Mucoceles are slow-growing paranasal sinus cystic masses whose clinical presentation varies according to the affected sinus. Diagnosis is often radiological, based essentially on CT scan. The aim of this work was to study the radiologic characteristics of mucoceles on CT scan and MRI. We conducted a retrospective study of patients with mucoceles explored by imaging and operated on in our department. In our series, fronto-ethmoidal sinuses were the most frequently affected (81%). Facial scan confirmed the diagnosis in the majority of cases. Magnetic resonance imaging (MRI) was performed in 4 cases. Eleven patients were operated on by endonasal approach, three by external approach and one by combined surgical approach. Recurrence was observed in two patients after an average delay of 24 months. CT scan is considered the method of choice in the investigation of mucoceles. MRI is indicated in some cases to assess any orbital or intracranial extension. Mucoceles are benign pseudo cystic, expansive, slow-growing paranasal sinus lesions, developed at the expense of sinus cavities and lined with an epithelium generally containing aseptic mucus ,2. DespiWe retrospectively analyzed the medical records of all patients whose were clinically and radiologically diagnosed with nasal sinus mucoceles and subsequently operated on in the ENT and Cervicofacial Surgery Department of Fattouma Bourguiba University Hospital in Monastir between January 2000 and December 2016.Our study included 16 patients with nasal sinus mucoceles. The patients' mean age was 47 years (extremes: 15 and 83 years). The sex ratio was 1.14. Two patients (13%) had a history of rhino-sinus surgery . Two patients reported a history of craniofacial trauma. One patient had chronic non-operated rhinosinusitis. The average consultation time was 16 months (1 month-84 months). The circumstances of discovery were varied. The essential mode of revelation was exophthalmia in 50% of cases . RhinoloMucocele is a benign and expansive pseudo cystic slow-growing paranasal sinus formation, developed at the expense of sinus cavities and lined with an epithelium generally containing aseptic mucus ,2. The tThe endo-orbital extension is often extraconic, On the CT it can be translated by a repression of the eyeball downwards, a repression of the internal and/or oblique rectus muscle. Sometimes, extrinsic compression of the lacrimal ducts is observed due to the mucocele protruding from the ethmoidal bulla . In our It respects the functional properties of the rhino-sinus mucosa, thus limiting the complications, the morbidity and the duration of hospitalization associated with the external surgery . HoweverSinonasal mucoceles are relatively rare benign pseudocystic lesions, with insidious evolution. Clinic suspicion of a mucocele is confirmed by tomodensitometry. CT scan is the first-line examination to conduct in case of clinical or endoscopic suspicion of a mucocele. MRI is indicated in cases of diagnostic doubt between a mucocele and other tumoral or inflammatory lesions or in case of intraorbital or intracranial extension and sphenoidal location.The increasing incidence of secondary sinonasal mucoceles;Despite their benign histological nature, sinonasal mucoceles can be potentially aggressive towards orbit and encephalon;The diagnosis is often radiological, based essentially on CT scan.The aim of this work was to study the contribution of imaging in the management of sinonasal mucoceles Facial scan is the first-line examination to be performed in case of clinical or endoscopic suspicion of mucocele;MRI to assess the relationship of the mucocele with meninges and orbital structure. These two exams are complementary for the management of sinonasal mucoceles.The authors declare no competing interests.


Various nanoscale fabrication techniques are elaborated to form artificial nanoporous/nanochannel membranes to be applied for biosensing: one of the most prevalent is the micro-electromechanical systems (MEMS) compatible focused ion beam (FIB) milling. This technique can be easily adopted in micro- and nanomachining process sequences to develop composite multi-pore structures, although its precision and reproducibility are key points in the case of these thick multi-layered membranes. This work is to demonstrate a comprehensive characterisation of FIB milling to improve the reliability of the fabrication of solid state nanopore arrays with precisely predetermined pore geometries for a targeted molecule type to be recognised. The statistical geometric features of the fabricated nanopores were recorded as the function of the process parameters, and the resulting geometries were analysed in detail by high resolution scanning electron microscope (SEM), transmission electron microscope (TEM) and ion scanning microscopy. Continuous function of the pore diameter evolution rate was derived from the experimental results in the case of different material structures, and compared to former dissentient estimations. The additional metal layer was deposited onto the backside of the membrane and grounded during the ion milling to prevent the electrical charging of dielectric layers. The study proved that the conformity of the pore geometry and the reliability of their fabrication could be improved significantly. The applicability of the developed nanopore arrays for molecule detection was also considered by characterising the pore diameter dependent sensitivity of the membrane impedance modulation based measurement method. Compared to the macroscopic case, self-confined nanoscale structures exhibit significantly different chemical and transport behaviours. The understanding of the involved chemical and physical phenomena opens the way to explore the “world of nanofluidics” , and to Regarding biosensor development, the application of microfluidic systems for liquid sample management, including particle separation, reagent mixing, transport, etc., is essential . By decrPermselectivity induces asymmetric pressure or electric field driven molecule transport through the nanochannels or nanopores.Size dependent transpore permeation of molecules is caused by the “Born repulsion” evolved due to the electrical interaction between the overlapping electron clouds of translocating molecules and atoms of the pore surface.Reconfiguration of macromolecules can also be experienced (in the case of deoxyribonucleic acid (DNA) chains) due to the entropic barrier conditions.The special effects revealed in the nanoconfinements are :PermseleConsidering dimension-dependent transport in the nanochannels, the pressure driven flow rates scale inversely to the channel cross section, contrary to the electroosmotic and electrophoretic flows.Development of robust and engineered fabrication techniques for reproducible nanostructure formation.Clarification the comprehensive theory and construction predictive modelling of nanoscale transport phenomena.Precise control and in-situ monitoring of physical or chemical parameters  inside the nanopores.The most relevant envisioned applications of nanofluidic systems range from molecule separation (both concentration and accumulation), molecule detection, to drug release and delivery, but 3rd generation DNA sequencing may also be one of the important fields utilising these structures. Concerning the widespread applications of nanofluidic structures, there are also several challenges to master. The main obstacles are ,4:DeveloOn the other hand, focusing on molecule recognition or concentration detection, the following strengths of nanofluidic structures should be underlined: the possibility of label-free, specific molecule (or single molecule) detection with extreme sensitivity and the transport modulation-based built-in amplification by nanoconfinement in nanopores, as discussed by Gyurcsányi .Two main molecule sensing principles based on the ionic current modulation are visualized in Biological nanoporous layers are mainly based on pore-forming transmembrane proteins embedded in lipid bilayer membranes.Hybrid type nanopore membranes consist of similar biological pore-forming molecules integrated in synthetic layers.Artificial nanopore structures are fabricated by dedicated nanoprocessing methods in synthetic materials, polymer, glass, quartz or dielectric layers compatible with silicon technology , or 2D materials .Extremely sensitive label free detection method can be achieved by monitoring pore-through transport modulated by translocation or binding of the target molecules in nanopores. The sensitivity of these mainly electrochemical (bio)sensors are determined not only by the biofuncionalisation but affected by the pore geometry also: it must be aligned to the size and conformation of the target molecule. Moreover, the comparability and repeatability of the measurements assumes similar pore parameters in case of different devices. Accordingly, the practical applicability and potential commercialisation of these nanopore membrane based devices depend on the successful elaboration of controllable and reproducible pore fabrication techniques. Generally, three typical nanopore membrane structures can be defined regarding their membrane materials and nanopore formation methods ,16,17:BiThe applicability of the biological nanopores or nanochannels for transport modulation based molecule recognition and counting was demonstrated extensively. Their main advantages are the self-controlled size and shape, and the favorable costs. It can be noticed that the limited geometrical and material variability, the uncertain integrability and the moderate resistivity of the biological structures against pH, ion concentration, temperature, mechanical stress, etc. however, restrict their reliable applicability in diagnostic systems . A well-etching after e-beam lithography based patterning ,34,35,37+, Ar+, He2+, Xe+, etc.) milling [ion sculpturing or Focused Ion Beam  ,micromachining (MEMS based) techniques as nanochannel formation and subsequent sealing by bonding .Several high-tech solutions were described for more or less precise nanopore fabrication in the range from 2 nm to several tens of nanometres utilizing the capabilities of nanofabrication equipment as summarized in x membrane. [Attaining nanometer scale pore sizes is doubtless challenging, and to shrink the previously formed pores additional deposition techniques are required, like electrochemical or chemical vapour and atomic layer deposition ,39 or loembrane.  The evolThe key to the commercialization of nanopore based biosensors or Lab-on-a-Chip devices is the development of adequate nanoprocessing techniques ensuring fast, high-throughput, controllable and reproducible formation of the application specific nanopore geometries in differently structured solid state membranes . AdequatThe direct milling of complex composite membrane structures by focused electron or ion beams could be an obvious solution to fabricate nanopore arrays with the proposed geometries. Note, that in the case of thicker or composite membranes the precise fine-tuning of the pore size can be a critical point of the reliable and reproducible fabrication due to the beam-shape (defocusing), redeposition and charging of the dielectric membranes . Accordi+ ions with different milling currents and doses, in order to achieve various pore geometries in multi-layered membranes made of different dielectrics. The adopted structural and material combination has to be compatible to the proposed biofunctionalisation strategies (see Solid state nanopores were prepared by computer controlled Focused Ion Beam (FIB) milling using accelerated Gagies see .3)/dichlorosilane (H2Cl2Si) mixture (with 1:8 flow rate ratio) at 180 mTorr backpressure and temperature of 830 °C. Non-stoichiometric silicon-nitride films have moderate mechanical stress ensuring a adequate mechanical stability of the suspended membrane. The covering gold layer (150 nm) was deposited in the same cycle by vacuum evaporation atop of 5 nm of titanium adhesion layer in an AJA Orion high vacuum system. The dielectric membrane was released by wet alkaline (KOH at 72 °C) or Deep Reactive Ion Etching (DRIE) etching using the „Bosch-process”  from the backside, and then the nanopores were drilled by employing a program controlled Ga+ FIB drilling using the feature milling option of the Zeiss LEO 1540XB  nanofabrication system. The schematic representation of the pore fabrication process and the sample placement in cross-beam position under the FIB/SEM guns is shown in + ion energy.The structures were fabricated by the combination of micro- and nanomachining technologies. The dielectric membrane was a 300 nm thick non-stoichiometric silicon-nitride film prepared by Low Pressure Chemical Vapour Deposition  using ammonia (NH5H4CH3Pt(CH3)3) was injected as precursor from the Gas Injection System (GIS). Resulting pore diameters and the development of the pore shape during ion milling  had to be deduced.The pore geometries were characterised by SEM, TEM and ion scanning microscopy after cross sectioning by FIB . The nan+ ion current, milling time or ion dose). The pore diameters were in-situ analysed using scanning ion- and electron microscopy as the Ga+ ions and electrons passing through the pores precisely map the fabricated pores, as plotted in The obtained main structural parameters of the nanopores  were recorded and analysed as a function of different manufacturing conditions  evolution can be described by power-laws with the distinction of two time or dose regimes. The equation was originated in the frequently applied logarithmic relationship defined between the pore diameter and the ion dose (D) in [tp was defined as perforation time indicating the transfixion event during the ion milling (when the ion beam is punching through the membrane). Parameter γ determines the pore evolution rate, which was found to change during the process. These parameters (tp and γ) are complexly influenced by the ion beam properties  and the properties of the layer structure .The time or dose dependent pore diameter (e (D) in ,51: log and focal plane setup of the focused ion beam.Therefore, a continuously decreasing pore diameter evolution rate is suggested, as the function of the milling time (or incident ion dose), instead of stationary rate regimes. The obtained function in The evolution of the pore shape during the milling process is demonstrated by the cross-sectional SEM views of the nanopores fabricated by different incident ion doses in x membrane from the direction of the dielectric layer. As pore diameter, the diameter of the hole obtained on the rare side of the membrane is defined. The evolution rate of the pore diameter is almost doubled comparing the cases of application 5 pA and 10 pA milling currents with the same Ga+ ion energy (30 keV).The milling current also has a significant effect on the evolving pore geometry due to the ion dose dependency of the sputtering process. This is plotted in dout > 0), i.e., the extrapolated intersection of the pore diameter vs. milling time curve with the x-axis (tp) in tp = 0), the resulting pore diameter ratios were calculated as the function of milling time elapsed after the membrane perforated and illustrated in x and Au) will cause an additional spread in the results, certainly. The variation is larger in the case of thicker membranes in accordance with the time dependent pore diameter functions in For a realistic comparison of the pore-shape development in the cases of drilling membranes of different thickness with changing milling conditions, a reference time has to be defined. This is the time span required to perforate the membrane  to improve the reproducibility of the nanopore formation process. Gold layers are adequate for the further thiol chemistry based biofunctionalisation, so hereinafter this layer structure will be discussed. The variance of the pore diameter distribution in + ion beam according to From the point of view of reproducibility, achieving a highly conformal pore size distribution with given milling conditions is a real challenge. The formed pore geometry can be significantly distorted due to the charging of the dielectric membranes and the defocusing of the incident milling GaAccording to the analysis of more than 100 nanopores, discharging of the membrane layer during milling significantly reduced the spread in the pore geometry, as reflected by the narrow statistical pore size distributions in Rpa) were calculated from the results of Electrochemical Impedance Spectroscopy (EIS) using the built-in impedance models of the applied EIS300 software  (see the inset in Rpa0) and 10, 20 and 30 min after (Rpa) the sample injection and the relative change (Rpa/Rpa0) was calculated. The relative impedance variation values were averaged and plotted vs. nanopore diameter in To underline the cardinal importance of the precise nanoengineering, the pore size dependent sensitivity of the impedance based molecule sensing was studied ,53. Goldn is the number, L is the length and din and dout are the characteristic inlet and outlet diameters of pores, respectively. σs represents the specific conductivity of the electrolyte that fills the nanochannel. This theoretical consideration can estimate adequately the pore resistance as demonstrated in a preliminary work in case multi-layered nanoporous membranes, as demonstrated in [Rpa/Rpa0) of the nanopore array, homogeneous monomolecular coverage of the gold surfaces was considered in the tapering (outlet) region of the pores, thus only the outlet diameter of the pore was decreased by the molecule size. The applied physical parameters for this estimation are summarised in The experimental pore array resistances were compared to the theoretical ones estimated as ,57:(3)Rprated in . To calcTo estimate the theoretical relative impedance change, the gold coated silicon-nitride membrane was modelled as two serially connected nanopore arrays. Contrary to the non-coated silicon-nitride layer, the pores formed in the gold layer can be easily functionalized. The resulting resistance variation is caused by the molecules having bonded in the golden pores, since the silicon-nitride layer exhibits a constant resistance . Accordingly, the comprehensive pore geometry engineering is essential for the reliable and reproducible manufacturing of integrable solid state nanopore arrays for molecule diagnostic devices. Respecting the need of mechanically robust structure and area selective functionalisation of the pore surfaces, a complex material structure and a precise pore fabrication technology has to be elaborated.+ ions. Based on the comprehensive characterization adequate milling parameters  could be defined to achieve a precise and predictable pore evolution in various membrane structure. The pore diameter variation can be reduced by avoiding to choose the time/current parameters close to the membrane perforation point.In this work, the FIB milling process was considered as a flexibly applicable MEMS compatible nanostructuring method for shaping composite nanopore arrays. The evolving pore diameter depends on the material composition, and the thickness of the membrane, as well as on the applied milling time, ion dose, current and energy. The continuous evolution of pore geometries was characterized in order to define the appropriate process parameters for the reliable and reproducible manufacturing of nanopore arrays in multi-layered membranes. The resulting time (and dose) dependent pore diameter functions were determined for differently structured silicon-nitride/gold multi-layers. As a novel approach time dependent pore diameter evolution rate parameter (γ) was defined, its continuous regression during the milling process verified and interpreted by the Gaussian profile of the spatial ion intensity distribution of the ion beam. The dependency of the pore formation on the ion current was also evaluated and a linear relationship was found between the pore diameter evolution rates, excluding the vicinity of the membrane perforation occurrence. The cross-sectional nanopore geometries were also analysed by high resolution SEM, TEM and ion scanning imaging. High throughput pore diameter detection method was elaborated by detection of secondary electrons generated by translocated scanning GaThe statistical geometric parameters of a large number of nanopores were recorded and analysed. The reproducibility of the FIB nanoprocessing was improved by neutralization (electrostatic grounding) of the sample surface applying an additional conducting layer. Preventing the electrical charging of the dielectric layers can significantly decrease the resulting deterioration of the ion beam shape. By this technique the distortion of the pore diameter could be reduced significantly, and the pore size variations kept reproducibly below 5 nm.The performance of membrane impedance analysis based molecule detection was studied by avidin-biotin binding in the nanopore array. The application of uniform pores is of pivotal importance according to theory and experiment as well, since the sensor response depends both on the concentration of the target molecule and the pore size. The development of precise nanoprocessing techniques of predictable yield is therefore an elementary requirement for molecule sensing. By this work, adequate process parameters and techniques were defined for computer-controlled FIB milling  of compo


Improving crash safety of cars has become an important content in the research of automotive safety. The optimum design of intelligent crash test technology and devices for automotive safety has become a hot issue in the field. In order to test active safety or passive safety by braking or crash tests, intelligent testing devices  or crash test dummies) need to describe and simulate the damage mechanism and the tolerance limit of biological characteristics of the human body, such as dynamics and kinematics response to impact or acceleration. This is essential to protect human beings from car accidents.Along with the increasing exploration of nature, organisms with rigid flexible coupling structures are gradually discovered, which have excellent performances such as impact resistance, abrasion resistance, and drag reduction. The combination of bionics and biomechanics constantly brings about new inspiration and innovation to the field of engineering and automotive safety. So, this special issue called for original research articles on basic biomechanical researches of the human body, computer simulation for human body modeling and analysis, new development of intelligent anthropomorphic test devices for measuring the response of the human body in certain environments where an impact or other loadings are applied to the body, and the application of bionic structures in automobiles to improve their anticollision performance. The contents can involve bionics, biomechanics, automobile engineering, human body modeling, impact and contact mechanics, materials science of skin, and high-precision sensor informatics and mechanical processing technology. The highly integrated dummy design is also subject to various standard calibration tests, so this special issue is a cross-discipline.In crash tests of cars, each part of the occupant could be injured to varying degrees. Some injury criteria of key parts are shown in This special issue accepted 5 papers out of 10 after careful reviewing by editors, which leads to an acceptance ratio of 50%. The 5 papers focuse on crash dummy improvement, injury characteristics of knee joints, and injury in some special conditions.T. Xu et al. review the development and validation of dummies and human models used in crash tests. The mechanical dummies are introduced according to the collision types: frontal impact dummy, side impact dummy, and rear impact dummy. And the human model section details WSU, HUMOS, THUMS, and GHBMC human models. From the article, we can see the technological progress of the dummies and the human body models. Injury criteria and biomechanical tests in early time are also introduced.Y. Xiong et al. explore the mechanical response and injury characteristics of knee joints at different speeds using impact experiment with cadaveric knee samples and finite element simulation. The tests are all carried under conditions of longitudinal impacts, and the results all show that low-speed impact mainly leads to medial injuries, while high-speed impact leads to both medial and lateral injuries. The study can provide research basis for the prevention and treatment of longitudinal impact injuries of knee joints.S. Wang et al. use finite element models to analyze how the panel design parameters can affect occupant head injuries. The paper focuses on the three factors of panel hardness, elastic modulus of the filling and frame, and the distance from fixed location. The findings indicate that a soft panel with a long fixing distance is beneficial for the head prevention.I. L. Cruz-Jaramillo et al. study the head injury criterion (HIC) and chest severity index (CSI) with a 6-year-old Hybrid III dummy in the low-back booster (LBB) passive safety system. The findings of this study suggest that using materials, the attachment system of the LBB and the belt restraint system properly placed over the infant trunk are the main factors to reduce the injury criterion rate.H. Guo et al. applied a novel biobjective algorithm Newton Neumann Series Expansion Frisch Algorithm (NNSEFA) to dummy head FE experiment. By optimizing the dummy head with the algorithm, the improved model has a better accuracy in the collision simulation. The application of the biobjective optimization algorithm provides new ideas for occupant safety design.


Patients presenting superior semicircular canal dehiscence (SSCD) can experience symptoms such as conductive hearing loss, pulsatile tinnitus, autophony, and pressure-induced vertigo. Decreased cervical vestibular-evoked myogenic potentials (cVEMPs) thresholds and high-resolution computed tomography (HRCT) of the petrous bone are essential for diagnosis of SSCD syndrome. We report the case of a 43-year-old man suffering from constant right pulsatile tinnitus, intermittent autophony, and unsteadiness induced by physical exercise. An SSCD by the superior petrosal sinus (SPS) was confirmed on the right side by axial HRCT of the temporal bone reformatted in the plane of Pöschl and ipsilateral abnormally low elicited cVEMPs. Treatment options were discussed with the patient since the pulsatile tinnitus progressively became debilitating. Two options were considered: surgery or a new endovascular treatment; the patient chose the latter option. After stenting the right SPS, the intensity of the pulsatile tinnitus dramatically decreased. As there was no complication the patient was discharged at Day 1. The other symptoms improved progressively. By the 60-day follow-up visit the patient only reported a slight tinnitus worsened by physical exercise. Angiographic follow-up at 5 months confirmed the patency of the SPS. Stenting the SPS in patients with SSCD by the SPS appears to be an alternative to the existing surgical treatments. The superior semicircular canal dehiscence (SSCD) syndrome was described by Minor in 1998 . Among tThe main symptoms of SSCD by the SPS are: conductive hearing loss, pulsatile tinnitus, autophony, and pressure-induced vertigo –8. As prTo date, surgery is the only effective treatment in patients with disabling SSCD by the SPS. Surgical techniques include plugging, resurfacing, and capping of the SSC, and these are frequently combined for a better result. Middle cranial fossa and transmastoid approaches are the two main surgical options –12. ResuPlugging the affected superior semicircular canal appears to be the most effective technique for improving symptoms; however, the main criticism of plugging is that it requires opening or manipulating the labyrinth, with variable impact on ipsilateral labyrinthine function. We therefore propose an alternative endovascular technique designed to reduce the dissipation of acoustic energy through the third window and to preserve the vestibular function. To the best of our knowledge, the case presented herein is the first SSCD patient to have benefited from an endovascular treatment.A 43-year-old male was referred to our otolaryngology department for constant right pulsatile tinnitus, intermittent autophony, and unsteadiness induced by physical exercise. The patient did not have any medical history before the progressive onset of the symptoms. He underwent successive clinical examinations, as well as auditory and vestibular assessment as follows: Pure Tone Audiometry  middle ear reflexes (Madsen Zodiac 901 tympanometer), videonystagmography , video head impulse test , and cVEMPs (Bio-Logic® Nav-Pro system) in air conduction stimuli with 750 Hz tone bursts. The patient completed before intervention a Tinnitus Handicap Inventory (THI) questionnaire adapted to French language. Another THI questionnaire was completed after the endovascular procedure at Day 1 and 60.A HRCT  of the petrous bone was performed. Slices were acquired helically in the axial plane, at a nominal 0.625 mm slice thickness with a 50% overlap of 0.312 mm as recommended when a SSCD syndrome is suspected . All imaThe audio-vestibular assessment was normal except a right-sided low frequency conductive hearing loss . As the cerebral and peri-petrosal vascular system was normal, the feasibility of an endovascular procedure was considered. The two main challenges were: (1) access and (2) rigidify the SPS wall in contact with the labyrinthine membrane  and a cerebral angiogram  on the right was normalized although right cVEMPs threshold remained unchanged. VNG was normal with no evidence of canal paresis. VHIT results were not different of those found before treatment Figure . The THIA 43-year-old man presented a typical SSCD syndrome related to SPS. The main auditory complaints were: constant pulsatile tinnitus and intermittent autophony. He also mentioned exercise-induced unsteadiness and showed progressively signs of depression that have been frequently reported in case of persistent tinnitus , 17. SinThe first was the surgical option. Surgical techniques such as resurfacing, plugging (or both combined) of the SSCD by a middle-fossa approach have been frequently reported in the literature , 11, 13.Bleeding or thrombosis of the SPS were two possible local complications in this technique. The risk of bleeding was estimated as minimal since the petrosal venous system was complete allowing a relatively easy retrograde access of the guiding catheter in the SPS via the cavernous sinus. This approach is frequently used by our neuro-interventional team in case of other neuro-vascular pathologies. The deployment of both stents in the lumen of the SPS was gentle and uneventful due to the patency of the SPS at the end of the procedure. The risk of an eventual secondary thrombosis on the stent was estimated low since the venous disposition through the cavernous sinus and to the inferior petrosal sinus was normal in shape and dimensions. In case of any local venous perturbation generated by the presence of the stent in the middle third of the SPS, an alternative drainage of the SPV through the jugular vein would still be possible in a retrograde way  with no hemodynamic impact. However, in case of important anatomical variations of the venous petrosal system  stenting the SPS would not be recommended. The reasons that finally accounted for the decision to perform the endovascular treatment were: a less invasive and (we believe) safer procedure for the inner ear, and the presence in our team of an experienced interventional-radiologist with particular expertise in neuro-vascular pathologic conditions affecting the peri-petrosal venous system. The patient recovered rapidly and was discharged the day after the procedure. The early Day 1 THI questionnaire showed a notable improvement that further improved by Day 60. Right cVEMPs threshold remained abnormally low although ipsi-lateral ABG normalized Figure , and theIn this patient with symptomatic SSCD by the SPS, the endovascular treatment appears to be an effective procedure. Although stenting the SPS was successful in this case, in the future similar cases should be carefully selected before proposing this approach. The main advantages which seem to emerge using this technique are the preservation of the vestibular function, a limited risk for hearing, and a limited risk of bleeding since the elastic tension exerted by the stent on SPS wall would be minimal and uniformly applied on the internal surface of the vessel. As for the surgical treatment, this technique should be reserved for very impaired patients. Normal anatomy of the petrosal and jugular venous system is necessary and should be determined by selective venogram prior to the procedure. Antithrombotic therapy for 9 months after the procedure would add minimal risk, but is important in order to avoid secondary thrombosis of the stent.https://www.has-sante.fr/portail/jcms/c_2036961/en/best-practice-guidelines), France. A written informed consent was obtained from the patient.This study/case report was carried out in accordance with the recommendations of Haute Autorité de Santé (EI imagined and elaborated the principle of the endovascular treatment. AC elaborated the diagnosis and wrote the manuscript with EI. Her contribution to this paper should be considered similar to EI. PR participated to the elaboration of the treatment principle and adapted with permission the scheme of the third window mechanism. ET, the surgeon of the team, he observed the patient evolution before and after the insertion of the ventilation tube in the right tympanic membrane. HT-V performed and verified the pertinence of the audio-vestibular assessment before and after the endovascular treatment. AL-B, the radiologist of the team referent for the pathology of the middle and inner ear pathology; she performed all specific radiologic exams and prepared the figures of this case report. FT with EI imagined the best approach to the right superior petrosal sinus and realized the procedure; his expertise as interventional neuroradiologist was decisive for the final decision to stent the superior petrosal sinus.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Recent structural studies suggest thatde novo insertion does not use the polypeptide-conducting channel; instead, it takes place directly at the lateral gate, which is prone to opening. We propose that thede novo insertion process, in concept, is similar to that of insertases (such as YidC in bacteria and EMC3 in eukaryotes), in which an intramembrane surface of the machinery provides the halfway point of insertion.The Sec translocon provides a polypeptide-conducting channel, which is insulated from the hydrophobic lipidic environment of the membrane, for translocation of hydrophilic passenger polypeptides. Its lateral gate allows a downstream hydrophobic segment (stop-transfer sequence) to exit the channel laterally for integration into the lipid phase. We note that this channel model only partly accounts for the translocon function. The other essential role of translocon is to facilitate At the same time, proteins that are integrated into the membrane or localized in extra-cytosolic locations require facilitation by specific cellular mechanisms in reaching their destinations and achieving their topographical relationships to the membrane. The difficulties arise because the cytosol, where the translation of genetic messages takes place, is compartmentalized by membranes to make it discrete from other cellular compartments and the surroundings. Consequently, newly synthesized polypeptides must follow a proper pathway typically involving bio-machinery to integrate into or cross the membrane. Such pathways alleviate the difficulty of overcoming specific energy barriers that the moving polypeptide encounters. Hydrophilic parts of polypeptides must overcome the hydrophobic barrier of the lipid hydrocarbon to cross the membrane, whereas hydrophobic polypeptide segments should overcome the hydrophilic barrier of the phospholipid head groups to partition into the lipidic membrane interior.In protein localization, hydrophobic segments of polypeptides play a central role by their ability to partition into the hydrophobic core of the membrane4. Specifically, we illuminate the importance ofde novo insertion of a hydrophobic polypeptide stretch into the membrane.In this review, we attempt to clarify the role of the Sec translocon, a principal and conserved cellular machine, in assisting protein translocation across and insertion into the membrane, corresponding to the cytoplasmic membrane in the case of bacteria and the endoplasmic reticulum (ER) membrane in the case of eukaryotic cellsde novo membrane insertion are called signal sequences in the case of secretory proteins and signal-anchor sequences in the case of integral membrane proteins. For this section, readers are advised to refer toin–Nout orientation is called type I and Nin–Cout type II (“in” indicates the cytosolic side and "out" thetrans side of the membrane [see1.Topogenic sequences responsible forrane see). The orin–Cout) orientation, hence inducing translocation of the mature region that follows it. The signal sequence then receives proteolytic cleavage on thetrans side by the processing enzyme, signal peptidase, which liberates the mature domain from the membrane. Membrane anchor sequences do not undergo cleavage. Although signal sequences and type II signal-anchor sequences are similar in their membrane topologies, they have different features, such as the length of the hydrophobic core7 and the predicted behaviors in lipidic environments8. Nevertheless, it is useful to assume that these two categories of topogenic sequences share the fundamental principle that underlies their membrane insertion. We point out two observations that support this view. First, leucine-based model sequences can use the common translocon (see below) and function like either a signal sequence or a signal-anchor sequence depending on the length of the leucine stretch and the presence or the absence of the signal peptidase cleavage motif7. Second, in engineered fusion proteins, transmembrane sequences can direct export of the mature domain of alkaline phosphatase9, a bacterial periplasmic protein, even with accompanying cleavage by signal peptidase10.A canonical signal sequence assumes the type II (Nin–Nout (type I) transmembrane state can be generated by an N-terminal type I signal-anchor sequence as well as by an internal "stop-transfer" sequence that follows ade novo insertion signal . Probably because the model of the polypeptide-conducting channel is so compelling, however, discussion of membrane integration processes of signal peptides and signal-anchor peptides sometimes starts with an implicit assumption that they reside initially within the polypeptide-conducting channel of the translocon. Recent studies disfavor this assumption (see below). It is of vital importance to elucidate the actual pathways and mechanisms used by Sec translocon forde novo membrane insertion of hydrophobic stretches. Before looking into this function of the translocon, we will summarize the importance and the mechanism of actions of the conserved membrane protein biogenesis factors called insertases.In the original publication of the translocon structure, the authors explained that the signal peptide may use a lipid-translocon interface at the lateral gate region to integrate into the membranede novo integration function of translocon can be viewed as similar in concept to that of “insertases”, which occur in bacteria (the plasma membrane), mitochondria, chloroplasts, and eukaryotes (the ER membrane). Among them, YidC in bacteria is best characterized in its high-resolution structures23 and its insertase function executed independently of the Sec machinery26. YidC facilitates the insertion of a class of simple membrane proteins with one or two transmembrane segment(s) and a small periplasmic (trans-side) domain. Structural, genetic, and biochemical studies suggest that the functional unit of YidC is a monomer28. Its transmembrane helices form an intramembrane cavity that is open toward the cytosol and the membrane interior  disturb the phospholipid organization and lessens the head group barrier against the hydrophobic segment partitioning into the lipidic phase, which will, in turn, drive concomitant translocation of the hydrophilic tail from the halfway point to the periplasmic side  subunit of the EMC46. However, the division of labor between insertase and Sec in inserting different transmembrane domains could also explain the apparent chaperone function of the EMC/YidC. Specifically, the EMC's ability to facilitate the insertion of the first transmembrane segment of a multi-spanning membrane protein substrate in the correct orientation allows for the correct insertion of the remaining transmembrane regions by the Sec machinery45. The general applicability of such a relay mechanism for insertase–Sec-mediated membrane protein biogenesis remains to be investigated.Both YidC and the EMC have been reported to cooperate with the Sec translocon in assisting the correct biogenesis of membrane proteins that have multiple transmembrane regions. They may contribute to this mode of function by fulfilling chaperone-like roles that facilitate the "folding" of membrane proteins15, reconstitution into the nanodisc bilayer48, and cryo-electron tomography of native membranes from cells49. A central point in understanding the roles of the Sec translocon in mediatingde novo membrane insertion of hydrophobic domains is the roles played by the lateral gate region. A current consensus is that the lateral gate region can accommodate (transiently) the signal sequence or the membrane anchor sequence of either orientation, in its “open” form with a ~22° relative rotation of the N- and C-terminalhalves of SecY/Sec61α53, which is also the case for the lateral exit of a stop-transfer-type hydrophobic segment54. The substrate helix enters this region in a manner replacing a "placeholder" helix of the translocon51 and opening the lateral gate toward the lipid phase and also to the trans-side (or the cytosolic side depending on the stages of insertion5) of the membrane57.High-resolution structural information on the Sec translocon in its working state started to accumulate recently through both X-ray crystallography and electron microscopy-based approaches, the latter of which is undergoing remarkable technical progress. Also, efforts are being made to determine structures of translocon that is membrane integrated, rather than after isolation in detergent-solubilized states, by use of lipidic cubic phase crystalsde novo inserting helix should end up in the lipid-embedded state58, the snapshot pictures do not reveal a temporal order of the events in the sequential insertion process. There are crucial questions: when and how is the lateral gate open partially or fully, and when is the plug helix displaced to create a trans-membrane channel? The literature on the timing of lateral gate opening is disparate at a glance, but we can extract one crucial characteristic of the lateral gate: it is mobile and prone to opening to varying extents under different conditions. Structural studies detected a crack on the cytosolic side of the translocon, where some polypeptide moiety from an adjacent molecule resided, possibly as a signal peptide mimic. Substrate polypeptides may use such a crack for the initial recognition and entry step in both the co- and post-translational pathways57  lateral gate accompanied by a ~22° oblique rotation of a set of helices51. Thus, dynamic conformational changes of translocon range from a crack formation on the cytosolic side, through the cytoplasmic opening of the lateral gate, to the full opening of the lateral gate (61.A recent study revealed an early intermediate structure of the signal peptide insertion process54. These observations indicate that early events of insertion proceed before the opening of the polypeptide-conducting channel (de novo insertion, substrate polypeptides interact directly with the lateral gate region, which undergoes dynamic remodeling of the constituent transmembrane helices. Although the signal sequence transiently intercalates between some transmembrane helices of the translocon51, its residues also face the lipid phase in the early and later steps of insertion56. We envision that the rearranging lateral gate region provides intramembrane platforms, whose hydropathic properties lower the energy cost of insertion by interacting with the incoming polypeptide. In an extreme case, the strongly hydrophobic substrate might slide along the lipid–translocon interface, as proposed by Cymeret al.1, which is supported by thermodynamic considerations1.With the current knowledge of the insertion process discussed above, it is still unclear how the “passenger” hydrophilic polypeptide following the N-terminal signal is accommodated within the polypeptide-conducting channel , C4. The62, suggesting that they share the underlying principles. While the initial crack on the cytosolic side of the translocon forms a hydrophobic patch51, the "primed" lateral gate has a hydrophilic seam51. Upon further opening, the lateral gate cavity will have hydrophobic helices in front51, but it could also have some hydrophilic parts on the wall deep inside50, potentially akin to the YidC cavity. Substrate polypeptides may use the changing hydropathic characters of the lateral gate in their membrane insertion steps. A recent report by Heet al.63 proposes that two transmembrane segments of Escherichia coli YidC provide a "greasy slide" for a hydrophobic core of a client polypeptide to interact transiently during the insertion process. The insertion of the hydrophobic segment in a loop-like conformation appears to precede the hydrophilic N-tail interaction with the hydrophilic groove of YidC. Thus, an insertase can have multiple intramembrane surfaces of different amphipathic characters, in line with our proposal that the Sec lateral gate could function in similar fashions.The Sec translocon and YidC provide the client polypeptide with thermodynamically similar environments that support membrane protein partition64, followed by genetic identification of SecY65 and Sec6166, biochemical demonstration of their translocase functions69, and, finally, the realization of its structural entity 29 years later by van den Berget al.13. These studies have been influential for our understanding of living cells. We now learn that the translocon must integrate its insertase-like functions and the polypeptide-conduction function to execute the biological task. The thermodynamic principle of membrane insertion suggests the importance of the lipidic constituents of the membrane inde novo polypeptide insertion. Indeed, Nishiyama and coworkers have identified a glycolipid molecule, termed MPIase, that is dedicated to protein integration into the membrane inEscherichia coli72. The responsible enzyme is conserved in prokaryotic and eukaryotic cells. Now, we are at a stage where studies from various directions merge to enable us to better understand the biogenesis of membrane proteins.The concept of the polypeptide-conducting channel goes back to the proposal by Blobel and Dobberstein in 1975


Ensuring malaria commodity availability at health facilities is a cornerstone of malaria control. Since 2013, the Guinea National Malaria Control Programme has been routinely collecting data on stock levels of key malaria commodities through a monthly routine malaria information system (RMIS). In parallel, biannual end-user verification (EUV) surveys have also assessed malaria commodity availability at a subset of health facilities, potentially representing a duplication of efforts.Data on 12 malaria commodity stock levels verified during four EUV surveys conducted between 2014 and 2016 was compared to data for the corresponding months submitted by the same health facilities through the RMIS. The sensitivity and specificity of the RMIS in detecting stock-outs was calculated, as was the percent difference between average stock levels reported through the two systems.Of the 171 health facilities visited during the four EUV surveys, 129 (75%) had data available in the RMIS. Of 351 commodity stock-outs observed during the EUV in the sampled reporting health facilities, 256 (73%) were also signaled through the corresponding RMIS reports. When the presence of malaria commodity stocks was confirmed during the EUV surveys, the RMIS also reported available stock 87% (677/775) of the time. For all commodities, the median percent difference in average stock levels between the EUV and RMIS was 4% (interquartile range − 7 to 27%).The concordance between stock levels reported through the RMIS and those verified during the EUV visits provides certain evidence that RMIS data can inform quantification and procurement decisions. However, lower than acceptable rates of reporting and incomplete detection of stock-outs from facilities that do report suggest that further systems strengthening is needed to improve RMIS reporting completeness and data quality. Malaria transmission occurs year-round throughout Guinea and is the principal cause of healthcare seeking in the public sector, responsible for 31% of all outpatient consults  to 15% iThe Guinea NMCP aims to reduce malaria morbidity and mortality through a combination of interventions aimed at prevention, consisting of the distribution of long-lasting insecticidal nets (LLINs), seasonal malaria chemoprevention, and intermittent preventive treatment of malaria during pregnancy, as well as interventions to ensure timely diagnosis and correct treatment of confirmed malaria cases. Ensuring effective treatment requires a steady and reliable supply of malaria tests and medicines at health facilities.Key malaria commodities include malaria rapid diagnostic tests (RDTs), medicines used for treatment of uncomplicated malaria by artemisinin-based combination therapy (ACT), quinine tablets, injectable forms of quinine and artemisinin for treatment of severe malaria, sulfadoxine–pyrimethamine (SP) for intermittent preventive treatment in pregnancy, and LLINs for routine distribution to pregnant women and infants. These commodities are financed and centrally procured by the government of Guinea and donors, primarily the Global Fund to Fight AIDS, Tuberculosis and Malaria (GF) and the U.S. President’s Malaria Initiative (PMI), and stored at the central medical stores. From there, they are distributed to regional depots, from which Guinea’s roughly 400 public hospitals and health centres are supplied when they directly request commodities from the regional depot based on needs, using a “pull system”. Health centres in turn supply the community health workers and health posts in their catchment area. Malaria commodities are provided free of charge to patients of all ages.Monitoring stocks of malaria commodities throughout the system is a priority activity for the NMCP and its partners. Stock availability is an important indicator of health system readiness and sudden interruptions in the supply chain may affect the quality of service and health programmes . MoreoveDuring initial expansion of malaria control efforts in Guinea, the country’s logistic management and information system (LMIS) at the time was originally targeted to manage and improve management of commodities at the level of the central medical stores and regional depots. Because the LMIS was not designed to collect data on commodity stocks at the health-facility level, the Guinea NMCP decided to include data on malaria commodity stocks as part of its monthly routine malaria information system (RMIS), parallel to and independent of the larger health management information system. A parallel malaria-only reporting system was deemed necessary in the absence of a functional health management information system at the time. The RMIS is supported by PMI and GF and was rolled out in 2013, reaching nationwide coverage in 2014. District-level reporting improved from 66% completeness in late 2014, shortly after expansion, to consistent 100% completeness since early 2016. Data on stock levels at the beginning of the month, stock levels at the end of the month, number of days of stock-out, and consumption rates, including use, expiration, and loss, are reported through the RMIS by hospitals and health centres for 12 malaria commodities. Monthly data are recorded in paper forms at health facilities, and then transferred to the district health authorities, where they are inputted into an electronic database and sent to the national level. The Guinea NMCP routinely analyses the reported data to identify areas with under- and over-stock of commodities and monitors stock levels and consumption rates to forecast commodity needs. The malaria monthly bulletin issued by NMCP has included district-level commodity indicators since its inception in late 2014 and is a key tool in allowing NMCP and its partners to track malaria commodity levels.When PMI was launched in Guinea in 2012 and the RMIS was not yet operational, PMI implemented periodic end-use verification (EUV) surveys to monitor malaria commodity availability at regional warehouses and in peripheral health facilities . OriginaSince 2016, the improved timeliness and completeness of the RMIS have raised the possibility that it might already be collecting sufficiently reliable commodity data to provide the same kind of accountability that the EUV surveys were originally designed to provide. If that were the case, then the resources currently devoted to the EUV surveys could be redirected to other monitoring and evaluation activities. To explore this possibility, NMCP and its partners undertook a systematic assessment comparing the RMIS commodity reporting to the results of the EUV.A retrospective analysis was conducted comparing data on commodity stock-outs and stock levels reported through the RMIS to data collected in health facilities during four EUV surveys. Using the EUV data as the gold standard, the RMIS data were evaluated on reporting completeness, sensitivity and specificity of stock-out detection, and the relative difference in reported stock levels. The RMIS data were obtained from the NMCP national malaria database, and the EUV data were provided by the PMI-funded Systems for Improved Access to Pharmaceuticals and Services project in Guinea.Four EUV surveys that occurred since the scale-up of the RMIS were included in the analysis: July 2014, December 2014, October 2015, and August 2016. The number of health facilities visited during the surveys varied from 31 in the two 2014 surveys to 64 in the most recent survey in August 2016. In total, the four surveys comprised 171 hospital and health centre visits throughout Guinea; 71 (42%) of these were to visits to health facilities visited more than once during the four rounds. Hospitals represented 19% of all health facility visits across the four surveys. The number of regions visited during the surveys was six in July 2014, increasing to seven in December 2014, and finally including all eight regions in the October 2015 and August 2016 surveys.For each health facility visited during the EUV surveys, the RMIS database was searched by matching on health facility name and district. Variations in spelling and health facility name required manual matching of health facilities in the two databases. Data on day-of-visit commodity stock levels verified during the surveys were abstracted from the EUV database. Data on beginning-of-month and end-of-month stock levels and the number of days with stock-out were abstracted from the RMIS for the month corresponding to the EUV visit for each health facility in the EUV. Data on twelve malaria commodities were analysed: RDTs, the four age/weight formulations of amodiaquine–artesunate (AS–AQ), oral quinine tablets, injectable quinine, injectable artesunate, intramuscular artemether, SP, and LLINs. Data on stocks of AL, which was not in wide use in Guinea in the period covered by the assessment, were considered separately. The July 2014 and December 2014 EUV surveys did not capture data on AL, so indicators for AL for these surveys were not calculated. Moreover, in the period covered by the four surveys, the RMIS data recording and reporting forms did not stratify AL stocks by its four age/weight formulations, so data on AL stocks collected during the EUV surveys, which did stratify by the different formulations, were considered together; AL was considered in stock if any formulation of AL was documented, and AL stock levels were considered to be the sum across all AL formulations.Reporting completeness of the RMIS was assessed by calculating the proportion of the health facilities included in each EUV survey that had submitted their monthly malaria report through the RMIS for the month of the survey.The sensitivity and specificity of the RMIS to detect stock-outs of malaria commodities were also assessed. Sensitivity was calculated as the proportion of health facilities with a stock-out during the EUV survey that also reported a stock-out in the RMIS report for the corresponding month. The specificity was defined as the proportion of health facilities without a stock-out during the EUV survey that did not report a stock-out in their corresponding RMIS report. Health facilities that had not submitted RMIS data during the month of the survey were excluded from the analysis of specificity and sensitivity. Stock-outs in the EUV were defined as zero stock level recorded during the day of the survey visit. In the RMIS data, a health facility was considered to have reported a stock-out if beginning-of-month stock levels were reported as zero, end-of-month stock levels were reported as zero, or the number of days of stock-out during the month were greater than zero. The sensitivity and specificity were calculated separately for each commodity and each survey.The stock levels reported through the RMIS and counted during the EUV visits were compared separately for each survey and then jointly across all surveys. Because day-of-visit data were not available from the RMIS, the average monthly stock levels were analysed, defined as the mean of the beginning-of-month and end-of-month stock levels. For each commodity, the total mean monthly stock level per health facility was calculated for the RMIS dataset, and the average percent difference between the RMIS and EUV datasets was calculated. Additionally, for each individual health facility, the percent difference between the EUV and RMIS data was calculated for each commodity. The distribution of health-facility-level percent difference was visualized using boxplots, stratifying by commodity. The proportion of health facilities with percent difference < 25%, 25–50%, and > 50% was calculated. Health facilities that had not submitted RMIS data during the month of the survey were excluded from the analysis of stock levels.Abstracted data were collected in an Excel  spreadsheet and data analysis was performed using R version 3.3.2 .Out of the 171 health facilities visited during the four EUVs, 75% (129/171) had submitted corresponding monthly reports through the RMIS  were also signaled through the corresponding RMIS reports  reporting platform. This new system has an integrated health-facility-level LMIS, whose framework is modeled on the commodity component of the RMIS. Eventually, the RMIS itself is planned to be fully integrated into the new HMIS, cementing it as a foundation of routine disease surveillance in Guinea.


Hog producers' operational decisions can be informed by an awareness of risks associated with emergent and endemic diseases. Outbreaks of porcine epidemic diarrhea virus (PEDv) have been re-occurring every year since the first onset in 2013 with substantial losses across the hog production supply chain. Interestingly, a decreasing trend in PEDv incidence is visible. We assert that changes in human behaviors may underlie this trend. Disease prevention using biosecurity practices is used to minimize risk of infection but its efficacy is conditional on human behavior and risk attitude. Standard epidemiological models bring important insights into disease dynamics but have limited predictive ability. Since research shows that human behavior plays a driving role in the disease spread process, the explicit inclusion of human behavior into models adds an important dimension to understanding disease spread. Here we analyze PEDv incidence emerging from an agent-based model (ABM) that uses both epidemiological dynamics and algorithms that incorporate heterogeneous human decisions. We investigate the effects of shifting fractions of hog producers between risk tolerant and risk averse positions. These shifts affect the dynamics describing willingness to increase biosecurity as a response to disease threats and, indirectly, change infection probabilities and the resultant intensity and impact of the disease outbreak. Our ABM generates empirically verifiable patterns of PEDv transmission. Scenario results show that relatively small shifts (10% of the producer agents) toward a risk averse position can lead to a significant decrease in total incidence. For significantly steeper decreases in disease incidence, the model's hog producer population needed at least 37.5% of risk averse. Our study provides insight into the link between risk attitude, decisions related to biosecurity, and consequent spread of disease within a livestock production system. We suggest that it is possible to create positive, lasting changes in animal health by nudging the population of livestock producers toward more risk averse behaviors. We make a case for integrating social and epidemiological aspects in disease spread models to test intervention strategies intended to improve biosecurity and animal health at the system scale. In recent years, the hog production industry has been subjected to incursions of both endemic and new diseases. In 2013, the first outbreak of porcine epidemic diarrhea virus (PEDv) in the U.S. shook the industry both economically and socially, and required us to rethink effective disease-prevention strategies . The virObserved data published by the United States Department of Agriculture  have been applied to study social phenomena and analyze macroscopic patterns that emerge from the interaction of a number of agents programmed to behave according to specified rules , 32. ABMTo form a better view of PEDv disease dynamics with the role of human behavior, we built an ABM at the scale of a regional hog production system. We modeled disease spread among a variety of different agents: (1) producers with different holding types , (2) feed mills, and (3) slaughter plants. The modeled hog supply chain includes both single- and multi-site production with networks of pig movement and feed deliveries. The other two main ABM components are the epidemiological and human decision-making components. The epidemiological component contains the mechanisms of PEDv transmission (direct and indirect), while the human behavioral component accounts for risk attitude and decision-making that influence biosecurity in the system. The elements of human decision-making and behavior were selected to reflect patterns observed by industry professionals to have major effects on farm biosecurity: (1) psychological distancing  that leaThis paper presents and compares the disease-spread consequences of human decision-making simulated using an ABM of a swine production system. To this end, we design agent populations with proportionately varied risk attitudes observed from an online digital field experiment. These range from risk averse strategies that allocate more preventative biosecurity during outbreaks to risk tolerant attitudes that gamble with very little biosecurity investment. As the risk attitude influences the agent behavior in our ABM, we analyzed temporal patterns of disease incidence emerging from the simulated scenarios of heterogeneity in risk attitudes within the population of producer agents.The agent-based model (ABM) used in this study was built off a previous ABM called “Regional U.S. Hog Production Network Biosecurity Model” (RUSHPNBM) originally created by Wiltshire et al.  and WiltThe structural component simulates a hog production system with agents representing production premises, feed mills and slaughter plants. The hog production chain simulated for this study is a system mirroring the density, operation types and sizes of production units found in North Carolina with data provided by the Farm Location and Agricultural Production Simulator (FLAPS) tool which draws from the USDA Census of Agriculture and aerial images . Feed miThe ABM epidemiological component is network-based and spatially explicit in that it simulates disease spread via both direct and indirect mechanisms related to the movement of animals and feed across the production network. It is coupled with a stochastic state transition model including Susceptible (S) and Infectious (I) states. Probability functions regulate the transmission of disease in single agent interactions while the network structure of animal and feed movement determine the ultimate pattern of disease spread. Each simulated agent  may become infected (state I) during an interaction with another agent with a probability that depends on the type of interaction, the agent's biosecurity and a seasonality factor. Specifically, each type of movement interaction is associated with an independent probability of infection calculated using a logistic function. The logistic functions describe the infection probability's dependence on the agent's biosecurity with coefficients derived from the estimates provided using expert opinion. The seasonal variability in PEDv infectivity is modeled as a sinusoidal adjustment on the logistic probability function that varies with time and ultimately generates higher infection probabilities in winter and lower in summer. Explicit representation of disease spread mechanisms and functions for our ABM are detailed in the Aside from the movement of contaminated pigs and feed, two additional sources of infection are implemented: (1) from visitors arriving at the production site and (2) from PEDv surviving in the environment within or around a production site , 13, 40.We explicitly investigated the importance of capturing human behavior with interaction and feedbacks between humans and the environment. The producer agents in our ABM have adaptive capabilities and are reactive in that they do not learn but simply respond to signals from other agents and the environment. In the model, a population of veterinarian agents is encoded, each with its own network of hog producers. Within the network, the veterinarian tracks the number of hog producers affected by disease and reports it back weekly. The producer agents are encoded with a set of rules to simulate decisions to alter biosecurity at their facility in response to the disease status in their veterinarian network. Our goal was to explore the influence of reactive behaviors on biosecurity and ultimately disease incidence.To reflect heterogeneity of human risk attitude and allow the evaluation of a variety of human behaviors, the ABM has underlying human processes with parameters for risk attitude, biosecurity investment, responsiveness to disease, and psychological distancing. In particular, the agents' risk-attitude is directly linked to their response to disease by determining the threshold number of neighboring infected production premises necessary for an agent to react and increase its biosecurity with a probability >0.9. We associate risk aversion with higher propensity to adopt biosecurity. For example, risk averse agents almost always increase biosecurity as soon as there are three production premises infected in their veterinarian network. On the opposite side of the risk spectrum, risk tolerant agents increase their biosecurity quasi certainly only when they know that there are nine or more infected production premises in their veterinarian network. In summary, the ABM agent behavior originates from a risk attitude distribution with four categories ; four forms of disease response, one for each risk attitude category are used to simulate biosecurity response-to-disease strategies; and a utility function for psychological distancing, which simulates the waning of biosecurity compliance since an infection event. The detailed description of parameters and methods for the ABM human behavioral component are provided in the The goal of this study was to better understand the extent to which shifts in the composition of risk attitudes in the agent population change the incidence of PEDv outbreaks. To this end, we ran a scenario analysis where we shifted fractions of the producer population between risk tolerant and risk averse categories and then evaluated the resulting PEDv incidence. Six model scenarios were compared to a reference baseline scenario , assignep > 0.0001 in Shapiro-Wilk test) or the assumption of equal variances (p > 0.0001 in both Brown-Forsythe test and Fligner-Killeen test). We first applied the k-sample Anderson-Darling test with all the distributions of total incidence and then compared the distributions pairwise with the two-sample Kolmogorov-Smirnov test. Box-plots were used to show the median, minimum, and maximum values and quantiles of the simulated incidence totals for each scenario.Total incidence: It is defined as the sum of incidence over the simulated time period. We built distributions of total incidence from the 800 Monte Carlo replicates for each scenario. We then compared the distributions across scenarios both visually with box-plots and statistically with non-parametric tests. We applied non-parametric tests because the data did not meet either the assumption of normality  or the assumption of equal variances . The Monte Carlo averages of both the simulated incidence and trend coefficients were calculated to display temporal patterns and trends for each scenario.Linear trend coefficients: A linear regression model was fit to each of the 800 simulation runs for all scenarios and the values for the coefficients intercept and slope were collected. Box plots of intercept and slope showed the characteristics of the underlying distribution of coefficients' datasets. The non-parametric k-sample Anderson-Darling test followed by the two-sample Kolmogorov-Smirnov test were applied to compare distributions across scenarios because the data did not meet either the assumption of normality .In all 5. Box-plots are presented to show overall patterns of three indicators and visualize their distribution characteristics across scenarios. The 12.5 and 37.5% averse represent the two extreme scenarios. The baseline is the scenario with an equal percentage (25%) of producers in both the risk averse and risk tolerant categories.The scenario analysis performed in the study addressed the sensitivity of PEDv incidence outputs given changes in the proportions of producer agents assigned to the risk averse and risk tolerant categories in the ABM. We performed statistical tests to measure the effect of seven distributions of risk attitudes  on the sThe compact letters in The comparative box-plots provided an unexpected result when analyzed in relation to the observed total incidence  and decreased with time. Fewer runs (<25%) in each scenario showed instead a positive trend indicating some model realizations in which the PEDv outbreak led to a growing incidence through time. These positive-trend cases emerge in the stochastic approach of Monte Carlo experiments where, by the law of large numbers (of simulations) more rare outcomes may also be realized. These cases accentuate and call the attention to the stochastic nature of disease spread dynamics indicating that there can be unexpected outcomes of disease spread even when the system is calibrated to contain and reduce infection.The observed intercept and slope falls either outside or at the edge of the inter-quartile range for all the scenarios indicating that most of the model simulations realized a weaker decreasing trend compared to the observed one. This means that the ABM parameterization tends to create dynamics of disease spread with overall lower incidence across time than what occurred in reality. The graphs in The epidemiological data on PEDv available for the period of June 1st, 2014 to February 25th, 2018 shows a decreasing trend in PEDv incidence. Because the characteristic pathways of infection of the virus have not changed over time, we deduced that something has been changing in the hog production system that has improved the control of the virus. Both the literature and collaborating stakeholders refer to human behaviors with respect to both in compliance with and investment in biosecurity as critical for disease-protection management. This implies a key role of humans in the processes of controlling virus transmission. To better understand how changes in behavioral patterns could reflect changes in PEDv incidence, we developed an agent-based model (ABM) able to examine the role of human risk attitude to PEDv incidence within a simulated production system. Our model outputs reproduced a significant decrease in PEDv incidence through time. An important finding from our scenario analysis was that the average decreasing trend is significantly affected by the model's initial state, defining the proportion of the producer agents assigned to two risk categories, risk averse and risk tolerant. An increase as small as 10% more risk averse producer agents resulted in a 19% decrease in the median total PEDv incidence, which is equivalent to 36 fewer PEDv cases over the course of the analysis period (~4 years). To observe a significantly steeper decrease in incidence requires that more than 37.5% of the population be in the risk averse category. The implication is that biosecurity adoption and influencing factors of adoption (for example risk attitude) are a critical consideration when creating strategic plans or policies for disease control. Our modeling analysis reinforces the message found not only in field-specific papers but also in general papers such as in  who callPEDv incidence data are highly variable and reflect the complex social-ecological structure of the swine industry. While the Monte Carlo results capture much of the system variability, different parameter sets appear to more closely align with the observed PEDv data –6, i.e.,An aspect of complexity present in the observed data is their variability at several time scales including weekly, seasonal, and inter-annual variability. The inter-annual variability for example is visible in the timing of the observed incidence peaks  is effective in the control and reduction of PEDv spread. Our study points at the substantial opportunity provided by shifting behavior; however, from a production system perspective, altering a substantial proportion of a population's behavior represents a significant challenge. Yet, significant progress has been shown in other industries, for example when we alter choice architecture and provide behavioral nudges , 50.Here we demonstrated the need to better understand the cognitive processes underlying decision-making about biosecurity, and highlight possible realizations of the impact of changing behavior on the spread of disease in the swine industry. However, in this research we coded biosecurity investment decisions based on the risk of acquiring a disease. Obviously, disease risk is an important factor when considering biosecurity, but it is not the only factor. A complex array of factors exists that influence biosecurity decisions that differ by individual and further depend upon the objectives of the organization, regional policies, logistical factors, and the array of behaviors by other actors in the swine network . Yet, research has shown that risk attitude can be an important decision-making factor. Like all models, our “model is wrong, but hopefully it is useful” (attributed to George Box 1976) because it provides a quantitative approximation for how human behavior and decisions can influence the spread of disease.The onset of PEDv in the U.S. hog industry was a singular experience for all stakeholders because of its high infectivity and rapid spread. Data show however that in 4 years, PEDv's potent spread appeared constrained with overall incidence reduced. Social dimensions can play a significant role in the biosecurity decisions of swine producers. We geared our epidemiological model with human behavioral processes connected to biosecurity and disease, and demonstrated the opportunity and impact associated with changing biosecurity behavior on PEDv incidence or, with a more positive spin, a healthier animal production systems. If on one side, targeted interventions to critical nodes of a production system may prove important to inhibit disease “super-spreaders,” on the other, our study shows that shifts in the overall industry toward a more risk averse culture can yield more biosecure facilities along with consistent and long-term industry-wide protection from disease.GB, SW, EC, and SCM assisted with design and conceptualization of the agent-based model. EC helped with data collection. GB, SCM, EC, and SMM worked on data analysis. Project funding was generated with the help of JS, SCM, CK, and AZ. Experiments were conducted by GB and EC. Software development was primarily led by GB, SW, and EC. Initial manuscript drafts were created by GB. Subsequent manuscript editing was completed by all authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Wear particle-induced biological responses are the major factors for the failure of total joint arthroplasties, but it is possible to improve the lubrication and reduce the wear of an artificial joint system. Polyetheretherketone (PEEK), with ultra-high molecular weight polyethylene, is a suitable bearing material due to its resistance to fatigue strain. However, the effects of major compositions of synovial fluid on the wear of PEEK are unclear. We characterized the effects of three major components of synovial fluid including albumin, globulin, and phospholipids on the morphology and wear rate of PEEK wear particles. Our results demonstrated that the concentrations of albumin and globulin could affect the morphology of PEEK wear particles. In addition, a higher concentration of globulin and phospholipids (12.5 mg/mL) resulted in an increase in the amount of wear particles by 2.8- and 1.7-fold, respectively. In contrast, increasing albumin caused a reduction of wear particle numbers. These results indicate increasing concentration of albumin or reducing concentration of globulin or phospholipids has a better effect on reducing the numbers of wear particles and provides a potential solution of reducing PEEK wear particles, thus it can be more effectively applied in other biomedical systems. The performance of total joint arthroplasties (TJAs) is mainly determined by their tribological properties because the wear particles that are generated from the tribological process play a key role in the lifetime of artificial joint system ,2,3. In Many studies have shown that the size of wear particles is critical for particle-induced biological responses ,16,17,18We investigated PEEK wear characteristics under the lubrication of three major components of synovial fluid in this study. A combined analysis of the wear particle morphology and numbers of PEEK wear particles during an accelerated wear process could help us to understand the lubricating effects of synovial fluid on the characteristics of wear particles. Our results may provide feasibility for developing lubricating additives to reduce the PEEK wear particle-induced biological responses in TJAs.PEEK cylinder pins were obtained from A-SPINE Asia Co. Ltd.  (batch number was SSR 0151). The pins were 6.35 mm in diameter and 25.4 mm in length with diamond turning on both end surfaces without polishing. Human serum albumin ,  human immunoglobulin G ,  and dipalmitoyl phosphatidyl choline   powders tested in this study were prepared in phosphate buffered saline ,  with four different concentrations . Because PEEK is hydroscopic, all PEEK pins were presoaked in PBS for at least 30 days at 25 °C so they would not absorb HSA, IgG, or DPPC during the tests. Thus, the consistency of tests could be maintained.By rubbing PEEK pin with the cutting edges of the silicon surface textures, the PEEK wear particles were generated. ASTM F732 was used as a guideline. The setup of the system was described and shown in The silicon wafer surface with controlled asperities was prepared by photolithography patterning and etching of the bulk substrate as previously described  and showPEEK particles were collected by repeated water rinsing of the sample in a sample holder, and parts that came into contact with particles were moved into a sterilized beaker. The process of isolation was previously described in detail .After wear particles were isolated, they were examined by using a scanning electron microscope (SEM). Micrographs of the particles were then analyzed by using an image analyzer software  to measure their dimensions. Measurements were made for at least 300 particles in each condition.Our results demonstrated that increasing concentration of DPPC had no effect on the aspect ratio of PEEK wear particles. The changes in aspect ratio of particles were opposite when rubbing PEEK in HSA and IgG: a higher concentration of HSA resulted in a rod-like shape of particles while a higher concentration of IgG caused a granular shape of particles a,b. It hr on PEEK  is manifested as an encounter force to prevent the PEEK being pushed away. If the component causes an increase of interfacial friction, it will lead to a larger downward force Ffz. Therefore, the surface feature shall slide longer to complete a wear process and results in an increase in aspect ratio of particles. In contrast, the accumulated layer of the component at the interface may reduce the actual penetration depth of the surface feature into PEEK. Thus, it would further shorten the lateral sliding distance, resulting in a reduction of aspect ratio of particles. Therefore, it is possible that IgG formed a thicker layer at the interface and reduced the penetration depth feature into PEEK. PEEK pin then decreased its lateral sliding distance, and was easily broken to form a granular shape of particles when concentration of IgG was increased. In contrast, immersing PEEK in HSA may increase the downward force, resulting in an increase of wear particles. However, the results suggested that DPPC may not change the penetration depth of the surface feature into PEEK, thus the aspect ratio remained the same when increasing the concentration of DPPC.The wear process of the surface feature over PEEK results in a resisting force F on PEEK . The verBoth rod-like and granular shapes of carbon fiber reinforced-PEEK (CFR-PEEK) wear particles were identified in macrophages in human tissue retrieval studies, although both cases were not associated with joint arthroplasty failure ,28. In pWhen PEEK pin was rubbed in HSA solution, increasing HSA concentration resulted in reducing wear rate . AlthougOur results demonstrated that the total wear rate was the lowest when PEEK was rubbing in IgG. The friction between artificial joints is boundary lubrication according to the Stribeck curve, and the lubricant will accumulate and form a thin layer on the surface to protect the joints . It is pDPPC carries positively charged quaternary ammonium ion, and usually could adhere to negatively charged proteoglycans on the surface of cartilage . The strAn accelerated wear testing procedure was established successfully to evaluate the lubrication effects of albumin, globulin, and phospholipids in this study. The morphologies of PEEK wear particles have been characterized, and the effects of different lubricants on the aspect ratio of wear particles have been investigated. The results for the wear rate can help us to discuss the lubricating ability of these three components. Although there is no conclusive trend for the wear rate obtained in this study, our scale-up testing system for generating PEEK wear particles has given us a rapid screening method for identifying the role of lubricants in the boundary lubrication of artificial joints. This testing method may be beneficial for further developing lubricating additives for total joint arthroplasties in the future.


This paper is focused on the utilisation of double edge notched tension, staggered and shear tests to determine fracture toughness and the formability limits by fracture in principal strain space. The experiments were performed in test specimens with different geometries and ligament angles, and the influence of strain hardening was taken into consideration by selecting two materials , with very different strain hardening exponents. Results are plotted in principal strain space, and the discussion is focused on the link between formability limits, fracture toughness and macroscopic fractography characteristics of the specimens that fail by mode I, mode II or mixed-mode. Failure in sheet metal forming can occur by necking, fracture or wrinkling. The formability limit by necking ) was originally presented by Keeler  for the The fracture forming limit line (FFL) defines failure by fracture in mode I, and is plotted as a straight line falling from left to right with a slope of ‘−1’ in principal strain space. The physics of the FFL is the condition of maximum admissible thickness reduction at fracture . The sheThe ‘upward curvature’ tails of the FFL and the SFFL that are plotted as dashed lines in The formability limit by wrinkling in sheet metal forming is given by the wrinkling-limit curve (WLC) located in the lower left-hand of the second quadrant of principal strain space .The experimental determination of the FLC and FFL is usually performed by means of tensile, bulge and Nakajima sheet formability tests , whereasFracture toughness is directly linked to failure by fracture in sheet metal forming, because it is the material property that accounts for the resistance of a material to crack initiation and propagation in tension or shear . There aLater, Cotterell et al.  extendedAtkins and Mai  also preHowever, they also concluded that materials with low strain hardening that experience intense necking , provide fracture toughness values that are sensitive to the ligament angle The second conclusion arising from Atkins and Mai  is not sThe link behind fracture toughness, macroscopic fractography and failure by fracture in principal strain space is the key motivation behind this investigation, but the two above-mentioned questions related to the uncertainty of using staggered DNTTs to determine fracture toughness and to characterise the formability limits by fracture in mixed-modes, are also important topics that will be addressed in the paper. For this purpose, the authors carried out a series of tests with DNTT specimens a, shear α b. The inThis section presents a summary of the methods and procedures utilised in the mechanical characterisation, in the definition of the formability limits and in the determination of fracture toughness for aluminium AA1050-H111 and copper sheets with 1 mm thickness.The aluminium alloy AA1050-H111 sheet is a common aluminium alloy for applications where moderate strength is needed, like pharmaceutical, food packaging and electronic industries. Its chemical composition is given in The copper sheet was cold rolled, and consists of an oxygen-free 99.9% copper . Copper The mechanical characterisation of the aluminium AA1050-H111 and copper sheets was performed by means of tensile tests on an INSTRON 5900 universal testing machine at room temperature. The specimens were cut by electrical discharge machining (EDM) out from the supplied sheets at 0, 45 and 90° degrees with respect to the rolling direction, to evaluate the influence of anisotropy. The tests followed the ASTM standard E8/E8M-16 , and theThe forming limit curve (FLC) was determined by means of tensile, bulge  and Nakajima tests to cover strain loading paths from uniaxial tension to equibiaxial stretching conditions. The fracture limit by tension (fracture forming limit line (FFL)) was determined by means of the same experimental tests that were used for obtaining the FLC, plus double notched tensile tests (DNTT) to get strain values near plane strain deformation conditions. The fracture limit by in-plane shear (shear fracture forming limit line (SFFL)) was determined by means of shear tests with different ligament sizes. In addition to what was said above, staggered DNTTs with different ligament sizes The bulge and Nakajima tests were performed in a hydraulic universal testing machine ERICHSEN 145/60 and allowed the obtaining of strain loading paths from plane strain to equibiaxial stretching conditions. All the remaining tests loaded in tension were performed in the INSTRON 5900 universal testing machine that was previously utilised for the material characterisation. The Nakajima and shear tests followed the procedures and recommendations included in the ISO 12004-2  and ASTMThe strains at the onset of necking (FLC) were obtained by means of position-dependent  or time-The Zürich n.5 procedure presented by Rossard , which eIn what regards the time-dependent method proposed by Martínez-Donaire et al. , the detThe procedure to obtain the fracture strains required measuring the thickness of the specimens before and after deformation c to obtaThe fracture strains of the DNTT specimens were determined by means of the procedure that had been successfully applied by Madeira et al. , and proThe staggered DNTT with different ligament sizes The fracture surfaces of the DNTT, staggered DNTT and shear test specimens were subsequently analysed in a scanning electron microscope (SEM). The hardware utilised was the Hitachi S-2400, and the analysis allowed analysing the fractography associated to crack opening by modes I, II and mixed-mode, for each test specimen, and to link these observations with the corresponding fracture strain pairs in principal strain space.The determination of fracture toughness nditions  that was size l0 b, and co is null c.The method utilised to obtain fracture toughness from the DNTTs was extrapolated to the shear and staggered DNTT specimens. The shear tests allowed determining fracture toughness for crack opening in mode II (in-plane shear), and the staggered DNTTs with different ligament sizes This section starts by presenting the formability limits of the aluminium AA1050-H111 and copper sheets, follows with the morphology of the fractured surfaces, and ends with the determination of fracture toughness.The formability limits by necking (FLC) were determined by means of tensile, Nakajima and bulge tests using the methods and procedures that were previously described in The staggered DNTT fracture strains pairs present smaller values of the minor strain A fractography analysis was performed on the fracture surface of the DNTT, staggered DNTT and shear test specimens to investigate the crack opening mode and to correlate the observations with the FFL and SFFL of aluminium AA1050-H111. The SEM images of the fracture surfaces are given in The analysis of the fracture surface of the DNTT specimen shown in Analogously, the fracture surface of the shear test specimen shown in The fracture surface of the staggered DNTT specimen shown in A staggered DNTT specimen with a ligament angle The first location, identified as region ‘I’ in Just as in aluminium AA1050-H111, the fracture strains obtained for the staggered DNTTs present smaller values of the minor strain The SEM images of the fracture surfaces of selected DNTT, staggered DNTT and shear test specimens of copper are given in The main difference to the results previously obtained for aluminium AA1050-H111 is that staggered DNTT specimens of copper fail by normal fracture and, therefore, are unable to provide fracture strains in the transition zone between the FFL and SFFL in principal strain space. The explanation for the different results provided by the staggered DNTTs of aluminium AA1050-H111 and copper is attributed to the fact that crack opening modes are not solely dependent on the geometry of the specimens, but also on the material properties, namely on strain hardening. This explanation is better understood by observing the experimental distributions of the major strain from DIC . As seen in On the other hand, it also justifies the larger slopes of the linear fittings of the total specific work per unit of area that were obtained for the copper specimens, when compared to those obtained for the aluminium AA1050-H111 specimens . This wiDetermination of fracture toughness 050-H111 a and cop050-H111 b. As seen, the evolutions are linear, and are in good agreement with the results obtained by Cotterell et al. , namely refer to . The values obtained for aluminium AA1050-H111 can be classified into three different groups, corresponding to fracture toughness Moreover, the results included in d by Mai  for alumIn contrast, the values obtained for copper can only be classified into two groups corresponding to fracture toughness in space  and the in space . In otheThis last conclusion is important, because it points out the paramount importance of combining the formability limits in principal strain space, and the SEM images to characterise the opening mode of staggered DNTT specimens. Otherwise, one may be wrongly assuming a type of fracture, when in fact it does not exist.Under these circumstances, the main conclusion derived from the experiments with copper is that fracture toughness The above-mentioned results reveal some dependency on the ligament angle Definition of the fracture forming limits by tension and in-plane shear in principal strain space must be accompanied by macroscopic SEM observations of the fracture surfaces, in order to validate the crack opening modes of the different tests that are used to obtain the fracture strains. The same connection is needed to associate the determination of fracture toughness to crack opening by tension, in-plane shear or mixed-mode, consisting of tension and in-plane shear.Staggered DNTTs can be successfully utilised to characterise the transition region between the fracture forming limit line (FFL) and the shear fracture forming line (SFFL) in principal strain space, and to determine fracture toughness in fracture mixed-mode. However, precaution should be taken to avoid using results from staggered DNTTs outside their fractography domain. Results show that staggered DNTTs performed on aluminium AA1050-H111 are capable of covering all opening modes from tensile to in-plane shear, whereas staggered DNTTs carried out in copper with large strain hardening coefficient, are unable to deliver fracture mixed-modes. This prevents staggered DNTTs performed in materials with large strain hardening coefficients to characterise the transition region between the FFL and SFFL in principal strain space, and to deliver fracture toughness in mixed-mode. The differences between these two types of behaviour are attributed to the influence of strain hardening on the degree of localisation of plastic deformation around the ligament that is observed in the experimental distributions of strain obtained from DIC.