an ultra-thin Al 2 O 3 film: From monomeric species to ice. Surf. Sci. 2003 , 543 , 131–140. [ Google Scholar ] [ CrossRef ] Musumeci, F.; Pollack, G.H. Influence of water on the work function of certain metals. Chem. Phys. Lett. 2012 , 536 , 65–67. [ Google Scholar ] [ CrossRef ] [ PubMed ] Langenbach, E.; Spitzer, A.; Lüth, H. The adsorption of water on Pt (111) studied by irreflection and UV-photoemission spectroscopy. Surf. Sci. 1984 , 147 , 179–190. [ Google Scholar ] [ CrossRef ] McCrum, I.T.; Akhade, S.A.; Janik, M.J. Electrochemical specific adsorption of halides on Cu 111, 100, and 211: A Density Functional Theory study. Electrochim. Acta 2015 , 173 , 302–309. [ Google Scholar ] [ CrossRef ] Gossenberger, F.; Roman, T.; Groß, A. Hydrogen and halide co-adsorption on Pt (111) in an electrochemical environment: A computational perspective. Electrochim. Acta 2016 , 216 , 152–159. [ Google Scholar ] [ CrossRef ] Bange, K.; Grider, D.; Sass, J.K. Coadsorption of water and ions on Cu (110): Models for the double layer. Surf. Sci. 1983 , 126 , 437–443. [ Google Scholar ] [ CrossRef ] Wasileski, S.A.; Janik, M.J. A first-principles study of molecular oxygen dissociation at an electrode surface: A comparison of potential variation and coadsorption effects. Phys. Chem. Chem. Phys. 2008 , 10 , 3613–3627. [ Google Scholar ] [ CrossRef ] Dieter, G.E. Mechanical Metallurgy ; McGraw-Hill Press: New York, NY, USA, 1986. [ Google Scholar ] Villars, P.; Calvert, L.D. Pearson’s Handbook of Crystallographic Data for Intermetallic Phases ; American Society of Metals: Cleveland, OH, USA, 1985. [ Google Scholar ] Jin, Y.; Liu, M.; Zhang, C.H.; Leygraf, C.; Wen, L.; Pan, J. First-principle calculation of Volta potential of intermetallic particles in aluminum alloys and practical implications. J. Electrochem. Soc. 2017 , 164 , C465–C473. [ Google Scholar ] [ CrossRef ] Delley, B. An all-electron numerical method for solving the local density functional for polyatomic molecules. J. Chem. Phys. 1990 , 92 , 508–517. [ Google Scholar ] [ CrossRef ] Delley, B. From molecules to solids with the DMol3 approach. J. Chem. Phys. 2000 , 113 , 7756–7764. [ Google Scholar ] [ CrossRef ] Pineau, N.; Minot, C.; Maurice, V.; Marcus, P. Density functional theory study of the interaction of Cl− with passivated nickel surfaces. Electrochem. Solid-Sate Lett. 2003 , 6 , B47–B51. [ Google Scholar ] [ CrossRef ] Björneholm, O.; Hansen, M.; Hodgson, A.; Liu, L.; Limmer, D.; Michaelides, A.; Pedevilla, P.; Rossmeisl, J.; Shen, H.; Tocci, G.; et al. Water at interfaces. Chem. Rev. 2016 , 116 , 7698–7726. [ Google Scholar ] Thiel, P.A.; Madey, T.E. The interaction of water with solid surfaces: Fundamental aspects. Surf. Sci. Rep. 1987 , 7 , 211–385. [ Google Scholar ] [ CrossRef ] Michaelides, A. Simulating ice nucleation, one molecule at a time, with the ‘DFT microscope’. Faraday Discuss. 2007 , 136 , 287–297. [ Google Scholar ] [ CrossRef ] Michaelides, A.; Alavi, A.; King, D.A. Insight into H 2 O-ice adsorption and dissociation on metal surfaces from first-principles simulations. Phys. Rev. B 2004 , 69 , 113404. [ Google Scholar ] [ CrossRef ] Guo, F.Y.; Long, C.G.; Zhang, J.; Zhang, Z.; Liu, C.H.; Yu, K. Adsorption and dissociation of H 2 O on Al (1 1 1) surface by density functional theory calculation. Appl. Surf. Sci. 2015 , 324 , 584–589. [ Google Scholar ] [ CrossRef ] Taheri, P.; Pohl, K.; Grundmeier, G.; Flores, J.R.; Hannour, F.; de Wit, J.H.W.; Mol, J.M.C.; Terryn, H. Effects of surface treatment and carboxylic acid and anhydride molecular dipole moments on the Volta potential values of zinc surfaces. J. Phys. Chem. C 2013 , 117 , 1712–1721. [ Google Scholar ] [ CrossRef ] Cai, N.; Zhou, G.; Müller, K.; Starr, D.E. Comparative study of the passivation of Al (111) by molecular oxygen and water vapor. J. Phys. Chem. C 2012 , 117 , 172–178. [ Google Scholar ] [ CrossRef ] Digne, M.; Raybaud, P.; Sautet, P.; Guillaume, D.; Toulhoat, H. Atomic scale insights on chlorinated γ-alumina surfaces. J. Am. Chem. Soc. 2008 , 130 , 11030–11039. [ Google Scholar ] [ CrossRef ] [ PubMed ] Huheey, J.E.; Ketter, E.A.; Ketter, R.L.; Medhi, O.K. Inorganic Chemistry: Principles of Structure and Reactivity ; Pearson Education India: Delhi, India, 1993. [ Google Scholar ] Bouzoubaa, A.; Costa, D.; Diawara, B.; Audiffren, N.; Marcus, P. Insight of DFT and atomistic thermodynamics on the adsorption and insertion of halides onto the hydroxylated NiO (111) surface. Corros. Sci. 2010 , 52 , 2643–2652. [ Google Scholar ] [ CrossRef ] Ren, J.; Meng, S. First-principles study of water on copper and noble metal (110) surfaces. Phys. Rev. B 2008 , 77 , 054110. [ Google Scholar ] [ CrossRef ][ Green Version ] Jin, X.; Yang, W.; Qian, Z.; Wang, Y.; Bi, S. DFT study on the interaction between monomeric aluminium and chloride ion in aqueous solution. Dalton Trans. 2011 , 40 , 5052–5058. [ Google Scholar ] [ CrossRef ] Leung, T.C.; Kao, C.L.; Su, W.S.; Feng, Y.J.; Chan, C.T. Relationship between surface dipole, work function and charge transfer: Some exceptions to an established rule. Phys. Rev. B 2003 , 68 , 195408. [ Google Scholar ] [ CrossRef ][ Green Version ] Zhu, Y.; Sun, K.; Frankel, G.S. Intermetallic phases in aluminum alloys and their roles in localized corrosion. J. Electrochem. Soc. 2018 , 165 , C807–C820. [ Google Scholar ] [ CrossRef ] Xue, M.; Xie, J.; Li, W.; Yang, C.; Ai, Y.; Wang, F.; Ou, J.; Yao, J. Dependence of electron work function of Al-Mg alloys on surface structures and relative humidity. Physica B 2011 , 406 , 4240–4244. [ Google Scholar ] [ CrossRef ] Crispin, X.; Geskin, V.; Crispin, A.; Cornil, J.; Lazzaroni, R.; Salaneck, W.R.; Bredas, J.L. Characterization of the interface dipole at organic/metal interfaces. J. Am. Chem. Soc. 2002 , 124 , 8131–8141. [ Google Scholar ] [ CrossRef ] Migani, A.; Illas, F. A systematic study of the structure and bonding of halogens on low-index transition metal surfaces. J. Phys. Chem. B 2006 , 110 , 11894–11906. [ Google Scholar ] [ CrossRef ] Andreatta, F.; Terryn, H.; de Wit, J.H.W. Effect of solution heat treatment on galvanic coupling between intermetallics and matrix in AA7075-T6. Corros. Sci. 2003 , 45 , 1733–1746. [ Google Scholar ] [ CrossRef ] Rossmeisl, J.; Nørskov, J.K.; Taylor, C.D.; Janik, M.J.; Neurock, M. Calculated phase diagrams for the electrochemical oxidation and reduction of water over Pt (111). J. Phys. Chem. B 2006 , 110 , 21833–21839. [ Google Scholar ] [ CrossRef ] [ PubMed ] Liu, M. a,b ; Busch, M. c ; Grönbeck, H. c ; Jin, Y. a ; Leygraf, C. b ; Pan, J. b Aqueous environment around chloride ion studied by first-principle theory, molecular dynamics and x-ray absorption fine structure. (a: University of Science and Technology Beijing, Beijing, China. b: Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden. c: Chalmers University of Technology, Göteborg). Unpublished work, 2019. Wei, X.; Dong, C.; Chen, Z.; Xiao, K.; Li, X. A DFT study of the adsorption of O 2 and H 2 O on Al (111) surfaces. RSC Adv. 2016 , 6 , 56303–56312. [ Google Scholar ] [ CrossRef ][ Green Version ] Figure 1. Top view depicting the different calculated configurations of adsorbed aqueous ad-layers: intact H 2 O (INT), water with one OH (DIS), and water with one Cl (SUB). The metallic surface for H 2 O adsorption is only a representative substrate. Note that in the SUB case, a surface bond is formed between the Cl and a surface atom. Figure 2. Adsorption energy of H 2 O on Al, Mg 2 Si–Si, Mg 2 Si–Mg, and Al 2 Cu–Cu surfaces versus H 2 O coverage. Figure 3. Optimized structure of H 2 O dissociation into OH and H (binding to surface Si) on Mg 2 Si–Si with 1ML H 2 O adsorption: ( a ) top view, ( b ) side view. Surface Si (Si s ) and bulk Si (Si b ) are indicated by dark and light orange color. Mg is in green, O in red, and H in white. Figure 4. Plots of H 2 O adsorption energy on different surfaces versus work function under different H 2 O coverage (see the values without unit for each surface shown in the figure). The work function for each bare surface is highlighted by a dashed bar. Work function values for intact H 2 O adsorption were reported in our previous work [ 10 ]. Figure 5. The minimum dissociation energy, E d min , as a function of H 2 O coverage for the four investigated surfaces. Figure 6. Work function change with adsorbed INT, DIS, SUB aqueous ad-layers on ( a ) Al and ( b ) Mg 2 Si–Si. Data for bare surfaces and INT aqueous ad-layer systems are from our earlier work [ 10 , 33 ]. Figure 7. Optimized structure of Cl-containing aqueous ad-layer on Al ( a ) and Mg 2 Si–Si ( b ). Deformation electron density (DED) maps on Al sliced through ( c ) one H 2 O plane, ( d ) the Cl atom, ( e ) both the Cl atom and H 2 O. DED maps on Mg 2 Si–Si ( f ) and schematic charge distribution in the surface layers ( g ) based on Figure 7 f. In Figure 7 c–f, the blue and red colors indicate electron deficiency and accumulation, respectively. Figure 8. Volta potential difference of Mg 2 Si–Si, Mg 2 Si–Mg, and Al 2 Cu–Cu relative to Al, with the adsorption of a Cl-containing aqueous ad-layer at different coverage levels. Sample Availability: Samples of the compounds are not available from the authors.
https://www.mdpi.com/1420-3049/24/23/4284
Traveling in Europe with Family - My Family Travels Traveling in Europe with Family I think it is always a god idea to travel with family to Switzerland. You can always find a beautiful Boutique Hotel and as well the mountains and nature everywhere can bring you and your family a lot of peace. Europe is an amazing destination for family travel. There’s so much to see and experience, from the historic landmarks to the diverse cultures and cuisines. And let’s not forget about the fun activities that the whole family can enjoy together, like theme parks, beaches, and outdoor adventures. If you’re planning a trip to Europe, don’t forget to do your research and plan ahead for a smooth and stress-free trip. And if you’re looking for another great destination, I highly recommend Bermuda – it’s a beautiful island paradise with stunning beaches, friendly locals, and plenty of fun activities for all ages. I’m sure you will enjoy your holiday in Bermudahttps://www.travelsafe-abroad.com/if you decide to go there one day. This sitehttps://www.responsibletravel.com/holidays/family-adventurehas one of the best family adventures holiday selections I’ve ever come across. We travelled with them to Spain last year (https://www.responsibletravel.com/holiday/7982/granada-activity-holiday-spain)and the trip was amazing, lovely hotel and the activities were perfect for children between 6 – 14 http://www.travelcool.co.U.K. is a new travel focused website based in England run by my family. We’ve travelled extensively in Europe including many Road trips. Our plan is to list these with other tips and ideas for travelling. Genuinely it would be a Thrilling and Chilled experience travelling to europe. Because europe is one of the Finest destination for Tour planning and. We can thoroughly enjoy the Travelling and sharing the wonderful experiences. Europe is the most choosy and the opted destination tourist attractions across the Globe to have some wonderful and unforgettable moments. Hence europe would be a Most choosy and Great option for tour planning. Europe is an amazing destination for family travel. There’s so much to see and experience, from the historic landmarks to the diverse cultures and cuisines. And let’s not forget about the fun activities that the whole family can enjoy together, like theme parks, beaches, and outdoor adventures. I would recommend Italy as a great European country to visit with your family. Italy is a country that is rich in history and culture, and there are so many amazing sights to see and experiences to be had. From the stunning architecture and art of cities like Rome and Florence to the beautiful beaches and countryside of the Amalfi Coast, there is something for everyone in Italy. Additionally, Italian food is world-renowned and the country is home to many delicious and unique dishes that the whole family can enjoy. Overall, Italy is a wonderful destination for families and offers something for everyone. I totally agree, we planned several trips to Italy for customers travelling with family. All their feedback were amazing! Europe has so much to offer whether you’re a backpacker type of traveler or you want a luxurious trip, Europe got you. As a traveler who has just been to Rome, it was really the best time of my life. The trip wouldn’t be so smooth without the help of the local tour guidehttps://gowithguide.com/italy/romebut if you are more into adventure and down for challenges then a DIY trip would exciting as well. There is also written in detail about Bishops park and Postman’s park – I really liked them I am coming to Frankfurt for a Business visit. I would like to know if there is any good Chauffeur service available in Frankfurt that you guys can recommend.One of my friends recommended FBL service, Let me know if anyone knows about this. Hi!If you would like to enjoy sun and warm water take a look at Southern Cyprus! Paphos, Coral Bay are wonderful places! [email protected] are some fine variants to find perfect summerhouse https://www.cyprusvillas.com/villas.htmlI left an email and here it is a link I enjoy reading your blog. Your post is interesting and enjoyable. Hello!I am student of the department of tourism at the University of Piraeus in Greece and i am excited that we are conducting a survey about Family Travel.I would be really happy if you completed this quick survey:https://docs.google.com/forms/d/1s1OjLYV6AtLcEgkaa6UsqtxjVCnLQ1NMjTGANmOqyAw/editThank you very much! Guys, hello everyone! I love traveling around Europe with my parents! Our last trip was to Germany. And we’re utterly in awe. We didn’t know where to go and what to see (except for the overused sights). My dad started looking on the Internet for a list of different places to walk or relax and found an exciting guide to Germany . And then it started …. all three days, we constantly walked, went to interesting museums, drank the most delicious beer and ate the most delicious Bavarian sausages. To be honest, it was the best trip of my entire life. wow still you guys made that trip awesomehats off to you If you’re planning a holiday in Sweden, come visithttps://cabinsinsweden.com/. They have the most amazing cabins that you can stay in. By the lake or near a river, whatever suits you the most. It’s the perfect holiday destination in wintere – lots of snow and Christmas vibes. Greetings from London! I was recently in the Maldives. It was the best vacation of my life! If you want to visit Barcelona this summer, which it is a fantastic idea according with all the culture, family and leisure offer that you can find in this mediterranean city, I recommend you to stay in a Barcelona luxury apartment called Mercedes Heritage rather than in a hotel because there you can enjoy of all commodities (the best of a house and the best of a hotel) and being in a very convenient location. Hi,i was reading and i taught i could help. if i,m a travel designer i will be happy to craft a tour for you if you like. With amazing discounts.Thanks I’m visiting Chernobyl with chernobyl tours in July (been watching the HBO series ‘Chernobyl’, would love to visit Pripyat!), and have 3 days in Kyiv after. Good techno club recommendations to go to at night are also welcome. I’d recommend one of theseYoga retreats, it will be good for both your soul and body Travelling to new places is my hobby. I love to gather interesting information related to that place. Iceland is such a wonderful place to visit. I had visited in 2019 at that time I had seen beautiful waterfalls, ice caves and volcanoes. I recommended Discover Iceland for my trip. I’m so envy of you guys folks! I’m still waiting to get my 2nd vaccine and start travelling in Europe again. My kids and I are planning on renting a 4×4 and visit all sorts of places in Italy and Greece this summer. We’ve been doing trips like this for the past four years with the exception of last year due to Covid restrictions on Americans. Hopefully we’ll join you guys soon! Last year I was lucky enough to visit a very interesting place. Pripyat in general has such a powerful atmosphere and energy that you can’t feel anywhere else in the world. And here is the information I took at a specialized resource chernobyl.org.uk/ where the history and stories about Chernobyl are fully described, as well as all of the possible risks associated with such a trip. But all went well and if anyone has not been there yet, I recommend confidently) The best way to make a low-budget trip is to walk more and to rest a hostel bed. that´s all. Hii,If you want to travel to Europe with family then you can visit the Amalfi Coast. I visited in September last year and I fell in love with the place. The scenery is dramatic, and breathtakingly beautiful, the food is superb and the Italian culture is so rich and welcoming. What do you guys think about this Travel blog? HelloIf you may be travelling with family then Europe is amazing with its stuffed with culture, art and good food & music. How about tours in other cities of Ukraine. I think the most populous is Chernobyl but there are a lot of small cities like Chernihiv. I would advise to visit them too. We cover the Pembrokeshire region of Wales (UK). Few people think of the UK for a place to visit, but we have some fantastic coastal areas, especially in Pembrokeshire! Marloes Sands Beach is one of my personal favourites! This stunning beach has been the location for several Hollywood movie backdrops, is packed with wildlife and is near the lovely town of Pembroke and its 1000yr old Pembroke Castle! Make sure you check these places out! A great and extraordinary experience in MasiaPiu Lodge near barcelona in Spain for a traveller and a person who loves to explore Beautiful locations…i’ve had a great experience here and i highly recommend this to you Guys…
https://myfamilytravels.com/forum/thread/62231?bbp_reply_to=107843&_wpnonce=54995aa885
Cells | Free Full-Text | Decidua Basalis Mesenchymal Stem Cells Favor Inflammatory M1 Macrophage Differentiation In Vitro Placental mesenchymal stem cells from maternal decidua basalis tissue (DBMSCs) are promising cells for tissue repair because of their multilineage differentiation and ability to protect endothelial cells from injury. Here, we examined DBMSC interaction with macrophages and whether this interaction could modulate the characteristics and functions of these macrophages. We induced monocytes to differentiate into M1-like macrophages in the presence of DBMSCs. DBMSC effects on differentiation were evaluated using microscopy, flow cytometry, and ELISA. DBMSC effects on M1-like macrophage induction of T cell function were also examined. The culture of DBMSCs with monocytes did not inhibit monocyte differentiation into M1-like inflammatory macrophages. This was confirmed by the morphological appearance of M1-like macrophages, increased expression of inflammatory molecules, and reduced expression of anti-inflammatory molecules. In addition, DBMSCs did not interfere with M1-like macrophage phagocytic activity; rather, they induced stimulatory effects of M1-like macrophages on CD4+ T cell proliferation and subsequent secretion of inflammatory molecules by T cells. We showed that DBMSCs enhanced the differentiation of M1-like inflammatory macrophages, which function as antitumor cells. Therefore, our findings suggest that DBMSCs are inflammatory cells that could be useful in cancer treatment via the enhancement of M1- like macrophages. Decidua Basalis Mesenchymal Stem Cells Favor Inflammatory M1 Macrophage Differentiation In Vitro by Mohamed H. Abumaree 1,2,* , Seham Al Harthy 3 , Abdullah M. Al Subayyil 1 , Manal A. Alshabibi 3 , Fawaz M. Abomaray 4,5 , Tanvier Khatlani 1 , Bill Kalionis 6 , Mohammed F. El- Muzaini 7 , Mohammed A. Al Jumah 1 , Dunia Jawdat 1 , Abdullah O. Alawad 3 and Ahmed S. AlAskar 1,8,9 1 Stem Cells and Regenerative Medicine Department, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Mail Code 1515, Saudi Arabia 2 College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, P.O. Box 3660, Riyadh 11481, Mail Code 3124, Saudi Arabia 3 National Center for Stem Cell Technology, Life Sciences and Environment Research Institute, King Abdulaziz City for Science and Technology, P.O Box 6086, Riyadh 11442, Saudi Arabia 4 Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynecology, Karolinska Institutet, 14186 Stockholm, Sweden 5 Center for Hematology and Regenerative Medicine, Karolinska Institutet, 14186 Stockholm, Sweden 6 Department of Maternal-Fetal Medicine Pregnancy Research Centre and University of Melbourne. Department of Obstetrics and Gynaecology, Royal Women’s Hospital, Parkville, Victoria 3052, Australia 7 Department of Obstetrics and Gynaecology, King Abdulaziz Medical City, Minstry of National Guard Health Affairs, P.O. Box 3660, Riyadh 11481, Mail Code 3124, Saudi Arabia 8 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, P.O. Box 3660, Riyadh 11481, Mail Code 3124, Saudi Arabia 9 Adult Hematology and Stem Cell Transplantation, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Mail Code 1515, Saudi Arabia * Author to whom correspondence should be addressed. Cells 2019 , 8 (2), 173; https://doi.org/10.3390/cells8020173 Received: 23 December 2018 / Revised: 25 January 2019 / Accepted: 28 January 2019 / Published: 18 February 2019 (This article belongs to the Special Issue Immunomodulation by Mesenchymal Stem Cells ) Abstract Placental mesenchymal stem cells from maternal decidua basalis tissue (DBMSCs) are promising cells for tissue repair because of their multilineage differentiation and ability to protect endothelial cells from injury. Here, we examined DBMSC interaction with macrophages and whether this interaction could modulate the characteristics and functions of these macrophages. We induced monocytes to differentiate into M1-like macrophages in the presence of DBMSCs. DBMSC effects on differentiation were evaluated using microscopy, flow cytometry, and ELISA. DBMSC effects on M1-like macrophage induction of T cell function were also examined. The culture of DBMSCs with monocytes did not inhibit monocyte differentiation into M1-like inflammatory macrophages. This was confirmed by the morphological appearance of M1-like macrophages, increased expression of inflammatory molecules, and reduced expression of anti-inflammatory molecules. In addition, DBMSCs did not interfere with M1-like macrophage phagocytic activity; rather, they induced stimulatory effects of M1-like macrophages on CD4 + T cell proliferation and subsequent secretion of inflammatory molecules by T cells. We showed that DBMSCs enhanced the differentiation of M1-like inflammatory macrophages, which function as antitumor cells. Therefore, our findings suggest that DBMSCs are inflammatory cells that could be useful in cancer treatment via the enhancement of M1- like macrophages. Keywords: placental stem cells ; inflammation ; M1 macrophages ; inflammatory cells 1. Introduction Macrophages are leukocytes and function as antigen presenting cells with distinctive role in tissue homeostasis [ 1 ]. Macrophages are generally distributed throughout many tissues and help repair injured tissues in several human diseases [ 2 ]. Monocytes are recruited from the circulation into tissues by chemotactic signals initiated in response to physiological phenomena or pathological insults, where they differentiate into macrophages [ 2 ]. In addition, macrophages are also involved in the clearance of dead cells as part of their role in the later phases of tissue homeostasis and repair [ 2 ]. Macrophages are grouped into classically activated macrophages (M1 inflammatory macrophages) and alternatively activated macrophages (M2 anti-inflammatory macrophages) [ 2 ]. During acute inflammation, M1 macrophages are activated by agonists recognized by Toll-like receptors (TLRs) and by cytokines secreted from T helper 1 (Th1) cells, such as interferon-γ (IFN-γ). This increases their phagocytic activity against pathogens, stimulates their production of inflammatory cytokines, such as interleukin-1β (IL-1β), IL-12, and tumor necrosis factor-α (TNF-α); induces their production of reactive oxygen species; and enables their ability to present antigens to T cells through major histocompatibility complex (MHC) class II molecules [ 3 , 4 ]. In addition, M1 macrophages function as tumor suppressive cells through the activation of a Th1 cell inflammatory response against tumor cells [ 5 ]. Conversely, macrophages are induced to differentiate into the M2 phenotype by cytokines secreted by Th2 cells, such as IL-4 and IL-13. These cells are characterized by secretion of high levels of the anti-inflammatory cytokine IL-10, low levels of inflammatory cytokines, increased ability to inhibit the adaptive immune cell response, and increased cell-surface expression of CD14 (pattern recognition receptor), CD36 (class B scavenger receptor), CD163 (hemoglobin scavenger receptor), CD204 (class A scavenger receptor), CD206 (mannose receptor), and B7-H4 (co-inhibitory molecule) [ 2 , 3 , 4 , 6 ]. After an acute inflammatory phase, M2 macrophages become activated to resolve inflammation and induce tissue remodeling and wound repair [ 2 , 3 , 7 ]. In addition, M2 macrophages provide an anti-inflammatory microenvironment that is essential for tumor growth and progression [ 8 ]. Protective therapeutic effects of macrophages in response to various tissue injuries, including the central nervous system, have also been demonstrated [ 9 ]. For instance, M1 macrophages induce neuronal damage, whereas M2 macrophages promote neuronal regeneration [ 9 ]. In addition, since macrophages have an important role in the development of tumor, they are a target for potential therapeutic strategy [ 1 ]. Few potential strategies have been proposed to treat cancers by preventing the recruitment of macrophages into the microenvironment of tumor and promote the differentiation of macrophages into the anti-tumorigenic phenotype [ 1 ]. Mesenchymal stem cells, also known as multipotent stromal cells (MSCs), modulate the functions of innate and adaptive immune cells, including lymphocytes (T cells, B cells, and natural killer cells) and macrophages as well as dendritic cells [ 10 ]. We have previously shown that MSCs from chorionic villi of the human term placenta (pMSCs) induce an anti-inflammatory phenotype in human macrophages [ 6 ] and dendritic cells [ 11 ], and inhibit proliferation of T cells [ 11 ]. Furthermore, we previously reported the isolation and characterization of mesenchymal stem/multipotent stromal cells from maternal decidua basalis tissue (DBMSCs) of the human term placenta [ 12 ]. These DBMSCs express a unique combination of molecules involved in many important cellular functions including migration, proliferation, differentiation, immunomodulation, and blood vessel formation [ 12 ]. In addition, DBMSCs protect endothelial cells from injury induced by monocytes [ 13 ]. These phenotypic and functional characteristics make DBMSCs suitable for cellular therapy. However, the modulatory effects of DBMSCs on human macrophages are currently unknown. For DBMSCs to be used in cellular therapy, it is essential to determine their effects on the phenotypic properties and functional activities of macrophages. Here, we examined whether the interaction of DBMSCs with human monocytes would result in shifting monocyte differentiation from M1 inflammatory macrophages into M2 anti-inflammatory macrophages, and to determine the characteristic and functions of these differentiated macrophages. We found that DBMSCs enhanced the differentiation of M1 inflammatory macrophages, which produce inflammatory molecules that are known for their anticancer properties. In addition, DBMSCs induced M1 macrophage stimulation of CD4 + T cell proliferation and secretion of inflammatory cytokines. DBMSCs have the potential to treat cancer by inducing the anticancer activities of M1 macrophages directly on cancer cells or through T cell stimulation. 2. Experimental Section 2.1. Ethics, Collection of Human Placentae, and Adult Peripheral Blood The institutional review board at King Abdulla International Medical Research Centre (KAIMRC), Saudi Arabia, approved this study. Samples [placentae from uncomplicated human pregnancies (38–40 weeks of gestation) and peripheral blood samples from healthy adult participants] were used immediately after obtaining informed consent. KAIMRC research guidelines and regulations were followed to conduct all clinical and experimental procedures of this study. 2.2. Isolation and Culture of DBMSCs MSCs were isolated from the decidua basalis (DBMSCs) of the maternal part of human term placenta using our previously published method [ 12 ]. DBMSCs were then cultured in a complete DBMSC culture medium (DMEM-F12 medium containing 10% MSCFBS (mesenchymal stem cell certified fetal bovine serum, catalogue number 12-662-011, Life Technologies, Grand Island, NE, USA), and antibiotics (100 µg/mL streptomycin and 100 U/mL Penicillin)), and then incubated at 37 °C in a humidified atmosphere containing 5% CO 2 and 95% air (a cell culture incubator). DBMSCs (passage 3) of 30 placentae were used in this study. 2.3. Isolation of Human Monocytes Mononuclear cells from peripheral blood (PBMNCs) of 30 normal healthy subjects were isolated using our previously published method [ 14 ]. Monocytes were isolated using human Monocyte Isolation Kit II (catalogue number 130-091-153, Miltenyi Biotec, Bergisch Gladbach, Germany) and a magnetic cell separation system (MACs: Miltenyi Biotec) as we previously described [ 14 ]. Trypan blue was used to determine the viability of monocytes while the purity was evaluated using anti-CD14 monoclonal antibody (R&D Systems, Systems, Abingdon, UK) in a flow cytometry. The purity was greater than 98%. 2.4. Culture of Monocyte Derived Macrophages with DBMSCs M1 macrophages were differentiated from monocytes as we previously described [ 6 ]. Monocytes were seeded in 6-well plates in M1 macrophage differentiation medium (RPMI-1640 medium containing 50 ng/mL GM-CSF (R and D Systems), 10% FBS, 2 mM L-glutamine, and antibiotics indicated above), and then cultured at 37°C as described above for six days ( Figure 1 ). For conditioned medium experiments (CMDBMSC), supernatant were prepared from the culture of unstimulated DBMSCs as previously described [ 6 ], and then added to the culture of monocytes ( Figure 1 ). For the coculture experiments [soluble factor (SFDBMSC) and intercellular direct contact (ICDBMSC)], cells (DBMSCs and monocytes) were separated by transwell chamber membrane culture system (catalogue number 657640, ThinCert™ Cell Culture Inserts, Greiner Bio-One, Germany). For the experiments of SFDBMSC, DBMSCs were seeded on the upper compartments while monocytes were seeded in the lower compartment ( Figure 1 ). For the experiments of ICDBMSC, DBMSCs were seeded on the reverse side of the membrane while monocytes were seeded on the upper side of the membrane ( Figure 1 ). These two culture systems separate DBMSCs from monocyte-derived macrophages and therefore allow macrophage harvesting without contamination by DBMSCs. In all culture systems, cells were cultured in M1 macrophage differentiation medium (above). On Day 7, macrophages were harvested with TrypLE™ Express detachment solution (Life Technologies) and characterized using macrophage markers, MHC molecules, and costimulatory molecule ( Table 1 ) in a flow cytometry technique as we previously described [ 6 ]. In some experiments, CMDBMSC, SFDBMSC, and ICDBMSC were added to the culture of monocyte-derived M1 macrophages on either Day 3 or Day 7 and then incubated for further three days and characterized as described above. In selected experiments, we added CMDBMSC, SFDBMSC, and ICDBMSC to the initial culture of monocyte- derived M1 macrophages incubated in RPMI-1640 medium without GM-CSF (spontaneous differentiation), incubated as described above, and the morphological changes were characterized by microscope examination. Different concentrations of DBMSC conditioned medium, 10, 20, 30, 40, 50, 60, 80, and 100% were tested. For SFDBMSC and ICDBMSC experiments, different ratios were used (1:1, 1:5, and 1:10 DBMSCs: monocyte-derived macrophages). Viability of macrophages were assessed using Trypan blue staining. Figure 1. M1 macrophage culture system. Untreated control experiment consisted of M1 macrophages cultured on a surface of 6-well culture plate in a medium containing GM-CSF, CMDBMSC experiment consisted of M1 macrophages cultured on a surface of 6-well culture plate in a medium containing GM-CSF and CMDBMSC (conditioned medium), SFDBMSC (soluble factor), and ICDBMSC (intercellular direct contact) experiments. In SFDBMSC and ICDBMSC experiment, cells (DBMSCs and monocytes) were separated by transwell chamber membrane culture system. For the experiments of SFDBMSC, DBMSCs were seeded on the upper compartments while monocytes were seeded in the lower compartment. For the experiments of ICDBMSC, DBMSCs were seeded on the reverse side of the membrane while monocytes were seeded on the upper side of the membrane. GM-CSF medium was added to SFDBMSC and ICDBMSC experiments. Effects of human DBMSCs on the morphology of human monocytes differentiated into macrophages by GM-CSF. ( A – F ) Represent phase-contrast microscopic images showing monocyte (round-shaped morphology) differentiation into M1-like macrophages (fried egg-shaped morphology) after six days of culture in a medium containing GM-CSF ( A ), in a medium containing GM-CSF and DBMSCs at a 20:1 monocyte: DBMSC ratio ( B ), at a 10:1 monocyte: DBMSC ratio ( C ), at a 1:1 monocyte: DBMSC ratio ( D ), in the presence of 10% CMDBMSC ( E ), or in the presence of 20% CMDBMSC ( F ). ( G – K ) Representative phase-contrast microscopic images showing monocyte-like cells after six days of culture in a medium containing GM-CSF and 30% CMDBMSC ( G ), 40% CMDBMSC ( H ), 50% CMDBMSC ( I ), 60% CMDBMSC ( J ), 80% CMDBMSC ( K ), or 100% CMDBMSC ( L ). Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. Scale bars represent 50 µm. Table 1. Markers used in this study. Before using DBMSCs in the coculture systems (SFDBMSC and ICDBMSC), DBMSCs were treated with 25 µg/mL Mitomycin C to inhibit their proliferation as we previously described [ 6 ]. To determine the reversibility of DBMSC effects on the differentiation of macrophages, CMDBMSC, SFDBMSC, and ICDBMSC were removed after three days of culturing with monocyte, and macrophages were then washed thoroughly and re-cultured in fresh M1 macrophage differentiation (above) for another three days. The negative control was monocyte-derived macrophages cultured alone in M1 macrophage differentiation. Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. 2.5. Phagocytic Activity of Monocyte-Derived Macrophages The phagocytic activity of monocyte-derived macrophages was studied using the CytoSelect™ phagocytosis kit (catalogue number CBA-224, Cell Biolabs, San Diego, CA, USA) as we previously published [ 6 ]. Briefly, macrophages were harvested from the three culture systems described above, and their phagocytic activities were then measured as we previously described [ 6 ]. Negative controls were monocyte-derived macrophages cultured alone in M1 macrophage differentiation, and macrophages cultured without Zymosan particles. Experiments were carried out in duplicate and repeated 10 times using 10 individual preparations of both monocyte-derived macrophages and DBMSCs. 2.6. T Cell Proliferation Assay Monocyte-derived macrophages cultured alone or cultured with DBMSCs in the culture system described above were harvested, washed with PBS, treated with 25 μg/mL Mitomycin C (described above), and different ratios of macrophages were then cultured with allogeneic CD4 + T cells (1:5, 1:10, and 1:20 macrophages: T cells) in triplicate in 96-well flat-bottomed plates. T cells were purified from PBMCs using CD4 + T Cell isolation Kit (catalogue number 130-096-533, Miltenyi Biotec) as we previously described [ 11 ]. All cultures were carried out in RPMI-1640 medium containing 10% FBS, 2 mM L-glutamine, and antibiotic as indicated above. After four days, T cell proliferation was measured using a tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2Htetrazolium, inner salt; MTS] kit (catalogue G5421, CellTiter 96® Aqueous Non-Radioactive Cell Proliferation Assay, Promega, Germany) as we previously described [ 11 ]. Experiments were carried out in triplicate and repeated 10 times using 10 individual preparations of T cells and macrophages harvested from 10 individual experiments of macrophages cultured with DBMSCs (CMDBMSC, SFDBMSC, and ICDBMSC). Results are presented as means of standard errors (± SE). T cell cultured alone served as a negative control. 2.7. Quantification of Human Cytokines ELISA Kits (R&D Systems or MyBiosource, California, USA) were used according to the manufacturer’s instructions to quantify IL-1β, IL-6, IL10, IL-12, and IFN-γ in the supernatants obtained from macrophages cultured alone or with DBMSCs in the culture systems described above and from the T cell cultured alone or cultured with macrophages as described above. Complete RPMI-1640 and DMEM-F12 media were included as a negative control. 2.8. Flow Cytometry Cells (1 × 10 5 ) were stained with antibodies listed in Table 1 for 30 min. Flow cytometry was then performed as we previously described [ 13 ]. Negative controls were cells stained with FITC or PE-labeled mouse IgG isotype antibody. 2.9. Statistical Analysis GraphPad Prism 5 was used to analyze data using non-parametric tests (Mann–Whitney U and Kruskal–Wallis). Data were deemed statistically significant if p < 0.05. 3. Results and Discussion 3.1. DBMSCs Effect on M1-like Macrophage Differentiation from Human Monocytes We used MSCs from decidua basalis of human term placenta (passage 3) as previously isolated and characterized by us [ 12 ]. DBMSCs at passage 3 are positive (> 95%) for MSC markers (CD44, CD90, CD105, CD146, CD166, HLA-ABC) and negative for hematopoietic markers (CD14, CD19, CD40, CD45, CD80, CD83, CD86, HLA-DR). DBMSCs at passage 3 also differentiate into adipocytes, chondrocytes and osteocytes [ 12 ]. Therefore, DBMSCs at passage 3 were used in all experiments. Monocytes were isolated from healthy human peripheral blood and induced to differentiate into M1-like macrophages using GM-CSF. After six days, cells exhibited a fried egg morphology a characteristic of M1-like macrophages ( Figure 1 A) [ 6 ]. These M1-like macrophages expressed CD14 (monocytic marker), but lacked expression of CD1a (dendritic cell marker) (data not shown). To study the effect of DBMSCs on macrophages, monocytes were cultured in an M1 macrophage differentiation medium in SFDBMSC and ICDBMSC culture systems at different cell ratios of macrophages: DBMSC (1:1, 10:1, and 20:1) and with 10, 20, 30, 40, 50, 60, 80, and 100% ( v / v ) CMDBMSCs. DBMSCs had no effect on the viability of macrophages as their viability was > 90%. Compared to untreated monocyte-derived macrophages, none of the DBMSC treatments inhibited the differentiation of monocytes into M1 macrophages, as cells exhibited a fried egg-shaped morphology indicative of M1 macrophages ( Figure 1 B–F). However, with increasing numbers and concentrations of DBMSCs, cells were smaller in size, showing a round morphology with reduced ability to adhere, suggesting that they were monocytes ( Figure 1 G–L). Cells that were differentiated in the presence of DBMSCs expressed CD14 in the absence of CD1a (data not shown). Next, we evaluated whether monocytes differentiated in the presence of DBMSCs at a ratio of 20:1 macrophages: DBMSC for both ICDBMSC and SFDBMSC culture systems and with 20% CMDBMSC expressed molecules characteristic of macrophages, as listed in Table 1 . These experimental conditions (20:1 macrophages: DBMSC ratio and 20% CMDBMSC) were used in all subsequent experiments. Expression of these functional markers was studied using flow cytometry. Their expression was recorded as mean fluorescence intensity (MFI). After six days in culture, compared to untreated macrophages, DBMSCs (CMDBMSC or SFDBMSC) significantly increased the expression of CD14 and CD163 on macrophages, p < 0.05 ( Figure 2 A and B). In addition, DBMSCs (SFDBMSC) significantly increased the expression of CD206 on macrophages compared with that on untreated macrophages, p < 0.05 ( Figure 2 D). By contrast, ICDBMSCs significantly decreased expression of CD163, CD204, CD206, and CD36 on macrophages compared to untreated macrophages, p < 0.05 ( Figure 2 B–E), but there was no significant effect on the expression of CD14 and B7-H4, p > 0.05 ( Figure 2 A and F). Similarly, CMDBMSCs and SFDBMSCs had no significant effect on either the expression of CD204, CD36, or B7-H4 on macrophages compared with to untreated macrophages, p > 0.05 ( Figure 2 C,E, and F). Finally, CMDBMSCs did not significantly affect the expression of CD206 on macrophages compared to untreated macrophages, p > 0.05 ( Figure 2 D). Figure 2. Effects of human DBMSCs on the expression of cell surface molecules CD14, CD163, CD204, CD206, CD36, and B7H4 on human monocytes differentiated into macrophages by GM-CSF, as analyzed by flow cytometry. After six days in culture, compared to untreated macrophages, CMDBMSCs significantly increased expression of CD14 ( A ) and CD163 ( B ) on macrophages while having no significant effect ( p > 0.05) on expression of CD204 ( C ), CD206 ( D ), CD36 ( E ), and B7H4 ( F ) on macrophages. Compared to untreated macrophages, SFDBMSC significantly increased expression of CD14 ( A ), CD163 ( B ), and CD206 ( D ) on macrophages while having no significant effects ( p > 0.05) on expression of CD204 ( C ), CD36 ( E ), and B7H4 ( F ) on macrophages. In addition, ICDBMSCs significantly decreased expression of CD163 ( B ), CD204 ( C ), CD206 ( D ) and CD36 ( E ) on macrophages while having no significant effects ( p > 0.05) on expression of CD14 ( A ) and B7H7 ( F ) compared with that on untreated macrophages. Levels of expression are presented as median fluorescent intensity (MFI) as determined by flow cytometry. Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. * p < 0.05. Bars represent standard errors. Next, the effects of DBMSCs on macrophage differentiation were evaluated after adding DBMSCs to monocyte cultures on Day 3 or Day 7 and culturing for a further three days. All DBMSC treatments showed similar effects on M1-like macrophage differentiation of monocytes as described above (data not shown). These results suggest that DBMSCs affect macrophage differentiation at various times during culture. Similarly, all three DBMSC culture systems showed a similar effects on M1-like macrophage differentiation after coculture with monocytes in the absence of GM-CSF for seven days (data not shown), suggesting that DBMSCs possess immunostimulatory properties. 3.2. DBMSC Effects on M1-like Macrophage Differentiation Are Irreversible Next, we evaluated the reversibility of the effects of DBMSCs on the differentiation of macrophages. DBMSCs were removed from the monocyte cultures on Day 3, and monocyte-derived macrophages were then washed and cultured again in fresh M1-like macrophage differentiation medium without DBMSCs for a further three days. M1-like macrophage differentiation occurred under these experimental conditions, as evidenced by macrophages exhibiting the fried egg-shaped morphology of M1-like macrophages on Day 7. Moreover, these M1-like macrophages expressed similar levels of CD14, CD163, CD204, CD206, and B7-H4 to those of M1-like macrophages differentiated in the presence of DBMSCs for six days ( Figure 3 ). These results suggest that the effect of DBMSCs on monocyte differentiation is irreversible. Figure 3. Reversibility effects of DBMSCs on macrophage differentiation. Human monocytes differentiated into macrophages by GM-CSF in the presence of DBMSCs. DBMSCs were removed from the monocyte cultures on Day 3, and monocyte-derived macrophages were then washed and cultured again in fresh M1-like macrophage differentiation medium without DBMSCs for a further three days. Macrophage differentiation was analyzed by morphological analysis using microscopic examination (Panels A , B , and C ) and flow cytometric analysis of cell surface molecules (CD14, CD163, CD204, CD206, and B7-H4). ( A – C ) Representative phase-contrast microscopic images showing monocyte (round-shaped morphology) differentiation into M1-like macrophages (fried egg-shaped morphology) after six days of culture ( A ), in a medium containing GM-CSF and DBMSCs at a 20:1 monocyte: DBMSC ratio ( B ), in the presence of 20% CMDBMSC ( C ) . After six days in culture, compared to untreated macrophages, CMDBMSCs significantly increased the expression of CD14 ( D ) and CD163 ( E ) on macrophages, but had no significant effect on the expression of CD204 ( F ), CD206 ( G ), and B7-H4 ( H ) on macrophages. Compared to untreated macrophages, SFDBMSC significantly increased the expression of CD14 ( D ), CD163 ( E ), and CD206 ( G ) on macrophages, but had no significant effect on the expression of CD204 ( F ), and B7-H4 ( H ) on macrophages. In addition, ICDBMSCs significantly decreased the expression of CD163 ( E ), CD204 ( F ), CD206 ( G ) on macrophages, but had no significant effect on the expression of CD14 ( D ) and B7-H7 ( H ) compared with the effect on untreated macrophages. Levels of expression are presented as median fluorescent intensity (MFI) as determined by flow cytometry. Experiments were carried out in duplicate and repeated 10 times using 10 individual preparations of both monocyte-derived macrophages and DBMSCs. * p < 0.05. Bars represent standard errors. 3.3. DBMSC Effects on Expression of CD80, CD86, CD273, CD274, and HLA-DR on Macrophages To determine the effect of DBMSCs on monocyte-derived macrophages with respect to macrophage function, a variety of immune functional markers ( Table 1 ) were examined using flow cytometry, and expression was recorded as MFI. After six days in culture, DBMSC-treated macrophages in the three culture systems expressed significantly less CD86 than untreated macrophages, p < 0.05 ( Figure 4 C), Table 2 . In addition, treatment with ICDBMSCs was associated with significantly decreased expression of co-inhibitory molecules (CD273 and CD274) on macrophages compared with that on untreated macrophages, p < 0.05 ( Figure 4 D,E), Table 2 . HLA-DR (antigen presenting molecule) and CD80 (co-stimulatory molecule) expression did not differ between treated and untreated macrophages for any culture system, p > 0.05 ( Figure 4 A,B), Table 2 . Similarly, CMDBMSC and SFDBMSCs did not significantly affect the expression of CD273 and CD274 on macrophages compared with that on untreated macrophages, p > 0.05 ( Figure 4 D,E), Table 2 . These data indicate that ICDBMSC maintained the antigen presentation activity of macrophages and with immunostimulatory effect by maintaining the expression of co-stimulatory molecule (CD80) and reducing the expression of the co-inhibitory molecules (CD273 and CD274). Figure 4. Effects of human DBMSCs on expression of the cell surface molecules HLADR, CD80, CD86, CD273, and CD274 by human monocytes differentiated into macrophages by GM-CSF, as analyzed by flow cytometry. After six days in culture, compared to untreated macrophages, CMDBMSCs and SFDBMSCs had no significant effects ( p > 0.05) on expression of HLA-DR ( A ), CD80 ( B ), CD273 ( D ), and CD274 ( E ) on macrophages while significantly decreasing expression of CD86 ( C ). Compared to untreated macrophages, ICDBMSCs had no significant effects ( p > 0.05) on expression of HLA-DR ( A ) and CD80 ( B ) on macrophages while significantly decreasing expression of CD86 ( C ), CD273 ( D ), and CD274 ( E ) on macrophages. Levels of expression are presented as median fluorescent intensity (MFI) as determined by flow cytometry. Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. * p < 0.05. Bars represent standard errors. Table 2. DBMSC (CMDBMSC, SFDBMSC, and ICDBMSC) effects on macrophage expression of different functional markers, costimulatory molecules, co-inhibitory molecules, antigen presenting molecule, inflammatory cytokines, and anti-inflammatory markers as compared to untreated macrophages by flow cytometry recorded by mean of fluorescent intensity (MFI). Increased (↑, p < 0.05), decreased (↓, p < 0.05)), and no change ( p > 0.05). 3.4. DBMSCs Modulate Expression by Macrophages of IL-1β, IL-6, IL-8, IL-12, IFN-γ, and TNF-α Next, we determined the effects of DBMSCs on expression by macrophages of the six inflammatory cytokines listed in Table 1 using flow cytometry, with expression recorded as MFI. After six days in culture, treatment with ICDBMSCs resulted in significantly increased expression of IL-1β, IFN-γ, and TNF-α by macrophages relative to untreated controls, p < 0.05 ( Figure 5 A,E and F, Table 2 . By contrast, ICDBMSCs significantly reduced the expression of IL-6 and IL-12 relative to controls, p < 0.05 ( Figure 5 B,D), while having no effects on the expression of IL-8, p > 0.05 ( Figure 5 C), Table 2 . Similarly, compared to untreated macrophages, SFDBMSCs significantly reduced the expression by macrophages of IL-1β and IL-12, p < 0.05 ( Figure 5 A,D), while significantly increasing the expression of IFN-γ, p < 0.05 ( Figure 5 E), Table 2 , and no effects on the expression of IL-6, IL-8, and TNF-α by macrophages were observed, p > 0.05 ( Figure 5 B,C, and F). In addition, CMDBMSCs significantly reduced the expression of IL-1β by macrophages relative to controls, p < 0.05 ( Figure 5 A), while having no effect on the expression of other inflammatory molecules, p > 0.05 ( Figure 5 B–F), Table 2 . Figure 5. Effects of human DBMSCs on expression of the intracellular cytokines IL-1β, IL-6, IL-8, IL-12, IFN-γ, and TNF-α by human monocytes differentiated into macrophages by GM-CSF, as analyzed by flow cytometry. After six days in culture, compared to untreated macrophages, CMDBMSCs significantly decreased expression of IL-1β ( A ) by macrophages while having no significant effects ( p > 0.05) on expression of IL-6 ( B ), IL-8 ( C ), IL-12 ( D ), IFN-γ ( E ), and TNF-α ( F ) by macrophages. Compared to untreated macrophages, SFDBMSCs significantly decreased expression of IL-1β ( A ) and IL-12 ( D ) while having no significant effects ( p > 0.05) on expression of IL-6 ( B ), IL-8 ( C ), and TNF-α ( F ), but significantly increasing expression of IFN-γ ( E ) by macrophages. In addition, compared to untreated macrophages, ICDBMSCs significantly increased expression of IL-1β ( A ), IFN-γ ( E ), and TNF-α ( F ) while decreasing IL-6 ( B ) and IL-12 ( D ), but having no significant effects ( p > 0.05) on expression of IL-8 ( C ) by macrophages. Levels of expression are presented as median fluorescent intensity (MFI) as determined by flow cytometry. Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. * p < 0.05. Bars represent standard errors. 3.5. DBMSC Effects on Expression by Macrophages of IDO, TGFβ1, TGFβ1, 2, 3, and HMOX-1 We additionally assessed the consequences of the interaction between DBMSCs and macrophages on the expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) and the anti-inflammatory molecules transforming growth factor-β 1 (TGFβ1), TGFβ1, 2, 3, and heme oxygenase 1 (HMOX-1) using flow cytometry, with expression recorded as MFI or median percentage of positive cells for HMOX-1. After six days of culture with ICDBMSCs, expression of IDO by macrophages was significantly decreased compared with that by untreated macrophages, p < 0.05 ( Figure 6 A), Table 2 . By contrast, CMDBMSCs and SFDBMSCs had no effect on expression of IDO by macrophages ( Figure 6 A), Table 2 . In addition, none of the DBMSC treatments significantly modulated the expression of TGFβ1, TGFβ1, 2, 3, or HMOX-1 by macrophages compared with that by controls, p > 0.05 ( Figure 6 B–D), Table 2 . Figure 6. Effects of human DBMSCs on expression of the intracellular molecules IDO, TGFβ1, TGFβ1, 2, 3, and HMOX-1 by human monocytes differentiated into macrophages by GM-CSF, as analyzed by flow cytometry. After six days in culture, compared to untreated macrophages, CMDBMSCs, and SFDBMSCs had no significant effects ( p > 0.05) on expression of IDO ( A ), TGFβ1 ( B ), TGFβ1, 2, 3 ( C ), and HMOX-1 ( D ) by macrophages. In addition, after six days in culture, compared to untreated macrophages, ICDBMSCs significantly decreased expression by macrophages of IDO ( A ) while having no significant effects ( p > 0.05) on expression of TGFβ1 ( B ), TGFβ1, 2, 3 ( C ), and HMOX-1 ( D ). Levels of expression are presented as median fluorescent intensity (MFI) or median percentage of HMOX-1 positive cells as determined by flow cytometry. Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. * p < 0.05. Bars represent standard errors. 3.6. DBMSCs Modulate Secretion by Macrophages of IL-1β, IL-6, IL-10, and IL-12 We further characterized the effect of DBMSCs on secretion of cytokines by macrophages, including IL-1β, IL-6, IL-10, and IL-12 (p70), into the supernatant of the three culture systems described above using ELISA. Compared with untreated macrophages, treatment with DBMSCs from all three culture systems was associated with significantly increased secretion by macrophages of IL-6, p < 0.05 ( Figure 7 B), Table 3 . In addition, CMDBMSCs significantly increased the secretion by macrophages of IL-10 relative to untreated controls, p < 0.05 ( Figure 7 C) Table 3 , while ICDBMSCs significantly decreased the secretion of IL-10, p < 0.05 ( Figure 7 C) Table 3 . None of the DBMSC treatments significantly affected secretion by macrophages of IL1β and IL-12, p > 0.05 ( Figure 7 A,D), Table 3 . Likewise, secretion of IL-10 was not significantly altered by SFDBMSCs compared with that of untreated macrophages ( Figure 7 C), Table 3 . Figure 7. Effects of DBMSCs on GM-CSF–stimulated human monocyte-to-macrophage differentiation, as analyzed by the secretion of IL-1β, IL-6, IL-10, and IL-12 using sandwich ELISA. CMDBMSCs had no significant effect ( p > 0.05) on the secretion profiles of IL-1β ( A ), significantly increased (* p < 0.05) the secretion profiles of IL-6 ( B ) and IL-10 ( C ), and had no significant effect ( Table 3. DBMSC (CMDBMSC, SFDBMSC, and ICDBMSC) effects on macrophage secretion of inflammatory and anti-inflammatory cytokines as compared to untreated macrophages by ELISA. Increased (↑) and decreased (↓). 3.7. DBMSCs Do Not Alter Macrophage Phagocytic Activity As described above, DBMSCs significantly modified the functions of macrophages by altering the expression of various immunological markers. Therefore, we tested whether DBMSCs affect the phagocytic activity of macrophages. For this purpose, phagocytic activity of macrophages cultured alone or initially cultured with CMDBMSCs, SFDBMSCs, or ICDBMSCs for six days was measured using the CytoSelect™ phagocytosis functional assay. None of the DBMSC treatments showed significant effects on the phagocytic activity of macrophages, p > 0.05 ( Figure 8 ). Figure 8. Functional assay of the phagocytic activity of monocytes differentiated into macrophages by GM-CSF in the presence of human DBMSCs. Phagocytosed Zymosan particles were measured by reading the optical density at 405 nm. Phagocytosis of Zymosan particles by macrophages was not significantly affected by DBMSC treatments compared to macrophages cultured alone. Experiments were carried out in duplicate and repeated 10 times using 10 individual preparations of both monocyte-derived macrophages and DBMSCs. Bars represent standard errors. 3.8. DBMSCs Induce M1-like Macrophage Effects on T Cell Function We further examined the combined effects of DBMSCs and M1-like macrophages on T cell function. Monocyte-derived M1-like macrophages that had either been cultured with DBMSCs (CMM1, SFM1, and ICM1) or cultured alone (M1) were added to allogenic CD4 + T cell cultures at T cell:M1-like macrophage ratios of 5:1, 10:1, and 20:1. T cell proliferation was then examined using the MTS assay. Compared to T cells alone, M1-like macrophages cultured either with DBMSC treatments (CMM1, SFM1, and ICM1) or without DBMSCs (M1) significantly increased T cell proliferation at all indicated ratios, p < 0.05 ( Figure 9 A). Similarly, ICM1 significantly increased T cell proliferation at all indicated ratios as compared to that with M1, p < 0.05 ( Figure 9 A). In addition, SFM1 significantly increased T cell proliferation at the 5:1 T cells: SFM1 ratio compared to that with M1, p < 0.05 ( Figure 9 A). By contrast, CMM1 significantly decreased T cell proliferation at the 10:1 and 20: 1 T cells: CMM1 ratios compared to that with M1, p < 0.05 ( Figure 9 A). Additionally, secretion of IL-10 by T cells stimulated with M1, CMM1, SFM1, and ICM1 was significantly reduced, p < 0.05 ( Figure 9 B), while the secretion of IL-12 and IFN-γ was significantly increased, p < 0.05 ( Figure 9 C,D), Table 4 . Figure 9. T cell proliferation by M1-like macrophages (M1) generated in the presence of DBMSCs. After culturing M1 alone or with CMDBMSC (CMM1), SFDBMSC (SFM1), and ICDBMSC (ICM1), M1 were harvested and added to allogeneic CD4 + T cells at 5:1, 10:1, and 20:1 T cells:M1 (M1, CMM1, SFM1, and ICM1) ratios. M1 pre-treated with DBMSCs (CMM1, SFM1, and ICM1) or without (M1) significantly increased T cell proliferation at all indicated ratios. Similarly, ICM1 significantly increased T cell proliferation at all indicated ratios compared to that with M1, while SFM1 significantly increased T cell proliferation at the 5:1 T cells: SFM1 ratio compared to that with M1. By contrast, CMM1 significantly decreased T cell proliferation at the 10:1 and 20: 1 T cells: CMM1 ratios compared to that with M1 ( A ). In addition, the secretion of IL-10 by T cells stimulated with M1, CMM1, SFM1, and ICM1 was significantly reduced ( B ), while the secretion of IL-12 and IFN-γ was significantly increased, p < 0.05 ( C and D ). Experiments were carried out in triplicate and repeated 10 times using 10 individual preparations of T cells and macrophages harvested from 10 individual experiments of macrophages cultured with DBMSCs (CMDBMSC, SFDBMSC, and ICDBMSC). * p < 0.05, Bars represent standard error. Table 4. DBMSC (CMDBMSC, SFDBMSC, and ICDBMSC) effects on macrophage stimulatory effects on T cell proliferation and secretion of inflammatory and anti-inflammatory cytokines as compared to untreated T cells measured by ELISA. Increased (↑) and decreased (↓). 3.9. Discussion In this study, we examined the modulatory effects of DBMSCs on human macrophages, by coculturing DBMSCs with macrophages, which were generated from monocytes cultured in M1 macrophage differentiation medium [ 6 ]. Monocytes differentiated after six days into cells exhibiting the typical fried egg-shaped morphology of M1-like macrophages ( Figure 1 A) and expressed the monocytic marker CD14 without expressing the dendritic cell marker CD1a [ 6 ]. Addition of DBMSCs to monocyte cultures induced to differentiate into M1-like macrophages did not reverse M1 polarization nor shift it to M2 differentiation (elongated, spindle-like cells), as previously reported by us using pMSCs and by other researchers using MSCs from bone marrow, adipose tissues, gingival, or cord blood [ 6 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Morphologically, cells exhibited the typical morphology of M1-like macrophages ( Figure 1 B–F). We also observed that higher ratios of DBMSCs in the coculture inhibited monocyte differentiation into M1-like macrophages, as evidenced by the presence of cells smaller than macrophages with a round morphology and less adhesion, suggesting that these cells remained monocytes ( Figure 1 G–L). Phenotypically, M2-like macrophages express high levels of a number of cell surface markers, including CD14, CD36, CD163, CD204, CD206, and B7-H4, as we previously demonstrated with pMSCs [ 6 ]. In the presence of DBMSCs, M1-like macrophages upregulated the expression of only a subset (i.e. CD14, CD163, and CD206; Figure 2 ) of the markers. In this study, direct intercellular contact of DBMSCs (ICDBMSC) with monocyte-derived macrophages significantly decreased expression of CD36, CD163, CD204, and CD206 on macrophages, while paracrine communication between DBMSCs and monocyte-derived macrophages (SFDBMSC) increased the expression of CD14, CD163, and CD206 on macrophages ( Figure 2 B and D). In addition, soluble factors secreted by unstimulated DBMSCs (CMDBMSC) increased the expression of CD14 and CD206 on macrophages ( Figure 2 D). These data show the experimental conditions (mechanism of DBMSC communication with monocytes) modulate the phenotypic characteristics (inflammatory or anti-inflammatory phenotypes) of differentiated macrophages. However, at least with ICDBMSC, M1-like macrophages do not upregulate all markers, which suggests that ICDBMSCs are unable to induce an anti-inflammatory phenotype in macrophages, but rather they promote monocyte differentiation into inflammatory M1-like macrophages. One obvious explanation for this is that the original microenvironment (i.e., the niche) from which the MSCs were derived may determine the functional activities of MSCs on macrophage differentiation. DBMSCs are located in the maternal tissue of the placenta, which is continuously exposed to increased levels of inflammation and oxidative stress throughout human pregnancy [ 22 , 23 ]. By contrast, pMSCs are exposed to the fetal circulation, which experience relatively low levels of inflammation and exposure to oxidative stress mediators during normal pregnancy [ 24 , 25 ]. Likewise, bone marrow MSCs are generally exposed to low levels of oxidative stress in their bone marrow niche and only experience increased oxidative stress during injury or disease [ 26 ]. This phenomenon of monocyte polarization into immunostimulatory or immunoinhibitory macrophages was also reported for MSCs. It was shown that MSCs can be polarized into immunostimulatory or immunosuppressive cells similar to monocytes [ 27 ]. Kinetic experiments with monocyte-derived macrophages showed that the addition of all DBMSC treatments to monocytes cultured in M1 macrophage differentiation medium on Day 3 did not alter monocyte differentiation into M1-like macrophages, and was comparable to the effects of DBMSCs when added to the culture on the first day. Importantly, coculture with monocytes in M1 macrophage differentiation medium and DBMSCs from the time of plating up to Day 3 showed that the effects of DBMSCs on the differentiation of monocytes were not altered, as we observed the M1-like macrophage morphology was maintained at the end of the culture period. Hence, the effect of DBMSCs on the differentiation of M1-like macrophages is likely to be irreversible ( Figure 3 ). CD163 is a hemoglobin scavenger receptor that mediates the resolution of inflammation by limiting damage induced by free hemoglobin [ 28 ] and stimulates the production of anti-inflammatory cytokines by M2-like macrophages [ 29 , 30 ]. Similarly, the scavenger receptor A (CD204), macrophage mannose receptor (CD206), and scavenger receptor B (CD36) are also involved in the resolution of inflammation by M2-like macrophages during the course of an innate immune response [ 31 , 32 , 33 ]. This further confirms that ICDBMSCs induced an inflammatory phenotype in macrophages. To support this observation, we demonstrated that ICDBMSCs decreased macrophage expression of CD273 and CD274 ( Figure 4 D,E), which are ligands for the inhibitory programmed death 1 (PD-1) receptor that signal to inhibit the function of T cells and to induce development of immunosuppressive regulatory T cells [ 34 ]. In addition, ICDBMSCs decreased macrophage expression of IDO ( Figure 6 A). IDO is an immunosuppressive enzyme that stimulates the catabolism of tryptophan, inhibiting the immune responses by repressing T cell function [ 35 ]. Moreover, ICDBMSCs decreased macrophage secretion of IL-10 ( Figure 7 C). IL-10 is an anti-inflammatory cytokine that inhibits the immune response by decreasing secretion of Th1 inflammatory cytokines and increasing the function of regulatory T cells [ 36 ]. Furthermore, ICDBMSC increased the secretion of IL-6 ( Figure 7 B). IL-6 activates the proliferative responses of lymphocytes, therefore shifting the immune response from an inhibitory to a stimulatory state [ 37 ]. These results suggest that intercellular contact between DBMSCs and monocyte-derived macrophages induces an inflammatory phenotype in macrophages. We further confirmed this by showing that ICDBMSCs increase the expression of inflammatory cytokines by M1-like macrophages, including IL-1β, IFN-γ, and TNF-α ( Figure 5 A,E and F). By contrast, ICDBMSCs decreased the expression of other inflammatory molecules by macrophages, including IL-6 and IL-12 ( Figure 5 B,D). Additionally, we showed that paracrine communication between DBMSCs (SFDBMSC) and monocyte-derived macrophages increased the expression of IFN-γ ( Figure 5 E) and secretion of IL-6 ( Figure 7 B) while decreasing the expression of IL-1β and IL-12 ( Figure 5 A,D) by macrophages. Likewise, soluble mediators secreted by unstimulated DBMSCs (CMDBMSC) decreased the expression of IL-1β ( Figure 5 A) and increased the secretion of IL-6 and IL-10 by macrophages ( Figure 7 B,C). Collectively, our data indicate that DBMSCs may exert opposing effects on the phenotype of macrophages. Several other studies support our findings that soluble factors secreted by MSCs mediate immunomodulatory effects on immune cells. Others have reported that separation of MSCs and immune cells by a semipermeable membrane does not prevent the immunomodulatory effects that MSCs exert [ 6 , 38 , 39 , 40 ]. Importantly, our results also demonstrate that the immune/inflammatory effects of DBMSCs on macrophages are mediated by soluble factors secreted by unstimulated DBMSCs, suggesting that direct crosstalk between DBMSCs and immune cells is unnecessary, as we previously reported [ 6 ]. However, this is in contrast with previous studies reporting that it is essential for MSCs to be activated in order to modulate responses of immune cells [ 20 , 41 , 42 ]. Activated M1-like macrophages usually phagocytose microbes, remove tumor cells, present antigen to T cells to trigger an immune response, and secrete high levels of inflammatory cytokines [ 43 ]. Although all DBMSC treatments did not affect expression of HLA-DR (antigen-presenting molecule) and CD80 (costimulatory molecule), and decreased the expression of another costimulatory molecule, CD86, on M1-like macrophages, they did not inhibit the phagocytic activities of M1-like macrophages ( Figure 8 ). In addition, all DBMSC treatments induced stimulatory effects of M1-like macrophages on the proliferation ( Figure 9 A) and production of high levels of inflammatory cytokines, including IL-12 and IFN-γ, and low levels of IL-10 ( Figure 9 B–D) by CD4 + T cells. These data demonstrate that although DBMSCs (ICDBMSC, SFDBMSC, and CMDBMSC) have differential effects on the inflammatory phenotype in M1-like macrophages, they induced similar modulatory effects on the functional activities of CD4 + T cells. This finding is important, because it suggests that DBMSCs are immune stimulatory cells with the potential for fighting cancer cells through their ability to induce the differentiation of M1-like macrophages, which have anticancer activity [ 5 , 44 ]. Additionally, DBMSCs induce an M1-like macrophage stimulatory effect on the function of CD4 + T cells, which also fight cancer cells [ 45 ]. The mechanisms by which DBMSCs stimulate M1 macrophage function are currently unknown. However, DBMSCs produce a large range of molecules that are involved in M1 macrophage differentiation. For example, DBMSCs produce IFN-γ and GM-CSF, which can induce M1 macrophage differentiation [ 46 , 47 ]. Therefore, these molecules may mediate the DBMSC effect on M1-like macrophages. However, further studies are required to elucidate these mechanisms and to determine the anticancer activities of DBMSCs. 4. Conclusions This is the first study to show that human DBMSCs favor differentiation of human M1 macrophages by direct or indirect contact mechanisms or through soluble factors secreted by unstimulated DBMSCs. We show for the first time that DBMSCs induce an inflammatory phenotype in M1 macrophages with functional activities that induce the T cell proliferation and cytokine secretion. In addition, we show that the effect of DBMSCs on macrophage differentiation is irreversible. However, a future study will be conducted to confirm this in vitro finding of DBMSCs favoring M1 macrophage differentiation by performing an in vivo study. In light of these results, we propose that human DBMSCs are immunostimulatory cells with the potential to target cancer cells by acting on macrophages to enhance macrophage anticancer activities either directly or indirectly through CD4 + T cells. Author Contributions M.H.A. proposed and supervised the project. M.H.A. designed the experiments. S.A.H., A.M.A.S., and M.A.A. performed the experiments. M.H.A. analyzed the data. M.H.A., F.M.A., T.K., B.K., M.F.E.-M., M.A.A.J., D.J., A.O.A., and A.S.A. wrote the manuscript. M.H.A., F.M.A., T.K., B.K., M.F.E.-M., M.A.A.J., D.J., A.O.A., and A.S.A. contributed to data analysis and interpretation of results. All authors reviewed the manuscript. Funding This study was supported by grants from KAIMRC (grant no. RC12/133). Acknowledgments We thank the staff and patients of the Delivery Unit, King Abdul Aziz Medical City for their help in obtaining placentae. Conflicts of Interest The authors declare no conflict of interest. Data Availability All data generated or analyzed during this study are included in this published article. Ethics approval and consent to participate The institutional review board (IRB) at King Abdulla International Medical Research Centre (KAIMRC), Saudi Arabia approved this study. Consent for publication All authors agree to publish this manuscript. Author Disclosure Statement No competing financial interests exist. The authors declare that there is no conflict of interest regarding the publication of this paper. References Nielsen, S.R.; Schmid, M.C. Macrophages as key drivers of cancer progression and metastasis. Mediat. Inflamm. 2017 , 2017 , 9624760. [ Google Scholar ] [ CrossRef ] [ PubMed ] Murray, P.J.; Wynn, T.A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 2011 , 11 , 723–737. [ Google Scholar ] [ CrossRef ] [ PubMed ] Biswas, S.K.; Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nat. Immunol. 2010 , 11 , 889–896. [ Google Scholar ] [ CrossRef ] Mantovani, A.; Sozzani, S.; Locati, M.; Allavena, P.; Sica, A. Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized m2 mononuclear phagocytes. Trends Immunol. 2002 , 23 , 549–555. [ Google Scholar ] [ CrossRef ] Ong, S.M.; Tan, Y.C.; Beretta, O.; Jiang, D.; Yeap, W.H.; Tai, J.J.; Wong, W.C.; Yang, H.; Schwarz, H.; Lim, K.H.; et al. Macrophages in human colorectal cancer are pro-inflammatory and prime t cells towards an anti-tumor type-1 inflammatory response. Eur. J. Immunol. 2012 , 42 , 89–100. [ Google Scholar ] [ CrossRef ] [ PubMed ] Abumaree, M.H.; Al Jumah, M.A.; Kalionis, B.; Jawdat, D.; Al Khaldi, A.; Abomaray, F.M.; Fatani, A.S.; Chamley, L.W.; Knawy, B.A. Human placental mesenchymal stem cells (pmscs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory m1 to anti-inflammatory m2 macrophages. Stem Cell Rev. 2013 , 9 , 620–641. [ Google Scholar ] [ CrossRef ] [ PubMed ] Gordon, S.; Martinez, F.O. Alternative activation of macrophages: Mechanism and functions. Immunity 2010 , 32 , 593–604. [ Google Scholar ] [ CrossRef ] Hao, N.B.; Lu, M.H.; Fan, Y.H.; Cao, Y.L.; Zhang, Z.R.; Yang, S.M. Macrophages in tumor microenvironments and the progression of tumors. Clin. Dev. Immunol. 2012 , 2012 , 948098. [ Google Scholar ] [ CrossRef ] Kigerl, K.A.; Gensel, J.C.; Ankeny, D.P.; Alexander, J.K.; Donnelly, D.J.; Popovich, P.G. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 2009 , 29 , 13435–13444. [ Google Scholar ] [ CrossRef ] Abumaree, M.H.; Abomaray, F.M.; Alshabibi, M.A.; AlAskar, A.S.; Kalionis, B. Immunomodulatory properties of human placental mesenchymal stem/stromal cells. Placenta 2017 , 59 , 87–95. [ Google Scholar ] [ CrossRef ] Abomaray, F.M.; Al Jumah, M.A.; Kalionis, B.; AlAskar, A.S.; Al Harthy, S.; Jawdat, D.; Al Khaldi, A.; Alkushi, A.; Knawy, B.A.; Abumaree, M.H. Human chorionic villous mesenchymal stem cells modify the functions of human dendritic cells, and induce an anti-inflammatory phenotype in cd1+ dendritic cells. Stem Cell Rev. 2015 , 11 , 423–441. [ Google Scholar ] [ CrossRef ] [ PubMed ] Abomaray, F.M.; Al Jumah, M.A.; Alsaad, K.O.; Jawdat, D.; Al Khaldi, A.; AlAskar, A.S.; Al Harthy, S.; Al Subayyil, A.M.; Khatlani, T.; Alawad, A.O.; et al. Phenotypic and functional characterization of mesenchymal stem/multipotent stromal cells from decidua basalis of human term placenta. Stem Cells Int. 2016 , 2016 , 5184601. [ Google Scholar ] [ CrossRef ] [ PubMed ] Alshabibi, M.A.; Al Huqail, A.J.; Khatlani, T.; Abomaray, F.M.; Alaskar, A.S.; Alawad, A.O.; Kalionis, B.; Abumaree, M.H. Mesenchymal stem/multipotent stromal cells from human decidua basalis reduce endothelial cell activation. Stem Cells Dev. 2017 , 26 , 1355–1373. [ Google Scholar ] [ CrossRef ] [ PubMed ] Abumaree, M.H.; Chamley, L.W.; Badri, M.; El-Muzaini, M.F. Trophoblast debris modulates the expression of immune proteins in macrophages: A key to maternal tolerance of the fetal allograft? J. Reprod. Immunol. 2012 , 94 , 131–141. [ Google Scholar ] [ CrossRef ] [ PubMed ] Kim, J.; Hematti, P. Mesenchymal stem cell-educated macrophages: A novel type of alternatively activated macrophages. Exp. Hematol. 2009 , 37 , 1445–1453. [ Google Scholar ] [ CrossRef ] [ PubMed ] Maggini, J.; Mirkin, G.; Bognanni, I.; Holmberg, J.; Piazzon, I.M.; Nepomnaschy, I.; Costa, H.; Canones, C.; Raiden, S.; Vermeulen, M.; et al. Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS ONE 2010 , 5 , e9252. [ Google Scholar ] [ CrossRef ] Zhang, Q.Z.; Su, W.R.; Shi, S.H.; Wilder-Smith, P.; Xiang, A.P.; Wong, A.; Nguyen, A.L.; Kwon, C.W.; Le, A.D. Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing. Stem Cells 2010 , 28 , 1856–1868. [ Google Scholar ] [ CrossRef ] Dayan, V.; Yannarelli, G.; Billia, F.; Filomeno, P.; Wang, X.H.; Davies, J.E.; Keating, A. Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction. Basic Res. Cardiol. 2011 , 106 , 1299–1310. [ Google Scholar ] [ CrossRef ] Nemeth, K.; Leelahavanichkul, A.; Yuen, P.S.; Mayer, B.; Parmelee, A.; Doi, K.; Robey, P.G.; Leelahavanichkul, K.; Koller, B.H.; Brown, J.M.; et al. Bone marrow stromal cells attenuate sepsis via prostaglandin e(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 2009 , 15 , 42–49. [ Google Scholar ] [ CrossRef ] Gupta, N.; Su, X.; Popov, B.; Lee, J.W.; Serikov, V.; Matthay, M.A. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J. Immunol. 2007 , 179 , 1855–1863. [ Google Scholar ] [ CrossRef ] Adutler-Lieber, S.; Ben-Mordechai, T.; Naftali-Shani, N.; Asher, E.; Loberman, D.; Raanani, E.; Leor, J. Human macrophage regulation via interaction with cardiac adipose tissue-derived mesenchymal stromal cells. J. Cardiovasc. Pharmacol. Ther. 2013 , 18 , 78–86. [ Google Scholar ] [ CrossRef ] [ PubMed ] Raijmakers, M.T.; Roes, E.M.; Poston, L.; Steegers, E.A.; Peters, W.H. The transient increase of oxidative stress during normal pregnancy is higher and persists after delivery in women with pre-eclampsia. Eur. J. Obstet. Gynecol. Reprod. Biol. 2008 , 138 , 39–44. [ Google Scholar ] [ CrossRef ] [ PubMed ] Burton, G.J.; Jauniaux, E. Oxidative stress. Best Pract. Res. Clin. Obstet. Gynaecol. 2011 , 25 , 287–299. [ Google Scholar ] [ CrossRef ] [ PubMed ] Braekke, K.; Harsem, N.K.; Staff, A.C. Oxidative stress and antioxidant status in fetal circulation in preeclampsia. Pediatric Res. 2006 , 60 , 560–564. [ Google Scholar ] [ CrossRef ] [ PubMed ] Kusuma, G.D.; Abumaree, M.H.; Pertile, M.D.; Perkins, A.V.; Brennecke, S.P.; Kalionis, B. Mesenchymal stem/stromal cells derived from a reproductive tissue niche under oxidative stress have high aldehyde dehydrogenase activity. Stem Cell Rev. 2016 , 12 , 285–297. [ Google Scholar ] [ CrossRef ] [ PubMed ] Urao, N.; Ushio-Fukai, M. Redox regulation of stem/progenitor cells and bone marrow niche. Free Radic. Biol. Med. 2013 , 54 , 26–39. [ Google Scholar ] [ CrossRef ] [ PubMed ] Schaer, D.J.; Alayash, A.I.; Buehler, P.W. Gating the radical hemoglobin to macrophages: The anti-inflammatory role of cd163, a scavenger receptor. Antioxid. Redox Signal. 2007 , 9 , 991–999. [ Google Scholar ] [ CrossRef ] Philippidis, P.; Mason, J.C.; Evans, B.J.; Nadra, I.; Taylor, K.M.; Haskard, D.O.; Landis, R.C. Hemoglobin scavenger receptor cd163 mediates interleukin-10 release and heme oxygenase-1 synthesis: Antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ. Res. 2004 , 94 , 119–126. [ Google Scholar ] [ CrossRef ] Hamann, W.; Floter, A.; Schmutzler, W.; Zwadlo-Klarwasser, G. Characterization of a novel anti-inflammatory factor produced by rm3/1 macrophages derived from glucocorticoid treated human monocytes. Inflamm. Res. 1995 , 44 , 535–540. [ Google Scholar ] [ CrossRef ] Goerdt, S.; Orfanos, C.E. Other functions, other genes: Alternative activation of antigen-presenting cells. Immunity 1999 , 10 , 137–142. [ Google Scholar ] [ CrossRef ] Poole, J.A.; Anderson, L.; Gleason, A.M.; West, W.W.; Romberger, D.J.; Wyatt, T.A. Pattern recognition scavenger receptor a/cd204 regulates airway inflammatory homeostasis following organic dust extract exposures. J. Immunotoxicol. 2015 , 12 , 64–73. [ Google Scholar ] [ CrossRef ] [ PubMed ] Woo, M.S.; Yang, J.; Beltran, C.; Cho, S. Cell surface cd36 protein in monocyte/macrophage contributes to phagocytosis during the resolution phase of ischemic stroke in mice. J. Biol. Chem. 2016 , 291 , 23654–23661. [ Google Scholar ] [ CrossRef ] [ PubMed ] Riella, L.V.; Paterson, A.M.; Sharpe, A.H.; Chandraker, A. Role of the pd-1 pathway in the immune response. Am. J. Transplant. 2012 , 12 , 2575–2587. [ Google Scholar ] [ CrossRef ] [ PubMed ] Soliman, H.; Mediavilla-Varela, M.; Antonia, S. Indoleamine 2,3-dioxygenase: Is it an immune suppressor? Cancer J. 2010 , 16 , 354–359. [ Google Scholar ] [ CrossRef ] [ PubMed ] Sato, T.; Terai, M.; Tamura, Y.; Alexeev, V.; Mastrangelo, M.J.; Selvan, S.R. Interleukin 10 in the tumor microenvironment: A target for anticancer immunotherapy. Immunol. Res. 2011 , 51 , 170–182. [ Google Scholar ] [ CrossRef ] [ PubMed ] Fisher, D.T.; Appenheimer, M.M.; Evans, S.S. The two faces of il-6 in the tumor microenvironment. Semin. Immunol. 2014 , 26 , 38–47. [ Google Scholar ] [ CrossRef ] Di Nicola, M.; Carlo-Stella, C.; Magni, M.; Milanesi, M.; Longoni, P.D.; Matteucci, P.; Grisanti, S.; Gianni, A.M. Human bone marrow stromal cells suppress t-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002 , 99 , 3838–3843. [ Google Scholar ] [ CrossRef ] Tse, W.T.; Pendleton, J.D.; Beyer, W.M.; Egalka, M.C.; Guinan, E.C. Suppression of allogeneic t-cell proliferation by human marrow stromal cells: Implications in transplantation. Transplantation 2003 , 75 , 389–397. [ Google Scholar ] [ CrossRef ] Rasmusson, I.; Ringden, O.; Sundberg, B.; Le Blanc, K. Mesenchymal stem cells inhibit the formation of cytotoxic t lymphocytes, but not activated cytotoxic t lymphocytes or natural killer cells. Transplantation 2003 , 76 , 1208–1213. [ Google Scholar ] [ CrossRef ] Groh, M.E.; Maitra, B.; Szekely, E.; Koc, O.N. Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive t cells. Exp. Hematol. 2005 , 33 , 928–934. [ Google Scholar ] [ CrossRef ] [ PubMed ] Corcione, A.; Benvenuto, F.; Ferretti, E.; Giunti, D.; Cappiello, V.; Cazzanti, F.; Risso, M.; Gualandi, F.; Mancardi, G.L.; Pistoia, V.; et al. Human mesenchymal stem cells modulate b-cell functions. Blood 2006 , 107 , 367–372. [ Google Scholar ] [ CrossRef ] [ PubMed ] Quatromoni, J.G.; Eruslanov, E. Tumor-associated macrophages: Function, phenotype, and link to prognosis in human lung cancer. Am. J. Transl. Res. 2012 , 4 , 376–389. [ Google Scholar ] [ PubMed ] De Palma, M.; Lewis, C.E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 2013 , 23 , 277–286. [ Google Scholar ] [ CrossRef ] [ PubMed ] Toes, R.E.; Ossendorp, F.; Offringa, R.; Melief, C.J. Cd4 t cells and their role in antitumor immune responses. J. Exp. Med. 1999 , 189 , 753–756. [ Google Scholar ] [ CrossRef ] [ PubMed ] Buechler, C.; Ritter, M.; Orso, E.; Langmann, T.; Klucken, J.; Schmitz, G. Regulation of scavenger receptor cd163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J. Leukoc. Biol. 2000 , 67 , 97–103. [ Google Scholar ] [ CrossRef ] [ PubMed ] Heusinkveld, M.; de Vos van Steenwijk, P.J.; Goedemans, R.; Ramwadhdoebe, T.H.; Gorter, A.; Welters, M.J.; van Hall, T.; van der Burg, S.H. M2 macrophages induced by prostaglandin e2 and il-6 from cervical carcinoma are switched to activated m1 macrophages by cd4 + th1 cells. J. Immunol. 2011 , 187 , 1157–1165. [ Google Scholar ] [ CrossRef ] Figure 1. M1 macrophage culture system. Untreated control experiment consisted of M1 macrophages cultured on a surface of 6-well culture plate in a medium containing GM-CSF, CMDBMSC experiment consisted of M1 macrophages cultured on a surface of 6-well culture plate in a medium containing GM-CSF and CMDBMSC (conditioned medium), SFDBMSC (soluble factor), and ICDBMSC (intercellular direct contact) experiments. In SFDBMSC and ICDBMSC experiment, cells (DBMSCs and monocytes) were separated by transwell chamber membrane culture system. For the experiments of SFDBMSC, DBMSCs were seeded on the upper compartments while monocytes were seeded in the lower compartment. For the experiments of ICDBMSC, DBMSCs were seeded on the reverse side of the membrane while monocytes were seeded on the upper side of the membrane. GM-CSF medium was added to SFDBMSC and ICDBMSC experiments. Effects of human DBMSCs on the morphology of human monocytes differentiated into macrophages by GM-CSF. ( A – F ) Represent phase-contrast microscopic images showing monocyte (round-shaped morphology) differentiation into M1-like macrophages (fried egg-shaped morphology) after six days of culture in a medium containing GM-CSF ( A ), in a medium containing GM-CSF and DBMSCs at a 20:1 monocyte: DBMSC ratio ( B ), at a 10:1 monocyte: DBMSC ratio ( C ), at a 1:1 monocyte: DBMSC ratio ( D ), in the presence of 10% CMDBMSC ( E ), or in the presence of 20% CMDBMSC ( F ). ( G – K ) Representative phase-contrast microscopic images showing monocyte-like cells after six days of culture in a medium containing GM-CSF and 30% CMDBMSC ( G ), 40% CMDBMSC ( H ), 50% CMDBMSC ( I ), 60% CMDBMSC ( J ), 80% CMDBMSC ( K ), or 100% CMDBMSC ( L ). Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. Scale bars represent 50 µm. Figure 2. Effects of human DBMSCs on the expression of cell surface molecules CD14, CD163, CD204, CD206, CD36, and B7H4 on human monocytes differentiated into macrophages by GM-CSF, as analyzed by flow cytometry. After six days in culture, compared to untreated macrophages, CMDBMSCs significantly increased expression of CD14 ( A ) and CD163 ( B ) on macrophages while having no significant effect ( p > 0.05) on expression of CD204 ( C ), CD206 ( D ), CD36 ( E ), and B7H4 ( F ) on macrophages. Compared to untreated macrophages, SFDBMSC significantly increased expression of CD14 ( A ), CD163 ( B ), and CD206 ( D ) on macrophages while having no significant effects ( p > 0.05) on expression of CD204 ( C ), CD36 ( E ), and B7H4 ( F ) on macrophages. In addition, ICDBMSCs significantly decreased expression of CD163 ( B ), CD204 ( C ), CD206 ( D ) and CD36 ( E ) on macrophages while having no significant effects ( p > 0.05) on expression of CD14 ( A ) and B7H7 ( F ) compared with that on untreated macrophages. Levels of expression are presented as median fluorescent intensity (MFI) as determined by flow cytometry. Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. * p < 0.05. Bars represent standard errors. Figure 4. Effects of human DBMSCs on expression of the cell surface molecules HLADR, CD80, CD86, CD273, and CD274 by human monocytes differentiated into macrophages by GM-CSF, as analyzed by flow cytometry. After six days in culture, compared to untreated macrophages, CMDBMSCs and SFDBMSCs had no significant effects ( p > 0.05) on expression of HLA-DR ( A ), CD80 ( B ), CD273 ( D ), and CD274 ( E ) on macrophages while significantly decreasing expression of CD86 ( C ). Compared to untreated macrophages, ICDBMSCs had no significant effects ( p > 0.05) on expression of HLA-DR ( A ) and CD80 ( B ) on macrophages while significantly decreasing expression of CD86 ( C ), CD273 ( D ), and CD274 ( E ) on macrophages. Levels of expression are presented as median fluorescent intensity (MFI) as determined by flow cytometry. Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. * p < 0.05. Bars represent standard errors. Figure 5. Effects of human DBMSCs on expression of the intracellular cytokines IL-1β, IL-6, IL-8, IL-12, IFN-γ, and TNF-α by human monocytes differentiated into macrophages by GM-CSF, as analyzed by flow cytometry. After six days in culture, compared to untreated macrophages, CMDBMSCs significantly decreased expression of IL-1β ( A ) by macrophages while having no significant effects ( p > 0.05) on expression of IL-6 ( B ), IL-8 ( C ), IL-12 ( D ), IFN-γ ( E ), and TNF-α ( F ) by macrophages. Compared to untreated macrophages, SFDBMSCs significantly decreased expression of IL-1β ( A ) and IL-12 ( D ) while having no significant effects ( p > 0.05) on expression of IL-6 ( B ), IL-8 ( C ), and TNF-α ( F ), but significantly increasing expression of IFN-γ ( E ) by macrophages. In addition, compared to untreated macrophages, ICDBMSCs significantly increased expression of IL-1β ( A ), IFN-γ ( E ), and TNF-α ( F ) while decreasing IL-6 ( B ) and IL-12 ( D ), but having no significant effects ( p > 0.05) on expression of IL-8 ( C ) by macrophages. Levels of expression are presented as median fluorescent intensity (MFI) as determined by flow cytometry. Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. * p < 0.05. Bars represent standard errors. Figure 6. Effects of human DBMSCs on expression of the intracellular molecules IDO, TGFβ1, TGFβ1, 2, 3, and HMOX-1 by human monocytes differentiated into macrophages by GM-CSF, as analyzed by flow cytometry. After six days in culture, compared to untreated macrophages, CMDBMSCs, and SFDBMSCs had no significant effects ( p > 0.05) on expression of IDO ( A ), TGFβ1 ( B ), TGFβ1, 2, 3 ( C ), and HMOX-1 ( D ) by macrophages. In addition, after six days in culture, compared to untreated macrophages, ICDBMSCs significantly decreased expression by macrophages of IDO ( A ) while having no significant effects ( p > 0.05) on expression of TGFβ1 ( B ), TGFβ1, 2, 3 ( C ), and HMOX-1 ( D ). Levels of expression are presented as median fluorescent intensity (MFI) or median percentage of HMOX-1 positive cells as determined by flow cytometry. Experiments were carried out in duplicate and repeated 30 times using 30 individual preparations of both monocyte-derived macrophages and DBMSCs. * p < 0.05. Bars represent standard errors. Figure 7. Effects of DBMSCs on GM-CSF–stimulated human monocyte-to-macrophage differentiation, as analyzed by the secretion of IL-1β, IL-6, IL-10, and IL-12 using sandwich ELISA. CMDBMSCs had no significant effect ( p > 0.05) on the secretion profiles of IL-1β ( A ), significantly increased (* p < 0.05) the secretion profiles of IL-6 ( B ) and IL-10 ( C ), and had no significant effect ( p > 0.05) on the secretion profiles of IL-12 ( D ) of macrophages. In addition, SFDBMSCs had no significant effect ( p > 0.05) on the secretion profiles of IL-1β ( A ), significantly increased (* p < 0.05) the secretion profiles of IL-6 ( B ) and had no significant effect ( p > 0.05) on the secretion profiles of IL-10 ( C ) and IL-12 ( D ). Moreover, ICDBMSCs had no significant effect ( p > 0.05) on the secretion profiles of IL-1β ( A ), significantly increased (* p < 0.05) the secretion profiles of IL-6 ( B ), significantly decreased (* p < 0.05) the secretion profiles of IL-10 ( C ), and had no significant effect ( p > 0.05) on the secretion profiles of IL-12 ( D ). Experiments were carried out in duplicate and repeated 10 times using 10 individual preparations of both monocyte-derived macrophages and DBMSCs. Bars represent standard errors. Figure 8. Functional assay of the phagocytic activity of monocytes differentiated into macrophages by GM-CSF in the presence of human DBMSCs. Phagocytosed Zymosan particles were measured by reading the optical density at 405 nm. Phagocytosis of Zymosan particles by macrophages was not significantly affected by DBMSC treatments compared to macrophages cultured alone. Experiments were carried out in duplicate and repeated 10 times using 10 individual preparations of both monocyte-derived macrophages and DBMSCs. Bars represent standard errors. Figure 9. T cell proliferation by M1-like macrophages (M1) generated in the presence of DBMSCs. After culturing M1 alone or with CMDBMSC (CMM1), SFDBMSC (SFM1), and ICDBMSC (ICM1), M1 were harvested and added to allogeneic CD4 + T cells at 5:1, 10:1, and 20:1 T cells:M1 (M1, CMM1, SFM1, and ICM1) ratios. M1 pre-treated with DBMSCs (CMM1, SFM1, and ICM1) or without (M1) significantly increased T cell proliferation at all indicated ratios. Similarly, ICM1 significantly increased T cell proliferation at all indicated ratios compared to that with M1, while SFM1 significantly increased T cell proliferation at the 5:1 T cells: SFM1 ratio compared to that with M1. By contrast, CMM1 significantly decreased T cell proliferation at the 10:1 and 20: 1 T cells: CMM1 ratios compared to that with M1 ( A ). In addition, the secretion of IL-10 by T cells stimulated with M1, CMM1, SFM1, and ICM1 was significantly reduced ( B ), while the secretion of IL-12 and IFN-γ was significantly increased, p < 0.05 ( C and D ). Experiments were carried out in triplicate and repeated 10 times using 10 individual preparations of T cells and macrophages harvested from 10 individual experiments of macrophages cultured with DBMSCs (CMDBMSC, SFDBMSC, and ICDBMSC). * p < 0.05, Bars represent standard error. Table 1. Markers used in this study. Macrophage Markers Costimulatory and HLA Molecules Inflammatory Molecules Anti-inflammatory Molecules CD14 CD40 IL-1β IDO CD11b CD80 IL-6 TGFβ1 CD36 CD86 IL-8 TGFβ1, 2, 3 CD163 CD273 IL-12 HMOX-1 CD204 CD274 IFN-γ CD206 HLA-DR TNF-α B7-H4 Table 2. DBMSC (CMDBMSC, SFDBMSC, and ICDBMSC) effects on macrophage expression of different functional markers, costimulatory molecules, co-inhibitory molecules, antigen presenting molecule, inflammatory cytokines, and anti-inflammatory markers as compared to untreated macrophages by flow cytometry recorded by mean of fluorescent intensity (MFI). Increased (↑, p < 0.05), decreased (↓, p < 0.05)), and no change ( p > 0.05). Markers Types CMDBMSC SFDBMSC ICDBMSC Markers Types CMDBMSC SFDBMSC ICDBMSC CD14 Functional Markers ↑ ↑ No Change IDO Anti-inflammatory Markers No Change No Change ↓ CD163 ↑ ↑ ↓ TGFβ1 No Change No Change No Change CD204 No Change No Change ↓ TGFβ1, 2, 3 No Change No Change No Change CD206 No Change ↑ ↓ HMOX-1 No Change No Change No Change CD36 No Change No Change ↓ B7H4 No Change No Change No Change CD80 Costimulatory Molecules No Change No Change No Change CD86 ↓ ↓ ↓ CD273 Co-Inhibitory Molecules No Change No Change ↓ CD274 No Change No Change ↓ HLA-DR Antigen Presenting Molecule No Change No Change No Change IL-1β Inflammatory Cytokines ↓ ↓ ↑ IL-6 No Change No Change ↓ IL-8 No Change No Change No Change IL-12 No Change ↓ ↓ IFN-γ No Change ↑ ↑ TNF-α No Change No Change ↑ Table 3. DBMSC (CMDBMSC, SFDBMSC, and ICDBMSC) effects on macrophage secretion of inflammatory and anti-inflammatory cytokines as compared to untreated macrophages by ELISA. Increased (↑) and decreased (↓). Markers Type CMDBMSC SFDBMSC ICDBMSC IL-1β Inflammatory Cytokines No Change No Change No Change IL-6 ↑ ↑ ↑ IL-10 ↑ No Change ↓ IL-12 Anti-inflammatory Cytokine No Change No Change No Change Table 4. DBMSC (CMDBMSC, SFDBMSC, and ICDBMSC) effects on macrophage stimulatory effects on T cell proliferation and secretion of inflammatory and anti-inflammatory cytokines as compared to untreated T cells measured by ELISA. Increased (↑) and decreased (↓). Markers Type CM1 CMM1 SFM1 ICM1 IL-12 Inflammatory Cytokine ↑ ↑ ↑ ↑ IFN-γ IL-10 Anti-inflammatory Cytokine ↓ ↓ ↓ ↓ MDPI and ACS Style Abumaree, M.H.; Al Harthy, S.; Al Subayyil, A.M.; Alshabibi, M.A.; Abomaray, F.M.; Khatlani, T.; Kalionis, B.; El- Muzaini, M.F.; Al Jumah, M.A.; Jawdat, D.; Alawad, A.O.; AlAskar, A.S. Decidua Basalis Mesenchymal Stem Cells Favor Inflammatory M1 Macrophage Differentiation In Vitro. Cells 2019, 8, 173. https://doi.org/10.3390/cells8020173 AMA Style Abumaree MH, Al Harthy S, Al Subayyil AM, Alshabibi MA, Abomaray FM, Khatlani T, Kalionis B, El- Muzaini MF, Al Jumah MA, Jawdat D, Alawad AO, AlAskar AS. Decidua Basalis Mesenchymal Stem Cells Favor Inflammatory M1 Macrophage Differentiation In Vitro. Cells. 2019; 8(2):173. https://doi.org/10.3390/cells8020173 Chicago/Turabian Style Abumaree, Mohamed H., Seham Al Harthy, Abdullah M. Al Subayyil, Manal A. Alshabibi, Fawaz M. Abomaray, Tanvier Khatlani, Bill Kalionis, Mohammed F. El- Muzaini, Mohammed A. Al Jumah, Dunia Jawdat, Abdullah O. Alawad, and Ahmed S. AlAskar. 2019. "Decidua Basalis Mesenchymal Stem Cells Favor Inflammatory M1 Macrophage Differentiation In Vitro" Cells8, no. 2: 173. https://doi.org/10.3390/cells8020173 Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here . Article Metrics MDPI and ACS Style
https://www.mdpi.com/2073-4409/8/2/173/htm
DNA Testing & General Genetics [Archive] - Eupedia Forum [Archive] Origin of human was an African European Haplogroups DNA tests for genealogy, any good ? Iceland is only half Scandinavian France: an unexplored paradise for geneticists Haplogroups of European kings and queens explanation please to those questions Founder effect European Admixture: Y-DNA and MtDNA linking haplogroups to tribes Where do the Cro-Magon 's descendants live now? Share your DNA with the world Maciamo please help! Review of the evolution of migration theories in European prehistory False study ?? What do you think Y-DNA correspondence for mtDNA haplogroups African mtDNA and Y-DNA in Iberia maciamo what haplogroups would maltese peoples have? Basque What's the origins of the Pasiegos and the Cantabrians ? Origin of the Libyans Orcadians related to Siberians? Why it is wrong to assume that a haplogroup originated where it is most frequent now Do you care about finding distant cousins ? Circassians Croatian genetics With what ancient ethnicity do you most identify, and what has DNA told you ? Origins of European haplogroups haplogroups and peoples origin of Celtic and Germanic tribes Genetics Section of Eupedia The Results are in for Ozzy Osborne's DNA. Genetic make up of the British Isles Were the Aryan who ruled the Mitanni the same as those of India ? The Laz Alexander the great French Ethnicity Northern & Southern Azerbaijanian Haplogroups? Amerindian dna in ethnic norwegians. Genetics and Anthropology of Indian Brahmins- presenting a theory. Does anyone know what haplogroup cromagnons where Requests HowTo create DNA-Maps, Haplo-Trees Software guess the haplogroups of famous people ICHG 2011 abstracts are online An urgent question of my dna!!!!! Nuristani DNA studies? Modern Assyrians (split from "Were the Aryan who ruled the Mitanni"...) influence of demography, timing and founder effects on HG repartitions African American Y-DNA & mtDNA Haplogroup Breakdown R1b domination in West Europe due to immunity for some diseases? Napoleon I Dr Alice Roberts What mtdna haplogroups emerged w/ y-dna haplogroup I in the mesolithc? the earlist Germanic Hello Question about Bulgarians and haplogroups! Can haplogroup G2 be associated with early Celtic tribes? The Battle of Hastings and Haplogroup Rb1-S21 and Rb1-S28 Does the Y-dna and mtDNA frequency distribution pages include recent immigration? Native Americans Hailed From Siberian Highlands, DNA Reveals How & why do SNPs and STR's change? haplogroups of historical and famous figures World Surname Profiler Austria's Y-haplo-groups. mtDNA Analysis Utility What do you think about? Your Haplogroup (are you pleased or disappointed with it?) Roman Emperor Y DNA Haplogroup Charts What ethnic groups have the least amount of Neanderthal genetic markers? High levels of Paleolithic Y-chromosome lineages characterize Serbia Scientists recover part of the genome of 2 hunter-gatherer individuals from 7,000 yea Is there anyway this guy is related to me? West asians vs Mediterranean neolithic farmers How much European Y DNA or MTDNA do you think was left in the Crusades? What percentage of ancestry is enough to make feel part of an ethnic group ? What percentage of ancestry is enough to make feel... OT @ the meaning of ethnicity Religious theory to genetics - ydna & mtdna New Study: Man Possibly NOT Related to Neanderthal Does Cparse/Dry Hair mean anything? It is a miracle any of us Haplogroup N1b The rise of PIEs in the steppes --- From the Ural or from the from the Caucasus? DNA has a 521-year half-life Carbon Dating Gets a Reset The North African Neandertal descendants Previously unknown human population boom revealed by DNA Understanding R1b: M42, M168, M89, P128, M45, M207, P231, M343 Howdy DNA from remains from Ireland? Huns, were they turkic, asian or indo european ? (OFFTOPIC from rise of PIEs in the steppes) Why no mtDna maps? Phylo-equivalency? Help for know my origins. How Old Prussian were the East Prussian Germans? Possible new cro magnon haplogroup? Haplogroup I in Finland Haplogroup I, is it European? New Findings on Neanderthal Admixture ( East Asians vs. Europeans ) Geno 2.0 Sale Understanding indo-european y-dna maternal haplogroup J1c neanderthal i haplogroup hunter gatherers paleoethic european Ancient Welsh DNA linked to local villager Jewish people, where they are from? All Europeans are related back to 1000 years ago. italian genetics Dutch genetics less homogeneous "populations" are Italians and French ? Middle to late Neolithic 6,625-4,025 year old mtDNA and Y DNA from German Rome spread Middle Eastern and North African Y DNA Native Americans come from one Family that migrated to America 20,000-30,000ybp STUNNING DNA EVIDENCE Caucasians migrated to North America 15,000-20,000ybp Early Indo Iranien remains Y DNA, mtDNA, hair color and eye color DNA has possibly found Europeans long lost brothers New member's mtDNA and Y-DNA haplogroup inquires Ordering a DNA test in France is a crime punishable by heavy fines and jail time Physical differences, same haplogroup Haplogroups of the world Alpine genetic papers WTY - Walk The Y-Chromosome WHAT? Azeris are 5 - 29% Mongoloid? is this true? Supposedly Euro pale skin genes, almost as popular in Mid east and North Africa Origin and ancient history of red hair British ancestry almost all from Celtic and Germanic Conqueres Hello everyone A quick intro and a hello Is distinctive DNA marker proof of ancient genocide? Volga Tatars are predominantly Caucasoid Auvergne genetic history Can Scientific And Engineering Success Be Attributed To One Grioup? Your Opnion. Which city states in east balkans had the most I2.. Haplogroup during Hellenistic age Haplogroup P-M45 link to Mound Building? england haplogroups link between Black Sea flooding and haplogroup G2a ? I Need Your Advise Automosal DNA test conflicting one another? A paternity puzzle... Hapolgroup origins - individuals What is a PCA plot really? Are Uralic language speakers more closely related to Altaic speakers than Europeans? Funny DNA Result. Why isn't "A" the most common y-DNA haplogroup? 9th Annual International Conference on Genetic Genealogy Mal'ta boy had autosomal genes present in populations with Y-haplogroups M, P, Q & R Did agriculture develop thanks to the original carriers of macro Y-haplogroup K ? Sima de los Huesos – Atapuerca Baffling 400,000-Year-Old Clue to Human Origins Correlating haplogroups with ancient admixture Correlating the mtDNA haplogroups of the original Y-haplogroup J1 and T1 herders Retracing the mtDNA haplogroups of the original R1b people SLC24A5 light skin pigmentation allele origin Rosses and Y-DNA Haplogroups New paper on Italian DNA 2014 Iberian searching Iberian Getting more from genetic testing What should population geneticists at universities be researching? My recommendations Postive for both R1a and R1b? Early Iberians in mexico and california Hello from Michigan Speculative Southern European ancestry on 23andme King Erik the Holy, unearthed and to have his DNA tested Please help this is my Y-DNA - Standard Y-STR Values and thats all I know. THANKS Roman Descent in South Germany? Greeks have no brothers in Europe New global analysis of Y-chromosomal haplotype 2014 Fallmerayer was wrong ... The Science of Blonde Hair Which DNA studies are reliable and which ones aren't? DNA from the Bronze Age Altai reveals signs of ancient admixture Proposed Y-dna marker changes Makin a map of EEF, WHG and ANE admixtures in Europe. Please post your data. The Mediterranean route into Europe (Paschou et al. 2014) New study claims that Irishmen descended from Turkish farmers ancient Adriatic cave findings swiss genetics Doubts about J2, G and E3b Bell Beaker As Intrusive Population Missing H ydna What is the DNA of the indegenous Basque people? What is the DNA of the indegenous Saami people? Anyone else here mtDNA H1j8? The Huns Study on Muslim & Christian Balkan people Hessian genetics Japanese genetics revised EEF-WHG-ANE AIMs Overestimate Admixture Kelteminar culture >> Pit–Comb Ware culture,,, which haplogroup did they had? Genetic history of the Iberian Peninsula Ancient DNA from Hungary-Christine Gamba et al Heritability Hello, and some info and questions Is Haplogroup C6 in australoid ? found in La brana australoid Structure of Ydna December 2014 Genetic Admixture Tools? Europe, West- and South_Central Asia and the unnatural gap.. Frequency of blood type O throughout the world will old age stop human evolution? Can this Iraqi lady pass in Greece? What haplo was among people of Keltiminar and among people of Pit-Comb ware cultures? Scytho-Sarmatian and Alan DNA in todays European population. Genetic history of the British Isles Post what haplogroups you think i am? Flemish DNA Are Balkanites the purest Slavs? Lombards on the move - austria/hungaria 23andme and FtDNA age estimates by YFull Origins of the Armenians during the Bronze Age Central italian ancient genetics Mesolithic source of Pale pigmentation in modern Europe? How to achieve info on genetic past further continuation of Haak paper 2015 Rh minus Haplogroup F bottleneck could have happened in SE Asia P haplogroup - The father of YDN q and R groups British origins Haplogroup G1 rare and interesting Was the teal admixture of Yamna brought to the steppe by Y-haplogroup G1 ? Y DNA Haplogroups associated with MtDNA Haplogroups P haplogroup - The father of YDN Q and R groups Slavs and Plague neanderthal admixture in Europe Expansion of European patrilineages DNA of Iberians from Europe New human ancestor species from Ethiopia Germany/ Anti-Communist/ Religion Genetic prehistory of domesticated cattle similar to People migration Very advanced Indoeuropeans - cows reveal their history! :-) Global counting of hg Northern-Centrism: Just Stop It!! New paper on E - early pastoralists in the African continent Neolithic western Carpathian Basin - 356 pages Indo european hypothesis Lionel Andrés Messi Cuccittini - Ydna G2a holmesr923 Effect of Neolithic Farmers on modern European population? Genetic signatures of the Hellenic colonisation in southern Italy and Sicily In what does iberia set apart from other countries in europe? Tuscany had a middle age admixture event? New (July 3, 2015) Allentoft and Haak Analysis Comparison of DNA The hidden Americans Faces of Real Arabs from Arabian peninsula ( Arabian Gulf People ) Arabs from Bilad Al-Sham - Shami Levantine Arabs North Italy - Rovigo Powered by vBulletin® Version 4.2.5 Copyright © 2023 vBulletin Solutions Inc. All rights reserved.
https://www.eupedia.com/forum/archive/index.php/f-219.html?s=922dc120372fbe4ee404bead701ee169
RCSB PDB - 7BYN: Cryo-EM structure of human KCNQ4 with linopirdine Cryo-EM structure of human KCNQ4 with linopirdine 7BYN Cryo-EM structure of human KCNQ4 with linopirdine PDB DOI: https://doi.org/10.2210/pdb7BYN/pdb EM Map EMD-30246: EMDB EMDataResource Classification: MEMBRANE PROTEIN Organism(s): Aequorea victoria , Homo sapiens Expression System: Homo sapiens Mutation(s): Yes Membrane Protein: Yes OPM PDBTM MemProtMD mpstruc Deposited: 2020-04-23 Released: 2020-12-02 Deposition Author(s): Shen, H. , Li, T. , Yue, Z. Experimental Data Snapshot Method: ELECTRON MICROSCOPY Aggregation State: PARTICLE Reconstruction Method: SINGLE PARTICLE Literature Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs. Li, T. , Wu, K. , Yue, Z. , Wang, Y. , Zhang, F. , Shen, H. (2021) Mol Cell81: 25 PubMed : 33238160 Search on PubMed DOI: https://doi.org/10.1016/j.molcel.2020.10.037 Primary Citation of Related Structures: 7BYL , 7BYM , 7BYN PubMed Abstract: Among the five KCNQ channels, also known as the K v7 voltage-gated potassium (K v) channels, KCNQ2-KCNQ5 control neuronal excitability. Dysfunctions of KCNQ2-KCNQ5 are associated with neurological disorders such as epilepsy, deafness, and neuropathic pain ... Among the five KCNQ channels, also known as the K v7 voltage-gated potassium (K v) channels, KCNQ2-KCNQ5 control neuronal excitability. Dysfunctions of KCNQ2-KCNQ5 are associated with neurological disorders such as epilepsy, deafness, and neuropathic pain. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 and its complexes with the opener retigabine or the blocker linopirdine at overall resolutions of 2.5, 3.1, and 3.3 Å, respectively. In all structures, a phosphatidylinositol 4,5-bisphosphate (PIP 2) molecule inserts its head group into a cavity within each voltage-sensing domain (VSD), revealing an unobserved binding mode for PIP 2. Retigabine nestles in each fenestration, inducing local shifts. Instead of staying within the central pore, linopirdine resides in a cytosolic cavity underneath the inner gate. Electrophysiological analyses of various mutants corroborated the structural observations. Our studies reveal the molecular basis for the modulatory mechanism of neuronal KCNQ channels and provide a framework for structure-facilitated drug discovery targeting these important channels. Organizational Affiliation : Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China. Electronic address: [email protected]. Macromolecules 100% 95% 90% 80% 70% 60% 50% 40% 30% (by identity cutoff)  | 3D Structure (by identity cutoff)  | 3D Structure Entity ID: 2 Molecule Chains Sequence Length Organism Details Image Calmodulin-3 E [auth B] , F [auth D] , G [auth F] , H 149 Homo sapiens Mutation(s) : 0 Gene Names: CALM3 , CALML2 , CAM3 , CAMC , CAMIII UniProt & NIH Common Fund Data Resources Find proteins for P0DP25 (Homo sapiens) Explore P0DP25 Go to UniProtKB: P0DP25 PHAROS: P0DP25 Entity Groups Sequence Clusters 30% Identity 50% Identity 70% Identity 90% Identity 95% Identity 100% Identity UniProt Group P0DP25 Protein Feature View Expand Reference Sequence Small Molecules Ligands 3 Unique ID Chains Name / Formula / InChI Key 2D Diagram 3D Interactions PT5 (Subject of Investigation/LOI) Query on PT5 Download Ideal Coordinates CCD File Download Instance Coordinates SDF format, chain I [auth A] SDF format, chain M [auth C] SDF format, chain P [auth G] SDF format, chain O [auth E] MOL2 format, chain I [auth A] MOL2 format, chain M [auth C] MOL2 format, chain P [auth G] MOL2 format, chain O [auth E] I [auth A], M [auth C], O [auth E], P [auth G] [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate C 47 H 85 O 19 P 3 CNWINRVXAYPOMW-HJBQCNPJSA-N Ligand Interaction FCC (Subject of Investigation/LOI) Query on FCC Download Ideal Coordinates CCD File Download Instance Coordinates SDF format, chain N [auth C] MOL2 format, chain N [auth C] N [auth C] 1-phenyl-3,3-bis(pyridin-4-ylmethyl)indol-2-one C 26 H 21 N 3 O YEJCDKJIEMIWRQ-UHFFFAOYSA-N Ligand Interaction K Query on K Download Ideal Coordinates CCD File Download Instance Coordinates SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain L [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] J [auth A], K [auth A], L [auth A] POTASSIUM ION K NPYPAHLBTDXSSS-UHFFFAOYSA-N Ligand Interaction Experimental Data & Validation Experimental Data Method: ELECTRON MICROSCOPY Resolution: 3.30 Å Aggregation State: PARTICLE Reconstruction Method: SINGLE PARTICLE Structure Validation Entry History Deposition Data Released Date: 2020-12-02 Deposition Author(s): Shen, H. , Li, T. , Yue, Z. Revision History (Full details and data files) Version 1.0: 2020-12-02 Type: Initial release Version 1.1: 2020-12-09 Changes: Database references Version 1.2: 2021-01-27 Changes: Database references Usage & Privacy
https://www.rcsb.org/structure/7byn