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Summer gazpacho with frozen olive oil
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Summer gazpacho with frozen olive oil
3h
35m prep 4 servings
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V
Valli Little
6.7
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Health Score*
MEDIUM
470 calories
per serve
Allergens:
Recipe may contain yeast, sulphites, gluten, wheat and alcohol.
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13
Ingredients
4
Method Steps
13 Ingredients
160ml extra virgin olive oil
2 slices Italian-style bread, crusts removed
2 tbsp sherry vinegar
1 garlic clove
1 tsp sugar
1 small red chilli, seeded, chopped
650g tomatoes, peeled, seeded and chopped
400g roasted red capsicum
1/2 (about 300g) rockmelon
1/2 telegraph cucumber, peeled, seeded
10 basil leaves
300ml tomato juice
4 spring onions, chopped
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4 Method Steps Step 1
Start several hours ahead by freezing 100ml of the oil ( 160ml extra virgin olive oil )
in small ice-cube trays (or use large trays and only half fill). Step 2
Place bread ( 2 slices Italian-style bread, crusts removed )
, vinegar ( 2 tbsp sherry vinegar )
, garlic ( 1 garlic clove )
, sugar ( 1 tsp sugar )
and chilli ( 1 small red chilli, seeded, chopped )
in a blender or food processor and process to combine. Step 3
Gradually add remaining oil, tomato ( 650g tomatoes, peeled, seeded and chopped )
, capsicum ( 400g roasted red capsicum )
, rockmelon ( 1/2 (about 300g) rockmelon )
, cucumber ( 1/2 telegraph cucumber, peeled, seeded )
, basil ( 10 basil leaves )
, tomato juice ( 300ml tomato juice )
and spring onion ( 4 spring onions, chopped )
. (If your blender is small, you may need to blend in batches - pour each blended batch in a bowl and stir well at the end.) Step 4
Season well with salt and black pepper. Serve chilled with the extra virgin olive oil ice-cubes. Did you make this? I MADE THIS 0 people made this
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NUTRITIONAL INFORMATION Nutrition per Serving %Daily Value# Energy 1965 kj (470cal) 23% Protein 3.9g 8% Total Fat 39.1g 56% Saturated 5.3g 22% Cholesterol 0g - Carbohydrate Total 27.1g 9% Sugars 14.8g 16% Dietary Fiber 3.5g 12% Sodium 475.4mg 21% Calcium 56.1mg 7% Magnesium 42.1mg 13% Potassium 749.2mg - Iron 3mg 25% Zinc 1mg 8% Phosphorus 83.5mg 8% Vitamin A 1900μg 253% Vitamin C 174.5mg 436% Thiamin B1 0mg 0% Riboflavin B2 0mg 0% Niacin B3 2.3mg 23% Vitamin B6 0mg 0% Folic Acid B9 93.2 47% Vitamin B12 0μg 0% Vitamin D 0μg 0% Vitamin E 6.7mg 67% Vitamin K 82.9μg 104%
Nutrition information and Health Score does not include ingredients listed as to serve or any serving
suggestions.
Nutrition information is calculated using an ingredient database and should be considered an
estimate.
# The % daily values indicates how much of a nutrient in a food serving contributes to a daily diet,
based on general nutritional advice for a diet of 2100 calories a day.
* Health Scores are calculated on a 1-10 scale based on nutrient density and USDA (global standard)
recommendations for a healthy diet. A higher Health Score indicates a healthier recipe. The value is
based on the impact of macronutrients and micronutrients in the recipe.
Image by Prue Ruscoe
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Nearby: Coles Karratha change
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Grape Perino Tomatoes Prepacked 200g
$ 3 . 50
$17.50 per 1kg
Prices available at displayed Coles store, may not be available at other stores or coles.com.au. Specials commence at 7am on start date, but may start before or extend beyond displayed dates. While stocks last. We reserve the right to limit sale quantities. Multi save price only available when purchased in the multiples specified.
Special available from 20/06/23 to 21/06/23
Garlic loose approx. 60g
$ 29 . 00
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Red Cayenne Chillies loose approx. 50g
$ 26 . 00
$26.00 per 1kg
Yellow Capsicum 1 each
$ 9 . 90
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Antioxidants | Free Full-Text | ROS Suppression by Egg White Hydrolysate in DOCA-Salt Rats& mdash;An Alternative Tool against Vascular Dysfunction in Severe Hypertension
This study aimed to evaluate the potential for lowering blood pressure and beneficial effects on mesenteric resistance arteries (MRA) and conductance vessels (aorta) produced by dietary supplementation of an egg white hydrolysate (EWH) in rats with severe hypertension induced by deoxycorticosterone plus salt treatment (DOCA-salt), as well as the underlying mechanisms involved. The DOCA-salt model presented higher blood pressure, which was significantly reduced by EWH. The impaired acetylcholine-induced relaxation and eNOS expression observed in MRA and aorta from DOCA-salt rats was ameliorated by EWH. This effect on vessels (MRA and aorta) was related to the antioxidant effect of EWH, since hydrolysate intake prevented the NF-κB/TNFα inflammatory pathway and NADPH oxidase-induced reactive oxygen species (ROS) generation, as well as the mitochondrial source of ROS in MRA. At the plasma level, EWH blocked the higher ROS and MDA generation by DOCA-salt treatment, without altering the antioxidant marker. In conclusion, EWH demonstrated an antihypertensive effect in a model of severe hypertension. This effect could be related to its endothelium-dependent vasodilator properties mediated by an ameliorated vessel’s redox imbalance and inflammatory state.
ROS Suppression by Egg White Hydrolysate in DOCA-Salt Rats—An Alternative Tool against Vascular Dysfunction in Severe Hypertension
by
Edina da Luz Abreu 1 ,
Camila Rodrigues Moro 1 ,
Samia Hassan Husein Kanaan 1 ,
Ricardo Bernardino de Paula 2 ,
Camila Teixeira Herrera 1 ,
Pedro Henrique Dorneles Costa 1 ,
Franck Maciel Peçanha 1 ,
Dalton Valentim Vassallo 3 ,
Luciana Venturini Rossoni 2 ,
Marta Miguel-Castro 4,* and
Giulia Alessandra Wiggers 1,*
1
Cardiovascular Physiology Laboratory, Universidade Federal do Pampa, BR 472, Km 592, Uruguaiana 97501-970, Brazil
2
Department of Physiology and Biophysics, Institute of Biomedical Science, University of São Paulo, Av. ProfessorLineu Prestes, nº 2415, São Paulo 97501-970, Brazil
3
Cardiac Electromechanical and Vascular Reactivity Laboratory, Universidade Federal do Espírito Santo, Av. Marechal Campos, 1468, Vitória 29040-090, Brazil
4
Instituto de Investigación en Ciencias de la Alimentación (CIAL, CSIC-UAM.), C/Nicolás Cabrera, 9, Campus Universitario de Cantoblanco, 28049 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Antioxidants 2022 , 11 (9), 1713; https://doi.org/10.3390/antiox11091713
Received: 27 July 2022 / Revised: 22 August 2022 / Accepted: 27 August 2022 / Published: 30 August 2022
(This article belongs to the Special Issue Antioxidant Properties and Potential Mechanisms of Protein Hydrolysates )
Abstract
This study aimed to evaluate the potential for lowering blood pressure and beneficial effects on mesenteric resistance arteries (MRA) and conductance vessels (aorta) produced by dietary supplementation of an egg white hydrolysate (EWH) in rats with severe hypertension induced by deoxycorticosterone plus salt treatment (DOCA-salt), as well as the underlying mechanisms involved. The DOCA-salt model presented higher blood pressure, which was significantly reduced by EWH. The impaired acetylcholine-induced relaxation and eNOS expression observed in MRA and aorta from DOCA-salt rats was ameliorated by EWH. This effect on vessels (MRA and aorta) was related to the antioxidant effect of EWH, since hydrolysate intake prevented the NF-κB/TNFα inflammatory pathway and NADPH oxidase-induced reactive oxygen species (ROS) generation, as well as the mitochondrial source of ROS in MRA. At the plasma level, EWH blocked the higher ROS and MDA generation by DOCA-salt treatment, without altering the antioxidant marker. In conclusion, EWH demonstrated an antihypertensive effect in a model of severe hypertension. This effect could be related to its endothelium-dependent vasodilator properties mediated by an ameliorated vessel’s redox imbalance and inflammatory state.
Keywords:
egg white hydrolysate
;
hypertension
;
deoxycorticosterone acetate (DOCA)-salt
;
oxidative stress
;
inflammation
;
mitochondria
1. Introduction
Hypertension is one of the most common chronic diseases worldwide. It is of multifactorial origin and results from a complex interaction between environmental (such as dietary) and genetic factors [ 1 , 2 , 3 ]. Although a larger number of pharmacological and non-pharmacological therapies are used, some patients are resistant to treatment, mainly those who present severe hypertension [ 2 , 4 ]. Thus, more studies are necessary to improve blood pressure control in hypertension. Interestingly, endothelial dysfunction is a hallmark of hypertension, and the resistance and conductance arteries are crucial for the regulation and maintenance of blood pressure [ 3 ]. In hypertension, oxidative stress is implicated in vascular injuries [ 5 , 6 , 7 ], and the main vascular sources of oxidative stress are the excessive production of superoxide anion (O 2 − ) by NADPH oxidase, xanthine oxidase, mitochondria, cyclooxygenase-2, and/or uncoupled nitric oxide (NO) synthase [ 6 , 7 , 8 ]. As a result of this oxidative stress, endothelium-dependent vasodilation is impaired, and vascular stiffness and peripheral vascular resistance are increased, contributing to the development and maintenance of arterial hypertension, leading to damage to end-organs [ 5 , 6 , 9 ].
Considering its complexity, hypertension is studied in different models of experimental rodents, including deoxycorticosterone acetate (DOCA)-salt hypertension, a volume-dependent hypertension model that combines DOCA treatment, and high salt intake with uninephrectomy. This model induces severe hypertension and impacts blood volume, cardiac output, and peripheral vascular resistance; thus, it is a helpful model for studies on resistant hypertension [ 7 , 10 , 11 ].
Non-pharmacological strategies to prevent or treat hypertension have gained attention. In this context, natural bioactive compounds from foods seem safe and low-cost alternatives. Moreover, this strategy generally does not present side effects common in the polytherapy usually used for the treatment of hypertension [ 4 , 12 ]. Among them, bioactive peptides derived from food proteins with antihypertensive and antioxidant properties have been reported to be successfully used to control hypertension and related disorders. In previous works, enzymatic hydrolysis of egg white proteins with pepsin for eight hours produced multifunctional peptides with angiotensin-converting enzyme (ACE) inhibitory action and antioxidant, anti-inflammatory, and vasorelaxant activities [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. A blood- pressure-lowering effect related to ACE inhibition and antioxidant activity was also demonstrated after short- and long-term administration of this hydrolysate on a genetic model of hypertension––spontaneously hypertensive rats (SHR) [ 14 , 15 ]. However, the effect and mechanisms of this functional food administration on blood pressure and vascular dysfunction in the severe hypertension model have been little explored.
This study aimed to evaluate the potential antihypertensive and vasculoprotective effects of dietary supplementation of an egg white hydrolysate (EWH) in DOCA-salt hypertensive rats and the mechanisms involved.
2. Material and Methods
2.1. Egg White Hydrolysate Preparation
EWH was obtained by enzymatic hydrolysis of raw egg whites after treatment with food-grade pepsin, as described previously by Garcés-Rimón et al., 2016 [ 20 ]. For eight hours, pasteurized egg white was hydrolyzed with pepsin BC 1:3000 (Biocatalyst, UK). Enzyme inactivation was achieved by increasing the pH to 7.0 with NaOH (5 N). The hydrolysate was centrifuged at 2500× g for 15 min, and the supernatant was frozen and lyophilized until used.
2.2. Animals and Treatment
Male Wistar rats (180–220 g) were obtained from the Central Animal Laboratory of the Federal University of Pelotas (Rio Grande do Sul, Brazil). Animals were maintained at standard conditions (constant room temperature, humidity, and 12:12 h light-dark) with water and fed
ad libitum
in the Federal University of Pampa vivarium. The experimental protocols were performed according to guidelines of the National Council of Ethics with Animals (CONCEA) and National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH, 1996), and the Local Institution Animal Care and Use Committee (protocol number 003/2020).
Rats were submitted to the tail-cuff plethysmography to evaluate the systolic blood pressure (SBP) levels before the uninephrectomy (time −1/week) and the induction of the hypertensive model. Afterward, all animals were submitted for right kidney removal as previously described [ 7 ]. Thus, the rats were anesthetized (64.9 mg/kg ketamine, 3.2 mg/kg xylazine, and 0.78 mg/kg acepromazine, i.p. ) and underwent a small incision in the right flank for kidney removal. All animals received analgesia for 3 days post-surgery (Ketofen @ 0.2 mg/kg, s.c. ).
As observed in
Figure 1
, seven days after surgery (time 0), rats were randomly divided into two groups: DOCA-salt and SHAM (Vehicle). Animals of the SHAM group received vehicle injections (1:1 mineral oil and propylene glycol) and drinking water. Animals of the DOCA-salt group received subcutaneous injections of DOCA (Sigma Aldrich, Darmstadt, Germany) diluted in 1:1 mineral oil and propylene glycol at the sequential doses of 20 mg/kg in the first week, 12 mg/kg in the second and third week, and 6 mg/kg from the fourth week to the eighth week of the experimental period, plus water supplemented with 1.0% of NaCl and 0.2% of KCl [
7
]. In the last four weeks of the experimental period, the groups were subdivided into animals treated with EWH diluted in water (1 g/kg/day, by gavage) [
21
] or water, by gavage. Thus, the animals constituted 4 experimental groups: SHAM, SHAM+EWH, DOCA, and DOCA+EWH.
Figure 1. Schematic representation of experimental groups, DOCA-salt hypertension induction model and EWH treatment period.
2.3. Systolic Blood Pressure Measurement
As described above, SBP was measured weekly using a standard non-invasive tail-cuff plethysmography method (Pneumatic transducer, AD Instruments Pty Ltd., Bella Vista, NSW, Australia) in conscious, restrained rats as described [ 25 ]. Briefly, rats were heated to 37 °C for 10 min to detect caudal artery pulsations. Afterward, the transducer was placed on the tail, and the average of ten collected times of SBP was used. To ensure the reliability of the measurements, all animals were previously acclimatized, and measurements were made for the same person at the same time of day. The measurements were made weekly in the following times: time −1 and 0, before, and 1 week after uninephrectomy; time 1 to 4, 1 to 4 weeks after DOCA-salt or SHAM treatment; and time 4–8, after the co-treatment with EWH or water ( Figure 1 ).
2.4. Blood, Tissue Collection, and Mesenteric and Aorta Vascular Reactivity Experiments
At the end of the experimental period, animals were anesthetized (87 mg/kg ketamine, and 13 mg/kg xylazine,
i.p.
) and euthanized. Blood samples, mesenteric resistance arteries (MRA), and thoracic aorta were removed. Arteries were cleaned of connective tissue, and some rings were inserted in a freezing medium (OCT) and frozen at −80 °C.
For vascular reactivity experiments, third order MRA (2 mm) and thoracic aorta (4 mm) segments with (E+) and without endothelium (E-, mechanically removed) were mounted in a wire myograph for small and larger vessels [
26
,
27
]. After 45 min of equilibration period in gassed (95% O
2
and 5% CO
2
) Krebs–Henseleit solution (in mM: 115 NaCl, 25 NaHCO
3
, 11.1 glucose, 4.7 KCl, 2.5 CaCl
2
, 1.2 MgSO
4
·7H
2
O, 1.2 KH
2
PO
4
, and 0.01 Na
2
EDTA; pH 7.4, 37 °C), MRA were stretched to their optimal lumen diameter to develop active tension, and aorta segments maintaining an optimal resting tension of 1.5 g. MRA diameter were similar among groups (SHAM: 292.2 ± 4.8 vs. SHAM+EWH: 291.1 ± 8.4 vs. DOCA: 288.5 ± 8.2 vs. DOCA+EWH: 291.1 ± 4.5 µm, n = 10; Two-way ANOVA,
p
> 0.05).
To verify the smooth muscle integrity and the maximal tension developed, MRA and aorta segments were exposed twice to a high-potassium solution (KPSS-120 or 75 mM, respectively). The vascular response to KPSS remained unaltered in MRA (SHAM: 4.0 ± 0.1 vs. SHAM+EWH: 4.2 ± 0.2 vs. DOCA: 4.0 ± 0.1 vs. DOCA+EWH: 4.3 ± 0.1 mN/mm, n = 10; Two-way ANOVA,
p
> 0.05) and in aorta (SHAM: 1.5 ± 0.1 vs. SHAM+EWH: 1.4 ± 0.1 vs. DOCA: 1.5 ± 0.1 vs. DOCA+EWH: 1.7 ± 0.1 g, n = 10; Two-way ANOVA,
p
> 0.05) among groups.
After 60 min, the endothelium-dependent relaxation to acetylcholine (ACh–Sigma-Aldrich, St. Louis, MO, USA) was assessed. MRA and aorta segments were pre-contracted with α-adrenergic agonists (norepinephrine–NE and phenylephrine–Phe, respectively; Sigma-Aldrich), in a concentration that produced tension close to 50% of those induced by KPSS and a concentration–response curve to ACh (1 nM–1 mM) was performed. To evaluate the endothelium-independent relaxation, concentration–response curves to NO donor sodium nitroprusside (SNP, 0.1 nM–300 µM; Sigma-Aldrich) were performed in NE or Phe pre-contracted segments.
To evaluate the participation of NO, reactive oxygen species (ROS), mitochondrial superoxide anion production, NF-κB activity on ACh-induced relaxation, and some MRA and/or aorta segments with intact endothelium (E+) were pre-incubated for 30 min with: (
i
) Nω-nitro-L-arginine methyl ester (L-NAME, 100 μM; Cat. Nº N5751—Sigma-Aldrich), a non-selective NO synthase (NOS) inhibitor (only in the aorta); (
ii
) superoxide dismutase (SOD, 750 U/mL; Cat. Nº s5395—Sigma-Aldrich), superoxide anion scavenger; (
iii
) MitoTEMPO (0.5 µM; Cat. Nº SML0737—Sigma-Aldrich), specific scavenger of mitochondrial O
2
−
; and (
iv
) BAY 117,082 (5 µM; Cat. Nº B5556- Sigma-Aldrich) NF-κB inhibitor (only in MRA), respectively.
2.5. Determination of Oxidative Stress Biomarkers in Plasma, MRA, and Aorta
To evaluate the oxidative stress biomarkers in MRA and aorta, the vessels were homogenized in Tris-HCl (50 mM, pH 7.4) and centrifuged at 2400×
g
for 10 min at 4 °C, and the supernatant fraction was used.
Malondialdehyde levels (MDA), a measure of lipid peroxidation, were performed using the colorimetric method. Briefly, thiobarbituric acid (TBA) 0.8%, acetic acid buffer (pH 3.2) plus sodium dodecyl sulfate (SDS) 8% were added to the samples, and the color reaction was measured against blanks (532 nm—SpectraMax M5 Molecular Devices, San Jose, CA, USA). The results were expressed as nmol MDA/g tissue [ 28 ].
ROS levels [ 29 ] were determined by 2′, 7′-dichlorofluorescein diacetate (DCF-DA) using the spectrofluorometric method. Briefly, after being diluted (1:5 in Tris-HCl 50 mM; pH 7.4), samples received 2′, 7′-dichlorofluorescein diacetate (DCF-DA, 1 mM; Cat. Nº 6883—Sigma-Aldrich). The DCF fluorescence intensity emission represents the amount of ROS formed (520 nm emission with 480 nm excitation for 60 min at 15 min intervals––SpectraMax M5 Molecular Devices, San Jose, CA, USA). The ROS levels were expressed as fluorescence units.
The total antioxidant capacity (FRAP) was measured by the Ferric Reducing/Antioxidant Power (FRAP) assay [ 30 ]. Briefly, the sample was added to FRAP reagent 10:1:1 [Sodium acetate buffer—300 mM pH 3.6; 2,4,6-Tri(2-pyridyl)-s-triazine– TPTZ—10 mM (Cat. Nº 93285, Sigma-Aldrich); Iron (III)—FeCl 3 —20 mM (Cat. Nº 157740, Sigma-Aldrich)] and incubated at 37 °C for 10 min. The absorbance was read at 593 nm (SpectraMax M5 Molecular Devices, San Jose, CA, USA). Data are expressed in reference to mM Trolox equivalents.
2.6. In Situ Detection of Vascular O 2 − Production in MRA and Aorta and NO Production in the Aorta
O
2
−
production in situ in MRA and aorta was measured by dihydroethidium (DHE) (Cat. Nº D2310, Invitrogen Life Technologies, Waltham, MA, USA), as previously described by Piech et al. (2003) [
31
]. To evaluate the source of the O
2
−
, mitochondrial and/or by the antioxidant activity of superoxide dismutase (SOD), some sections were incubated with DHE plus Mito-Tempo a scavenger of mitochondrial superoxide anion (0.5 mM—Sigma Aldrich) or MnTMPyP, a mimetic of SOD (25 μM; Cat. Nº ALX-430-07—Enzo Life Sciences, Farmingdale, NY, USA), respectively. The mean fluorescence densities were calculated using NIH ImageJ software V1.56 (National Institutes of Health, Bethesda, MD, USA) using the same imaging settings in each case. The results are expressed as arbitrary units (AU) of fluorescence intensity.
NO production was measured in the aorta sections using the NO-sensitive fluorescent dye 4,5-diaminofluorescein diacetate (DAF-2; Cat. Nº D225, Sigma Aldrich), according to Couto et al. (2015) [
32
]. The aortic sections were equilibrated for 10 min in phosphate buffer (0.1 mol/L, pH 7.4) that contained CaCl
2
(0.45 mmol/L). The fresh buffer that contained DAF-2 (8 μmol/L) was topically applied to each tissue section and incubated in a light-protected humidified chamber at 37 °C. After 25 min of incubation, sections of each artery were stimulated without (Basal) or with ACh (100 μmol/L) for 15 min. The concentration of ACh used to evaluate the NO production in the aorta was selected based on functional vascular experiments. The images were analyzed with Image J software using the integrative density of the fluorescence observed in the artery in relation to the background staining in sections with and without Ach stimulation.
2.7. Immunofluorescence in MRA and Aorta
Arterial segments of MRA and aorta were prepared and analyzed according to Jimenez-Altayó et al. (2005) [ 33 ]. The primary antibodies used were against NOX1 (1:400; Cat. 2108601, Sigma Aldrich), eNOS (1:400; Cat. SAB4502615, Sigma Aldrich), NF-kB (1:400; Cat. 4502615, Sigma Aldrich), and TNFα (1:400; Cat. 5700627, Sigma Aldrich). Alexa 488-conjugated goat anti-mouse immunoglobulin G [IgG]) was diluted at 1:400 (Cat. Nº A11001, Invitrogen Life Technologies). DAPI (1:500; Cat. MBD0015, Sigma Aldrich) to stain nuclei was used. In the preparation of negative control sections, we omitted the primary antibody. Images were acquired using an EVOS ® Floid ® Cell Imaging Station (Life Technologies, Carlsbad, CA, USA). For quantification, sections with the same capture parameters were analyzed. The mean fluorescence densities (histogram) using ImageJ were calculated. Data are expressed as fluorescence intensity.
2.8. Statistical Analysis
Data are expressed as the mean ± SEM. Vasodilator responses to ACh or SNP were expressed as a percentage of relaxation of the pre-contraction induced by NE or Phe. Results were analyzed using two-way ANOVA followed by a post hoc Bonferroni test (GraphPad Prism 8 software, San Diego, CA, USA). Differences were considered statistically significant with values of p < 0.05.
3. Results
SBP was similar among groups before starting the experimental period ( Figure 2 , time −1), and the uninephrectomy did not alter this parameter ( Figure 2 , time 0). As expected, DOCA-salt treatment progressively increased SBP from week 1 to week 4 ( Figure 2 , time 1–4). After the 4th week of treatment, DOCA animals maintained high blood pressure levels as compared to SHAM, but DOCA+EWH animals present lower SBP values than DOCA animals ( Figure 2 , time 4–8). This reduction was 36% compared to the untreated DOCA group, without reaching the SBP values of the SHAM group ( Figure 2 ). SHAM+EWH animals maintained blood pressure levels similar to those observed in SHAM animals ( Figure 2 ).
Figure 2. Effect of EWH on SBP in DOCA-salt hypertensive rats. SBP values of SHAM, SHAM+EWH, DOCA, and DOCA+EWH groups, measured before and after nephrectomy (−1 and 0 weeks), during DOCA-salt model induction (1 to 4th week), and during the maintenance of the DOCA-salt hypertensive model co-treated or not with EWH (5th to 8th week). The EWH treatment started on the 4th week after DOCA-salt or SHAM treatment (orange-marked line). Data are expressed as mean ± SEM. The number of rats is indicated in parentheses. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
The endothelium-dependent relaxation induced by ACh, in both arteries, was reduced in the DOCA group as compared to SHAM ( Figure 3 A,B). EWH co-treatment improved ACh-induced relaxation in MRA and aorta of DOCA animals and did not change it in SHAM animals ( Figure 3 A,B). The SNP-induced relaxation was not altered in both vessels among groups ( Figure 3 C,D).
Figure 3. Effect of EWH in endothelium-dependent and -independent relaxation of MRA and aorta segments from DOCA-salt rats. Concentration–response curves to ACh ( A , B ) and SNP ( C , D ) in MRA and aorta segments from SHAM, SHAM+EWH, DOCA, and DOCA+EWH groups. The results are expressed (mean ± SEM) as the percentage of relaxation responses in norepinephrine or phenylephrine precontracted rings. The number of rats is indicated in parentheses. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
The removal of the endothelium (E-) reduced the ACh-induced relaxation in MRA and aorta of all groups as compared to the respective E+ segments ( Figure 4 ). The role of the endothelium in the relaxation response to ACh was strongly reduced in MRA and aorta of DOCA animals compared to SHAM, whereas EWH co-treatment partially restores this response in both arteries ( Figure 4 ).
Figure 4. The role of endothelium on the effect of EWH in ACh-induced relaxation of MRA and aorta segments from DOCA-salt rats. Concentration–response curve to ACh in the presence (E+) and absence of endothelium (E−) in MRA (Upper graphics) and aorta (Bottom graphics) segments from rats SHAM, SHAM+EWH, DOCA, and DOCA+EWH. The results are expressed (mean ± SEM) as the percentage of relaxation responses in norepinephrine or phenylephrine precontracted rings. The number of rats is indicated in parentheses. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. E+.
To investigate whether the ROS could be involved in the vascular protective action induced by EWH, the participation of the O 2 − at the cellular (SOD) or mitochondrial (Mito-Tempo) level was investigated in both vessels ( Figure 5 and Figure 6 ). In MRA, SOD incubation did not alter the relaxation induced by Ach in any group ( Figure 5 ). However, Mito-Tempo improved the Ach-induced relaxation in the DOCA group ( Figure 6 ). Moreover, in the MRA of SHAM, SHAM+EWH, and DOCA+EWH, Mito-Tempo did not change the ACh-induced response ( Figure 6 ). This finding demonstrated the pivotal role of mitochondrial ROS in MRA endothelial dysfunction of the DOCA salt hypertensive model and the role of EWH in restoring this oxidative status. On the other hand, in aorta segments, only SOD ( Figure 5 ), but not Mito-Tempo ( Figure 6 ), was able to improve the ACh-induced relaxation in DOCA group, suggesting a dysfunctional action of the SOD in the aorta of the DOCA group and an antioxidant effect of EWH.
Figure 5. The role of EWH in ROS-mediated ACh-induced relaxation in MRA and aorta of DOCA-salt rats. Concentration–response curves to ACh were obtained in MRA (Upper graphics) and aorta (Bottom graphics) segments from rats from SHAM, SHAM+EWH, DOCA, and DOCA+EWH groups before (E+) and after incubation with scavenger reactive oxygen species, the superoxide dismutase (SOD, 750/mL). The results are expressed (mean ± SEM) as the percentage of relaxation responses in norepinephrine or phenylephrine precontracted rings. The number of animals in each group is in parentheses. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. E+.
Figure 6. The role of EWH on mitochondrial ROS-mediated, ACh-induced relaxation in MRA and aorta of DOCA-salt rats. Concentration–response curves to ACh were obtained in MRA (Upper graphics) and aorta (Bottom graphics) segments from rats from SHAM, SHAM+EWH, DOCA, and DOCA+EWH groups before (E+) and after incubation with specific scavenger of mitochondrial superoxide, Mito-TEMPO (0.5 µmol/L). The results are expressed (mean ± SEM) as the percentage of relaxation responses in norepinephrine or phenylephrine precontracted rings. The number of animals in each group is in parentheses. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. E+.
To corroborate these findings, in situ vascular ROS detection was evaluated. In MRA and aorta sections of the DOCA group, higher O
2
−
detection was observed, whereas EWH co-treatment restored this detection towards SHAM levels (
Figure 7
). The incubation of Mito-Tempo in MRA or MnTMPyP in aorta sections decreased the DHE fluorescence intensity in DOCA group, without additional effect in the section of the DOCA+EWH group (
Figure 7
). Interestingly, the NOX1 protein levels were increased in MRA and aorta of DOCA rats, and the co-treatment with EWH, once again, reduced these levels towards SHAM values (
Figure 8
).
Figure 7. The role of EWH on O 2 − production in MRA and aorta section of DOCA-salt rats. Typical images of sensitive fluorescent dye Dihydroethidium (DHE) in the absence or presence of Mito-TEMPO (0.5 µmol/L—third line panel A ) or MnTMPyP (25 µM—third line panel B ) in MRA and aorta sections of SHAM, SHAM+EWH, DOCA, or DOCA+EWH rats. The basal images are the negative control pictures without DHE. The histogram ( a —MRA and b —Aorta) shows in white bars the DHE fluorescence and in black bars the DHE fluorescence after Mito-TEMPO or MnTMPyP incubation. The results are expressed as representative fluorescence intensity in arbitrary units. The results are expressed as mean ± SEM (n = 6). Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
Figure 8.
The role of EWH on NOX1 expression in MRA and aorta section of DOCA-salt rats. Representative photomicrographs (×40 magnification) and histogram of NOX1 immunofluorescence in MRA and aortic sections of SHAM, SHAM+EWH, DOCA, and DOCA+EWH arteries. Data are expressed as mean ± SEM, n = 8. The images correspond to the merge of the marking of the colors by the DAPI in blue and the NOX-1 in green. Two-way ANOVA followed by Bonferroni post-test:
p
< 0.05 * vs. SHAM; # vs. DOCA.
Vascular inflammatory mechanisms play an essential role in the development of hypertension and oxidative stress [
5
]; thus, we investigated the expression of NF-kB and TNFα in MRA and aorta segments. Higher NF-kB and TNFα protein levels were observed in MRA and aorta of DOCA than in the SHAM group (
Figure 9
), and a significant reduction was observed in arteries of DOCA co-treated with EWH (
Figure 9
). In addition, NF-kB inhibitor BAY 117,082 enhances ACh-induced relaxation in MRA of DOCA group compared to SHAM, but not in the SHAM, SHAM +EWH, and DOCA+EWH groups (
Supplemental Figure S1
), suggesting a greater activation of NF-kB in MRA segments from DOCA-salt animals that was restored by EWH co-treatment.
Figure 9. The role of EWH on NF-kB and TNFα expression in MRA and aorta section of DOCA-salt rats. Representative photomicrographs (×40 magnification) and histogram of NF-kB (left) and TNFα (right) immunofluorescence of MRA and aorta sections of SHAM, SHAM+EWH, DOCA, and DOCA+EWH arteries. Data are expressed as mean ± SEM, n = 8. The images correspond to the merge of the marking of the colors by the DAPI in blue and the NF-kB and TNFα in green. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
Lipid peroxidation and ROS levels were increased in both plasma and arteries of the DOCA group compared to SHAM, and the co-treatment with EWH restored those parameters ( Figure 10 ). However, DOCA-salt treatment or EWH co-treatment did not change the antioxidant capacity in plasma or arteries ( Figure 10 ). These results suggest a redox imbalance in the DOCA group that was restored after EWH co-treatment.
Figure 10. Effects of EWH on the oxidative stress (ROS and TBARS) and antioxidant (FRAP) capacity in plasma, MRA, and aorta of DOCA-salt rats. ROS, TBARS, and FRAP values were assessed in plasma, MRA, and aorta of SHAM, SHAM+EWH, DOCA, and DOCA+EWH rats. The results are expressed as mean ± SEM, and the number of animals is indicated as dots in the bars. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
Additionally, the involvement of the NO pathway was also investigated. In aorta segments, a reduced relaxation response to ACh was observed in all groups after the non-selective NOS inhibition with L-NAME (
Supplemental Figure S2
). However, in the DOCA group, the magnitude of the reduction was smaller compared to SHAM, and EWH co-treatment improved it (
Supplemental Figure S2
). To corroborate these findings, we observed a significant reduction in ACh-induced NO levels in aortic sections of the DOCA group as compared to SHAM and its recovery in the aortic section of EWH co-treated rats (
Supplemental Figure S3
). In addition, the eNOS expression was lower in MRA and aorta of the DOCA group than in SHAM; once again, EWH co-treatment restored eNOS expression to SHAM levels (
Figure 11
).
Figure 11. The role of EWH on endothelial NO synthase (eNOS) expression in MRA and aorta section of DOCA-salt rats. Representative photomicrographs (×40 magnification) and histogram of eNOS immunofluorescence of MRA (left panels) and aortic (right panels) sections of SHAM, SHAM+EWH, DOCA, and DOCA+EWH arteries. Data are expressed as mean ± SEM, n = 8. The images correspond to the merge of the marking of the colors by the DAPI in blue and the eNOS in green. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
4. Discussion
Previously our group demonstrated that EWH has antihypertensive, vasorelaxant, antioxidant, and anti-inflammatory properties, observed in a genetic model of hypertension SHR and metals-induced hypertension [ 15 , 21 , 22 , 23 , 24 ]. In this work, for the first time, we show a significant antihypertensive effect of EWH in a model of severe hypertension induced by DOCA-salt treatment in uninephrectomized rats. The beneficial effects of EWH supplementation are associated with local (mitochondrial) and systemic antioxidant effects and anti-inflammatory action, through NF-kB and TNFα inhibition, which improves NO bioavailability and endothelium-dependent relaxation in MRA and aorta.
The relationship between hypertension and redox imbalance has been demonstrated in experimental rodent models and human hypertension [ 7 , 10 , 33 , 34 ]. Diets with high antioxidant content may reduce blood pressure and cardiovascular complications. In contrast, some randomized clinical and population studies have shown disappointing results, in part associated with several specific points in the trial design or dosing regimens. However, the potential pro-oxidant activity of antioxidants is a phenomenon that should not be ignored [ 35 ]. Since antioxidant food compounds have different mechanisms of action, such as activation of antioxidant enzymes, chelation of metals, blocking of lipid peroxidation, or elimination of O 2 − , therapeutic alternatives derived from them may be an additional tool for controlling severe hypertension [ 4 , 12 ]. In this sense, bioactive peptides released during food processing or after the digestion of food proteins, such as EWH, can exert different powerful biological activities [ 16 , 36 ]. Specifically, it is well known that peptides with antioxidant properties play a beneficial multifunctional role in the cardiovascular system and blood pressure control [ 4 , 37 ].
The DOCA-salt model is recognized for inducing hypertension to malignant levels and promoting vascular dysfunction, as observed in the animals in this study. Furthermore, this response was associated with an impaired synthesis or NO bioavailability and increased myogenic tone, endothelin-1 activation, ROS production by NADPH oxidase, cyclooxygenase-2, proinflammatory cytokines, NF-kB activation, and macrophage infiltration [
7
,
10
,
38
,
39
]. In addition, our study found increased ROS at systemic, cellular, and mitochondrial levels, and NF-kB and TNFα pro-inflammatory activation and reduced eNOS expression in MRA and aorta. Altogether, these results strengthen the pivotal role of vascular dysfunction in malignant hypertension and the end-organ damage observed in DOCA-salt rats. In addition, the results reinforced this model as an important model with which to study non-controlled and severe hypertension and revealed potential tools to reverse this condition.
Daily doses of EWH after the onset of DOCA-salt hypertension prevented the increase in SBP by 36% in this experimental model, as shown in Figure 2 . The antihypertensive effect of EWH was previously demonstrated. EWH supplementation reduced and prevented the development of hypertension in SHR rats [ 14 , 15 ]. In addition, in animals exposed to toxic metals such as mercury and aluminum, EWH can reduce blood pressure to control levels. However, in this metal’s exposure models, the blood pressure levels were within normal limits [ 21 , 23 ] or in stage 1 of hypertension [ 2 , 22 ]. Moreover, in rats exposed to high concentrations of cadmium, which showed hypertension at high levels, EWH also reversed high blood pressure levels towards those of the control animals [ 24 ]. An essential point on which those results differ from those observed in the present study is that in animals exposed to toxic metals, the treatment was performed as a preventive tool, during the development of hypertension. By contrast, in the present study, the treatment was performed as a therapeutic tool, when hypertension was established.
As we described above, hypertension in the DOCA-salt model impairs vasodilator responses [ 7 , 10 , 40 , 41 , 42 ], and these vascular effects are strongly related to systemic and locally promoted oxidative stress and inflammation [ 7 , 10 , 43 ]. However, until now, there have been no studies in this model evaluating the effect of dietary EWH supplementation on vascular damage. The direct vasorelaxant effect of EWH and its isolated bioactive peptides were previously described in conductance and resistance arteries [ 15 , 16 , 19 , 21 , 22 , 23 , 24 ]. Fujita et al. (1995) isolated ovokinin peptide, whose amino acid sequence (Phe-Arg-Ala-Asp-His-Pro-Phe-Leu) was also identified in this EWH. Ovokinin showed a significant vasorelaxant response in the MRA of SHR rats [ 44 ]. Furthermore, other isolated peptide sequences (RADHPFL, RADHP, YRGGLEPINF, RDILNQ) of EWH also showed vasodilator properties in MRA, associated with increased NO synthesis, probably due to its amino acid composition and mainly due to the N-terminal position of Arg or Tyr [ 19 ]. In the present study, the improvement in ACh-induced endothelium-dependent relaxation in MRA and aorta of the DOCA-salt rats supplemented with EWH was due to the increase in endothelial function, as NO donor did not change its response among groups. The present results agree with previous results using models of exposure to different metals, in which the protective effect of EWH on the endothelium was observed in resistance and conductance vessels [ 21 , 22 , 23 , 24 ].
The bioavailability of NO is an important modulating factor of vascular vasodilator responses [ 7 , 45 ]. The present results demonstrated that the lower eNOS expression observed in MRA and aorta was restored towards the SHAM levels. In addition, using aorta segments as a model that represents the pivotal role of NO for endothelium-dependent relaxation, the present results also demonstrated that EWH supplementation in DOCA-salt rats recovered the NO-dependent participation in the ACh-induced relaxation, suggesting that EWH supplementation could improve NO bioavailability. Likewise, EWH restored the decreased NO levels in the arteries of rats exposed to mercury [ 23 ], and this effect was related to its capacity to increase NO release by enhancing eNOS activity [ 37 ]. Furthermore, the relaxation promoted by the RADHPFL, a peptide included in EWH, was endothelium-dependent and mediated by NO production via bradykinin B1 receptor activation [ 17 ]. In SHR rats treated with ovotransferrin-derived peptide, one of the main proteins present in raw egg white, NO levels were preserved in MRA [ 46 ].
NO bioavailability is the balance between NO synthesis and degradation. Thus, the restored endothelial function induced by EWH supplementation in MRA and aorta of DOCA-salt rats may be related to the antioxidant profile of EWH. This mechanism was confirmed in the present study by the reduction of oxidative stress (MDA and ROS) parameters in plasma and arteries, and by functional and immunohistochemical data. The antioxidant capacity of EWH and its bioactive peptides has been also previously described in models of genetic obesity [
47
] and metabolic syndrome [
48
]. In those studies, the antioxidant properties of EWH are related to some peptides, particularly by the Tyr-Ala-Glu-Glu-Arg-Tyr-Pro-Ile-Leu (YAEERYPIL) sequence, which has high radical scavenging activity.
An important source of O 2 − at the vascular level is the activation of the NADPH oxidase enzyme, related to the increase of NOX1 expression and activation [ 7 , 49 , 50 , 51 ]. In the present study, we observed that EWH was able to restore NOX-1 expression and O 2 − production in MRA and aorta of the DOCA-salt group. In line with these results, previously we reported that EWH also prevents the increase in ROS arising from the activation of NADPH oxidase and activation of NOX-1 and/or NOX-4 in animal exposure to heavy metals [ 21 , 22 ]. In the last two decades, the vital role of mitochondria in maintaining vascular homeostasis and ROS production has been highlighted [ 52 , 53 ]. In addition, mitochondrial O 2 − generation promoted vascular dysfunction in resistance and conductance arteries of the DOCA-salt model was described [ 8 ]. In part, that endothelial dysfunction is related to depletion of Sirt3 (a protein essential for mitochondrial health) and mitochondrial ROS generation [ 45 ]. In our study, MRA O 2 − generation was derived from two distinct sources, NADPH oxidase and mitochondria, and Mito-Tempo incubation and EWH supplementation restored the in situ and ex vivo mitochondrial ROS production observed in DOCA-Salt rats. Previously, EWH has described increasing mitochondrial DNA gene expression in brown fat tissue in a metabolic syndrome model [ 54 ]. However, the present study is the first that demonstrated EWH scavenging action on mitochondrial O 2 − generation in MRA; by this mechanism, EWH contributes to the restoration of endothelial function.
Another important mechanism related to excessive ROS production in the DOCA-salt model is the activation of transcription factors, which seems to be related to an inflammatory response and endothelial dysfunction [ 4 , 15 , 49 ]. Moreover, TNFα deficiency improved endothelial function and cardiovascular injury in hypertension [ 55 ]. Our study also demonstrated that in MRA and aorta of DOCA-salt hypertensive rats, increased NF-kB and TNFα expression by immunofluorescence and EWH supplementation restored the pro-inflammatory markers towards SHAM levels. In addition, we also observed the restoration of endothelial dysfunction in MRA of DOCA-salt rats by the blockage of NF-kB activation and no additional effect in MRA of DOCA-salt rats supplemented with EWH. In vessels exposed to metals, the anti-inflammatory role of EWH was previously described and related to cyclooxygenase-2 inhibition [ 21 , 22 , 23 , 24 ]. In addition, EWH was effective in reducing the systemic plasma levels of TNFα in obese rats [ 20 ]. Thus, the present results also show that by its anti-inflammatory effect and inhibition of NF-kB and TNFα expression, EWH may improve endothelial dysfunction in arteries of DOCA-salt rats.
5. Conclusions
The EWH supplementation in DOCA-salt rats, when the hypertension was stabilized, restored the mitochondrial and cellular ROS production, NF-kB activation, and TNFα pro-inflammatory levels, improving the eNOS expression and endothelial function in MRA and aorta and reducing blood pressure levels. EWH could be used as a natural functional food ingredient or as an adjuvant supplement in the treatment of vascular dysfunction related to malignant hypertension.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/antiox11091713/s1 , Figure S1: The role of EWH in NF-κB-induced impairment on acetylcholine (ACh) relaxation in MRA of DOCA-salt rats; Figure S2: The role of EWH in NO-mediated acetylcholine (ACh)-induced relaxation in the aorta of DOCA-salt rats; Figure S3: NO production is recovered by EWH treatment in aortic sections of DOCA-salt rats.
Author Contributions
E.d.L.A.: Investigation, Conceptualization, Methodology, Formal analysis, Visualization, Writing—original draft, review & editing. C.R.M.: Investigation, Methodology, Formal analysis, Writing—original draft, review & editing. S.H.H.K.: Investigation, Formal analysis, Writing—review & editing. R.B.d.P.: Methodology, Writing—review & editing. C.T.H.: Investigation, Writing—review & editing. P.H.D.C.: Investigation, Writing—review & editing. F.M.P.: Conceptualization, Methodology, Validation, Writing—original draft, review & editing. D.V.V.: Resources, Funding acquisition, Writing—original draft, review & editing. L.V.R.: Conceptualization, Methodology, Validation, Writing –original draft, review & editing. M.M.-C.: Conceptualization, Methodology, Validation, Resources, Project administration, Funding acquisition, Writing—original draft, review & editing. G.A.W.: Conceptualization, Methodology, Formal analysis, Validation, Visualization, Data curation, Supervision, Project administration, Resources, Funding acquisition, Writing—original draft, review & editing. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by the National Council for Scientific and Technological Development—CNPq [Edital Universal/CNPq No 44181/2014-9 and PQ/CNPq 311834/2020-5]; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES); Fundação de Amparo à Pesquisa do Rio Grande do Sul—FAPERGS/Brazil [PQG:19/2551-0001810-0]; Programa Nacional de Cooperação Acadêmica; Pró-reitoria de Pesquisa—Universidade Federal do Pampa [N. 20180615102630]; FAPES/CNPq/PRONEX [N. 80598773], Foundation for Research Support of the State of Sao Paulo (FAPESP 2019/08026-5), and Spanish Goverment by the Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) [AGL2017-89213]; I-COOP+2020 (COOPA 20453). ELA were supported by CAPES/Brazil, CRM by FAPERGS/Brazil and PHD, CTH by Unipampa. LVR are research fellows from CNPq (312237/2021-9).
Institutional Review Board Statement
The animal study protocol was approved by National Council of Ethics with Animals (CONCEA) and National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH, 1996), and the Local Institution Animal Care and Use Committee (protocol number 003/2020).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the manuscript or supplementary material .
Conflicts of Interest
The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.
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Figure 1. Schematic representation of experimental groups, DOCA-salt hypertension induction model and EWH treatment period.
Figure 2. Effect of EWH on SBP in DOCA-salt hypertensive rats. SBP values of SHAM, SHAM+EWH, DOCA, and DOCA+EWH groups, measured before and after nephrectomy (−1 and 0 weeks), during DOCA-salt model induction (1 to 4th week), and during the maintenance of the DOCA-salt hypertensive model co-treated or not with EWH (5th to 8th week). The EWH treatment started on the 4th week after DOCA-salt or SHAM treatment (orange-marked line). Data are expressed as mean ± SEM. The number of rats is indicated in parentheses. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
Figure 3. Effect of EWH in endothelium-dependent and -independent relaxation of MRA and aorta segments from DOCA-salt rats. Concentration–response curves to ACh ( A , B ) and SNP ( C , D ) in MRA and aorta segments from SHAM, SHAM+EWH, DOCA, and DOCA+EWH groups. The results are expressed (mean ± SEM) as the percentage of relaxation responses in norepinephrine or phenylephrine precontracted rings. The number of rats is indicated in parentheses. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
Figure 4. The role of endothelium on the effect of EWH in ACh-induced relaxation of MRA and aorta segments from DOCA-salt rats. Concentration–response curve to ACh in the presence (E+) and absence of endothelium (E−) in MRA (Upper graphics) and aorta (Bottom graphics) segments from rats SHAM, SHAM+EWH, DOCA, and DOCA+EWH. The results are expressed (mean ± SEM) as the percentage of relaxation responses in norepinephrine or phenylephrine precontracted rings. The number of rats is indicated in parentheses. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. E+.
Figure 5. The role of EWH in ROS-mediated ACh-induced relaxation in MRA and aorta of DOCA-salt rats. Concentration–response curves to ACh were obtained in MRA (Upper graphics) and aorta (Bottom graphics) segments from rats from SHAM, SHAM+EWH, DOCA, and DOCA+EWH groups before (E+) and after incubation with scavenger reactive oxygen species, the superoxide dismutase (SOD, 750/mL). The results are expressed (mean ± SEM) as the percentage of relaxation responses in norepinephrine or phenylephrine precontracted rings. The number of animals in each group is in parentheses. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. E+.
Figure 7. The role of EWH on O 2 − production in MRA and aorta section of DOCA-salt rats. Typical images of sensitive fluorescent dye Dihydroethidium (DHE) in the absence or presence of Mito-TEMPO (0.5 µmol/L—third line panel A ) or MnTMPyP (25 µM—third line panel B ) in MRA and aorta sections of SHAM, SHAM+EWH, DOCA, or DOCA+EWH rats. The basal images are the negative control pictures without DHE. The histogram ( a —MRA and b —Aorta) shows in white bars the DHE fluorescence and in black bars the DHE fluorescence after Mito-TEMPO or MnTMPyP incubation. The results are expressed as representative fluorescence intensity in arbitrary units. The results are expressed as mean ± SEM (n = 6). Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
Figure 8. The role of EWH on NOX1 expression in MRA and aorta section of DOCA-salt rats. Representative photomicrographs (×40 magnification) and histogram of NOX1 immunofluorescence in MRA and aortic sections of SHAM, SHAM+EWH, DOCA, and DOCA+EWH arteries. Data are expressed as mean ± SEM, n = 8. The images correspond to the merge of the marking of the colors by the DAPI in blue and the NOX-1 in green. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
Figure 9. The role of EWH on NF-kB and TNFα expression in MRA and aorta section of DOCA-salt rats. Representative photomicrographs (×40 magnification) and histogram of NF-kB (left) and TNFα (right) immunofluorescence of MRA and aorta sections of SHAM, SHAM+EWH, DOCA, and DOCA+EWH arteries. Data are expressed as mean ± SEM, n = 8. The images correspond to the merge of the marking of the colors by the DAPI in blue and the NF-kB and TNFα in green. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
Figure 10. Effects of EWH on the oxidative stress (ROS and TBARS) and antioxidant (FRAP) capacity in plasma, MRA, and aorta of DOCA-salt rats. ROS, TBARS, and FRAP values were assessed in plasma, MRA, and aorta of SHAM, SHAM+EWH, DOCA, and DOCA+EWH rats. The results are expressed as mean ± SEM, and the number of animals is indicated as dots in the bars. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
Figure 11. The role of EWH on endothelial NO synthase (eNOS) expression in MRA and aorta section of DOCA-salt rats. Representative photomicrographs (×40 magnification) and histogram of eNOS immunofluorescence of MRA (left panels) and aortic (right panels) sections of SHAM, SHAM+EWH, DOCA, and DOCA+EWH arteries. Data are expressed as mean ± SEM, n = 8. The images correspond to the merge of the marking of the colors by the DAPI in blue and the eNOS in green. Two-way ANOVA followed by Bonferroni post-test: p < 0.05 * vs. SHAM; # vs. DOCA.
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Water | Free Full-Text | Entropy-Based Research on Precipitation Variability in the Source Region of China’s Yellow River
The headwater regions in the Tibetan Plateau play an essential role in the hydrological cycle, however the variation characteristics in the long-term precipitation and throughout-the-year apportionment remain ambiguous. To investigate the spatio-temporal variability of precipitation in the source region of the Yellow River (SRYR), different time scale data during 1979& ndash;2015 were studied based on Shannon entropy theory. Long-term marginal disorder index (LMDI) was defined to evaluate the inter-annual hydrologic budget for annual (AP) and monthly precipitation (MP), and annual marginal disorder index (AMDI) to measure intra-annual moisture supply disorderliness for daily precipitation (DP). Results reveal that the AP over the SRYR exhibits remarkable variation, with an inclination rate of 2.7 mm/year, and a significant increasing trend. The climatic trend reversed from warm& ndash;dry to warm& ndash;wet around the turn of this century. The start of the wet season has advanced from May instead of June, supported by the proportion of MP in AP and the LMDI for May are both comparable with the values during June& ndash;September. May contributes the main changes in AP, as it is the only month in the wet season which shows a significant increasing trend during 1979& ndash;2015, and has a value in the LMDI that divides the basin in half spatially, the same as AP, with a high value in the northwest and low in the southeast. The AMDI roughly rises with latitude in spatial distribution, with wetlands and glaciers disturbing the continuity of the pattern for a relatively perennial moisture supply. AP has increased on northwest high-altitude areas first and then the southern corner since the beginning of this century. Wetting is mainly attributed to the enhanced southwest monsoon and the warming-induced freeze-thaw process. Meanwhile, AMDI variation concentrated on the Zoige Plateau Wetland, the headwater corner, the summit and part of the North Slope in the Bayan Har Mountain, as a result of a single or combined effect of global climate change and human protection.
Entropy-Based Research on Precipitation Variability in the Source Region of China’s Yellow River
by Henan Gu 1,2,* , Zhongbo Yu 1,2,* , Guofang Li 2 , Jian Luo 2 , Qin Ju 1,2 , Yan Huang 3 and Xiaolei Fu 4
1
2
College of Hydrology and water resources, Hohai University, Nanjing 210098, China
3
Fujian Provincial Investigation, Design & Research Institute of Water Conservancy & Hydropower, Fuzhou 350001, China
4
College of Civil Engineering, Fuzhou University, Fuzhou 350116, China
*
Authors to whom correspondence should be addressed.
Water 2020 , 12 (9), 2486; https://doi.org/10.3390/w12092486
Received: 15 August 2020 / Revised: 25 August 2020 / Accepted: 3 September 2020 / Published: 5 September 2020
(This article belongs to the Section Hydrology )
Abstract
:
The headwater regions in the Tibetan Plateau play an essential role in the hydrological cycle, however the variation characteristics in the long-term precipitation and throughout-the-year apportionment remain ambiguous. To investigate the spatio-temporal variability of precipitation in the source region of the Yellow River (SRYR), different time scale data during 1979–2015 were studied based on Shannon entropy theory. Long-term marginal disorder index (LMDI) was defined to evaluate the inter-annual hydrologic budget for annual (AP) and monthly precipitation (MP), and annual marginal disorder index (AMDI) to measure intra-annual moisture supply disorderliness for daily precipitation (DP). Results reveal that the AP over the SRYR exhibits remarkable variation, with an inclination rate of 2.7 mm/year, and a significant increasing trend. The climatic trend reversed from warm–dry to warm–wet around the turn of this century. The start of the wet season has advanced from May instead of June, supported by the proportion of MP in AP and the LMDI for May are both comparable with the values during June–September. May contributes the main changes in AP, as it is the only month in the wet season which shows a significant increasing trend during 1979–2015, and has a value in the LMDI that divides the basin in half spatially, the same as AP, with a high value in the northwest and low in the southeast. The AMDI roughly rises with latitude in spatial distribution, with wetlands and glaciers disturbing the continuity of the pattern for a relatively perennial moisture supply. AP has increased on northwest high-altitude areas first and then the southern corner since the beginning of this century. Wetting is mainly attributed to the enhanced southwest monsoon and the warming-induced freeze-thaw process. Meanwhile, AMDI variation concentrated on the Zoige Plateau Wetland, the headwater corner, the summit and part of the North Slope in the Bayan Har Mountain, as a result of a single or combined effect of global climate change and human protection.
Keywords:
precipitation
;
;
variability
;
the source region of the Yellow River
1. Introduction
The analysis of the long-term time series of hydro-meteorological variables is vital to assess potential water resources and to study environmental changes. Precipitation is one of the principal factors in terrestrial water cycles, and its spatial-temporal distribution is as important as the amount, if not more, since the type of water demands vary with time and location [ 1 ]. Besides, global climate change has intensified the hydrological cycle with increasing evidence supporting the continued occurrence of temporal and spatial variations in precipitation around the world, which would affect the availability of water resources and accelerate the ongoing competitions. Therefore, further study into the mechanisms responsible for the variability in precipitation has become quite essential. The distribution of precipitation at multi spatio-temporal scales and its effects on ecosystems has been popular in hydrology and ecology, as a hot issue, for some time. Some methods have been developed, including the Shannon entropy method [ 2 ], principal component analysis [ 3 ], harmonic analysis techniques [ 4 ], etc. Entropy-based measures contain more information about the probability distribution among diversified statistics that generally delineate variability [ 5 ], and they also have advantages in flexibility, by which the dispersion of precipitation could be measured at multi-scales, such as annual, seasonal, or monthly. Disorder index serves as the standardized information entropy in this study to evaluate the spatial and temporal characteristics of rainfall.
Although precipitation distribution is a continuous concern in the field of water science, very little research has been conducted in mountainous areas, much less the plateau mountainous area in cold regions. Complex terrain and sparse observation stations are major difficulties for such studies [
6
]. Weather stations tend to be built on flat terrain or in places that are easy to access and record, and that leaves a lingering problem in mountainous areas with measuring the orographic precipitation, which causes different rainfall on two sides. High elevation worsens the situation as the measurement conditions are much harsher for people to install equipment and record data. Therefore, except for the observation records, datasets from other sources should be employed for a better representation of the natural precipitation process. The application of the remote sensing product with fine resolution also enables the research on the spatial distribution of temporal variation in precipitation.
The entropy-based marginal disorder index is applied to quantify the variability of the precipitation spatiotemporal distribution in the source region of the Yellow River (SRYR). Datasets employed for the entire study period between 1979–2015 are time series with an annual, monthly, and daily resolution from an assimilation precipitation product. Annual and monthly precipitation series are used in the investigation of long-term inter-annual variability, and daily series are applied to analyze the over-a-year precipitation apportionment within each year. The following aspects of temporal trends and their spatial distribution patterns of precipitation are addressed in the study: to investigate the spatio-temporal distribution of the variability of long-term precipitation over the SRYR and to determine the possible monthly series dominating the disorder of annual series, based on annual and monthly precipitation datasets; to probe the intra-annual distribution of precipitation series with daily resolution within each year and to find the time and location with a high value; to detect the stationarity and trend in long-term precipitation and its variability using the Pettitt and M–K tests, and divide the study period into stages according to typical characteristics; to evaluate the features and changes in the spatial distribution of precipitation and its variability on a decadal scale and to compare disorderliness within each decade. The specific flow is shown in
Figure 1
.
2. Materials
2.1. Study Basin
The Tibetan Plateau (TP) is the world’s highest and largest plateau, termed “the Third Pole of the earth”, with an average elevation exceeding 4500 m and an area of 2.5 × 10 6 km 2 . It is also known as the Asia’s “water tower”, for it is covered with a remarkable number of glaciers, snow, permafrost and lakes, which contain the mountainous headwaters of the Yangtze, Salween, Mekong, Indus, Brahmaputra and Yellow rivers. The TP is one of the most vulnerable areas to environmental changes for its typical hydrological, geographical and ecological features [ 7 ]. The source region of the Yellow River (SRYR) spreads most alpine meadow grassland and wetland of the TP and thus its ecosystem is strongly related to the variation in precipitation, and it is selected as a case to study the changing features of precipitation. The SRYR in the study refers to the basin above the Tangnaihai hydrological station (100.15° E, 35.5° N), which controls a drainage area of 121,972 km 2 between 95.88° E–103.42° E and 32.15° N–35.73° N in the northeastern TP ( Figure 2 ). The SRYR generates 34.5% of the total annual runoff and accounts for only 16% of the basin area of the Yellow River. The Yellow River originates in the Mt. Bayan Har and flows eastward in general, with its altitude decreasing from 6253 m to 2677 m. The highest elevation is found at the summit of Mt. Amne Machin, Machin Kangri (summit M), which is covered with permanent snow and contributes about 98% of total glacier areas (164 km 2 ) over the basin [ 8 ]. The SRYR contains 5300 lakes with a total area of 2000 km 2 [ 9 ]. SRYR covers with the typical alpine meadow steppe, covering 80% of the area, and is part of the Four Major Pastoral Areas in China. However the degradation in its ecosystem has been prevailing [ 10 ]. Because of no large dams and a low population density, the impact of human activities is relatively low in the area [ 11 ].
There are roughly two climate seasons in the SRYR, the wet season and dry the season, and about 75–90% precipitation falls in June–September as a result of the southwest monsoon from the Bay of Bengal [ 12 ]. The regional average AP over the SRYR is about 540 mm, and the amount decreases from southeast (SE) to northeast (NW). The annual mean air temperature is about −2.5 °C over the SRYR, and is negatively related with the altitude in spatial distribution.
2.2. Precipitation Datasets
Traditionally, the characteristics of rainfall are investigated based on the meteorological observation datasets [
7
]. Over the SRYR, there are twelve national rain gauges, among which four were removed from the China Meteorological Administration (CMA) station list gradually before 1998. The geographical information of the meteorological stations is listed in
Table 1
. Moreover, the eight weather stations with long-term datasets are in the elevation range from 3440 m to 4272 m, while the elevation of SRYR stretches from 2677 m to 6253 m, with an average elevation of 4126 m. That is to say, only an 833 m range out of the altitude difference of 3576 m was observed, with one station located above the mean height. Besides, weather stations tend to be built on flat terrain for easy access by recorders. Therefore, the datasets of sparse meteorological stations over the SRYR are not adequate replacements for the natural precipitation process in the basin.
To overcome the defects by only adopting observation datasets, an assimilation precipitation product CMFD (China Meteorological Forcing Dataset) [ 13 ] is applied in the research, which is derived from CMA station data and remote sensing datasets, and is available from the National Tibetan Plateau Data Center. The remote sensing data sources include TRMM (Tropical Rainfall Measuring Mission) satellite precipitation analysis data (3B42), GLDAS (Global Land Data Assimilation System) data, GEWEX (Global Energy and Water cycle Experiment)-SRB (Surface Radiation Budget) downward shortwave radiation data, and Princeton forcing data [ 14 ]. It currently covers the period from 1979 to 2015, with spatial resolution 0.1 × 0.1° and temporal resolution 3 h., containing seven variables such as air temperature, surface pressure, relative humidity, wind, downward shortwave radiation, downward longwave radiation and precipitation rate. The effectiveness of CMFD was demonstrated with its high performance in the study of the spatiotemporal characteristics of climate-related factors, like surface temperature, precipitation and radiation [ 15 , 16 , 17 ].
Fifty one grids at 0.5 × 0.5° intervals were selected as feature objects out of the 1200 grids covering the SRYR. According to the Natural Breaks (Jenks) classification system and the ASTER (Advanced Spaceborne Thermal Emission and Reflection Radiometer)-GDEM (Global Digital Elevation Model) [
13
], 10 grids each located in the area with the elevation ranges of 2677–3651 m, 4001–4305 m, 4305–4553 m, 4553–6253 m, and 11 fall in the 3651–4001 m elevation range. In other words, the selected grids are evenly distributed both horizontally and vertically (see
Figure 2
). Daily, monthly and annual precipitation series are employed, abbreviated as DP, MP and AP respectively in the study. The basic statistical properties for the selected AP series during 1979–2015 are displayed in
Table 2
, as mean annual precipitation (Mean), maximum annual precipitation (Max), minimum annual precipitation (Min) and coefficient of variation (CV). The grids with a high CV are mainly concentrated in the western mountainous area and on the northern edge, where AP is generally low. The range of mean, maximum and minimum AP is 270–839 mm, 482–1076 mm and 153–591 mm, respectively. The mean and minimum AP share a similar distribution; both have 28 girds lower than the average and only two do not overlap in
Figure 2
. While 27 maximum AP series are higher than average, among them 20 are located at low altitude regions where the mean and minimum are also high, and the other numbers are 7, 10, 13, 23, 32, 33 and 37, concentrated in a small range of two latitudes.
2.3. Land Cover Map
The land cover type is crucial to estimate water and carbon cycles, ecosystem dynamics and climate change. The Multi-source Integrated Chinese Land Cover (MICLCover) map is adopted in the study for its high accuracy in China [
18
]. The MICLCover map was derived from multi-local-source land cover and land use classification datasets including a 1:1,000,000 vegetation map, a 1:100,000 land use map for the year 2000, a 1:1,000,000 swamp-wetland map, a glacier map, and a Moderate-Resolution Imaging Spectroradiometer land cover map for China in 2001 (MODIS2001), which were integrated through the practical evidence generation scheme. The map uses the widely applied International Geosphere-Biosphere Programme (IGBP) land cover classification system, with 1 km resolution. The MICLCover map provides more spatial details at the local scale compared with other popular products, e.g., IGBP DISCover and MODIS2001, particularly for cropland, urban, glacier, wetland and water body.
3. Methods
3.1. Calculation of Variability
3.1.1. Entropy
Shannon introduced entropy as a measure of information, dispersion, uncertainty and disorder. The simplified expression of the discrete form of informational entropy, termed as Shannon entropy [
19
], is:
H
(
=
−
∑
k
=
1
n
p
(
x
k
)
l
o
g
2
[
p
(
x
k
(1)
where
n
is the number of possible events,
k
represents a discrete temporal interval,
x
k
is its corresponding result,
p
(
x
k
)
denotes the probability of
x
k
, and
H
(
X
)
is the entropy expressed in bits as the base of logarithm takes 2.
Shannon entropy reflects the uncertainty information about a certain distribution. For a variable X, H reaches its maxima
log
2
n
if all outcomes are equiprobable with
p
(
x
k
)
= 1/
n
, while quite the opposite, H equals its minima zero if every
p
(
x
k
)
but one is zero. The value of entropy varies within the range of zero to
log
2
n
, according to the pattern of the distribution.
There are other measures of dispersion degree of a random variable, among them variance is the most well-known one. The equation of variance is as below [
20
]:
σ
2
=
∑
(
X
−
μ
)
N
(2)
where
σ
2
represents the population variance,
X
represents the random variable,
μ
represents population expectation and
N
is population size.
According to the equation, variation measures the deviation extent of the random variable compared with the population expectation or the mean, thus variation reflects the uncertainty related to the expectation. The same goes for the measures based on variation, like standard deviation and CV. While the entropy reflects the overall uncertainty, as it neither relies on the expectation nor on the sample of the population, but only on its probability. Thus entropy has obvious advantages in measuring the uncertainty of a certain distribution.
3.1.2. Entropy Application in Precipitation Analysis
Shannon entropy can be served as a functional estimate of the uncertainties in a long-term time series of rainfall. In statistics, variability is the extent to which a distribution is stretched or squeezed, whose measure is a nonnegative real number that is zero if all the data are the same and increases as the data become more diverse [
21
]. From this aspect, the variability of precipitation can be quantitatively measured by using an entropy concept. In its previous application, precipitation time series at different temporal scales, like annual, seasonal and monthly, were considered individually, to better understand the uncertainty or variability within each scale and to make a comparison among them.
Take a daily series of an entire year at a fixed location, for example, to explain the application of entropy concept in precipitation time series. Daily precipitation could be viewed as a discrete equal-interval random variable. Let the discrete temporal interval be the number of days in a year (
nd
), e.g., 365, and its corresponding outcome is daily precipitation apportionment, and then the probability of each event is the daily precipitation (
DP
) divided by the aggregate precipitation during the year (
AP
). Hence the uncertainty degree can be determined by entropy in terms of the probability density of precipitation randomly apportioned over fragmented times. This entropy is also called marginal entropy (ME) with the annual expression as follows:
ME
=
−
∑
k
=
1
n
D
P
)
=
∑
k
=
1
n
d
D
P
k
.
If the scale changes, DP k refers to the data on that scale, and the total number ( nd ) and the sum ( AP ) change accordingly.
3.1.3. Disorder Index
Entropy evaluates the uncertainty degree of time series at certain points. A quantitative measure of variability should be comparable among temporal and spatial results. The Disorder index (DI) serves as a standardized measure based on entropy, which is defined as the difference between the possible entropy maxima and the actual entropy calculated from a certain series. The maximum possible entropy refers to the value from the uniform distribution. For example, the maximum possible marginal entropy is
log
2
n
, for a daily precipitation series with size
n
. DI measures the degree away from the hypothetic most-scattered distribution, the distribution with low DI is dispersive, on the contrary, the high DI distribution is non-uniformed. That is to say, the value of DI is in accordance with the degree of variation of a series.
Mishra, et al. [
2
] defined the marginal disorder index (MDI) as the disorder index for marginal entropy. And the mean disorder index is formed as the arithmetic average of the values of DI within a given period. There are several kinds of MDI involved in the study, long-term MDI (LMDI), based on long-term annual or monthly precipitation series; annual MDI (AMDI), based on the daily precipitation series within each year; and the decadal averaged annual MDI (DAMDI). Among the derived MDI, AMDI is a series with the same length as the study years, which refers to the MDI of each year, based on daily precipitation, specifically used for revealing the throughout-the-year precipitation apportionment. And DAMDI is its decadal average value to uncover the intra- and inter-decadal variations of precipitation apportionment on a yearly basis. The equations related to the description above is listed below:
MDI
=
l
o
g
2
n
d
−
ME
(4)
where
nd
is the total number, and ME can be calculated by Equation (3);
LMDI
=
l
o
g
2
n
y
+
∑
k
=
1
n
y
(
P
k
L
S
P
)
l
o
g
2
(
P
k
L
S
P
)
(5)
where
ny
is number of years during the entire study period,
LSP
represents the long-term sum of precipitation, and
P k
is a certain precipitation data with a given resolution, e.g., if analyzing the disorderliness in the long-term
AP
,
P k
is
AP k
, an
AP
data during the period, else if the aim is an individual month, then
P k
is
MP k
, a monthly data of the target month within the period. Thus, the LMDI always appears with an explanation.
3.2. Statistical Test
The monotonic trend and the abrupt change of precipitation time series were detected by non-parametric tests, the Mann–Kendall (M–K) test [
22
,
23
] and the Pettitt test [
24
], respectively. The M–K test and the Pettitt test, with a rejection rate of 5%, were applied in the study. If
U
M
K
> 1.96 or
U
M
K
< −1.96, a significant increased or decreased trend of the targeted time series could be accepted. When
p
p
e
t
t
i
t
t
≤ 0.05, the stationarity hypothesis would be rejected and the change-point would be determined correspondingly. Because the Pettitt test checks the stationarity assumption among populations and a population should contain at least ten elements, the detected abrupt change-points are taken between the elevenths from the head and the end.
4. Results and Discussion
4.1. Variability of Precipitation
4.1.1. Inter-Annual Variation of Annual and Monthly Precipitation
The LMDI mainly indicates the variation of local precipitation in a fixed time interval during a period, and it takes a longer interval to achieve a detectable level of changes. If a fixed day was selected, for example, the first day of each year, and the changes of daily rainfall happened on that day every year were examined for a period, the high randomness would make the results meaningless. In the study, monthly and annual datasets are selected in the long-term variability of precipitation analysis. The LMDI is calculated for the selected 51 annual and monthly series during 1979–2015, and the statistics of results are displayed in
Figure 3
. It is obvious that the LMDI on an annual timescale is lower than those of each month. The uncertainty of precipitation distribution in the dry season (October to next April) is much higher, and contributes to the main variability within a year; we take May as the start of the wet season in this study. The average LMDIs in the wet season are all about 0.1. November to next February have the highest LMDIs, the averages of which are above 0.3. The rest three months, March, April and October, have similar mean LMDIs of about 0.2. The dry season has a more nonuniform precipitation distribution than the wet season, which applies to spatial distribution as well, as the range of the LMDI in the dry season is wider.
To better delineate the spatial distribution of the LMDI for AP, the method is generalized to all 1200 series and the mean values are drawn in
Figure 4
. High LMDI clusters are on the NW side of the basin, with the highest LMDI in red appearing mainly in the northern highest attitude area in the SRYR, which basically matches with the white color on north part in
Figure 2
; to be exact, the NW edge and the summit M.
Figure 4
have also exhibited the distribution of regions with significant trends in long-term AP series during 1979–2015, detected by the M–K test with a rejection rate of 5%. The regions covered by plus signs (+), most of the NW part, have significant increasing trends in the amount of AP, and the regions with slashes (\), covering a small area on the north edge of the SE corner, have significant decreasing trends.
The M–K test is also applied to detect the trends of the MP series individually for the 1200 grid during 1979–2015 in the SRYR; the regional mean statistic results as well as the multi-year average of each month are shown in
Figure 5
. About 83% annual precipitation falls in the wet season, the range of MP in May–September is from 62 mm to 111 mm, and from June–July is above 100 mm. The seven MPs in the dry season range from 3 mm to 35 mm, the highest month is October, and the value of November to next February is not higher than 6 mm. Every month shows an increasing trend in precipitation, among which the trends of three months are statistically significant: January, February and May. The disorderliness and trends of the MP series in these three month are detailed in
Figure 6
. Comparing the LMDI of the months from different perspectives, from the magnitude, May has the lowest LMDI, ranging from 0.03 to 0.29, and the LMDI of January and February is much higher, the maximum is both over 1.0; from the spatial distribution, May gradually increases from SE to NW, while the other two months have more than one high value region. All three months show an increasing trend over the SRYR, and the significant regions are marked in
Figure 6
with plus signs (+), and the area with marks in May shows much less than the other months. The precipitation almost increases all over the SRYR in January, except in the Northern Amne Machin Mountain. The area in February with a significantly increased trend, covers the whole middle region. There are three marked parts in May, the Summit M neighborhood, and the NW, SW corner. Compared to
Figure 4
, the high LMDI for AP clusters in the north edge on both annual and monthly scales, and the LMDI in May has a similar pattern.
4.1.2. Intra-Annual Distribution of Daily Precipitation
The daily precipitation time series is employed in the calculation of the annual marginal disorder index (AMDI). A similar approach in inter-annual analysis is applied to investigate the long-term AMDI series, while different from LMDI, AMDI is a series instead of a single value. The AMDI series ranges from 1.52–1.93 during 1979–2015, with the minimum and maximum in 1989 and 2002, respectively. There is an insignificant trend in the AMDI on the basin scale during study period, with a statistic as 0.6 according to the M–K test. The spatial distribution of the multi-year average AMDI over the SRYR during 1979–2015 is displayed in
Figure 7
. The multi-year mean AMDI ranges from 1.46 to 2.17, with the mean and standard deviation at 1.75 and 0.15, respectively. The value roughly increases with latitude, with wetlands and glaciers disturbing the continuity of the pattern by about −0.1 in AMDI. Moreover, the southern edge and the summit M have the lowest AMDI, and the northern edge has the highest AMDI, especially in regions around the Tangnaihai station (Grid 29).
Figure 8
serves as a profile chart interpreting the feature of the long-term AMDI series in each grid, and wide ranges exist in most selected series. The variance tendency of AMDI would help in the understanding of the temporal distribution, and thus the trends at each grid were computed and the significant ones were also displayed in
Figure 7
.
4.2. Variation of Precipitation Distribution
4.2.1. Abrupt Change Analysis and Stages Division
The Pettitt test with a rejection rate of 5% is applied to the selected 51 AP and AMDI series from 1979 to 2015, and valid results are listed in
Table 3
. Thirty nine AP series show abrupt changes, from which 59% was detected in 2002 and 2003, 14 and 9 grids respectively, and no abrupt change occurred from 1990 to 1996 and after 2005. While 32 AMDI series showed abrupt changes, and 53% in 1997 and 1998, 12 and 5 grids respectively, no abrupt change was detected in the years before 1991, 1993, 1994 and after 2003. That is to say, the breaks in the stationarity of AP and the AMDI series is mainly concentrated during 1997–2004 and 1995–2002 respectively, and the AMDI series varied generally earlier. Moreover, the spatial distribution of the abrupt changes of precipitation amount and variability is also asynchronous. Examining the means for clustered grids numbered 1–4, for example, the AP series all demonstrated strong increases in 2003, while the means of the AMDI at Grids 1 and 3 changed abruptly in 1995. For Grid 4, the AMDI mean changed abruptly in 2001, but no abrupt changes were noted in Grid 2.
Abrupt changes of the amount and variability of precipitation occurred gradually over the SRYR, and it is necessary to divide the whole study period (37 years). According to the results in
Table 3
, four equal stages were adopted, 1979–1988, 1988–1997, 1997–2006 and 2006–2015, by duplicating the breakpoints in the previous decade to the following. The first decade, 1979–1988, with scarce sudden changes, represents a “natural decade”; the second, 1988–1997, is a stage with little changes before the end, making it a “pre-change decade” when environmental changes were conceived; the third, 1997–2006, is a “changing decade”, when the effects of climate change emerged and abrupt change was concentrated; and the last, 2006–2015, during which most statistic characteristics transformed to a new population due to a changing environment, is taken as “impact decade”.
4.2.2. Annual Precipitation and Intra-Annual Variability Distribution in Stages
There are widespread changes in the distribution of the decadal averaged annual precipitation (DAP). The regional mean and extremes of DAP and its inclination rate are listed in
Table 4
. The range of AP during each decade is 186–890 mm, 166–844 mm, 237–896 mm and 314–920 mm successively. The value shows that the DAP decreases before 1997 and then increases, and the maximum value is the most sensitive statistic according to the inclination rate over each decade. The M–K test, with a rejection rate of 5% only detected an insignificant trend during each decade on the basin scale, with the statistic as −1.25, 0.36, 1.43 and 0 in sequence. The distribution patterns of DAP over each decade are shown in
Figure 9
. It is observed that the average of AP over the first and second decade roughly trend in the NW direction as bandings, with the highest value at the SE corner and decreasing forward. The pattern became more and more unorganized ever since 1997, and the precipitation over the summit M changed more dramatically than that of the rest of the central and upper basin. The regions with significant trends detected by the M–K test are also displayed in
Figure 9
. In the first decade, the precipitation weakened at the range from 600 mm to 700 mm. The second decade scarcely has areas with significant trends. Most of the dry west region experienced an increased period over the third decade, and the wet southern corner increases afterwards over the most recent decade. AP increased on the NW high-altitude areas first and then in the southern corner, the summit M changed from 390 mm to the 680 mm level, and the southern corner was raised by about 50 mm.
Extensive changes exist among the distribution patterns of the decadal averaged annual marginal disorder index (DAMDI), which are displayed in
Figure 10
. The DAMDI roughly increased with latitude before 1997, and the pattern has been broken by the summit M neighborhood afterwards. It is a remarkable fact that the highest DAMDI gathers around the basin export (Grid 29). The range of DAMDI during each decade over the SRYR is 1.41–2.27, 1.32–2.27, 1.30–2.41 and 1.34–2.37 successively, and the regional mean first decreases and then increases then decreases again, however the change is slight, with the inclination rate of −0.10 (10·a
−1
), 0.08 (10·a
−1
), 0.08 (10·a
−1
) and −0.04 (10·a
−1
) in sequence, according to the statistic in
Table 4
. The maximum is the most sensitive value, and the rate of the mean DAMDI is 0.01 over the study period. The M–K test, with a rejection rate of 5%, did not detect any significant trend during each decade on the basin scale, the statistics are −0.72, 0.36, 0.54 and −0.18 in sequence, while certain parts show significant trends within a small area during one decade. For the first decade, the Grid 11 neighborhood shows decreasing trends with vertical strip shape; the second decade has a circle shape increasing trend around Grids 27–28; there were two spots with trends in the third decade, one decreasing at the WN origin corner, the other increasing around the SE Grid 45; the most recent decade has multiple small areas with trends, two decreasing ones are noticeable, the Summit Grid 18 and Grid 46 near the Zoige wetland.
The evolution of annual precipitation and its variability was studied above through four single continuous decades. The regional average DAP and DAMDI generally reduced first and increased later, and patterns varied towards the irregular mainly due to interference from the shift in values over the summit and NW regions. The DAMDI has a barely changed mean, a slightly decreased minimum, and an increased maximum. The statistics all increase in the DAP, and the greatest rate in the mean of DAP emerged in the last decade, later than the extremes of 1997–2006. The distribution is distinguishable, which means that the nature of precipitation is different from its variability.
4.3. Implication of Precipitation and Its Variability
4.3.1. Long-Term Precipitation Variation Characteristics
The AP series shows a significantly increased trend during 1979–2015, and the monotonic trends of AP reversed from downwards to upwards gradually over the SRYR from the end of the last century to the beginning of this century. The increase in the MP in May contributes the main changes in AP, and May should be the start of the wet season, instead of the traditional season between June–September. May has a great share of AP, it accounts for about 11.6%, while the other months in the dry season accounted for no more than 6.5%; during 1979–2015, the proportion of MP in May is comparable to that of MP during June–September, which ranges from 15.3% to 20.6% (see
Figure 5
). Moreover, the magnitude of LMDI in May is much less than that in other months in the dry season, the value is around 0.1 during May–September, and in the other months, all are above 0.2 (see
Figure 3
). That is to say that, during the study period, the MP in May, as well as its variability, is close to the value of the traditional wet season, thus May should be classified as a wet season. MP in May is the only month in the wet season in sync with AP and the significantly increasing trend during 1979–2015 on the basin scale, according to the M–K test (see
Figure 5
). Additionally, the spatial distribution of LMDI in May is conformed to that of AP, dividing the basin into two halves based on a value, which for MP in May is 0.1m within the range 0.03–0.29 and for AP is 0.02, within 0.01–0.10, with NW over the value and SE under it (see
Figure 11
). Overall, the wet season begins from May to September over the SRYR during 1979–2015, and the changes in AP series mainly attributes to the variation in May.
LMDI of the AP series indicated an unevenly distributed hydrologic budget over the SRYR, and the changes in the Northern edge and the summit M are more concentrated and prominent on an annual basis, see
Figure 4
. There are high LMDI regions covering with a significantly increasing trend. The overlap region means on the one hand that it has a non-uniformed moisture supply annually, and on the other, the casual input of precipitation generally became abundant in amount. That is to say, the long-term precipitation in the most NW area is both scarce in amount and sparse in distribution on an annual time scale. The summit M neighborhood is a typical overlap area, which is involved in the water circle during the last two decades, by disturbing the original stair-step shape in
Figure 9
.
The variation of DAP among decades indicates that the nature of precipitation has been disturbed and affected by global climate change during the study period. Warming is a key feature of the global climate change in the Tibetan Plateau. For the unique permafrost ecosystem in the SRYR, soil freezing and thawing is highly depend on temperature, thus the region is very vulnerable to warming. The freeze-thaw process in the SRYR has drawn lots of attention worldwide [
25
]. Thawing of soil is accompanied with moisture transfer and heat exchange, therefore releasing water into the dynamic hydrologic cycle. The regional mean temperature of the SRYR is −2.5 °C, and the climate inclination rate was 6.7 °C (100a)
−1
during 1979–2015. The whole region shows a temperature-raising trend, and except for the small area in the NW corner, it is significant during this period, which is shown in
Figure 12
a. The regional mean temperature is above 0 °C during May–September, according to the distribution of the average value of monthly temperatures in
Figure 12
b, and the raising trend is significant every month during the period. Warming and human construction is threatening the glaciers and permafrost, the water used to be on hold in ice was thought to be now releasing gradually into the local hydrological cycle. Another impact of rising temperatures lies in the precipitation transformation. Due to the low temperature and dramatic daily temperature differences, precipitation is mostly in the form of hailstorms, and warming helps in solid-to-liquid changes. Thus physical state changes related to warming is another reason for the high LMDI.
The reason for the variation in precipitation could also be drawn from the spatial and temporal distribution of inter-annual amounts and variability. Given that the main moisture source of precipitation is the summer monsoon, the big leap in minimum DAP of 71 mm at the headwater NW corner between the decades before and after 1997 in Figure 9 implies that moisture was further transmitted. There were three regions concentrated with a significant increasing trend over the SRYR at two stages after 1997, the central and upper regions during 1997–2006 in Figure 9 c, and the lower SE region around the inlet of the summer monsoon during the last decade in Figure 9 d. From the perspective of a summer monsoon, the increasing trend in the central and upper regions supported the monsoon enhancement first and then the increase in the lower region forecasts the enhancement persistence. From the perspective of the freeze-thaw process, the central and upper regions including the summit M are the permafrost areas, and the lower region is the seasonal frozen area, both concentrated with the effects of thaws. Thus the water vapor could be from the release of the freeze-thaw process. May contributes the main changes in the increase of AP. Zhang, et al. [ 26 ] uncovered that the wetting trend over the TP in May has resulted directly from the earlier onset of the South Asian summer monsoon since the late 1970s and is associated with the phase transition of Inter decadal Pacific Oscillation around the late 1990s, and that the South Asian summer monsoon explains 95% of the increase in the total amount of precipitation in May. The results in this study support this conclusion. High LMDI for MP in May is in the NW part, and May has three regions with significant increasing trends—the SE corner, the Middle region and NW corner, in Figure 6 c. According to the route of the summer monsoon in the SRYR, these regions could represent the inlet, barriers and hard-to-reach destinations. As is well-known, summer monsoons have a lower entrance in the SE corner, and mainly travel along the south edge before the rising high altitude block their way, and then climb up and spread out while losing moisture [ 27 ]. That is to say, the increasing precipitation in May could hint at the early onset of a summer monsoon.
4.3.2. Throughout-the-Year Moisture Supply
The AMDI calculates the uniformity of the apportionment of AP and reflects the moisture persistence within a year at a fixed location. High AMDI indicates an unsustainable water supply, while low AMDI indicates a relatively more stable moisture supply. The origin of precipitation could be water vapor transportation and local evapotranspiration, and thus the supply could be from outside or from a local cycle.
Figure 7
displays the distribution of AMDI and the variation trend; for easy interpretation, the information is combined with a land cover map in
Figure 13
. Extensive differences exist among the distinctive underlying surfaces, and three regions disturb the continuity of contour lines, due to a relatively low AMDI compared with the neighborhood, marked with
a , b
and
c
. Region
a
is in the Maduo country [
28
], which has the nickname “thousand-lakes country”, with one third of the area being wetland; Region
b
is around the summit M, the highest point in the basin, covered with permanent snow and glaciers; Region
c
is the Zoige Plateau Wetland, the main grazing place. Region
a
and Region
c
are both covered with wetland; abundant water reserves and evaporation helps in the supply and offers a low AMDI. Region
b
used to be scarcely involved in the local exchange of water and energy, but it was slightly interrupted by the active hydrological cycle, which could be the explanation for its low AMDI.
To better understand the variation of AMDI, especially the four regions with significant trends during 1979–2015, local environment should be involved. Firstly, the Zoige Plateau Wetland is the only region located in the SE part, with the largest increasing area among the four. It is the most famous grazing place over the SRYR, since its lower altitude makes it easier to access and warmer to protect the animals in the cold dry season. However, it is suffering from a continuous shrinking problem related to over-grazing and rodent damage, as well as climate change [ 29 ]. The degradation could be the reason that there is damage in the sustainable water supply, which is supported by Figure 9 c and Figure 10 c during 1997–2006, when the DAP did not significantly vary and the DAMDI had an increasing trend. Secondly, the summit M neighborhood has a decreasing trend, which means that the supply tends to be perennial. Considering the altitude, a monsoon could barely disturb the water income in this region. The water transformed from a solid state is more likely to be the main source of the local cycle, and the low and raising temperature could guarantee that the supply would be slow and stable. DAP increases during 1997–2006 in Figure 9 c, and the decreasing trend in DAMDI, appears afterwards in Figure 10 d, when temperatures are higher. Thirdly, the decreasing trend in the headwater NW corner could be a mixed result of more water transfer from the summer monsoon and snow and permafrost thaws, together with warming, giving a more perennial supply. This deduction could be supported with the increasing DAP in Figure 9 c and the decreasing DAMDI in Figure 10 c during 1997–2006 over the corner. Lastly, the region between the headwater NW corner and the summit M is part of the North Slope in the Bayan Har Mountain, which could most easily be influenced by the enhanced southwest monsoon, thus resulting in a more concentrated supply. The scale jumps in DAP between Figure 9 c,d, meanwhile DAMDI generally remainsing over the region could serve as a proof.
Another noticeable point in the DAP and DAMDI from the last decade is the SE wetlands at the neighborhood of Grid 46, where DAP increases and DAMDI decreases. This means that the local water supply tends to be perennial under the condition of wetting. This could be the joint effect of global climate change and ecological and environmental protection directed by the government. It is near the inlet of a summer monsoon, and is downstream of the mountainous regions, and thus more water vapor would be from enhanced monsoon and runoff due to the freeze-thaw process. If the increase is mainly contributed by monsoon, there would be a bigger DAMDI for temporal supply. Runoff could offer a relatively long-lasting supply of water only if the underlying surface has the storage capacity. Due to long-term over-grazing, the wetlands in the SRYR have experienced a severe shrinking period, as herd livestock is the dominating economic activity for local residents. The number of sheep has reduced by 71.7% since 1990 in the Maduo country, and large-scale ecological immigration has been implemented by the government [
30
]. This fact offers us some inspiration for how to deal with the impact of global environmental change.
5. Conclusions
In order to investigate the spatio-temporal distribution of variability of long-term and intra-annual precipitation, the marginal disorder index based on entropy theory was calculated respectively for annual, monthly and daily series. The reasons for variation of precipitation and its apportionment variability were analyzed, and the main conclusion were as follows:
(1)
The AP series shows a significantly increasing trend during 1979–2015 measured by the M–K test and the inclination rate is 2.7 mm·a
−1
, with a reverse in climate trend from warm-dry to warm-wet. Wetting is mainly attributed to the growing impact of global climate change, in particular the enhanced southwest monsoon and a warming-induced freeze-thaw process, with summer monsoons making the biggest contribution.
(2)
The arrival of the summer monsoon was advanced, which makes May the beginning of the wet season, and the increase in the MP in May contributes to the main changes in AP. There are four quantitative pieces of evidence to support this view. The proportion of MP in AP during May–September ranges between 11.6–20.6%, while in the other months it is no higher than 6.5%; the average LMDI during May–September is about 0.1, the other months are all above 0.2; the MP in May is the only month during May–September in sync with the significantly incrasing AP trend during 1979–2015; the spatial distribution of LMDI in May is conformed with that of the AP, dividing the basin in half based on a value, which for MP in May is 0.1 within the range 0.03–0.29 and for AP is 0.02 within 0.01–0.10, with NW over the value and SE under it.
(3)
The variability of the throughout-the-year precipitation apportionment based on daily precipitation is measured by AMDI. The long-term AMDI time series ranges between 1.52–1.93 during 1979–2015, and no significant trend was detected during 1979–2006. The multi-year average AMDI roughly increased with latitude in space, with a range of 1.46–2.17. The Zoige Plateau Wetland (wetlands on the SE), the Maduo country (wetlands on the West) and the summit M (peak of the SRYR) is more uniform than the neighborhood by about 0.1 in AMDI, as a result of a relatively perennial local water supply.
(4)
The increase in precipitation amounts were concentrated in the period after 1997, especially in the decade of 1997–2006, according to a segmented study. During 1979–2006, the mean, minimum and maximum regional averages of AP reached their biggest rising rate, as 9.8 mm·a
−1
, 12.0 mm·a
−1
and 15.3 mm·a
−1
, respectively. The big increase in the minimum is a remarkable feature in wetting. Meanwhile, the intra-annual apportionment variability slightly increased in the mean and the maximum, and decreased in the minimum, the rate is 0.008 a
−1
, 0.009 a
−1
and -0.003 a
−1
, successively.
(5)
From a spatial distribution perspective, the increase in AP after 1997 was concentrated on the NW high-altitude areas first and then the lower southern corner. AP in the summit M changed from 390 mm to 680 mm during 1997–2006, and the southern corner was raised by about 50 mm in AP during the last decade. The degradation problem drove the moisture supply on the Zoige Plateau Wetland towards non-uniformity mainly during 1997–2006, when its AMDI raised from 1.4 to 1.7; the supply on the summit M and the headwater NW corner varied towards perennial with the AMDI dropping from 1.8/2.0 to 1.5/1.8, respectively, and part of the North Slope in the Bayan Har Mountain towards temporary, as the AMDI increased from 1.4 to 1.6, due to the single or combined effect of enhanced monsoon and/or a freeze-thaw process after 1997.
Author Contributions
Conceptualization, H.G.; data curation, H.G., Z.Y. and J.L.; formal analysis, H.G.; funding acquisition, Z.Y., G.L. and X.F.; investigation, H.G. and Q.J.; methodology, H.G.; project administration, Z.Y.; resources, Z.Y., Q.J. and Y.H.; software, H.G. and J.L.; supervision, G.L.; validation, Y.H.; visualization, H.G.; writing—review and editing, H.G. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by the National Key R&D Program of China (Grant Nos. 2018YFC1508205, 2016YFC0402710, 2018YFC1508001); the National Natural Science Foundation of China (Grant Nos. 51479061, 51539003, 41761134090, 51709046); National Science Funds for Creative Research Groups of China (No. 51421006) and the Special Fund of State Key Laboratory of Hydrology-Water Resources and Hydraulic Engineering (Grant No. 20185043812, 20185044012).
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Flow Chart. AP, MP and DP stand for annual, monthly and daily precipitation, respectively.
Figure 1. Flow Chart. AP, MP and DP stand for annual, monthly and daily precipitation, respectively.
Figure 2. The source region of the Yellow River with 12 meteorological stations (in red) and 51 CMFD (China Meteorological Forcing Dataset) grids (in black).
Figure 2. The source region of the Yellow River with 12 meteorological stations (in red) and 51 CMFD (China Meteorological Forcing Dataset) grids (in black).
Figure 3. The mean and extreme of LMDI (long-term marginal disorder index) for annual and monthly precipitation series at 51 CMFD grids during 1979–2015.
Figure 3. The mean and extreme of LMDI (long-term marginal disorder index) for annual and monthly precipitation series at 51 CMFD grids during 1979–2015.
Figure 4. The spatial distribution of LMDI (long-term marginal disorder index) based on AP (annual precipitation) and the Mann–Kendall (M–K) test statistic of the AP series during 1979–2015 in the source region of the Yellow River (SRYR).
Figure 4. The spatial distribution of LMDI (long-term marginal disorder index) based on AP (annual precipitation) and the Mann–Kendall (M–K) test statistic of the AP series during 1979–2015 in the source region of the Yellow River (SRYR).
Figure 5. The average of regional mean monthly precipitation and the M–K test statistic during 1979–2015 in the SRYR.
Figure 5. The average of regional mean monthly precipitation and the M–K test statistic during 1979–2015 in the SRYR.
Figure 6. The spatial distribution of the LMDI (long-term marginal disorder index) and the significant increasing trend of the MP (monthly precipitation) time series by the M–K test in January, February and May during 1979–2015 over the SRYR.
Figure 6. The spatial distribution of the LMDI (long-term marginal disorder index) and the significant increasing trend of the MP (monthly precipitation) time series by the M–K test in January, February and May during 1979–2015 over the SRYR.
Figure 7. The spatial distribution of the multi-year average AMDI (annual marginal disorder index) based on daily precipitation and its significant trends by the M–K test during 1979–2015 over the SRYR.
Figure 7. The spatial distribution of the multi-year average AMDI (annual marginal disorder index) based on daily precipitation and its significant trends by the M–K test during 1979–2015 over the SRYR.
Figure 8. The mean and extreme of the long-term AMDI (annual marginal disorder index) of daily precipitation during 1979–2015 at selected grid.
Figure 8. The mean and extreme of the long-term AMDI (annual marginal disorder index) of daily precipitation during 1979–2015 at selected grid.
Figure 9. Average values and monotonic trends of annual precipitation over a decade for ( a ) 1979–1988, ( b ) 1988–1997, ( c ) 1997–2006 and ( d ) 2006–2015.
Figure 9. Average values and monotonic trends of annual precipitation over a decade for ( a ) 1979–1988, ( b ) 1988–1997, ( c ) 1997–2006 and ( d ) 2006–2015.
Figure 10. Decadal average intra-annual variability for daily precipitation series and its trends measured by decadal averaged annual marginal disorder index (DAMDI) and U MK respectively, for ( a ) 1979–1988, ( b ) 1988–1997, ( c ) 1997–2006 and ( d ) 2006–2015.
Figure 10. Decadal average intra-annual variability for daily precipitation series and its trends measured by decadal averaged annual marginal disorder index (DAMDI) and U MK respectively, for ( a ) 1979–1988, ( b ) 1988–1997, ( c ) 1997–2006 and ( d ) 2006–2015.
Figure 11. Spatial distribution of LMDI for AP ( a ) and MP in May ( b ) during 1979–2015, with a dividing line.
Figure 11. Spatial distribution of LMDI for AP ( a ) and MP in May ( b ) during 1979–2015, with a dividing line.
Figure 12. The average annual ( a ) and monthly ( b ) air temperature and the M–K test statistic during 1979–2015 in the SRYR.
Figure 12. The average annual ( a ) and monthly ( b ) air temperature and the M–K test statistic during 1979–2015 in the SRYR.
Figure 13. Land cover map combined with the information in Figure 7 , the isolines of the mean value of AMDI during 1979–2015 and the areas with AMDI significant trends over the SRYR, and three regions with typical underlying surface, marked with a , b and c .
Figure 13. Land cover map combined with the information in Figure 7 , the isolines of the mean value of AMDI during 1979–2015 and the areas with AMDI significant trends over the SRYR, and three regions with typical underlying surface, marked with a , b and c .
Table 1. Meteorological stations in the source region of the Yellow River.
Table 1. Meteorological stations in the source region of the Yellow River.
ID Name Longitude (°E) Latitude (°N) Altitude (m) Period (Year) 52957 1 Tongde 100.65 35.27 3289.4 1954–1998 52968 Zeku 101.47 35.03 3662.8 1957–1990 56033 Maduo 98.22 34.92 4272.3 1953– 56041 Zhongxin 99.2 34.27 4211.1 1959–1997 56043 Guoluo 100.25 34.47 3719 1991– 56046 Dari 99.65 33.75 3967.5 1956– 56065 Henan 101.6 34.73 3500 1959– 56067 Jiuzhi 101.48 33.43 3628.5 1958– 56074 Maqu 102.08 34 3471.4 1967– 56075 Langmusi 102.63 34.08 3362.7 1957–1988 56079 Ruoergai 102.97 33.58 3439.6 1957– 56173 Hongyuan 102.55 32.8 3491.6 1960–
1 gray shaded represents an historical national station.
Table 2. The mean, extremes and CV of the selected 51 AP series (1979–2015).
Table 2. The mean, extremes and CV of the selected 51 AP series (1979–2015).
No. Mean (mm) Max (mm) Min (mm) CV No. Mean (mm) Max (mm) Min (mm) CV 1 321 505 197 0.24 27 532 679 394 0.14 2 453 635 263 0.19 28 494 657 307 0.17 3 347 527 197 0.24 29 429 613 285 0.19 4 474 725 285 0.22 30 622 767 460 0.14 5 348 505 219 0.20 31 573 745 417 0.15 6 270 482 153 0.37 32 521 788 372 0.19 7 498 810 329 0.25 33 442 810 307 0.24 8 350 569 241 0.22 34 727 920 569 0.12 9 287 548 153 0.38 35 691 876 527 0.13 10 488 767 329 0.23 36 625 832 438 0.15 11 339 504 220 0.17 37 536 767 372 0.18 12 533 725 350 0.16 38 413 613 286 0.22 13 515 835 372 0.23 39 763 1029 571 0.14 14 382 548 264 0.18 40 687 898 527 0.14 15 613 769 460 0.14 41 623 767 438 0.14 16 549 701 372 0.14 42 535 723 372 0.16 17 503 679 350 0.19 43 839 1076 526 0.13 18 455 679 286 0.23 44 810 1007 526 0.14 19 349 591 220 0.25 45 729 964 571 0.13 20 611 788 416 0.14 46 628 876 504 0.14 21 551 679 372 0.14 47 747 964 504 0.13 22 525 679 394 0.16 48 693 878 483 0.13 23 521 832 329 0.26 49 661 986 482 0.17 24 404 657 242 0.25 50 735 920 591 0.12 25 632 854 416 0.16 51 675 898 504 0.14 26 592 810 460 0.14 Avg 542 754 377 0.18
Table 3. Abrupt change detection results of the AP (annual precipitation) series and AMDI (annual marginal disorder index) series during 1979–2015 at 51 selected grids.
Table 3. Abrupt change detection results of the AP (annual precipitation) series and AMDI (annual marginal disorder index) series during 1979–2015 at 51 selected grids.
Year AP AMDI Year AP AMDI Grid Count Grid Count Grid Count Grid Count 1989 34; 45 2 - 0 1999 9 1 11; 43 2 1990 - 0 - 0 2000 6; 22 2 23; 33 2 1991 - 0 - 0 2001 5; 13; 14 3 4; 41 2 1992 - 0 27; 28 2 2002 7; 8; 10; 12; 15; 16; 17; 21; 31; 35; 36; 40; 41; 51 14 18; 19; 24 3 1993 - 0 - 0 1994 - 0 - 0 1995 - 0 1; 3; 46 3 1996 - 0 40 1 1997 19; 23; 50 3 12; 16; 21; 36; 37; 42; 44; 47; 48; 49; 50; 51 12 2003 1; 2; 3; 4; 28; 30; 32; 37; 38 9 - 0 2004 11; 29; 33 3 - 0 1998 18; 24 2 7; 10; 14; 39; 45 5 2005 - 0 - 0 SUM 39 32
Table 4. The regional mean and extreme values of averaged AP and AMDI with inclination rates during different periods over the SRYR.
Table 4. The regional mean and extreme values of averaged AP and AMDI with inclination rates during different periods over the SRYR.
Period Avg AP (mm)/Rate (mm·a −1 1 ) Avg AMDI/Rate (10·a −1 ) Mean Min Max Mean Min Max 1979–1988 523/−5.4 186/−0.1 890/−14.6 1.75/−0.10 1.41/−0.09 2.27/−0.24 1988–1997 497/−2.0 166/1.8 844/−13.4 1.69/0.08 1.32/−0.02 2.27/0.14 1997–2006 529/9.8 237/12.0 896/15.3 1.77/0.08 1.30/−0.03 2.41/0.09 2006–2015 596/2.8 314/4.9 920/9.2 1.78/−0.04 1.34/0.02 2.37/0.09 1979–2015 540/2.7 229/5.0 895/1.4 1.75/0.01 1.35/−0.03 2.34/0.04
1 a represents year in this article.
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(PDF) Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: A long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity
PDF | We have performed a long-term study into the use of a lipophilic amino-acid dendrimer to deliver an anti-vascular endothelial growth factor (VEGF)... | Find, read and cite all the research you need on ResearchGate
Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: A long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity
November 2005
Gene Therapy 12(21):1544-50
DOI: 10.1038/sj.gt.3302579
Norbert Wimmer
Abstract and Figures
We have performed a long-term study into the use of a lipophilic amino-acid dendrimer to deliver an anti-vascular endothelial growth factor (VEGF) oligonucleotide (ODN-1) into the eyes of rats and inhibit laser-induced choroidal neovascularization (CNV). In addition, the uptake, distribution and retinal tolerance of the dendrimer plus oligonucleotide conjugates were examined. Analysis of fluorescein angiograms of laser photocoagulated eyes revealed that dendrimer plus ODN-1 significantly inhibited (P<0.05) the development of CNV for 4-6 months by up to 95% in the initial stages. Eyes similarly injected with ODN-1 alone showed no significant difference (P>0.05) in mean severity score at 2 months (2.86+/-0.09), 4 months (2.15+/-0.17) or 6 months (2.7+/-0.12) compared to the vehicle-injected controls. Furthermore, we showed that intravitreally injected ODN-1 tagged with 6-fam was absorbed by a wide area of the retina and penetrated all of the retinal cell layers to the retinal pigment epithelium. Ophthalmological examinations indicated that the dendrimers plus ODN-1 conjugates were well tolerated in vivo, which was later confirmed using immunohistochemistry, which showed no observable increase in antigens associated with inflammation. We conclude that the use of such dendrimers may provide a viable mechanism for the delivery of therapeutic oligonucleotides for the treatment of angiogenic eye diseases.
Color fundus photography and FA of dendrimer plus ODN-1-injected eyes. Representative CFP and FAs of laser photocoagulated eyes at showing the laser lesions and extent of CNV formation in controls (a, b), at 2 months post injection (c, d), 4 months (e, f) and 6 months (g, h). Laser lesions are indicated in the CFPs by white arrowheads while fluorescein leakage due to CNV development is indicated by the black arrowhead in the FAs. The reduced effectiveness of dendrimer plus ODN-1 to control CNV with the progression of time is clearly shown in the FAs. …
Analysis of CNV development. Using the densitometry method, the extent of CNV was calculated and statistically analyzed. When injected alone, ODN-1 had no significant effect (P>0.05) on the development of CNV compared to the dendrimer-treated control eyes at each time point measured. However, CNV was significantly reduced in eyes injected with dendrimer plus ODN-1 at the 2- and 4-month time points (*P<0.05). By 6 months, this effect was no longer considered significant (P>0.05). …
Figures - uploaded by
Piroska Elizabeth Rakoczy
RESEARCH ARTICLE
Dendrimer delivery of an anti-VEGF oligonucleotide
into the eye: a long-term study into inhibition of laser-
induced CNV, distribution, uptake and toxicity
RJ Marano
1
, I T oth
2,3
, N W immer
2,3
, M Brankov
1
and PE Rakoczy
4
1
Department of Molecular Ophthalmology, Lions Eye Institute, Nedlands, W A, Australia;
2
School of Molecular and Microbial Sciences,
University of Queensland, Brisbane, QLD, Australia;
3
School of Pharmacy, University of Queensland, Brisbane, QLD, Australia; and
4
Centre for Ophthalmology and V isual Science, Lions Eye Institute, University of Western Australia, Nedlands, W A, Australia
We have perfo rmed a long-term study int o the use of a
lipop hilic am ino-ac id dendrimer to del iver an anti-vasc ular
endot helial growt h factor (VEGF) oligonucle otide (ODN-1)
into the eyes of rats and inhibit laser- induced choroida l
neova scularizat ion (CNV). In add ition, the uptak e, dist ribution
and retinal toler ance of the dendrimer plus oligon ucleot ide
conju gates were exa mined. Analys is of fluore scein ang io-
grams of las er pho tocoag ulated eyes revea led tha t dendri mer
plus ODN-1 significan tly inhibite d (P o 0.05) the developm ent
of CN V fo r 4–6 month s by up to 95 % in the initial stages . Eyes
simil arly inj ected with ODN-1 alo ne sho wed no sign ificant
differ ence (P 4 0.05) in mean sever ity scor e at 2 months
(2.86 7 0.09), 4 months (2.15 7 0. 17) or 6 months (2.7 7 0.12)
compa red to the ve hicle-injec ted contro ls. Furthe rmore, we
showed that intravitre ally inj ected ODN-1 tagged with 6-fam
was absorbed by a wide area of the reti na and penetrated all
of the retinal cell layers to the re tinal pigment epithe lium.
Ophtha lmological ex amination s indicat ed that the den drimers
plus ODN-1 conju gates were well toler ated in vivo, whi ch was
later confir med using immunohi stochemist ry, which showed
no obser vable incre ase in antigen s associate d with inflam -
mation . We conclude that the use of such dendr imers may
provid e a viable me chanis m for the deliv ery of therapeut ic
oligon ucleotides for the treat ment of angioge nic eye diseas es.
Gene Ther apy (2005) 12, 15 44–1 550 . doi :10.1038/
sj.gt.3302579; published online 30 June 2005
Keywords: dendrimer; oligonucleotide; VEGF; neovascularization; angiogenesis; laser photocoagulation
Introduction
Overexpression of vascular endothelial growth factor
(VEGF) has been implicated in a number of diseases
associated with angiogenesis including age-rel ated ma-
cular degeneration (AMD),
1
diabetic retinopathy (DR)
2,3
and tumor development.
4
Several gene therapies are
being developed and trialed for the control of such
diseases and much of the technology centers on the
inhibition of VEGF and consequently the inhibition of
angiogenesis, a process that is essential to disease
progression. These therapies include gene transfer and
endogenous expression of recombinant proteins,
5,6
use of
pegalated aptamers to bind and inhibit activity of excess
VEGF
7
and oligonucleotide gene therapy .
8–10
Previously ,
we have r eported on the discovery and use of a sense
oligonucleotide (ODN-1) that is complimentary to a
section of sequence in the 5
0
untranslated region of
VEGF , for the inhibition of VEGF expression both in vitro
and in vivo . W e subsequently tested the efficacy of ODN-
1 in reducing the extent of laser photocoagulation
induced choroidal neovascularisation (CNV) in a rodent
model.
11
However , like most other genetic-based thera-
pies, delivery and longevity of the effects remain a
limiting factor . More recently , we described the synthesis
and use of lipophilic amino-acid dendrimers that
enhanced the delivery of ODN-1 into the retinal tissue
of rats.
12,13
In addition, the data from this earlier study
suggested that the dendrimers served as a protective
agent against the effects of nucleases while enabling
ODN-1 to interact with its target site within the gene.
In this study , we extend the initial research of Marano
et al
12
and examine the issue of longevity of dendrimer
plus ODN-1 conjugates. The duration of the study was
extended to 6 months, and the efficacy of the conjugates
to inhibit laser -induced CNV was examined at various
time points. In addition, the uptake and distribution was
assessed.
Results
CNV inhi bition
The laser photocoagulation CNV model is an effective
means of analyzing the longevity and bioavailability of
an antiangiogenic compound in the eye. Following
injection with ODN-1, dendrimer and dendrimer con-
jugated to ODN-1, laser photocoagulation was per-
formed at 2, 4 and 6 months. The lesions were
confirmed using color fundus photography (CFP)
(Figure 1a, c, e and g) where typically they appear as
white patches. The progress of CNV associated with the
Received 10 December 2004; accepted 12 May 2005; published
online 30 June 2005
Correspondence: Dr RJ Marano, Molecular Ophthalmology, Lions Eye
Institute, 2 V erdun Street, Nedlands, Western Australia 6009, Australia
Gene Therapy (2005) 12 , 1544–1550
&
lesions were initially monitored and documented in vivo
using fluorescein angiography (F A) (Figure 1b, d, f and
h) and subsequently post mortem by measuring the
choroidal thickness at the lesion and nonlesion sites
and calculating the B / C ratio.
FA. In eyes treated with dendrimer alone, leakage due
to CNV determined by clinical examination were
determined to be severe at all examination time points.
It was decided to cease data collection of this group after
4 months and use the available information as control
data. In these eyes, CNV appears as densely colored
patches due to leakage of fluorescein from the newly
developing blood vessels (Figure 1b) and remains
consistent throughout the study period. The introduction
of lesions 2 months post injection revealed that ODN-1,
when injected alone, had no observable inhibitory effect
on the extent of CNV development when compared to
the controls. Subsequent examinations of laser lesions
that this result r emained unchanged in eyes injected with
ODN-1 alone (data not shown). Conversely , in eyes
injected with dendrimer plus ODN-1, the severity of
CNV development viewed using F A appeared greatly
reduced at 2 months (Figure 1d). However , at 4 months,
CNV development appeared more severe (Figure 1e)
than that seen at 2 months, and at 6 months, no
discernable difference could be distinguished from the
controls (Figure 1g). These observations were confirmed
using the densitometry method to calculate the extent of
CNV and assigned a mean severity score to each lesion in
the F As (Figure 2). The mean severity score calculated for
eyes injected with ODN-1 alone (2.86 7 0.09, 2.15 7 0.17
and 2.7 7 0.12, respectively) did not differ significantly
( P 4 0.01) at 2, 4 or 6 months, from the scores calculated
for the controls. However , the mean CNV severity score
for eyes injected with dendrimer plus ODN-1 was
significantly ( P o 0.05) lower at both 2 months
(0.18 7 0.12) and 4 months (1.39 7 0.17) post injection
compared to the controls and eyes injected with ODN-1
alone at the same time. By 6 months, the mean severity
score (2 7 0.18) was no longer considered significant
indicate that there was a progressive decrease in the
ability of dendrimer plus ODN-1 to inhibit CNV .
B/C ratio. A second method that measures the B / C
ratio ( B refers to the maximum thickness of the lesion
and C is the thickness of the normal RPE-choroidal layers
adjacent to the lesion) was used to determine the extent
of CNV . Unlasered, the choroidal bed of the retina
Figure 1 Color fundus photography and F A of dendrimer plus ODN-1-
injected eyes. Representative CFP and F As of laser photocoagulated eyes at
showing the laser lesions and extent of CNV formation in controls (a, b), at
2 months post injection (c, d), 4 months (e, f) and 6 months (g, h). Laser
lesions are indicated in the CFPs by white arrowheads while fluorescein
leakage due to CNV development is indicated by the black arrowhead in the
F As. The reduced effectiveness of dendrimer plus ODN-1 to control CNV
with the progression of time is clearly shown in the F As.
Figure 2 Analysis of CNV development. Using the densitometry method,
the extent of CNV was calculated and statistically analyzed. When injected
alone, ODN-1 had no significant effect (P 4 0.05) on the development of
CNV compared to the dendrimer-treated control eyes at each time point
measured. However , CNV was significantly reduc ed in eyes injected with
dendrimer plus ODN-1 at the 2- and 4-month time points ( * P o 0.05). By
6 months, this effect was no longer considered significant (P 4 0.05).
RJ Marano et al
1545
Gene Therapy
possesses a near uniform thickness (Figure 3a). However ,
introduction of a laser lesion produces a thickening in
this area (Figure 3b and c). This thickening appeared less
pronounced in eyes injected with dendrimer plus ODN-1
(Figure 3b) compared to eyes injected with ODN-1 alone
(Figure 3c), which also exhibited the formation of blood
vessels within the retinal cell layers extending from the
choroid. Measurement of the thickness ratio of lesions in
eyes from each group of injected rats confirmed a
significant reduction of B / C in rats treated with
dendrimer plus ODN-1 ( P o 0.05) compar ed to all other
groups at 2 and 4 months post injection (Figure 4), but
not at 6 months, supporting the data obtained from the
angiograms. The control data consisted of pooled results
from all lasered eyes treated with dendrimer alone at all
time points.
Uptake and distribution
Uptake and distribution of ODN-1
6-F AM
plus ODN-1
6-F AM
conjugate were monitored using
fluorescence microscopy . Distribution was initially ex-
amined using whole mounts of retinal tissue, which
revealed that at 2 weeks post injection, ODN-1
6-F AM
and
dendrimer plus ODN-1
6-F AM
were detected over a wide
area of the retina (Figure 5a). Frozen sections were
subsequently processed by initially incubating in Sudan
black to quench background signal resulting from
autofluorescence. In uninjected control eyes, autofluor-
escence was eliminated in all retinal cell layers with
some minor fluorescence still present in the sclera
(Figure 5b). In eyes injected with ODN-1
6-F AM
alone, no
fluorescent signal could be detected following treatment
with Sudan black from 2 months post injection onwards.
However , in eyes injected with dendrimer plus ODN-1
6-
FA M
, a fluorescent signal could be seen in the retinal
pigment (RP) layer in addition to the outer nuclear layer ,
inner nuclear layer and the ganglion cell layer (Figure 5c
and d) of eyes enucleated at 2 and 4 months post
injection. At 4 months, the signal had become more
centralized within the RP cells while in other layers, the
signal appeared to be reduced in intensity and distribu-
tion. In addition, it should be noted that the signal
appeared to be localized to the nuclei of cells and absent
from the cytoplasmic compartment. No signal was
evident by 6 months post injection with dendrimer plus
ODN-1
6-F AM
.
Toxicity
Ophthalmological examinations performed at regular
intervals revealed no adverse effects resulting from the
Figure 3 Histological analysis of H&E-stained paraffin-embedded eyes. In
a normal section (a), the choroid possesses a uniform thickness. A
representative section of a mild lesion (b) shows thickening at the lesion
site. In a severe lesion (c), the thickening is more pronounced and a
magnified section (d) shows the presence of blood vessels within the retinal
cell layers (black arrowheads). The B/C ratio was determined from
maximum thickness of session (B) and thickness of adjacent normal RPE-
choroid (C).
Figure 4 Comparison of B/C ratios from injected eyes. The control
consisted of the pooled B/C ratios of eyes injected with dendrimer alone. In
eyes injected with dendrime r plus ODN-1, analysi s of the B/C ratios
indicates a significant decrease (P o 0.05) in CNV at the 2 and 4 month
time points ( * P o 0.05) compared to the control and all other treatment
groups. However , no effect was calculated for eyes injected with ODN-1
alone compared to the control group.
Figure 5 Frozen sections of eyes injected with ODN-1
6-F AM
. A whole
mount of a retina (a) shows the area over which ODN-1 and dendrimer
plus ODN-1 were taken up by retinal cells. Subsequent frozen sections of
retina treated with Sudan black to quench autofluorescence revealed
dendrimer-treated eyes to possess no signal (b). In eyes injected with
dendrimer plus ODN-1
6-F AM
, signal was present in the retinal pigment
epithelium (RPE), outer nuclear layer (ONL), inner nuclear layer (INL)
and the ganglion cells (GC) at both 2 months (c) and 4 months (d). Both
intensity and distribution appear to be reduced at 4 months compared to 2
months. No signal was detected at 6 months or in eyes injected with ODN-
1
6-F AM
alone at any time point (photo not shown).
Dendrimer delivery of oligonucleotides into eye’s
RJ Marano et al
1546
Gene Therapy
injection of either ODN-1, dendrimer or a conjugate of
the two compounds. In addition, analysis of sectioned
eyes using immunohistochemistry revealed no observa-
ble increase in the presence on inflammation-specific
components such as macrophages’ indicating that the
compounds were well tolerated at the concentrations
used.
Discussion
At present, the most common forms of treatments for
blinding eye diseases associated with CNV include laser
photocoagulation, photodynamic therapy , or a combina-
tion of both. However , the effects of these treatments are
limited, varied and generally do not result in improved
eyesight. The major contributing factor underlying the
proliferation of choroidal blood vessels is the upregula-
tion of VEGF , where increased levels have been found in
the vitreous of patients suffering from AMD.
2
Recent
research has, therefore, centered on the control of VEGF
expression or on limiting its biological activity .
14–16
ODNs have recently come to the forefront of technology
for the control of gene expression but some issues still
need to be addressed. The most prominent of these
issues are longevity of the ODN in situ coupled with an
efficient delivery mechanism.
Previously in our laboratories, we have sought to
overcome both of these problems with the introduction
of a dendrimer-mediated delivery system for ODN-1, an
anti-VEGF sense oligonucleotide, initially in vitro and
subsequently in vivo .
12,13
In this instance, the dendrimer
under investigation provided the conjugated ODN-1 a
high degree of protec tion against nucleases in addition to
effective time of this protection, and its comparison to
other methods of improving longevity had not yet been
fully explored. In this paper , we report on a follow up,
long-term study of these previous r esults in an attempt to
address these issues. Rats were injected in both eyes with
either ODN-1 or ODN-1 conjugated to a previously
described dendrimer .
12
CNV was induced using the laser
photocoagulation method
17
at 2, 4 and 6 months post
injection. The eyes were subsequently examined using
CFP , F A, histology and immunohistochemistry and
evaluated for the extent of neovascularization in addition
to uptake, distribution and toxicity of both ODN-1 alone
and dendrimer plus ODN-1.
The densitometry technique performed on the fluor-
escein angiograms proved effective in calculating the
extent of laser-induced CNV . These data were later
supported by the B / C ratio measurements on H&E-
stained paraffin sections. In the groups of rats injected
CNV development compared to the controls could be
detected at any of the time points. This result was not
surprising, as the ODN used in this study possessed a
native phosphodiester backbone, which is highly sus-
ceptible to the effects of nucleases. However , in the
groups that were injected with dendrimer plus ODN-1,
the level of CNV development was significantly reduced
( P o 0.05) at the initial 2-month period compared to the
controls. This result was in accordance with our previ ous
study
12
and indicates that the dendrimer not only
protects ODN-1 from the effects of nucleases but also
mediates its delivery to the site of activity . Further
evaluation at the 4-month time point later revealed that
the level of CNV inhibition was reduced but still
statistically significant ( P o 0.05). However , by the 6-
month time point, the level of inhibition was no longer
considered statistically significant compared to the
control. This suggests that the protection afforded by
the dendrimer was not permanent, due to either ODN-1
being degraded by nucleases or the dendrimer plus
its reduced presence within the tissue, and hence to a
lowered capacity to inhibit CNV .
The ef fect of diminishing ef fectiveness for dendrimer
plus ODN-1 to inhibit laser induced CNV seemed to be
paralleled by the histology on the frozen eyes. At 2
months post injection, fluorescence microscopy revealed
the presence of ODN-1
6-F AM
within the major cellular
layers of the retina (Figure 6c). However , this signal
became reduced by 4 months post injection, and at 6
months, no signal was detected in the sectioned tissue
(Figure 3d). In addition, the signal seemed to be confined
to the nuclei of the cells and absent from the cytoplasmic
compartment. This observation would be in keeping
with our previous hypothesis that the ODN-1 inhibits
transcription of VEGF by binding to dsDNA (which is
confined to the nuclei) resulting in polymerase arrest.
12
Based on these data and in respect to possible
treatments for CNV , we can infer that the effective
lifespan (and hence the treatment interval) of ODN-1
extent of neovascularization was documented using CFP
and F A. This procedure was repeated at 4 and 6 months
post injection on a further five rats from groups 1a, b and
c for each time point. In additions to this, one rat from
groups 2a and 2b were euthanized and the eyes
enucleated at 2 weeks, 2 months, 4 months and 6 months
post injection and the eyes frozen in optimal cutting
temperature (OCT) compound for sectioning or used as a
whole mount. The sections and whole mounts were
viewed using fluorescence microscopy to determine the
uptake and distribution of ODN-1
6-F AM
and the dendri-
mer plus ODN-1
6-F AM
conjugate within the retinal tissue
both in the initial stage and progressively throughout the
course of the experiments. Controls consisting of one rat
injected with vehicle were used for each of the time
points.
Injections
All animal experiments were performed in accordance
and Ophthalmic Research. Preinjection, animals were
anaesthetized with a mixture of ketamine (50 mg/kg
body weight) and xylazine (8 mg/kg body weight). T ears
Naturale
s
(Alcon, Frenches Forrest, NSW , Australia)
were applied topically to prevent eyes from drying
during the injection process.
In all, 2 m lo fa7 5 m
M concentration of ODN-1,
dendrimer plus ODN-1 complex (relative to ODN-1),
dendrimer without ODN-1, 6-F AM-tagged ODN-1
(ODN-1
6-F AM
) or dendrimer plus ODN-1
6-F AM
complex
was injected into the vitreous of both eyes of 8-week-old
rcs/rdy
+
-pigmented rats.
Induction of CNV by krypton laser phot ocoagulation
System, CA, USA) was delivered to both eyes of each
animal from group 1a, 1b and 1c through a Zeiss slit
lamp with a hand-held coverslip serving as a contact
lens. A total of 6–9 laser burns were applied to each eye
surrounding the optic nerve at the posterior pole at a
setting of 100 m
M diameter , 0.1 s duration and 150 mW
intensity .
Quantization of CNV
The formation and extent of CNV in the eye using this
model was monitored using CFP and F A. Anaesthetized
animals were injected intraperitoneally with 0.3–0.4 ml of
10% sodium fluorescein and the eyes photographed
using fluorescence fundus photography . The extent of
fluorescein leakage was calculated using a previously
described densitometry method.
25
The mean score
between paired dendrimer/ODN-1 complexes and den-
drimer without ODN-1 were compared by ANOV A with
a post hoc T uckey/Kramer analysis. Differences were
considered significant at P o 0.05.
dendrimer used in this study to mediate the delivery of ODN-1 into the
retinal tissue of rats.
Dendrimer delivery of oligonucleotides into eye’s
RJ Marano et al
1548
Gene Therapy
In addition to the densitometry method, the extent of
CNV was evaluated by measuring the lesion thickness.
Serial paraffin sections were stained with H&E and
digital microscopic images were acquired using a video
camera (Olympus DP70, T okyo, Japan). The sections
containing the largest area of subretinal membrane for
each lesion was identified. Using a measurement
technique that accounts for the position and angle of
sections,
26
the thickness from the bottom of the choroidal
layer to the top of the subr etinal membrane was recorded
using the software Carnoy .
27
The level of NV was
determined by the B / C ratio, where B refers to the
... Employed in an in vivo setting the formulations were retained between three-five days in the rat vitreous [19]. Marano et al. showed that by applying a dendrimer drug delivery system intravitreally injected oligonucleotides against VEGF penetrated all of the retinal cell layers to the retinal pigment epithelium and were detectable for up to four months post injection in rats
[20]
. Sadeghi et al. examined the retention of liposomes manufactured out of a DSPC, DOPC, DSPG and DSPE-PEG mix in the vitreous body of rat eyes via fundus imaging for different formulations and could prove a retention period of up to 20 days in the case of the 1160 nm diameter formulations [21]. ...
Lipid-DNA Nanoparticles as Drug-Delivery Vehicles for the Treatment of Retinal Diseases
Retinal eye diseases are the leading cause of blindness in the Western world. Up to date, the only efficient treatment for many retinal diseases consists of invasive intravitreal injections of highly concentrated drugs. Despite the fact that these injections are unpleasant for the patients, they potentially cause serious side effects, e.g., infections, bleeding within the eye or retinal detachment, especially when performed on a monthly basis, thus decreasing the injection frequency and lowering the desired drug dose. Therefore, a sustained released at the region of interest with a sustained release is desired. Recently, novel lipid-DNA nanoparticles (NPs) were shown to be an efficient drug delivery platform to the anterior segment of the eye. In this study, we investigated the distribution and tropism of the NPs when applied intravitreally, as a potential medication carrier to the posterior part of the eye. This technology is perfectly suited for the delivery of low molecular weight drugs to the back of the eye, which so far is greatly hindered by fast diffusion rates of the free drugs in the vitreous body and their intrinsically low retainability in ocular tissue. Excellent biodistribution, adherence and presence for up to five days was found for the different tested nanoparticles ex vivo and in vivo. In conclusion, our lipid-DNA based nanocarrier system was able to reach the retina within minutes and penetrate the retina providing potentially safe and long-term carrier systems for small molecules or nucleotide-based therapies.
... Dendrimers are composed of amine-containing cationic polymers such as poly-L-lysine and have been investigated for (anti-VEGF) delivery to RPE cells in vitro. They induce long-term (4-6 months) inhibition (up to 95%) of laserinduced CNV after intravitreal injection as shown in a rat model, without any observable adverse effects
(Marano et al. 2005)
. PEI dendrimers have also been tested as a vehicle for the delivery of an shRNA expression plasmid to retinal ganglion cells via intravitreal injection. ...
Nanomedicine and drug delivery to the retina: current status and implications for gene therapy
| https://www.researchgate.net/publication/7711716_Dendrimer_delivery_of_an_anti-VEGF_oligonucleotide_into_the_eye_A_long-term_study_into_inhibition_of_laser-induced_CNV_distribution_uptake_and_toxicity |
Materials | Free Full-Text | Biodegradable Polymers
Biodegradable materials are used in packaging, agriculture, medicine and other areas. In recent years there has been an increase in interest in biodegradable polymers. Two classes of biodegradable polymers can be distinguished: synthetic or natural polymers. There are polymers produced from feedstocks derived either from petroleum resources (non renewable resources) or from biological resources (renewable resources). In general natural polymers offer fewer advantages than synthetic polymers. The following review presents an overview of the different biodegradable polymers that are currently being used and their properties, as well as new developments in their synthesis and applications.
Biodegradable Polymers
by Isabelle Vroman * and Lan Tighzert
Ecole Supérieure d'Ingénieurs en Emballage et Conditionnement (ESIEC), Esplanade Roland Garros - Pôle Henri Farman, BP 1029, 51686 Reims Cedex 2, France
Author to whom correspondence should be addressed.
Materials 2009 , 2 (2), 307-344; https://doi.org/10.3390/ma2020307
Received: 25 February 2009 / Revised: 25 March 2009 / Accepted: 30 March 2009 / Published: 1 April 2009
(This article belongs to the Special Issue Biodegradability of Materials )
Abstract
:
1. Introduction
The same durability properties which make plastics ideal for many applications such as in packaging, building materials and commodities, as well as in hygiene products, can lead to waste-disposal problems in the case of traditional petroleum-derived plastics, as these materials are not readily biodegradable and because of their resistance to microbial degradation, they accumulate in the environment. In addition in recent times oil prices have increased markedly. These facts have helped to stimulate interest in biodegradable polymers and in particular biodegradable biopolymers. Biodegradable plastics and polymers were first introduced in 1980s. There are many sources of biodegradable plastics, from synthetic to natural polymers. Natural polymers are available in large quantities from renewable sources, while synthetic polymers are produced from non renewable petroleum resources.
Biodegradation takes place through the action of enzymes and/or chemical deterioration associated with living organisms. This event occurs in two steps. The first one is the fragmentation of the polymers into lower molecular mass species by means of either abiotic reactions, i.e. oxidation, photodegradation or hydrolysis, or biotic reactions, i.e. degradations by microorganisms. This is followed by bioassimilation of the polymer fragments by microorganisms and their mineralisation. Biodegradability depends not only on the origin of the polymer but also on its chemical structure and the environmental degrading conditions. Mechanisms and estimation techniques of polymer biodegradation have been reviewed [ 1 ]. The mechanical behaviour of biodegradable materials depends on their chemical composition [ 2 , 3 ], the production, the storage and processing characteristics [ 4 , 5 ], the ageing and the application conditions [ 6 ].
2. Biodegradable Polymers Derived from Petroleum Resources
These are synthetic polymers with hydrolysable functions, such as ester, amide and urethane, or polymers with carbon backbones, in which additives like antioxidants are added. Recent developments in this area have been reported [ 7 ]. Synthesis, properties and biodegradability of the main classes and new families of synthetic polymers are discussed below.
2.1. Polymers with additives
Most conventional polymers derived from petroleum resources are resistant to degradation. To facilitate their biodegradation, additives are added. One method to degrade polyolefins consists in the introduction of antioxidants into the polymer chains. Antioxidants will react under UV, inducing degradation by photo-oxidation. Nevertheless the biodegradability of such systems is still controversial. We prefer to consider them as oxo-degradable polymers.
Polyolefins are resistant to hydrolysis, to oxidation and to biodegradation due to photoinitiators and stabilizers [ 8 ]. They can be made oxo-degradable by use of pro-oxidant additives. These additives are based on metal combinations, such as Mn 2+ /Mn 3+ . The polyolefin will then degrade by a free radical chain reaction. Hydroperoxides are first produced and then thermolysed or pyrolysed to give chain scission, yielding low molecular mass oxidation products with hydrophilic properties favourable to microorganisms.
2.2. Synthetic polymers with hydrolysable backbones
Polymers with hydrolysable backbones are susceptible to biodegradation under particular conditions. Polymers that have been developed with these properties include polyesters, polyamides, polyurethanes and polyureas, poly(amide-enamine)s, polyanhydrides [ 9 , 10 ].
2.2.1. Aliphatic polyesters
The aliphatic polyesters are almost the only high molecular weight biodegradable compounds [
9
] and thus have been extensively investigated. Their hydrolysable ester bonds make them biodegradable. Aliphatic polyesters can be classified into two types according to the bonding of the constituent monomers. The first class consists of the polyhydroxyalkanoates. These are polymers synthesized from hydroxyacids, HO-R-COOH. Examples are poly(glycolic acid) or poly(lactic acid). Poly(alkene dicarboxylate)s represent the second class. They are prepared by polycondensation of diols and dicarboxylic acids. Examples are poly(butylene succinate) and poly(ethylene succinate).
Polyglycolide (PGA):
PGA is the simplest linear aliphatic polyester. It is prepared by ring opening polymerization of a cyclic lactone, glycolide. It is highly crystalline, with a crystallinity of 45-55% and thus is not soluble in most organic solvents. It has a high melting point (220-225 °C) and a glass transition temperature of 35-40 °C [
10
]. PGA has excellent mechanical properties. Nevertheless its biomedical applications are limited by its low solubility and its high rate of degradation yielding acidic products. Consequently, copolymers of glycolide with caprolactone, lactide or trimethylene carbonate have been prepared for medical devices [
10
,
13
].
Polylactide (PLA): PLA is usually obtained from polycondensation of D- or L-lactic acid or from ring opening polymerization of lactide, a cyclic dimer of lactic acid. Two optical forms exist: D-lactide and L-lactide. The natural isomer is L-lactide and the synthetic blend is DL-lactide. Other different synthetic methods have been studied too. They have been reported in detail in [ 14 ].
PLA is a hydrophobic polymer due to the presence of –CH 3 side groups. It is more resistant to hydrolysis than PGA because of the steric shielding effect of the methyl side groups. The typical glass transition temperature for representative commercial PLA is 63.8 °C, the elongation at break is 30.7% and the tensile strength is 32.22 MPa [ 15 ]. Regulation of the physical properties and biodegradability of PLA can be achieved by employing a hydroxy acids comonomer component or by racemization of D- and L- isomers [ 16 ]. A semi-crystalline polymer (PLLA) (crystallinity about 37%) is obtained from L-lactide whereas poly(DL-lactide) (PDLLA) is an amorphous polymer [ 17 ]. Their mechanical properties are different as are their degradation times [ 18 ]. PLLA is a hard, transparent polymer with an elongation at break of 85%-105% and a tensile strength of 45-70 MPa. It has a melting point of 170-180 °C and a glass transition temperature of 53 °C [ 19 ]. PDLLA has no melting point and a Tg around 55 °C. It shows much lower tensile strength [ 20 ]. PLA has disadvantages of brittleness and poor thermal stability.
PLA can be plasticized to improve the chain mobility and to favor its crystallization. Plasticization is realized with oligomeric acid, citrate ester or low molecular polyethylene glycol [ 21 ].
High molecular weight PLAs are obtained through ring opening polymerization. This route allows also the control of the final properties of PLA by adjusting the proportions of the two enantiomers [ 11 ]. Other routes are melt/solid state polymerization [ 14 ], solution polymerization or chain extension reaction [ 22 ]. High molecular weight PLA has better mechanical properties [ 23 ]. Different companies commercialize PLA with various ratios of D/L lactide and trade names and suppliers of different grades of PLA are listed in Table 1 .
Table 1. Trade names and suppliers of PLA.
Table 1. Trade names and suppliers of PLA. Trade name Company Country NatureWorks ® Cargill Dow USA Galacid ® Galactic Belgium Lacea ® Mitsui Chem. Japan Lacty ® Shimadzu Japan Heplon ® Chronopol USA CPLA ® Dainippon Ink Chem. Japan Eco plastic ® Toyota Japan Treofan ® Treofan Netherlands PDLA ® Purac Netherlands Ecoloju ® Mitsubishi Japan Biomer ® L Biomer Germany
The rate of degradation of PLA depends on the degree of crystallinity. The degradation rate of PLLA is very low compared to PGA, therefore, some copolymers of lactide and glycolide have been investigated as bioresorbable implant materials [
24
]. The biodegradability of PLA can also be enhanced by grafting. The graft copolymerization of L-lactide onto chitosan was carried out by ring opening polymerization using a tin catalyst. The melting transition temperature and thermal stability of graft polymers increase with increasing grafting percentages. As the lactide content increases, the degradation of the graft polymer decreases [
25
].
Poly(lactide-co-glycolide) (PLGA):
L-lactide and DL-lactide (L) have been used for copolymerization with glycolic acid monomers (G). Different ratios of poly(lactide-co-glycolide) have been commercially developed. Amorphous polymers are obtained for a 25L:75G monomer ratio. A copolymer with a monomer ratio of 80L:20G is semi-crystalline. When the ratio of monomer L/G increases, the degradation rate of the copolymer decreases.
Polycaprolactone (PCL):
ε-caprolactone is a relatively cheap cyclic monomer. A semi-crystalline linear polymer is obtained from ring-opening polymerization of ε-caprolactone in presence of tin octoate catalyst [
19
]. PCL is soluble in a wide range of solvents. Its glass transition temperature is low, around -60 °C, and its melting point is 60 – 65 °C. PCL is a semi-rigid material at room temperature, has a modulus in the range of low-density polyethylene and high-density polyethylene, a low tensile strength of 23 MPa and a high elongation to break (more than 700%). Thanks to its low Tg, PCL is often used as a compatibilizer or as a soft block in polyurethane formulations.
Enzymes and fungi easily biodegrade PCL [ 9 , 26 ]. To improve the degradation rate, several copolymers with lactide or glycolide have been prepared [ 10 ]. PCL is commercially available under the trade names CAPA ® (from Solvay, Belgium), Tone ® (from Union Carbide, USA) or Celgreen ® (from Daicel, Japan). Possible applications in the medical field have been investigated.
Poly(butylene succinate) (PBS) and its copolymers:
They belong to the poly(alkenedicarboxylate) family. They are obtained by polycondensation reactions of glycols, such as ethylene glycol and 1,4-butanediol, with aliphatic dicarboxylic acids, such as succinic and adipic acid [
27
]. They were invented in 1990 and developed by Showa High Polymer (Japan) under the trade name Bionolle
®
. EnPol
®
is the trade name of the same class of polymers commercialized by Ire Chemical (Korea). Different poly(alkenedicarboxylate)s have been prepared: PBS, poly(ethylene succinate) (PES) and a copolymer i.e. poly(butylene succinate-co-adipate) (PBSA). PBSA is obtained by addition of adipic acid. Their molecular weights range from several tens to several hundreds of thousands. The use of a small amount of coupling agents as chain extenders allows the molecular weight to be increased [
28
]. Another copolymer was prepared by condensation of 1,2-ethylenediol, 1,4-butanediol with succinic and adipic acids by SK Chemicals (Korea) and commercialized under the trade name Skygreen
®
. Lunare SE
®
trademark is another aliphatic copolyester commercialized by Nippon Shokubai (Japan). The structure of those copolymers, i.e. the nature of diacids and diols used, influences their properties [
29
] as well as their biodegradation rates [
27
].
PBS is a white crystalline thermoplastic, having a melting point of around 90 – 120 °C. Its glass transition temperature of about -45 °C to -10 °C is between the Tgs of PE and PP. The crystallization and the melting behavior of PBS have been reported in the literature [ 30 , 31 ]. Its mechanical properties resemble to those of polyethylene or polypropylene. Elongation at break is about 330% and tensile strength is 330 kg/cm 2 . In addition PBS has good processability, better than that of PLA and PGA [ 32 ]. Another polymer with a long chain branch has been prepared for specific applications (stretched blown bottles as well as foams) [ 33 ]. The biodegradation of the three grades are different according to the physical environment [ 34 , 35 ]. Because PBS suffers from insufficient biocompatibility and bioactivity for medical applications, surface modification was used to modify the PBS surface by means of plasma treatment [ 36 ].
In the case of copolyester (PBSA), polyester tensile strength decreases with the introduction of the secondary component (adipate), exhibiting a tendency similar to that of the other physical properties. PBS is the polyester with the highest tensile strength, while the copolymers PBSA (80/20) and PBSA (60/40) shows improved elongation [ 37 ].
Poly(p-dioxanone) (PPDO):
It is a well-known aliphatic polyester having good physical properties. It is prepared by ring opening polymerisation of
p
-dioxanone. PPDO is semi-crystalline, with a low glass transition temperature in the range -10 °C to 0 °C. The properties of PPDO with different molecular weights have been investigated [
38
]. The increase of molecular weight can improve the thermal stability of PPDO. According to the results of rheological tests PPDO exhibits a shear-thinning behaviour. The tensile strength and modulus increase with molecular weights. PPDO has ultimate biodegradation because of the esters bonds in the polymer chains.
Many microorganisms in nature can degrade PPDO; it is then a good material for general uses. Nevertheless PPDO is more expensive than PBS. Novel biodegradable polyester was prepared by chain extension of PPDO with PBS [ 39 ]. Toluene diisocyanate was used as chain extender. Both polymers have good compatibility.
Polycarbonate:
Poly(trimethylene carbonate) (PTMC) is obtained by ring opening polymerization of trimethylene carbonate, catalysed with diethylzinc. A high molecular weight flexible polymer was prepared, but displays poor mechanical performance [
40
]. Due to this property, its applications are limited and copolymers are more often used. Copolymers with glycolide and dioxanone have been prepared [
10
]. Poly(propylene carbonate) (PPC) is synthesized via copolymerization of propylene oxide and carbon dioxide. It has good properties such as compatibility, impact resistance. Its thermal stability and biodegradation need to be improved. A classical way is to blend it with other polymers [
41
]. Mitsubishi Gas Chemical Co. (Japan) commercializes a copolyester carbonate (PEC) namely poly[oligo(tetramethylene succinate)-co(tetramethylene carbonate)]. The content of carbonate inside the copolymer is changeable. The melting point of PEC is about 100-110 °C. Introducing carbonate into PTMS probably caused disorder in the crystal structure, thus lowering its melting point and increasing its susceptibility to enzymatic and microbial attacks, compared to polyolefins. The microbial degradability of PEC was confirmed to be higher than those of both of its constituents [
42
].
2.2.2. Aromatic copolyesters
A large range of polyesters or copolyesters with aliphatic monomeric units of different sizes has been developed. Nevertheless mechanical properties of such polyesters are lower than those of non biodegradable polymers. Besides, aromatic polyesters are insensitive to hydrolytic degradation and to enzymatic or microbial attack. To improve them, aliphatic-aromatic copolyesters were made. Aliphatic-aromatic copolyesters consist in mixture of aliphatic and aromatic monomers. They are often based on terephatalic acid. Shaik [
43
] has presented a large range of aliphatic-aromatic copolyesters of different sizes.
The most frequently studied copolyester is poly(butylene adipate-co-terephtalate) (PBAT). Its commercial names are Ecoflex ® , prepared by BASF (Germany), Easter Bio ® from Eastman Chemical (USA), Origo-Bi ® from Novamont (Italy). It is obtained by polycondensation between 1,4-butanediol and a mixture of adipic acid and terephtalic acid. It shows good mechanical and thermal properties at a concentration in terephtalic acid higher than 35% mol. The biodegradation rate decreases rapidly when the concentration became higher than 55% [ 44 , 45 ].
In 1997 Dupont (USA) launched a biodegradable copolyester resin, called Biomax ® . It is a modified form of poly(ethylene terephtalate), with a high terephtalic acid content. It has a relatively high melting point of around 200 °C. Biodegradation of Biomax ® first begins with hydrolysis. Moisture fragments the polymers into small molecules which are bioassimilated and mineralized by naturally occurring microorganisms [ 46 ].
More recently, some studies have been published on various copolyesters including terephtalic acid and aliphatic acid used in biodegradable aliphatic polyesters. Lactic acid [ 47 ], glycolic acid [ 48 ] or succinic acid [ 49 ] were used to prepare novel biodegradable polymers by melt reaction. Synthesis and hydrolytic degradation of those new polymers are described.
2.2.3. Polyamides and poly(ester-amide)s
Polyamides contain the same amide bound as in polypeptides. Nevertheless polyamides have a high crystallinity and strong chains interactions so that the rate of biodegradation is lower than that of polypeptides. Enzymes and microorganisms can degrade low molecular weight oligomers [ 9 , 50 ]. Biodegradation could be increased by the introduction of various side groups as benzyl, hydroxyl and methyl groups, through copolymerization for instance.
Copolymers with amide and ester groups are found to be readily degraded. The rate of degradation increases with increasing ester content. Aliphatic poly(ester-amide)s have been synthesized from 1.6-hexanediol, glycine and diacids with a various number of methylene groups varying from 2 to 8 [ 51 ]. All these polymers are highly crystalline.
Another series was prepared from 1,2-ethanediol, adipic acid and aminoacids, including glycine and phenylalanine [ 52 ]. In all cases, the polymers showed a high susceptibility to enzymatic degradation. The degradation rate could be controlled by modifying the phenylalanine:glycine ratio. Cameo is a poly(ester-amide) blend based on leucine or phenylalanine.
Bayer (Germany) presented in 1995 its first commercial polyester amide called Bak 1095
®
but they stopped production in 2001. Bak 1095
®
is based on caprolactam, butanediol and adipic acid. It has mechanical and thermal properties close to those of polyethylene [
53
]. High toughness and tensile strain at break are its characteristics. The crystallisation temperature of Bak 1095
®
is 66 °C and the melting point is 125 °C. Because of its low crystallisation rate, Bak 1095
®
is not suitable for injection moulding, so another grade, Bak 2195
®
, was launched in 1997. It was specially developed for injection moulding. Its crystallisation temperature is 130 °C and the melting point is 175 °C [
46
].
2.2.4. Polyurethanes
Polyurethane, a unique polymeric material with a wide range of physical and chemical properties, has been extensively tailored to meet the highly diversified demands of modern technologies such as coatings, adhesives, fiber, foams, and thermoplastic elastomers [ 54 ].
Polyurethanes are prepared from three constituents: a diisocyanate, a chain extender and a polyol. They react to form a segmented polymer with alternating hard segment and soft segment. Soft segment is derived from polyols such as polyester polyols and polyether polyols. Hard segment is formed from the diisocyanate and the chain extender. The biodegradation of polyurethanes depends on the chemical nature of the segments.
The degradation can be tailored through an appropriate choice of the soft segment. Polyether-based polyurethanes are resistant to biodegradation. If the polyol is a polyester, then polyurethanes are readily biodegradable [ 55 ]. Biodegradable polyesters used are PCL, PLA and PGA [ 56 , 57 ]. It is assumed that the degradation rate is governed by soft segments, where esters bounds are located. The urethane bounds, which are located in hard segment, are not easily hydrolysed.
Novel biodegradable poly(ester urethane)s have thus been synthesized. The first consists of poly(L-lactic acid) and poly(butylene succinate) blocks [ 22 ]. It has been prepared via a chain extension reaction of dihydroxyl terminated PLLA and PBS prepolymers. Toluene-2,4-diisocyanate was used as chain extender. The crystallisation of the copolymer was caused by PBS segment. The extensibility of PLLA was largely improved by incorporating PBS segment.
The second is based on chitin /1,4-butane diol blends. The first step is the synthesis of a prepolymer of poly(ε-caprolactone) and 4,4-diphenylmethane diisocyanate. The prepolymer was extended with chitin and 1,4-butane diol. Different mass ratio of the two extenders has been used. When the content in chitin increased, the mechanical properties of prepolymers were improved [ 58 , 59 ]. Materials made of chitin have attractive advantages as the presence of chitin increases biodegradability, which offers applications in medicine.
The influence of the nature of the chain extender on biodegradability was studied only recently [ 60 ]. Introducing a chain extender with hydrolysable ester linkage allowed to the polyurethane hard segment to be degradable.
Most common isocyanates, however, are toxic, so aliphatic biocompatible diisocyanates have been used. Poly(ester urethane)s were prepared by reaction of lysine diisocyanate with polyester diols based on lactide or ε-caprolactone [ 61 , 62 ]. 1,4-diisocyanatobutane is another biocompatible diisocyanate.
In addition, driven by the continuous reduction in costs and the control of volatile organic compound emissions, the development of waterborne polyurethane or poly(urethane-urea) formulations has dramatically increased [ 63 , 64 ]. The resulting water-borne polyurethane materials present many of features related to conventional organic solvent-borne ones with the advantage of low viscosity at high molecular weight, non-toxicity, and good applicability [ 65 ]. They are more environmentally-friendly and their biodegradation is easier than that of conventional polyurethanes. Environmental protection can be better realized when the polyol is replaced with renewable sources, such as some vegetable oils, to synthesize the water-borne urethane materials. A novel waterborne polyurethane using rapeseed oil based polyol as soft segment was synthesized. The utilization of the rapeseed oil has recently become very widespread, including end products that range from margarine to a refined biodiesel fuel, and from environmentally friendly lubricants to meal for livestock. Castor oil is another vegetal oil that can also be used. Good mechanical properties of both tensile strength [9.3G (±1.5 MPa)] and elongation at break [520 (±20%)] were obtained. These waterborne polyurethanes were used to modify plasticized starch to prepare novel biodegradable materials with high performances [ 66 , 67 ]. PCL was also used as soft segment material to synthesize a waterborne polyurethane, which was used to plasticize starch [ 68 ].
2.2.5. Polyanhydrides
An overview of polyanhydrides has been recently published [ 69 ]. Polyanhydrides are interesting biodegradable materials because they have two hydrolysable sites in the repeating unit. The degradation rate depends on the polymer backbone. Aromatic polyanhydrides will degrade slowly over a long period, while aliphatic polyanhydrides can degrade in a few days. Various routes have been investigated to their preparation: melt condensation of diacids (or diacid esters); ring opening polymerization of anhydrides; interfacial condensation; reaction of diacyl chloride with coupling agents [ 70 ].
Aliphatic homo-polyanhydrides have limited applications because of their high crystallinity and fast degradation. This is the case of poly(sebacic anhydride). The degradation rate of polyanhydride can be managed by adjusting the hydrophobic and hydrophilic components in the copolymer. Increase in the hydrophobicity of the diacid building blocks of the polymers resulted in slower degradation. Copolymers with a hydrophobic aromatic comonomer such as carboxyphenoxypropane have been extensively investigated as biomaterials [
71
]. Their degradation products are non-toxic and biocompatible.
As a large range of diacid monomers is available, polyanhydrides with different linkages have been developed. These include ether, ester and urethane linkages. To improve mechanical properties of polyanhydrides for specific medical applications, copolymers of anhydride with imide were also developed [
72
]. Their good mechanical performance has been demonstrated. Another approach is the incorporation of acrylic functional groups in the monomeric unit. This leads to photocrosslinkable polyanhydrides. The mechanical strength and degradation rate of these crosslinked polyanhydrides depend on the nature of the monomeric species.
2.3. Synthetic polymers with carbon backbones
Polymers with carbon backbones, such as vinyl polymers, require an oxidation process for biodegradation. Hydrolysis cannot occur.
2.3.1. Vinyl polymers
Vinyl polymers are generally not susceptible to hydrolysis. An oxidation process is required for their biodegradation. Most of biodegradable vinyl polymers contain an easily oxidizable functional group and catalyst is added to promote their oxidation or photooxidation [ 9 ].
Polyvinyl alcohol is widely used because of its solubility in water. It can be easily biodegraded by microorganisms as well as enzymes [ 73 ]. It has been developed by Environmental Polymers (UK) under the trade name Depart ® . The incorporation of photosensitive group into the polymers as ketones yields to poly(enol-ketone). They are easier hydrolysed and biodegraded than polyvinyl alcohol.
Polyacrylates are generally resistant to biodegradation [
9
]. Biodegradable segments, as peptides, have been incorporated into the polymer chains yielding to biodegradable polymers. In the field of biomedical applications poly(alkylcyanoacrylate)s are extensively used. They are prepared by an anionic polymerization of alkyl cyanoacrylic monomers. A little amount of moisture is used as initiator. Those polymers are the fastest degrading polymers. Degradation time ranges from few hours to few days. It depends on the length of the alkyl side substituent. When the alkyl side group is short, very fast degradation is noticed, however degradation products are toxic. Polymers with a longer alkyl substituent are thus preferred [
10
].
Other biodegradable polymers have been studied especially for biomedical applications, because each of these applications requires materials with specific properties. This includes poly(ortho ester)s, poly(propylene fumarate), poly(amino acid)s, polyphosphazenes and polyphosphoesters. They are covered in another review [ 10 ].
3. Biodegradable Polymers Derived from Renewable Resources
Biodegradable polymers obtained from renewable resources have attracted much attention in recent years. This new interest results from global environmental respect awareness and the fossil depletion problem. Biopolymers research and development as well as their production have been the fastest for several years.
3.1. Natural polymers or agro-polymers
Natural polymers are formed in nature during the growth cycles of all organisms. Natural biodegradable polymers are called biopolymers. Polysaccharides, as starch and cellulose, represent the most characteristic family of these natural polymers. Other natural polymers as proteins can be used to produce biodegradable materials. These are the two main renewable sources of biopolymers. Another resource is lipids. To improve the mechanical properties of such polymers or to modify their degradation rate, natural polymers are often chemically modified.
3.1.1. Proteins
Proteins are thermoplastic heteropolymers. They are constituted by both different polar and non polar α-aminoacids. Aminoacids are able to form a lot of intermolecular linkages resulting in different interactions. These offer a wide possibility of chemical functionalities and functional properties. Most of the proteins are neither soluble nor fusible, especially fibrous proteins as silk, wool and collagen [
9
]. So they are used in their natural form. Casting of film-forming solutions allows the preparation of films. To process protein based bioplastics, classical way is the thermoplastic processing, which consists of mixing proteins and plasticizers. Flexibility and extensibility of films are improved by the use of plasticizers [
74
,
75
]. The biodegradation of proteins is achieved by enzymes, as protease, and is an amine hydrolysis reaction. Grafting of protein is a mean to control the rate of biodegradation [
9
].
3.1.1.1. Proteins from animal sources
Collagen is the primary protein component of animal connective tissues. Twenty two types of collagen exist. Collagen is composed of different polypeptides, which contain mostly glycine, proline, hydroxyproline and lysine. The flexibility of the collagen chain depends on the glycine content. More flexibility is obtained with an increase content of glycine [ 76 ]. Collagen is enzymatically degradable and has unique biological properties. It has been extensively investigated for biomedical applications [ 10 ].
Collagen molecules were linked onto the surface of cellulose and poly(vinyl alcohol) films via covalent bonding [ 77 ]. Activation methods using cyanogen bromide or p -toluenesulphonyl chloride were used. The amount of bound protein was lower for PVA than for cellulose. The cellulose film was found to become brittle and weak after activation, but the PVA films was not. Changes in degree of swelling and solubility of both activated films have been reported.
By denaturation and/or physical – chemical degradation of collagen, a high molecular weight polypeptide is produced, called gelatine [ 78 ]. Gelatine is also a protein. It consists of 19 aminoacids. It is water soluble. Gelatine has good film forming abilities. The mechanical and barrier properties of these films depend on the physical and chemical characteristics of the gelatine, especially the aminoacid composition and the molecular weight distribution. Combining gelatine with other biopolymers as soy protein, oils and fatty acids or certain polysaccharides may improve the physical properties of gelatine films [ 79 ]. Mechanical and water vapour barrier properties of gelatine films also depend on the plasticizers used [ 80 ]. Grafting was also used for the modification of gelatine [ 81 ]. Methyl methacrylate and poly(ethyl acrylate) were grafted onto gelatines by radical initiators. The composition of the graft copolymer depended on the temperature used in the process. Generally the number of branches is small whereas the molecular weight of the branches is high. It was noticed that the extent of degradation seems to decrease with increasing grafting efficiency. Proteases degrade gelatine by hydrolysing the amide function [ 9 ]. Elastin, albumine and fibrin are other proteins from animal sources. They have been investigated especially for various biomedical applications [ 10 ].
3.1.1.2. Proteins from vegetal sources
Proteins derived from plants are produced at a kilo tonne per annum scale. Wheat gluten is a protein by-product of the starch fabrication. It is readily available in high quantity and at low cost. Wheat gluten contains two main groups of proteins, gliadin and glutenin. Gliadins are proteins molecules with disulphide bonds. They have low molecular weight and a low level of aminoacids with charged side groups. Glutenins are more sophisticated proteins, with a three dimensional structure. Their molecular weight is at least ten times higher than that of gliadins. Wheat gluten materials have the fastest degradation rates. Gluten is fully biodegradable and the products obtained are non-toxic.
Wheat gluten has been proven to be an excellent film forming agent. Without plasticizer, wheat gluten films are brittle [ 82 ]. The effects of water, glycerol and sorbitol on the glass transition temperature of wheat gluten were studied [ 83 ]. Compared to water, glycerol and sorbitol have higher molecular weights and lower evaporation rates, so their accessibility to various zones is limited. Thus the plasticizing effect of glycerol and sorbitol is less important than that of water. It was shown that by plasticizing gluten with glycerol, a malleable phase can be obtained [ 84 , 85 ]. This phase resembles a structured viscoelastic solid with pseudo-plastic behaviour. As crosslinking reactions occur at temperature higher than 60 °C, the temperature range of the use of wheat gluten is limited [ 82 ].
Soy protein: It has been used since 1959 as an ingredient in a variety of foods for its functional properties, which include emulsification and texturizing. Recently the popularity of soy protein has been increasing, mainly because of its health benefits. It has been proven that soy protein can help to prevent heart problems. According to the production method different categories of soy proteins exist: soy protein isolate, soy protein concentrate and textured soy protein. Soy protein isolate is the most refined form of soy protein and contains about 90 percent protein. Soy protein concentrate is basically soybean without the water soluble carbohydrates. It contains about 70 percent of protein. Textured soy protein, often called TSP, is made from soy protein concentrate by giving it some texture. As for soy protein concentrate, it contains about 70 percent protein [
86
]. Soy protein films do not have good mechanical and barrier properties as most of protein films, due to their hydrophilic nature. They are used to produce flexible and edible films.
3.1.2. Polysaccharides
The principal polysaccharides used in materials applications are cellulose and starch, but other are also exploited on a lesser scale.
3.1.2.1. Polysaccharides from marine sources
Chitin: It is the second most abundant natural biopolymer. It is a linear copolymer of
N
-acetyl-glucosamine and
N
-glucosamine with β-1,4 linkage. These units are randomly or block distributed throughout the biopolymer chain depending on the processing method used to obtain the biopolymer. Chitin is usually found in the shells of crabs, shrimp, crawfish and insects. It could be considered as amino cellulose. Recent advances in fermentation technology suggest that the cultivation of fungi can provide an alternative source of chitin [
87
]. The study reports the exploitation of both sources to produce chitin. The protein content in chitin obtained form these two methods is different. It is less than 5% for the chitin extracted from shells and reaches 10 – 15% for the chitin produced by fungi. The molecular weights for all chitin samples were in the same range. A review of chitin and chitosan has been recently published [
88
]. It details the distribution of chitin and chitosan in nature and the biosynthesis of chitin and chitosan by applying microorganisms. Chitinase, an enzyme, degrades chitin. As chitin has a poor solubility, it is often substituted for many applications [
89
].
Chitosan: Chitin is processed to chitosan by partial alkaline
N
-deacetylation. In chitosan glucosamine units are predominant. The ratio of glucosamine to acetyl glucosamine is reported as the degree of deacetylation. This degree may range from 30% to 100% depending on the preparation method and it affects the crystallinity, surface energy and degradation rate of chitosan.
Chitosan is insoluble in water and alkaline media. This is due to its rigid and compact crystalline structure and strong intra- and intermolecular hydrogen bonding. Chitosan can only soluble in few dilute acid solutions. Then chitosan is dissolved in acidic solutions before its incorporation into biodegradable films [ 90 ]. Enzymes such as chitosanase or lysozymes are known to degrade chitosan.
The applications of chitin and chitosan are limited because of their insolubility in most solvents. As chitosan has amino and hydroxyl reactive groups, chemical modifications can be proceeded. Modified chitosan have been prepared as N -carboxymethylchitosan or N -carboxyethylchitosan. They have been prepared for use in cosmetics and in wound treatment [ 91 ].
Chemical modifications of both polymers are of interest. These modifications do not change the fundamental skeleton of polymers and keep their physicochemical and biochemical properties. New properties could be introduced depending on the chemical nature of the group introduced. A lot of different derivatives have been prepared [ 92 , 93 , 94 ].
3.1.2.2. Polysaccharides from vegetal sources
Starch: it is a well–known hydrocolloid biopolymer. It is a low cost polysaccharide, abundantly available and one of the cheapest biodegradable polymers. Trade names and suppliers of starch are reported in
Table 2
. Starch is produced by agricultural plants in the form of granules, which are hydrophilic. Starch is mainly extracted from potatoes, corn, wheat and rice. It is composed of amylose (poly-α-1,4-D-glucopyranoside), a linear and crystalline polymer and amylopectine (poly-α-1,4-D-glucopyranoside and α-1,6-D-glucopyranoside), a branched and amorphous polymer. The relative amounts and molar masses of amylose and amylopectine vary with the starch source, yielding to materials of different mechanical properties and biodegradability [
95
,
96
]. As the amylose content of starch increases, the elongation and strength increase too.
Table 2. Commercially available Starch and blends with polyesters.
Table 2. Commercially available Starch and blends with polyesters. Trade name Company Country Mater-Bi ® , Biocool ® Novamont Italy Solanyl ® Rodenburg Biopolymers Netherlands Ecofram ® National Starch USA Vegeplast ® Végémat France Biolice ® Limagrain France Biotech ® Biotech Germany Bioplast ® Biotec England Plantic ® Plantic Technologies Australia
The stability of starch under stress is not high. The glucoside links start to break at 150 °C and above 250 °C the granules collapse. Retrogradation, i.e. reorganization of hydrogen bonds, is observed at low temperatures, during cooling.
In its applications starch can be either mixed, kept intact, in used in various resins as a filler or melt for blending compounds. In the former form, fillers are starch whiskers used with polymer resins. Starch nanocrystals can be obtained by partial acid hydrolysis of the amorphous regions of granules. It is then incorporated into natural polymers as PHA natural rubber or starch itself [ 97 , 98 , 99 ].
In the latter form, the molecular order inside the granules must be destroyed to improve starch processability. Granules are gelatinized in water at 130 °C. Starch is usually used as a thermoplastic. It is plasticized through destructuration in presence of specific amounts of water or plasticizers and heat and then it is extruded [
100
]. The most common plasticizers are polyols as glycerol [
101
]. When used, polyols may induce a recrystallisation reaction called retrogradation. The properties of the extruded starch depend on the water content and relative humidity [
102
]. Thermoplastic starch (TPS) has a high sensitivity to humidity. Thermal properties of TPS have been shown to be more influenced by the content water than the starch molecular weight [
103
]. TPS thus obtained is almost amorphous. A new crystalline form induced by the process can remain in the thermoplasticized product.
The plasticizer content is another important parameter. The interactions between the plasticizer and starch are weak for a plasticizer amount below 10% wt. The material is then fragile and it is difficult to work with it. When the plasticizer content becomes higher than 20% wt, flexibility and elongation properties improved [ 104 ].
Biodegradation of starch is achieved via hydrolysis at the acetal link by enzymes [ 9 , 105 ]. The α-1,4 link is attacked by amylases while glucosidases attack the α-1,6 link. The degradation products are not toxic.
Thermoplastic starch or plasticized starch offers an interesting alternative for synthetic polymers in specific applications. It is used for example in starch-based composites. Significant research is done in developing a new class of fully biodegradable “green” composites called biocomposites [ 106 ]. They consist in biodegradable plastics with reinforcements of biodegradable natural fibers. Starch can be used as the biodegradable polymeric compound.
However starch-based products suffer from water sensibility, brittleness and poor mechanical properties. To solve these problems various approaches are possible. They include chemical modification. Starch has two important functional groups, hydroxyl groups (-OH) and ether bonds (C-O-C). The hydroxyl group has a nucleophilic character and is susceptible to substitution reactions. To improve the mechanical properties of starch, it can be modified by acetylation [
107
]. Starch acetate is prepared by acetylation of starch with a mixture of pyridine and acetic acid. Casting of acetylated starch was realized from solutions of formic acid. The wet strength of the films could be maintained when the acetyl content is sufficient. The starch acetate has a high content of linear amylose and it is consequently more hydrophobic than starch. By reducing the water sensibility, mechanical properties are improved [
104
]. Polymers with various degrees of acetylation could be easily produced yielding to a broad range of hydrophobicities. Grafting of monomers like styrene and methylmethacrylate to the starch backbone is another strategy, but the grafted chains are not easily biodegradable [
108
].
Another approach to improve the mechanical properties of starch-films is blending. Starch blends with synthetic biodegradable polymers have been extensively studied [ 109 , 110 ]. Those systems are described in Section 4 . Intensive research work has also been devoted to developing blends with nonbiodegradable polymers [ 8 , 111 ]. Nevertheless such systems are not considered to be biodegradable materials but may be partially biodegradable. Only the fraction of starch in the mixture which is accessible to enzymes could be degraded. Those systems are not being developed in this review.
Cellulose: it is another widely known polysaccharide produced by plants. It is a linear polymer with very long macromolecular chains of one repeating unit, cellobiose. Cellulose is crystalline, infusible and insoluble in all organic solvents [ 9 ]. Biodegradation of cellulose proceed by enzymatic oxydation, with peroxidase secreted by fungi. Cellulose can also be degraded by bacteria. As for starch degradation products are non toxic [ 112 ].
Because of its insolubility and infusibility, cellulose should be transformed to be processable. Important derivatives of cellulose are produced by reaction of one or more of the hydroxyl groups present in the repeating unit. Ethers, esters and acetals are the main derivatives. Tenite
®
(Eastman, USA), Bioceta
®
(Mazzucchelli, Italy), Fasal
®
(IFA, Austria) and Natureflex
®
(UCB, Germany) are trade names of cellulose-based polymers.
Cellulose esters are modified polysaccharides. Various degrees of substitution can be obtained. Their mechanical properties and their biodegradation decrease when the degree of substitution increases [
113
,
114
]. Cellulose acetate (CA) is one of the most important cellulose derivatives. Commercially available cellulose acetate has a degree of substitution between 1.7 and 3. Tensile strength of cellulose acetate films is comparable to polystyrene. Bioceta
®
produced by Mazzuccheli (IT) and EnviroPlastic Z
®
produced by Planet Polymer (US) are two of the commercially available acetate celluloses. Cellulose acetate can be obtained from agricultural by-products [
115
]. Agricultural products based on lignocellulose can be used for production of fuel ethanol. Lignocellulose is converted into ethanol via a four step process including enzymatic saccharification and fermentation of hemicellulosic sugars. Cellulose is then obtained as a residue. It could be used for CA preparation.
CA is currently used in fiber or film applications. CA has a high glass transition temperature, which limits its thermal processing. Most CA must be plasticized if they are used in thermoplastic applications because its decomposition temperature is lower than its melt processing temperature. [
116
]. An alternative way is blending CA with flexible polymers. Another method to overcome this problem is the synthesis of thermoplastic derivatives of CA by graft reaction. Different ways of graft copolymerization of cellulose diacetate onto PLA have been reported [
117
]. Cellulose diacetate-graft-poly(lactic acid)s were synthesized through a copolymerization of lactic acid, or through a ring-opening copolymerization of L-lactide either in dimethylsulfoxide or in bulk. All the copolymers have the same glass transition temperature of around 60 °C, close to that of PLA homopolymer. The drawability of copolymers increases a lot with increasing content of PLA. When the %wt of PLA reached 79%, the elongation at break reaches a maximum of around 2,000%.
Alginic acid or alginate: is another polysaccharide, present in brown algae. It contains carboxyl groups in each constituent residue. Alginates are extracted from the algae using a base solution. Its reaction with acid yields to alginic acid. Alginate is a non-branched, binary copolymer. It is composed of β-D-mannuronic acid monomer linked to α-L-guluronic acid monomer, through a 1,4-glycoside linkage. The ratio between the two monomers varies with the sources. Alginic acid is able to form gels in the presence of counterions, as divalent cations, such as Ca
2+
. The pH, type of counterion and the functional charge density of this polymer affect the degree of crosslinking [
118
]. This gelling property allows the encapsulation of various components.
Polysaccharides, such as hyaluronic acid and chondroitin sulphate, are of human origin. Their use so far has been in specific biomaterial applications [ 10 ]. They are not being described here.
3.2. Bacterial Polymers
They are polyesters obtained by polymerisation of monomers prepared by fermentation process (semi-synthetic polymers) or produced by a range of microorganisms, cultured under different nutrient and environmental conditions (microbial polymers) [ 119 ]. These materials are accumulated in microorganisms as storage materials.
3.2.1. Semi-synthetic polymers
The fermentation of sugars produces different monomers, which are converted to polymers [ 120 , 121 ]. A new range of PLA was first manufactured by Cargill Dow Polymers [ 122 ]. PLA is synthesized from lactic acid produced via starch fermentation from lactic bacteria. Starch is converted into sugar which is then fermented to give lactic acid [ 123 ]. The lactic acid prepared by this biotechnological method is almost exclusively L-lactic acid [ 124 ]. PLA is completely degraded under compost conditions. PLA is not soluble in water; nevertheless microorganisms in marine environments can degrade it. PLA is a hard material. Its hardness is similar to acrylic plastic. Others characteristics have been reported in Section 2.2.1 .
3.2.2. Microbial polymers
Most of studies deal with poly(β-hydroxyalcanoate)s (PHA). They represent natural polyesters. Nevertheless, increasing attention is given recently to carbohydrate polymers produced by fermenting a sugar feedstock with bacteria or fungi [ 125 , 126 ]. They are xanthan, curdlan, pullulan and hyaluronic acid. Biosynthesis of poly(amino acid)s from microorganism was also reported [ 127 ].
3.2.2.1. Microbial polyesters
In the future PHAs may be produced by plants [ 128 ] or transgenic plants [ 129 ]. A number of bacteria can accumulate PHAs as intracellular reserve materials. Some organisms accumulate PHA from 30% to 80% of their cellular dry weight, in the presence of an abundant source of carbon and under limited nitrogen [ 130 ]. The general formulae of the monomer unit is -[O-CH(R)-CH 2 -CO]-. According to the size of the alkyl substituent (R) mechanical properties of PHA differ [ 9 , 131 ]. Rigid brittle plastics to flexible plastics or strong tough elastomers can be obtained. PHAs are wholly biodegradable. Biodegradation occurs via linkage break by esterases of the terminal monomer from the chain ends [ 132 ].
Poly(hydroxybutyrate) (PHB): Since 1925, this polyester is produced biotechnologically and was attentively studied as biodegradable polyester [ 133 ]. The R alkyl substituent group is methyl. PHB is highly crystalline with crystallinity above 50%. Its melting temperature is 180 °C. The pure homopolymer is a brittle material. Its glass transition temperature is approximately of 55 °C. It has some mechanical properties comparable to synthetic degradable polyesters, as PLA [ 134 ]. During storage time at room temperature a secondary crystallization of the amorphous phase occurs. As a result, stress and elongation modulus increase (E = 1.7 GPa) while the polymer becomes more brittle and hard. Elongation at break is then much lower (10%) [ 135 ]. Compared to conventional plastics, it suffers from a narrow processability window [ 136 ]. PHB is susceptible to thermal degradation at temperatures in the region of the melting point [ 137 ]. To make the process easier, PHB can be plasticized, with citrate ester.
PHB is degraded by numerous microorganisms (bacteria, fungi and algae) in various environments [ 138 ]. The hydrolytic degradation yields to the formation of 3-hydroxy butyric acid, a normal constituent of blood, nevertheless with a relatively low rate.
Different monomers have been grafted onto PHB to prepare biodegradable polymers to be used for wastewater treatments. The grafted monomers were either hydrophilic as acrylic acid or sodium-p-styrene sulfonate, or hydrophobic as styrene or methyl acrylate [ 139 ]. The degree of grafting was different according to the monomers, increasing with the following order styrene, sodium-p-styrene sulfonate, methyl acrylate and acrylic acid.
Multicomponent polymeric systems containing PHB have been obtained by two ways. The first is a radical polymerization of an acrylic polymer in the presence of PHB. The second consists in melt mixing PCL with PHB. Peroxide is used in both processes to form intergrafted species responsible for compatibilization [ 140 ]. These methods have been considered as reactive blending.
It should be noted that apart from the bacterial synthetic way, other chemical ways have been developed for the production of PHB. The ring opening polymerization of β-butyrolactone yields to PHB too [ 141 , 142 , 143 ]. Different structures are obtained according to the synthesis route. An isotactic polymer with random stereosequences is obtained via bacterial process while a polymer with partially stereoregular block is obtained via chemical synthesis.
Poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV): Among PHAs, the main biodegradable microbial polymer studied is a copolymer of hydroxybutyrate and hydroxyvalerate (HV). It was first synthesized by ICI in 1983. It can be produced by adding propionic acid to nutrient feedstock supplied to bacteria. Mixed carbon source is also used [ 144 ]. PHBV is a highly crystalline polymer with a melting point of 108 °C and glass transition temperature in the range -5 °C to 20 °C [ 140 ]. The pure copolymer is also brittle, less than PHB. Elongation at break is lower than 15% and elastic modulus is 1.2 GPa.
The melting temperature and the mechanical properties can be modified by changing the hydroxyvalerate unit content. The melting point of the copolymer, as well as the glass transition temperature and the crystallinity decrease as the hydroxyvalerate unit content increases [ 46 , 145 ]. The impact strength increases and the tensile strength decreases with an increase of the HV units [ 145 , 146 ].
The rate of degradation of PHBV is faster than that of PHB. The degradation kinetics depend on the structure (copolymer or homopolymer) and the crystallinity, and as a consequence, on the processing conditions [ 147 ].
PHB and PHBV are commercially available under different trade names: Biopol
®
from Mosanto (USA), Nodax
®
from Procter & Gamble (US) and Kaneka corporation (Japan), Eamat
®
from Tianan (China) and Biomer P
®
from Biomer (Germany).
To overcome the poor mechanical properties of PHB or PHBV and to increase the rate of degradation of those polymers, they can be mixed with other polymers or additives [ 148 , 149 ]. Nevertheless blends with other polymers are difficult to obtain because of chemical incompatibility. Additives can be chosen between the following list [ 135 ]: nucleating agents as saccharin, plasticizers as glycerol, triacetin or tributyrin, processing lubricants like glycerol mono(or tri)stearate. When plasticization is obtained the PHBV properties are modified [ 150 ].
PHAs are sensitive to the process conditions. A quick diminution of viscosity is obtained during the extrusion process. By increasing the shear level, the temperature and the residential time the molecular weight of PHA decreases [ 151 ].
It has also been reported that feeding the bacteria with different carbon sources led to the productions of materials with better mechanical properties [ 152 , 153 ]. Polyesters with longer alkyl substituent have lower degree of crystallinity, lower melting and glass transition temperatures.
Other microbial polyesters are also available. The specificity of the matrices of microorganisms is such that culture conditions, for example pH, temperature, concentration, carbon sources, and the kind of microorganisms lead to the production of various polymers [
154
,
155
]. Ninety one different hydroxyalkanoic acids have been reviewed [
156
]. Marine microorganisms could also be used [
157
]. Nevertheless only very few PHAs are available in sufficient amounts to allow their study, which limits their commercialization. PHAs are expensive when they are used alone, so they are often blended with other less expensive polymers having complementary characteristics.
4. Blends of Biodegradable Polymers
Mixing biopolymers or biodegradable polymers with each other can improve their intrinsic properties.
4.1. Starch-based blends
Starch is totally biodegradable and is an environmentally friendly material. In addition starch has a low cost. Nevertheless, since starch is highly sensible to water and has relatively poor mechanical properties compared to other petrochemical polymers, its use is limited. A solution may be to blend it with other synthetic polymers. Many biodegradable starch-based thermoplastic blends have been developed and studied extensively. A lot of research work deals with the development of blends of starch with synthetic biodegradable polymers. These blends present several advantages [
15
,
111
]. The material properties can be adjusted to the needs of the application by modifying the composition. The blending process is low cost compared to the cost of the development of new synthetic materials. These kinds of blends are intended to be more biodegradable than traditional synthetic plastics [
158
].
Starch-poly(ethylene-co-vinyl alcohol) (EVOH): Blown films were prepared from native corn starch and EVOH with different ratios. The mechanical properties depended strongly on starch and moisture content and processing. A higher extension to break and lower tensile strength and modulus were obtained when the blend was processed at a 5 °C higher temperature. Interactions between both components have been outlined thanks to differential scanning calorimetry and dynamic mechanical analysis [ 159 ].
Starch-polyvinyl alcohol: TPS and PVOH have excellent compatibility and their blends are of particular interest. TPS and starch can be blended at various ratios to tailor the mechanical properties of the final material. Compared to pure TPS materials, blends present improved tensile strength, elongation and processability [ 160 , 161 ]. Their biodegradability has been recently investigated [ 162 ]. The PVOH content has an important impact on the rate of starch degradation: increasing the amount of PVOH will decrease this rate.
Starch-PLA:
The mechanical properties of blends of starch with PLA using conventional processes are poor due to incompatibility. An elongation increase can be achieved by using plasticizers or reacting agents during the extrusion process. Coupling agents like isocyanates have been used. The hydroxyl groups of starch could react with the isocyanate group resulting in urethane linkages and compatibilization of these systems. The effect of gelatinization of starch was also investigated [
163
]. It has been shown that in PLA/gelatinized starch blends, starch could be considered as a nucleating agent, resulting in an improvement of crystallinity in PLA blends and a greater superiority of mechanical properties.
Another way to improve compatibilization is to use a compatibilizer. Maleic anhydride can be used for this purpose [
164
]. An initiator was used to create free radicals on PLA and improved the reaction between maleic acid and PLA. The anhydride group on maleic acid could react with the hydroxyl groups present in starch. Interfacial adhesion between starch and PLA was then significantly improved. The mechanical properties obtained for PLA/starch blends compatibilized with maleic acid are higher than those obtained for virgin PLA/starch blends. A biodegradable PLA-grafted amylose copolymer has been synthesized, to be used as compatibilizer agent in starch/PLA blends [
165
].
Starch – PCL:
To prepare films by using the film blowing technique, TPS was blended with PCL to adjust the rheological properties of the melt before the process [
166
]. Novamont (Italy) produces a class of starch blend with different synthetic components. Its trade name is Mater-Bi
®
. Four grades are available; one of them consists of PCL (Mater-Bi
®
Z). The highest amount of starch allows the acceleration of the degradation of PCL. The behaviour of some PCL-modified starch blends has been studied [
167
]. The addition of modified starch leads to an increase of the Young’s modulus of PCL and a decrease in tensile strength and elongation at break values. The blend becomes less ductile [
168
]. Some synthetic polymers with lower biodegradabilty are used to control the rate of biodegradation according to the applications.
The modulus of blends of high-amylose corn starch (25% wt.) and PCL was 50% higher than that of PCL and the tensile strength 15% lower. The reason why good mechanical properties compared to other blends were obtained is the good dispersion of the granules in the PCL matrix. At higher starch levels a very important decrease in mechanical properties is noticed [
169
]. To increase the mechanical properties of PCL/starch, blends with LDPE were prepared. It has been shown that thermal properties of blends could be improved by crosslinking with organic peroxides. Bioplastics Inc. (USA) extrudes films based on such blend, which have properties similar to those of low density polyethylene. The biodegradation rate of PCL, which is very low, can be significantly increased by the presence of starch [
170
].
Starch – PBS: PBS was blended with granular corn starch [ 171 ]. By increasing the starch content it was shown that elongation at break and tensile strength decreased. The addition of starch fillers significantly improved the degradation rate.
Starch – PHB:
Blends incorporating PHB or PHBV were previously reviewed [
172
]. It was shown that poly(hydroxyalkanoate)s can form miscible blends with polymers which contain an appropriate functional group i.e. capable of hydrogen bonding or donor-acceptor interactions. The effect of blending starch in PHB was also studied [
150
].The properties of blend films with various proportions of starch are identical. A single glass transition temperature is obtained for all the samples, which are semi-crystalline. The tensile strength was optimum for a PHB/starch ratio of 70/30 (% wt/wt) [
173
]. In this particular case, an advantageous cost reduction and an improvement of mechanical properties compared to pure PHB are obtained.
PHBV blends with corn starch had poor mechanical behavior because of a poor adhesion between the starch granules and the polymer matrix [ 174 ]. Biodegradation profiles of individual polymers in the blend were studied and modeled.
Wheat starch was blended with PHBV at 160 °C. The results showed that the incorporation of 50% starch led to a decrease by half in the mechanical properties of PHBV and flexibility diminished too [ 175 ]. On the contrary Young’s modulus increased by 63%. Degradation of this blend proceeded very quickly.
The studies of blends of starch with aliphatic polyesters (PCL, PBS, PHBV) showed in all cases that only a modest level of starch is possible. To improve compatibility between the starch and the aliphatic polyester, a compatibilizer was used. It contains an anhydride functional group and was incorporated onto the polyester backbone. The tensile strength obtained for such blends was close to that of synthetic polyester, only with a small amount of compatibilizer [ 176 ].
4.2. Others blends
PHB or PHBV are brittle polymers. To improve their mechanical properties they are mixed with other biodegradable materials. When nucleating agents are added, smaller spherulites are formed, thus the mechanical properties are improved. In addition these properties depend on the processing conditions, morphology, crystallinity and glass temperature transition [ 135 ].
Another class of biodegradable PHB can be prepared by blending a basic PHB with cellulose esters [
177
]. Blends of PHBV and cellulose acetate butyrate were prepared by thermal compounding. The thermal process did not induce transesterification, nor molecular weight changes. The structure and mechanical properties depended on the PHBV content. When the PHBV content is lower than 50%, blends are amorphous, while with a higher content they become semi-crystalline. At this high content PHBV is partially miscible with cellulose acetate butyrate. These authors also studied blends of cellulose acetate propionate with poly(tetramethylene glutarate) [
116
]. A range of 50 to 90% wt of cellulose acetate propionate was investigated. The same process was used. The blends are amorphous.
Blends of PHBV and PPC were also studied. The crystallinity and morphology of those blends have been reported [
178
]. A transesterification reaction between PHBV and PPC has been outlined. The melting temperature of the blend composed of 70%wt PPC was 4 °C lower than that of pure PHBV, and the crystallization temperature decreased by about 8 °C. The effect of polyvinyl acetate (PVAc) used as compatibilizer on the thermal behavior and the mechanical properties of those blends was reported [
179
]. The melting point and the crystallization temperature of PHBV in blends decrease with the increase content of PVAc. Morphology analysis shows that the addition of the compatibilizer can decrease the size of dispersed phase. Young’s modulus, elongation at break and tensile strength increase in the presence of PVAc. The degradation of those blends in soil suspension was recently investigated [
41
]. Enzymes will preferentially degrade PHBV whereas PPC is degraded by hydrolysis.
Studies concerning blends containing PHA have been summarized in a review [ 172 ]. PHAs can form miscible blends with other polymers containing appropriate functional groups. The miscibility is obtained through hydrogen bonding or donor-acceptor interactions.
Many studies have been reported on PLA blends with various polymers. In most of systems, PLA and other polymers are immiscible. It is essential to compatibilize such blends to have good properties. Blends of PLA with PCL were prepared by melt blending and using
in situ
reactions. In this case an ester exchange reaction by alcoholysis was described [
180
]. In EVOH/PLA blends, the hydroxyl groups of EVOH could react with the carboxyl group of PLA through an esterification reaction in the presence of catalyst [
181
]. Reactive blending of PLA with ethylene copolymer gave an important improvement of mechanical properties of PLA. This was attributed to an interfacial reaction between the components [
182
].
Poly(aspartic acid-co-lactide) (PAL) was used to blend various polymers such as PLLA, PBS and PCL [ 183 ] in order to increase their biodegradability i.e. their degradation rate. In the case of PLLA, the mechanical properties of such blends were similar to that of non-blended PLLA but the hydrolysis rate of the PLLA was effectively enhanced. In the case of PCL melt blended with PAL, a sufficient percentage of poly(aspartic acid-co-lactide) to have an increase in degradation rate is 20% [ 184 ]. PAL was shown to improve the thermal stability of PLA in PAL/PLA blend films.
PCL blends with chitin were prepared as biodegradable composites by melt blending [ 185 ]. Increasing the amount of chitin has no effect on the melting or crystallization temperature. This was attributed to a non miscible blend. Another blending route is solvent casting [ 186 ]. The degree of crystallinity of PCL decreases upon blending with chitin. Same results are obtained with PCL/chitosan blends. These blends are expected to have good mechanical properties.
5. Applications
Biodegradable polymers can be processed by most conventional plastics processing techniques, with some adjustments of processing conditions and modifications of machinery. Film extrusion, injection moulding, blow moulding, thermoforming are some of the processing techniques used. The three main sectors where biodegradable polymers have been introduced include medicine, packaging and agriculture. Biodegradable polymers applications include not only pharmacological devices, as matrices for enzyme immobilization and controlled-release devices [
187
] but also therapeutic devices, as temporary prostheses, porous structure for tissue engineering.
As biopolymers have a low solubility in water and a very important water uptake, they could be used as absorbent materials in horticulture, healthcare and agricultural applications [ 188 ]. Packaging waste has caused increasing environmental concerns. The development of biodegradable packaging materials has received increasing attention [ 189 ]. Table 3 regroups some materials and their use.
5.1. Medicine and pharmacy
Biodegradable polymers used as biomaterials have been recently reviewed [ 7 , 10 , 190 ]. To be used as biomaterials, biodegradable polymers should have three important properties: biocompatibility, bioabsorbility and mechanical resistance. The use of enzymatically degradable natural polymers, as proteins or polysaccharides, in biomedical applications began thousand of years ago whereas the application of synthetic biodegradable polymers dates back some fifty years.
Current applications of biodegradable polymers include surgical implants in vascular or orthopaedic surgery and plain membranes. Biodegradable polyesters are widely employed as porous structure in tissue engineering because they typically have good strength and an adjustable degradation speed [ 191 , 192 ]. In these papers, the polymers are described in terms of their chemical composition, breakdown products and mechanism of breakdown, mechanical properties, and clinical limitations.
Table 3. Some applications of biodegradable polymers.
Table 3. Some applications of biodegradable polymers. Product Society Composition Applications Mater-Bi ® Novamont (Italy) Starch and polyester Collection bags for green waste, agricultural films, disposable items. Polynat ® Roverc’h (France) Rye flower (80%) Disposable items, flower containers Ecofoam ® American Excelsior Company (USA) Starch Wrapping plastics Biopol ® Goodfellow (Great Britain) PHB/PHV Razors, bottles Eco-pla ® Cargill Dow (USA) PLA Sanitary products, sport clothes, conditioning and packaging Bio-D ® Cirad (France) Proteins extracted from cotton seed Agricultural films Ecoflex ® BASF (Germany) Co-polyester Agricultural films Eastar Bio ® Eastman (Great Britain) Co-polyester Agricultural films BAK 1095 ® Bayer (Germany) Polyester amide Disposable items, flower containers
Biodegradable polymers are also used as implantable matrices for the controlled release of drugs inside the body or as absorbable sutures. Some commercial biodegradable medical products and their applications have been listed previously [ 13 ].
5.1.1. Natural or bacterial polymers
Medical applications of biopolymers have been reported in a previous paper [ 193 ]. Proteins are the major components of many tissues and thus they have been extensively used as biomaterials for sutures, haemostatic agents, scaffolds for tissue engineering and drug delivery systems. Gelatin was used for coatings and microencapsulating various drugs for biomedical applications [ 194 ]. It has also been employed for preparing biodegradable hydrogels [ 195 ].
Chitin and its derivatives have been used as drug carriers and anti-cholesterolemic agents, blood anticoagulants, anti-tumor products and immunoadjuvants [ 10 , 196 ]. More recently some studies have shown the anti-oxidative and radical scavenging activities of chitosans. As a matter of fact, a primary actor in various degenerative diseases as well as in the normal process of aging is oxidative stress, induced by oxygen radicals [ 80 , 197 , 198 ]. Chitin, collagen and poly-L-leucine have been used to prepare skin substitutes or wound dressing [ 199 ]. Alginate gels have been extensively used in controlled release drug delivery systems [ 118 ]. Herbicides, microorganisms and cells have been encapsulated by alginates.
PHB and PHBV are soluble in a wide range of solvents and can be process in various shapes. Nevertheless, as PHB is brittle, its application in biomaterials is limited. As PHBV is less brittle it is potentially usable. In addition PHBV has the unique property of being piezoelectric. It is used in applications where electrical simulation is applied [ 10 ]. PHB has the advantageous property of being degraded in D-3-hydroxybutyrate, a natural constituent of human blood. As a consequence, PHB is suitable for biomedical applications. It is used in drug carriers and tissue engineering scaffolds [ 154 , 200 , 201 ].
5.1.2. Synthetic polymers
Synthetic polymers are widely used in biomedical implants and devices because they can be fabricated into various shapes. In this area interest in biodegradable polymers has increased. PGA and PLA can be considered as the first biodegradable polymers used in biomedical applications. Due to their good mechanical properties, PGA and PLLA have been used as bone internal fixation devices. They also have excellent fiber forming properties and thus PGA was used to prepare absorbable sutures and PLLA to replace ligament and non-degradable fibers. Non woven PGA fabrics have been investigated as scaffolding matrices for tissue regeneration [
10
]. As PDLLA has lower mechanical properties and faster degradation rate than PLLA, it is often used in drug delivery systems and scaffolding matrices for tissue engineering. PLGA has shown to have a good cell adhesion and could be used for tissue engineering applications [
202
]. PLGA is used as polymeric shell in nanoparticules used as drug delivery systems.
Other polyesters like PBS, PPDO, PCL and their copolymers are also utilized as biomedical materials [
13
]. PCL is used as a matrix in controlled release systems for drugs, especially those with longer working lifetimes [
203
]. PCL has a good biocompatibility and is used as scaffolds for tissue engineering. PBS is a promising substance for bone and cartilage repair [
36
]. Its processability is better than that of PGA or PLA. It has higher mechanical properties than PE or PP. Its insufficient biocompatibility could be enhanced by plasma treatment. PPDO was used to prepare the first monofilament sutures. They have a lower risk of infection when used and are thus more interesting than multifilaments. PPDO was also used as fixation screws for bones [
204
].
Polyurethanes and poly(ether urethane)s have good biocompatibility and mechanical properties and have thus been used as medical implants. Polyanhydrides have been investigated in controlled release devices for drugs treating eyes disorder. They have been used as chemotherapeutic agents, local anesthetics, anticoagulants, neuro-active drugs and anticancer agents [ 72 ].
5.2. Packaging
In everyday life, packaging is another important area where biodegradable polymers are used. In order to reduce the volume of waste, biodegradable polymers are often used. Besides their biodegradability, biopolymers have other characteristics as air permeability, low temperature sealability and so on [ 189 ]. Biodegradable polymers used in packaging require different physical characteristics, depending on the product to be packaged and the store conditions.
Due to its availability and its low price compared to other biodegradable polyesters, PLA is used for lawn waste bags. In addition, PLA has a medium permeability level to water vapor and oxygen. It is thus developed in packaging applications such as cups, bottles, films [ 18 , 205 ]. PCL finds applications in environment e.g. soft compostable packaging.
Several polysaccharide-based biopolymers such as starch, pullulan and chitosan, have been investigated as packaging films. Starch films have low permeability and are thus attractive materials for food packaging. When composed of proteins and polysaccharides, the films have good mechanical and optical properties, but they are very sensitive to moisture. They also have poor water barrier properties. When composed of lipids, films are more resistant to moisture. The problem is their opacity. Moreover they are sensitive to oxidation. The current trend in food packaging is thus the use mixtures of different biopolymers [
206
]. Chitosan was used in paper-based packaging as a coating, to produce an oil barrier packaging [
207
]. Results showed that chitosan coatings can be used as fat barriers, but the treatment cost was relatively high compared to the fluorinated coatings usually used. Chitosan based films have proven to be effective in food preservation and can be potentially used as antimicrobial packaging [
208
].
PHB has been used in small disposable products and in packing materials [ 209 ]. Bucci [ 210 ] investigated the use of PHB in food packaging, comparing it to PP. The deformation value of PHB was about 50% lower than that of PP. PHB is more rigid and less flexible than PP. The performances of PHB tend to be lower than those of PP under normal freezing conditions. Nevertheless at higher temperatures PHB performed better than PP.
In 2002, DuPont and EarthShell commercialized food packaging and containers composed of starch and Biomax
®
. APACK
®
is a thermoformed packaging based on starch, from Switzerland.
5.3. Agriculture
For this application, the most important property of biodegradable polymers is in fact their biodegradability [ 211 ]. Starch-based polymers are the most used biopolymers in this area. They meet the biodegradability criteria and have a sufficient life time to act.
Plastic films were first introduced for greenhouse coverings fumigation and mulching in the 1930s. Young plants are susceptible to frost and must be covered. The main actions of biodegradable cover films are to conserve the moisture, to increase soil temperature and to reduce weeds in order to improve the rate of growth in plants. At the end of the season, the film can be left into the soil, where it is biodegraded [
212
]. Another application bases on the production of bands of sowing. It is bands which contain seeds regularly distributed as well as nutriments. In the field of geotextiles, we can mention the use of textiles based on biopolymers for filtration and drainage and the use of the geogrilles [
213
].
Biodegradable polymers can be used for the controlled release of agricultural chemicals. The active agent can either be dissolved, dispersed or encapsulated by the polymer matrix or coating, or is a part of the macromolecular backbone or pendent side chain. The agricultural chemicals concerned are pesticides and nutrients, fertilizer, pheromones to repel insects. The natural polymers used in controlled release systems are typically starch, cellulose, chitin, aliginic acid and lignin [ 9 ].
In horticulture threads, clips, staples, bags of fertilizer, envelopes of ensilage and trays with seeds are applications mentioned for biopolymers. Containers such as biodegradable plant pots and disposable composting containers and bags are other agricultural applications. The pots are seeded directly in the soil, and break down as the plant begins to grow.
In marine agriculture, biopolymers are used to make ropes and fishing nets. They are also used as support for the marine cultures [ 214 ].
In mulching and low-tunnel cultivation, to enhance sustainability and environmentally friendly agricultural activities, a promising alternative is the use of biodegradable materials. Agricultural films placed in the soil are susceptible to ageing and degradation during their useful lifetime, so they need to have some specific properties [ 15 ].
When starch is placed in contact with soil microorganisms, it degrades into non toxic products. This is the reason why starch films are used as agricultural mulch films. Mater-Bi based biodegradable films were developed and tested [ 148 ]. Water and high temperatures do not affect the mechanical behavior of the biodegradable films. Negative effects on the elongation at break were obtained with a high dose of UV radiation.
5.4. Others fields
Biopolymers are also used in shape specific applications such as in the automotive, electronics or construction sectors.
Automotive: The automotive sector aims to prepare lighter cars by use of bioplastics and biocomposites. Natural fibers can replace glass fibers as reinforcement materials in plastic car parts [ 215 ]. We await the development of the bio-composite materials. For example the PLA is mixed with fibers of kenaf for replace the panels of car doors and dashboards (Toyota Internet site). Starch-based polymers are used as additive in the manufacturing of tires. It reduces the resistance to the movement and the consumption of fuel and in fine greenhouse gas emissions (Novamont Internet site).
Electronics: PLA and kenaf are used as composite in electronics applications. Compact disks based on PLA are also launched on the market by the Pioneer and Sanyo groups. Fujitsu Company has launched a computer case made of PLA [ 216 ].
Construction:
PLA fiber is used for the padding and the paving stones of carpet. Its inflammability, lower than that of the synthetic fibers, offers more security. Its antibacterial and antifungal properties avoid allergy problems . The fiber is also resistant to UV radiation.
Sports and leisure:
Some fishing hooks and biodegradable golf tees (Vegeplast, France) are based on starch. PLA fiber is used for sports clothes. It combines the comfort of the natural fibers and the resistance of synthetic fibers.
Biotechnological applications: Chitin acts as an absorbent for heavy and radioactive metals, useful in wastewater treatment.
Applications with short-term life character and disposability:
Aliphatic polyesters like PLA, PBS, PCL and their copolymers are used as biodegradable plastics for disposable consumer products, like disposable food service items (disposable cutlery and plates, for example). Other products are diapers, cotton stalk and sanitary products.
Unusual applications: There are a lot of other applications which do not fit into any of the previous categories. Thus combs, pens (Begreen ® from Pilot Pen or Green Pen ® from Yokozuna), and mouse pads made of biodegradable polymers have also been invented, mostly for use as marketing tools. Biodegradable polymers can be used to modify food textures. Due to its non toxicity, alginate has been used as a food additive and a thickener in salad dressings and ice creams. Chitin and chitosan are used as food and feed additives [ 217 ]. PLA (semi-synthetic polymers) is used for compostable food.
6. Conclusions
Biodegradable polymers have received much more attention in the last decades due their potential applications in the fields related to environmental protection and the maintenance of physical health. At present only few groups of the mentioned biopolymers are of market importance. The main reason is their price level, which is not yet competitive. The future of each biopolymer is dependent not only on its competitiveness but also on the society ability to pay for it. The future outlook for development in the field of biopolymers materials is promising.
To improve the properties of biodegradable polymers, a lot of methods have been developed, such as random and block copolymerization or grafting. These methods improve both the biodegradation rate and the mechanical properties of the final products. Physical blending is another route to prepare biodegradable materials with different morphologies and physical characteristics.
To provide added value to biodegradable polymers, some advanced technologies have been applied. They include active packaging technology and natural fiber reinforcements. Recently different studies have been reported concerning the use of nanoclay with biodegradable polymers, especially with starch and aliphatic polyesters. Nano-biocomposites or bio-nanocomposites are under investigation.
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MDPI and ACS Style
Vroman, I.; Tighzert, L. Biodegradable Polymers. Materials 2009, 2, 307-344.
https://doi.org/10.3390/ma2020307
AMA Style
Vroman I, Tighzert L. Biodegradable Polymers. Materials. 2009; 2(2):307-344.
https://doi.org/10.3390/ma2020307
Chicago/Turabian Style
Vroman, Isabelle, and Lan Tighzert. 2009. "Biodegradable Polymers" Materials2, no. 2: 307-344.
https://doi.org/10.3390/ma2020307
| https://www.mdpi.com/1996-1944/2/2/307 |
Tumour necrosis factor-α-induced glucose-stimulated insulin secretion inhibition in INS-1 cells is ascribed to a reduction of the glucose-stimulated Ca2+ influx in: Journal of Endocrinology Volume 198 Issue 3 (2008)
The present study was undertaken to determine how tumour necrosis factor-α (TNF-α) elicits the inhibition of glucose-stimulated insulin secretion (GSIS) in rat insulinoma cells (INS)-1 β-cells. TNF-α pretreatment did not change the expression levels of insulin, PDX-1, glucose transporter 2, glucokinase, KATP channels, Ca2+ channels, and exocytotic molecules and, furthermore, did not reduce the glucose-stimulated ATP level. On the other hand, TNF-α reduced the glucose-stimulated influx of Ca2+. The TNF-α treatment was thought to activate c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and NF-κB inflammatory signals, since TNF-α increased phospho-JNK and phospho-p38 and reduced IκB levels. Inhibitors of these signaling pathways prevented the TNF-α-induced reduction of the Ca2+ influx and GSIS. Overexpression of MEKK3, a possible mediator from the TNF-α receptor to the JNK/p38 and NK-κB signaling cascade, increased the levels of phospho-JNK, phospho-p38, and NF-κB, and reduced the glucose-stimulated Ca2+ influx and GSIS. The reduction of the Ca2+ influx and GSIS in MEKK3-overexpressing INS-1 cells was also prevented by inhibitors of JNK, p38, and NF-κB. These data demonstrate that TNF-α inhibits GSIS by reducing the glucose-stimulated Ca2+ influx, possibly through the activation of JNK and p38 MAPK and NF-κB inflammatory signals. Thus, our findings suggest that the activation of stress and inflammatory signals can contribute to the inhibition of GSIS in the development of diabetes.
Abstract
The present study was undertaken to determine how tumour necrosis factor-α (TNF-α) elicits the inhibition of glucose-stimulated insulin secretion (GSIS) in rat insulinoma cells (INS)-1 β-cells. TNF-α pretreatment did not change the expression levels of insulin, PDX-1, glucose transporter 2, glucokinase, KATPchannels, Ca2+channels, and exocytotic molecules and, furthermore, did not reduce the glucose-stimulated ATP level. On the other hand, TNF-α reduced the glucose-stimulated influx of Ca2+. The TNF-α treatment was thought to activate c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and NF-κB inflammatory signals, since TNF-α increased phospho-JNK and phospho-p38 and reduced IκB levels. Inhibitors of these signaling pathways prevented the TNF-α-induced reduction of the Ca2+influx and GSIS. Overexpression of MEKK3, a possible mediator from the TNF-α receptor to the JNK/p38 and NK-κB signaling cascade, increased the levels of phospho-JNK, phospho-p38, and NF-κB, and reduced the glucose-stimulated Ca2+influx and GSIS. The reduction of the Ca2+influx and GSIS in MEKK3-overexpressing INS-1 cells was also prevented by inhibitors of JNK, p38, and NF-κB. These data demonstrate that TNF-α inhibits GSIS by reducing the glucose-stimulated Ca2+influx, possibly through the activation of JNK and p38 MAPK and NF-κB inflammatory signals. Thus, our findings suggest that the activation of stress and inflammatory signals can contribute to the inhibition of GSIS in the development of diabetes.
Introduction
Secretion of insulin from pancreatic β-cells is an essential prerequisite to maintaining an appropriate level of blood glucose. For appropriate glucose-stimulated insulin secretion (GSIS) to occur, all steps, from glucose sensing to insulin granule exocytosis in β-cells, should be optimally processed (Rorsmanet al. 2000). Glucose is first transported into β-cells and metabolized, and the ATP/ADP level is then increased. Elevation of ATP/ADP closes KATPchannels and elicits membrane depolarization. The change of membrane potential triggers the opening of voltage-dependent calcium channels (VDCC) and increases the flux of Ca2+. The elevated [Ca2+]ielicits insulin exocytosis through fusion between insulin granules and the plasma membrane. Thus, the Ca2+-requiring exocytotic pathway is KATPchannel dependent and plays a major role in the first phase of insulin secretion (Henquinet al. 2003,Seino & Miki 2003). Conversely, KATP-independent amplifying pathways are also required for the secretion of sufficient amounts of insulin in response to continuing exposure to glucose (Henquinet al. 2003). The amplification signals mainly operate at the level of granule mobilization from cytosol to the plasma membrane and, thus, determine the second phase of insulin secretion (Troitzaet al. 2002). Although the identities of amplifying signals have not been examined completely, intermediates generated from the TCA cycle and lipogenic pathway have been thought to contribute to the amplification of Ca2+-mediated insulin exocytosis (Troitzaet al. 2002,Wiederkehr & Wollheim 2006). Protein kinase A (PKA) and protein kinase C (PKC), which are activated by cAMP and diacylglycerol respectively, and Ca2+-activated calcium/calmodulim kinase II are known to be typical amplification signals (Nesheret al. 2002).
The inhibition of GSIS as a functional defect of pancreatic β-cells was reported to be a characteristic of the pre-diabetic stage in autoimmune type 1 diabetic subjects (Congetet al. 1993,Sherryet al. 2005), but this inhibition could be restored inin vitrocultures (Strandellet al. 1990,Lupiet al. 2004). This finding suggests that chronic exposure of β-cells in inflamed islets to high glucose or inflammatory cytokines may reduce GSIS. Failure of insulin secretion is also observed in patients with type 2 diabetes (Polonskyet al. 1988). During progression to type 2 diabetes, selective loss of GSIS was observed as an initial defect of diabetes, whereas secretion in response to other secretagogues such as sulfonylureas, arginine, and KCl was preserved (Porte 1991). Many studies have suggested that functional impairment of β-cells in type 2 diabetes results from chronic exposure of β-cells to high glucose and free fatty acids (Grill & Bjorklund 2000,McGarry 2002,Kjorholtet al. 2005). A proinflammatory cytokine, tumour necrosis factor-α (TNF-α), which is produced from activated macrophages or adipocytes, was also suggested to be a stimulus that plays a role in impaired secretion of insulin, which frequently occurs in type 2 diabetes (Donathet al. 2003,Scheen 2003). Specifically,in vitrostudies demonstrated that TNF-α alone could induce the inhibition of GSIS in various β-cells (Campbellet al. 1988,Zhang & Kim 1995,Dungeret al. 1996,Parket al. 1999,Tsiotraet al. 2001).
TNF-α is a pleiotropic cytokine that elicits a wide spectrum of physiological events, including cell proliferation, differentiation, and apoptosis (Locksleyet al. 2001). TNF-α-induced responses are mediated through a TNF-α receptor (Locksleyet al. 2001). Binding of TNF-α to the TNF-α receptor leads to the recruitment of the TNF receptor-associated death domain (TRADD) and subsequent recruitment of the FAS-associated death domain (FADD), TNF-associated factor 2 (TRAF2), and receptor-interacting protein (RIP). While the association of FADD with TRADD triggers an apoptotic signal, the binding of TRAF2 and RIP to TRADD activates c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and IκB kinase (Wajantet al. 2003). MEKK3 was reported to be an essential mediator for TNF-α-induced activation of NF-κB through interaction with RIP (Yanget al. 2001) or for JNK and p38 activation through interaction with TRAF 6 and TRAF 7 (Huanget al. 2004,Xuet al. 2004).
This study was initiated to determine how TNF-α elicits the impaired secretion of insulin in INS-1 rat β-cells. First, we determined whether TNF-α had a pleiotropic inhibitory effect on insulin secretion stimulated by various insulin secretagogues. Secondly, we investigated which of the steps, from glucose sensing to insulin granule exocytosis, was involved in TNF-α-induced inhibition of GSIS. We specifically focused on the reducing effect of TNF-α on the glucose-stimulated influx of Ca2+. Thirdly, to determine which TNF-α-mediated signals were involved in TNF-α-induced inhibition, the effects of different pharmacological inhibitors of JNK, p38, NF-κB, inducible nitric oxide synthase (iNOS), and reactive oxygen species (ROS) on TNF-α-induced GSIS inhibition were investigated. Lastly, the involvement of JNK/p38 MAPK and NF-κB inflammatory signals in GSIS inhibition was studied using an MEKK3 expression system.
Materials and Methods
Materials
Recombinant murine TNF-α was purchased from R& D Systems (Minneapolis, MN, USA). Specialty chemicals, i.e. glucose, leucine, glutamine, pyruvate, tolbutamide, glimepiride, repaglinide, efaroxan, phentolamine, KCl, Bay K8633, phorbol 12-myristate 13-acetate (PMA), forskolin, glucagon-like peptide 1 (GLP-1),NG-methyl-l-arginine acetate,N-acetyl-l-cysteine (NAC), Fluo-3/AM, and doxycycline, were purchased from Sigma–Aldrich. Inhibitors such as SP600125, SB203580, and SN50 were obtained from Merck Bioscience. Chemicals were dissolved in either appropriate medium solution or dimethyl sulfoxide and were then used for treatment at the required working dilution. Anti-Kir 6.2, anti-sulfonylurea receptor 1 (SUR1), anti-NF-κB p50, anti-lamin B, anti-Na+/K+ATPase, anti-actin, and anti-α-tubulin antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA) and anti-Cav 1.3 (α1D) antibody was purchased from Alomone Labs (Jerusalem, Israel). Anti-phospho-JNK, anti-JNK, anti-phospho-p38 MAPK, anti-p38, and anti-IκB-α antibodies were purchased from Cell Signaling Technology (Beverly, MA, USA). Anti-MEKK3 antibody was purchased from Upstate (Charlottesville, VA, USA).
Cells and culture
INS-1 rat insulinoma cells were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum (Life Technology Inc., Gaithersburg, MD, USA), 100 U/ml penicillin, and 100 μg/ml streptomycin (Life Technology Inc).
Methyl thiazol tetrazolium (MTT) cell viability assay
Cell viabilities were determined using an MTT assay. In brief, the cells were incubated in the presence of MTT (0.5 mg/ml) solution for 2 h at 37 °C. Medium supernatants were discarded and acidic isopropanol (0.04 M HCl) was added. After further incubation for 30 min, absorbency was measured at 570 nm using a microplate reader (BioRad).
Semi-quantitative RT-PCR
Expression levels of mRNAs were compared using the semi-quantitative RT-PCR technique. Semi-quantitative RT-PCR was carried out with Takara RNA PCR kit Ver 3.0 (Takara, Shiga, Japan). In brief, INS-1 cell cDNAs were synthesized with avian myeloblastosis virus (AMV) reverse transcriptase and random 9-mers, and were then subjected to PCR amplification with primer sets of different genes. The nucleotide sequences of primer sets and reaction conditions used are listed inTable 1. The amplified DNA was analyzed by agarose gel electrophoresis. The relative quantities of amplified DNA was compared on the basis of amplified cyclophilin DNA.
Table 1
Primer sequence and the reaction conditions for semi-quantitative RT-PCR
GenesPrimer sequence(5′→3′)Annealing Tm(°C)CycleLength(bp)
Insulin(F) ccaggcttttgtcaaacagcac6021267
(R) cagttgcagtagttctccagttg
PDX-1(F) tgctaatccccctgcgtgcctgta5926349
(R) ctcctccggttctgcgtatgc
GLUT2(F) tgggttccttccagttcg5528183
(R) aggcgtctggtgtcgtatg
Glucokinase(F) tgacagagccaggatggag6132299
(R) tcttcacgctccactgcc
iNOS(F) gcagaatgtgaccatcatgg5533356
(R) acaaccttggtgttgaaggc
Kir 6.2(F) ccatgtccttcctgtgcagctg6430954
(R) ccgcaactcaggacaaggaatc
SUR1(F) ttgctgaaactgtggaaggactcac64301048
(R) ttcaggaccatcactaggtctgcac
α1D(F) gaggcaaactatgcaagaggcac6430868
(R) ctgactcagatatagtagctgaag
β3(F) ccatccctggacttcag6030415
(R) ctaacgccaatctaactcc
Cyclophilin(F) ccaaagacagcagaaaactt6026410
(R) gaaattagagttgtccacag
Real-time quantitative PCR
Real-time quantitative PCR was performed in triplicate using the ABI Prism 7900 sequence detection system (PE Applied Biosystems). The fluorescence emission from each sample was collected by a charge-coupled device camera, and the quantitative data were then analyzed using Sequence Detection System software (SDS version 2.0, PE Applied Biosystems). Reaction mixtures contained 10 pmol/μl of each primer and 2X SYBR PCR master mix (PE Applied Biosystems), which includes the HotStarTaq DNA polymerase, dNTP mix, SYBR Green I fluorescent dye, and ROX dye as a passive reference. Serial dilutions (1/2, 1/4, 1/8, and 1/16) of cDNA were used to generate relative standard curves. Thermal cycling conditions were 50 °C for 2 min and 95 °C for 10 min, followed by 40 cycles of 95 °C for 30 s, different annealing temperatures (Table 2) for 30 s, and 72 °C for 30 s. In order to exclude the presence of non-specific products, a melting curve analysis of products was performed routinely by high-resolution data collection during an incremental temperature increase from 60 to 95 °C, with a ramp rate of 0.21 °C/s. Real-time PCR cycle numbers were converted to gene amounts on the basis of the equation (ABI Prism 7900 sequence detection system).
Table 2
Primer sequence and the reaction conditions for real-time PCR
GenesPrimer sequence(5′→3′)Annealing Tm(°C)Length(bp)
Rab3a(F) gtcagcactgtgggcataga55188
(R) tgcactgcattgaaggactc
Rab3-GAP(F) ttacctagtggggaaatgga55198
(R) gtcttcgctcacttgaaggt
VAMP2(F) ccagtttgaaacaagtgcag55203
(R) gatatggctgagaggtggag
Synaptotagmin V(F) ggatgggcaaaaagagtcag55200
(R) ctggccagtctggaagtcat
SNAP25(F) caacgtgcaacaaagatgct55197
(R) caatgggggtgactgactct
Syntaxin1α(F) gccctcagtgagatcgagac55200
(R) tacttgacggccttcttggt
Granuphilin(F) gagaatgccgagttctggag55214
(R) gtctgctgaaggagggactg
NOC2(F) gagaggtctggaagaggtca55200
(R) gtcactgtcactggaaacca
Munc18(F) gaagacatcaacaaacggagaga55200
(R) atgggccagctgggctgtgtc
iNOS(F) agacccacatctggcaggat55207
(R) acaaccttggtgttgaaggc
Cyclophilin(F) ccaaagacagcagaaaactt55410
(R) gaaattagagttgtccacag
Measurement of cellular ATP
Cellular ATP content was determined using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega). To measure the glucose-stimulated increase of ATP in INS-1 cells, cells were seeded in 24-well plates at a density of 1.5×105cells per well and were cultured for 2 days. After treatment with TNF-α for 16 h, the cells were washed with KRB buffer (0.2 mM glucose, 24 mM NaHCO2, 1.2 mM MgCl2, 1 mM HEPES, 129 mM NaCl, 4.8 mM KCl, 1.2 mM KH2PO4, 2.5 mM CaCl2, and 0.5% BSA). The cells were stimulated by 16.7 mM glucose for 5 min. After the supernatant was discarded, the cells were disrupted by sonication (10 s, four times) in the presence of 0.2 ml of 5% trichloroacetic acid. Cell pellets were removed by centrifugation (12 000 g, 10 min), and the trichloroacetic acid was extracted from the supernatant by repetitive extraction with ether. After neutralization by the addition of the same amount of HEPES buffer (20 mM HEPES and 3 mM MgCl2(pH 7.5)), the sample solution was mixed with the same volume of CellTiter-Glo reagent. Luminescence was measured with a luminometer (Turner Design Instrument, Sunnyvale, CA, USA). The quantity of ATP was determined using a standard ATP curve.
Measurement of [Ca2+]i
[Ca2+]ilevels were determined by the measurement of Fluo-3/AM fluorescence using a confocal laser scanning microscope (Zeiss, Jena, Germany). Dispersed INS-1 cells were plated onto glass bottom culture dishes (MatTeck Co., Ashland, MA, USA) at 37 °C in 10% FBS-RPMI 1640 culture medium for 24 h. The cells were then loaded with Fluo-3/AM (5 μM) for 30 min at 37 °C in Hank's balanced salt solution (HBSS; 145 mM NaCl, 2.5 mM KCl, 1.8 mM MgCl2, 1 mM CaCl2, 10 mM glucose, and 20 mM HEPES (pH 7.4)). After stimulation with glucose (16.7 mM) or KCl (30 mM), the fluorescent images were captured (excitation: 488 nm and emission: 505 nm) and subsequently digitalized. The calcium intensities were calculated (DVC-1310, DVC Co., Austin, TX, USA) and presented as percent changes compared with the basal level (F/Fo).
Quantitation of insulin
To measure the insulin secreted in INS-1 cells, cells were seeded in 48-well plates at a density of 1×105cells per well and were cultured for 2 days. After treatment with TNF-α for 16 h, the cells were washed with KRB buffer and then incubated with the same KRB buffer for 1 h. Insulin secretion was elicited by incubation for 2 h with appropriate insulin secretagogues. The insulin concentration in supernatant was determined with a Rat Insulin RIA kit (Linco Research, St Charles, MO, USA).
Immunoblotting
Cells were suspended in radio-immuno precipitation assay (RIPA) buffer (150 mM NaCl, 1% NP-40, 0.5% DOC, 0.1% SDS, 50 mM Tris–Cl (pH 7.5), protease inhibitor cocktail (Roche Applied Science) and were then incubated on ice for 15 min. Whole proteins were extracted by differential centrifugation (10 000 g, 10 min). Protein concentrations were determined using protein assay kits (BioRad). An equal volume of 2× SDS sample buffer (125 mM Tris–Cl (pH 6.8), 4% sodium dodecyl sulfate, 4% 2-mercaptoethanol, 20% glycerol) was added to cell lysates. Equivalent amounts of protein (30 μg) were loaded onto 10–15% polyacrylamide gels, electrophoresed, and then transferred to polyvinylidine flouride (PVDF) membranes (Millipore, Bedford, MA, USA). After these membranes had been blocked 5% skim milk for 1 h, target antigens were reacted with primary antibodies. After washing with PBS, secondary antibodies, i.e., horseradish peroxidase-conjugated anti-mouse immunoglobulin G (IgG) or anti-rabbit IgG antibodies, were then bound. The immunoreactive bands were then detected using an enhanced chemiluminescence detection system (Amersham Pharmacia Biotech).
Extraction of nuclear and membrane proteins
Cells (1×106) were suspended in 1 ml RSB buffer (10 mM NaCl, 1.5 mM MgCl2, 10 mM Tris–Cl (pH 7.4), 0.5% NP-40, protease inhibitor cocktail, and 0.2 mM PMSF) and were then incubated on ice for 5 min. After centrifugation at 500gfor 5 min, the pellets were re-suspended with 1 ml RSB buffer. Production of nuclei was evaluated by microscopic observation. To obtain intact nuclei, repetitive extraction was carried out with RSB buffer. After the nuclear pellets were suspended in RIPA buffer, nuclear protein was extracted by differential centrifugation (10 000 g, 10 min). To obtain membrane proteins, cells were first suspended in a lysis buffer (150 mM NaCl, 50 mM Tris–Cl (pH 7.4), 1 mM EDTA, 1 mM EGTA, 1 mM dithiothreitol, and protease inhibitor cocktail), disrupted by sonication (10 s, five times), and centrifuged at 700 gfor 15 min. After the pellets containing nuclei and undisrupted cells were discarded, the supernatant was centrifuged at 12 000 gfor 15 min. The pellets that contained plasma membranes were suspended in RIPA buffer and used for immunoblotting.
Construction of MEKK3-expressing INS-1 cells (TRE-MEKK3) using the Tet-On system
INS-1 β-cell cDNAs were synthesized with AMV reverse transcriptase (Takara) using random 9-mers and were then subjected to PCR amplification using mouse MEKK3 primers (5′-gaagtcgacatggatgaacaagaggcattagactc-3′ and 5′-gctctagagctcagtacactagctgtgcaa-3′). After the amplified DNAs were cut with SalI and XbaI, the MEKK3 fragments were subcloned to the pTRE2 vector (Clontech) in order to construct pTRE-MEKK3. The mouse MEKK3 nucleotide sequences were confirmed using the ABI BigDye sequencing kit (Applied Biosystems, Foster City, CA, USA). The stable INS-1 cells containing pTK-Hyg (Clontech) were transfected with the pTRE-MEKK3 DNAs, and the stable INS-1 cells (TRE-MEKK3) that were able to express MEKK3 following treatment with doxycycline were then selected.
Statistical analysis
Data are presented as means±s.d.of at least three independent experiments. Statistically significant differences between groups were determined using Student'st-test.P< 0.05 were considered to be statistically significant.
Results
TNF-α-induced inhibition of GSIS in INS-1 β-cells
To determine whether treatment with TNF-α inhibits GSIS in β-cells, INS-1 rat β-cells were treated with different concentrations of TNF-α for 16 h, and the amount of insulin secreted by glucose stimulation (16.7 mM, 2 h) was then measured by insulin RIA. The cytotoxic effect of TNF-α on INS-1 cells was investigated before determining the inhibitory effect of TNF-α on GSIS. Cell viability was little affected by treatment with 20 ng/ml TNF-α for 16 h (Fig. 1A). As shown inFig. 1B and C, pretreatment with TNF-α significantly reduced GSIS in a concentration- and time-dependent manner, while the same treatment of TNF-α did not affect basal secretion of insulin. Pretreatment with 10 ng/ml TNF-α for 16 h reduced GSIS by one-third of its maximal secretion and was sufficient for obtaining a maximal inhibitory effect. To determine whether the inhibitory effect of TNF-α on GSIS is reversible, GSIS was re-assessed with the INS-1 cells incubated in TNF-α-free media after TNF-α pretreatment (10 ng/ml, 16 h). INS-1 cells that had been incubated again in the absence of TNF-α showed similar GSIS capacity compared with INS-1 cells that had never been treated with TNF-α (Fig. 1C), which demonstrated that the inhibitory effect of TNF-α on insulin secretion was reversible.
Figure 1
Inhibition of GSIS by TNF-α treatment. INS-1 cells were incubated with different concentrations of TNF-α for 16 h. (A) Viability of TNF-α-treated INS-1 cells was measured by MTT assay. (B) Insulin secretion was stimulated with 16.7 mM glucose (HG) for 2 h. The insulin released into medium was quantified by insulin RIA. *P< 0.05, **P< 0.01 versus glucose-stimulated insulin from TNF-α-untreated INS-1 cells. (C) INS-1 cells were incubated with 10 ng/ml TNF-α for the indicated amounts of time. TNF-α-treated cells (10 ng/ml, 16 h) were further incubated in the absence of TNF-α for the indicated amounts of time. Insulin secretion was stimulated with 16.7 mM glucose (HG) for 2 h. The insulin released into medium was quantified by insulin RIA. *P< 0.05 and **P< 0.01 versus glucose-stimulated insulin from TNF-α-untreated INS-1 cells.#P< 0.05 and##P< 0.01 versus glucose-stimulated insulin from TNF-α-treated cells.
Citation: Journal of Endocrinology 198, 3;10.1677/JOE-08-0131
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Download figure as PowerPoint slide
Figure 1
Inhibition of GSIS by TNF-α treatment. INS-1 cells were incubated with different concentrations of TNF-α for 16 h. (A) Viability of TNF-α-treated INS-1 cells was measured by MTT assay. (B) Insulin secretion was stimulated with 16.7 mM glucose (HG) for 2 h. The insulin released into medium was quantified by insulin RIA. *P< 0.05, **P< 0.01 versus glucose-stimulated insulin from TNF-α-untreated INS-1 cells. (C) INS-1 cells were incubated with 10 ng/ml TNF-α for the indicated amounts of time. TNF-α-treated cells (10 ng/ml, 16 h) were further incubated in the absence of TNF-α for the indicated amounts of time. Insulin secretion was stimulated with 16.7 mM glucose (HG) for 2 h. The insulin released into medium was quantified by insulin RIA. *P< 0.05 and **P< 0.01 versus glucose-stimulated insulin from TNF-α-untreated INS-1 cells.# | https://joe.bioscientifica.com/view/journals/joe/198/3/549.xml?result=189&rskey=1FywQB |
A Photosensitizer Verteporfin Has Light-Independent Anti-Leukemic Activity for Ph-Positive Acute Lymphoblastic Leukemia and Synergistically Works with Dasatinib in Vivo | Blood | American Society of Hematology
Abstract. Despite of great improvement of treatment outcome by ABL kinase inhibitors, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is
A Photosensitizer Verteporfin Has Light-Independent Anti-Leukemic Activity for Ph-Positive Acute Lymphoblastic Leukemia and Synergistically Works with Dasatinib in Vivo
Takanobu Morishita, MD
,
Takanobu Morishita, MD *
1 Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Fumihiko Hayakawa, MD PhD
,
Fumihiko Hayakawa, MD PhD *
1 Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Keiki Sugimoto, PhD
,
Keiki Sugimoto, PhD *
2 Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., Otsu, Japan
Abstract
Despite of great improvement of treatment outcome by ABL kinase inhibitors, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph +ALL) is still intractable disease, and novel therapeutic agents are anticipated. We recently developed a high-throughput drug screening system using patient-derived xenograft (PDX) cells. PDX cells highly maintain phenotypes of primary malignant cells, such as heterogeneity of cancer cells, slower growth rate than cell lines, and microenvironment dependency. Drug screening by PDX cells can pick up anti-tumor reagents with new mechanisms that were overlooked by conventional cell-line based screenings. Here, we discovered verteporfin, an approved drug for macular degeneration, as a candidate for novel therapeutic agent of Ph +ALL.
We established PDX of 3 Ph +ALL patients (PhLO, PhLK, and PhLH) by transplanting primary Ph +ALL cells into NOD/SCID/IL-2Rg null(NOG) mice. We developed a high-throughput drug screening system using one of these PDX cells (PDX screening) and screened the library of 3440 compounds containing approved drugs and pharmacologically active reagents. The profile of drugs selected by PDX screening was quite different from that by the screening using Ph +ALL cell line (Cell line screening). Verteporfin was selected by PDX screening, whereas it did not demonstrate very high anti-leukemic effect in Cell line screening.
We confirmed the anti-leukemic effect of verteporfin ex vivousing the 3 PDX cells and ALL-1, the cell line used in the Cell line screening. All 3 PDX cells were more sensitive to verteporfin than ALL-1 (EC 50: PhLO cells, 228 nM; PhLK cells, 1.8 µM; PhLH cells; 395 nM; ALL-1, 3.93 µM). In addition, combined use of verteporfin and dasatinib, an ABL kinase inhibitor used for the treatment of Ph +ALL, showed synergistic growth suppression of PhLO cells. Combination index (CI) values calculated by combination index algorism were less than 1.0 in most combinations of 16 data points (CI mean, 0.73; CI range, 0.28-1.34).
Furthermore, the mechanism of action of verteporfin was intensively investigated. In combination with red light irradiation, verteporfin induces apoptosis of tumor cells through production of reactive oxygen species (ROS), which is known as photodynamic therapy. We revealed that verteporfin produced ROS light-independently in PhLO cells and induced their apoptosis. Verteporfin-induced apoptosis was inhibited by the addition of reduced glutathione to the culture medium, suggesting the large involvement of ROS production in the verteporfin-induced apoptosis.
Finally, we assessed the in vivoeffect of verteporfin. NOG mice transplanted with PhLO cells were treated with vehicle, verteporfin (140mg/kg/day), dasatinib (20mg/kg/day), or both of them from day 22 to day 28. Dasatinib was intraperitoneally injected and verteporfin was administered by continuous subcutaneous injection using osmotic pumps because of its very short half-life. We measured the ratios of leukemic PDX cells in bone marrow and spleen on day 28. Both single therapies by verteporfin and dasatinib significantly reduced the leukemia cell ratios in spleen and the combination therapy of them further reduced leukemia cells in spleen (Figure A). In bone marrow, both single therapies demonstrated weaker anti-leukemic effect than in spleen, but the combination therapy showed significantly enhanced effect, indicating the synergistic effect between them in vivo(Figure B). These results indicate the promisingness of verteporfin as a new anti-leukemic reagent and PDX screening as a new strategy for the development of anti-cancer drug.
Figure 1.
Disclosures
Naoe: Pfizer Inc.:Research Funding; Toyama Chemical Co.,LTD.:Research Funding; Otsuka Pharmaceutical Co.,Ltd.:Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.:Research Funding; Kyowa-Hakko Kirin Co.,Ltd.:Patents & Royalties, Research Funding; Fujifilm Corporation:Patents & Royalties, Research Funding; Chugai Pharmaceutical Co.,LTD:Patents & Royalties; Celgene K.K.:Research Funding; Astellas Pharma Inc.:Research Funding.Kiyoi: Yakult Honsha Co.,Ltd.:Research Funding; Novartis Pharma K.K.:Research Funding; MSD K.K.:Research Funding; Eisai Co., Ltd.:Research Funding; Alexion Pharmaceuticals:Research Funding; FUJIFILM Corporation:Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.:Research Funding; Nippon Shinyaku Co., Ltd.:Research Funding; FUJIFILM RI Pharma Co.,Ltd.:Research Funding; Teijin Ltd.:Research Funding; Japan Blood Products Organization:Research Funding; Astellas Pharma Inc.:Consultancy, Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.:Research Funding; Takeda Pharmaceutical Co., Ltd.:Research Funding; Pfizer Inc.:Research Funding; Mochida Pharmaceutical Co., Ltd.:Research Funding; Zenyaku Kogyo Co., Ltd.:Research Funding; Sumitomo Dainippon Pharma Co., Ltd.:Research Funding; Kyowa Hakko Kirin Co., Ltd.:Consultancy, Research Funding; Bristol-Myers Squibb:Research Funding; Chugai Pharmaceutical Co., Ltd.:Research Funding.
Topics:
acute lymphocytic leukemia
,
culture media
,
dasatinib
,
photosensitizing agents
,
verteporfin
,
screening
,
drug screening
,
combined modality therapy
,
kinase inhibitors
,
Asterisk with author names denotes non-ASH members.
| https://ashpublications.org/blood/article-split/126/23/1331/104872/A-Photosensitizer-Verteporfin-Has-Light |
Publications - Global Disability Innovation Hub
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Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
Tigmanshu Bhatnagar
, Nicolai Marquardt, Mark Miodownik,
Catherine Holloway
Shape changing materials create a unique opportunity to design reconfigurable tactile display actuators. In this paper, we present a method that transforms a single thin monolithic sheet of Nitinol into a passive reconfigurable tactile pixel array at Braille resolution. We have designed a 27x27 tactile pixel array in which each pixel can be selectively actuated with an external source of heat. The pixels rise 0.4mm vertically with a peak blocked force of 0.28kg and have an average blocked force of 0.23kg at room temperature. After cooling, the pixels can be mechanically reconfigured back to their flat state for repeatable actuation. We demonstrate this actuator’s interactive capabilities through a novel erasable tactile drawing interface.
IEEE World Haptics Conference; 2021
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Abstract
Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
Shape changing materials create a unique opportunity to design reconfigurable tactile display actuators. In this paper, we present a method that transforms a single thin monolithic sheet of Nitinol into a passive reconfigurable tactile pixel array at Braille resolution. We have designed a 27x27 tactile pixel array in which each pixel can be selectively actuated with an external source of heat. The pixels rise 0.4mm vertically with a peak blocked force of 0.28kg and have an average blocked force of 0.23kg at room temperature. After cooling, the pixels can be mechanically reconfigured back to their flat state for repeatable actuation. We demonstrate this actuator’s interactive capabilities through a novel erasable tactile drawing interface.
Cite
Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
T. Bhatnagar, N. Marquardt, M. Miodownik and C. Holloway, "Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution," 2021 IEEE World Haptics Conference (WHC)
, 2021, pp. 409-414, doi: 10.1109/WHC49131.2021.9517239.
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Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
Type
Editorial
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Assistive & Accessible Technology
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Giulia Barbareschi
& Tom Shakespeare
Assistive products (APs) are broadly defined as “
any product (including devices, equipment, instruments, and software), either specially designed and produced or generally available, whose primary purpose is to maintain or improve an individual’s functioning and independence and thereby promote their wellbeing
” (Khasnabis et al., 2015
). Although the concept of wellbeing is extremely slippery and researchers have yet to agree on a single definition for it, as individuals we instinctively develop mental models about what does, and does not, promote our happiness and wellbeing. Considerations about values, wellbeing and happiness are extremely personal and are shaped by a variety of factors ranging from our age and socio-cultural background to our life experiences (Schwartz & Bardi, 2001
).
RESNA
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Abstract
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Assistive products (APs) are broadly defined as “ any product (including devices, equipment, instruments, and software), either specially designed and produced or generally available, whose primary purpose is to maintain or improve an individual’s functioning and independence and thereby promote their wellbeing
” (Khasnabis et al., 2015
). Although the concept of wellbeing is extremely slippery and researchers have yet to agree on a single definition for it, as individuals we instinctively develop mental models about what does, and does not, promote our happiness and wellbeing. Considerations about values, wellbeing and happiness are extremely personal and are shaped by a variety of factors ranging from our age and socio-cultural background to our life experiences (Schwartz & Bardi, 2001
).
However, when it comes to assistive technology (AT) research, our focus seems to be primarily geared toward values and activities in the domains of education, employment, transport or health, often framed according to an outcome driven perspective that is heavily influenced by what is seen as useful (often what is measurable), vs what is frivolous (less tangible social or emotional aspects).
This disparity parallels the priorities of the disability rights movement and disability studies research that have helped to shape the research agenda around disability and AT. Often influenced by labor movement politics, or feminism, there appears to have been more concern with public and practical aspects of social life as opposed to the more private and sensitive ones (Shakespeare, 2014
). The focus on the public utilitarian function of AT becomes even more evident when we consider AT research carried out in the Global South. In this context the success of an intervention is usually assessed using measures of outcome and impact which can be somehow linked to economic improvement (Alkire, 2016
).
In this editorial, we are not suggesting that enabling people with disabilities to gain a good education, obtain a fulfilling job or be able to vote are not important goals for the APs we develop and research. But are those the only worthwhile goals? Should we not also enquire whether existing and future APs could help people with disabilities to develop meaningful friendships, enjoy fulfilling sex lives with their partners of choice, cook sociable dinners, or engage in their favorite hobbies? Although sporadic publications focus on the role of APs in the context of personal relationships, sexuality, or fun and play for people with disabilities do exist, these are rare, and often framed around utilitarian goals. For example, research around AT and play is largely focused on children and often examined in connection to learning outcomes. Similarly, sex and sexuality are often explored solely in connection to dysfunction, abuse or sexual health (Shakespeare & Richardson, 2018
).
These unbalanced narratives show how the AT research agenda is dictated by a set of universal priorities that are largely focused on global measurable goals that do not necessarily match the everyday values of people with disabilities. We invite researchers and practitioners to consider ways to find a better balance between public and private aspects of life, and between utilitarian and emotional values. Both approaches have a significant impact on the lives of people with disabilities.
Ultimately, as AT researchers we need to actively engage with people with disabilities to uncover their priorities, understand what different people with disabilities most value in life, and identify how current and future APs might help to make a positive impact on wellbeing. Aspects of life such as friendship, socialization, sexuality, love and play might indeed be more frivolous than practical ones such as education, health, employment and civil rights, but they are inherent to our shared humanity and fundamental to our happiness.
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A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Giulia Barbareschi & Tom Shakespeare (2021) A right to the frivolous? Renegotiating a wellbeing agenda for AT research, Assistive Technology, 33:5, 237, DOI: 10.1080/10400435.2021.1984112
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A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Type
Conference Paper
Themes
Assistive & Accessible Technology
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Giulia Barbareschi
, Norah Shitawa Kopi,
Ben Oldfrey
, Catherine Holloway
In this paper, we examine how young Kenyans without disabilities view people with disabilities and AT users. Findings show that while the portrayal of disability is often shaped by negative emotion, participants felt that many of the barriers affecting people with disabilities were created by society. Perceptions of AT differed –devices were not only seen as a mark of disability but also as a sign of access to resources. Therefore, what we see is an emergent picture where social barriers can be reinforced by poverty, and where poverty reinforces social barriers faced by people with disabilities. We conclude that access to appropriate technology alongside societal interventions tackling incorrect beliefs about disability can help to overcome the stigma faced by people with disabilities.
ASSETS '21: Proceedings of the 23rd International ACM SIGACCESS Conference on Computers and Accessibility
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Abstract
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Most research which investigates stigma towards with people with disabilities and the use of Assistive Technology (AT) are based in the Global North and focus on the experiences of people with disabilities and the consequences that stigma has on choices surrounding AT. However, stigma is a societal construct rooted in the attitude and beliefs that people without disabilities hold on disability and AT. Furthermore, the portrayal of people with disabilities and AT is dependent on the social context. In this paper, we examine how young Kenyans without disabilities view people with disabilities and AT users. Findings show that while the portrayal of disability is often shaped by negative emotion, participants felt that many of the barriers affecting people with disabilities were created by society. Perceptions of AT differed –devices were not only seen as a mark of disability but also as a sign of access to resources. Therefore, what we see is an emergent picture where social barriers can be reinforced by poverty, and where poverty reinforces social barriers faced by people with disabilities. We conclude that access to appropriate technology alongside societal interventions tackling incorrect beliefs about disability can help to overcome the stigma faced by people with disabilities.
Cite
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Giulia Barbareschi, Norah Shitawa Kopi, Ben Oldfrey, and Catherine Holloway. 2021. What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT. In The 23rd International ACM SIGACCESS Conference on Computers and Accessibility
( ASSETS '21
). Association for Computing Machinery, New York, NY, USA, Article 18, 1–13. DOI: https://doi.org/10.1145/3441852.3471226
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What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Type
Conference Paper
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Assistive & Accessible Technology
Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People
Maryam Bandukda
, Catherine Holloway
, Aneesha Singh, Giulia Barbareschi
, Nadia Berthouze
We conducted semi-structured interviews with 20 BPS people and 8 Mobility and Orientation Trainers (MOT). The interviews were thematically analysed and organised into four overarching themes discussing factors influencing the self-efficacy belief of BPS people: Tools and Strategies for O&M training, Technology Use in O&M Training, Changing Personal and Social Circumstances, and Social Influences. We further highlight opportunities for combinations of multimodal technologies to increase access to and effectiveness of O&M training.
ASSETS '21: Proceedings of the 23rd International ACM SIGACCESS Conference on Computers and Accessibility
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Abstract
Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People
Orientation and mobility (O&M) training provides essential skills and techniques for safe and independent mobility for blind and partially sighted (BPS) people. The demand for O&M training is increasing as the number of people living with vision impairment increases. Despite the growing portfolio of HCI research on assistive technologies (AT), few studies have examined the experiences of BPS people during O&M training, including the use of technology to aid O&M training. To address this gap, we conducted semi-structured interviews with 20 BPS people and 8 Mobility and Orientation Trainers (MOT). The interviews were thematically analysed and organised into four overarching themes discussing factors influencing the self-efficacy belief of BPS people: Tools and Strategies for O&M training, Technology Use in O&M Training, Changing Personal and Social Circumstances, and Social Influences. We further highlight opportunities for combinations of multimodal technologies to increase access to and effectiveness of O&M training.
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Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People
Type
PhD
Themes
Assistive & Accessible Technology
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Anna Vlachaki
The literature shows that research into the aesthetic aspects of prostheses is limited. Although there are suggestions that prostheses with high levels of emotionally-driven design may improve users’ well-being, they are based only on theoretical findings. Therefore, in this thesis the effects of emotionally-driven prostheses on users’ lives and society’s attitudes were explored, with respect to culture and more specifically, the theories of individualism/ collectivism. In order to investigate the effects of culture, the research was conducted in two countries with different cultures; the UK (individualistic) and Greece (collectivistic). The thesis began with a literature review across three core areas: user, product and environment, and revealed the importance of investigating an additional area; that of prosthetists. The research employed a qualitative approach and consisted of four studies.
Loughborough University
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Abstract
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
The literature shows that research into the aesthetic aspects of prostheses is limited. Although there are suggestions that prostheses with high levels of emotionally-driven design may improve users’ well-being, they are based only on theoretical findings. Therefore, in this thesis, the effects of emotionally-driven prostheses on users’ lives and society’s attitudes were explored, with respect to culture and more specifically, the theories of individualism/ collectivism. In order to investigate the effects of culture, the research was conducted in two countries with different cultures; the UK (individualistic) and Greece (collectivistic). The thesis began with a literature review across three core areas: user, product and environment, and revealed the importance of investigating an additional area; that of prosthetists. The research employed a qualitative approach and consisted of four studies. Study I was an online questionnaire to explore users’ preferences towards prostheses, with respect to their culture. Study II consisted of semi-structured interviews and informational probes to comprehend the role of prostheses on users’ lives, with respect to prosthetic appearance. In Study III, the aim was to investigate prosthetists’ attitudes towards the needs of prosthetic users by conducting semi-structured interviews. Finally, Study IV was an online questionnaire to explore non-users’ attitudes towards the design of prostheses. The research showed that the use of prostheses for the completion of users’ body was not an adequate factor to improve their well-being, and a shift on users’ desires towards emotionally-driven prostheses has occurred. From the variables that were tested, sex, age, cause and area of limb-loss may affect people’s attitudes towards the design of prostheses. Furthermore, the results showed that prostheses with high emotionally-driven design evoked emotions, in both users and non-users, with higher levels of pleasantness and arousal than the emotions that were elicited by the prostheses of lower emotionally-driven designs and thus, they may trigger a greater behavioural reaction. This suggested that emotionally-driven prostheses may eliminate users’ stigmatisation by increasing their self-confidence and altering society’s attitudes. However, attention needs to be paid in collectivistic countries, as emotionally-driven prostheses may enhance users’ stigmatisation.
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Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Vlachaki, Anna (2020): Emotionally-driven prostheses: exploring the effects on users’ lives and societies’ attitudes in the UK and Greece. Loughborough University. Thesis. https://doi.org/10.26174/thesi...
;
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Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Design rules for additively-manufactured wrist splints
Sarah Kelly
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University.
Loughborough University
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Abstract
Design rules for additively-manufactured wrist splints
Additive Manufacturing (AM) often known by the term three-dimensional printing (3DP) has been acknowledged as a potential manufacturing revolution. AM has many advantages over conventional manufacturing techniques; AM techniques manufacture through the addition of material - rather than traditional machining or moulding methods. AM negates the need for tooling, enabling cost-effective low-volume production in high-wage economies and the design & production of geometries that cannot be made by other means. In addition, the removal of tooling and the potential to grow components and products layer-by-layer means that we can produce more from less in terms of more efficient use of raw materials and energy or by making multifunctional components and products. The proposed Centre for Doctoral Training (CDT) in Additive Manufacturing and 3D Printing has the vision of training the next generation of leaders, scientists and engineers in this diverse and multi-disciplinary field. As AM is so new current training programmes are not aligned with the potential for manufacturing and generally concentrate on the teaching of Rapid Prototyping principles, and whilst this can be useful background knowledge, the skills and requirements of using this concept for manufacturing are very different. This CDT will be training cohorts of students in all of the basic aspects of AM, from design and materials through to processes and the implementation of these systems for manufacturing high value goods and services. The CDT will also offer specialist training on aspects at the forefront of AM research, for example metallic, medical and multi-functional AM considerations. This means that the cohorts graduating from the CDT will have the background knowledge to proliferate throughout industry and the specialist knowledge to become leaders in their fields, broadening out the reach and appeal of AM as a manufacturing technology and embedding this disruptive technology in company thinking. In order to give the cohorts the best view of AM, these students will be taken on study tours in Europe and the USA, the two main research powerhouses of AM, to learn from their international colleagues and see businesses that use AM on a daily basis. One of the aims of the CDT in AM is to educate and attract students from complementary basic science, whether this be chemistry, physics or biology. This is because AM is a fast moving area. The benefits of having a CDT in AM and coupling with students who have a more fundamental science base are essential to ensure innovation & timeliness to maintain the UK's leading position. AM is a disruptive technology to a number of industrial sectors, yet the CDTs industrial supporters, who represent a breadth of industrial end-users, welcome this disruption as the potential business benefits are significant. Growing on this industry foresight, the CDT will work in key markets with our supporters to ensure that AM is positioned to provide a real and lasting contribution & impact to UK manufacturing and provide economic stability and growth. This contribution will provide societal benefits to UK citizens through the generation of wealth and employment from high value manufacturing activities in the UK.
Cite
Design rules for additively-manufactured wrist splints
Kelly, Sarah (2020): Design rules for additively-manufactured wrist splints. Loughborough University. Thesis. https://doi.org/10.26174/thesi...
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RFC 2402: IP Authentication Header
Errata Exist
Network Working Group S. Kent
Request for Comments: 2402 BBN Corp
Obsoletes: 1826 R. Atkinson
Category: Standards Track @Home Network
November 1998 IP Authentication Header Status of this Memo
This document specifies an Internet standards track protocol for the
Internet community, and requests discussion and suggestions for
improvements. Please refer to the current edition of the "Internet
Official Protocol Standards" (STD 1) for the standardization state
and status of this protocol. Distribution of this memo is unlimited.
Copyright Notice
Copyright (C) The Internet Society (1998). All Rights Reserved.
Table of Contents 1 . Introduction...................................................... 2 2 . Authentication Header Format...................................... 3 2.1 Next Header................................................... 4 2.2 Payload Length................................................ 4 2.3 Reserved...................................................... 4 2.4 Security Parameters Index (SPI)............................... 4 2.5 Sequence Number............................................... 5 2.6 Authentication Data .......................................... 5 3 . Authentication Header Processing.................................. 5 3.1 Authentication Header Location............................... 5 3.2 Authentication Algorithms.................................... 7 3.3 Outbound Packet Processing................................... 8 3.3.1 Security Association Lookup............................. 8 3.3.2 Sequence Number Generation.............................. 8 3.3.3 Integrity Check Value Calculation....................... 9 3.3.3.1 Handling Mutable Fields............................ 9 3.3.3.1.1 ICV Computation for IPv4..................... 10 3.3.3.1.1.1 Base Header Fields....................... 10 3.3.3.1.1.2 Options.................................. 11 3.3.3.1.2 ICV Computation for IPv6..................... 11 3.3.3.1.2.1 Base Header Fields....................... 11 3.3.3.1.2.2 Extension Headers Containing Options..... 11 3.3.3.1.2.3 Extension Headers Not Containing Options.11 3.3.3.2 Padding........................................... 12 3.3.3.2.1 Authentication Data Padding.................. 12 Kent & Atkinson Standards Track [Page 1]
RFC 2402 IP Authentication Header November 1998 3.3.3.2.2 Implicit Packet Padding...................... 12 3.3.4 Fragmentation.......................................... 12 3.4 Inbound Packet Processing................................... 13 3.4.1 Reassembly............................................. 13 3.4.2 Security Association Lookup............................ 13 3.4.3 Sequence Number Verification........................... 13 3.4.4 Integrity Check Value Verification..................... 15 4 . Auditing......................................................... 15 5 . Conformance Requirements......................................... 16 6 . Security Considerations.......................................... 16 7 . Differences from RFC 1826 ........................................ 16 Acknowledgements.................................................... 17 Appendix A -- Mutability of IP Options/Extension Headers............ 18 A1. IPv4 Options................................................. 18 A2. IPv6 Extension Headers....................................... 19 References.......................................................... 20 Disclaimer.......................................................... 21 Author Information.................................................. 22 Full Copyright Statement............................................ 22 1 . Introduction The IP Authentication Header (AH) is used to provide connectionless
integrity and data origin authentication for IP datagrams (hereafter
referred to as just "authentication"), and to provide protection
against replays. This latter, optional service may be selected, by
the receiver, when a Security Association is established. (Although
the default calls for the sender to increment the Sequence Number
used for anti-replay, the service is effective only if the receiver
checks the Sequence Number.) AH provides authentication for as much
of the IP header as possible, as well as for upper level protocol
data. However, some IP header fields may change in transit and the
value of these fields, when the packet arrives at the receiver, may
not be predictable by the sender. The values of such fields cannot
be protected by AH. Thus the protection provided to the IP header by
AH is somewhat piecemeal.
AH may be applied alone, in combination with the IP Encapsulating
Security Payload (ESP) [ KA97b ], or in a nested fashion through the
use of tunnel mode (see "Security Architecture for the Internet
Protocol" [ KA97a ], hereafter referred to as the Security Architecture
document). Security services can be provided between a pair of
communicating hosts, between a pair of communicating security
gateways, or between a security gateway and a host. ESP may be used
to provide the same security services, and it also provides a
confidentiality (encryption) service. The primary difference between
the authentication provided by ESP and AH is the extent of the
coverage. Specifically, ESP does not protect any IP header fields Kent & Atkinson Standards Track [Page 2]
RFC 2402 IP Authentication Header November 1998 unless those fields are encapsulated by ESP (tunnel mode). For more
details on how to use AH and ESP in various network environments, see
the Security Architecture document [ KA97a ].
It is assumed that the reader is familiar with the terms and concepts
described in the Security Architecture document. In particular, the
reader should be familiar with the definitions of security services
offered by AH and ESP, the concept of Security Associations, the ways
in which AH can be used in conjunction with ESP, and the different
key management options available for AH and ESP. (With regard to the
last topic, the current key management options required for both AH
and ESP are manual keying and automated keying via IKE [ HC98 ].)
The keywords MUST, MUST NOT, REQUIRED, SHALL, SHALL NOT, SHOULD,
SHOULD NOT, RECOMMENDED, MAY, and OPTIONAL, when they appear in this
document, are to be interpreted as described in RFC 2119 [ Bra97 ]. 2 . Authentication Header Format The protocol header (IPv4, IPv6, or Extension) immediately preceding
the AH header will contain the value 51 in its Protocol (IPv4) or
Next Header (IPv6, Extension) field [ STD-2 ].
0 1 2 3
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1
+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+
| Next Header | Payload Len | RESERVED |
+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+
| Security Parameters Index (SPI) |
+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+
| Sequence Number Field |
+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+
| |
+ Authentication Data (variable) |
| |
+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+
The following subsections define the fields that comprise the AH
format. All the fields described here are mandatory, i.e., they are
always present in the AH format and are included in the Integrity
Check Value (ICV) computation (see Sections 2.6 and 3.3.3 ). Kent & Atkinson Standards Track [Page 3]
RFC 2402 IP Authentication Header November 1998 2.1 Next Header The Next Header is an 8-bit field that identifies the type of the
next payload after the Authentication Header. The value of this
field is chosen from the set of IP Protocol Numbers defined in the
most recent "Assigned Numbers" [ STD-2 ] RFC from the Internet Assigned
Numbers Authority (IANA). 2.2 Payload Length This 8-bit field specifies the length of AH in 32-bit words (4-byte
units), minus "2". (All IPv6 extension headers, as per RFC 1883 ,
encode the "Hdr Ext Len" field by first subtracting 1 (64-bit word)
from the header length (measured in 64-bit words). AH is an IPv6
extension header. However, since its length is measured in 32-bit
words, the "Payload Length" is calculated by subtracting 2 (32 bit
words).) In the "standard" case of a 96-bit authentication value
plus the 3 32-bit word fixed portion, this length field will be "4".
A "null" authentication algorithm may be used only for debugging
purposes. Its use would result in a "1" value for this field for
IPv4 or a "2" for IPv6, as there would be no corresponding
Authentication Data field (see Section 3.3.3.2.1 on "Authentication
Data Padding"). 2.3 Reserved This 16-bit field is reserved for future use. It MUST be set to
"zero." (Note that the value is included in the Authentication Data
calculation, but is otherwise ignored by the recipient.) 2.4 Security Parameters Index (SPI) The SPI is an arbitrary 32-bit value that, in combination with the
destination IP address and security protocol (AH), uniquely
identifies the Security Association for this datagram. The set of
SPI values in the range 1 through 255 are reserved by the Internet
Assigned Numbers Authority (IANA) for future use; a reserved SPI
value will not normally be assigned by IANA unless the use of the
assigned SPI value is specified in an RFC. It is ordinarily selected
by the destination system upon establishment of an SA (see the
Security Architecture document for more details).
The SPI value of zero (0) is reserved for local, implementation-
specific use and MUST NOT be sent on the wire. For example, a key
management implementation MAY use the zero SPI value to mean "No
Security Association Exists" during the period when the IPsec
implementation has requested that its key management entity establish
a new SA, but the SA has not yet been established. Kent & Atkinson Standards Track [Page 4]
RFC 2402 IP Authentication Header November 1998 2.5 Sequence Number This unsigned 32-bit field contains a monotonically increasing
counter value (sequence number). It is mandatory and is always
present even if the receiver does not elect to enable the anti-replay
service for a specific SA. Processing of the Sequence Number field
is at the discretion of the receiver, i.e., the sender MUST always
transmit this field, but the receiver need not act upon it (see the
discussion of Sequence Number Verification in the "Inbound Packet
Processing" section below).
The sender's counter and the receiver's counter are initialized to 0
when an SA is established. (The first packet sent using a given SA
will have a Sequence Number of 1; see Section 3.3.2 for more details
on how the Sequence Number is generated.) If anti-replay is enabled
(the default), the transmitted Sequence Number must never be allowed
to cycle. Thus, the sender's counter and the receiver's counter MUST
be reset (by establishing a new SA and thus a new key) prior to the
transmission of the 2^32nd packet on an SA. 2.6 Authentication Data This is a variable-length field that contains the Integrity Check
Value (ICV) for this packet. The field must be an integral multiple
of 32 bits in length. The details of the ICV computation are
described in Section 3.3.2 below. This field may include explicit
padding. This padding is included to ensure that the length of the
AH header is an integral multiple of 32 bits (IPv4) or 64 bits
(IPv6). All implementations MUST support such padding. Details of
how to compute the required padding length are provided below. The
authentication algorithm specification MUST specify the length of the
ICV and the comparison rules and processing steps for validation. 3 . Authentication Header Processing 3.1 Authentication Header Location Like ESP, AH may be employed in two ways: transport mode or tunnel
mode. The former mode is applicable only to host implementations and
provides protection for upper layer protocols, in addition to
selected IP header fields. (In this mode, note that for "bump-in-
the-stack" or "bump-in-the-wire" implementations, as defined in the
Security Architecture document, inbound and outbound IP fragments may
require an IPsec implementation to perform extra IP
reassembly/fragmentation in order to both conform to this
specification and provide transparent IPsec support. Special care is
required to perform such operations within these implementations when
multiple interfaces are in use.) Kent & Atkinson Standards Track [Page 5]
RFC 2402 IP Authentication Header November 1998 In transport mode, AH is inserted after the IP header and before an
upper layer protocol, e.g., TCP, UDP, ICMP, etc. or before any other
IPsec headers that have already been inserted. In the context of
IPv4, this calls for placing AH after the IP header (and any options
that it contains), but before the upper layer protocol. (Note that
the term "transport" mode should not be misconstrued as restricting
its use to TCP and UDP. For example, an ICMP message MAY be sent
using either "transport" mode or "tunnel" mode.) The following
diagram illustrates AH transport mode positioning for a typical IPv4
packet, on a "before and after" basis.
BEFORE APPLYING AH
----------------------------
IPv4 |orig IP hdr | | |
|(any options)| TCP | Data |
----------------------------
AFTER APPLYING AH
---------------------------------
IPv4 |orig IP hdr | | | |
|(any options)| AH | TCP | Data |
---------------------------------
|<------- authenticated ------->|
except for mutable fields
In the IPv6 context, AH is viewed as an end-to-end payload, and thus
should appear after hop-by-hop, routing, and fragmentation extension
headers. The destination options extension header(s) could appear
either before or after the AH header depending on the semantics
desired. The following diagram illustrates AH transport mode
positioning for a typical IPv6 packet.
BEFORE APPLYING AH
---------------------------------------
IPv6 | | ext hdrs | | |
| orig IP hdr |if present| TCP | Data |
---------------------------------------
AFTER APPLYING AH
------------------------------------------------------------
IPv6 | |hop-by-hop, dest*, | | dest | | |
|orig IP hdr |routing, fragment. | AH | opt* | TCP | Data |
------------------------------------------------------------
|<---- authenticated except for mutable fields ----------->|
* = if present, could be before AH, after AH, or both Kent & Atkinson Standards Track [Page 6]
RFC 2402 IP Authentication Header November 1998 ESP and AH headers can be combined in a variety of modes. The IPsec
Architecture document describes the combinations of security
associations that must be supported.
Tunnel mode AH may be employed in either hosts or security gateways
(or in so-called "bump-in-the-stack" or "bump-in-the-wire"
implementations, as defined in the Security Architecture document).
When AH is implemented in a security gateway (to protect transit
traffic), tunnel mode must be used. In tunnel mode, the "inner" IP
header carries the ultimate source and destination addresses, while
an "outer" IP header may contain distinct IP addresses, e.g.,
addresses of security gateways. In tunnel mode, AH protects the
entire inner IP packet, including the entire inner IP header. The
position of AH in tunnel mode, relative to the outer IP header, is
the same as for AH in transport mode. The following diagram
illustrates AH tunnel mode positioning for typical IPv4 and IPv6
packets.
------------------------------------------------
IPv4 | new IP hdr* | | orig IP hdr* | | |
|(any options)| AH | (any options) |TCP | Data |
------------------------------------------------
|<- authenticated except for mutable fields -->|
| in the new IP hdr |
--------------------------------------------------------------
IPv6 | | ext hdrs*| | | ext hdrs*| | |
|new IP hdr*|if present| AH |orig IP hdr*|if present|TCP|Data|
--------------------------------------------------------------
|<-- authenticated except for mutable fields in new IP hdr ->|
* = construction of outer IP hdr/extensions and modification
of inner IP hdr/extensions is discussed below. 3.2 Authentication Algorithms The authentication algorithm employed for the ICV computation is
specified by the SA. For point-to-point communication, suitable
authentication algorithms include keyed Message Authentication Codes
(MACs) based on symmetric encryption algorithms (e.g., DES) or on
one-way hash functions (e.g., MD5 or SHA-1). For multicast
communication, one-way hash algorithms combined with asymmetric
signature algorithms are appropriate, though performance and space
considerations currently preclude use of such algorithms. The
mandatory-to-implement authentication algorithms are described in Section 5 "Conformance Requirements". Other algorithms MAY be
supported. Kent & Atkinson Standards Track [Page 7]
RFC 2402 IP Authentication Header November 1998 3.3 Outbound Packet Processing In transport mode, the sender inserts the AH header after the IP
header and before an upper layer protocol header, as described above.
In tunnel mode, the outer and inner IP header/extensions can be
inter-related in a variety of ways. The construction of the outer IP
header/extensions during the encapsulation process is described in
the Security Architecture document.
If there is more than one IPsec header/extension required, the order
of the application of the security headers MUST be defined by
security policy. For simplicity of processing, each IPsec header
SHOULD ignore the existence (i.e., not zero the contents or try to
predict the contents) of IPsec headers to be applied later. (While a
native IP or bump-in-the-stack implementation could predict the
contents of later IPsec headers that it applies itself, it won't be
possible for it to predict any IPsec headers added by a bump-in-the-
wire implementation between the host and the network.) 3.3.1 Security Association Lookup AH is applied to an outbound packet only after an IPsec
implementation determines that the packet is associated with an SA
that calls for AH processing. The process of determining what, if
any, IPsec processing is applied to outbound traffic is described in
the Security Architecture document. 3.3.2 Sequence Number Generation The sender's counter is initialized to 0 when an SA is established.
The sender increments the Sequence Number for this SA and inserts the
new value into the Sequence Number Field. Thus the first packet sent
using a given SA will have a Sequence Number of 1.
If anti-replay is enabled (the default), the sender checks to ensure
that the counter has not cycled before inserting the new value in the
Sequence Number field. In other words, the sender MUST NOT send a
packet on an SA if doing so would cause the Sequence Number to cycle.
An attempt to transmit a packet that would result in Sequence Number
overflow is an auditable event. (Note that this approach to Sequence
Number management does not require use of modular arithmetic.)
The sender assumes anti-replay is enabled as a default, unless
otherwise notified by the receiver (see 3.4.3). Thus, if the counter
has cycled, the sender will set up a new SA and key (unless the SA
was configured with manual key management). Kent & Atkinson Standards Track [Page 8]
RFC 2402 IP Authentication Header November 1998 If anti-replay is disabled, the sender does not need to monitor or
reset the counter, e.g., in the case of manual key management (see Section 5 .) However, the sender still increments the counter and when
it reaches the maximum value, the counter rolls over back to zero. 3.3.3 Integrity Check Value Calculation The AH ICV is computed over:
o IP header fields that are either immutable in transit or
that are predictable in value upon arrival at the endpoint
for the AH SA
o the AH header (Next Header, Payload Len, Reserved, SPI,
Sequence Number, and the Authentication Data (which is set
to zero for this computation), and explicit padding bytes
(if any))
o the upper level protocol data, which is assumed to be
immutable in transit 3.3.3.1 Handling Mutable Fields If a field may be modified during transit, the value of the field is
set to zero for purposes of the ICV computation. If a field is
mutable, but its value at the (IPsec) receiver is predictable, then
that value is inserted into the field for purposes of the ICV
calculation. The Authentication Data field is also set to zero in
preparation for this computation. Note that by replacing each
field's value with zero, rather than omitting the field, alignment is
preserved for the ICV calculation. Also, the zero-fill approach
ensures that the length of the fields that are so handled cannot be
changed during transit, even though their contents are not explicitly
covered by the ICV.
As a new extension header or IPv4 option is created, it will be
defined in its own RFC and SHOULD include (in the Security
Considerations section) directions for how it should be handled when
calculating the AH ICV. If the IP (v4 or v6) implementation
encounters an extension header that it does not recognize, it will
discard the packet and send an ICMP message. IPsec will never see
the packet. If the IPsec implementation encounters an IPv4 option
that it does not recognize, it should zero the whole option, using
the second byte of the option as the length. IPv6 options (in
Destination extension headers or Hop by Hop extension header) contain
a flag indicating mutability, which determines appropriate processing
for such options. Kent & Atkinson Standards Track [Page 9]
RFC 2402 IP Authentication Header November 1998 3.3.3.1.1 ICV Computation for IPv4 3.3.3.1.1.1 Base Header Fields The IPv4 base header fields are classified as follows:
Immutable
Version
Internet Header Length
Total Length
Identification
Protocol (This should be the value for AH.)
Source Address
Destination Address (without loose or strict source routing)
Mutable but predictable
Destination Address (with loose or strict source routing)
Mutable (zeroed prior to ICV calculation)
Type of Service (TOS)
Flags
Fragment Offset
Time to Live (TTL)
Header Checksum
TOS -- This field is excluded because some routers are known to
change the value of this field, even though the IP
specification does not consider TOS to be a mutable header
field.
Flags -- This field is excluded since an intermediate router might
set the DF bit, even if the source did not select it.
Fragment Offset -- Since AH is applied only to non-fragmented IP
packets, the Offset Field must always be zero, and thus it
is excluded (even though it is predictable).
TTL -- This is changed en-route as a normal course of processing
by routers, and thus its value at the receiver is not
predictable by the sender.
Header Checksum -- This will change if any of these other fields
changes, and thus its value upon reception cannot be
predicted by the sender. Kent & Atkinson Standards Track [Page 10]
RFC 2402 IP Authentication Header November 1998 3.3.3.1.1.2 Options For IPv4 (unlike IPv6), there is no mechanism for tagging options as
mutable in transit. Hence the IPv4 options are explicitly listed in Appendix A and classified as immutable, mutable but predictable, or
mutable. For IPv4, the entire option is viewed as a unit; so even
though the type and length fields within most options are immutable
in transit, if an option is classified as mutable, the entire option
is zeroed for ICV computation purposes. 3.3.3.1.2 ICV Computation for IPv6 3.3.3.1.2.1 Base Header Fields The IPv6 base header fields are classified as follows:
Immutable
Version
Payload Length
Next Header (This should be the value for AH.)
Source Address
Destination Address (without Routing Extension Header)
Mutable but predictable
Destination Address (with Routing Extension Header)
Mutable (zeroed prior to ICV calculation)
Class
Flow Label
Hop Limit 3.3.3.1.2.2 Extension Headers Containing Options IPv6 options in the Hop-by-Hop and Destination Extension Headers
contain a bit that indicates whether the option might change
(unpredictably) during transit. For any option for which contents
may change en-route, the entire "Option Data" field must be treated
as zero-valued octets when computing or verifying the ICV. The
Option Type and Opt Data Len are included in the ICV calculation.
All options for which the bit indicates immutability are included in
the ICV calculation. See the IPv6 specification [ DH95 ] for more
information. 3.3.3.1.2.3 Extension Headers Not Containing Options The IPv6 extension headers that do not contain options are explicitly
listed in Appendix A and classified as immutable, mutable but
predictable, or mutable. Kent & Atkinson Standards Track [Page 11]
RFC 2402 IP Authentication Header November 1998 3.3.3.2 Padding 3.3.3.2.1 Authentication Data Padding As mentioned in section 2.6 , the Authentication Data field explicitly
includes padding to ensure that the AH header is a multiple of 32
bits (IPv4) or 64 bits (IPv6). If padding is required, its length is
determined by two factors:
- the length of the ICV
- the IP protocol version (v4 or v6)
For example, if the output of the selected algorithm is 96-bits, no
padding is required for either IPv4 or for IPv6. However, if a
different length ICV is generated, due to use of a different
algorithm, then padding may be required depending on the length and
IP protocol version. The content of the padding field is arbitrarily
selected by the sender. (The padding is arbitrary, but need not be
random to achieve security.) These padding bytes are included in the
Authentication Data calculation, counted as part of the Payload
Length, and transmitted at the end of the Authentication Data field
to enable the receiver to perform the ICV calculation. 3.3.3.2.2 Implicit Packet Padding For some authentication algorithms, the byte string over which the
ICV computation is performed must be a multiple of a blocksize
specified by the algorithm. If the IP packet length (including AH)
does not match the blocksize requirements for the algorithm, implicit
padding MUST be appended to the end of the packet, prior to ICV
computation. The padding octets MUST have a value of zero. The
blocksize (and hence the length of the padding) is specified by the
algorithm specification. This padding is not transmitted with the
packet. Note that MD5 and SHA-1 are viewed as having a 1-byte
blocksize because of their internal padding conventions. 3.3.4 Fragmentation If required, IP fragmentation occurs after AH processing within an
IPsec implementation. Thus, transport mode AH is applied only to
whole IP datagrams (not to IP fragments). An IP packet to which AH
has been applied may itself be fragmented by routers en route, and
such fragments must be reassembled prior to AH processing at a
receiver. In tunnel mode, AH is applied to an IP packet, the payload
of which may be a fragmented IP packet. For example, a security
gateway or a "bump-in-the-stack" or "bump-in-the-wire" IPsec
implementation (see the Security Architecture document for details)
may apply tunnel mode AH to such fragments. Kent & Atkinson Standards Track [Page 12]
RFC 2402 IP Authentication Header November 1998 3.4 Inbound Packet Processing If there is more than one IPsec header/extension present, the
processing for each one ignores (does not zero, does not use) any
IPsec headers applied subsequent to the header being processed. 3.4.1 Reassembly If required, reassembly is performed prior to AH processing. If a
packet offered to AH for processing appears to be an IP fragment,
i.e., the OFFSET field is non-zero or the MORE FRAGMENTS flag is set,
the receiver MUST discard the packet; this is an auditable event. The
audit log entry for this event SHOULD include the SPI value,
date/time, Source Address, Destination Address, and (in IPv6) the
Flow ID.
NOTE: For packet reassembly, the current IPv4 spec does NOT require
either the zero'ing of the OFFSET field or the clearing of the MORE
FRAGMENTS flag. In order for a reassembled packet to be processed by
IPsec (as opposed to discarded as an apparent fragment), the IP code
must do these two things after it reassembles a packet. 3.4.2 Security Association Lookup Upon receipt of a packet containing an IP Authentication Header, the
receiver determines the appropriate (unidirectional) SA, based on the
destination IP address, security protocol (AH), and the SPI. (This
process is described in more detail in the Security Architecture
document.) The SA indicates whether the Sequence Number field will
be checked, specifies the algorithm(s) employed for ICV computation,
and indicates the key(s) required to validate the ICV.
If no valid Security Association exists for this session (e.g., the
receiver has no key), the receiver MUST discard the packet; this is
an auditable event. The audit log entry for this event SHOULD
include the SPI value, date/time, Source Address, Destination
Address, and (in IPv6) the Flow ID. 3.4.3 Sequence Number Verification All AH implementations MUST support the anti-replay service, though
its use may be enabled or disabled by the receiver on a per-SA basis.
(Note that there are no provisions for managing transmitted Sequence
Number values among multiple senders directing traffic to a single SA
(irrespective of whether the destination address is unicast,
broadcast, or multicast). Thus the anti-replay service SHOULD NOT be
used in a multi-sender environment that employs a single SA.) Kent & Atkinson Standards Track [Page 13]
RFC 2402 IP Authentication Header November 1998 If the receiver does not enable anti-replay for an SA, no inbound
checks are performed on the Sequence Number. However, from the
perspective of the sender, the default is to assume that anti-replay
is enabled at the receiver. To avoid having the sender do
unnecessary sequence number monitoring and SA setup (see section 3.3.2 ), if an SA establishment protocol such as IKE is employed, the
receiver SHOULD notify the sender, during SA establishment, if the
receiver will not provide anti-replay protection.
If the receiver has enabled the anti-replay service for this SA, the
receiver packet counter for the SA MUST be initialized to zero when
the SA is established. For each received packet, the receiver MUST
verify that the packet contains a Sequence Number that does not
duplicate the Sequence Number of any other packets received during
the life of this SA. This SHOULD be the first AH check applied to a
packet after it has been matched to an SA, to speed rejection of
duplicate packets.
Duplicates are rejected through the use of a sliding receive window.
(How the window is implemented is a local matter, but the following
text describes the functionality that the implementation must
exhibit.) A MINIMUM window size of 32 MUST be supported; but a
window size of 64 is preferred and SHOULD be employed as the default.
Another window size (larger than the MINIMUM) MAY be chosen by the
receiver. (The receiver does NOT notify the sender of the window
size.)
The "right" edge of the window represents the highest, validated
Sequence Number value received on this SA. Packets that contain
Sequence Numbers lower than the "left" edge of the window are
rejected. Packets falling within the window are checked against a
list of received packets within the window. An efficient means for
performing this check, based on the use of a bit mask, is described
in the Security Architecture document.
If the received packet falls within the window and is new, or if the
packet is to the right of the window, then the receiver proceeds to
ICV verification. If the ICV validation fails, the receiver MUST
discard the received IP datagram as invalid; this is an auditable
event. The audit log entry for this event SHOULD include the SPI
value, date/time, Source Address, Destination Address, the Sequence
Number, and (in IPv6) the Flow ID. The receive window is updated
only if the ICV verification succeeds. Kent & Atkinson Standards Track [Page 14]
RFC 2402 IP Authentication Header November 1998 DISCUSSION:
Note that if the packet is either inside the window and new, or is
outside the window on the "right" side, the receiver MUST
authenticate the packet before updating the Sequence Number window
data. 3.4.4 Integrity Check Value Verification The receiver computes the ICV over the appropriate fields of the
packet, using the specified authentication algorithm, and verifies
that it is the same as the ICV included in the Authentication Data
field of the packet. Details of the computation are provided below.
If the computed and received ICV's match, then the datagram is valid,
and it is accepted. If the test fails, then the receiver MUST
discard the received IP datagram as invalid; this is an auditable
event. The audit log entry SHOULD include the SPI value, date/time
received, Source Address, Destination Address, and (in IPv6) the Flow
ID.
DISCUSSION:
Begin by saving the ICV value and replacing it (but not any
Authentication Data padding) with zero. Zero all other fields
that may have been modified during transit. (See section 3.3.3.1 for a discussion of which fields are zeroed before performing the
ICV calculation.) Check the overall length of the packet, and if
it requires implicit padding based on the requirements of the
authentication algorithm, append zero-filled bytes to the end of
the packet as required. Perform the ICV computation and compare
the result with the saved value, using the comparison rules
defined by the algorithm specification. (For example, if a
digital signature and one-way hash are used for the ICV
computation, the matching process is more complex.) 4 . Auditing Not all systems that implement AH will implement auditing. However,
if AH is incorporated into a system that supports auditing, then the
AH implementation MUST also support auditing and MUST allow a system
administrator to enable or disable auditing for AH. For the most
part, the granularity of auditing is a local matter. However,
several auditable events are identified in this specification and for
each of these events a minimum set of information that SHOULD be
included in an audit log is defined. Additional information also MAY
be included in the audit log for each of these events, and additional
events, not explicitly called out in this specification, also MAY Kent & Atkinson Standards Track [Page 15]
RFC 2402 IP Authentication Header November 1998 result in audit log entries. There is no requirement for the
receiver to transmit any message to the purported sender in response
to the detection of an auditable event, because of the potential to
induce denial of service via such action. 5 . Conformance Requirements Implementations that claim conformance or compliance with this
specification MUST fully implement the AH syntax and processing
described here and MUST comply with all requirements of the Security
Architecture document. If the key used to compute an ICV is manually
distributed, correct provision of the anti-replay service would
require correct maintenance of the counter state at the sender, until
the key is replaced, and there likely would be no automated recovery
provision if counter overflow were imminent. Thus a compliant
implementation SHOULD NOT provide this service in conjunction with
SAs that are manually keyed. A compliant AH implementation MUST
support the following mandatory-to-implement algorithms:
- HMAC with MD5 [ MG97a ]
- HMAC with SHA-1 [ MG97b ] 6 . Security Considerations Security is central to the design of this protocol, and these
security considerations permeate the specification. Additional
security-relevant aspects of using the IPsec protocol are discussed
in the Security Architecture document. 7 . Differences from RFC 1826 This specification of AH differs from RFC 1826 [ ATK95 ] in several
important respects, but the fundamental features of AH remain intact.
One goal of the revision of RFC 1826 was to provide a complete
framework for AH, with ancillary RFCs required only for algorithm
specification. For example, the anti-replay service is now an
integral, mandatory part of AH, not a feature of a transform defined
in another RFC. Carriage of a sequence number to support this
service is now required at all times. The default algorithms
required for interoperability have been changed to HMAC with MD5 or
SHA-1 (vs. keyed MD5), for security reasons. The list of IPv4 header
fields excluded from the ICV computation has been expanded to include
the OFFSET and FLAGS fields.
Another motivation for revision was to provide additional detail and
clarification of subtle points. This specification provides
rationale for exclusion of selected IPv4 header fields from AH
coverage and provides examples on positioning of AH in both the IPv4 Kent & Atkinson Standards Track [Page 16]
RFC 2402 IP Authentication Header November 1998 and v6 contexts. Auditing requirements have been clarified in this
version of the specification. Tunnel mode AH was mentioned only in
passing in RFC 1826 , but now is a mandatory feature of AH.
Discussion of interactions with key management and with security
labels have been moved to the Security Architecture document.
Acknowledgements
For over 3 years, this document has evolved through multiple versions
and iterations. During this time, many people have contributed
significant ideas and energy to the process and the documents
themselves. The authors would like to thank Karen Seo for providing
extensive help in the review, editing, background research, and
coordination for this version of the specification. The authors
would also like to thank the members of the IPsec and IPng working
groups, with special mention of the efforts of (in alphabetic order):
Steve Bellovin, Steve Deering, Francis Dupont, Phil Karn, Frank
Kastenholz, Perry Metzger, David Mihelcic, Hilarie Orman, Norman
Shulman, William Simpson, and Nina Yuan. Kent & Atkinson Standards Track [Page 17]
RFC 2402 IP Authentication Header November 1998 Appendix A -- Mutability of IP Options/Extension Headers
A1. IPv4 Options
This table shows how the IPv4 options are classified with regard to
"mutability". Where two references are provided, the second one
supercedes the first. This table is based in part on information
provided in RFC1700 , "ASSIGNED NUMBERS", (October 1994).
Opt.
Copy Class # Name Reference
---- ----- --- ------------------------ ---------
IMMUTABLE -- included in ICV calculation
0 0 0 End of Options List [ RFC791 ]
0 0 1 No Operation [ RFC791 ]
1 0 2 Security [RFC1108(historic but in use)]
1 0 5 Extended Security [RFC1108(historic but in use)]
1 0 6 Commercial Security [expired I-D, now US MIL STD]
1 0 20 Router Alert [ RFC2113 ]
1 0 21 Sender Directed Multi- [ RFC1770 ]
Destination Delivery
MUTABLE -- zeroed
1 0 3 Loose Source Route [ RFC791 ]
0 2 4 Time Stamp [ RFC791 ]
0 0 7 Record Route [ RFC791 ]
1 0 9 Strict Source Route [ RFC791 ]
0 2 18 Traceroute [ RFC1393 ]
EXPERIMENTAL, SUPERCEDED -- zeroed
1 0 8 Stream ID [RFC791, RFC1122 (Host Req)]
0 0 11 MTU Probe [RFC1063, RFC1191 (PMTU)]
0 0 12 MTU Reply [RFC1063, RFC1191 (PMTU)]
1 0 17 Extended Internet Proto [RFC1385, RFC1883 (IPv6)]
0 0 10 Experimental Measurement [ZSu]
1 2 13 Experimental Flow Control [Finn]
1 0 14 Experimental Access Ctl [Estrin]
0 0 15 ??? [VerSteeg]
1 0 16 IMI Traffic Descriptor [Lee]
1 0 19 Address Extension [Ullmann IPv7]
NOTE: Use of the Router Alert option is potentially incompatible with
use of IPsec. Although the option is immutable, its use implies that
each router along a packet's path will "process" the packet and
consequently might change the packet. This would happen on a hop by
hop basis as the packet goes from router to router. Prior to being
processed by the application to which the option contents are
directed, e.g., RSVP/IGMP, the packet should encounter AH processing. Kent & Atkinson Standards Track [Page 18]
RFC 2402 IP Authentication Header November 1998 However, AH processing would require that each router along the path
is a member of a multicast-SA defined by the SPI. This might pose
problems for packets that are not strictly source routed, and it
requires multicast support techniques not currently available.
NOTE: Addition or removal of any security labels (BSO, ESO, CIPSO) by
systems along a packet's path conflicts with the classification of
these IP Options as immutable and is incompatible with the use of
IPsec.
NOTE: End of Options List options SHOULD be repeated as necessary to
ensure that the IP header ends on a 4 byte boundary in order to
ensure that there are no unspecified bytes which could be used for a
covert channel.
A2. IPv6 Extension Headers
This table shows how the IPv6 Extension Headers are classified with
regard to "mutability".
Option/Extension Name Reference
----------------------------------- ---------
MUTABLE BUT PREDICTABLE -- included in ICV calculation
Routing (Type 0) [ RFC1883 ]
BIT INDICATES IF OPTION IS MUTABLE (CHANGES UNPREDICTABLY DURING TRANSIT)
Hop by Hop options [ RFC1883 ]
Destination options [ RFC1883 ]
NOT APPLICABLE
Fragmentation [ RFC1883 ]
Options -- IPv6 options in the Hop-by-Hop and Destination
Extension Headers contain a bit that indicates whether the
option might change (unpredictably) during transit. For
any option for which contents may change en-route, the
entire "Option Data" field must be treated as zero-valued
octets when computing or verifying the ICV. The Option
Type and Opt Data Len are included in the ICV calculation.
All options for which the bit indicates immutability are
included in the ICV calculation. See the IPv6
specification [ DH95 ] for more information.
Routing (Type 0) -- The IPv6 Routing Header "Type 0" will
rearrange the address fields within the packet during
transit from source to destination. However, the contents
of the packet as it will appear at the receiver are known
to the sender and to all intermediate hops. Hence, the Kent & Atkinson Standards Track [Page 19]
RFC 2402 IP Authentication Header November 1998 IPv6 Routing Header "Type 0" is included in the
Authentication Data calculation as mutable but predictable.
The sender must order the field so that it appears as it
will at the receiver, prior to performing the ICV
computation.
Fragmentation -- Fragmentation occurs after outbound IPsec
processing ( section 3.3 ) and reassembly occurs before
inbound IPsec processing ( section 3.4 ). So the
Fragmentation Extension Header, if it exists, is not seen
by IPsec.
Note that on the receive side, the IP implementation could
leave a Fragmentation Extension Header in place when it
does re-assembly. If this happens, then when AH receives
the packet, before doing ICV processing, AH MUST "remove"
(or skip over) this header and change the previous header's
"Next Header" field to be the "Next Header" field in the
Fragmentation Extension Header.
Note that on the send side, the IP implementation could
give the IPsec code a packet with a Fragmentation Extension
Header with Offset of 0 (first fragment) and a More
Fragments Flag of 0 (last fragment). If this happens, then
before doing ICV processing, AH MUST first "remove" (or
skip over) this header and change the previous header's
"Next Header" field to be the "Next Header" field in the
Fragmentation Extension Header.
References
[ ATK95 ] Atkinson, R., "The IP Authentication Header", RFC 1826 ,
August 1995.
[ Bra97 ] Bradner, S., "Key words for use in RFCs to Indicate
Requirement Level", BCP 14 , RFC 2119 , March 1997.
[ DH95 ] Deering, S., and B. Hinden, "Internet Protocol version 6
(IPv6) Specification", RFC 1883 , December 1995.
[ HC98 ] Harkins, D., and D. Carrel, "The Internet Key Exchange
(IKE)", RFC 2409 , November 1998.
[ KA97a ] Kent, S., and R. Atkinson, "Security Architecture for the
Internet Protocol", RFC 2401 , November 1998.
[ KA97b ] Kent, S., and R. Atkinson, "IP Encapsulating Security
Payload (ESP)", RFC 2406 , November 1998. Kent & Atkinson Standards Track [Page 20]
RFC 2402 IP Authentication Header November 1998 [ MG97a ] Madson, C., and R. Glenn, "The Use of HMAC-MD5-96 within
ESP and AH", RFC 2403 , November 1998.
[ MG97b ] Madson, C., and R. Glenn, "The Use of HMAC-SHA-1-96 within
ESP and AH", RFC 2404 , November 1998.
[ STD-2 ] Reynolds, J., and J. Postel, "Assigned Numbers", STD 2, RFC 1700 , October 1994. See also: http://www.iana.org/numbers.html Disclaimer
The views and specification here are those of the authors and are not
necessarily those of their employers. The authors and their
employers specifically disclaim responsibility for any problems
arising from correct or incorrect implementation or use of this
specification.
Author Information
Stephen Kent
BBN Corporation
70 Fawcett Street
Cambridge, MA 02140
USA
Phone: +1 (617) 873-3988
EMail: [email protected]
Randall Atkinson
@Home Network
425 Broadway,
Redwood City, CA 94063
USA
Phone: +1 (415) 569-5000
EMail: [email protected] Kent & Atkinson Standards Track [Page 21]
Copyright (C) The Internet Society (1998). All Rights Reserved.
This document and translations of it may be copied and furnished to
others, and derivative works that comment on or otherwise explain it
or assist in its implementation may be prepared, copied, published
and distributed, in whole or in part, without restriction of any
kind, provided that the above copyright notice and this paragraph are
included on all such copies and derivative works. However, this
document itself may not be modified in any way, such as by removing
the copyright notice or references to the Internet Society or other
Internet organizations, except as needed for the purpose of
developing Internet standards in which case the procedures for
copyrights defined in the Internet Standards process must be
followed, or as required to translate it into languages other than
English.
The limited permissions granted above are perpetual and will not be
revoked by the Internet Society or its successors or assigns.
This document and the information contained herein is provided on an
"AS IS" basis and THE INTERNET SOCIETY AND THE INTERNET ENGINEERING
TASK FORCE DISCLAIMS ALL WARRANTIES, EXPRESS OR IMPLIED, INCLUDING
BUT NOT LIMITED TO ANY WARRANTY THAT THE USE OF THE INFORMATION
HEREIN WILL NOT INFRINGE ANY RIGHTS OR ANY IMPLIED WARRANTIES OF
MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE.
Kent & Atkinson Standards Track [Page 22]
| https://www.rfc-editor.org/rfc/rfc2402 |
(PDF) Preliminary analysis of New Zealand scampi ( Metanephrops challengeri ) diet using metabarcoding
PDF | Deep sea lobsters are highly valued for seafood and provide the basis of important commercial fisheries in many parts of the world. Despite their... | Find, read and cite all the research you need on ResearchGate
Preliminary analysis of New Zealand scampi ( Metanephrops challengeri ) diet using metabarcoding
DOI: 10.7717/peerj.5641
Authors:
Abstract and Figures
Deep sea lobsters are highly valued for seafood and provide the basis of important commercial fisheries in many parts of the world. Despite their economic significance, relatively little is known about their natural diets. Microscopic analyses of foregut content in some species have suffered from low taxonomic resolution, with many of the dietary items difficult to reliably identify as their tissue is easily digested. DNA metabarcoding has the potential to provide greater taxonomic resolution of the diet of the New Zealand scampi ( Metanephrops challengeri ) through the identification of gut contents, but a number of methodological concerns need to be overcome first to ensure optimum DNA metabarcoding results. In this study, a range of methodological parameters were tested to determine the optimum protocols for DNA metabarcoding, and provide a first view of M . challengeri diet. Several PCR protocols were tested, using two universal primer pairs targeting the 18S rRNA and COI genes, on DNA extracted from both frozen and ethanol preserved samples for both foregut and hindgut digesta. The selection of appropriate DNA polymerases, buffers and methods for reducing PCR inhibitors (including the use of BSA) were found to be critical. Amplification from frozen or ethanol preserved gut contents appeared similarly dependable. The COI gene was found to be more effective than 18S rRNA gene for identifying large eukaryotic taxa from the digesta; however, it was less successfully amplified. The 18S rRNA gene was more easily amplified, but identified mostly smaller marine organisms such as plankton and parasites. This preliminary analysis of the diet of M . challengeri identified a range of species (13,541 reads identified as diet), which included the ghost shark ( Hydrolagus novaezealandiae ), silver warehou ( Seriolella punctata ), tall sea pen ( Funiculina quadrangularis ) and the salp ( Ihlea racovitzai ), suggesting that they have a varied diet, with a high reliance on scavenging a diverse range of pelagic and benthic species from the seafloor.
Taxa identified from the diet of M. challengeri using the PR2, SILVA and NCBI databases for the 18S sequences. Full-size DOI: 10.7717/peerj.5641/fig-2 …
DNA metabarcoding samples, comprised of six individuals and one DNA negative control (Fro1 and Fro2 are two individuals). …
Figures - available via license: CC BY
Submitted 9 March 2018
Accepted 25 August 2018
Published 20 September 2018
Corresponding author
Aimee L. van der Reis,
[email protected]
Academic editor
Mikhail Gelfand
Additional Information and
Declarations can be found on
page 17
DOI 10.7717/peerj.5641
Copyright
2018 van der Reis et al.
Distributed under
Creative Commons CC-BY 4.0
OPEN ACCESS
Preliminary analysis of New Zealand
scampi ( Metanephrops challengeri ) diet
using metabarcoding
Aimee L. van der Reis 1 , Olivier Laroche 2 , Andrew G. Jeffs 1 , 2 and
Shane D. Lavery 1 , 2
1 Institute of Marine Science, University of Auckland, Auckland, New Zealand
2 School of Biological Sciences, University of Auckland, Auckland, New Zealand
ABSTRACT
Deep sea lobsters are highly valued for seafood and provide the basis of important
commercial fisheries in many parts of the world. Despite their economic significance,
relatively little is known about their natural diets. Microscopic analyses of foregut
content in some species have suffered from low taxonomic resolution, with many of
the dietary items difficult to reliably identify as their tissue is easily digested. DNA
metabarcoding has the potential to provide greater taxonomic resolution of the diet
of the New Zealand scampi ( Metanephrops challengeri ) through the identification of
gut contents, but a number of methodological concerns need to be overcome first to
ensure optimum DNA metabarcoding results. In this study, a range of methodological
parameters were tested to determine the optimum protocols for DNA metabarcoding,
and provide a first view of M . challengeri diet. Several PCR protocols were tested, using
two universal primer pairs targeting the 18S rRNA and COI genes, on DNA extracted
from both frozen and ethanol preserved samples for both foregut and hindgut digesta.
The selection of appropriate DNA polymerases, buffers and methods for reducing
PCR inhibitors (including the use of BSA) were found to be critical. Amplification
from frozen or ethanol preserved gut contents appeared similarly dependable. The
COI gene was found to be more effective than 18S rRNA gene for identifying large
eukaryotic taxa from the digesta; however, it was less successfully amplified. The 18S
rRNA gene was more easily amplified, but identified mostly smaller marine organisms
such as plankton and parasites. This preliminary analysis of the diet of M . challengeri
identified a range of species (13,541 reads identified as diet), which included the ghost
shark ( Hydrolagus novaezealandiae ), silver warehou ( Seriolella punctata ), tall sea pen
( Funiculina quadrangularis ) and the salp ( Ihlea racovitzai ), suggesting that they have a
varied diet, with a high reliance on scavenging a diverse range of pelagic and benthic
species from the seafloor.
Subjects Aquaculture, Fisheries and Fish Science, Bioinformatics, Genetics, Marine Biology,
Molecular Biology
Keywords Metanephrops challengeri, New Zealand scampi, Metabarcoding, PCR inhibition,
Database analysis, Next generation sequencing, DNA polymerase, COI, 18S rRNA, Diet
How to cite this article van der Reis et al. (2018), Preliminary analysis of New Zealand scampi ( Metanephrops challengeri ) diet using
metabarcoding. PeerJ 6:e5641; DOI 10.7717/peerj.5641
INTRODUCTION
Commercial fisheries for deep sea lobster species, those typically captured below 50 m
depth, are occurring in many parts of the world, currently producing total annual landings
of around 50,000 t ( Jeffs, 2010 ; FAO, 2016 ). Many of the targeted species are of high value,
with wholesale export prices of over $40 kg − 1 common for some species, such as the
New Zealand (NZ) scampi Metanephrops challengeri ( Balss, 1914 ; Seafood New Zealand,
2017 ). Despite the economic importance of deep sea lobsters, the knowledge of their
feeding ecology and diet is limited. Improved information on diet in deep sea lobsters has
potential uses in identifying effective baits for trap fishing, development of suitable feeds
for aquaculture, as well as understanding differences in growth rates in natural populations
to help improve the management of the fisheries.
Species in two genera of deep-sea lobster, Metanephrops and Nephrops , are widely targeted
by commercial fisheries, share similar ecology and are genetically closely related ( Tshudy,
Chan & Sorhannus, 2007 ). The Norway lobster, Nephrops norvegicus, has a varied diet,
which is necessary to achieve optimal growth ( Cristo & Cartes, 1998 ; Mente, 2010 ). Similar
varied diets have been suggested for some Metanephrops species (excluding M . challengeri ),
and include fish, crustaceans, polychaetes and amphipods, although these have only been
identified at a crude taxonomic level using microscopic analysis of foregut contents ( Choi et
al., 2008 ; Sahlmann, Chan & Chan, 2011 ; Wahle et al., 2012 ; Bell, Tuck & Dobby, 2013 ). A
significant problem with microscopic analysis of gut contents is poor taxonomic resolution,
due to difficulties in identification of partly-digested specimens, which typically require an
expert for reliable taxonomic identification ( Dunn et al., 2010 ; Pompanon et al., 2012 ; Zhan
et al., 2013 ; Berry et al., 2015 ; Young et al., 2015 ; Crisol-Martínez et al., 2016 ; Harms-Tuohy,
Schizas & Appeldoorn, 2016 ; Sousa et al., 2016 ). Also, soft-bodied animals are frequently
suspected of being under-represented in such analyses as they are highly digestible ( Bell,
Tuck & Dobby, 2013 ).
A more promising tool for diet analysis, DNA metabarcoding, combines universal DNA
primers with high-throughput (next-generation) sequencing to identify a variety of species
from a mixture of gut content DNA ( Kress et al., 2015 ). A single universal primer pair has
the ability to amplify a diverse range of species by targeting a single gene region that has
been conserved among phylogenetically distinct taxa (e.g., the cytochrome oxidase I [COI]
region in the mitochondrial DNA or the 18S ribosomal RNA [rRNA] region in the nuclear
DNA; Aylagas et al., 2016 ). This molecular method has been successfully applied in diet
studies of a variety of lobster larvae and marine fish species ( O’Rorke et al., 2012 ; O’Rorke et
al., 2014 ; Berry et al., 2015 ; Harms-Tuohy, Schizas & Appeldoorn, 2016 ). One of the major
advantages of this method of gut analysis is that a high degree of taxonomic resolution
can be achieved, with the identification of individual species frequently possible. Also, the
digested or liquid gut content, which would normally be of no value for visual identification
of morphology, can provide additional dietary information that would otherwise have been
missed. The potential difficulties of this approach include the sequencing and labour costs,
the sensitivity of detection, and the taxonomic coverage of the reference sequence databases
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 2/25
at the time of study. These difficulties will likely fade as research progresses in this field
( Cowart et al., 2015 ; Srivathsan et al., 2016 ).
With sequencing cost and sensitivity being the major restrictions, it is in the best interest
of researchers to first address methodological issues before a full analysis is conducted,
in order to ensure the best possible results are obtained. One of the potential difficulties
in metabarcoding is polymerase chain reaction (PCR) inhibition, which has often been
found when using template genomic DNA extracted from biological material with a high
proportion of organic (i.e., bile salts) or inorganic (i.e., calcium ions) compounds, or
from body fluids or some difficult organs ( Rossen et al., 1992 ; Kreader, 1996 ; Rådström
et al., 2004 ; Farell & Alexandre, 2012 ; Schrader et al., 2012 ). Another matter to address
is determining which DNA polymerases are more susceptible to the effects of specific
PCR inhibitors present that impede DNA amplification ( Rådström et al., 2004 ). A third
potential problem is the taxonomic coverage and resolution possible from the different
reference sequences in the databases available, with some databases targeting different
genes or different organisms. Other sampling factors may also be important in determining
the success of metabarcoding for diet analysis. These include the preservation method
(e.g., frozen or in ethanol) and the location of the gut contents to be analysed (from the
foregut or hindgut), with the potential for these two locations to provide different results
due either to the state of DNA degradation or the differences in timing of intake and
digestive processing of dietary items.
The natural diet of M . challengeri is largely unknown, despite forming the basis of an
important commercial fishery in New Zealand, and currently being of some interest for
aquaculture development. The goal of this study is to provide a preliminary examination
of the natural diet of this species using metabarcoding methods, by firstly addressing
the optimisation of selected methodological factors, including issues of tissue choice and
preservation, target gene, PCR inhibition, PCR reagents and reference database coverage.
MA TERIALS & METHODS
Sample collection and locations
Samples of M . challengeri were collected in September of 2016 from the seafloor of the
Chatham Rise, New Zealand, at depths ranging from 200–500 m from the R.V. Kaharoa
by towing benthic trawl nets with a 45 mm cod-end. Upon landing the trawl on the deck,
the M . challengeri that were intact were euthanized by immersing them in chilled 95%
ethanol as soon as possible to avoid any degradation. The samples were transferred to the
University of Auckland’s laboratories (Auckland, New Zealand) for further examination.
A single trawl location (start − 42.9952 ◦ , 177.2367 ◦ at a depth of 322 m; end − 43.0210 ◦ ,
177.1800 ◦ at a depth of 252 m) and the individuals collected there were selected for the
purpose of this study. For comparison, frozen individuals of commercially harvested M .
challengeri were supplied by Sanford Ltd (Auckland, New Zealand) that were collected from
the seafloor using a benthic trawl on the continental shelf off New Zealand’s Auckland
Islands (the trawl took place within a quadrant: corner A − 49.0 ◦ , 168.5 ◦ ; corner B − 51.5 ◦ ,
168.5 ◦ ; corner C − 52.0 ◦ , 164.5 ◦ ; corner D − 49.0 ◦ , 164.5 ◦ ) and snap frozen immediately
after collection.
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 3/25
A special permit (#549) for M . challengeri collection was provided by New Zealand’s Min-
istry of Primary Industries. The specimens for this study were collected in accordance with
approvals under New Zealand’s Animal Welfare Act 1991 approved by the Animal Ethics
Committee of the Nelson, Marlborough Institute of Technology (AEC2014-CAW-02).
Specimen dissection, gut content removal and DNA e xtraction
The ethanol preserved individuals were placed on a paper towel to remove the excess
ethanol, and the frozen individuals were thawed at room temperature until each individual’s
gut contents could be removed separately. Sterile dissection kits were used for each
collection of M . challengeri (frozen and ethanol) and the dissection tools were thoroughly
cleaned between every individual in each collection; as well as between every individual’s
hindgut and foregut digesta removal. The gut digesta remained separated throughout the
extraction process for each individual, and were placed into separate 1.5 mL microcentrifuge
tubes, prior to DNA extraction.
A close microscopic examination of samples of digesta found an almost complete
absence of gut items that were sufficiently visually recognisable for them to be reliably
assigned to taxa.
Three individuals that contained a large quantity of foregut contents were each
mixed independently by vortexing briefly before subsamples of each were taken to be
extracted using each of the following DNA extraction kits by following the manufacturers’
instructions; Gentra R
Puregene R
Tissue Kit (Qiagen R
, Hilden, Germany), E.Z.N.A. R
Mollusc DNA Kit (OMEGA Bio-tek, Inc., Georgia, USA), DNeasy R
Tissue and Blood
Kit (Qiagen R
), and Mo Bio’s Powerbiofilm R
DNA Isolation Kit (now Qiagen R
DNeasy
PowerBiofilm Kit). The concentration of recovered DNA was measured for each using the
NanoPhotometer R
N60 (Implen, Munich, Germany; Table S1 ). Comparisons of the DNA
integrity revealed the Gentra R
Puregene R
Tissue Kit had superior DNA recovery and was
used for subsequent DNA extraction of all M . challengeri gut samples.
Primer selection and PCR protocol
Two universal primer pairs were identified and selected from the literature: mlCOIintF
( Leray et al., 2013 ) and jgHCO2198 ( Geller et al., 2013 ) targeting a 313 base pair (bp) region
of the mitochondrial COI gene, and Uni18SF and Uni18SR ( Zhan et al., 2013 ) targeting a
425 bp region of the nuclear 18S rRNA V4 variable region. All primers included Illumina
Nextera TM library transposase adapters ( Table 1 ). Primers to block the amplification of
host DNA were not used, as previous related work on lobsters ( O’Rorke et al., 2012 ; O’Rorke
et al., 2014 ) had shown that they also block amplification of related crustaceans, which
could be an important part of the diet of M . challengeri .
After preliminary trials of a variety of DNA polymerases and buffer mixes, two were
tested extensively, Platinum Taq (Invitrogen TM , Thermo Fisher Scientific Inc., Waltham,
MA, USA; Table S2 ) and the MyTaq TM Red Mix (Bioline, London, UK; Table S3 ). The
PCR temperature profile was optimised to provide the best amplification for both the COI
and 18S primers ( Fig. S1 ). Each PCR cycle included a negative control (no DNA added) to
check PCR reagents were not contaminated. The PCR products were run on 1.6% agarose
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 4/25
Table 1 Universal primer pairs used to target the selected regions of the COI and 18S genes. The COI primers, mlCOIintF and jgHCO2198,
target a 313 base pair (bp) region. The 18S rRNA primers, Uni18SF and Uni18SR, target a 425 bp V4 variable region. Illumina Nextera TM library
adapters (NexAd) have been added to the primers and are underlined.
Primer Name Target Sequence (adapters underlined) GC%
mlCOIintF_NexAd (Forward) COI 313 bp region 5 0 TCG TCG GCA GCG TCA GAT GTG TAT AAG AGA CAG
GGW ACW GGW TGA ACW GTW TAY CCY CC 3 0
48.3
jgHCO2198_NexAd (Reverse) COI 313 bp region 5 0 GTC TCG TGG GCT CGG AGA TGT GTA TAA GAG ACA
G TA IAC YTC IGG RTG ICC RAA RAA YCA 3 0
42.6
Uni18SF_NexAd (Forward) 18S V4 425 bp region 5 0 TCG TCG GCA GCG TCA GAT GTG TAT AAG AGA CAG
AGG GCA AKY CTG GTG CCA GC 3 0
54.7
Uni18SR_NexAd (Reverse) 18S V4 425 bp region 5 0 GTC TCG TGG GCT CGG AGA TGT GTA TAA GAG ACA
G GR CGG TAT CTR ATC GYC TT 3 0
49.1
gel and viewed in a Gel Doc TM XR+ (Bio-Rad Laboratories Inc., California, USA). The
PCR products were visualised using Gel Red R
(Biotium, Fremont, CA, USA).
The effect of both genomic DNA template concentration and BSA concentration were
tested to try to reduce PCR inhibition. BSA (1%) was tested with volumes of 1 µ l, 2 µ l and
5 µ l per 25 µ l reaction. A range of different DNA dilutions (1:10, 1:50 and 1:100) were also
tested.
Inconsistent PCR amplification of both genes was observed in the gut content samples,
but not from muscle DNA extracts from the same individuals, likely due to the presence of
PCR inhibitors. To test the effects of the presumed PCR inhibitors, gut content template
DNA (1 µ l) was added to tail muscle template DNA (1 µ l of 10 ng µ l − 1 ) in the standard
PCRs. Each individual was tested in three replicate PCRs.
DNA metabarcoding and analyses
Selection of individuals for metabarcoding
The PCR products for sequencing were selected from six individuals (70.2, 70.3, 70.9, Fro1,
Fro2 and Fro3), as they provided consistent and strong amplifications for COI and/or 18S
genes. The PCR products encompassed the range of methodological factors that were to
be addressed ( Table 2 ). Individual 70.9 was used for comparison of the PCRs to determine
which DNA polymerase and buffer mix was better (i.e., samples 1 and 2 versus 3 and 4).
Preliminary data suggested the Platinum Taq reactions were inferior, so the remainder
of the comparisons focussed on the Bioline reactions. The taxa that were identified from
the digesta of the foregut and the hindgut were compared for the individuals 70.2 and
70.9 (i.e., samples 1 and 5 versus 2 and 6) to identify if the hindgut digesta could provide
useful additional information about the diet, i.e., successive meals may be represented in
the hindgut contents. The ethanol and frozen preservation methods were compared using
the 18S sequences for three individuals each (i.e., samples 1, 2, 5, 6 and 7 versus 8 and 9),
to assess the effects (if any) of differential DNA degradation of the digesta. All individuals
were used for the comparison of the database identifications for the COI and 18S genes
and thus a preliminary analysis of the diet was evaluated. Potential diet false positives were
identified by evaluating the DNA negative.
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 5/25
Table 2 DNA metabarcoding samples, comprised of six individuals and one DNA negative control
(Fro1 and Fro2 are two individuals).
Sample Individuals Digesta source PCR reagent Preservation Gene region
1 70.9 Hindgut Bioline Ethanol COI & 18S
2 70.9 Foregut Bioline Ethanol COI & 18S
3 70.9 Hindgut Platinum Taq Ethanol COI & 18S
4 70.9 Foregut Platinum Taq Ethanol COI & 18S
5 70.2 Hindgut Bioline Ethanol COI & 18S
6 70.2 Foregut Bioline Ethanol COI & 18S
7 70.3 Foregut Bioline Ethanol COI & 18S
8 Fro1 & Fro 2 Foregut Bioline Frozen 18S
9 Fro3 Foregut and Hindgut Bioline Frozen COI & 18S
10 DNA Negative NA Bioline NA COI & 18S
DNA purification and pooling of selected samples
NucleoSpin R
Gel and PCR Clean-up (Macherey-Nagel, Düren, Germany) was used
according to manufacturer’s instructions to purify the PCR products and remove fragments
of less than 164 bp in length for all selected individuals. The amplified DNA concentration
of those products was determined using Qubit TM dsDNA HS Assay Kit (Invitrogen TM ,
Thermo Fisher Scientific Inc.) following the manufacturer’s protocol.
The purified COI and 18S PCR products from each sample were pooled and brought to
equal molarity where possible. Sequencing was done through New Zealand Genomics Ltd
(Auckland, New Zealand) at Massey University (Palmerston North, New Zealand) where
indexing occurred using the Nextera TM DNA library Prep Kit (Illumina, San Diego, CA,
USA) before sequencing on an Illumina MiSeq TM System (2 × 250 pair-end protocol).
Metabarcoding protocol
The raw Illumina sequences were analysed through the New Zealand eScience Infrastructure
(NeSI; Auckland, New Zealand) high performance computing (HPC) facility. The resulting
Illumina metabarcoding sequenced reads were processed by firstly removing the primers
(no mismatch tolerated) using fastq-multx (version 1.3.1) and by pairing the reads with
SolexaQA++. Low quality 3 0 end sequences (Phred scores below 3) were truncated and
reads merged using the sequence analysis tool VSEARCH version 2.3.0 ( Rognes et al.,
2016 ), allowing a maximum of five non-matching nucleotides in the overlap region.
Merged reads were quality filtered on the expected error value (<1) and dereplicated.
Chimera checking and removal was performed on the dereplicated sequences with the
QIIME package ( Caporaso et al., 2010 ) based on the de novo and reference based methods
of Usearch61 ( Edgar, 2010 ). Reference based chimera detection of 18S was performed with
the largest curated database available (SILVA; Quast et al., 2013 ) and for COI, using the
Midori database ( Machida et al., 2017 ). The cleaned reads ( Table S4 ) were clustered into
OTUs with the Swarm methodology (clustering threshold of d2; Mahé et al., 2014 ).
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 6/25
Sequence assignment and analysis
Representative OTU sequences (seed sequence of each OTU) were taxonomically assigned
with the Ribosomal Database Project (RDP) classifier (minimum confidence level of 80%;
Wang et al., 2007 ) using the curated databases Protist Ribosomal Reference (PR2; Guillou
et al., 2013 ) and SILVA for 18S, and Midori database for COI. Representative sequences
were also assigned to reference sequences from the National Center for Biotechnology
Information (NCBI) Genbank database ( Benson et al., 2013 ), using the megablast option of
BLASTn ( Morgulis et al., 2008 ) with an e-value threshold of 0.001. Only the best hit for each
sequence was kept. NCBI Genbank is an all-inclusive database and thus was used for both
the 18S gene sequences and COI gene sequences, however, sequences were only assigned to
a taxon if the sequence could be assigned to a genus or species. NCBI Genbank is also not
a curated database. The Midori database is specifically for metazoan mitochondrial DNA
sequences. The PR2 database consists mainly of nuclear-encoded protistan sequences,
and SILVA is an aligned database of small and large subunit rRNA genes. Taxonomically
assigned OTUs were filtered for potential PCR or sequencing artefacts by selecting OTUs
with five or more sequence reads (‘‘hits’’). The resulting filtered OTUs for COI were then
further refined to keep only the OTUs that could be identified to either a genus or species
level by Midori and the NCBI databases. The same was done for 18S with PR2, SILVA and
NCBI. The resulting data for genus or species were used for assessing the methodological
factors and preliminary diet which was analysed using Rstudio R
( R Core Team, 2017 ) and
the collection of R packages in tidyverse ( Wickham, 2017 ).
To determine a list of identified taxa that were most likely to form part of the true diet
of M . challengeri , taxa identified as contamination were removed from the final data. Any
sequence reads identified as lobster (Astacidea) were presumed to be host contamination
and removed. Sequence reads were also removed from further analysis if they matched to
any taxa identified from the sequenced DNA negative sample, or to any taxa that could not
be part of the M . challengeri diet (e.g., terrestrial species). The final ‘‘hit counts’’ pertaining
to digesta are referred to as ‘‘diet hit counts’’.
Taxa were defined as ‘‘exclusive’’ if they were identified in only a single source, such as
taxa identified in the foregut digesta but not in the hindgut digesta, or solely identified in
one PCR but not another.
RESUL TS
Factors affecting PCR amplification success
Several important factors were identified that affected PCR amplification success prior
to metabarcoding. These factors included PCR inhibition (and its reduction with BSA),
optimal template DNA dilution, PCR reagents (particularly the DNA polymerase and
buffer), and the success of amplification of different target genes (18S and COI). The
success of the PCRs was determined by the presence and intensity of an appropriately-sized
fragment on an agarose gel.
The sample DNA concentrations had a wide range (selected individuals ranged from
1.4–290.3 ng µ l − 1 ) and, overall, had relatively poor purity ratios (as measured by A260:A280
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 7/25
ratios; Table S5 ). PCR inhibition was minimised (visible increase in DNA amplification
on agarose gel) when an optimal volume of 2 µ l of 1% BSA was used in each 25 µ l
PCR, with some beneficial effect when using 1 µ l or 5 µ l of 1% BSA. PCR inhibition was
found to occur inconsistently at a range of DNA concentrations, even with the addition of
BSA. The inhibitory effect of the DNA extracted from gut material was demonstrated when
amplifying both genes with DNA extracted from tail muscle tissue. PCR amplification from
muscle DNA alone was usually strong, whereas PCR amplification was often dramatically
reduced when DNA extracted from the gut (digesta DNA) was added. Amplification
from digesta DNA was often very inconsistent between PCR replicates. Different dilutions
of template DNA (1:10, 1:50 and 1:100) were also tested in an attempt to reduce PCR
inhibition and provide optimal DNA amplification at the concentration best suited to the
conditions of the individual sample, with the 1:10 dilution proving to result in the strongest
DNA amplification overall.
Two different sets of PCR reagents (which differed primarily in their DNA polymerase
and buffer) were compared. The Bioline reaction was generally more reliable in DNA
amplification, as not only was the intensity of the products generally greater, but the
digesta DNA was more likely to produce PCR products for both the COI gene and 18S
gene.
When comparing PCR amplification of the two target genes from digesta DNA, in
general the COI gene did not amplify as well as the 18S. For several individuals, no PCR
products were seen for the COI gene, while for the same DNA, the 18S gene amplified well.
In addition, DNA from hindgut contents amplified more readily than DNA extracted from
the foregut contents.
Factors affecting metabarcode sequencing results
PCR reagents (DNA polymerase and buffer)
A comparison between the Platinum Taq and the Bioline PCR reagents was made for
individual 70.9, for which both sets of reagents were used ( Table 2 ). Metabarcode sequences
from both foregut and hindgut digesta were pooled for each set of reagents (thus comparing
samples 1 and 2 with 3 and 4). The total number of taxa identified and the total number
of exclusive taxa identified (i.e., those found only in one category) was greater for both
the COI and 18S genes when using the Bioline reaction (11 different taxa in total and six
exclusive taxa), compared to the Platinum Taq reaction (six different taxa identified and
one exclusive taxon; Table 3 ). The total diet hit count (number of sequence reads matching
a potential dietary reference sequence in that database—i.e., excluding host matches) was
also greater for the Bioline reaction.
Five of the taxa identified by Platinum Taq were a subset of those found in Bioline,
which had a low summed hit count of 55 compared to Bioline’s 468 hit count for the same
taxa. Moreover, Bioline identified a higher number of exclusive taxa which averaged a hit
count of ∼ 32 hits per taxa whereas Platinum Taq only identified one exclusive taxon with
a hit count of 13.
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 8/25
Table 3 A comparison of the number of assigned diet taxa using the Bioline and the Platinum Taq re-
actions. The taxa identified in each of the reactions pertain to diet taxa, therefore taxa identified as lob-
ster (Astacidea), matching the DNA negative sample or identified as terrestrial were removed. The ‘diet hit
count’ refers to the number of sequence reads matching a potential dietary reference sequences (identified
as diet taxa) in the databases. The ‘exclusive taxa’ are those taxa found only in one category i.e., in the Bio-
line reaction but not in the Platinum Taq reaction.
Taxa identified in
the Bioline reaction
(diet hit count)
Taxa identified in the
Platinum Taq reaction
(diet hit count)
Midori/NCBI (COI) 9 (648) 5 (62)
NCBI/PR2/SILVA (18S) 2 (10) 1 (6)
Total taxa 11 (658) 6 (68)
Total exclusive taxa 6 (190) 1 (13)
Table 4 A comparison of the total and exclusive diet taxa identified in the foregut and hindgut digesta. The taxa identified in each of the re-
actions pertain to diet taxa, therefore taxa identified as lobster (Astacidea), matching the DNA negative sample or identified as terrestrial were re-
moved. The ‘diet hit count’ refers to the number of sequence reads matching a potential dietary reference sequences (identified as diet taxa) in the
databases. The ‘exclusive taxa’ are those taxa found only in one category i.e., in the foregut digesta but not in the hindgut digesta.
Database Total taxa identified
(diet hit count)
in the foregut digesta
Total taxa identified
(diet hit count)
in the hindgut digesta
Exclusive taxa
identified
in the foregut digesta
Exclusive taxa
identified
in the hindgut digesta
Midori/NCBI (COI) 3 (448) 12 (274) 2 11
NCBI/PR2/ SILVA (18S) 14 (736) 2 (14) 13 1
Foregut versus hindgut digesta
The taxa identified from the hindgut and foregut digesta of two individuals were compared
(i.e., samples 1 and 5 versus 2 and 6). The hindgut digesta contained a higher number of
both total taxa and exclusive taxa compared to the foregut digesta, when the sequences were
matched to the COI gene databases ( Table 4 ). Conversely, the foregut digesta contained a
higher number of total taxa and exclusive taxa with the 18S gene databases ( Table 4 ).
Sample preservation method
The effects of potential differential DNA degradation due to the method of preservation
were more difficult to assess directly, as the same individuals could not be compared across
the two conditions, and the comparison was somewhat confounded by being collected
in different locations. Instead, broad comparisons were made between the pooled results
from the three individuals preserved for each of the ethanol and frozen methods. Firstly,
the potential differential effects on preservation of diet DNA was assessed by calculating
the diet hit count as a percentage of the overall hit count (for samples 1, 2, 5, 6 and 7 versus
8 and 9; Table 5 ). No difference was seen between the ethanol and frozen individuals for
the 18S results, as both had a diet hit count percentage of 1% (Fro3 was the only frozen
individual to have any diet hit counts; Table S6 ).
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 9/25
Table 5 A comparison of the digesta amplification, using the 18S gene region, from ethanol and frozen
preserved individuals. The ‘genus/species hit count’ refers to the number of sequence reads that matched
a high degree of taxonomic resolution (genus and/or species level) from the 18S databases (NCBI, PR2
and SILVA). The ‘diet hit count’ refers to the number of sequence reads matching potential dietary refer-
ence sequences in the databases. The ‘diet hit count (%)’ is the percentage of the ‘diet hit count’ out of the
total ‘genus/species hit count’.
Preservation Genus/species
hit count
Diet hit count Diet hit count
(%)
Ethanol 165,566 2,028 1
Frozen 94,218 902 1
Figure 1 Taxa identified from the diet of M. challengeri using the Midori and NCBI databases for the
COI sequences.
Full-size DOI: 10.7717/peerj.5641/fig-1
Database comparison and preliminary assessment of M. challengeri
diet
All individuals and their digesta amplified using Bioline were used to provide a preliminary
assessment of the diet of M . challengeri . A total of 13,541 sequences were used to analyse
the diet: 22 taxa were identified from 10,611 COI sequences, and 25 taxa from 2,930
18S sequences. Among the 22 taxa identified from the COI databases were seven fish
taxa ( Epinephelus epistictus , Helicolenus barathri, Hydrolagus novaezealandiae , Macruronus
magellanicus , Notophycis marginata , Seriolella punctata and Thyrsites atun ), crab taxa
( Neosarmatium fourmanoiri , Microphrys branchialis and Homola sp.), a marine worm
( Laonice cirrata ) and an anemone ( Diadumene leucolena ) ( Fig. 1 ; Tables S7 and S8 ). The
18S databases identified 25 taxa, which included a sea pen ( Umbellula sp.), salps ( Pyrosoma
sp. and Ihlea racovitzai ) and many parasites (i.e., apicomplexan Eimeria variabilis and
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 10/25
Figure 2 Taxa identified from the diet of M. challengeri using the PR2, SILVA and NCBI databases for
the 18S sequences.
Full-size DOI: 10.7717/peerj.5641/fig-2
dinoflagellate Duboscquella ) ( Fig. 2 ; Tables S9 and S10 ). There were no common taxa
identified between the reference databases when comparing 18S OTUs to COI OTUs.
DISCUSSION
Methodological issues in PCR amplification success
PCR inhibition
PCR inhibition is a substantial factor in this study. The spectrophotometer ratios of purity
provided initial indicators of the presence of inhibitors in the extracted DNA ( Watts, 2014 ).
An optimal volume of 2 µ l 1% BSA successfully reduced PCR inhibition by increasing the
amplification efficiency. An additional step effective in reducing PCR inhibition, was 1:10
dilution of the template genomic DNA, thus diluting the PCR inhibitors it presumably
contained.
The presence of organic compounds in the foregut (i.e., bile salts in the gastric juices)
is thought to be one of the main contributors to PCR inhibition which cannot always be
alleviated by BSA ( Lorenz, 2012 ; Schrader et al., 2012 ; Harms-Tuohy, Schizas & Appeldoorn,
2016 ). Bile salts often found in vertebrate gastric juices, are similar to an organic compound
in crustaceans such as crabs, lobsters and crayfish, and suggests why BSA is not an alleviator
in all DNA amplifications tested in this study ( Borgström, 1974 ). Different diets would also
affect the secretion of the gastric juices, which may play a role in determining which PCR
inhibitors are present and in what concentration in different parts of the gut ( Rotllant et al.,
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 11/25
2014 ). This demonstrates the problematic, high levels of PCR inhibition present in many
genomic DNA extracts, and its influence on successfully amplifying gut content DNA.
Increased quantitative monitoring of the PCR success, such as by utilising quantitative
PCR, may be required in future.
One solution to PCR inhibition may be to pool replicate PCR products together. Another
is the addition of the T4 gene 32 protein (gp32), which can be effective against inhibitors
for which BSA is not, such as sodium dodecyl sulfate (SDS), sodium chloride and bile salts
( Schrader et al., 2012 ).
PCR reagents (DNA polymerase and buffer)
Different DNA polymerases and buffers are available and are two of the key reagents
for DNA amplification, each being susceptible to various components in the biological
environment in which they amplify, thus affecting their performance ( Rådström et al., 2004 ;
Wolffs et al., 2004 ). A substantial difference could be seen visually in the DNA amplification
when using the Bioline reaction compared to the Platinum Taq reaction. The Platinum Taq
reaction appeared to be more susceptible to the effects of PCR inhibitors, and the DNA
amplification was not as effective as in the Bioline reaction.
Amplification of the loci
The 18S gene region ( ∼ 425 bp), in general, amplified more successfully compared to the
COI gene region ( ∼ 313 bp) targeted here. It is not common for shorter gene fragments
to be more difficult to amplify, but it is relatively common to see some difficulties in
amplification of the COI gene in some species, likely due to the greater sequence variation
in the primer annealing sites ( Chen, Jiang & Qiao, 2012 ; Lv et al., 2014 ). However, when
both genes amplified, their PCR product intensity appeared consistent between sample
conditions, i.e., if the PCR product was more intense for the foregut digesta for the 18S
gene the same would be seen for the COI gene in the same individual.
Methodological issues in metabarcoding success
PCR reagents (DNA polymerase and buffer)
Visualization of the PCR amplification can only suggest if amplification is occurring and not
necessarily what the quality of amplification is. So although it was visually determined that
the Bioline reaction generally resulted in stronger PCR amplifications, it was possible that
it was amplifying only a subset of the possible templates compared to that of the Platinum
Taq reaction. Individual 70.9 amplified equally well for both the Platinum Taq and Bioline
reactions, and also for both the hindgut and foregut digesta. The DNA sequencing revealed
that the Bioline reaction amplified a higher number of taxa from the same individual’s gut
content DNA.
This was likely due to a higher tolerance of PCR inhibitors from the DNA polymerase
and buffer in Bioline. This is suggested by the shared taxa, as Bioline (hit count 468)
amplified approximately nine times more diet fragments than Platinum Taq (hit count
55). The six exclusive taxa, presumed to have the lower DNA concentrations, identified
by Bioline have ∼ 32 hit counts per exclusive taxon, whereas, Platinum Taq only identified
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 12/25
one exclusive taxon with a hit count of 13, thus indicating that the Bioline reaction appears
to be more efficient at amplifying DNA from the digesta of M . challengeri .
Foregut versus hindgut digesta
The examination of both the foregut and hindgut digesta provided a broader overview of
the diet of M . challengeri . There was an increase in the number of taxa when the entire
gut digesta was used, compared to using digesta from only the hindgut or the foregut.
As ingested food takes a few hours to pass through the foregut and into the hindgut,
the examination of the digesta from both may permit the assessment of successive meals
over a broader time period before capture, or differences in gut transit times for different
dietary items ( Simon & Jeffs, 2008 ; Lee, Hartstein & Jeffs, 2015 ; Kamio et al., 2016 ). Also, as
the chemical environment (i.e., pH) and degree of degradation of digesta differ between
the gut sections, an assessment of both foregut and hindgut digesta appears to maximise
the opportunity to detect the widest possible breadth of diet per individual.
It was initially expected that the hindgut contents may provide lower quality sequencing
results, because it was more difficult to eliminate host tissue contamination during
dissection, the more advanced state of degradation of the food, and the higher ratio of
sediment to dietary items. However, a higher number of taxa of smaller marine organisms
(i.e., dinoflagellates) were identified in the foregut digesta than in the hindgut digesta, and
a higher number of taxa of larger marine organisms (i.e., mostly fish) were identified in
the hindgut digesta than in the foregut digesta. Thus, to dismiss sampling from either the
foregut or the hindgut digesta would have narrowed the number of taxa that were able to
be identified.
Host contamination
In most metabarcoding studies of diet in predators, host contamination of the PCR
amplicons is an issue. However, the overall impact of host contamination can be reduced
by introducing several molecular techniques that will help decrease any biased amplification
of the host’s DNA, and may broaden the taxonomic analysis ( Polz & Cavanaugh, 1998 ;
Green & Minz, 2005 ; Vestheim & Jarman, 2008 ; Pompanon et al., 2012 ; Harms-Tuohy,
Schizas & Appeldoorn, 2016 ; Devloo-Delva et al., 2018 ). PCR ‘‘clamping’’, using additional
DNA or peptide nucleic acid (PNA) oligonucleotide primers to bind to, and inhibit PCR
amplification of host DNA, is a favoured method for suppressing host DNA amplification
in PCRs, and has been successful in diet studies ( Egholm et al., 1993 ; Orum et al., 1993 ;
Vestheim & Jarman, 2008 ; Chow et al., 2011 ; O’Rorke et al., 2012 ). In this study, PCR
clamping was not used, as previous research in lobsters had shown that it also restricted
amplification from related crustaceans, many of which could be potential prey of M .
challengeri. Other diet studies have also shown that the resulting sequences are sufficient to
describe the diet without the use of PCR clamping ( Piñol et al., 2014 ) and that there would
not necessarily be any significant increase in diversity if they were used ( Devloo-Delva et al.,
2018 ). The metabarcoding results showed that host DNA amplification did not completely
outcompete the amplification of prey DNA, and there were sufficient sequence reads to
identify a broad range of diet taxa.
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Preservation methods
The quality of DNA extracted from the digesta is affected by the state of degradation
due to the digestion rate in the gut ( Rådström et al., 2004 ; Deagle & Tollit, 2007 ; Troedsson
et al., 2009 ). As the two different preservation methods used would have different rates
in which the digesta was preserved, it was thought that one method may provide better
preservation of digesta than the other. Determining which preservation method, frozen
or ethanol, is better was relatively problematic to assess, due to the relatively high level
of inter-individual variation and the confounded nature of the sample collection. Due to
logistic constraints on the field sampling, different preservation methods could only be
undertaken on different individuals taken from different locations.
The diet hit count percentage from the 18S databases were both ∼ 1% for ethanol and
frozen individuals. Although not a particularly robust test due to sample size, it may suggest
that both the frozen and ethanol preservation methods are similarly dependable.
Amplification of the loci and database review
Although there were difficulties in gaining equal success in the DNA amplification from
both genes, together they provided a much broader overview of M . challengeri diet at the
highest resolution possible.
The 18S gene and the COI gene identified a variety of taxa ( Figs. 1 and 2 ). The COI
gene is more commonly used than the 18S gene in studies of molecular taxonomy of
large eukaryotes and is one of the pillars of DNA barcoding, making it a sought-after gene
region for the discrimination of closely related Metazoan species ( Hebert, Ratnasingham
& DeWaard, 2003 ; Derycke et al., 2010 ; Tang et al., 2012 ). The 18S gene is more frequently
used in molecular taxonomic studies for microbial organisms (i.e., micro-plankton and
parasites; Wu, Xiong & Yu, 2015 ).
Using a combination of databases to identify the OTUs, from a selected gene, to genus
or species level proved invaluable; where the curated databases (Midori, PR2 and SILVA)
could not provide a high resolution identification (i.e., only to order or family), NCBI was
usually able to. Also, targeting two genes has allowed for a more inclusive capture of the
different taxonomic groups because of the more complete coverage from distinct reference
databases. For further analyses of the diet of M . challengeri both genes should be used, as
this lobster, being relatively small in size, appears to take advantage of the availability of
both large and small prey, both dead and alive.
Preliminary assessment of M. challengeri diet
This study undertook the first assessment of M . challengeri diet using DNA metabarcoding
methods. Although this study investigated only a small number of individuals in this
preliminary analysis, it has already provided a fascinating snapshot of their diet, confirming
some previous expectations, and providing a broader understanding of their feeding
ecology.
The components of the diet were identified at a much finer taxonomic level than
any other previous studies undertaken microscopically on any Metanephrops species.
The diets previously determined microscopically are at a poor taxonomic resolution,
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 14/25
and included crustaceans, fish, annelids and bivalves ( Choi et al., 2008 ; Sahlmann, Chan &
Chan, 2011 ; Wahle et al., 2012 ). Metanephrops challengeri are thought to be benthic foragers
and scavengers, relying heavily on chemosensory detection of potential food items ( Major
& Jeffs, 2017 ). They are likely to be scavengers of fish remains whether it is from trawl
debris, sunken carcasses or faeces, as well as foraging for smaller dietary items such as sea
pens. Using metabarcoding methods on digesta also allowed identification of parasites
that are either from the diet source or from M . challengeri individuals sampled. Below,
we examine some of the most interesting and prominent taxa identified in the diet of M .
challengeri , and suggest likely species identifications for those taxa not classified to species
or those whose counterparts are more likely to be the closest match.
Metanephrops challengeri have been reported to reside at a depth ranging from 140–640 m
( Holthuis, 1991 ). Diet taxa were closely matched to several common fish species that reside
within this depth range on the Chatham Rise, including H. novaezealandiae (ghost shark),
N. marginata (dwarf codling), S. punctata (silver warehou) and T. atun (snoek) ( Francis,
1998 ; Ministry for Primary Industries, 2006b ; Ministry for Primary Industries, 2006a ; Luna,
2008 ; Ministry for Primary Industries, 2008 ; Priede, 2017 ). The OTU identified as M.
magellanicus is likely instead to be Macruronus novaezelandiae (New Zealand hoki), as M.
magellanicus is located off the southern coast of Chile and Argentina and M. novazealandiae
is located in the Chatham Rise at depths from 209–904 m ( D’Amato, 2006 ; Connell, Dunn &
Forman, 2010 ; Kobayashi, Mizuguchi & Matsuoka, 2014 ). The OTU identified as H. barathri
(sea perch) is likely to be Helicolenus percoides, a sea perch (Scorpaenidae) found at depths
between 250–700 m in the Chatham Rise ( Anderson et al., 1998 ; Horn, Forman & Dunn,
2012 ). Epinephelus epistictus (grouper) is another OTU that probably belongs instead to
its sibling species found in New Zealand waters at the appropriate depth, Epinephelus
octofasciatus .
The only sea pen to be identified in the COI databases, Funiculina quadrangularis , is
a common tall deep-sea sea pen that grows on muddy substrates and has been found
between 20–2,000 m in New Zealand waters ( Hughes, 1998 ). Umbellula sp. is a sea pen taxa
identified by the 18S databases and has a world-wide distribution in depths 200–6,260 m
( Williams, 1995 ; Williams, Tracey & Mackay, 2014 ).
There are several OTUs identified as belonging to the Brachyuran crabs. Many families
of this infraorder occur in New Zealand waters in the area of the Chatham Rise ( Wilkens
& Ahyong, 2015 ), but it is not possible at this stage to identify the OTUs to their likely
species from this region. OTUs identified to species in this infraorder include M. branchialis
(Majidae, spider crabs—12 species found on the Chatham Rise, according to the Ocean
Biogeographic Information System ( http://www.iobis.org ; OBIS, 2017 ), and N. fourmanoiri
(Grapsidae), although none are known to be found in New Zealand. It is likely that these
OTUs belong to genetically similar species that exist at the depth in which M . challengeri
are found on the Chatham Rise. The Homola sp. may be Homola orientalis , as this crab is
known to be distributed in New Zealand waters, living at depths of 500 m ( Eldredge, 1980 ).
The marine polychaete OTU was identified as L. cirrata , but this species has not been
found in New Zealand waters, and it is likely to be DNA signal from a closely related
benthic worm species. Numerous plankton were identified, such as the deep-water salp, I.
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 15/25
racovitzai (tunicate), which can grow to over 20 mm in diameter and are an appropriate
size for M . challengeri to handle with their feeding appendages ( Pakhomov et al., 2011 ).
This species is known to more commonly occur in the high Antarctic cold-water zone,
but has been found to occur in waters south of Australia ( Casareto & Nemoto, 1986 ;
Pakhomov et al., 2011 ; Ono & Moteki, 2013 ). Ebria tripartita (Rhizaria) has been reported
world-wide, has oval cells 21–35 µ m in length and 13–25 µ m in width, and is likely to be
consumed unintentionally due to their size ( Tong et al., 1998 ). It is known to be a grazer
of phytoplankton (nanoplanktonic diatoms and dinoflagellates) and has been reported in
the Hauraki Gulf, New Zealand ( Gordon et al., 2012 ).
It is noticeable that no molluscs were detected, which may be due to more rapid
degradation of their soft tissues ( Bell, Tuck & Dobby, 2013 ). It will be interesting to examine
the ratios of OTU hit counts across a larger number of individuals from several locations.
At present it is impossible to entirely differentiate between OTUs that were directly
consumed by M . challengeri , and those that were consumed by their prey, i.e., secondary
predation. However, it is expected that, due to rapid decomposition, secondary predation
is likely to account for only a very small proportion of the taxa detected in M . challengeri
digesta. It also cannot be dismissed that M . challengeri may be cannibalistic, but for the
purpose of this study sequences identified as lobsters were removed from the diet data and
considered as host contamination.
The parasites that have been identified are likely to be residing either within the gut of
M . challengeri or within the individuals that were consumed. Parasites known to infect
fish were identified, such as Eimeria percae which is known to parasitize the European
perch, Perca fluviatilis ( Molnár et al., 2012 ). Syndiniales Dino-Group I and II are known
to parasitize a variety of marine organisms, including crustaceans ( Guillou et al., 2010 ).
Previous studies of gut contents of lobster larvae using DNA methods have also identified
a range of microscopic parasites suggesting they may be a common component of the gut
( O’Rorke et al., 2012 ; O’Rorke et al., 2015 ).
There was a small proportion of OTU sequences that were not matched to known
sequences in the databases and demonstrate the limitations of the reference databases. This
is largely due to the small amount of material from New Zealand deep-sea marine life that
has been sequenced and uploaded to the various databases. A possible short term solution
for the analysis of the diet would be to collect samples of bycatch species from the trawls,
identify them, extract their DNA and sequence the genes of interest. This would create a
database against which the diet sequences could be compared, potentially revealing more
specific matches or even assigning identities to unassigned sequences. Further insight into
the diet of M . challengeri will come with a greater number of individuals analysed. Data
on the availability of prey will be needed in order to determine diet preference, as relative
concentration in the diet may simply be related to what is more prevalent in their foraging
area.
CONCLUSION
Many methodological issues have been addressed in this study, which has provided solutions
for alleviating them, such as template DNA dilution and BSA addition for minimising PCR
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 16/25
inhibition. The study has also identified considerable variation in PCR inhibition among
individual samples, which indicates that it will be necessary to optimise PCR amplification
for each sample. The study has also determined the optimum PCR reagents (particularly
the DNA polymerase and buffer) and the benefit of using a selection of different databases
for assigning OTUs to taxa for different genes.
The preliminary insight from this study into the varied diet of M . challengeri provides a
foundation for both the production of a nutritional feed for aquaculture and an attractive
bait for fishery pots. However, further examination of the diet is clearly needed. Given the
variability among individuals, the minimum sample number that is analysed per collection
site should be of around 10 individuals that have a moderate amount of digesta for DNA
extraction. This will help in quantifying if M . challengeri have a diet preference and if it
is related to sex, size and/or location. A future study should also proceed in collecting
by-catch when M . challengeri are trawled, which will assist in determining prey availability,
and provide a more complete sequence reference DNA database for comparison. It is clear
that there is considerably more insight provided from identification using metabarcoding
than from traditional microscopic identification. A further benefit is the store of diet DNA
sequences that can be retained for future analysis (against updated reference databases),
whereas microscopy results cannot be further analysed. Overall, this study shows there is
great promise in analysing M . challengeri diet using metabarcoding methods.
ACKNOWLEDGEMENTS
We would like to thank Dr Ian Tuck (NIWA) and Mr Dean Stotter (NIWA) for providing
recorded information and access to samples. We thank the captain and crew of the R.V.
Kaharoa in facilitating the collection of the samples for this study. Lastly, thank you to
Andrew Stanley (Sanford) and Sophar Rach (Sanford) for assistance with the commercially
harvested samples.
ADDITIONAL INFORMA TION AND DECLARA TIONS
Funding
This study is part of ‘Ka Hao te Rangatahi: Revolutionary Potting Technologies and
Aquaculture for Scampi’ (CAWX1316) funded by the New Zealand Ministry of Business
Innovation and Employment. There was no additional external funding received for this
study. The funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Grant Disclosures
The following grant information was disclosed by the authors:
New Zealand Ministry of Business Innovation and Employment.
Competing Interests
The authors declare there are no competing interests.
van der Reis et al. (2018), PeerJ , DOI 10.7717/peerj.5641 17/25
Author Contributions
• Aimee L. van der Reis conceived and designed the experiments, performed the
experiments, analyzed the data, contributed reagents/materials/analysis tools, prepared
figures and/or tables, authored or reviewed drafts of the paper, approved the final draft.
• Olivier Laroche contributed reagents/materials/analysis tools, authored or reviewed
drafts of the paper, approved the final draft.
• Andrew G. Jeffs conceived and designed the experiments, contributed reagents/mate-
rials/analysis tools, authored or reviewed drafts of the paper, approved the final draft,
oversaw logistics and administration.
• Shane D. Lavery conceived and designed the experiments, contributed reagents/materi-
als/analysis tools, authored or reviewed drafts of the paper, approved the final draft.
Ethics
The following information was supplied relating to ethical approvals (i.e., approving body
and any reference numbers):
Specimens for this study were collected in accordance with approvals under New
Zealand’s Animal Welfare Act 1991. The transport and holding of the scampi, as well as the
experimental procedures, were approved by the Animal Ethics Committee of the Nelson
Marlborough Institute of Technology (AEC2014-CAW-02).
Field Study Permissions
The following information was supplied relating to field study approvals (i.e., approving
body and any reference numbers):
A special permit (#549) for M. challengeri collection was provided by New Zealand’s
Ministry of Primary Industries.
DNA Deposition
The following information was supplied regarding the deposition of DNA sequences:
The sequences of the scampi diet matching genus/species are available as Supplemental
Files ; Table S8 contains the COI sequences and Table S10 contains the 18S sequences.
Data Availability
The following information was supplied regarding data availability:
Figshare: https://doi.org/10.17608/k6.auckland.5928400 .
Supplemental Information
Supplemental information for this article can be found online at http://dx.doi.org/10.7717/
peerj.5641#supplemental-information .
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Supplementary resources (11)
Table S9
Data
September 2018
Aimee van der Reis · Olivier Laroche · Andrew Jeffs · Shane D. Lavery
Table S2
Data
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Table S10
Data
September 2018
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Table S4
Data
September 2018
Aimee van der Reis · Olivier Laroche · Andrew Jeffs · Shane D. Lavery
Table S3
Data
Aimee van der Reis · Olivier Laroche · Andrew Jeffs · Shane D. Lavery
Table S1
Data
Aimee van der Reis · Olivier Laroche · Andrew Jeffs · Shane D. Lavery
Table S8
Data
September 2018
Aimee van der Reis · Olivier Laroche · Andrew Jeffs · Shane D. Lavery
Table S7
Data
September 2018
Aimee van der Reis · Olivier Laroche · Andrew Jeffs · Shane D. Lavery
Table S6
Data
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Table S5
Data
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Figure S1
Data
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Aimee van der Reis · Olivier Laroche · Andrew Jeffs · Shane D. Lavery
... influence PCR amplification (van der
Reis et al., 2018)
. For more accurate identification and 335 quantification of diet components, the following strategies could be considered to overcome 336 DNA degradation and PCR inhibition: 1) DNA extraction protocols with tailored inhibition 337 removal steps(Sellers et al., 2018); 2) incorporation of alternative proteins to enhance PCR 338 amplification such as bovine serum albumin (BSA) or T4 gene 32 protein (gp32)(Schrader et al., 339 2012; van derReis et al., 2018); 3) performing a DNA repair procedure on genomic DNA 340 template to allow increased PCR amplification success(Ambers et al., 2014; Davidov et al., 341 2020) and 4) targeting a shorter fragment than the COI (313bp) such as the 18S rRNA V9 (~134 342 bp) to account for advanced digestion and DNA damage(Albaina et al., 2016). ...
... influence PCR amplification (van derReis et al., 2018). For more accurate identification and 335 quantification of diet components, the following strategies could be considered to overcome 336 DNA degradation and PCR inhibition: 1) DNA extraction protocols with tailored inhibition 337 removal steps(Sellers et al., 2018); 2) incorporation of alternative proteins to enhance PCR 338 amplification such as bovine serum albumin (BSA) or T4 gene 32 protein (gp32)(Schrader et al., 339 2012; van der
Reis et al., 2018)
; 3) performing a DNA repair procedure on genomic DNA 340 template to allow increased PCR amplification success(Ambers et al., 2014; Davidov et al., 341 2020) and 4) targeting a shorter fragment than the COI (313bp) such as the 18S rRNA V9 (~134 342 bp) to account for advanced digestion and DNA damage(Albaina et al., 2016). ...
DNA metabarcoding reveals the dietary profiles of a benthic marine crustacean, Nephrops norvegicus
Preprint
Full-text available
Dec 2022
Peter Shum
Janine Wäge-Recchioni
Graham S. Sellers
Domino A Joyce
Norwegian lobster, Nephrops norvegicus , are a generalist scavenger and predator capable of short foraging excursions but can also suspension feed. Existing knowledge about their diet relies on a combination of methods including morphology-based stomach content analysis and stable isotopes, which are time and experience costly and often lack the resolution to distinguish prey items to species level. DNA metabarcoding overcomes many of the challenges associated with traditional methods and it is an attractive approach to study the dietary profiles of animals. Here, we present the diet of the commercially valuable Nephrops norvegicus using DNA metabarcoding of gut contents. Despite difficulties associated with host amplification, our cytochrome oxidase I (COI) molecular assay successfully achieves higher resolution information than previously used traditional approaches. We detected taxa that were likely consumed during different feeding strategies. Dinoflagellata, Chlorophyta and Bacillariophyta accounted for almost 50% of the prey items consumed, and are associated with suspension feeding, while fish with high discard rates were detected which are linked to active foraging. In addition, we were able to characterise biodiversity patterns by considering Nephrops as natural samplers, as well as detecting parasitic dinoflagellates (e.g., Hematodinium sp.) in over 50% of the samples, which are known to influence burrow related behaviour in infected individuals. The metabarcoding data presented here greatly enhances a better understanding of a species' ecological role that can be applied as a routine procedure in future studies for proper consideration in the management and decision-making of fisheries.
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Show abstract
... However, the in situ and mesocosm experiments in our study provide strong evidence that eDNA is not reliably recovered from bivalve gill-tissue dissections. However, given the huge potential of incorporating bivalves into eDNA surveys, we recommend additional research to be undertaken to investigate if eDNA is accumulated in other tissues, such as the gastrointestinal tract, targeted in invertebrate diet metabarcoding analyses(Siegenthaler et al., 2019;
van der Reis et al., 2018;
Yeh et al., 2020). ...
Assessing the utility of marine filter feeders for environmental DNA (eDNA) biodiversity monitoring
Article
Jan 2023
MOL ECOL RESOUR
Gert-Jan Jeunen
Jasmine S Cane
Sara Ferreira
Miles D Lamare
Aquatic environmental DNA (eDNA) surveys are transforming how marine ecosystems are monitored. The time-consuming pre-processing step of active filtration, however, remains a bottleneck. Hence, new approaches that eliminate the need for active filtration are required. Filter-feeding invertebrates have been proven to collect eDNA, but side-by-side comparative studies to investigate the similarity between aquatic and filter-feeder eDNA signals are essential. Here, we investigated the differences among four eDNA sources (water; bivalve gill-tissue; sponges; and ethanol in which filter-feeding organisms were stored) along a vertically stratified transect in Doubtful Sound, New Zealand using three metabarcoding primer sets targeting fish and vertebrates. Combined, eDNA sources detected 59 vertebrates, while concurrent diver surveys observed eight fish species. There were no significant differences in alpha and beta diversity between water and sponge eDNA and both sources were highly correlated. Vertebrate eDNA was successfully extracted from the ethanol in which sponges were stored, although a reduced number of species were detected. Bivalve gill-tissue dissections, on the other hand, failed to reliably detect eDNA. Overall, our results show that vertebrate eDNA signals obtained from water samples and marine sponges are highly concordant. The strong similarity in eDNA signals demonstrates the potential of marine sponges as an additional tool for eDNA-based marine biodiversity surveys, by enabling the incorporation of larger sample numbers in eDNA surveys, reducing plastic waste, simplifying sample collection, and as a cost-efficient alternative. However, we note the importance to not detrimentally impact marine communities by, for example, non-lethal subsampling, specimen cloning, or using bycatch specimens.
... Furthermore, frequency of occurrence data obtained by this classical methodological approach can be strongly affected by level of detail during stomach content identification [67]. Recently, DNA metabarcoding has been successfully applied to dietary studies of economically important lobsters Panulirus cygnus [71], Jasus edwardsii [72] and Metanephrops challengeri
[73]
. Given the cryptic nature of investigated crab, a better understanding of its trophic interactions could be achieved by using DNA metabarcoding in future studies [74,75]. ...
Revealing the Shamefaced Crab Calappa granulata (Crustacea: Brachyura) from the Adriatic Sea, Northern Basin of the Mediterranean
Article
Full-text available
Dec 2022
Mirela Petrić
Marina Mihaljević
This study presents the first data on morphometry, length–weight relationship, diet, reproductive biology, epibionts and genetic identity of the shamefaced crab Calappa granulata from the central eastern Adriatic Sea. A total of 92 crabs were collected during 2011, 2014 and 2015, of which 64 were females and 28 were males. Overall, 11 morphometric characteristics were measured. Carapace length of sampled individuals ranged from 48.46 to 76.09 mm, and body weight from 47.06 to 221.39 g. The length–weight relationship showed negative allometry for males and isometric growth for females. Analysis of the stomach content revealed the crab’s preference for crustaceans (20.28%) and cephalopods (10.58%), less for fish (3.4%) and shellfish (0.28%). Size at first sexual maturity (CL50%) of 59.25 and 66.92 mm was estimated for males and females, respectively. Epibiotic serpulid polychaetes were recorded on the crab exoskeleton with an overall prevalence of 29.3%. Analyses of a partial sequence of mtCOI showed high haplotype (Hd = 0.964) and low nucleotide diversity (π = 0.00598). Phylogenetic inference and estimation of population differentiation (FST = 0.013, p = 0.271) with publicly available Mediterranean sequences currently imply one homogenous population unit. To the best of our knowledge, these are the first nucleotide sequences of C. granulata from the Adriatic Sea made publicly available.
... Typically, this method is used in large-scale species identification studies where the source material is composed of many species. This technique has been increasingly used in dietary studies where the primary samples are gut content, regurgitated and/or fecal matter (e.g., Berry et al., 2015;Carroll et al., 2019;De Barba et al., 2014;Kartzinel et al., 2015;Oehm et al., 2017;
van der Reis et al., 2018)
Nanopore short‐read sequencing: A quick, cost‐effective and accurate method for DNA metabarcoding
Dietary and predator–prey studies are more frequently relying on DNA metabarcoding methods, typically achieving results that have a better taxonomic resolution (e.g., species‐level) than previous methods. With the continuous advancement in sequencing technology, what was previously accessible only as a large, fixed structure in a laboratory, which had a limited number of users, has now advanced to a small and readily usable device. In this study, we used the gut (content and lining) from juvenile lanternfish (Hygophum) specimens to compare the short‐read sequencing capability of the portable Nanopore MinION with the Illumina MiSeq. Primers common in dietary DNA metabarcoding work (COI “Leray primers” and 18S rRNA V4 “Zhan primers”) were used, with an additional comparison of cost‐effective COI “Lobo primers” (targeting the same COI fragment) for the proficiency in species detection of a broad range of taxa. Our results indicate high congruency between sequencing machines for, not only taxonomic assignments, but also relative read abundance of the main dietary items. We also identified that Nanopore sequencing is more cost‐effective. The Lobo primers are comparable to that of Leray, but substantially reduce the primer set price without compromising detection of taxa. Using both COI and 18S broadened the taxonomic scope, providing greater prey detection. Overall, this preliminary study was successful in creating a foundation for future dietary work involving larvae and transformation stage fishes whereby the content of the gut need not be separated from the gut lining to detect prey. The Hygophum diet detected here aligns with previous research that suggests the main dietary items to be calanoid copepods, but using molecular methods, soft prey was more readily identified compared to studies using visual methods of identification of dietary items. Overall, this study found that Nanopore sequencing is suitable for short‐read DNA metabarcoding and can provide rapid access to sequencing results. Advances in sequencing technologies are revolutionising studies of animal diets and resolving complex predator‐prey relationships. In this study, we compared the short‐read sequencing capability of the portable Nanopore MinION to that of the Illumina MiSeq for determining the diet of juvenile lanternfish living in the mesopelagic zone of the Indian Ocean. The high congruency in taxonomic assignments and relative read abundance between sequencing machines identify Nanopore as a quick, cost‐effective and accurate method for DNA metabarcoding studies.
... [44] in sea lions) or different parts of the gut (i.e.
[45]
in deep sea lobsters) could reflect successive meals and therefore show distinct digestive profiles. Faeces rarely contain DNA from prey eaten more than a few days before faecal release [44,46]. ...
Gut content metabarcoding and citizen science reveal the earthworm prey of the exotic terrestrial flatworm, Obama nungara
The metabarcoding of digestive contents is a powerful approach to study the diet of newly introduced predatory species, and therefore to forecast their potential impact on native species. Obama nungara (Platyhelminthes: Geoplanidae) is an exotic terrestrial flatworm, which recently invaded several Western European countries and predates on earthworms. Because O. nungara is known to live above ground, we hypothesize that it consumes earthworms living on or coming frequently to the soil surface i.e. epigeic or anecic species, respectively. In this study, we undertook the metabarcoding of O. nungara gut contents to characterize more precisely the earthworm prey it consumes in its invaded range. This species is only known to date in anthropized, mostly privately-owned, environments and the contribution of citizen science volunteers to the reporting of species and their collection is of critical value. We first validated the development of the method, by extracting the digestive contents of O. nungara obtained through citizen science contributions throughout France, amplifying a 70bp earthworm-specific fragment of the 16S RNA gene and sequencing amplicons with a high-throughput approach. Secondly, the taxonomic affiliation of the sequences allowed identifying one to five species of earthworms in the digestive content of each flatworm. Contrary to our hypothesis, O. nungara seems also to consume endogeic species living within the soil and rarely coming out to the surface, as well as intermediate ecological categories. These results, by expanding the range of potential prey of O. nungara, confirm its status as a threat to native soil fauna.
... With the advent of DNA metabarcoding, the diets of many marine predators have been established from gut content DNA [14][15][16]
[17]
. These high-throughput amplicon sequencing technologies have extremely high detection sensitivity and bypass the biases posed by visual methods. ...
Characterizing the secret diets of siphonophores (Cnidaria: Hydrozoa) using DNA metabarcoding
Siphonophores (Cnidaria: Hydrozoa) are abundant and diverse gelatinous predators in open-ocean ecosystems. Due to limited access to the midwater, little is known about the diets of most deep-dwelling gelatinous species, which constrains our understanding of food-web structure and nutrient flow in these vast ecosystems. Visual gut-content methods can rarely identify soft-bodied rapidly-digested prey, while observations from submersibles often overlook small prey items. These methods have been differentially applied to shallow and deep siphonophore taxa, confounding habitat and methodological biases. DNA metabarcoding can be used to assess both shallow and deep species’ diets under a common methodological framework, since it can detect both small and gelatinous prey. We (1) further characterized the diets of open-ocean siphonophores using DNA metabarcoding, (2) compared the prey detected by visual and molecular methods to evaluate their technical biases, and (3) evaluated tentacle-based predictions of diet. To do this, we performed DNA metabarcoding analyses on the gut contents of 39 siphonophore species across depths to describe their diets, using six barcode regions along the 18S gene. Taxonomic identifications were assigned using public databases combined with local zooplankton sequences. We identified 55 unique prey items, including crustaceans, gelatinous animals, and fish across 47 siphonophore specimens in 24 species. We reported 29 novel predator-prey interactions, among them the first insights into the diets of nine siphonophore species, many of which were congruent with the dietary predictions based on tentilla morphology. Our analyses detected both small and gelatinous prey taxa underrepresented by visual methods in species from both shallow and deep habitats, indicating that siphonophores play similar trophic roles across depth habitats. We also reveal hidden links between siphonophores and filter-feeders near the base of the food web. This study expands our understanding of the ecological roles of siphonophores in the open ocean, their trophic roles within the ‘jelly-web’, and the importance of their diversity for nutrient flow and ecosystem functioning. Understanding these inconspicuous yet ubiquitous predator-prey interactions is critical to predict the impacts of climate change, overfishing, and conservation policies on oceanic ecosystems.
... It is unclear how well this translates to non-piscivorous birds such as passerines, many of which consume a diet dominated by a wide variety of arthropods. Despite the lack of experimental studies, dietary metabarcoding has been widely applied to study passerine diet (Jedlicka et al. 2016, Trevelline et al. 2016
, 2018
, McClenaghan et al. 2019, Ribeiro et al. 2019, da Silva et al. 2019. In these studies, fecal samples are the predominant sample type used, raising the question of biases in prey detection and diet characterization due to digestion. ...
Metabarcoding of stomach contents and fecal samples provide similar insights about Seaside Sparrow diet
DNA metabarcoding is a popular tool for animal diet studies to address a variety of research topics across disciplines and taxa. Despite its widespread use, there has been relatively little focus on how digestion influences prey DNA detection and the description of a predator’s diet. Fecal samples are a compelling source of dietary DNA because they are collected non-invasively. However, these samples may provide incomplete or inaccurate descriptions of diet because of differential digestion and DNA degradation across prey taxa during gut passage. This is especially pertinent for avian diet studies, which have widely adopted the use of fecal samples as a proxy for overall diet. To explore how digestion affects the recovery and detection of prey DNA in passerines, we used DNA metabarcoding to compare the recovery of prey DNA from paired stomach contents and fecal samples in Seaside Sparrows (Ammospiza maritima). Stomach contents produced ~2.5 times greater DNA concentrations than fecal samples and—while this difference in DNA concentration was not statistically significant—stomach contents produced significantly more read identifications than fecal samples. However, these differences did not influence the description of diet, as similar measures of richness and diversity were found in both sample types. The relative read abundance of common prey families remained consistent between sample types, suggesting that while less DNA may survive digestion, the proportions of prey remain largely unaffected. We found no difference in the description of diet based on sample type at the population level, but our results show that comparing stomach and fecal samples from the same individual can reveal distinct foraging bouts. With no clear benefit to using stomach contents, we conclude that fecal samples are the preferred sample type for avian metabarcoding diet studies, unless research goals necessitate otherwise.
... HTS also allows processing of a large number of samples at a time and reduces the per-sample cost of trophic assessments (Binladen et al., 2007). Given an extensive reference sequence database, DNAmetabarcoding can provide highly reliable identification of prey items (Nielsen et al., 2018), and the use of high-resolution markers can even retrieve intra-specific taxonomic information
(Turon, Antich, Palacín, Praebel, & Wangensteen, 2020)
. Recent studies indicate the usefulness of DNA-metabarcoding in the detectability of elusive prey, such as soft-bodied organisms (Boyer et al., 2015;McInnes et al., 2017) which often were believed to be dead ends of food chains (Hays et al., 2018). ...
DNA‐metabarcoding reveals the importance of gelatinous zooplankton in the diet of Pandalus borealis , a keystone species in the Arctic
Dec 2021
Paulina Urban
Information about the dietary composition of a species is crucial to understanding their position and role in the food web. Increasingly molecular approaches such as DNA-metabarcoding are used in studying trophic relations, not least because they may alleviate problems such as low taxonomic resolution or underestimation of digestible taxa in the diet. Here, we used DNA-metabarcoding with universal primers for cytochrome c oxidase I (COI), to study the diet composition of the Northern shrimp (Pandalus borealis), an Arctic keystone species with large socio-economic importance. Across locations, jellyfish and chaetognaths were the most important components in the diet of P. borealis, jointly accounting for 40-60% of the total read abundance. This dietary importance of gelatinous zooplankton contrasts sharply with published results based on SCA. At the same time, diet composition differed between fjord and shelf locations, pointing to different food webs supporting P. borealis in these two systems. Our study underscores the potential of molecular approaches to provide new insights into the diet of marine invertebrates that are difficult to obtain with traditional methods, and calls for a revision of the role of gelatinous zooplankton in the diet of the key Arctic species P. borealis, and in extension, Arctic food webs.
New epibiotic association in the deep-sea: the amphipod Caprella ungulina and the Patagonian lobsterette Thymops birsteini in the South-western Atlantic
The present study reports for the first time the association between the decapod Thymops birsteini (Nephropidae) and the amphipod Caprella ungulina (Caprellidae). A benthic biodiversity survey was carried out to explore the Mar del Plata Submarine Canyon, off the Argentine coast, in the South-western Atlantic Ocean. A total of 205 caprellids (181 juveniles, 4 males and 20 not-classified individuals) were found attached to 7 specimens of T. birsteini caught between 1087–2212m depth. The epibiotic parameters showed that the prevalence of C. ungulina on T. birsteini was 50%; the mean abundance was 14.64 and the intensity value was 29.29. In addition, specimens of C. ungulina were recorded mainly on mouthparts of T. birsteini (31.22%), followed by chelipeds (18.05%), cephalothorax (4.88%) and pereiopods (0.98%). Our finding of C. ungulina provides the deepest record until now; additionally, this epibiont is reported in a new host belonging to an infraorder and a family of crustacean that had not previously been found as basibionts. The potential mechanisms implied in the wide distribution of C. ungulina are discussed.
Metabarcoding hyperdiverse kelp holdfast communities on temperate reefs: An experimental approach to inform future studies
J. David Aguirre
| https://www.researchgate.net/publication/327778713_Preliminary_analysis_of_New_Zealand_scampi_Metanephrops_challengeri_diet_using_metabarcoding |
VASQUEZ v. RIDGE TOOL PAT | 2020 NY Slip Op 32218(U) | 20200713271 | Leagle.com
DECISION AND ORDER LUCY BILLINGS J.S.C. I. BACKGROUND Plaintiff was employed by nonparty Gael Hardwood Flooring during renovation...20200713271
VASQUEZ v. RIDGE TOOL PATTERN CO.
Docket No. 158040/2015.
View Case
Cited Cases
2020 NY Slip Op 32218(U)
TEOFANES CRUZ VASQUEZ, Plaintiff,
v.
RIDGE TOOL PATTERN COMPANY a/k/a RIDGE TOOL, HOME DEPOT U.S.A., INC., NINETY RIVER WEST CORP., ORSID REALTY CORP., J. CALLAHAN CONSULTING, INC., CFS ENGINEERING, D.P.C., BERNARD M. PLUM, and PETER DINATALE & ASSOCIATES, Defendants.
NINETY RIVER WEST CORP. and ORSID REALTY CORP., Third Party Plaintiffs,
v.
BERNARD M. PLUM and PETER DINATALE & ASSOCIATES, Third Party Defendants.
Supreme Court, New York County. https://leagle.com/images/logo.png
June 30, 2020.
June 30, 2020.
Attorney(s) appearing for the Case
Paul E. Carney Esq. , Ras Associates, PLLC, 2500 Westchester Avenue, Purchase, NY 10577, For Plaintiff .
Rosario M. Vignali Esq. , Wilson, Elser, Moskowitz, Edelman & Dicker, LLP, 150 East 42nd Street, New York, NY 10017, For Defendants Ridge Tool Pattern Company and Home Depot, U.S.A., Inc.
Jeffrey Fippinger Esq. , Law Offices of Margaret G. Klein & Associates, 200 Madison Avenue, New York, NY 10016, For Defendants Ninety River West Corp. and Orsid Realty Corp.
Laura R. Efrati Esq. and Amanda Prescott Esq. , Correia, King, Fodera, McGinnes & Liferiedge, 1 Battery Park Plaza, New York, NY 10004, For Defendants Plum and Peter DiNatale & Associates .
DECISION AND ORDER
LUCY BILLINGS , J.S.C.
I.
BACKGROUND
Plaintiff was employed by nonparty Gael Hardwood Flooring during renovation of an apartment leased by defendant Plum in a cooperative building owned by defendant Ninety River West Corp. and managed by defendant Orsid Realty Corp. Plaintiff sues to recover damages for personal injuries sustained May 14, 2014, while using a router sold by defendant Ridge Tool Pattern Company or defendant Home Depot U.S.A., Inc. Although Ninety River West and Orsid Realty commenced a third party action against Plum and the general contractor Peter Dinatale & Associates, plaintiff then joined these third party defendants as defendants in the main action, so that the third party claims are now cross-claims.
Plum and Dinatale & Associates move for summary judgment dismissing the complaint and all cross-claims against these defendants. C.P.L.R. § 3212(b). Plaintiff cross-moves for summary judgment in his favor against DiNatale & Associates on his claims for negligence and violation of Labor Law §§ 200 and 241(6). C.P.L.R. § 3212(b) and (e).
Ninety River West and Orsid Realty move for summary judgment dismissing the complaint and all cross-claims against these defendants and for summary judgment in their favor on their contractual indemnification claims against Plum. Plaintiff also cross-moves for summary judgment in his favor against Ninety River West and Orsid Realty on his claims for negligence and violation of Labor Law §§ 200 and 241(6).
Ridge Tool and Home Depot move for summary judgment dismissing the complaint against them. Plaintiff cross-moves for summary judgment against them on his claims for negligent product design and strict product liability.
In a stipulation dated July 11, 2019, the parties discontinued all claims against defendants J. Callahan Consulting, Inc., and CFS Engineering, D.P.C. In a stipulation dated August 13, 2019, plaintiff discontinued his (1) Labor Law § 240(1) claim, (2) claims against defendant Plum, and (3) claims for a manufacturing defect, for breach of an express warranty, and for violation of Labor Law §§ 200 and 241(6) against Ridge Tool and Home Depot.
II.
PLAINTIFF'S LABOR LAW CLAIMS
A.
TIMELINESS OF PLAINTIFF'S CROSS-MOTIONS AGAINST DINATALE & ASSOCIATES AND AGAINST NINETY RIVER WEST AND ORSID REALTY
Since plaintiff filed a note of issue December 21, 2018, the deadline for summary judgment motions was April 20, 2019. C.P.L.R. § 3212(a). DiNatale & Associates timely served its motion for summary judgment February 14, 2019. C.P.L.R. § 2211;
Derouen v. Savoy Park Owner, L.L.C.
,
109 A.D.3d 706
, 706 (1st Dep't 2013);
Esdaille v. Whitehall Realty Co.
,
61 A.D.3d 435
, 436 (1st Dep't 2009);
Aqeel v. Tony Casale, Inc.
,
44 A.D.3d 572
, 572 (1st Dep't 2007);
Gazes v. Bennett
,
38 A.D.3d 287
, 288 (1st Dep't 2007). Ninety River West and Orsid Realty timely served their motion for summary judgment April 11, 2019. Plaintiff's cross-motions against DiNatale & Associates and against Ninety River West and Orsid Realty served May 10, 2019, were untimely. C.P.L.R. § 3212(a). The court may consider plaintiff's cross-motions, however, to the extent that they respond to and address claims "nearly identical" to the timely motions for summary judgment by DiNatale & Associates and by Ninety River West and Orsid Realty dismissing plaintiff's negligence and Labor Law §§ 200 and 241(6) claims.
Jarama v. 902 Liberty Ave. Haus. Dev. Fund Corp.
,
161 A.D.3d 691
, 692 (1st Dep't 2018);
Alonzo v. Safe Harbors of the Hudson Hous. Dev. Fund Co., Inc.
,
104 A.D.3d 446
, 449 (1st Dep't 2013).
B.
LABOR LAW § 200 AND NEGLIGENCE CLAIMS
At oral argument July 11, 2019, DiNatale & Associates conceded that it was the general contractor on the renovation project. DiNatale & Associates and the owner and its managing agent, Ninety River West and Orsid Realty, deny liability because they did not supervise or control plaintiff's work. Plaintiff claims that all three defendants were negligent and violated Labor Law § 200 because they failed to provide gloves, a table, and a tool suitable for the work plaintiff was to perform, and they were aware of those work conditions. He was injured while using the router when it kicked back after striking a hard piece of the wood he was working on, causing the bit to lacerate and sever his left thumb.
Labor Law § 200 codifies an owner's and a general contractor's duty to maintain construction site safety.
Rizzuto v. L.A. Wegner Contr. Co.
,
91 N.Y.2d 343
, 352 (1998);
Comes v.
New York State Elec. & Gas Corp.
,
82 N.Y.2d 876
, 877-78 (1993). An owner's managing agent also may be subject to liability under Labor Law § 200.
Burgund v. Cushman & Wakefield, Inc.
,
167 A.D.3d 441
, 442 (1st Dep't 2018);
DeJesus v. 888 Seventh Ave. LLC
,
114 A.D.3d 587
, 588 (1st Dep't 2014). If a dangerous condition arising from subcontractor Gael Hardwood Flooring's work caused plaintiff's injury, DiNatale & Associates, Ninety River West, and Orsid Realty may be liable for negligently allowing that condition and violating Labor Law § 200, if they supervised or exercised control over the activity that caused his injury.
Rizzuto v. L.A. Wegner Contr. Co.
, 91 N.Y.2d at 352;
Comes v. New York State Elec. & Gas Corp.
, 82 N.Y.2d at 877;
Maggio v. 24 W. 57 APF, LLC
,
134 A.D.3d 621
, 626 (1st Dep't 2015);
Cappabianca v. Skanska USA Bldg. Inc.
,
99 A.D.3d 139
, 144 (1st Dep't 2012).
See Ocampo v. Bovis Lend Lease LMB, Inc.
,
123 A.D.3d 456
, 457 (1st Dep't 2014);
Francis v. Plaza Constr. Corp.
,
121 A.D.3d 427
, 428 (1st Dep't 2014). If a dangerous condition on the work site caused plaintiff's injury, liability depends on these defendants' creation or actual or constructive notice of the condition.
Maggio v. 24 W. 57 APF, LLC
, 134 A.D.3d at 626;
Cappabianca v. Skanska USA Bldg. Inc.
, 99 A.D.3d at 144.
Contrary to plaintiff's contention, his injury arose from the methods or means of his work, rather than any condition of the premises.
Gilligan v. CJS Bldrs.
, 178 A.D.3d 566, 566 (1st Dep't 2019);
Nelson v. E&M 2710 Clarendon LLC
,
129 A.D.3d 568
, 569 (1st Dep't 2015);
Castellon v. Reinsberg
,
82 A.D.3d 635
, 636 (1st Dep't 2011). Plaintiff identifies defects related only to the router that caused his injury and not any defect inherent in the site.
Villanueva v. 114 Fifth Ave. Assoc. LLC
,
162 A.D.3d 404
, 406 (1st Dep't 2018);
Singh v. 1221 Ave. Holdings, LLC
,
127 A.D.3d 607
, 608 (1st Dep't 2015);
Castellon v. Reinsberg
, 82 A.D.3d at 636.
Plaintiff testified at his deposition that he only followed instructions and used equipment from his employer Gael Hardwood Flooring's owner Roland Stuttard or its foreman Oscar Hernandez and that no one else instructed him.
See Haynes v. Boricua Vil. Hous. Dev. Fund Co., Inc.
, 170 A.D.3d 509, 511 (1st Dep't 2019);
Howard v. Turner Constr. Co.
,
134 A.D.3d 523
, 525 (1st Dep't 2015);
Singh v. 1221 Ave. Holdings, LLC
, 127 A.D.3d at 608. Santos Tricoche, Ninety River West's superintendent at the premises, testified at his deposition that he did not instruct any workers involved in the renovation. Peter DiNatale, the owner of DiNatale & Associates, testified at his deposition that he did not observe any building personnel supervising the renovation workers. Harvey Ginsberg, Orsid Realty's property manager, testified that he never visited the apartment under renovation and did not know who directed the work for the renovation.
See Maggio v. 24 W. 57 APF, LLC
, 134 A.D.3d at 626;
Singh v. 1221 Ave. Holdings
, LLC, 127 A.D.3d at 608.
Plaintiff nevertheless maintains that Ninety River West's superintendent Tricoche monitored the progress of the work, that its Alteration Agreement imposed requirements for the work, and that DiNatale & Associates was at the apartment daily, directed the work there, and bore contractual responsibilities to supervise the project and oversee safety. Supervisory and overall safety responsibilities,
Haynes v. Boricua Vil. Hous. Dev. Fund Co., Inc.
, 170 A.D.3d at 511;
McLean v. Tishman Constr. Corp.
,
144 A.D.3d 534
, 535 (1st Dep't 2016);
Howard v. Turner Constr. Co.
, 134 A.D.3d at 525, regular inspections,
Varona v. Brooks Shopping Ctrs. LLC
,
151 A.D.3d 459
, 460 (1st Dep't 2017);
Singh v. 1221 Ave. Holdings, LLC
, 127 A.D.3d at 608, and the ability to stop unsafe work practices do not establish the requisite control.
Villanueva v. 114 Fifth Ave. Assoc. LLC
, 162 A.D.3d at 406;
Galvez v. Columbus 95th St. LLC
,
161 A.D.3d 530
, 531-32 (1st Dep't 2018);
Varona v. Brooks Shopping Ctrs. LLC
, 151 A.D.3d at 460;
McLean v. Tishman Constr. Corp.
, 144 A.D.3d at 535. Tricoche's daily presence at the worksite without exercising supervisory authority over plaintiff does not establish Ninety River West's liability.
De La Rosa v. Philip Morris Mgt. Corp.
,
303 A.D.2d 190
, 192 (1st Dep't 2003). The managing agent Orsid Realty, conceding it was a statutory agent of Ninety River West, is likewise neither negligent nor liable under Labor Law § 200 because the managing agent owed no obligation to oversee operations in the apartment where the renovation occurred.
See Burgund v. Cushman & Wakefield, Inc.
, 167 A.D.3d at 442. DiNatale testified that he or his foreman merely reported unsafe conditions to the subcontractor and otherwise exercised no responsibilities for them. For all these reasons, the court grants the motions by DiNatale & Associates and by Ninety River West and Orsid Realty for summary judgment to the extent of dismissing plaintiff's Labor Law § 200 and negligence claims against these defendants and denies plaintiff's cross-motion for summary judgment on their liability for violation of Labor Law § 200 and for negligence. C.P.L.R. § 3212(b).
C.
LABOR LAW § 241(6) CLAIM
The duty to comply with the regulations under Labor Law § 241(6) is non-delegable, subjecting the owner and general contractor to liability for a violation even if the owner and general contractor exercised no supervision or control over plaintiff's work and received no notice of work site conditions.
Balbuena v. IDR Realty LLC
,
6 N.Y.3d 338
, 361 n.8 (2006);
Comes v. New York State Elec. & Gas Corp.
, 82 N.Y.2d at 878;
Ross v. Curtis-Palmer Hydro-Elec. Co.
,
81 N.Y.2d 494
, 502-503 (1993). While a failure to take the safety measures required by this statute, proximately causing injury, does not impose absolute liability absent negligence, the statute imposes liability on an owner and general contractor for injuries caused by another party's negligence regardless of the owner's or general contractor's own negligence.
Rizzuto v. Wegner Contr. Co.
,
91 N.Y.2d 343
, 349-50 (1998);
Ross v. Curtis-Palmer Hydro-Elec. Co.
, 81 N.Y.2d at 502 n.4.
In the stipulation dated August 13, 2019, plaintiff limited his Labor Law § 241(6) claim to violations of 12 N.Y.C.R.R. §§ 23-1.12(a), (c), and (f) and 23-9.2(a), (b), and (d). Although the written stipulation cites 12 N.Y.C.R.R. § 23-1.2, the court assumes that the parties intended to write § 23-1.12, consistent with plaintiff's pleadings and the parties' stipulation on the record July 11, 2019. Plaintiff claims the failure by DiNatale & Associates, Ninety River West, and Orsid Realty to provide a guard and guide bar for the router violated these regulations. DiNatale & Associates, Ninety River West, and Orsid Realty maintain that the regulations cited by plaintiff are inapplicable or do not impose sufficiently specific safety standards to support liability under Labor Law § 241(6).
12 N.Y.C.R.R. § 23-1.12(a) only imposes unspecific safety standards and directs compliance with Industrial Code Part 19, a regulation that has been repealed. 12 N.Y.C.R.R. 23-1.12(c) does not apply because the tool plaintiff used was not a saw, but a router.
See Hernandez v. Seadvck Realty Co., LLC
,
137 A.D.3d 656
, 657 (1st Dep't 2016);
Sovulj v. Procida Realty & Constr. Corp. of N.Y.
,
129 A.D.3d 414
, 415 (1st Dep't 2015). Contrary to plaintiff's contention, his engineer James Pugh does not attest that a router is a saw. Pugh simply concludes that defendants violated 12 N.Y.C.R.R. § 23-1.12(c), an ultimate legal determination reserved for the court or the jury and not a question on which the court may consider an expert witness' opinion.
Morris v. Pavarini Constr.
,
9 N.Y.3d 47
, 51 (2007);
Buchholz v. Trump 767 Fifth
,
5 N.Y.3d 1
, 7 (2005);
Lopez v. Chan
,
102 A.D.3d 625
, 626 (1st Dep't 2013);
McCoy v. Metropolitan Transp. Auth.
,
53 A.D.3d 457
, 459 (1st Dep't 2008). Similarly, since no evidence establishes that the router was a friction-disc drive, plaintiff fails to establish a violation of 12 N.Y.C.R.R. § 23-1.12(f).
DiNatale & Associates, Ninety River West, and Orsid Realty maintain that 12 N.Y.C.R.R. § 23-9.2 does not apply because it is limited to heavy equipment. "The provisions of this Subpart shall apply to power-operated heavy equipment or machinery used in construction, demolition and excavation operations." 12 N.Y.C.R.R. § 23-9.1. These defendants interpret "heavy" as modifying both "equipment" and "machinery" and rely on
Misicki v. Caradonna
,
12 N.Y.3d 511
(2009), to support their contention, but the Court of Appeals expressly ruled that it was not determining whether § 23-9.2 applied to the hand held grinder in that action.
Id.
at 519.
12 N.Y.C.R.R. § 23-9.2(b)(1), which requires that all "power-operated equipment used in construction, demolition or excavation operations shall be operated only by trained, designated persons and all such equipment shall be operated in a safe manner at all times," does not impose a sufficiently specific safety command to support liability under Labor Law § 241(6).
Scott v. Westmore Fuel Co., Inc.
,
96 A.D.3d 520
, 521 (1st Dep't 2012). 12 N.Y.C.R.R. § 23-9.2(d) requires that: "Gears, belts, sprockets, drums, sheaves and any points of contact between moving parts of power-operated equipment or machines when not guarded by location shall be guarded in compliance with this Part (rule) and with Industrial Code Part (rule) 19." No evidence shows that the listed parts were not guarded.
See Fisher v WNY Bus Parts, Inc.
,
12 A.D.3d 1138
, 1140 (4th Dep't 2004). The part that injured plaintiff was not guarded, but did not contact another moving part. The regulation also requires a guard in compliance with the rule that has been repealed.
12 N.Y.C.R.R. § 23-9.2(a) applies to machinery that is not heavy,
Alameda-Cabrera v. Noble Elec. Contr. Co., Inc.
,
117 A.D.3d 484
, 485-86 (1st Dep't 2014);
Cappabianca v. Skanska USA Bldg. Inc.
, 99 A.D.3d at 147, but only the third sentence of § 23-9.2(a) constitutes a concrete specification supporting a Labor Law § 241(6) claim: "Upon discovery, any structural defect or unsafe condition in such equipment shall be corrected by necessary repairs or replacement."
Becerra v. Promenade Apts. Inc.
,
126 A.D.3d 557
, 558 (1st Dep't 2015).
See Misicki v. Caradonna
, 12 N.Y.3d at 521. For defendants to be liable for violating § 23-9.2(a), they must have received actual notice of the defect or unsafe condition,
Misicki v. Caradonna
, 12 N.Y.3d at 521;
Shields v. First Ave. Bldrs. LLC
,
118 A.D.3d 588
, 589 (1st Dep't 2014), and the violation must be a proximate cause of plaintiff's injury.
Misicki v. Caradonna
, 12 N.Y.3d at 521;
Salsinha v. Malcolm Pirnie, Inc.
,
76 A.D.3d 411
, (1st Dep't 2010).
Ninety River West and Orsid Realty demonstrate their lack of notice of the router's unsafe condition. The testimony by Ginsberg and Tricoche establishes that Ginsberg never visited the apartment during the renovation, and Tricoche visited the apartment occasionally to check on plumbing.
DiNatale testified that he was at the apartment once or twice a week, but did observe not any routers. Plaintiff attests, however, that DiNatale & Associates' employees, in particular its project manager at the apartment, were aware that the router plaintiff was using lacked a guide bar to keep the blade from kicking back and a guard around the spinning bit that injured him. Pugh concludes that the router was unsafe and caused plaintiff's injury because the router lacked a guide attachment to stabilize the router and prevent kickback injuries and lacked a "point of contact" guard. Aff. of Jim Pugh ¶ 18. He does not clarify whether or not the latter safeguard refers to a point of contact between moving parts, which does not apply to the part that injured plaintiff, as it did not contact another moving part. Plaintiff points out that he worked in plain view in the apartment and that the foreman had observed plaintiff's co-worker using the unguarded router 4-8 times and plaintiff using it at least once before his injury.
These allegations about the router's condition and use observed by DiNatale & Associates' foreman raise an issue whether the general contractor violated 12 N.Y.C.R.R. § 23-9.2(a) and thus Labor Law § 241(6), for which the owner Ninety River West is vicariously liable. Plaintiff's failure to establish that the lack of a guard around the spinning bit was unsafe or that the foreman, while observing the lack of a guide bar, discovered that the router was unsafe without that attachment, on the other hand, precludes summary judgment to plaintiff based on this regulatory provision. It requires actual, not just constructive, notice of an unsafe condition.
Misicki v. Caradonna
, 12 N.Y.3d at 521;
Shields v. First Ave. Bldrs. LLC
, 118 A.D.3d at 589.
Finally, DiNatale & Associates contends that plaintiff's misuse of the router by placing the wood on which he was using the router on an overturned bucket instead of on an available table to support the wood was the sole proximate cause of his injury. While plaintiff admitted that his failure to use the table was unwise, he does not attribute his injury to his use of the bucket, but rather to the router kicking back after hitting a hard piece of wood. If the lack of safeguards to prevent the router from kicking back or to protect plaintiff's hands from laceration by the router's blade contributed to his injury, plaintiff was not the sole proximate cause of his injury.
Ferguson v Durst Pyramid, LLC
, 178 A.D.3d 634, 635 (1st Dep't 2019);
Cuentas v Sephora USA, Inc.
,
102 A.D.3d 504
, 504 (1st Dep't 2013).
For all the above reasons, the court grants the motions by DiNatale & Associates and by Ninety River West and Orsid Realty for summary judgment dismissing plaintiff's Labor Law § 241(6) claims against these defendants except to the extent that the claim is against DiNatale & Associate and Ninety River West based on 12 N.Y.C.R.R. § 23-9.2(a). C.P.L.R. § 3212(b) and (e). The court denies plaintiff's cross-motion for summary judgment on all three defendants' liability for violation of Labor Law § 241(6). C.P.L.R. § 3212(b).
III.
CROSS-CLAIMS
Plum, DiNatale & Associates, Ninety River West, and Orsid Realty seek dismissal of all cross-claims against them because they are not liable to plaintiff. Ninety River West and Orsid Realty only oppose dismissal of their cross-claims against Plum for contractual indemnification and seek summary judgment in their favor on those cross-claims for their defense expenses. Ridge Tool and Home Depot do not oppose dismissal of their cross-claims.
Ninety River West and Orsid Realty base their contractual indemnification claims on the Alteration Agreement executed by Plum, a shareholder in the cooperative corporation, and Ninety River West, the corporation, which the parties stipulate is authenticated and admissible for purposes of the current motions. The agreement identifies Orsid Realty as the managing agent and provides that:
Shareholder hereby indemnifies and holds harmless the Corporation, the Corporation's Designated Engineer and employees, the Managing Agent, and other shareholders and residents of the Building against any damages suffered to persons or property as a result of the Work. Shareholder shall reimburse the Corporation, the Corporation's Designated Engineer, Managing Agent, and other shareholders and residents of the Building for any losses, costs, fines, fees and expenses (including, without limitation, reasonable attorney's fees and disbursements) incurred as a result of the Work.
Aff. of Harvey Ginsberg Ex. 2 ¶ 6.
New York General Obligations Law § 5-321 provides that:
Every covenant, agreement or understanding in or in connection with or collateral to any lease of real property exempting the lessor from liability for damages for injuries to person or property caused by or resulting from the negligence of the lessor, his agents, servants or employees, in the operation or maintenance of the demised premises or the real property containing the demised premises shall be deemed to be void as against public policy and wholly unenforceable.
Plum contends that General Obligations Law § 5-321 prohibits enforcement of the Alteration Agreement's indemnification provision because it allows Ninety River West and Orsid Realty to recover for their own negligence. Since Ninety River West and Orsid Realty were not negligent in causing plaintiff's injury, General Obligations Law § 5-321 poses no bar to contractual indemnification against Plum.
Guzman v. 170 W. End Ave. Assoc.
,
115 A.D.3d 462
, 464 (1st Dep't 2014);
Dwyer v. Central Park Studios, Inc.
,
98 A.D.3d 882
, 884 (1st Dep't 2012). Therefore Ninety River West and Orsid Realty are entitled to their defense expenses.
See Ajche v. Park Ave. Plaza Owner, LLC
, 171 A.D.3d 411, 414 (1st Dep't 2019);
Michigan Mut. Ins. Co. v. American & Foreign Ins. Co.
,
251 A.D.2d 141
, 141 (1st Dep't 1998).
IV.
PLAINTIFF'S CLAIMS AGAINST RIDGE TOOL AND HOME DEPOT
Plaintiff held a Ridgid Model 2401 router in his right hand and the wood on which he was working in his left hand. As set fort above, he was injured when the router kicked back after striking a hard piece of the wood, causing the bit to lacerate and sever his left thumb. He claims negligent design of the router, strict product liability, and breach of implied warranties against Ridge Tool and Home Depot. Ridge Tool and Home Depot seek dismissal of all those claims. Plaintiff seeks summary judgment on his negligent design and strict product liability claims.
A.
TIMELINESS OF PLAINTIFF'S CROSS-MOTION
Ridge Tool and Home Depot timely served their motion for summary judgment March 15, 2019. C.P.L.R. § 2211;
Derouen v. Savoy Park Owner, L.L.C.
,
109 A.D.3d 706
;
Esdaille v. Whitehall Realty Co.
, 61 A.D.3d at 436;
Aqeel v. Tony Casale, Inc.
,
44 A.D.3d 572
;
Gazes v. Bennett
, 38 A.D.3d at 288. Plaintiff's cross-motion against Ridge Tool and Home Depot served May 8, 2019, was untimely. C.P.L.R. § 3212(a). The court may not consider plaintiff's untimely cross-motion for summary judgment on his negligent design and strict product liability claims except to the extent that he claims the router lacked an interlock, because his cross-motion otherwise is not nearly identical to the motion by Ridge Tool and Home Depot.
Muqattash v. Choice One Pharm. Corp.
,
162 A.D.3d 499
, 500 (1st Dep't 2018);
Rubino v. 330 Madison Co., LLC
,
150 A.D.3d 603
, 604 (1st Dep't 2017);
Belgium v. Mateo Prods., Inc.
,
138 A.D.3d 479
, 480 (1st Dep't 2016);
Maggio v. 24 W. 57 APF, LLC
, 134 A.D.3d at 628.
B.
A TRADEMARK LICENSOR'S LIABILITY
Ridge Tool claims that it is merely affiliated with the entities that licensed the router's trade name. A trademark licensor uninvolved in the manufacture, design, sale, distribution, or quality control of a defective product is not liable for it.
Harrison v. ITT Corp.
,
198 A.D.2d 50
, 50 (1st Dep't 1993);
Bova v. Caterpillar, Inc.
,
305 A.D.2d 624
, 626 (2d Dep't 2003);
D'Onofrio v. Boehlert
,
221 A.D.2d 929
, 929 (4th Dep't 1995);
Porter v. LSB Indus.
,
192 A.D.2d 205
, 215 (4th Dep't 1993). A trademark licensor is not liable based on either strict product liability or breach of a warranty.
Laurin Mar. AB v. Imperial Chem. Indus.
,
301 A.D.2d 367
, 367-68 (1st Dep't 2003).
Daniel Terpstra, Ridge Tool's consultant, attests that Ridgid is a trademark that Emerson and Ridgid Inc. licensed to Home Depot to market power tools. He attests that Ridge Tool never designed or manufactured Ridgid power tools and was uninvolved in their product warnings or instructions.
Terpstra also attests, however, that Ridge Tool's business purpose and role were sale and service of Ridgid products. Terpstra relied on plaintiff's testimony that the router that injured him was purchased at Home Depot, but that testimony is based on inadmissible hearsay from a co-worker. Therefore Ridge Tool fails to demonstrate that it was uninvolved in sale of the product that injured plaintiff.
C.
PRODUCT DEFECT CLAIMS
The product defects for which product manufacturers and sellers are liable are defects in manufacturing or design or inadequacies in warnings about use of the product.
Matter of New York City Asbestos Litig.
,
27 N.Y.3d 765
, 787 (2016);
Doomes v. Best Tr. Corp.
,
17 N.Y.3d 594
, (2011);
Amatulli v. Delhi Const. Corp.
,
77 N.Y.2d 525
, 532 (1991).
1.
Design Defect Based on a Missing Interlock
A product is defectively designed if, when it leaves the seller, it poses a danger for its intended use and is not in a condition reasonably contemplated by the consumer, and the inherent danger from its introduction into the stream of commerce outweighs its utility.
Fasolas v. Bobcat of N.Y., Inc.
, 33 N.Y.3d 421, 429-30 (2019);
Hoover v. New Holland N. Am., Inc.
,
23 N.Y.3d 41
, 53-54 (2014);
Adams v. Genie Indus., Inc.
,
14 N.Y.3d 535
, 542 (2010);
Voss v. Black & Decker Mfg. Co.
,
59 N.Y.2d 102
, 107 (1983). Plaintiff identifies the absence of an interlock on the router among its defects.
The sole defense of Ridge Tool and Home Depot to this claim is that the absence of an interlock is an insufficient basis for liability as a matter of law, citing
Patino v. Lockformer Co.
,
303 A.D.2d 731
, 733 (2d Dep't 2003), and
Giunta v. Delta Intern. Mach.
,
300 A.D.2d 350
, 351 (2d Dep't 2002), which so held without explanation.
Giunta
cites
David v. Makita U.S.A., Inc.
,
233 A.D.2d 145
(1st Dep't 1996), and
Banks v. Makita, U.S.A.
,
226 A.D.2d 659
(2d Dep't 1996), as authority for that conclusion, but neither of these decisions involved an interlock.
Pugh attests that the absence of an interlock device, which would have stopped rotation of the bit when it lost contact with the cutting surface, was a defect in the router. Because an interlock automatically interrupts operation of a machine,
Adams v. Genie Indus., Inc.
,
14 N.Y.3d 535
, 540 (2010), absence of an interlock may form the basis for a product liability claim.
Id.
at 543;
Daley v. Gemini Bakery Equip. Co.
,
228 A.D.2d 210
, 211 (1st Dep't 1996).
See Sanchez v. Martin Maschinenbau GmbH & Co.
,
281 A.D.2d 284
, 285 (1st Dep't 2001). Having presented no evidence to show that the router was safe without an interlock, Ridge Tool and Home Depot fail to meet their initial burden in moving for summary judgment dismissing plaintiff's claim that the absence of an interlock was an actionable defect in the router.
Daley v. Gemini Bakery Equip. Co.
, 228 A.D.2d at 212. The court may not consider the expert affidavit presented for the first time by Ridge Tool and Home Depot in reply.
Eujoy Realty Corp. v. Van Wagner Communications, LLC
,
22 N.Y.3d 413
, 422-23 (2013);
Amtrust-NP SFR Venture, LLC v. Vazquez
,
140 A.D.3d 541
, 541-42 (1st Dept 2016);
Friedman v. BHL Realty Corp.
,
83 A.D.3d 510
, 510 (1st Dep't 2011);
Kennelly v. Mobius Realty Holdings LLC
,
33 A.D.3d 380
, 381 (1st Dep't 2006).
Pugh's affidavit is the only evidence regarding the danger posed by a router lacking an interlock,
see Adams v. Genie Indus., Inc.
, 14 N.Y.3d at 543, but this evidence is scant. It fails to establish any of the elements of a defectively designed product.
See Fasolas v. Bobcat of N.Y.
Inc., 33 N.Y.3d at 429-30;
Hoover v. New Holland N. Am., Inc.
, 23 N.Y.3d at 53-54;
Adams v. Genie Indus., Inc.
, 14 N.Y.3d at 542;
Voss v. Black & Decker Mfg. Co.
, 59 N.Y.2d at 107. Pugh's conclusory affidavit thus fails to support plaintiff's cross-motion for summary judgment finding a design defect.
Ford v. Riina
,
160 A.D.3d 588
, 590 (1st Dep't 2018);
Caruso v. John St. Fitness Club, LLC
,
34 A.D.3d 296
, 296 (1st Dep't 2006);
Finguerra v. Conn
,
252 A.D.2d 463
, 466 (1st Dep't 1998).
2.
Failure to Warn
A product manufacturer or seller is liable for failing to warn of its product's hidden dangers "resulting from foreseeable uses of its product of which it knew or should have known."
Matter of Eighth Jud. Dist. Asbestos Litig.
, 33 N.Y.3d 488, 495 (2019);
Liriano v. Hobart Corp.
,
92 N.Y.2d 232
, 237 (1998);
Hartnett v. Chanel, Inc.
,
97 A.D.3d 416
, 419 (1st Dep't 2012);
Stewart v. Honeywell Intl. Inc.
,
65 A.D.3d 864
, 865 (1st Dep't 2009). A product manufacturer or seller owes the duty to warn to the product's purchaser, the purchaser's employees, and third persons subject to foreseeable and unreasonable risks of harm arising from the failure to warn.
Matter of Eighth Jud. Dist. Asbestos Litig.
, 33 N.Y.3d at 495;
Matter of New York City Asbestos Litig.
, 27 N.Y.3d at 788-89.
See Hartnett v. Chanel, Inc.
, 97 A.D.3d at 419. Plaintiff is not required to specify a defect other than the failure to warn of hidden dangers in the product's intended use or reasonably foreseeable unintended use.
Matter of Eighth Jud. Dist. Asbestos Litig.
, 33 N.Y.3d at 499;
Matter of New York City Asbestos Litig.
, 27 N.Y.3d at 778, 788;
Lugo v. LJN Toys
,
75 N.Y.2d 850
, 852 (1990);
Hartnett v. Chanel, Inc.
, 97 A.D.3d at 419. A product manufacturer or seller owes no duty, however, to warn of patently dangerous or open and obvious hazards.
Liriano v. Hobart Corp.
, 92 N.Y.2d at 241;
Narvaez v. Wadsworth
,
165 A.D.3d 407
, 408 (1st Dep't 2018);
Hartnett v. Chanel, Inc.
, 97 A.D.3d at 420.
Ridge Tool and Home Depot urge that the danger of operating the router near one's hand was open and obvious, negating the duty to warn.
Shamir v. Extrema Mach. Co., Inc.
,
125 A.D.3d 636
, 637 (2d Dep't 2015);
Cwiklinski v. Sears, Roebuck & Co., Inc.
,
70 A.D.3d 1477
, 1479 (4th Dep't 2010);
Lamb v. Kysor Indus. Corp.
,
305 A.D.2d 1083
, 1084 (4th Dep't 2003);
Banks v. Makita, U.S.A.
, 226 A.D.2d at 660. Factors to considered in determining whether a hazard is open and obvious are plaintiff's experience,
Stewart v. Honeywell Intl. Inc.
, 65 A.D.3d at 865;
Shamir v. Extrema Mach. Co., Inc.
, 125 A.D.3d at 637;
Rodriguez v. Sears, Roebuck & Co.
,
22 A.D.3d 823
, 824 (2d Dep't 2005);
Lamb v. Kysor Indus. Corp.
, 305 A.D.2d at 1084, and prior use of the allegedly defective tool.
Shamir v. Extrema Mach. Co., Inc.
, 125 A.D.3d at 637;
Sugrim v. Ryobi Tech., Inc.
,
73 A.D.3d 904
, 905 (2d Dep't 2010).
Plaintiff testified that he had experience using a metal cutting machine and powered saws and was aware of the dangers in using them, but had not used a router before the renovation and had used it only once before his injury. He attests further in his affidavit that "amputating a finger ... does not appear possible by the look of the device." Aff. of Teofanes Cruz Vasquez ¶ 15. Pugh concurs that "the spinning bit ... was somewhat innocuous to the novice user such as Plaintiff, as it appears to be a small and therefore minor although important feature of the unit." Pugh Aff. ¶ 10.
Unlike
Cwiklinski v. Sears, Roebuck & Co., Inc.
, 70 A.D.3d at 1479, where the plaintiff read the product manual, plaintiff here was not even provided the manual. This evidence raises a factual issue whether the dangers of using the router were open and obvious.
Narvaez v. Wadsworth
, 165 A.D.3d at 408. While evidence that plaintiff read warnings in the product manual,
Achatz v. Rollerblade, Inc.
,
227 A.D.2d 199
, 199 (1st Dep't 1996), or failed to read the manual before using the product may defeat a claim for failure to warn,
Boyle v. City of New York
,
79 A.D.3d 664
, 665 (1st Dept 2010), plaintiff not only testified that he was never given the manual for the router, but also attests that, had the instructions for the router been available to him, he would have read them.
A warning on a product to read its manual before operating the product also may satisfy the duty to warn.
David v. Makita U.S.A., Inc.
, 233 A.D.2d at 146;
Banks v. Makita, U.S.A.
, 226 A.D.2d at 660. As depicted in a photograph of the router taken by an expert for Ridge Tool and Home Depot and authenticated by plaintiff, the router bore a label directing the user to read the Operator's Manual. As Pugh observes, the warning on the router itself nowhere warned of the risk of amputation from use of the router. Although the Operator's Manual for the router warned about the circumstances that caused plaintiff's particular injury, Pugh also concludes that the warning to read the Operator's Manual was an inadequate warning of the hazards to the user that these circumstances caused. The manual warns that:
Because of the extremely high speed of cutter rotation during a proper feeding operation, there is very little kickback to contend with during normal conditions. However, should the cutter strike a knot, hard grain, foreign object, etc., that would affect the normal progress of the cutting action, there could be a slight kickback. Kickback could be sufficient to spoil the trueness of your cut if you are not prepared. Such a kickback is always in the direction opposite the direction of cutter rotation.
Aff. of Rosario Vignali Ex. G, at 10. Notably, this advisory fails to warn of amputation or other injury from a kickback, although the manual does separately warn of cut or burn injuries from positioning hands near the cutter. Therefore factual issues remain regarding the adequacy of the warnings provided by the router and its Operator's Manual to the extent that they do not warn of amputation or other injury from a kickback.
Anaya v. Town Sports Int'l, Inc.
,
44 A.D.3d 485
, 487 (1st Dep't 2007).
D.
IMPLIED WARRANTIES
At oral argument August 13, 2019, Ridge Tool and Home Depot conceded that the implied warranties of merchantability and fitness for a particular purpose apply to plaintiff. The Operator's Manual for the router, however, includes an express disclaimer of the implied warranties of merchantability and fitness for a particular purpose. N.Y.U.C.C. § 2-316(2);
West 63 Empire Assoc., LLC v. Walker & Zanger, Inc.
,
107 A.D.3d 586
, 586 (1st Dep't 2013). Plaintiff merely points out that his claim for breach of the implied warranties is separate from his strict product liability claim, but does not challenge the disclaimer, which requires dismissal of his claim for breach of the implied warranties.
Denny v. Ford Motor Co.
,
87 N.Y.2d 248
V.
CONCLUSION
In sum, for the reasons explained above, the court grants defendants' motions for summary judgment to the following extent. C.P.L.R. § 3212(b) and (e). The court dismisses plaintiff's Labor Law § 200 and implied warranty claims and the negligence claims and all cross-claims against defendants Peter DiNatale & Associates, Plum, Ninety River West Corp., and Orsid Realty Corp., except Ninety River West Corp.'s and Orsid Realty Corp.'s cross-claims for contractual indemnification against Plum. The court dismisses plaintiff's Labor Law § 241(6) claim against Peter DiNatale & Associates and against Ninety River West Corp. and Orsid Realty Corp., except to the extent that the claim is against Peter DiNatale & Associates and Ninety River West Corp. based on 12 N.Y.C.R.R. § 23-9.2(a). The court also grants Ninety River West Corp.'s and Orsid Realty Corp.'s motion for summary judgment on their contractual indemnification claims against Plum. The court grants the motion by defendants Ridge Tool Pattern Company and Home Depot U.S.A., Inc., for summary judgment dismissing plaintiff's implied warranty claims, but otherwise denies their motion, and denies plaintiff's cross-motions for summary judgment on defendants' liability in full. C.P.L.R. § 3212(b).
This decision constitutes the court's order and judgment. The Clerk shall enter a judgment accordingly.
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Download Table | from publication: Escitalopram Versus SNRI Antidepressants in the Acute Treatment of Major Depressive Disorder: Integrative Analysis of Four Double-Blind, Randomized Clinical Trials | Recent data suggest that escitalopram may be more effective in severe depression than other selective serotonin reuptake inhibitors. Individual patient data from four randomized, double-blind comparative trials of escitalopram versus a serotonin/norepinephrine reuptake... | Citalopram, Major Depressive Disorder and Anti Depressant | ResearchGate, the professional network for scientists.
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Source publication
Escitalopram Versus SNRI Antidepressants in the Acute Treatment of Major Depressive Disorder: Integrative Analysis of Four Double-Blind, Randomized Clinical Trials
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Dayong Li
[...]
Recent data suggest that escitalopram may be more effective in severe depression than other selective serotonin reuptake inhibitors.
Individual patient data from four randomized, double-blind comparative trials of escitalopram versus a serotonin/norepinephrine reuptake inhibitor (SNRI) (two trials with duloxetine and two with venlafaxine extended r...
Antidepressants for anxiety disorders in late-life: A systematic review
Article
Full-text available
Meera Balasubramaniam
Pallavi Joshi
Poorvanshi Alag
[...]
Rajesh R Tampi
Background:
Anxiety in late-life is a frequently encountered condition. The aim of this review is to systematically examine the efficacy and tolerability of antidepressants for treating anxiety disorders among older adults.
Methods:
Electronic searches of The Cochrane Central Register of Controlled Trials and the standard bibliographic databases...
Citations
... This treatment assignment of SSRI vs. placebo was used as a covariate in the predictive models developed from the study.The SSRI, escitalopram (ESC) was approved by the US Food and Drug Administration (FDA) in 2002 for treatment of major depression. Its wide usage and efficacy in MDD were the reasons behind the selection of this particular SSRI.
73
ESC demonstrates higher selectivity of serotonin transporter compared to other FDA-approved SSRIs that contributes to its minor side effect profile.29,75 ...
Identifying Biomarkers for Treatment Response in Depression Using Neuroimaging and Actigraphy A Dissertation Presented by
Thesis
Dec 2022
Farzana Ali
No biomarkers for antidepressant efficacy in major depressive disorder (MDD) are available that can reduce patient suffering and healthcare costs from ineffective trials. This dissertation examined such biomarkers using modalities such as pretreatment neuroimaging including structural magnetic resonance imaging (sMRI), positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose (FDG), magnetic resonance spectroscopy (MRS) and actigraphy. The data came from a double-blind, randomized, placebo-controlled antidepressant trial in participants with MDD whose depression severity was quantified before, after one week and after eight weeks of treatment. The most promising neuroimaging biomarkers were detected from pretreatment PET/MRS (n=60) data using machine learning with a split of 67% for training and cross-validation, and 33% for testing. The training data underwent Synthetic Minority Over-sampling Technique and outlier removal using OneClassSVM, before being used in the eXtreme Gradient Boosting (XGBoost) algorithm to predict remission following eight weeks of treatment. The hyperparameters including subsampling, tree depth, number of trees and L1 and L2 regularization were optimized using GridSearchCV with 3 repetitions of stratified 10-fold cross-validation. In the test set, this model showed 62% sensitivity and 92% specificity with 77% weighted accuracy. Pretreatment metabolism of left hippocampus was the most predictive of all features.
In addition, cost-effective measures of motor activity related to circadian rhythm (CR), recorded using actigraphy devices, were collected from 40 participants during this trial. Parametric measures of average of CR (midline estimating statistic of rhythm, MESOR), amplitude, circadian quotient (CQ: amplitude/MESOR) and time of peak activity (acrophase) were obtained by applying cosinor analysis. Nonparametric measures including the average activity over 10 most and 5 least active hours were extracted along with intradaily variability and interdaily stability. These actigraphy measures from the first week of treatment did not predict depression severity after eight weeks of treatment. However, each percent improvement in depression from baseline during first week was associated with lower CQ (48.78 units) during that week (p<0.05).
The findings suggest that any predictive value gained from 60 minutes of pretreatment neuroimaging can save patients from weeks of ineffective trials. Moreover, motor activity can be valuable for remotely monitoring patients with limited access to mental health care.
... Our study findings are in keeping with the results of previous studies which report that escitalopram has a better tolerability profile as compared to venlafaxine. [25][26][27]29,
[32]
[33][34][35][36][37][38][39] It is noteworthy, however, that the evidence available is Western and the reported adverse effects in our checklist for both the molecules, has strengthened the present evidence in the literature, especially in an Indian context. It was seen that sexual dysfunction was negligible with venlafaxine which is in keeping with the evidence present in literature. ...
... The pattern of prescription is influenced by many factors, and tolerability is an important one. The literature strongly recommends SSRIs as a better-tolerated molecule as compared to SNRIs [25][26][27]29,
[32]
[33][34][35][37][38][39] such as venlafaxine, but it is important to note that Indian data are lacking. It can be safely said that the anticipated early adverse effects including hypertension affect a clinician's prescription in routine clinical practice. ...
Comparison of efficacy and tolerability of escitalopram and venlafaxine in treatment-naïve patients with unipolar nonpsychotic depression: Is there a need to revisit the prescription patterns?
Article
Full-text available
Harneet Kaur
Ajeet Sidana
ThiyamKiran Singh
Background: Depression is a common mental illness for which guidelines recommend selective serotonin reuptake inhibitors as the first-line treatment. As per the Sequenced Treatment Alternatives to Relieve Depression trial, the first antidepressant needs to be chosen carefully so that the number of treatment changes and therefore treatment resistance can be reduced. This study compared the efficacy and tolerability of escitalopram and venlafaxine, in treatment-naïve patients with first-episode, nonpsychotic unipolar depression. Methodology: In this prospective, randomized, open-label study, 77 patients with the International Classification of Disease-10 Diagnostic Criteria for Research diagnosis of depression were inducted and randomly assigned using a computer-generated random table to receive either escitalopram (10–20 mg/day) or venlafaxine (75–225 mg/day) in therapeutic range for a period of 12 weeks. The assessments included the Hamilton Depression Rating Scale (HDRS) and physical investigations at baseline and weeks 2, 6, and 12. A total of 60 patients completed the study and were included in the final analysis. Results: Thirty patients in each group (n = 60) enrolled with comparable baseline assessment except significantly higher HDRS in the venlafaxine group (29.87 ± 10.58) compared to escitalopram group (21.80 ± 4.41). At 12 weeks, the reduction in HDRS was significantly early and higher in the venlafaxine group (26.3 ± 9.7) than the escitalopram group (21.3 ± 4.2). Common adverse effects in the venlafaxine group included Gastrointestinal (GI) activation and vivid dreams which were seen till 2 weeks; the escitalopram group included sexual dysfunction which lasted till the end of the study. Conclusions: Both the molecules lead to significant reduction in HDRS scores across assessment. However, venlafaxine demonstrated superior efficacy and transient adverse effects compared to escitalopram, despite having higher HDRS scores at baseline. The results of the current study indicate that serotonin–norepinephrine reuptake inhibitors such as venlafaxine should be prescribed more often in routine clinical practice.
... This is in agreement with previous findings that chronic Reboxetine is associated with elevated NE levels ( Hajos et al., 2004). However, antidepressants acting selectively on one monoamine, such as Reboxetine, alleviate symptoms of depression in a limited percentage of patients (
Kornstein et al., 2009;
Eyding et al., 2010), suggesting that elevating NE alone may not be sufficient to alleviate depressive symptomatology in most depressed patients. The combination of Escitalopram and Reboxetine has been studied in clinical trials with limited placebo controls, and it was found that the combination reduced depressive symptomatology in some SSRI non-responders ( Rubio et al., 2004). ...
Computational Model of Antidepressant Response Heterogeneity as Multi-pathway Neuroadaptation
Article
Full-text available
Dec 2017
Mariam B. Camacho
Thomas J. Anastasio
Current hypotheses cannot fully explain the clinically observed heterogeneity in antidepressant response. The therapeutic latency of antidepressants suggests that therapeutic outcomes are achieved not by the acute effects of the drugs, but rather by the homeostatic changes that occur as the brain adapts to their chronic administration. We present a computational model that represents the known interactions between the monoaminergic neurotransmitter-producing brain regions and associated non-monoaminergic neurotransmitter systems, and use the model to explore the possible ways in which the brain can homeostatically adjust to chronic antidepressant administration. The model also represents the neuron-specific neurotransmitter receptors that are known to adjust their strengths (expressions or sensitivities) in response to chronic antidepressant administration, and neuroadaptation in the model occurs through sequential adjustments in these receptor strengths. The main result is that the model can reach similar levels of adaptation to chronic administration of the same antidepressant drug or combination along many different pathways, arriving correspondingly at many different receptor strength configurations, but not all of those adapted configurations are also associated with therapeutic elevations in monoamine levels. When expressed as the percentage of adapted configurations that are also associated with elevations in one or more of the monoamines, our modeling results largely agree with the percentage efficacy rates of antidepressants and antidepressant combinations observed in clinical trials. Our neuroadaptation model provides an explanation for the clinical reports of heterogeneous outcomes among patients chronically administered the same antidepressant drug regimen.
... An investigation into adverse drug effects of venlafaxine and duloxetine, which are both SNRIs, revealed that both these drugs had higher discontinuation rates as compared to SSRIs [28,29]. Additionally, other studies comparing the safety of venlafaxine versus escitalopram reported that even though the two drugs had comparable efficacy, escitalopram was better tolerated and was more cost-effective [30][31]
[32]
. There is some evidence that SNRIs are less well tolerated than SSRIs, and therefore SSRIs users might be more likely to continue their therapy and have better mental health outcomes as compared to SNRIs users. ...
Assessment of health-related quality of life, mental health status and psychological distress based on the type of pharmacotherapy used among patients with depression
Article
Full-text available
Apr 2017
QUAL LIFE RES
Drishti Shah
Varun Vaidya
Amit Patel
Mary Borovicka
Monica-Holiday Goodman
Abstract
PURPOSE:
Effectiveness of antidepressants is generally comparable between and within classes. However, real-world studies on antidepressant treatment and its consequences on the overall quality of life and mental health of individuals are limited. The purpose of this study was to examine the association of specific class of antidepressants with the health-related quality of life, psychological distress and self-reported mental health of individuals suffering from depression who are on monotherapy.
METHODS:
This retrospective, longitudinal study included individuals with depression who were on antidepressant monotherapy, using data from 2008 to 2011 Medical Expenditure Panel Survey (MEPS). Changes in health-related quality of life, self-reported mental health and psychological distress over a year's time were observed. A multinomial logistic regression model was built to examine the association between the class of antidepressant medications and the dependent variables.
RESULTS:
A total of 688 adults met the study inclusion criteria. No significant difference was observed in the change in Physical Component Summary (PCS), self-reported mental health and psychological distress based on the class of antidepressants. However, individuals on serotonin-norepinephrine reuptake inhibitors (SNRIs) (OR 0.337, 95 % CI 0.155-0.730) were significantly less likely to show improvement on Mental Component Summary (MCS) scores as compared to those on selective serotonin reuptake inhibitors (SSRIs).
CONCLUSIONS:
The study findings suggest that practitioners should be aware of the differences in the health-related quality of life of those taking SSRIs versus other classes of antidepressants. Further research needs to be done to determine the reason for SSRIs to show greater improvement on mental health as compared to SNRIs.
KEYWORDS:
Antidepressants; Depression; Health-related quality of life; Mental health; Psychological distress
... 8 The dimensional criterion (MDD with high levels of anxiety symptoms) is also introduced in a lot of clinical studies. 1,9,10 Anxious depression is often associated with MDD and concurrent high levels of anxiety (defined as a baseline anxiety/ somatization factor score of $7 from the 17-item or 21-item Hamilton Depression Rating Scale [HAM-D]) with a score on the Hamilton Anxiety Rating Scale (HAM-A) of $20 or HAM-A $9. 8 Based on these criteria, Fava et al found that
44
.0%-53.1% of MDD patients in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study had anxious depression. 1,9 According to the US National Comorbidity Survey, about 58% of those with lifetime MDD had comorbid anxiety disorders. ...
... However, results from various studies have shown that when compared to other SSRIs, escitalopram was associated with increased remission regardless of the baseline depression severity and was found to be effective in the treatment of severe depression. 23,[42][43]
[44]
The present study confirms this observation with the remission rates comparable at the end of the study between patients with different baseline anxiety and depression levels. ...
Efficacy and tolerability of escitalopram in treatment of major depressive disorder with anxiety symptoms: A 24-week, open-label, prospective study in Chinese population
Article
Full-text available
Lingjiang Li
Wang Xueyi
Maosheng Fang
Cuili Hu
Background
Significant anxiety symptoms are associated with poor clinical course and outcome in major depressive disorder (MDD). This single-arm, open-label study aimed to evaluate the efficacy and tolerability of escitalopram treatment in patients with MDD and anxiety symptoms.
Methods
Adult patients with MDD and anxiety symptoms (Montgomery–Asberg Depression Rating Scale [MADRS] ≥22 and Hamilton Anxiety Rating Scale [HAM-A] ≥14) were enrolled and received escitalopram (10–20 mg/day) treatment for 24 weeks. Symptom status was assessed by MADRS, 17-item-Hamilton Depression Rating Scale, HAM-A, and Clinical Global Impression Scale at baseline and the following visits. Quality of life was assessed by Short Form-12, and safety was evaluated by adverse events, laboratory investigations, vital signs, and physical findings.
Results
Overall, 200 of 318 (66.2%) enrolled patients completed the 24-week treatment. The remission (MADRS ≤10 and HAM-A ≤7) rate in the full analysis set (N=285) was 73.3% (95% confidence interval: 67.80, 78.38) at week 24. Mean (± standard deviation) MADRS total score was 33.4 (±7.13) and HAM-A score was 27.6 (±7.26) at baseline, which reduced to 6.6 (±10.18) and 6.0 (±8.39), respectively, at week 24. Patients with higher baseline depression and anxiety level took longer to achieve similar remission rates. Overall, 80 of the 302 (26.5%) patients included in the safety set reported at least 1 treatment-emergent adverse event (TEAE). Most frequently reported TEAEs (>2%) were headache (4.0%), nasopharyngitis (3.6%), nausea (3.0%), and dizziness (2.6%). Serious TEAEs were reported by 1.3% patients; no deaths were reported.
Conclusion
Escitalopram 10–20 mg/day was effective and well-tolerated in the long-term treatment of MDD with anxiety symptoms in adult Chinese population.
... Different defi nitions of TRD have been suggested (Berlim and Turecki 2007), from the lack of response to a single antidepressant (Souery et al. 1999;Thase 2001;Fava 2003), to the lack of response to two or more antidepressants of different classes (Thase 2001;CHMP 2002). In particular, the most widely used defi nition has been proposed in the Committee for Medicinal Products for Human Use (CHMP) guidelines: " a patient is considered therapy resistant when consecutive treatment with two products of different classes, used for a suffi cient length of time treating severely depressed patients (Bielski et al. 2004;Kennedy et al. 2009;Kilts et al. 2009;
Kornstein et al. 2009
) and patients who had not responded to a previous antidepressant (Lam et al. 2010), however this was a retrospective study and resistance was defi ned as non-response to only one previous treatment. ...
... The differences in effi cacy appeared more clear-cut in severely depressed patients (Kennedy et al. 2009;Ali and Lam 2011). When compared to venlafaxine or duloxetine (alone or pooled), escitalopram was found to be likewise more effective and better tolerated in MDD treatment (Montgomery and Andersen 2006;Kennedy et al. 2009;
Kornstein et al. 2009
). In a specifi c study, escitalopram was found to more likely result in remission without concurrent side effects in comparison with SNRIs (Signorovitch et al. 2011). ...
What to expect from a third step in treatment resistant depression: A prospective open study on escitalopram
Article
Dec 2014
WORLD J BIOL PSYCHIA
Daniel Souery
Raffaella Calati
Konstantinos Papageorgiou
Alzbeta Juven-Wetzler
Julien Mendlewicz
Objectives. Only few studies investigated treatment strategies for treatment resistant depression (TRD). The objective of this multicentre study was to evaluate TRD patients who did not respond to at least two antidepressants. Methods. A total of 417 patients, who failed to respond to a previous retrospectively assessed antidepressant (AD1), were firstly included in a 6-week venlafaxine treatment (AD2); secondly, those who failed to respond were treated for further 6 weeks with escitalopram (AD3). Results. Out of 417 patients who had failed to respond to previous treatment (AD1), 334 completed treatment with venlafaxine to prospectively define TRD. In the intent to treat (ITT) population in the first phase of the trial (AD2), responders to venlafaxine were 151 (36.21%) out of which remitters were 83 (19.90%). After phase one, 170 non-responders, defined as TRD, were included in the second phase and 157 completed the course. Of the 170 ITT entering the second phase (AD3), responders to escitalopram were 71 (41.76%) out of which remitters were 39 (22.94%). After the third treatment, patients showed a dropout rate of 7.65% and a rate of presence of at least one serious adverse event of 19.18%. Conclusions. Relevant rates of response and remission may be observed after a third line treatment in patients resistant to two previous treatments. A relevant limitation of this study was represented by the design: naturalistic, non-randomized, open-label, without a control sample and with unblinded raters.
... The findings showed that escitalopram might be superior to SSRIs and comparable to venlafaxine in the treatment of patients with MDD (Kennedy et al., 2006).The results of a recently meta-analysis in eight-week treatment trials of MDD indicated that escitalopram (10-20 mg/day) is superior to and more tolerable than duloxetine (60 mg/day) (Lam et al., 2008). Another systemic review involving clinical trials of escitalopram versus SNRIs (two trials with duloxetine and two with venlafaxine extended release) in outpatients (18-85 years of age) with moderate-to-severe MDD summarized that, over the eight week treatment period, escitalopram was as effective as but more tolerable than SNRIs (venlafaxine XR and duloxetine) (
Kornstein et al., 2009
). In addition, two meta-analyses showed that the efficacy and tolerability of escitalopram was superior to SSRIs and SNRIs (Kennedy et al., 2009; Lam et al., 2010). ...
Cognitive-Behavioural Therapy Combined with Antidepressants for Major Depressive Disorder
Chapter
Full-text available
Jan 2012
Narong Maneeton
... After sustained administration, escitalopram produces a faster desensitization of somatodendritic 5-HT1A autoreceptors in the DR than citalopram (El Mansari et al., 2005), an effect that probably accounts for the robust increase in cortical extracellular 5-HT levels ([5-HT]ext) observed after only 2 weeks of treatment (Ceglia et al., 2004). In humans, escitalopram demonstrates a rapid onset of antidepressant action, and recent data suggest that it may be more effective than other SSRIs and at least as effective as dual 5-HT/noradrenaline reuptake inhibitors in the treatment of major depression (Kennedy et al., 2009;
Kornstein et al., 2009;
Garnock-Jones and McCormack, 2010). Interestingly, SSRIs, such as paroxetine, fluoxetine and citalopram can also inhibit uptake of [3H]noradrenaline in rat cortical synaptosomes in vitro (Hughes and Stanford, 1996) and consequently enhance extracellular noradrenaline levels ([NA]ext) in the FCx and hippocampus after acute administration in rodents (Jordan et al., 1994;Shachar et al., 1997;Millan et al., 2001;Beyer et al., 2002;Bymaster et al., 2002;Koch et al., 2002;David et al., 2003;Kobayashi et al., 2008). ...
Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: An in vivo microdialysis study in mice
Jan 2012
BRIT J PHARMACOL
Hai T Nguyen
Bruno P Guiard
Alexandre Bacq
Denis J David
Alain M Gardier
BACKGROUND AND PURPOSE Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT]ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined.
EXPERIMENTAL APPROACH This study examined the effects of escitalopram, on both [5-HT]ext and [NA]ext in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT−/−) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]ext, either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT]ext elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT]ext and/or [NA]ext affected the antidepressant-like activity of escitalopram.
KEY RESULTS In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT]ext and [NA]ext. As expected, escitalopram failed to increase cortical [5-HT]ext in SERT−/− mice, whereas its neurochemical effects on [NA]ext persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters.
CONCLUSIONS AND IMPLICATIONS These experiments suggest that escitalopram enhances, although moderately, cortical [NA]extin vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET).
... For example, in the nonsponsored study by Cipriani et al. (2009), a multiple treatment meta-analysis of 117 randomized controlled trials (25,928 participants) from 1991 to 2007 showed that escitalopram is one of the two favored treatments in both efficacy and acceptability. When compared to serotonin and norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD), escitalopram is associated with a significantly lower duration of sick leave (Wade et al. 2008), as well as a better efficacy and tolerability profile
(Kornstein et al. 2009;
Lam et al. 2010). In addition, escitalopram has demonstrated a statistically significant doseresponse relationship in severely depressed patients on multiple outcome scales (Bech et al. 2004), which is not the case for other antidepressants. ...
Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter-a review of current understanding of its mechanism of action
Article
Sep 2011
PSYCHOPHARMACOLOGY
Huailing Zhong
Nasser Haddjeri
Connie Sánchez
Escitalopram is a widely used antidepressant for the treatment of patients with major depression. It is the pure S-enantiomer of racemic citalopram. Several clinical trials and meta-analyses indicate that escitalopram is quantitatively more efficacious than many other antidepressants with a faster onset of action.
This paper reviews current knowledge about the mechanism of action of escitalopram.
The primary target for escitalopram is the serotonin transporter (SERT), which is responsible for serotonin (or 5-hydroxytryptamine [5-HT]) reuptake at the terminals and cell bodies of serotonergic neurons. Escitalopram and selective serotonin reuptake inhibitors bind with high affinity to the 5-HT binding site (orthosteric site) on the transporter. This leads to antidepressant effects by increasing extracellular 5-HT levels which enhance 5-HT neurotransmission. SERT also has one or more allosteric sites, binding to which modulates activity at the orthosteric binding site but does not directly affect 5-HT reuptake by the transporter. In vitro studies have shown that through allosteric binding, escitalopram decreases its own dissociation rate from the orthosteric site on the SERT. R-citalopram, the nontherapeutic enantiomer in citalopram, is also an allosteric modulator of SERT but can inhibit the actions of escitalopram by interfering negatively with its binding. Both nonclinical studies and some clinical investigations have demonstrated the cellular, neurochemical, neuroadaptive, and neuroplastic changes induced by escitalopram with acute and chronic administration.
The findings from binding, neurochemical, and neurophysiological studies may provide a mechanistic rationale for the clinical difference observed with escitalopram compared to other antidepressant therapies.
... -Axis I and II compensated mental disorders do not constitute a contraindication to therapy if the subject is highly motivated and assisted by a psychiatrist and a multidisciplinary team[73,90] (B2). -If anti-depressant drugs are needed, serotonin re-uptake inhibitors are preferable (higher tolerability profile), especially escitalopram; antidepressant treatment should begin before antiviral therapy initiation[93,94,
95]
(B2). If antipsychotics are necessary, second-generation drugs are recommended (olanzapine, aripiprazole)[96][97][98] (B2). ...
Recommendations for the prevention, diagnosis, and treatment of chronic hepatitis B and C in special population groups (migrants, intravenous drug users and prison inmates)
Article
Full-text available
Aug 2011
DIGEST LIVER DIS
Piero L Almasio
Sergio Babudieri
Giorgio Barbarini
Maurizia Brunetto
Giulio Starnini
The global spread of hepatitis B virus (HBV) and hepatitis C virus (HCV), their high chronicity rates and their progression to cirrhosis and hepatocellular carcinoma, are major public health problems. Research and intervention programmes for special population groups are needed in order to assess their infection risk and set up suitable prevention and control strategies. Aim of this paper is to give health care professionals information on HBV and HCV infections amongst migrants, drug users and prison inmates. The manuscript is an official Position Paper on behalf of the following Scientific Societies: Italian Association for the Study of the Liver (A.I.S.F.), Italian Society of Infectious and Tropical Diseases (S.I.M.I.T.), Italian Federation Department's Operators and Addiction Services (FederSerD), Italian Prison Medicine and Healthcare Society (S.I.M.S.Pe.). The considered population groups, having a high prevalence HBV and HCV infections, require specific interventions. In this context, the expression "special population" refers to specific vulnerable groups at risk of social exclusion, such as migrants, prison inmates, and intravenous drug users. When dealing with special population groups, social, environmental and clinical factors should be considered when selecting candidates for therapy as indicated by national and international guidelines.
Join for free
| https://www.researchgate.net/figure/46_tbl3_26729732 |
Annular Solar Eclipse of 0203 Jan 30
This page is part of the EclipseWise.com Website. It uses Google Maps to create an interactive map of the Annular Solar Eclipse of 0203 Jan 30.
Annular Solar Eclipse of 0203 Jan 30
Introduction
This page features an interactive Google map
[1]
showing the regional visibility of the
Annular Solar Eclipse of 0203 Jan 30
. The Google map allows the user to zoom and scroll the map as desired. Clicking the cursor on any location will immediately generate a prediction of the eclipse circumstances from that location. The small global map to the right is for reference and illustrates the overall visibility of the eclipse (for an explanation of this map's features, see
Key to Solar Eclipse Maps
).
The interactive Google map below uses the
Web Mercator
projection to display the eclipse track. The large saddle-shapped region is the path of the Moon's penumbral shadow.This is the geographic region from which a partial eclipse can be seen. The northern and/or southern penumbral shadow path limits are plotted as green curves. The magenta loops represent the locus of all locations where the partial eclipse begins or ends at sunrise or sunset. Inside these regions the partial eclipse is in progress at sunrise or sunset. An orange curve also appears inside this region and represents the locus of all locations where the partial eclipse is at its maximum phase at sunrise or sunset. The
Key to Google Eclipse Maps
illustrates a map with each of these curves. You
MUST
be somewhere within the region enclosed by these curves in order to see the partial eclipse. Outside this region
no eclipse is visible
.
The narrow track running through rhe penumbral shadow is the path of the Moon'santumbralshadow. This is the geographic region from which the annulareclipse can be seen.The northern and southern path limits are blue and the central line is red. You
MUST
be somewhere within the central path (shaded zone framed by the blue lines) to see the annularphase of the eclipse. The eclipse is longest on the central line (red). The yellow lines crossing the path indicate the position of maximum eclipse at 10-minute intervals.
The red marker labeled
GE
is the point of
Greatest Eclipse
. The green marker labeled
GD
is the point of
Greatest Duration
. This is the location where the annulareclipse lasts the longest along the entire path. In this case, the
Greatest Duration
is 01m56.4s. This prediction does not take into account the mountains and valleys along the edge of the Moon. For the sake of speed and simplicity, the effects of the
lunar limb profile
are
NOT
used in the predictions and map presented on this page.
You can be hundreds of miles from the theoretical point of
Greatest Duration
and still enjoy annularitylasting within a second of the maximum possible (as long as you stay within several miles of the central line). It's much more important to watch the weather forecasts a day or two before the eclipse and choose a location with the best chance of a cloud-free sky during the eclipse.Good weather is the key to successful eclipse viewing - better to see a shorter eclipse from clear sky that a longer eclipse under clouds
[2]
.
Google Maps uses the
Web Mercator
projection, and therefore cannot accurately show areas around the poles. As a consequence, eclipse paths at high latitudes will appear highly distorted and may degrade into a series of straight line segments.
Note: Your web browser must have Javascript turned on in order to see a solar eclipse path plotted on Google Maps . See compatible browsers for more information.
Map centered on (latitude, longitude): Cursor position (latitude, longitude): Distance from last marker: on Show marker on click Clear Markers on Large map Eclipse Times in Pop-up Time Zone: Select a time zone UT1 GMT/London UT1+1 MET/MEZ UT1+2 EET UT1+3 Moscow UT1+4 GST UT1+5 PKT UT1+6 Bangladesh UT1+7 Java UT1+8 China UT1+9 JST UT1+10 Guam UT1+11 UT1+12 NZT UT1-11 Somoa UT1-10 Hawaii UT1-9 AKST/YST UT1-8 PST UT1-7 MST/PDT UT1-6 CST/MDT UT1-5 EST/CDT UT1-4 AST/EDT UT1-3 BST/ART UT1-2 VZT UT1-1 AT
User Directions
The zoom buttons (the 'plus' and 'minus' buttons to the lower right corner of map) are used to change the magnification
[3]
. The user's cursor can be used for navigating around the map. Just hold the left mouse button down while the cursor is on the map, and drag the map around to reposition it.The two map buttons (top left) let you switch between
map view
and
satellite view
.
Click anywhere on the map to add a blue marker. A pop-up window appears above the marker with the calculated eclipse times and duration of annularityfor that location (see explanation of
Eclipse Circumstances
below). The 'x' in the upper right corner of the pop-up window closes the pop-up window. Additional markers can be placed anywhere on the map. Move the cursor over a marker to reveal a pop-up window with the eclipse times for that position. The predictions in the pop-up window can also be displayed in a new web page via the
Eclipse Times Pop-up
button (just below the map and to the right). You can select and copy this infomation to paste into a word processor.
All the markers can be removed by using the
Clear Marker
button (below the eclipse map). Choose the
Large Map
check box to produce a bigger map (hint: enlarge the browser window to its maximum size before selecting the
Large Map
check box). This option is especially useful to users with large monitors.
Below the lower left corner of the map are three readouts. The first gives the geographic coordinates (latitude and longitude) of the map center while the second gives the geographic coordinates of the cursor. The third line gives the distance of the cursor from the last marker. For more information, see
Google Eclipse Map Instructions
.
Eclipse Circumstances
When you click on the map a blue marker is added and a pop-up window opens giving the
Eclipse Circumstances
calculated for that location. The predictions in the pop-up window can be divided into two sections.
In the top part of the window, the decimal
Latitude
and
Longitude
of the marker are given. The
Eclipse Type
(either
total
,
annular
or
partial
) seen from that position is given. The duration of
Totality
(or duration of
Annularity
) lists the length of the total (or annular) phase in minutes and seconds. The
Eclipse Magnitude
is the fraction of the Sun's
diameter
eclipsed. The
Eclipse Obscuration
is the fraction of the Sun's
area
eclipsed.
The bottom part of the window consists of a table listing the times for important stages of the eclipse. The
Event
column lists eclipse phase, followed by the date and time (both in
Universal Time
). Finally, the
Altitude
and
Azimuth
of the Sun is given for each event. The altitude is measured from the horizon (0°) to the zenith (90°). The azimuth is measured from due North and rotating eastward (North = 0°, East = 90°, South = 180°, and West = 270°).
Below the lower left corner of the map is a drop-down menu labeled
Time Zone
. By default, the
Time Zone
is set to UT1 (GMT/London). This is the time zone used in the
Eclipse Circumstances
pop-up window described above. The drop-down menu offers the user the choice of twenty-four different time zones around the world. After choosing a new time zone,click on a marker (or create a new one). The
Eclipse Circumstances
pop-up windows will now display eclipse times for this new time zone.
Important Note:
The eclipse predictions in this interactive map
DO NOT
include the effects of mountains and valleys along the edge of the Moon. Such corrections for the
lunar limb profile
may change the contact times and eclipse durations by ~1-3 seconds. The exact location of
Greatest Duration
may also change by ~10-20 kilometers.
Footnotes
1. Other interactive Google eclipse maps include those by
Xavier Jubier
and
Bill Kramer
.
↩
2. An excellent source for weather prospects for upcoming eclipses is meteorologist Jay Anderson's
Eclipsophile Eclipse Weather Page
.
↩
Prime Page: Annular Solar Eclipse of 0203 Jan 30
Orthographic Map: Annular Solar Eclipse of 0203 Jan 30 - global map of eclipse visibility
Google Map: Annular Solar Eclipse of 0203 Jan 30 - interactive map of the eclipse path
Path Table: Annular Solar Eclipse of 0203 Jan 30 - coordinates of the central line and path limits
Circumstances Table: Annular Solar Eclipse of 0203 Jan 30 - eclipse times for hundreds of cities
Saros 63 Table - data for all eclipses in the Saros series
| https://www.eclipsewise.com/solar/SEgmapx/0201-0300/SE0203Jan30Agmapx.html |
Hain Celestial benefiting from s.k.u. rationalization, cost savings | Bakingbusiness.com | August 29, 2017 20:21 | Baking Business
A strategic plan announced during the third quarter is bearing positive results.
Hain Celestial benefiting from s.k.u. rationalization, cost savings
The Hain Celestial Group’s net income for the year totaled $67,430,000, up from $47,429,000 the year before.
LAKE SUCCESS, N.Y. – The changes the Hain Celestial Group’s management team outlined this past June took hold in the fourth quarter of the company’s fiscal year and yielded results executives said are positive. While the company’s leadership team conceded there is more work to be done, they also presented a positive outlook for the year ahead.
Net income for the year ended June 30 totaled $67,430,000, equal to 65c per share on the common stock and an improvement compared to the previous fiscal year when the company earned $47,429,000, or 46c per share.
Sales for the year fell slightly to $2,853,111,000 from $2,885,374,000 a year earlier.
Irwin D. Simon, president and c.e.o. of the Hain Celestial Group
“We are pleased to have achieved sales growth in all of our business segments on a constant currency basis in the fourth quarter, despite an ever changing operating environment for food manufacturers and retailers,” said Irwin D. Simon, president and chief executive officer of the Hain Celestial Group, during an Aug. 28 conference call with financial analysts. “Building upon our core platforms and cost savings initiatives, our global team has made significant progress during the year executing on our strategic plan. The business momentum and operational improvements we experienced in the fourth quarter of fiscal 2017 reinforce our confidence in the tremendous opportunities ahead to generate the growth we know we are capable of achieving over the next several years.”
Hain Celestial's s ales for the period fell to $725,085,000 from $737,547,000 the previous year.
Sales for the period fell to $725,085,000 from $737,547,000 the previous year.
Key corporate initiatives outlined this past June included a focus on products and brands that represent 90% of the company’s business, stock-keeping unit (s.k.u.) rationalization and cost elimination through its Project Terra program.
For the quarter, Project Terra generated approximately $45 million in savings, in line with company expectations, Mr. Simon said. In fiscal 2018, the company has identified approximately $100 million in savings from its global operations.
Gary Tickle, c.e.o. of Hain Celestial North America
“Our s.k.u. rationalization program announced to you in June continues and impacted fourth-quarter top-line sales by $5 million, or 1.5% of net sales, which was in line with our expectations,” said Gary W. Tickle, c.e.o. of Hain Celestial North America. “As we mentioned, it was approximately 20% of our s.k.u.s in the U.S. that were rationalized. We had minimal impact of inventory realignment in our supply chain this quarter.”
Mr. Tickle called fiscal 2017 a “year of significant transformation” that included an investment and brand equity and consumer engagement across the company’s top 500 s.k.u.s and top 11 brands. In fiscal 2018, he expects the strategy to drive low- to mid-single-digit growth on the top line while improving EBITDA performance in line with sales growth.
During the call with the analysts, several asked about Hain Celestial’s relationships with Whole Foods Market and Amazon, and how Amazon’s effort to sell Whole Foods’ 365 brand on-line may affect the company. Mr. Simon said Hain Celestial does business with and has strong relationships with both and added:
“… We are a manufacturer and marketer of organic and natural foods,” he said. “We’ve got the infrastructure and supply (chain) in place that we built over the last 24 years. So, it’s just when you say you’re bringing this on, we’re bringing on private label, supply, manufacturing, it’s just not easy to push a button, go out there to get products like a conventional product.”
Amazon’s focus on low prices was also a topic of discussion.
“ … In regards to pricing, I think Amazon sees the opportunity of where Whole Foods prices were to bring them down,” he said. But, he added, Hain Celestial has profit margins it has to achieve and he expects the company to hit those margins.
Business Companies Baking Manufacturers Hain Celestial Group Financial Performance
| https://www.bakingbusiness.com/articles/32615-hain-celestial-benefiting-from-s-k-u-rationalization-cost-savings |
Remote Sensing | Free Full-Text | Power Line Extraction and Reconstruction Methods from Laser Scanning Data: A Literature Review
Electricity has become an indispensable source of energy, and power lines play a crucial role in the functioning of modern societies. It is essential to inspect power lines promptly and precisely in order to ensure the safe and secure delivery of electricity. In steep and mountainous terrain, traditional surveying methods cannot inspect power lines precisely due to their nature. Remote sensing platforms, such as satellite and aerial images, thermal images, and light detection and ranging (LiDAR) points, were utilised for the detection and inspection of power lines. Nevertheless, with the advancements of remote sensing technologies, in recent years, LiDAR surveying has been favoured for power line corridor (PLC) inspection due to active and weather-independent nature of laser scanning. Laser ranging data and the precise location of the LiDAR can be used to generate a three-dimensional (3D) image of the PLC. The resulting 3D point cloud enables accurate extraction of power lines and measurement of their distances from the forest below. In the literature, there have been many proposals for power line extraction and reconstruction for PLC modelling. This article examines the pros and cons of each domain method, providing researchers involved in three-dimensional modelling of power lines using innovative LiDAR scanning systems with useful guidelines. To achieve these objectives, research papers were analysed, focusing primarily on geoscience-related journals and conferences for the extraction and reconstruction of power lines. There has been a growing interest in examining the extraction and reconstruction of power line spans with single and multi-conductor configurations using different image and point-based techniques. Our study provides a comprehensive overview of the methodologies offered by various approaches using laser scanning data from the perspective of power line extraction applications, as well as to discuss the benefits and drawbacks of each approach. The comparison revealed that, despite the tremendous potential of aerial and mobile laser scanning systems, human intervention and post-processing actions are still required to achieve the desired results. In addition, the majority of the methods have been evaluated on the small datasets, and very few methods have been focused on multi-conductor extraction and reconstruction for power lines modelling. These barriers hinder the automated extraction and reconstruction of power line using LiDAR data and point to unexplored areas for further research and serve as useful guidelines for future research directions. Several promising directions for future LiDAR experiments using deep learning methods are outlined in the hope that they will pave the way for applications of PLC modelling and assessment at a finer scale and on a larger scale.
Power Line Extraction and Reconstruction Methods from Laser Scanning Data: A Literature Review
by Nosheen Munir * , Mohammad Awrangjeb and Bela Stantic
Institute for Integrated and Intelligent Systems, Griffith University, Nathan, QLD 4111, Australia
*
Author to whom correspondence should be addressed.
Remote Sens. 2023 , 15 (4), 973; https://doi.org/10.3390/rs15040973
Received: 25 October 2022 / Revised: 30 January 2023 / Accepted: 6 February 2023 / Published: 10 February 2023
(This article belongs to the Special Issue Remote Sensing for Power Line Corridor Surveys )
Abstract
Electricity has become an indispensable source of energy, and power lines play a crucial role in the functioning of modern societies. It is essential to inspect power lines promptly and precisely in order to ensure the safe and secure delivery of electricity. In steep and mountainous terrain, traditional surveying methods cannot inspect power lines precisely due to their nature. Remote sensing platforms, such as satellite and aerial images, thermal images, and light detection and ranging (LiDAR) points, were utilised for the detection and inspection of power lines. Nevertheless, with the advancements of remote sensing technologies, in recent years, LiDAR surveying has been favoured for power line corridor (PLC) inspection due to active and weather-independent nature of laser scanning. Laser ranging data and the precise location of the LiDAR can be used to generate a three-dimensional (3D) image of the PLC. The resulting 3D point cloud enables accurate extraction of power lines and measurement of their distances from the forest below. In the literature, there have been many proposals for power line extraction and reconstruction for PLC modelling. This article examines the pros and cons of each domain method, providing researchers involved in three-dimensional modelling of power lines using innovative LiDAR scanning systems with useful guidelines. To achieve these objectives, research papers were analysed, focusing primarily on geoscience-related journals and conferences for the extraction and reconstruction of power lines. There has been a growing interest in examining the extraction and reconstruction of power line spans with single and multi-conductor configurations using different image and point-based techniques. Our study provides a comprehensive overview of the methodologies offered by various approaches using laser scanning data from the perspective of power line extraction applications, as well as to discuss the benefits and drawbacks of each approach. The comparison revealed that, despite the tremendous potential of aerial and mobile laser scanning systems, human intervention and post-processing actions are still required to achieve the desired results. In addition, the majority of the methods have been evaluated on the small datasets, and very few methods have been focused on multi-conductor extraction and reconstruction for power lines modelling. These barriers hinder the automated extraction and reconstruction of power line using LiDAR data and point to unexplored areas for further research and serve as useful guidelines for future research directions. Several promising directions for future LiDAR experiments using deep learning methods are outlined in the hope that they will pave the way for applications of PLC modelling and assessment at a finer scale and on a larger scale.
Keywords:
power lines
;
LiDAR
;
span
;
conductor
;
extraction
1. Introduction
Electricity is essential to the functioning of contemporary societies. To ensure the uninterrupted distribution of electricity, power lines must be effectively monitored and maintained. Transmission networks, regional networks, and distribution networks are typical components of electrical networks. One of the most important parts of the power transmission system is the high-voltage power line, which makes it possible to send electricity over long distances with little power loss [ 1 ]. The transmission system network is expanding as a result of population growth and increased reliance on electricity. Due to the rapid expansion of transmission networks, it is therefore impossible to avoid mountainous terrains and forests within a power line corridor (PLC) [ 2 ]. The global length of high-voltage power lines has increased from 5.5 million kilometres in 2014 to 6.8 million kilometres in 2020 [ 3 ]. In the long-term, power lines are frequently obstructed by severe weather conditions (e.g., high temperature differences, humidity, and vegetation encroachment [ 4 , 5 ], which can amplify flash over discharge leading to large area blackouts, resulting in substantial financial costs and heavy national economic losses [ 6 , 7 ]. In order to ensure the safe and secure delivery of electricity, it is crucial to inspect the power lines promptly and precisely [ 8 ].
Traditional power line inspections are carried out through the use of field surveys. The inspectors keep an eye on the power lines and make estimation about the distance between them and the forest floor [
9
,
10
]. Due to the nature of this approach, the inspection cycle is lengthy and the workload is heavy. Some power line segments cannot be inspected on a regular basis due to the steep terrain and dense forest that surround them. On the other hand, helicopter methods have a lower detection rate because of the high speeds used and the crew’s inability to simultaneously observe all possible problem types. Both methods, however, are reliant on the observations of the human eye. The use of video recordings and various cameras in addition to visual inspections is now commonplace. It is necessary to cover a large area when conducting power line surveys, and remote sensing techniques offer interesting alternatives.
Recent developments in hardware and data processing techniques have advanced remote sensing technology. There are various modern remote sensing methods (optical sensors [ 11 , 12 ], synthetic aperture radars (SAR) [ 13 ], thermal imaging [ 14 ], mobile laser scanning (MLS) [ 15 ], and light detection and ranging (LiDAR) [ 1 , 7 , 16 ] as well as several other monitoring devices (such as satellite, airborne, and unmanned aerial vehicles (UAVs) [ 17 ]. Each of these techniques has its own advantages and disadvantages in terms of PLC mapping. Optical satellite and aerial images, for instance, operate near infra-red wavelengths and passively gather energy from the earth’s surface; these images are unsuitable for PLC mapping due to their passive mode; images cannot be captured in the dark and cannot extract or model power lines due to their thinness and proximity; however, they can detect wires [ 18 ]. In thermal imaging, sensors detect the infra-red radiation emitted by an object and create an image based on this data. Thermal imaging is not typically used for power line mapping and extracting PLC objects, but it is useful for detecting wire faults. SAR sensors take microwave images that can be taken in clouds as well but geometrical deformations and multipath scattering make SAR image analysis problematic for intricate power line structures.
Laser scanning technology captures and measures objects in the environment using laser beams. The 3D data generated by laser scanning are also referred to as a LiDAR point cloud. Scanning with lasers has come a long way in the last few years. Laser scanning systems, in contrast to conventional camera sensors, are not affected by lighting conditions because LiDAR can operate in the absence of external illumination [ 19 ]. Laser ranging information and the precise location of the LiDAR point can be used to create a 3D view of PLC [ 20 ], which is an excellent starting point for automated analysis. The resulting 3D point cloud makes it possible to accurately extract power lines and measure the distances between them and the forest beneath [ 21 , 22 , 23 ]. A point cloud created by LiDAR can be extremely dense and contains a wealth of information, thanks to its high precision, quick scanning speed, and ability to gather a large amount of spatial data.
A comprehensive review on various PLC surveying methods is given in Matikainen et al. [ 15 ], and it was concluded that airborne and land-based systems provide more detailed data than satellite images and are the most practical remote sensing method for extracting power lines. Numerous publications have focused on automated classification and reconstruction techniques for the extraction of power lines, specifically conductors. A typical procedure involves the generation of a digital terrain model (DTM), classification of the laser data to distinguish power line points from other objects, especially vegetation, and 3D modelling of the individual conductors. Previously, emphasis was placed on classifying power line points using supervised and unsupervised ALS methods; in addition, the methods were tested on very small datasets or without visual or quantitative results [ 24 , 25 ]. With the advancement of ALS technologies, however, new methods are focusing on robust approaches for single and multi-conductor extraction and have been tested on complex terrains with large data sets [ 26 , 27 ]. In addition, with the advent of mobile laser Scanning MLS and UAV, numerous researchers have proposed new extraction and reconstruction techniques for power lines utilising MLS and UAV platforms [ 28 , 29 ]. The purpose of this review is to provide a critical review of the state-of-the-art laser scanning-based techniques for the extraction and reconstruction of overhead power lines. The review will provide an overview of the techniques and discuss the advantages and disadvantages of each technique.
Nearly 35 studies are included in total, the majority of which were published in scientific journals and conference proceedings. Following the overarching objective stated previously, our focus will be on discussing various applications in which the proposed algorithms have been used, as well as their applicability in real-world situations. The fundamental concepts of analysis methods are presented, along with some representative quantitative analysis results, in order to demonstrate the capabilities of various remote sensing techniques.
Due to the broad scope of the subject and the volume of research articles, it was not possible to include all studies or details of analysis methods. To begin, the data collection methods used in the PLC survey using LiDAR technology have been discussed in
Section 2
. For each type of data, some fundamental principles are introduced first, with an emphasis on aspects pertinent to power line surveys. This enables us to discuss the general merits and drawbacks of various approaches. Then, studies in the literature pertaining to power line mapping are reviewed and discussed in light of the findings of previous studies on power line extraction and reconstruction in
Section 3
. Finally, a summary including the future possibilities is presented in
Section 4.1
and concluding remarks in
Section 5
.
2. LiDAR Data Collection Systems
Figure 1 shows categories of LiDAR data collection. In general, laser scanning systems are divided into two main categories:airborne- and terrain/ground-based systems [ 30 ]. Airborne acquisition allows us to cover large areas quickly. A terrain or ground-based acquisition system employs a LiDAR mounted on a vehicle or on a device on the ground (see Figure 2 ).
Figure 1. Different LiDAR data collection systems.
2.1. Basic Principles of Airborne- and Ground Based Laser Scanning
ALS uses LiDAR measurements from an aircraft (fixed-wings, rotary wings, UAV) to acquire environmental data (see
Figure 2
). The GNSS (Global Navigation Satellite System) and IMU (Inertial Measurement Unit) measurements reveal the sensor’s orientation. The sensor generates data in the form of point clouds with coordinates (
x
,
y
,
z
). Additionally, the location of the pulses as well as their intensity are recorded. When a laser ray is pointed at an object, the receiver can detect up to four echoes per pulse [
31
]. Targets produce different echo signals for the same ray. Multiple echoes can represent detect treetops, intermediate plants, the ground, and other objects. The number of returning echoes and height discrepancies can be used to analyse the data. Full-waveform laser scanning records the shape of returning echoes.
In recent years, rapid technological advances in UAV component and battery technologies have increased the viability of UAV-based data collection for power line inspection. The increased availability of lightweight sensor systems and the development of UAV-related legislation have contributed to UAVs’ commercial applicability.
Terrain laser scanning used ground-based remote sensing systems. These systems can be mounted on static tripods (Terrestrial Laser Scanning, TLS) or on vehicles (Mobile Laser Scanning, MLS). TLS scans closer to targets than ALS systems, allowing for collecting data with greater precision. In spite of this, MLS must travel on roads that do not always exist because of overhead high-voltage power lines.
The basic working principle of TLS and MLS is same as that of ALS, in In ground-based systems (TLS and MLS), the INS and the GNSS are mounted on vehicles or on tripods. These systems can move in all directions, including upwards. Once scans of a single area are complete, the tripod or vehicle is moved to another location to scan from another angle or capture data from a new area.
Stationary systems can produce more detailed and high-density point clouds because the sensor is kept perfectly still throughout the scan. This reduces the risk of point cloud outliers. Static systems can also move so multiple scans can be carried out of a single area from various angles, creating a more accurate and detailed picture of the environment.
2.2. Mapping of Power Lines from Airborne and Ground-Based Laser Scanning
The ALS data over power lines are typically collected by helicopter or by fixed-wing air planes, and the point density is typically in the tens of points per m
2
but can reach hundreds. On hard surfaces, the points have an absolute accuracy of 5–10 cm in the horizontal plane and 2–5 cm in the vertical direction [
32
]. Such information can be used to precisely map the shape of power lines. Because of the density and accuracy of the points, detailed mapping and monitoring of power lines and their surroundings are possible. Commercial companies have been mapping PLCs with LiDAR since 1995, and FLI-MAP has recently mapped thousands of kilometres of power lines [
31
,
33
]. A complete work flow of processing, analysis, and corridor clearance can be completed in less than 72 h as a state-of-the-art data acquisition method, allowing an airborne LiDAR data processing platform to provide uninterrupted rapid mapping services [
The use of UAVs carrying new sensors for electric power inspection has been developed largely since the end of the 20th century [ 35 ]. Given that the high-voltage power line facilities in remote or harsh environments are generally difficult to reach, UAV mapping presents huge advantages by saving manpower and producing more reliable results. UAV systems have been increasingly used by communities due to their low cost, less strict requirements for take-off and landing, and their ability to load different types of sensors (e.g., camera and LiDAR) [ 36 ]. As a light-weight and close-range ALS technology, UAV LiDAR, usually equipped with middle-sized or small laser sensors, has been rapidly developed for transmission line inspection as a time-saving and cost-friendly solution. It can directly generate dense point clouds in 3D with a higher level of precision compared to aerial optical imagery and video [ 37 , 38 , 39 ] because image-based techniques can produce noisy results from the stereo-matching stage [ 39 ]. According to comparative studies of power line monitoring, the accuracy of height estimation for poles and trees is clearly better when using UAV LiDAR data than aerial images [ 9 , 40 ]. Compared to robotic inspection [ 9 ], UAVs have higher flexibility and larger coverage.
UAV is likely to become a popular technique in the future because it increases data acquisition flexibility while decreasing costs. ALS sees power lines and their surroundings from above, whether from helicopters or UAVs, which is useful for mapping power lines and trees near them. However, it also means that vertical poles and small components are not always visible in the data. Tree cover can also reduce power line visibility, and weather conditions can limit the ability to fly over power lines [ 29 ].
A variety of UAV platforms have been used for power line surveys. Fixed-wing UAVs, in general, must fly higher and faster and are best suited for vegetation monitoring and rough inspection of long power lines, whereas helicopter and multi-rotor UAVs can acquire detailed images by hovering close to the objects [ 17 , 41 ]. Deng et al. [ 41 ] proposed a multi-platform system made up of different types of UAVs designed for specific missions.
Ground-based laser scanning is a relatively new technology that has been primarily used to precisely map urban and street environments. It is particularly well-suited for corridor-type applications (for example, roads), and power lines are well-defined corridor-type objects of interest to some extent. MLS and TLS enable simple deployment and data collection with high precision and detail for asset modelling and monitoring. The mapping is not limited to the power line; it can also generate accurate data on the terrain and vegetation adjacent to the line. Outside of the corridor’s roads, mobility can be accomplished by deploying an all-terrain vehicle (ATV) or a backpack-mounted LiDAR mapping system, also known as personal laser scanning (PLS) [ 42 ].
Figure 2. Power lines’ mapping systems [ 43 ].
Figure 2. Power lines’ mapping systems [ 43 ].
2.3. Advantages and Disadvantages of ALS, MLS and TLS in Power Line Mapping
The above-mentioned laser scanning systems types have their own advantages and disadvantages depending upon the application as shown in Table 1 . They are further described in detail below.
Table 1. Comparison of LiDAR systems mounted on different platforms.
The primary advantages of ground-based surveys over ALS surveys are the increased detail obtained from close proximity to the objects of interest and the ability to operate in inclement weather (e.g., wind). For example, MLS operates on the vehicle, brings it much closer to power lines than ALS (0–20 m in MLS vs. typically tens of metres in ALS). Thus, both the point density of TLS (up to 1000 points per m 2 at a 10-m range from the scanner) and the three-dimensional precision of MLS (2–3 cm in good GNSS conditions (see [ 44 , 45 , 46 ]) are significantly greater than those of the ALS data. Increased point density enables a more thorough mapping of the surrounding environment, while increased point cloud accuracy enables the retrieval of more precise features such as surface normals and pole or trunk diameters. Additionally, the MLS/TLS laser beam is smaller in size (i.e., footprint) than the ALS laser beam, allowing for more detailed mapping of pylons and assets. As a result, TLS and MLS produce a more precise map of the power line components and corridor than ALS does. MLS and TLS scanning geometry, in comparison to ALS’s, is better suited to mapping the components of power lines [ 15 ]. Because the ALS data are scanned vertically, it is difficult to detect power lines stacked on top of one another. From above, the uppermost power line casts a shadow on the ones below.
However, such power lines are easily visible in MLS data [ 21 ], as it is straightforward to control the sensor’s trajectory to collect complete data on the power line components. Cameras are frequently included in MLS systems, and image data can be used to model and monitor the condition of power line components such as insulators [ 47 ]. The MLS is an excellent choice for collecting up-to-date information about power lines and potential damage, which would be extremely valuable following a natural disaster such as a storm. The effort required to collect data for an MLS campaign is significantly less than that required to shoot an ALS campaign and flying in restricted areas and in moderate wind poses no problems. When a LiDAR system is mounted on a tripod to collect data statically, it suffers from two major drawbacks: (1) point density decreases as the proximity from the scanner increases, and (2) occlusion occurs when other objects are present in between.
The use of MLS to map power lines in urban areas is justified, given the difficulty and inefficiency of flying a UAV or helicopter there. There have been few reports on the use of MLS in areas other than the road network, including forests. When mapping power line corridors, areas outside the road network differ in several ways from urban and road environments, including the roughness of the ground surface, mobility constraints (e.g., vegetation, rough terrain, and rocks) and satellite visibility (trees blocking signals). As a result, the positioning accuracy of the MLS system is reduced, and the point density along the trajectory in the point clouds becomes more heterogeneous outside of the road environment. Thus, extracting power line components automatically outside of a road network is more difficult than in an urban or road environment.
Acquiring an TLS system is less expensive, and a variety of LiDAR sensors are available to meet the grid operator’s needs. Additionally, the operating costs are significantly lower than those associated with ALS. On the other hand, the TLS system cannot provide data covering a large area, particularly when the terrain is impassable to ATVs or other wheeled vehicles. Due to the lower acquisition and maintenance costs, multiple systems can be purchased for the price of a single ALS system, allowing for the use of a more time- and space-efficient fleet for increased mileage. However, ALS systems are often cost-effective for locating and surveying high voltage transmission lines in wide and forest areas where personnel surveys and access by vehicles and humans are exceedingly difficult. However, for larger projects, the airborne LiDAR system could be more cost-effective. This is because an airborne LiDAR system can cover more ground in a shorter space of time than terrestrial LiDAR system—saving time and budget.
3. Processing Methods
Figure 3 shows how LiDAR data are processed for power line extraction. Processing issues with point clouds are typically brought on by their high data volume. Point clouds’ high levels of detail make it difficult to properly extract power lines because they are packed with a variety of noise and other objects. To address this issue, methods available in literature first classify the power line scene to obtain power line points. Then, points for single conductors or multi-conductors are extracted to reconstruct them using mathematical models.
This section summarises numerous existing approaches that tend to remove undesired objects from the power line scenes to obtain the power line point class. They may begin with ground filtering, then execute supervised classification, or follow rules to identify power line points; however, the purpose is to obtain the power line point class. This step is an important prerequisite for the extraction and reconstruction of single or multiple conductor power lines.
Table 2 shows the summary of power line scene classification methods. The table details the classification procedures involved for extraction of power line points as a pre-processing step to remove unwanted object points or to extract power line points as one class. Typically, methods used supervised [ 48 ] or rules [ 49 ] to obtain power line points. The second column in Table 2 shows the classification type, followed by the method used for the given classification in the third column. The fourth column indicates whether ground filtering was applied prior to classification. The fifth and sixth columns describe the neighbourhood and features used for classification, followed by the density of evaluated data sets and the precision of the results in seventh and eight columns, respectively. Each of these columns of Table 2 is explained below in detail:
Figure 3. LiDAR data processing methods for power line mapping. ( a ) LiDAR point cloud data; ( b ) separation of power line points Section 3.1 , Table 2 ; ( c ) single power line extraction and reconstruction Section 3.2 , Table 3 ; ( d ) multi-conductor power line extraction and reconstruction, Section 3.2 , Table 4 .
Figure 3. LiDAR data processing methods for power line mapping. ( a ) LiDAR point cloud data; ( b ) separation of power line points Section 3.1 , Table 2 ; ( c ) single power line extraction and reconstruction Section 3.2 , Table 3 ; ( d ) multi-conductor power line extraction and reconstruction, Section 3.2 , Table 4 .
3.1. Classification of Power Line Scene
3.1.1. Classification Type
The second column of Table 2 shows the classification type. The present methods for classifying power lines can be divided into supervised classification and rules-based/unsupervised classification depending on the approaches used to solve the classification problem.
Table 2. Power line scene classification. PCA—Principal component analysis; ML—Machine learning; HT—Hough transform; NA—Not available; TIN—Triangulated irregular network; CSF—Cloth simulation filtering; RTF—Recursive terrain filter; DTM Digital terrain model; DSM—Digital surface model; RF—Random forest; JB—Joint boost; SVM—Support vector machine; EC—Euclidean distance.
Table 2. Power line scene classification. PCA—Principal component analysis; ML—Machine learning; HT—Hough transform; NA—Not available; TIN—Triangulated irregular network; CSF—Cloth simulation filtering; RTF—Recursive terrain filter; DTM Digital terrain model; DSM—Digital surface model; RF—Random forest; JB—Joint boost; SVM—Support vector machine; EC—Euclidean distance.
Author Method Density Results Accuracy (%) Type Technique Ground Filtering Neighbourhood Feature (Pt/m 2 ) Jwa [ 50 ] -Rules -Segmentation -Filtering × -Voxel -HT -Eigen -Density 24 NA Munir [ 51 ] -Rules -Statistical analysis -Height -Voxel -Vertical profile 24 NA Huan [ 52 ] -ML -Object-based -RF × -Segment surface -Eigen -Intensity NA 75.3 Liang [ 25 ] -Rules -Software × NA NA 1.2 NA Yang [ 53 ] -Rules -Height filtering TIN NA NA 41–100 NA Melzer [ 54 ] -Rules -Culling filtering -DTM -2D grid NA 25.5 NA Otega [ 55 ] -Rules -Statistical -Image-based × -Pixel -Height -Intensity -Return number 307–402 97.4 Zhang [ 29 ] -Rules -Statistical -Height -DEM -DSM -2D grid -Density -Height 307–402 96 Guo [ 56 ] -ML -Point-based -JB × -Voxel -Sphere -Cylindrical -Geometric -Radiometric -Topographic NA 88.69 Zhou [ 57 ] -Rules -Segmentation -Height -2D grid -3D grid -Height 213.6 98.18 Jung [ 28 ] -Rules -Height -Image filtering -Morphological -3D grid -Eigen 213.6 NA Lehtomaki [ 58 ] -Rules -PCA -Software -Voxel -Eigen NA NA Zhenwei [ 59 ] -Rules -PCA -CSF -K-d tree -Eigen NA NA Fan [ 60 ] -Rules -Filtering -DTM -Height -Voxel NA NA NA Gaha [ 61 ] -Rules -EC -RANSAC -Morphological -Cylindrical NA NA NA Yadav [ 19 ] -Rules -Segmentation -Height -2D grid -Density NA NA Cheng [ 21 ] -Rules -Filtering -Height -Voxel -Density -Eigen -HT 19 NA Guan [ 22 ] -Rules -Filtering -TIN -Voxel -Density -size -shape 286.4 NA zhang [ 62 ] -ML -Object-based -RF × -Segment surface -Eigen -Intensity 1.2 75.3 Kim [ 48 ] -ML -Object-based -RF -RTF -Segment -line 30 98.5 Kim [ 63 ] -ML -Point-based RF -RTF -Voxel -Sphere - Geometric -Radiometric -Topographic 30.29 98.5 Wang [ 10 ] -ML -Point-based -SVM Tiff toolbox -Cylindrical - Sphere -Slant cylindrical -Geometric distribution 30 98.04
Supervised classification is the classification of PLC points into different classes using a machine learning classifier. Machine learning is a powerful supervised statistical method that can be used to separate power line points from 3D LiDAR data. Popular classifiers for laser point classification include Support Vector Machine (SVM) [ 10 , 62 ], Random Forests [ 48 , 64 ], JointBoost [ 56 ], and others. Thus, supervised classification necessitates training data, features, and a classifier.
The need for training data is the greatest drawback of supervised algorithms, yet they are excellent for multi-class classification. By utilising machine learning and automatic feature selection, a significant amount of the arduous design and programming work inherent in conventional voxel feature classification methods is eliminated. Consequently, for complicated landscapes due to their efficiency, machine learning classification techniques are preferred to traditional/rule-based classification techniques for classifying objects with many kinds.
Rule-based classification attempts to discover general rules that are based on piecewise linearity and other geometric characteristics of power lines. Usually, this approach focuses on specific object types. It can attempt to discover general rules that can be used to classify point clouds of many different kinds of landscapes, but a disadvantage is that it makes many assumptions. This classification approach does not require training data; hence, it is unsupervised. As rules are derived from the data sets, therefore the classification rules are not necessarily transferable from one point cloud to another.
3.1.2. Method
An approach based on supervised classification is typically used object-based [ 48 ] and/or point-based [ 63 ] methods for classification (see Column 3, Table 2 ). Segmentation-based classification methods aggregate related objects in segments using different algorithms such as surface-grown [ 62 ], region-grown [ 52 ], and extract features from each segment. Usually, this approach focuses on classification of specific object type and divides all point clouds into one geometric form, which is irrational. Despite the limitations, segment-based classification methods have two main benefits over point-based classification methods: (i) segments help compute geometric features, relieving the need for neighbourhood optimisation [ 56 , 65 ] and (ii) segments give several new attributes that can be used to apply semantic rules [ 52 ]. On the contrary, the point-based classification separates the point clouds into different classes directly. Segment-based classification methods produced low accuracy for wire class if planes are used to detect object which is not suitable for wires [ 52 , 62 ]. These methods are good for building classification but offer low accuracy for wires as wires are of line geometric shape. Kim et al. [ 48 ] achieved better accuracy as they remove the ground point beforehand and used lines to detect segments which are suitable for wires.
On the other hand, rule-based classification is on hierarchical rules to achieve classification [ 28 , 60 ]. These rules may include statistical analysis [ 50 , 51 ] or hierarchical filtering procedures [ 21 , 28 ].
3.1.3. Ground Filtering
The fourth column of Table 2 shows different methods to perform ground filtering prior to classification. Ground and height filtering is critical prerequisites for reducing unwanted objects. The point cloud data for power line extraction include not only power lines but also a large number of outliers that are lower than power lines (ground, shrubs, low buildings, and so on), which will impede extraction. Ground is considered the most dominant class in datasets, whether from the urban or forest areas. The elimination of the dominant class improves classification accuracy [ 48 ] and makes the following step more efficient [ 28 ]. Ground point classification is an important step in creating a DTM (Digital Terrain Model) from LiDAR point cloud.
Researchers have used a variety of LiDAR data ground filtering algorithms, such as morphological ground filtering [ 28 , 61 ], cloth simulation [ 60 ], triangulated irregular network (TIN) [ 22 ], and RTF (Recursive Terrain Filter) [ 63 ]. The TIN densification filtering algorithm is thought to be robust and stable for modelling discontinuous surfaces such as urban areas [ 66 , 67 ]. In addition, a simple morphological filter (SMRF) and a multi resolution hierarchical filter (MHF) rank first in urban and forest areas, respectively [ 68 ]. The cloth simulation filtering (CSF) algorithm has recently gained popularity on relatively flat terrain. Because it has small number of parameters and simple to configure, most objects in the cropped data are lower than power lines.
Since there is typically vegetation below power lines, some methods use height criteria to remove LiDAR points below or above the lines. These height thresholds are 4 m [ 28 ], 6 m [ 22 ], and 5 m [ 60 ]. However, height filtering alone is ineffective because tall or long buildings or trees will not be eliminated. For example, points which are 4 m above the ground are the candidate points for power lines. However, If the terrain is complicated, it is impossible to eliminate ground points using the absolute height of the data points alone.
3.1.4. Neighbourhoods
For classification of power lines either by using supervised or unsupervised methods, methods make use of different 2D [ 19 , 55 ] and 3D [ 50 ] neighbourhoods to compute the properties of individual points for power line point classification (see forth column Table 2 ). The 2D neighbourhood either utilize a grid to interpolate the 3D point cloud into 2D grid as a raster image, and each grid (pixel) represents one object points [ 55 ], or the methods divide the point cloud onto 2D grid data [ 19 ]. The 2D neighbourhood provides the advantages of efficient management of enormous quantities of LiDAR. However, the grid-based neighbourhoods implicitly assume that each grid represents one object only; however, pixel represents only, vertical overlaps exist between wire and terrain, vegetation and wire, wire and pylon, so this the main limitation of the grid-based neighbourhood.
Determining the type and size of a neighbourhood is vital [ 63 ]. Methods select scale values using heuristic or empirical knowledge of the scene or data. Large neighbourhood sizes are efficient, but they may contain several object points, whereas small neighbourhood sizes may have few or no object points and require more time to estimate features. The smaller neighbourhood makes it more difficult to identify wires and other objects. Neighbourhoods can be spherical [ 56 ], cylindrical [ 64 ], voxel [ 63 ], or k-closest [ 10 ]. Wang et al. [ 10 ] introduced a new neighbour (slant cylindrical) based on power line direction. Mclaughlin [ 69 ] discussed the disadvantage of using ellipsoid neighbourhood in their paper, i.e., if neighbourhood has the intersection for vegetation and transmission line will lead to in classified data. If an ellipsoid grid has a few points in direction of power lines, they will be classified as vegetation. Features can be derived from one neighbourhood type with a variable scale parameter or from many neighbourhoods.
The sphere-based method was more exact and reliable and had a high success rate than the voxel-based method. Nevertheless, due to its quick feature extraction, voxel-based neighbourhood can rapidly categorise large-scale corridor data. Mostly, the methods voxel-based neighbour hood for rules-based classification (see Table 2 ). Wang et al. [ 10 ] compared the classification of power line scene and argued that spherical neighbourhood yielded superior results in comparison to voxel, cylindrical, and k-nearest neighbourhood, and also claimed that slant cylindrical provided the best performance. Determining the ideal neighbourhood size for each location is still challenging unfortunately, as these neighbourhood optimisation methods necessitate repeated calculations of eigenvectors and eigenvalues for each point; hence, they are somewhat time-consuming; this is the primary drawback of this type of classification [ 52 ]. In object-based supervised classification, the segment is considered as neighbourhood, and each segment represents geometric structure by using model-fitting-based methods or region-growing-based methods [ 52 ].
3.1.5. Feature
The proper identification of power line points is contingent on the extraction of valuable features that can differentiate power lines from other objects [ 10 ]. There are two primary kinds of features for identification power line points: reflectance-based or radiometric features and topographic or geometric features. These features can be estimated using 2D or 3D neighbourhood or directly from the segments. Frequently, radiometric parameters are associated with the intensity [ 25 ] and echo [ 55 ] captured by scanner systems. Therefore, the uniqueness of these types of characteristics is strongly dependent on the signal quality of the scanner. The common sets of features that are used for a 2D neighbourhood are Hough transform (HT), height, intensity and return number. The groups for power line components have lower and less diverse returns than the rest of the categories [ 55 ]. Power lines, pylons or dense vegetation areas imply a low reflectivity and hence show low intensity values. However, power lines have very similar low intensity values to trees, which made it difficult to discriminate them from their intensity values [ 25 ]. The initial classification by using intensity, echo, and return by the first can include false positives and require post processing to improve classification accuracy [ 25 , 55 ].
The 3D features are computationally extensive but preserve the 3D details. The common sets of features in 3D neighbourhood are eigenvalues (power lines represent very large); HT to find the lines and density which is low for power line points in a given neighbourhood as compared to pylons and vegetation. The HT is an effective tool for straight line detection. However, the standard HT incurs a high computational cost and often results in the detection of spurious lines [ 25 , 55 ]. The computation of eigenvalue ratio is much faster than HT [ 50 ]. The contemporary methods for determining power line characteristics make extensive use of geometric features [ 52 ]. The 3D features provide greater precision than grid-based features [ 63 ]. Their characteristics are more suited for objects that overlap.
It is important to note here, for object-based supervised classification, that the features are extracted from segment characteristics. These characteristics contain qualities between objects. Segmentation-based features are helpful to compute geometric features, relieving the need for neighbourhood optimisation [ 56 , 65 ] methods, and segments give several new attributes that can be used to apply semantic rules [ 52 ]. However, this approach focuses on classification of specific object type.
3.1.6. Density and Classification Accuracy
The last column of Table 2 shows the classification accuracy. Most of the rule-based methods lack classification accuracy results. The majority of methods for rule-based classification use this technique as a pre-processing step for the extraction of single power lines. The elimination of ground points prior to classification improving the classification accuracy can be seen in Table 2 [ 10 , 63 ]. This is due to the fact that ground is a major class while pylons and wires are minor classes, so the imbalanced training will affect the classification accuracies. Kim et al. [ 64 ] observed that imbalanced learning reduced classification accuracy. It can also noted that the RF [ 63 ] and SVM [ 10 ] classifiers yielded better classification accuracies, i.e., 98% as compared to the JB classifier [ 56 ], i.e., 88%. In addition, Kim et al. [ 48 ] used segment as a line for feature extraction as compared to surface [ 52 , 62 ] and yielded better results. Overall, classification using multi-classifier achieved the highest classification accuracy [ 64 ]. Post-processing, such as contextual limitations, can also improve classification. Guo et al. [ 56 ] improved power line classification accuracy from 86.5% to 87.1% by adding graph-cut segmentation as a post-processing step.
3.2. Power Line Extraction and Reconstruction
After separating power line points from other object points such as vegetation, pylons, and buildings, the next step is to identify the points that belong to individual power lines. As mentioned in Section 3.1 , the previous methods classified PLC points into various classes using both supervised and unsupervised methods. However, for reconstruction, the point cloud data have to be classified, and points on single power lines need to be rendered. The wires are very thin as compared to buildings, trees and pylons; thus, the actual number of points reflected from wires is far smaller than the number of input points. This issue makes single power line rendering very difficult [ 27 ]. In this category, the techniques for single and multi-conductor power line extraction and reconstruction have been reviewed. The proposed methods, algorithms, and results are compared, and their real-time application effectiveness is estimated.
Table 3. Single power line extraction using ALS. LS—Least square; PL—Power line; HT—Hough transform; CLF—Compass line filter; EC—Euclidean clustering; NM—Numerical method; SC Stochastic constraints; NA—Not available; C p —Completeness; C r —Correctness.
Table 3. Single power line extraction using ALS. LS—Least square; PL—Power line; HT—Hough transform; CLF—Compass line filter; EC—Euclidean clustering; NM—Numerical method; SC Stochastic constraints; NA—Not available; C p —Completeness; C r —Correctness.
Author Method Extraction Reconstruction Density Results Extraction Results Reconstruction Grid Span Curve Technique Pt/m 2 Point-Based Object-Based Fitting Error Mclaughlin [ 69 ] -Piecewise -Mean and dominant Eigen -Ellipsoid ✓ -Catenary -NM 2.5 NA C r 72.1 NA Jwa [ 50 ] -Piecewise -CLF outlier testing -Cuboid ✓ -Catenary -SC 24 NA -C p 96 <0.05 m sohn [ 70 ] -Piecewise -CLF outlier testing -Cuboid ✓ -Catenary -SC NA NA -C p 100 <0.05 m Guo [ 71 ] -Profile segmentation -Geometry matching ratio NA ✓ -Polynomial -RANSAC NA NA -C r 89.8 NA Munir [ 72 ] -Profile segmentation -HT -Geometry matching ratio NA ✓ -Polynomial -LS 23.6 to 56.4 NA -C p 97.6 -C r 99.5 0.0001 m Liang [ 25 ] -CLF -RANSAC -Linear model NA × -Polynomial -NM 1.2 C r 96.5 NA NA Yang et al. [ 53 ] -EC -RANSAC 3D grid × -Catenary -LS 1.2 NA -C p 98.1 -C r 95.9 NA Melzer [ 54 ] -Clustering -HT -Neural gas network NA ✓ -Catenary -RANSAC NA NA NA NA Zhang [ 29 ] -Clustering -Eigen -Height -Spatial continuity -CLF -3D grid ✓ -Catenary -RANSAC 307–402 -C p 96.3 -C r 96 AN 0.241 m
Table 3 , Table 4 and Table 5 summarise the methods used for single conductor and multi-conductor extraction using ALS and MLS data, respectively. All of these approaches use some methods such as clustering and geometry matching, segmentation to extract the points belonging to each power line in single or multi-conductor configuration (see Column 2 of Table 3 , Table 4 and Table 5 ).
3.2.1. Method
The traditional single power line extraction methods are mainly based on region growing [ 50 , 69 ]. The algorithms begin with an arbitrarily chosen neighbourhood (ellipsoid or voxel) in the direction of power line, and then generate models by estimating parameter of members in group and iteratively add adjacent matched neighbourhoods with similar parameters, progressively refining the catenary parameters. However, the extraction and reconstruction of individual power lines could fail in some situations causing power line to be divided in two or more power lines or undetected. This is primarily due to sparseness of the data, resulting in a failure to first compute a reliable local model or to find the connected neighbourhood. These approaches are extremely dependent on the direction of the power line. Using campus line filter (CLF), Jwa and Sohn [ 50 ] approximated the power line direction of a classified power line points. Similarly, Mclughlin [ 69 ] emphasised in their work that the orientation of the power lines should be parallel to the major axis of the ellipsoid neighbourhood; otherwise, the approach will fail to extract power lines.
In order to overcome these challenges, several clustering techniques, such as Euclidean clustering [ 53 ] and agglomerative clustering [ 73 ], have been utilised to group individual power line points into clusters and power line clusters merged using spatial continuity and local collinearity [ 29 , 53 , 74 ]. However, clustering can work in ideal situations when the density of data is high, and there are moderate gaps between power lines. However, in practice, the extraction and reconstruction of power line could fail in certain situations, resulting in multiple clusters for the same power line because the algorithm is unable to find the merging clusters due to the gap [ 28 , 53 , 74 ].
Typically, prior to clustering, some approaches convert the classified data to a 2D grid [ 19 ] or an image [ 75 ], and then utilise HT [ 75 ] or RANSAC [ 58 , 61 ] to extract the lines from the classified power line points. In the grid size, the power line should be isolated within a horizontal segment. In addition, the resolution of the grid is determined by the sparsity of a given LiDAR point cloud. A low resolution will reduce the size of the image, making the individual objects on the power line appear too small, but a high resolution will make the points in image too sparse.
The HT algorithm is an effective tool for obtaining the straight line detection. However, the standard HT incurs a high computational cost and often results in the detection of spurious lines [ 25 , 25 ]. However, for the RANSAC algorithm, the computational complexity is highly sensitive to the user parameters. In both cases, if the two wires are located close to each other, it is difficult to separate them.
Some other approaches [ 71 , 76 ] used profile segmentation with a region growing algorithm to connect comparable points belonging to each individual line in a given span in order to circumvent the limitations of clustering and piecewise algorithms; however, they largely relied on pylon positions.
3.2.2. Grid Transformation
For extraction of single or multi-conductor power lines, some methods transform the point cloud into a 2D grid [ 19 , 69 ] or to a 3D voxel grid [ 28 , 51 , 77 ]. The 2D grid-based methods have limitations, as they interpolate the 3D point cloud into a 2D grid, which causes the overlapping of multiple objects [ 51 , 73 ]. Among these grids, a voxel grid is considered as more efficient and reliable [ 29 ]. The grid selection and size is an important factor for the extraction of single power line points. The 3D voxel grid helped to compute the geometric features of power line by ensuring that other objects were separated from voxel blocks containing power lines [ 29 ].
The size of grid depends on various factors such as sparseness of data [ 69 ], the cross section of bundle conductors [ 29 ], and span length [ 50 ]. To determine an adequate neighbourhood size, two parameters were considered: the distance between two power lines to avoid a situation in which the target points are mixed with other power line points; and the density of the community to provide sufficient points. Usually, the size of 5 × 5 × 5 m 3 for voxel is used in many papers [ 29 , 51 ].
3.2.3. Sub-Conductor
Extraction of individual sub-conductors from bundles is generally an uncommon area of research; most existing methods extract power line points as a class or consider bundle conductors as a single conductor for power lines extraction and modelling [ 51 ]. Multi-conductor spans comes in different configurations, i.e., four sub-conductors in a bundle or two sub-conductors in a bundle. As shown in Figure 4 , these conductors in a bundle are very close to each other, and the extraction of sub-conductors is not an easy task. Notably, the precise modelling of power line is highly reliant on the accurate extraction of each sub-conductor. Identification and extraction of bundle conductors are essential for accurate modelling and mapping of each power line. A few studies have concentrated on extraction and reconstruction of sub-conductors.
Figure 4. Sub-conductors configuration. ( a ) high-voltage transmission line tower with bundles in sub-conductors configuration; ( b ) magnified version of bundle from ( a ); ( c ) LiDAR data for span with bundles in four sub-conductors configuration; ( d ) magnified version of bundle from ( c ); ( e ) LiDAR data for span with single power line; ( f ) magnified version of bundle from ( e ).
These methods start with classification of the power lines scene using the method described in Section 3.1 . Column 4 of Table 4 shows the methods which attempt to extract and reconstruct a sub-conductor. For sub-conductor extraction, most of the work conducted by Munir et al. [ 26 , 51 , 75 , 76 ] using both image-based and point-based methods. All techniques utilised ALS data with multi-bundle configurations on corridors that traverse outside of urban regions. These approaches have been evaluated on datasets with a very low point density. With excellent precision, Munir et al. [ 26 ] and Zohu [ 74 ] are able to extract up to four sub-conductors.
3.2.4. Span
A few approaches also indicated that pylon placement can facilitate the extraction of power lines in the form of spans [ 27 , 51 ]. These methods make use of the distribution characteristics of power lines, i.e., similarity, parallelism, identical sag and direction between neighbouring pylons. The additional information, e.g., power line distribution within a span and contextual pylon data, helps with the improvement of power line extraction and reconstruction. Locating spans relies heavily on pylon detection. These methods first detect the location of pylons in order to locate spans, or they use predefined locations from the dataset. This will reduce the size of the point cloud, making it easier to extract power lines in each span [ 71 ]. Additionally, it reduces the difficulty of analysing LiDAR data.
Extracting pylons prior to power lines is easier in forest settings because the size and height of pylons is much larger than that of trees, and pylons in forest locations are in predefined corridors [ 26 ], Nonetheless, if pole recognition had been performed prior to the removal of electricity lines in metropolitan areas, a significant proportion of tree trunks would have been misidentified as poles because of height similarities [ 58 ].
3.2.5. Reconstruction
After rendering individual power lines, they are using different fitting algorithm. Due to the fact that the power line model is nearly identical to the catenary and, with sagging posture, power lines are often modelled with a second order polynomial equation in 3D [ 27 , 78 ], catenary [ 29 ], and parabola [ 19 ]. As discussed above, some methods have carried out extraction and reconstruction together using a piece-wise technique [ 69 , 79 ]. Alternatively, power lines can be modelled separately with a straight line in the horizontal plane and catenary in the vertical plane by estimating parameters using numerical methods [ 73 ].
In literature, many mathematical models such as catenary curve, piecewise line, and parabola have mostly been used in conjunction with a RANSAC [ 29 , 54 , 71 ] or least square (LS) [ 53 ] algorithm for power line reconstruction. Many methods used CLF to find direction and then used RANSAC [ 78 ] orthogonal distance [ 29 ] to find the points that belong to each line. RANSAC [ 71 , 74 ] and least square [ 53 ] algorithms are also used for estimating parameters for the catenary curve. The RANSAC algorithm is more robust to the outliers [ 72 ], but the reconstruction model heavily relies on reliable initial parameter settings [ 71 ] and on effective seed section [ 71 ].
3.2.6. Results
Although there have been many advances in power line extraction from point clouds, notable limitations can be summarized in terms of efficiency, versatility, and robustness. Reliance on supplemental data, such as predefined pylon locations [ 71 ] and pre-classified data, limit the versatility of the approaches to a specific system (e.g., MLS, ALS, TLS)). Furthermore, many approaches have been tested and optimised on a limited number of datasets and, therefore, may not scale to work effectively with other datasets acquired in diverse conditions (e.g., urban, rural, and forest areas) and a reliable parameter setting is still an issue in many studies. It is impossible to draw a precise conclusion about achievable accuracy or compare various approaches due to the wide variety of study areas and quality evaluation methods. Some methods [ 26 , 27 , 28 ], have collected the ground truth points to estimate the point-based completeness, correctness and quality. While some other methods [ 19 , 50 , 61 ], have estimated the object-based accuracy by counting and comparing the number of power lines detected, undetected, and split.
Only a few visual demonstrations have been used to present the findings in numerous studies. Studies with larger tests conducted under realistic conditions and numerical quality analyses appear to be rare. Due to the slenderness of power lines, the laser point density must be relatively high for effective power line extraction. The extraction process can be complicated by vegetation and the complexity of the power line network. Because power lines are such narrow objects, the density of the laser points should be relatively high in order to achieve good power line extraction results. The surrounding vegetation and the complexity of the power line network can make extraction more difficult.
Table 4 and Table 5 show point-based and object-based power line extraction accuracies for these methods. Mostly, the methods which have extracted power lines in the form of spans have achieved high completeness and correctness [ 26 , 50 ] as compared to others which did not consider pylon locations [ 28 , 58 ].
Table 4. Power line multi-conductor extraction using ALS. LS—Least square; PL—Power line; HT—Hough transform; CLF-Compass line filter; EC—Euclidean clustering; NM—Numerical method; SC Stochastic constraints; NA—Not available; C p —Completeness; C r —Correctness.
Table 4. Power line multi-conductor extraction using ALS. LS—Least square; PL—Power line; HT—Hough transform; CLF-Compass line filter; EC—Euclidean clustering; NM—Numerical method; SC Stochastic constraints; NA—Not available; C p —Completeness; C r —Correctness.
Author Method Extraction Reconstruction Density Results Extraction Results Reconstruction Grid Sub-Conductor Span Curve Technique Pt/m 2 Point-Based Object-Based Fitting Error Munir [ 72 ] -HT -Profile segmentation -NA 4 ✓ -Catenary -RANSAC -LS 23.6–56.4 NA -C p 95.9 -C r 100 Munir [ 26 ] -Image-based -Clustering NA 4 ✓ NA NA 23.6–56.4 -C p 97.1 -C r 100 -C p 92 -C r 95 NA Awrangjeb [ 27 ] -Segmentation -Image-based 2D plane 2 ✓ -Polynomial -NM 23.4–56.4 -C p 95 -C r 100 -C p 92.6 -C r 99.6 0.012 m Munir [ 76 ] -EC -Line fitting 2D plane 4 ✓ NA NA 23.6–56.4 -C p 99.15 -C r 100 -C p 99 -C r 100 NA Munir [ 51 ] -Point-based -Voxel alignment -Voxel 2 ✓ NA NA 23.6–56.4 -C p 97.9 -C r 98.9 -C p 92.5 -C r 96 NA Zohu [ 74 ] -2D plane projection -Line fitting NA 4 × -Catenary -RANSAC NA -C p NA -C r 98.9 0.02 m
Table 5. Power line extraction using MLS. LS—Least square; PL—Power line; C p —Completeness C r —Correctness; EC—Euclidean clustering (EC); Ht—hough transform; NA—Not available.
Table 5. Power line extraction using MLS. LS—Least square; PL—Power line; C p —Completeness C r —Correctness; EC—Euclidean clustering (EC); Ht—hough transform; NA—Not available.
Author Method Extraction Reconstruction Density Results Extraction (%) Results Reconstruction (m) Grid Span Curve Technique Pt/m 2 Point-Based Object-Based Fitting Error Jung [ 28 ] -Filtering -EC -Voxel × -Straight line on X-Y plane polynomial on Y-Z plane -Numerical method 213.6 -C p 93.9 -C r 96.65 NA 0.007 Lehtomaki [ 58 ] -RANSAC -2D plane × NA -NA 24 -C p 93.6 -C r 93.9 NA NA Zhenwi [ 59 ] -EC -PL direction -NA × -Catenary -Numerical method NA -C p 98.06 -C r 99.8 NA NA Fan [ 60 ] -EC -Segment matching NA ✓ -Straight line on X-Y plane polynomial on Y-Z plane -LS NA -C p 10 -C r 98 NA 0.015 Gaha [ 61 ] -RANSAC NA ✓ -Straight line on X-Y plane polynomial on Y-Z plane -Numerical method NA NA -C p NA -C r 98.9 NA Guan [ 22 ] -HT -EC NA ✓ -Polynomial -Numerical method 286.4 NA -C p 98.84 -C r 99 0.06 Yadav [ 19 ] -HT -EC 2D plane ✓ -Parabola -LS 16.70 NA -C p 90.84 -C r 98.84 NA
Only a few methods have been able to estimate the root means square error (RMSE). The overall comparison shows that the methods based on span locations for the extraction and reconstruction comparatively showed better completeness and correctness [ 51 , 70 ]. The Guo et al. [ 71 ] method based on segmentation achieved 90% completeness while the Zhang [ 29 ] method based on clustering achieved 100% completeness. However, Guo et al. [ 71 ] claimed that their method can reconstruct power lines with a gap of 10 m, whereas the Zhang [ 29 ] method will be affected if the gap is greater than 4 m, and the Zhou [ 74 ] method would fail if the gap is greater than 6 m. Munir et al. [ 26 ] and Zhou et al. [ 74 ] were able to reconstruct four sub-conductors with a precision of 0.2 m, respectively, while Awrangjeb [ 27 ] was able to reconstruct two sub-conductors with a modelling error of 0.001 m.
Until now, only a few studies have focused exclusively on the extraction of power lines from MLS point clouds. Mostly, these studies have concentrated on urban environments and extracted single power line spans, not only due to the obvious mobility limitations of a standard MLS mounted on a car, but also due to the technology’s relatively recent emergence.
4. Discussion
4.1. Summary of Methods for Power Lines Extraction and Reconstruction
Based on our examination in Section 3 , we may assume that, when LiDAR technology was originally released, the classification of power line scenes was the primary focus. The classification findings obtained using machine learning techniques are more applicable and accurate than rule-based classification. Furthermore, some studies trained the data with numerous classifiers and neighbourhoods, resulting in higher precisions and accuracies [ 48 ]. Using post-processing procedures can help improve classification [ 56 ]. On the other hand, the rule-based classification does not require training data, but methods rely on a number of parameter settings.
As LiDAR technology matured, utility companies looked for improved PLC survey alternatives. Power line modelling calls for conductor-specific points to simulate 3D power lines. Numerous studies have examined the extraction of a single power line using fixed-wing and rotor-wing aircraft.
The majority of methods employ some common steps, i.e., classification of power line scene first using machine learning classifiers [ 74 ] or pre-processing steps to remove ground and other non-power line points using various filtering techniques such as density and height filtering [ 28 ]. To find individual power line points, many studies used Euclidean clustering algorithms as well [ 76 ]. In addition, some methods use the HT algorithm [ 75 ] to detect power lines and then apply clustering to connect the power line segments.
As research increased, the point cloud grew in size, and managing the big file size became a new difficulty. In numerous studies, a voxel grid was utilised to address this issue by transforming the irregular structure of point clouds into regularly spaced sub-sampled points or filtering features to preserve the essential details contained in the point cloud while drastically reducing the dataset size [ 28 , 51 ]. Some approaches have also showed that the location of pylons can facilitate the extraction of power lines in the form of spans [ 76 ]. As the configuration of power lines remains the same in each span, extracting the spans first will aid in extracting the bundle conductors and modelling the power lines with the same parameters. This will reduce the size of the point cloud, making it easier to isolate the power lines from each span [ 27 ]. Additionally, it minimises the effort required to process LiDAR data.
For reconstruction of power lines, the studies given in literature are grouped into two categories. The first category of studies used the idea of extracting the un-organised candidate power line points and then employed clustering algorithms to group power line points into clusters. Mathematical models were then fitted to seed clusters, which were grown by adding adjacent points consistent with the trend of the model [ 21 , 28 , 69 ].
However, in other categories, the mechanism is developed using image-and point-based methods to extract the segments of power lines and then the segments are modelled using the mathematical models such as parabola [ 19 ], catenary [ 69 , 71 , 79 , 80 ], and these segments are considered as seed regions and extended by estimating the parameters using the algorithms such as the RANSAC and least square algorithms [ 71 , 74 ].
High voltage wires in bundle configuration as shown in Figure 4 are required to meet the increased demand of electricity and to transfer electricity city-to-city. In order to perform maintenance of high voltage PLC, sub-conductor modelling is required which subsequently required sub-conductors points extraction from the bundle.
As discussed in Section 3.2 and depicted in Figure 4 , extracting the sub-conductor from the bundle is not a simple task. With a distance of 0.25 metres, the sub-conductors from the bundle are located very close together. Their separation is extremely difficult. Awrangjeb [ 27 ] first proposed the concept of sub-conductor extraction and was able to extract bundles with two sub-conductors in each. Only a few studies in literature have focused on this problem, and among these these studies, Munir et al. [ 26 , 51 , 75 , 76 ] was capable of extracting and reconstructing up to our sub-conductors in each bundle with high precision and accuracy.
MLS/TLS data have been utilised in numerous power line extraction studies in recent years. These methods provide techniques for the extraction of a single power line but make no provisions for the extraction of multiple conductors. As an MLS system generates extremely dense point clouds, they can be combined with multi-conductor extraction techniques to detect buildings and other undesirable objects. Most studies employed the filtering algorithm to refine numerous points [ 19 , 22 , 60 ] and to extract candidate power line points by means of segmentation [ 28 ]. Then, clusters are filtered using RANSAC [ 61 ] or PCA [ 58 , 59 ].
The testing area of these methods was mostly on urban areas [ 22 ] or rural areas near road way environments [ 19 ], due to mobility issues of MLS. However, there are few studies [ 28 , 61 ] that have tested their methods on forest locales as well and achieve good accuracies. As MLS is a relatively new technology, the datasets have high densities, which is very important for the accurate extraction of power lines.
Due to the variety of study topics and evaluation methods, it is impossible to compare accuracies of the available methods for power line extraction and reconstruction.
4.2. Topics for Further Research
PLC modelling, particularly the automated extraction of power lines, is one of the most commonly explored applications of LiDAR data. In terms of overall feasibility for reliable automatic detection and detailed 3D reconstruction of conductors and poles, ALS and MLS point clouds appear to be the most promising technologies. The methodologies and expected level of information in the results vary substantially depending on the datasets and the quality of the LiDAR data. However, due to the diversity of study topics and quality assessment methodologies, it was hard to draw broad judgements about the amount of accuracy that could be attained or to compare different approaches. Findings of many studies have merely been provided in a few figures. Larger real-world tests, as well as numerical quality analyses, appear to be unusual. This, in conjunction with the vast amount of continuing research, shows that even simple problems, such as automatic recognition of power line conductors from point clouds, have yet to be fully solved and tested. Comparing the available options to assess their applicability in real time required the usage of common data sets and evaluation tools. As demonstrated in the tables, some approaches used point-based quality assessments, while others used object-based quality measurements.
In recent years, feature learning approaches have been adapted to address point clouds [ 81 , 82 , 83 ], inspired by dense convolution, which can acquire translation in variance. The possibility of applying deep learning (DL) to ALS point cloud for power line scene classification using the graph data structure was recently investigated in [ 84 ] with some initial results. DL approaches for categorising power line scenes are currently in their infancy and require further development.
Multi-source data, on the other hand, are rarely used in research. The following are some possible future research topics in this area: Optimal integration of ALS and MLS data for detailed but cost-effective 3D mapping of power lines. To achieve versatile and detailed monitoring capability, standard remote sensing techniques are combined with climbing robots and camera systems on power line structures. Remote sensing techniques such as UAVs and laser scanning from airborne and land-based platforms should be given special attention in any future development.
Typically, the starting point for power line extraction in the existing literature is typically remotely sensed data from a single date, with no prior knowledge of the power line structures’ location. However, some map data are available in many cases, and the map data could be used as a starting point for change detection or as a guide for the detection and modelling process. This is a topic that should be investigated in order to maximise the use of existing data and possibly achieve a higher level of automation. This is also critical in terms of map data updates. Furthermore, existing map data can be used to guide UAVs flying around power lines.
Change detection based on remote sensing, in which datasets from two or more dates are compared to each other, is another topic worth investigating in the context of power line monitoring. This could be a good way to detect network component problems. Remote sensing techniques such as UAVs and laser scanning from airborne and land-based platforms, which are rapidly developing, should be given special attention. These techniques will almost certainly be used to develop effective, flexible, and highly automated monitoring methods, allowing commercial applications.
Large test datasets in various environments and realistic monitoring conditions are required to demonstrate and verify the capabilities of automated monitoring approaches. These should also cover difficult situations such as power lines in the forests. Careful quality analyses and comparisons between different data sources, methods, and individual algorithms are required to develop efficient integrated approaches.
5. Conclusions
LiDAR surveying is preferred for regular power line corridor (PLC) inspection. The literature contains many state-of-the-art laser scanning-based techniques for the extraction and reconstruction of overhead power lines. Laser scanning techniques are commonly used in ALS (fixed-wing aircraft, helicopters, unmanned aerial vehicles (UAVs), and terrain-based (mobile laser Scanning (MLS)/terrestrial laser scanning (TLS)) approaches. ALS is commonly used for power line detection due to its large scanning range, but its low accuracy is due to the long distance between the destination and its scanner. MLS, on the other hand, scans closer to targets than ALS, allowing for more precise data collection.
Numerous publications have focused on classification and reconstruction techniques for power line extraction, specifically conductor extraction. A typical procedure includes creating a DTM, classifying the laser data to distinguish power line points from other objects, particularly vegetation, and modelling the individual conductors in 3D. Previously, the emphasis was on classifying power line points using supervised and unsupervised ALS methods, but there has been a growing interest in recent years in examining the extraction and reconstruction of power line spans with single and multi conductor configurations using various image and point-based techniques.
This research looked at the technical and methodological limitations and provided a comprehensive overview of the methodologies offered by various approaches using laser scanning data from the perspective of power line extraction applications, as well as discussed the benefits and drawbacks of each approach. This article summarised the findings of existing works, and major issues are highlighted for power line extraction and reconstruction using LiDAR point cloud data.
Despite the tremendous potential of aerial and mobile scanning systems, the comparison revealed that human intervention and post-processing actions are still required to achieve the desired results. Furthermore, the majority of the methods were evaluated on small datasets on spans rather than large datasets, and only a few methods were focused on multi-conductor extraction and reconstruction for power line modelling. These impediments impede the automated extraction and reconstruction of power lines from LiDAR data. Several promising directions for future LiDAR experiments using deep learning methods are outlined in the hope that they will pave the way for PLC modelling and assessment applications at a finer and larger scale.
Author Contributions
Conceptualization, N.M. and M.A.; methodology, N.M. and M.A; software, N.M.; validation, N.M. and M.A.; formal analysis, M.A.; investigation, N.M.; resources, N.M.; data curation, M.A.; writing—original draft preparation, N.M.; writing—review and editing, M.A.; visualization, M.A.; supervision, M.A. and B.S. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Data Availability Statement
Datasets are unavailable due to privacy or ethical restrictions.
Acknowledgments
The authors would like to express their gratitude to the editors and the reviewers for their constructive and helpful comments for the substantial improvement of this paper.
Conflicts of Interest
The authors declare no conflict of interest.
Abbreviations
The following abbreviations are used in this manuscript: PLC Power line corridor CLF Campus Line Filter DL Deep Learning
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Figure 1. Different LiDAR data collection systems.
Figure 4. Sub-conductors configuration. ( a ) high-voltage transmission line tower with bundles in sub-conductors configuration; ( b ) magnified version of bundle from ( a ); ( c ) LiDAR data for span with bundles in four sub-conductors configuration; ( d ) magnified version of bundle from ( c ); ( e ) LiDAR data for span with single power line; ( f ) magnified version of bundle from ( e ).
Table 1. Comparison of LiDAR systems mounted on different platforms.
Platforms System Scanning Density PL Mapping Weakness and Abbreviation Perspective Application Strength Airborne ALS Top view low Forest mountain terrains cost-effective and time-saving for large areas Airborne UAV Top view high Forest mountain Light weight, time-saving Mobile/vehicle MLS side view high Urban areas, road side cost-effective for small areas Tripod/static TLS side view high Urban areas cost-effective for small areas
AMA Style
Munir N, Awrangjeb M, Stantic B. Power Line Extraction and Reconstruction Methods from Laser Scanning Data: A Literature Review. Remote Sensing. 2023; 15(4):973.
https://doi.org/10.3390/rs15040973
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Munir, Nosheen, Mohammad Awrangjeb, and Bela Stantic. 2023. "Power Line Extraction and Reconstruction Methods from Laser Scanning Data: A Literature Review" Remote Sensing15, no. 4: 973.
https://doi.org/10.3390/rs15040973
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Munir, N.; Awrangjeb, M.; Stantic, B. Power Line Extraction and Reconstruction Methods from Laser Scanning Data: A Literature Review. Remote Sens. 2023, 15, 973.
https://doi.org/10.3390/rs15040973
AMA Style
Munir N, Awrangjeb M, Stantic B. Power Line Extraction and Reconstruction Methods from Laser Scanning Data: A Literature Review. Remote Sensing. 2023; 15(4):973.
https://doi.org/10.3390/rs15040973
Munir, Nosheen, Mohammad Awrangjeb, and Bela Stantic. 2023. "Power Line Extraction and Reconstruction Methods from Laser Scanning Data: A Literature Review" Remote Sensing15, no. 4: 973.
https://doi.org/10.3390/rs15040973
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Forkhead box P3 and indoleamine 2,3-dioxygenase co-expression in Pakistani triple negative breast cancer patients
Forkhead box P3 and indoleamine 2,3-dioxygenase co-expression in Pakistani triple negative breast cancer patients
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Dec 24, 2020 (publication date) through May 29, 2023
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Journal Information of This Article
Publication Name
World Journal of Clinical Oncology
ISSN
2218-4333
Publisher of This Article
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
Retrospective Study Open Access
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Dec 24, 2020; 11(12): 1018-1028 Published online Dec 24, 2020. doi: 10.5306/wjco.v11.i12.1018
Forkhead box P3 and indoleamine 2,3-dioxygenase co-expression in Pakistani triple negative breast cancer patients
Kashif Asghar, Asif Loya, Iftikhar Ali Rana, Muhammad Abu Bakar, Asim Farooq, Muhammad Tahseen, Muhammad Ishaq, Iqra Masood, Muhammad Usman Rashid
Kashif Asghar, Muhammad Usman Rashid, Department of Basic Science Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab 54000, Pakistan
Asif Loya, Iftikhar Ali Rana, Muhammad Tahseen, Muhammad Ishaq, Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab 54000, Pakistan
Muhammad Abu Bakar, Department of Cancer Registry and Clinical Data Management, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab 54000, Pakistan
Asim Farooq, Iqra Masood, Department of Clinical Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab 54000, Pakistan
ORCID number: Kashif Asghar ( 0000-0002-6855-5008 ); Asif Loya ( 0000-0003-2716-5027 ); Iftikhar Ali Rana ( 000-0001-9012-3706 ); Muhammad Abu Bakar ( 0000-0001-9387-6287 ); Asim Farooq ( 0000-0002-4309-3353 ); Muhammad Tahseen ( 0000-0002-5240-7721 ); Muhamamd Ishaq ( 0000-0003-2230-0330 ); Iqra Masood ( 0000-0001-6000-6656 ); Muhammad Usman Rashid ( 0000-0002-7684-3122 ).
Author contributions
: Asghar K generated the hypotheses, designed experiments, carried out lab work and data analysis, and wrote the manuscript; Loya A evaluated the IHC slides and scored them, analyzed the data, and contributed to manuscript writing; Rana IA evaluated the IHC slides and scored them; Bakar MA and Farooq A conducted statistical analysis, analyzed data, and participated in writing the manuscript; Tahseen M and Ishaq M retrieved the blocks and performed IHC; Masood I performed patient data collection and verification from the electronic hospital information system and contributed to manuscript writing; Rashid MU assisted in hypothesis generation and critical appraisal of data.
Institutional review board statement : The study was reviewed and approved by the Shaukat Khanum Memorial Cancer Hospital and Research Centre Institutional Review Board.
Conflict-of-interest statement : Authors declare no conflict of interests for this manuscript.
Data sharing statement
: Technical appendix, statistical code, and dataset available from the corresponding author at
[email protected]
. Consent was not obtained but the presented data are anonymized and risk of identification is low. No additional data are available.
Open-Access : This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author
: Kashif Asghar, DVM, PhD, Research Scientist, Department of Basic Science Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, 7A, Block R3, Johar Town, Lahore, Punjab 54000, Pakistan.
[email protected]
Received:
April 13, 2020
Peer-review started
: April 13, 2020
First decision
: August 9, 2020
Revised:
August 24, 2020
Accepted:
October 27, 2020
Article in press
: October 27, 2020
Published online:
December 24, 2020
Abstract
BACKGROUND
Forkhead box P3 (FOXP3) is a specific marker for immunosuppressive regulatory T (T-reg) cells. T-regs and an immunosuppressive enzyme, indoleamine 2,3-dioxygenase (IDO), are associated with advanced disease in cancer.
AIM
To evaluate the co-expression of FOXP3 and IDO in triple negative breast cancer (TNBC) with respect to hormone-positive breast cancer patients from Pakistan.
METHODS
Immunohistochemistry was performed to analyze the expression of FOXP3, IDO, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor on tissues of breast cancer patients ( n= 100): Hormone-positive breast cancer ( n= 51) and TNBC ( n= 49). A total of 100 patients were characterized as FOXP3 negative vspositive and further categorized based on low, medium, and high IDO expression score. Univariate and multivariate logistic regression models were used.
RESULTS
Out of 100 breast tumors, 25% expressed FOXP3 positive T-regs. A significant co-expression of FOXP3 and IDO was observed among patients with TNBC ( P= 0.01) compared to those with hormone-positive breast cancer. Two variables were identified as significant independent risk factors for FOXP3 positive: IDO expression high (adjusted odds ratio (AOR) 5.90; 95% confidence interval (CI): 1.22-28.64; P= 0.03) and TNBC (AOR 2.80; 95%CI: 0.96-7.95; P= 0.05).
CONCLUSION
Our data showed that FOXP3 positive cells might be associated with high expression of IDO in TNBC patients. FOXP3 and IDO co-expression may also suggest its involvement in disease, and evaluation of FOXP3 and IDO expression in TNBC patients may offer a new therapeutic option.
Key Words: Forkhead box P3 , Indoleamine 2,3-dioxygenase , Triple negative breast cancer , T-regs , Immunotherapy , Cancer
Core Tip:Forkhead box P3 (FOXP3) positive cells might be associated with high expression of indoleamine 2,3-dioxygenase (IDO) in triple negative breast cancer (TNBC) patients. Evaluation of FOXP3 and IDO expression in TNBC patients may provide a novel effective therapeutic strategy.
Citation: Asghar K, Loya A, Rana IA, Bakar MA, Farooq A, Tahseen M, Ishaq M, Masood I, Rashid MU. Forkhead box P3 and indoleamine 2,3-dioxygenase co-expression in Pakistani triple negative breast cancer patients. World J Clin Oncol 2020; 11(12): 1018-1028
URL: https://www.wjgnet.com/2218-4333/full/v11/i12/1018.htm
DOI: https://dx.doi.org/10.5306/wjco.v11.i12.1018
INTRODUCTION
Forkhead box P3 (FOXP3) is a part of the forkhead/winged-helix family of transcription regulators[1]. FOXP3 is a specific marker for regulatory T cells (T-regs)[2], which are crucial mediators of peripheral tolerance[3]. FOXP3 expression has been reported in breast cancer[4 -6], and its quantification in this malignancy can be used as an effective tool to monitor disease progression and predict prognosis[7]. The cell count of FOXP3 expressing T-regs increases steadily in breast cancer with increasing stage of disease[7]. The mechanisms underlying are still not clear. High numbers of FOXP3 expressing T-regs provide poor prognosis for relapse-free survival in patients with invasive carcinoma[7], but Lee et al[8] observed the prognostic significance of FOXP3-positive T-regs compared to FOXP3-negative T-regs in triple negative breast cancer (TNBC). Furthermore, they found that improved survival was linked with FOXP3-postive T-regs in TNBC. This finding was in contrast with other types of cancers[8]. Therefore, further studies are required to link FOXP3- positive T-regs to good or worse prognosis.
An immunosuppressive enzyme, indoleamine 2,3-dioxygenase (IDO), catabolizes tryptophan into kynurenines[9,10]. IDO has the ability to inhibit the immune responses and produce immunosuppression through the differentiation and maturation of T-regs[11]. On the other hand, tryptophan depletion by IDO affects the cytotoxicity of T cells[12]. It has been reported that tryptophan downstream metabolites induce apoptosis of T cells in vitro[13]. IDO plays a role in the cancer immune-escape mechanism[14,15]. Evidence has suggested that overexpression of IDO has been observed in both antigen-presenting cells and tumor cells in tumor draining lymph nodes[16]. IDO overexpression may lead to recruitment of T-regs in breast tumor microenvironment and promote metastasis[17].
TNBC is characterized by lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2)[18]. TNBC is a more aggressive tumor than other breast cancers types[19]. Our goal was to quantify FOXP3 expression in relation with IDO expression in patients diagnosed with breast cancer from Pakistan. Pakistan has the highest incidence of breast cancer cases in its region. We further investigated the numbers of FOXP3-positive T-regs in TNBC patients compared to hormone-positive breast cancer patients.
MATERIALS AND METHODS
Sampling and patient data
For this retrospective analysis, archived formalin-fixed paraffin-embedded (FFPE) blocks of 100 breast cancer patients were retrieved from the pathology department. The study was conducted at Shaukat Khanum Memorial Cancer Hospital and Research Center (SKMCH&RC) Lahore, Pakistan. All the patients were diagnosed with breast cancer between 2007 and 2009, and all patients selected were treatment naïve. Tumor grade was allocated using the Nottingham Histologic Score. Immunohistochemistry was performed to identify the expression of ER, PR, and HER2 by using standard methods[20]. Clinico-pathological data were obtained from medical reports of the patients. The current study was approved by the Institutional Review Board (IRB) of the SKMCH&RC (#IRB-16-08) and was exempted from informed consent in agreement with the Declaration of Helsinki Guidelines. We used the specimens of hospital registered patients. The data were recorded in such a manner that the individual identity could not be recognized. This study does not include any procedures that would normally require informed consent outside the context of the study.
Immunohistochemical staining of FOXP3 and IDO
Bond III Leica automated system (Leica Biosystems Melbourne, Australia) was used to perform the immunohistochemistry. Briefly, two sections of FFPE blocks of the same patients were obtained. Bond Dewax solution (#AR922, Leica) was used to deparaffinize the slides. Bond ER-2 (#AR9640, Leica) was used to perform heat induced epitope retrieval on the automated system for 20 min. The primary antibodies FOXP3 (Abcam, #ab22510, Cambridge, United Kingdom) or IDO1 (Abcam, #ab55305) were used at a 1:50 and 1:200 dilution, respectively, in primary antibody diluent and incubated for 5 min. Bond TMpolymer refine detection kit was used to visualize FOXP3 and IDO labeling. Peroxidase block was applied for 5min. The slides were then incubated with post primary rabbit anti mouse immunoglobulin G for 8 min, followed by incubation with polymer anti-rabbit poly-horseradish peroxidase-immunoglobulin G for 8 min. Three prime-diaminobenzidine tetrahydrochloride hydrate was applied for 10 min. Counterstaining was performed with hematoxylin for 5 min. Two pathologists were involved in the study, and they conducted a blind histopathologic assessment. The discrepancies between the two pathologists were reviewed mutually to reach the consensus. The mean score of both pathologists was considered as the final score. Staining of at least 25% of cells was considered positive for FOXP3. FOXP3 expression had nuclear localization[6]. IDO staining evaluation was based on two factors: (1) Intensity of cytoplasmic staining (0 to 3); and (2) Percentage of cells staining positive (0 to 3). They were categorized as low (1-3), medium (4-6), and high (7-9).
Statistical analysis
Statistical analysis was carried out using SPSS software (version 20.0; SPSS, Armonk, NY, United States). For continuous variables, mean and standard deviation were used. For categorical variables, percentages (proportions) were used. Chi-square or Fisher exact test was performed for bivariate analysis. Independent t-test was performed for continuous explanatory variables such as age. Risk factors were identified by using the univariable and multivariable logistic regression model.
RESULTS
Patient baseline characteristics
A total of 100 breast cancer patients were included in this study with an average age of 48 years. Majority of patients belonged to the Punjab region (88%). Fifty-seven percent of tumors were T2/T3, and 7% tumors were T1 (Tumor Node Metastasis classification). According to the grade distribution, 56% presented grade III. Fifty percent of patients were positive for node, and 49% were positive for metastasis. PR (26%), HER2-neu (26%), and ER (31%) were expressed in the tumor tissue (Table1). We have further categorized baseline characteristics based on TNBC and hormone positive breast cancer in Table2.
Table 1 Baseline characteristics of breast cancer patients.
Variables Levels Total, n % Age mean ± SD 48.28 ± 11.83 Region Punjab 88 (88.0%) Khyber Pakhtunkhwa 7.0 (7.0%) Kashmir 3.0 (3.0%) Sindh 2.0 (2.0%) Histology Ductal 91 (91.0%) Others 9.0 (9.0%) Grade II 35 (35.0%) III 56 (56.0%) UNK 09 (9.0%) Tumor size T1 7.0 (7.0%) T2/T3 57 (57.0%) UNK 36 (36.0%) Nodes Negative 37 (37.0%) Positive 50 (50.0%) UNK 13 (13.0%) Metastasis Negative 38 (38.0%) Positive 49 (49.0%) UNK 13 (13.0%) Estrogen receptor Negative 69 (69.0%) Positive 31 (31.0%) Progesterone receptor Negative 74 (74.0%) Positive 26 (26.0%) HER2 status Negative 74 (74.0%) Positive 26 (26.0%) TNBC No 51 (51.0%) Yes 49 (49.0%) Status Alive 50 (50.0%) Death 35 (35.0%) Lost to follow-up 15 (15.0%) FOXP3 Negative 75 (75.0%) Positive 25 (25.0%) IDO score Low 24 (24.0%) Medium 27 (27.0%) High 49 (49.0%)
UNK: Indicates missing data. FOXP3: Forkhead box P3; HER2: Human epidermal growth factor receptor; IDO: Indoleamine 2,3-dioxygenase; TNBC: Triple negative breast cancer; SD: Standard deviation.
Table 2 Comparative characteristics of triple negative breast cancer and hormone positive breast cancer patients.
Variables Levels Triple negative breast cancer, n (%) Hormone positive breast cancer, n (%) Age mean ± SD 47.24 ± 11.5 49.27 ± 12.0 Histology Ductal 46 (50.5) 45 (49.5) Others 3 (33.3) 6 (66.7) Total 49 (49.0) 51 (51.0) Grade II 9 (25.7) 26 (74.3) III 37 (66.1) 19 (33.9) UNK 3 (33.3) 6 (66.7) Total 49 (49.0) 51 (51.0) Tumor size T1 4 (57.1) 3 (42.9) T2/T3 26 (45.6) 31 (54.4) UNK 19 (52.8) 17 (47.2) Total 49 (49.0) 51 (51.0) Nodes Negative 23 (62.1) 14 (37.8) Positive 21 (42.0) 29 (58.0) UNK 5 (38.4) 8 (61.6) Total 49 (49.0) 51 (51.0) Metastasis Negative 23 (60.5) 15 (39.5) Positive 21 (42.8) 28 (57.2) UNK 5 (38.4) 8 (61.6) Total 49 (49.0) 51 (51.0)
UNK: Indicates missing data. SD: Standard deviation.
Clinicopathological characteristics of breast cancer patients with FOXP3 expression
There were 25 out of 100 FOXP3 positive cases (Table3). Based on immunohistochemistry analysis, FOXP3 expression had nuclear localization. All the cases were invasive ductal carcinoma. Furthermore, 18 out of 25 were TNBC patients. The data of 75 out of 100 FOXP3 negative cases are provided in supplementary data (Supplementary Table 1).
Table 3 Clinicopathological characteristics of breast cancer patients with nuclear forkhead box P3 expression.
Case Histology Age in yr Grade Nodes Metastasis ER PR HER2 TNBC 1 Ductal 28 3 0 - - - - + 2 Ductal 54 3 14 + - - - + 3 Ductal 67 3 1 + - - - + 4 Ductal 65 2 UNK UNK - - - + 5 Ductal 45 3 13 + - - - + 6 Ductal 45 3 0 - - - - + 7 Ductal 55 3 0 - - - - + 8 Ductal 23 3 0 - - - - + 9 Ductal 47 2 0 - - - - + 10 Ductal 73 3 2 + - - - + 11 Ductal 35 3 0 - - - - + 12 Ductal 35 3 0 - - - - + 13 Ductal 52 3 UNK UNK - - - + 14 Ductal 39 3 0 - - - - + 15 Ductal 48 3 0 - - - - + 16 Ductal 70 3 2 + - - - + 17 Ductal 40 3 13 + - - - + 18 Ductal 35 3 13 + - - - + 19 Ductal 43 3 0 UNK - - + - 20 Ductal 36 2 1 + - - + - 21 Ductal 45 3 UNK UNK + + - - 22 Ductal 71 2 6 + + - - - 23 Ductal 30 2 17 + + + - - 24 Ductal 40 2 UNK UNK - - + - 25 Ductal 62 2 0 - + + + -
UNK: Indicates missing data; Grade: Nottingham Histologic Score; Nodes: No. of nodes involved. ER: Estrogen receptor; HER2: Human epidermal growth factor receptor; PR: Progesterone receptor; TNBC (+): Triple negative breast cancer; TNBC ( - ): Hormone-positive breast cancer.
FOXP3 and IDO co-expression is associated with TNBC
In order to validate the immunosuppressive effect of FOXP3 and IDO co-expression, we categorized the patients into TNBC and hormone-positive breast cancer groups. The mean age at diagnosis of FOXP3 positive vsnegative breast cancer cases was 47.32 ± 14.19 years and 48.60 ± 11.02 years, respectively ( P= 0.64). The majority of patients had grade III tumor ( n= 18) and grade II tumor ( n= 07). There was a statistically significant association between FOXP3 and high expression of IDO ( P= 0.01) and TNBC ( P= 0.01), respectively. Remaining explanatory variables are presented in Table4.
Table 4 Patients and tumor characteristics of forkhead box P3 negative vs positive.
Variables Characteristics FOXP3 negative 75 (75.0%) FOXP3 positive 25 (25.0%) P value Age (yr) mean ± SD 48.60 ± 11.02 47.32 ± 14.20 0.64 IDO score Low 22 (91.7%) 2 (8.3%) 0.01 a Medium 23 (85.2%) 4 (14.8%) High 30 (61.2%) 19 (38.8%) Grade II 28 (80.0%) 7 (20.0%) 0.21 III 38 (67.9%) 18 (32.1%) Metastasis Negative 27 (71.1%) 11 (28.9%) 0.45 Positive 39 (79.6%) 10 (20.4%) Tumor size T1 4 (57.1%) 3 (42.9%) 0.15 T2/T3 46 (80.7%) 11 (19.3%) Lymph nodes involvement Negative 26 (70.3%) 11 (29.7%) 0.29 Positive 40 (80.0%) 10 (20.0%) Estrogen receptor Negative 48 (69.6%) 21 (30.4%) 0.06 Positive 27 (87.1%) 4 (12.9%) Progesterone receptor Negative 52 (70.3%) 22 (29.7%) 0.06 Positive 23 (88.5%) 3 (11.5%) HER2–neu receptor Negative 53 (71.6%) 21 (28.4%) 0.19 Positive 22 (84.6%) 4 (15.4%) Triple negative breast cancer No 44 (86.3%) 7 (13.7%) 0.01 a Yes 31 (63.3%) 18 (36.7%)
a P < 0.05. IDO: Indoleamine 2,3-dioxygenase; HER2: Human epidermal growth factor receptor; FOXP3: Forkhead box P3; SD: Standard deviation.
FOXP3 and IDO immunostaining
To evaluate the expression of FOXP3 and IDO, we selected FFPE tumor specimens of the same patients ( n= 100). Out of 100 patients, 25 expressed FOXP3-positive T-regs, and 75 expressed FOXP3-negative T-regs (Figure1). IDO positivity was found in all breast tumor specimens. Synchronal expression of FOXP3 and IDO is shown in Figure1. Immunostaining of low, medium, and high IDO expression is provided insupplementary data(Figure1).
Figure 1 Formalin-fixed paraffin-embedded tumor specimens. A and B: Forkhead box P3 (FOXP3) immunohistochemical staining; A: Invasive ductal carcinoma with FOXP3-negative expression; B: FOXP3-positive lymphocytic infiltration in invasive ductal carcinoma. The staining was nuclear; C and D: Co-expression of FOXP3 and indoleamine 2,3-dioxygenase (IDO), FOXP3 and IDO expression in breast cancer tissues ( n = 100) were evaluated; C: FOXP3 positive cells infiltrated in invasive ductal carcinoma (nuclear staining). Sections from matched breast cancer patients were stained for IDO; D: Strong and diffuse IDO staining in invasive ductal tumor cells (cytoplasmic staining). Images were captured at × 40 magnification.
Univariable and multivariable analysis
Table5summarizes the several clinicopathological features that were included in unadjusted and adjusted logistic regression model to identify the FOXP3 correlation with IDO expression and TNBC. Two variables were identified as significant independent risk factors for FOXP3 positive: IDO expression high [adjusted odds ratio (AOR) 5.90; 95% confidence interval (CI): 1.22-28.64; P= 0.03) and TNBC (AOR 2.80; 95%CI: 0.96-7.95, P= 0.05) in multivariable analysis.
Table 5 Univariable and multivariable logistic regression analysis for forkhead box P3-negative (reference) vs forkhead box P3-positive.
Variables Characteristics Univariable analysis odds ratio (95%CI), P value Multivariable analysis odds ratio (95%CI), P value IDO score Low Ref. Ref. Medium 1.91 (0.32-11.52), 0.50 2.32 (0.37-14.50), 0.37 High 6.97 (1.50-33.10), 0.01 a 5.90 (1.22-28.64), 0.03 a Triple negative breast cancer No Ref. Ref. Yes 3.65 (1.36-9.80), 0.01 a 2.80 (0.96-7.95), 0.05 a
a P < 0.05. IDO: Indoleamine 2,3-dioxygenase.
DISCUSSION
The role of immunosuppression in cancer progression is currently evaluated in various cancers[21 -23]. It has been established that immunological factors such as T-regs are involved in the progression of tumor through induction of immune tolerance in the tumor microenvironment[7,22]. T-regs are effective inhibitors of the immune system[22]. T-regs create immunosuppressive environment by suppressing effector immune cells[22]. They are also associated with poor clinical outcomes in various tumors[4,7]. FOXP3 is a specified marker for T-regs[2]. Several studies identified that FOXP3 +T-regs infiltration in tumor microenvironment may affect breast cancer progression[7,24]. Bates et al[7] demonstrated that a high ratio of FOXP3 cells predict worse relapse-free survival and shorten overall survival in patients with invasive breast carcinoma[7]. In another study the researchers observed no difference in overall survival among patients expressing high or low FOXP3[25]. There is contradictory data regarding the involvement of FOXP3 +T-regs in breast cancer patients. Nevertheless, we investigated FOXP3 positive vsnegative expression in the current study. FOXP3 expression was identified in 25 breast cancer patients, and a majority of these patients displayed TNBC phenotype. Overall, 36.73% of TNBC patients expressed FOXP3 positive cells, while 13.72% of hormone positive breast cancer patients expressed FOXP3 positive cells. On the other hand, FOXP3 expression was not detected in 63.26% of TNBC patients and 86.27% of hormone positive breast cancer patients. Our findings of FOXP3 T-regs infiltration in TNBC patients is similar to several studies published before that identified the involvement of FOXP3 positive cells in breast cancer progression[7,24].
FOXP3 +T-regs can restrain effector T cells by an IDO dependent mechanism[9]. IDO plays a critical role in the pathogenesis of breast cancer[26]. IDO overexpression is linked with shorter overall survival and poor prognosis[27 -34]. FOXP3 +T-regs have prognostic implications in TNBC[8]. IDO expression is also associated with TNBC[26]. Previously we showed high IDO expression in TNBC patients from Pakistan[35]. The aim of our current study was to identify the substantial association between FOXP3-positive T-regs and IDO in TNBC patients. There was a statistically significant association of FOXP3 with high IDO expression ( P= 0.01) and TNBC ( P= 0.01) respectively. Two variables were recognized as significant independent risk factors for FOXP3 positive: IDO expression high (AOR 5.90; 95%CI: 1.22-28.64; P= 0.03) and TNBC (AOR 2.80; 95%CI: 0.96-7.95; P= 0.05) in multivariable analysis. Although several studies focus on the role of immunosuppression in TNBC, our data provide some insight regarding immunosuppression in association with simultaneous expression of FOXP3 and IDO in TNBC patients.
Our study has some limitations, which have to be mentioned. The study population ( n= 100) did not permit us to draw any strong conclusion. Forthcoming projects on breast cancer patients from Pakistan with inclusive cohort studies are required to authenticate conclusive associations.
Identification of an appropriate immunotherapeutic target for TNBC is currently a hot-topic. FOXP3 and IDO co-expression has the ability to inhibit anti-tumor immune responses and may be considered one of the hurdles in the development of successful immunotherapy for cancer. The role of FOXP3 and IDO co-expression is still a subject of rigorous research in breast cancer.
CONCLUSION
In conclusion, the current data revealed that FOXP3 positive cells might be associated with high IDO expression in TNBC patients. FOXP3 and IDO expression monitoring in TNBC patients may provide an effective therapeutic strategy.
ARTICLE HIGHLIGHTS
Research background
Forkhead box P3 (FOXP3) and indoleamine 2,3-dioxygenase (IDO) are associated with advanced disease in cancer ( e.g.,breast cancer).
Research motivation
To quantify FOXP3 expression in relation with IDO expression in patients diagnosed with breast cancer from Pakistan.
Research objectives
Our objective was to identify the co-expression of FOXP3 and IDO in triple negative breast cancer (TNBC) patients.
Research methods
Immunohistochemistry was performed to analyze the expression of FOXP3, IDO, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor in human breast cancer tissues.
Research results
A significant association of FOXP3 and IDO co-expression was observed among patients with TNBC ( P= 0.01).
Research conclusions
FOXP3 positive cells might be associated with high expression of IDO in TNBC patients.
Research perspectives
Evaluation of FOXP3 and IDO expression in TNBC patients may be implemented in the future as a therapeutic strategy.
Footnotes
Manuscript source: Unsolicited manuscript
Specialty type: Oncology
Country/Territory of origin: Pakistan
Peer-review report’s scientific quality classification
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Grade C (Good): C, C
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P-Reviewer: Scaggiante B S-Editor: Fan JR L-Editor: Filipodia P-Editor: Wang LL
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28. Okamoto A , Nikaido T, Ochiai K, Takakura S, Saito M, Aoki Y, Ishii N, Yanaihara N, Yamada K, Takikawa O, Kawaguchi R, Isonishi S, Tanaka T, Urashima M. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res . 2005; 11 :6030-6039. [ PubMed ] [ DOI ] [ Cited in This Article: 1 ] [ Cited by in Crossref: 284 ] [ Cited by in F6Publishing: 296 ] [ Article Influence: 15.8 ] [ Reference Citation Analysis (0) ]
29. Ino K , Yoshida N, Kajiyama H, Shibata K, Yamamoto E, Kidokoro K, Takahashi N, Terauchi M, Nawa A, Nomura S, Nagasaka T, Takikawa O, Kikkawa F. Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer. Br J Cancer . 2006; 95 :1555-1561. [ PubMed ] [ DOI ] [ Cited in This Article: 1 ] [ Cited by in Crossref: 176 ] [ Cited by in F6Publishing: 185 ] [ Article Influence: 10.4 ] [ Reference Citation Analysis (0) ]
30. Huang A , Fuchs D, Widner B, Glover C, Henderson DC, Allen-Mersh TG. Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer. Br J Cancer . 2002; 86 :1691-1696. [ PubMed ] [ DOI ] [ Cited in This Article: 1 ] [ Cited by in Crossref: 171 ] [ Cited by in F6Publishing: 178 ] [ Article Influence: 8.1 ] [ Reference Citation Analysis (0) ]
31. Ino K , Yamamoto E, Shibata K, Kajiyama H, Yoshida N, Terauchi M, Nawa A, Nagasaka T, Takikawa O, Kikkawa F. Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res . 2008; 14 :2310-2317. [ PubMed ] [ DOI ] [ Cited in This Article: 1 ] [ Cited by in Crossref: 153 ] [ Cited by in F6Publishing: 159 ] [ Article Influence: 10.2 ] [ Reference Citation Analysis (0) ]
32. Astigiano S , Morandi B, Costa R, Mastracci L, D'Agostino A, Ratto GB, Melioli G, Frumento G. Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer. Neoplasia . 2005; 7 :390-396. [ PubMed ] [ DOI ] [ Cited in This Article: 1 ] [ Cited by in Crossref: 111 ] [ Cited by in F6Publishing: 117 ] [ Article Influence: 6.2 ] [ Reference Citation Analysis (0) ]
33. Weinlich G , Murr C, Richardsen L, Winkler C, Fuchs D. Decreased serum tryptophan concentration predicts poor prognosis in malignant melanoma patients. Dermatology . 2007; 214 :8-14. [ PubMed ] [ DOI ] [ Cited in This Article: 1 ] [ Cited by in Crossref: 130 ] [ Cited by in F6Publishing: 137 ] [ Article Influence: 8.1 ] [ Reference Citation Analysis (0) ]
34. Takao M , Okamoto A, Nikaido T, Urashima M, Takakura S, Saito M, Saito M, Okamoto S, Takikawa O, Sasaki H, Yasuda M, Ochiai K, Tanaka T. Increased synthesis of indoleamine-2,3-dioxygenase protein is positively associated with impaired survival in patients with serous-type, but not with other types of, ovarian cancer. Oncol Rep . 2007; 17 :1333-1339. [ PubMed ] [ DOI ] [ Cited in This Article: 1 ] [ Cited by in Crossref: 11 ] [ Cited by in F6Publishing: 12 ] [ Article Influence: 0.7 ] [ Reference Citation Analysis (0) ]
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Language Editing Process for Manuscripts Submitted by Non-Native Speakers of English
| https://www.wjgnet.com/2218-4333/full/v11/i12/1018.htm |
2 Peter 1:5 (ASV) - Jamieson, Fausset, and Brown Book Notes
Yea, and for this very cause adding on your part all diligence, in your faith supply virtue; and in `your' virtue knowledge;
2 Peter 1:5 ( American Standard Version )
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Book Notes:
Jamieson, Fausset, and Brown Book Notes II Peter
AUTHENTICITY AND GENUINENESS.—If not a gross imposture, its own internal witness is unequivocal in its favor. It has Peter's name and apostleship in its heading: not only his surname, but his original name Simon, or Simeon, he thus, at the close of his life, reminding his readers who he originally was before his call. Again, in II Peter 1:16-18, he mentions his presence at the Transfiguration, and Christ's prophecy of his death! and in II Peter 3:15, his brotherhood with Paul. Again, in II Peter 3:1, the author speaks of himself as author of the former Epistle: it is, moreover, addressed so as to include (but not to be restricted to) the same persons as the first, whom he presupposes to be acquainted with the writings of Paul, by that time recognized as "Scripture" (II Peter 3:15, "the long-suffering ofGod," compareRomans 2:4). This necessarily implies a late date, when Paul's Epistles (including Romans) already had become generally diffused and accepted as Scripture in the Church. The Church of the fourth century had, besides the testimony which we have of the doubts of the earlier Christians, other external evidence which we have not, and which, doubtless, under God's overruling providence, caused them to accept it. It is hard to understand how a book palpably false (as it would be if Peter be not the author) could have been accepted in the Canon as finally established in the Councils of Laodicea, AD360 (if the fifty-ninth article be genuine), Hippo, and Carthage in the fourth century (393 and 397). The whole tone and spirit of the Epistle disprove its being an imposture. He writes as one not speaking of himself, but moved by the Holy Ghost (II Peter 1:21). An attempt at such a fraud in the first ages would have brought only shame and suffering, alike from Christians and heathen, on the perpetrator: there was then no temptation to pious frauds as in later times. That it must have been written in the earliest age is plain from the wide gulf in style which separates it and the other New Testament Scriptures from even the earliest and best of the post-apostolic period. DAILLE well says, "God has allowed a fosse to be drawn by human weakness around the sacred canon to protect it from all invasion."
Traces of acquaintance with it appear in the earliest Fathers. HERMAS [Similitudes, 6.4] (compare II Peter 2:13), Greek, "luxury in the day . . . luxuriating with their own deceivings"; and [Shepherd, Vision 3.7], "They have left their true way" (compare II Peter 2:15); and [Shepherd, Vision 4.3], "Thou hast escaped this world" (compare II Peter 2:20). CLEMENT OF ROME, [Epistle to the Corinthians, 7.9; 10], as to Noah's preaching and Lot's deliverance, "the Lord making it known that He does not abandon those that trust in Him, but appoints those otherwise inclined to judgment" (compare II Peter 2:5-7, II Peter 2:9). IRENÆUS, AD178 ("the day of the Lord is as a thousand years"), and JUSTIN MARTYR seem to allude to II Peter 3:8. HIPPOLYTUS [On Antichrist], seems to refer to II Peter 1:21, "The prophets spake not of their own private (individual) ability and will, but what was (revealed) to them alone by God." The difficulty is, neither TERTULLIAN, CYPRIAN, CLEMENT OF ALEXANDRIA, nor the oldest Syriac (Peschito) version (the later Syriac has it), nor the fragment known as Muratori's Canon, mentions it. The first writer who has expressly named it is ORIGEN, in the third century (Homily on Joshua; also Homily 4 on Leviticus, and Homily 13 on Numbers), who names it "Scripture," quoting II Peter 1:4; II Peter 2:16; however (in EUSEBIUS [Ecclesiastical History, 6.25]), he mentions that the Second Epistle was doubted by some. FIRMILIAN, bishop of Cappadocia, in Epistle to Cyrpian speaks of Peter's Epistles as warning us to avoid heretics (a monition which occurs in the Second, not the First Epistle). Now Cappadocia is one of the countries mentioned (compare I Peter 1:1 with II Peter 3:1) as addressed; and it is striking, that from Cappadocia we get the earliest decisive testimony. "Internally it claims to be written by Peter, and this claim is confirmed by the Christians of that very region in whose custody it ought to have been found" [TREGELLES].
The books disputed (Antilegomena), as distinguished from those universally recognized (Homologoumena), are Epistles Second Peter, James, Second and Third John, Jude, the Apocalypse, Epistle to Hebrews (compare EUSEBIUS [Ecclesiastical History, 3.3,25]). The Antilegomena stand in quite a different class from the Spurious; of these there was no dispute, they were universally rejected; for example, the Shepherd of Hermas, the Revelation of Peter, the Epistle ofBarnabas. CYRIL OF JERUSALEM (A.D. 348) enumerates seven Catholic Epistles, including Second Peter; so also GREGORY NAZIANZEN (A.D. 389), and EPIPHANIUS (A.D. 367). The oldest Greek manuscripts extant (of the fourth century) contain the Antilegomena. JEROME [On Illustrious Men], conjectured, from a supposed difference of style between the two Epistles, that Peter, being unable to write Greek, employed a different translator of his Hebrew dictation in the Second Epistle, and not the same as translated the First into Greek. Mark is said to have been his translator in the case ofthe Gospelaccording to Mark; but this is all gratuitous conjecture. Much of the same views pervade both Epistles. In both alike he looks for the Lord's coming suddenly, and the end ofthe world(compare II Peter 3:8-10 with I Peter 4:5); the inspiration of the prophets (compare I Peter 1:10-12 with II Peter 1:19-21; II Peter 3:2); the new birth by the divine word a motive to abstinence from worldly lusts (I Peter 1:22; I Peter 2:2; compare II Peter 1:4); also compare I Peter 2:9 with II Peter 1:3, both containing in the Greek the rare word "virtue" (I Peter 4:17 with II Peter 2:3).
It is not strange that distinctive peculiarities of STYLE should mark each Epistle, the design of both not being the same. Thus the sufferings of Christ are more prominent in the First Epistle, the object there being to encourage thereby Christian sufferers; the glory of the exalted Lord is more prominent in the Second, the object being to communicate fuller "knowledge" of Him as the antidote to the false teaching against which Peter warns his readers. Hence His title of redemption, "Christ," is the one employed in the First Epistle; but in the Second Epistle, "the Lord."Hopeis characteristic of the First Epistle; full knowledge, of the Second Epistle. In the First Epistle he puts his apostolic authority less prominently forward than in the Second, wherein his design is to warn againstfalse teachers. The same difference is observable in Paul's Epistles. Contrast I Thessalonians 1:1; II Thessalonians 1:1;Philippians 1:1, withGalatians 1:1; I Corinthians 1:1. The reference to Paul's writings as already existing in numbers, and as then a recognized part of Scripture (II Peter 3:15-16), implies that this Epistle was written at a late date, just before Peter's death.
Striking verbal coincidences occur: compare I Peter 1:19, end, with II Peter 3:14, end; "His own," Greek, II Peter 1:3, II Peter 2:16; II Peter 3:17 with I Peter 3:1, I Peter 3:5. The omission of the Greek article, I Peter 2:13 with II Peter 1:21; II Peter 2:4-5, II Peter 2:7. Moreover, two words occur, II Peter 1:13, "tabernacle," that is, the body, and II Peter 1:15, "decease," which at once remind us of the transfiguration narrative in the Gospel. Both Epistles refer to the deluge, and to Noah as the eighth that was saved. Though the First Epistle abounds in quotations of the Old Testament, whereas the Second contains none, yet references to the Old Testament occur often (II Peter 1:21; II Peter 2:5-8, II Peter 2:15; II Peter 3:5-6, II Peter 3:10, II Peter 3:13). Compare Greek, "putting away," I Peter 3:21, with II Peter 1:14; Greek, "pass the time," I Peter 1:17, with II Peter 2:18; "walked in," I Peter 4:3, with II Peter 2:10; II Peter 3:3; "called you," I Peter 1:15; I Peter 2:9; I Peter 5:10, with II Peter 1:3.
Moreover, more verbal coincidences with the speeches of Peter in Acts occur in this Second, than in the First Epistle. Compare Greek, "obtained," II Peter 1:1 withActs 1:17; Greek, "godliness," II Peter 1:6, withActs 3:12, the only passage where the term occurs, except in the Pastoral Epistles; and II Peter 2:9 withActs 10:2,Acts 10:7; "punished," II Peter 2:9, withActs 4:21, the only places where the term occurs; the double genitive, II Peter 3:2, withActs 5:32; "the day of the Lord," II Peter 3:10, withActs 2:20, where only it occurs, except in I Thessalonians 5:2.
The testimony of Jude,Judges 1:17-18, is strong for its genuineness and inspiration, by adopting its very words, and by referring to it as received by the churches to which he, Jude, wrote, "Remember the words which were spoken before of the apostles of our LordJesus Christ; how that they told you there should be mockers in the last time, who should walk after their own ungodly lusts." Jude, therefore, must have written after Second Peter, to which he plainly refers; not before, as ALFORD thinks. No less than eleven passages of Jude rest on similar statements of Second Peter.Judges 1:2, compare II Peter 1:2;Judges 1:4, compare II Peter 2:1;Judges 1:6, compare II Peter 2:4;Judges 1:7, compare II Peter 2:6;Judges 1:8, compare II Peter 2:10;Judges 1:9, compare II Peter 2:11;Judges 1:11, compare II Peter 2:15;Judges 1:12, compare II Peter 2:17;Judges 1:16, compare II Peter 2:18;Judges 1:18, compare II Peter 2:1; II Peter 3:3. Just in the same way Micah,Micah 4:1-4, leans on the somewhat earlier prophecy of Isaiah, whose inspiration he thereby confirms. ALFORD reasons that because Jude, in many of the passages akin to Second Peter, is fuller than Second Peter, he must be prior. This by no means follows. It is at least as likely, if not more so, that the briefer is the earlier, rather than the fuller. The dignity and energy of the style is quite consonant to what we should expect from the prompt and ardent foreman of the apostles. The difference of style between First and Second Peter accords with the distinctness of the subjects and objects.
THE DATE, from what has been said, would be about AD68 or 69, about a year after the first, and shortly before the destruction of Jerusalem, the typical precursor of the world's end, to which II Peter 3:10-13 so solemnly calls attention, after Paul's ministry had closed (compare Greek aorist tense, "wrote," past time, II Peter 3:15), just before Peter's own death. It was written to include the same persons, and perhaps in, or about the same place, as the first. Being without salutations of individuals, and entrusted to the care of no one church, or particular churches as the first is, but directed generally "to them that have obtained like preciousfaithwith us" (II Peter 1:1), it took a longer time in being recognized as canonical. Had Rome been the place of its composition or publication, it could hardly have failed to have had an early acceptance—an incidental argument against the tradition of Peter's martyrdom at Rome. The remote scene of its composition in Babylon, or else in some of the contiguous regions beyond the borders of the Roman empire, and of its circulation in Cappadocia, Pontus, etc., will additionally account for its tardy but at last universal acceptance in the catholic Church. The former Epistle, through its more definite address, was earlier in its general acceptance.
OBJECT.—In II Peter 3:17-18 the twofold design of the Epistle is set forth; namely, to guard his readers against "the error" of false teachers, and to exhort them to grow in experimental "knowledge of our Lord and Saviour" (II Peter 3:18). The ground on which this knowledge rests is stated, II Peter 1:12-21, namely, the inspired testimony of apostles and prophets. The danger now, as of old, was about to arise from false teachers, who soon were to come among them, as Paul also (to whom reference is made, II Peter 3:15-16) testified in the same region. The grand antidote is "the full knowledge of our Lord and Saviour," through which we know God the Father, partake of His nature, escape from the pollutions of the world, and have entrance into Christ's kingdom. The aspect of Christ presented is not so much that of the past suffering, as of the future reigning, Saviour, His present power, and future new kingdom. This aspect is taken as best fitted to counteract the theories of the false teachers who should "deny" His Lordship and His coming again, the two very points which, as an apostle and eye-witness, Peter attests (His "power" and His "coming"); also, to counteract their evil example in practice, blaspheming the way of truth, despising governments, slaves tocovetousnessand filthy lusts of the flesh, while boasting of Christian freedom, and, worst of all, apostates from the truth. The knowledge of Christ, as being the knowledge of "the way of righteousness," "the right way," is the antidote of their bad practice. Hence "the preacher" of righteousness, Noah, and "righteous Lot," are instanced as escaping the destruction which overtook the "unjust" or "unrighteous"; and Balaam is instanced as exemplifying the awful result of "unrighteousness" such as characterized the false teachers. Thus the Epistle forms one connected whole, the parts being closely bound together by mutual relation, and the end corresponding with the beginning; compare II Peter 3:14, II Peter 3:18 with II Peter 1:2, in both "grace" and "peace" being connected with "the knowledge" of our Saviour; compare also II Peter 3:17 with II Peter 1:4, II Peter 1:10, II Peter 1:12; and II Peter 3:18, "grow in grace and knowledge," with the fuller II Peter 1:5-8; and II Peter 2:21; and II Peter 3:13, "righteousness," with II Peter 1:1; and II Peter 3:1 with II Peter 1:13; and II Peter 3:2 with II Peter 1:19.
The germs of Carpocratian and Gnosticheresiesalready existed, but the actual manifestation of these heresies is spoken of as future (II Peter 2:1-2, etc.): another proof that this Epistle was written, as it professes, in the apostolic age, before the development of the Gnostic heresies in the end of the first and the beginning of the second centuries. The description is too general to identify the heresies with any particular one of the subsequent forms of heresy, but applies generally to them all.
Though altogether distinct in aim from the First Epistle, yet a connection may be traced. The neglect of the warnings to circumspection in the walk led to the evils foretold in the Second Epistle. Compare the warning against the abuse of Christian freedom, I Peter 2:16 with II Peter 2:19, "While they promise them liberty, they themselves are the servants of corruption"; also the caution against pride, I Peter 5:5-6 with II Peter 2:18, "they speak great swelling words of vanity."
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NCHR Letter to Senate HELP and House Energy & Commerce Committees Regarding the VALID Act | National Center for Health Research
We support the inclusion of the VALID Act in the omnibus spending package to provide FDA authority to ensure that diagnostic tests are valid and reliable.
The Honorable Patty Murray The Honorable Richard BurrChair Ranking MemberSenate Health, Education, Senate Health, Education,Labor & Pensions Committee Labor & Pensions CommitteeWashington, DC 20515 Washington, DC 20515
The Honorable Frank Pallone The Honorable Cathy McMorris RodgersChair Ranking MemberHouse Energy & Commerce Committee House Energy & Commerce CommitteeWashington, DC 20515 Washington, DC 20515
Dear Chair Murray, Ranking Member Burr, Chair Pallone, and Ranking Member Rodgers:
Thank you for your continued work to strengthen the oversight of laboratory-developed diagnostic tests (LDTs). We strongly support the inclusion of the VALID Act in the year-end omnibus spending package. This important bill will provide the FDA with the authority and resources necessary to ensure that the highest-risk diagnostic tests are valid and reliable. We have seen the importance of diagnostic tests throughout the COVID-19 pandemic and the potential harm from an inaccurate result. Increasing numbers of patients make life-altering decisions based on diagnostic tests; in addition to tests to diagnose cancer, many genetic tests are being used to predict increased risk of cancer and other serious diseases or life-threatening fetal abnormalities. Physicians are often unaware of the origin of the tests, assuming proper oversight and evaluation has taken place. The provisions of the VALID Act will help give physicians the necessary assurances that the tests they are using on their patients are accurate.
While we support the urgent need to pass VALID in order to protect patients from inaccurate tests, we have significant concerns regarding an exemption for academic medical centers. This exemption would undercut the core goal of this necessary reform: creating more rigorous, standardized oversight requirements for all tests no matter where they are made. We also remain concerned about the grandfathering of all tests currently on the market, regardless of the potential risk category. This is troubling given the broad range of tests currently on the market that are known to be inaccurate or to fail to reliably capture important medical information. For example, a
New York Times
review found that the five most common prenatal genetic tests performed were
incorrect 85% of the time
, and yet they are able to be advertised as “reliable” and “highly accurate” due to a lack of FDA oversight and regulation. One test for Prader-Willi syndrome, a very serious condition that can cause seizures and makes it unlikely that an adult can live independently, was found to produce a false-positive result more than 90% of the time. Based on the current lack of FDA authority, companies can legally develop and sell these important tests without physicians or patients realizing how inaccurate they are.
All labs and tests should be held to the highest standards when it comes to providing physicians and patients with critical medical information. As currently drafted, the standards in VALID would be unacceptably low for what the FDA considers “low-risk” and “medium-risk” tests, such as genetic tests. The higher standards would focus instead on only the highest risk tests, such as those diagnosing cancer. The degree of scrutiny for genetic tests that inform patients whether they are likely to develop specific types of cancer or other serious diseases remains unclear, even though such a test result could convince the patient to undergo irreversible surgery, such as a mastectomy, hysterectomy, or stomach removal. The same is true for prenatal tests that could result in extreme parental stress or decisions to terminate a wanted pregnancy. These genetic tests should be categorized as high risk in the legislation.
We understand the competing interests from the multiple stakeholders involved and appreciate your efforts to narrow any exemption for academic medical centers. However, we continue to have concerns regarding high-risk tests currently being used and the FDA’s tendency to have low standards of evidence for moderate risk devices that patients and families would consider high risk. We strongly urge you to keep patients in mind as you finalize this important piece of legislation. The results from these tests have the potential to lead to life-changing medical decisions. Patients and physicians have the right to know they can trust the results being provided, regardless of where and when the test was developed.
Sincerely,
Diana Zuckerman, PhDPresidentNational Center for Health Research
| https://www.center4research.org/senate-help-energy-commerce-letter-valid-act/ |
The Oxford Oratory
A sanctuary in the midst of the city
The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman.
Heart of Jesus, all-holy! Fountain of all blessings, I adore thee, I love thee, and with a lively sorrow for my sins, I offer thee this poor heart of mine. Make me humble, patient, pure, and wholly obedient to thy will. Good Jesus, grant that I may live in thee and for thee. Protect me in the midst of danger; comfort me in my afflictions; give me health of body, assistance in my temporal needs, thy blessing on all that I do, and the grace of a holy death. Amen.
#oxfordoratory
A photo from Sunday’s Solemn Mass for Corpus Christi.
#oxfordoratory
June Music
Sunday 4 JuneSolemn Mass 11:00The Most Holy TrinityKyrie MundyMissa Euge bone TyeLibera nos SheppardHonor, virtus et potestas Tallis
Sunday 11 JuneSolemn Mass 11:00Corpus ChristiMissa Pange lingua JosquinLauda Sion PalestrinaOculi omnium Byrd
Friday 16 JuneSolemn Mass 18:00The Most Sacred Heart of JesusMissa Dormendo un giorno GuerreroImproperium PalestrinaSancte Deus Tallis
Sunday 18 JuneSolemn Mass 11:0011th Sunday of the YearMissa Brevis in F Op.117 RheinbergerBenedicam Dominum VictoriaSalve Regina Poulenc
Wednesday 21 JuneSolemn Mass 18:00St Aloysius GonzagaMissa O quam gloriosum VictoriaJustitiae Domini A ScarlattiO bone Jesu Anchieta
Sunday 25 JuneSolemn Mass 11:0012th Sunday of the YearMissa Repleatur os meum PalestrinaPerfice gressus meos LassusHomo quidam fecit coenam magnam Mouton
Thursday 29 JuneSolemn Mass 18:00St Peter and St PaulMissa Petre ego pro te rogavi LoboPetre ego pro te rogavi GuerreroJanitor caeli Ortiz
The Sacred Heart
Love is a funny thing. Materialists will tell us that it is purely the result of a series of electro-chemical responses in the brain, and yet others will tell us that it is the result of fate, the conspiracy of the alignment of the planets or the times we find ourselves in. The heart has long been understood as the centre of a person, a place of knowledge as much as will. It makes us do unreasonable things like acts of unwarranted kindness and altruism and by the edge of its blade we can be hurt in ways that we just can’t speak about. And yet none of these express what love is in itself — only God does that.
On Friday we venerate the Heart of our Lord as the symbol of his human love in which God’s divine love is revealed to us. In most of the prayers to or the meditations on the Sacred Heart, even those very ancient prayers, the woundedness of our Lord’s heart comes to the fore. That heart pierced with a lance and bruised with outrages and blasphemies is a stark and realistic image of the extent to which Christ loves us. Christ, who is the image of the unseen God, the Icon of the Father, shows us precisely what God’s love for us looks like. And it looks like a heart pierced and bruised on account of our sins, yet burning with ardent love for you and for me. This divine love is not for softies.
The time when we celebrate this feast is very fitting. We have come to the end of the Church’s celebration of the mysteries of our redemption: the Passion, the Cross, the Resurrection, the Ascension, Pentecost, the Feast of the Blessed Trinity and Corpus Christi. But today we commemorate the divine-human love which motivated them all. In adoring the Sacred Heart, we adore the totality of Christ’s saving work — it represents the way in which God holds nothing back from us. And in order to share his divine life with us, he reaches down into the very depths of our life, even — and especially — where it is painful, difficult to speak of, hidden. By taking it all and joining it to himself, he scoops us up, he enables us to become like him. By sharing our life, and by sharing our pains, he heals us, he sanctifies us, and he strengthens us.
It is also true that his heart welcomes us precisely so that we might become like it. The whole thrust of our Christian life is that we might be conformed to our Saviour, that we might resemble him, and in this sense, in the life of faith, we should ask ourselves continually whether our heart resembles his. His Sacred Heart is both the example and the cause of our becoming like him. His love is attractive. The more we consider the love with which Jesus acted, and spoke and gave of himself for us, the more we can begin, by his grace, to imitate him — it is truly the school of Christian perfection.
And we begin in that school by prayer. When St John Henry Newman, our Cardinal, chose his motto, he looked to St Francis de Sales’ Treatise on the Love of God. The phrase he chose and paraphrased, Cor ad Cor loquiturrepresents for us the central mystery of the prayer that can begin to transform us. St Francis de Sales wrote:
Truly the chief exercise in mystical theology is to speak to God and to hear God speak in the bottom of the heart; and because this discourse passes in most secret aspirations and inspirations, we term it a silent conversing. Eyes speak to eyes, and heart to heart, and none understand what passes save those who speak.
We may be no great shakes at the spiritual life, or prayer, or we may feel that excelling in virtue is beyond us, but if we can in the simplest of ways open our poor heart to his Sacred Heart, and speak to him as to a friend, if we can entrust our lives to him and ask him devoutly and sincerely to shape us after the model of his Heart, then our Christian life will be all the more graced.
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The Corpus Christi procession concluded with Benediction at the University Chaplaincy. #oxfordoratory
The procession finished at the University’s Catholic Chaplaincy. #oxfordoratory
The numbers caught the attention of the local media:
https://www.oxfordmail.co.uk/news/23582016.oxfords-catholic-congregations-take-part-corpus-christi-procession/
#oxfordoratory
Children scattered flower petals before the Blessed Sacrament all the way. #oxfordoratory
Tuesday 13 June 2023
Our route now passes through the city in a straight line, taking us directly through the busiest shopping areas. #oxfordoratory
The canopy was carried by members of the University of Oxford wearing their academic dress. #oxfordoratory
Fr Robert Ombres OP preached a sermon. #oxfordoratory
We paused at Blackfriars. #oxfordoratory
We were joined by local clergy and religious orders as we processed through the streets to the Dominican Priory at Blackfriars. #oxfordoratory
The processions sets off… #oxfordoratory
Tuesday 13 June 2023
We had record numbers for the procession this year. There wasn’t space in church for everyone at the beginning! There were more people outside too. #oxfordoratory
The beginning of our Corpus Christi procession last Sunday.#oxfordoratory
The Oratory Prayer Book is now shipping internationally!
We’ve made it even easier to buy the Oratory Prayer Book from anywhere in the world.
And we’ve made it easier to order multiple copies too — in the UK and worldwide.
Order your copy here:https://tinyurl.com/opb-buy
If you have one, we’d love to hear what you think about it. Let us know in the comments, or tag a photo of your prayer book in the wild with #oratoryprayerbook
Thanks to @acatholicinoxford for the photo.
#oxfordoratory
Worship
What does it actually mean to worship God? In the New Testament, the word we most often translate as ‘worship’ doesn’t mean to reverence another in some abstract sense. It always involves some kind of bodily action. When we think about the magi visiting the Holy Family, we sometimes convey this motion by describing them — after they fall to their knees — as ‘doing homage’. But it’s actually that same word here we might translate elsewhere as ‘worship’. It’s just that we recognise the need to describe the bodily sign of their submission and adoration of the new born King with something that sounds a bit more physical.
The word we usually translate as ‘worship’ ( proskuneo) comes literally from a root meaning ‘to make yourself like a dog before the other person’. It originally meant prostrating yourself on the floor to show your humble submission before another. By the time of the New Testament, people wouldn’t necessarily have had the root of this word in mind whenever they used it,* but the word still carries with it the idea of doing something with your body to express your worship.
The feast of Corpus Christi is all about this kind of bodily worship. It’s tied to the fact that we are not pure spirits, but that we are human beings, body and soul. To worship God is not just a spiritual act. The right worship of God does not consist in simply having the right kinds of thoughts towards him. But the worship of God involves the humble submission of our entire human being, body and soul, before the God who is greater than all of us.
And ever since the Incarnation, we do this not just before an abstract spirit. Because, from the moment of the Incarnation, God really does have a human body, that we can worship, that we fall down on our knees before, like the magi and the Canaanite woman, and so many others in the Gospel who kneel down and worship Christ. When we worship God, we kneel before God who is present in the flesh, under the appearances of bread and wine, in our churches all over the world.
Corpus Christi is a joyful celebration of Christ’s presence among us, and it gives us an opportunity to think about how we respond to that gift. All this talk of kneeling and worship might not sound so joyful, but one of the great paradoxes of Christianity is that we find our greatest freedom in the humble service of God. Our greatest joy really should be found in finding ways to express this loving worship. So at least once a year, it is no bad thing to think about how we express with our own bodies that worship of God’s body, and what ways we can find to worship him even more perfectly.
This Sunday, we will carry Christ’s Body through the streets of our city. We have a chance to demonstrate to the world our love, our joyful service, our worship of him, through our presence. The procession leaves our church at 2:30pm. Make sure you are there.
But we should also think about the more ordinary things, like making sure we show that worship whenever we are in his presence. We should show through our behaviour in church that we believe him to be there: by genuflecting before him in the tabernacle of the church, and by keeping the church quiet and prayerful.
We show our worship above all by kneeling down before him — like all those people in the Gospel — for the moment of Holy Communion. And we allow the priest to place the Host on our tongues, so that we don’t handle unnecessarily what is holy and precious, and no particles of Our Lord’s Body are ever dropped or lost through carelessness.
We continue that worship in our prayers of thanksgiving after Communion and once the Mass has ended. We certainly never leave church during Communion. And we might think of ways of extending the time we spend with Christ present in the Blessed Sacrament: by attending Mass during the week sometimes, or visiting him during the times each week when his Body is exposed solemnly on the altar for Adoration, or even just by visiting an empty church, where he is waiting for us to show him our worship.
Our Lord is hidden there, waiting for us to come and visit him, and make our request to him. See how good he is! He is there in the Sacrament of his love, sighing and interceding incessantly with his Father for sinners. To what outrages does he not expose himself, that he may remain in the midst of us! He is there to console us; and therefore we ought often to visit him. How pleasing to him is the short quarter of an hour that we steal from our occupations, from something of no use, to come and pray to him, to visit him, to console him for all the outrages he receives! When he sees pure souls coming eagerly to him, he smiles upon them. They come with that simplicity which pleases him so much, to ask his pardon for all sinners, for the outrages of so many ungrateful men. What happiness do we not feel in the presence of God, when we find ourselves alone at his feet before the holy tabernacles! ‘Come, my soul, redouble thy fervour; thou art alone adoring thy God. His eyes rest upon thee alone.’
— St John Mary Vianney
* One exception is that I do think Christ had this root meaning in mind when he spoke to the Canaanite woman in Matthew 15:21–28. He wasn’t randomly insulting her by comparing her to a dog, but drawing attention to the fact that she was making herself like a dog before him — i.e. worshipping him — because she recognised him to be God. In other words, he was acknowledging her worship as proof of her faith and humility.
These reflections are sent out each Wednesday to all those on our mailing list. Click here to sign up to our mailing list , and receive our Sunday E-newsletter and these reflections straight to your inbox.
Monday 5 June 2023
On Saturday, Fr Rupert led Men’s Oratory on a walking pilgrimage to Islip, birthplace of St Edward the Confessor. #oxfordoratory
Congratulations to Elizabeth who was received into the Church yesterday evening on the Feast of the Visitation. #oxfordoratory
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AIDS and injecting drug use in the United Kingdom, 1987-1993: the policy response and the prevention of the epidemic
Download Citation | AIDS and injecting drug use in the United Kingdom, 1987-1993: the policy response and the prevention of the epidemic | This paper assesses policy development, service changes and trends in HIV infection and risk behavior among injecting drug users (IDUs) in the... | Find, read and cite all the research you need on ResearchGate
AIDS and injecting drug use in the United Kingdom, 1987-1993: the policy response and the prevention of the epidemic
October 1995
Social Science & Medicine 41(5):699-716
DOI: 10.1016/0277-9536(94)00435-V
Abstract
This paper assesses policy development, service changes and trends in HIV infection and risk behavior among injecting drug users (IDUs) in the United Kingdom. In 1986, the U.K. was faced with the possible rapid spread of HIV infection among IDUs. The combination of an outbreak of HIV infection with prevalence levels of 50% or more in Edinburgh, the recent diffusion of drug injecting, and high levels of syringe-sharing risk behaviour, suggested that HIV infection might spread rapidly through IDU populations. HIV prevention activities commenced in 1986 and developed in 1987. The first report on AIDS and Drugs Misuse by the Advisory Council on the Misuse of Drugs in 1988 was a major catalyst for change. It supported and legitimized emergent views on new ways of working with drug users. Between 1988 and 1993 innovative public health projects increased the ability to target vulnerable populations through syringe distribution, expansion of methadone treatment and outreach to hard-to-reach populations. There were major changes in service philosophy and practices, as ideas of harm minimization, accessibility, flexibility and multiple and intermediate goals were developed. There is evidence that these public health projects encouraged extensive changes in the health behaviour of IDUs. There have been major reductions in syringe-sharing risk behaviour and sharing syringes is no longer the norm. Evaluation of specific interventions (e.g. syringe-exchange) shows their importance in encouraging reductions in risk behaviour. Levels of HIV infection in IDUs remain low by international standards. Outside of London rates of about 1% have been reported; London has a low and declining prevalence of infection to around 7% in 1993; previous high levels in Edinburgh (55%) have since declined to 20%. Britain has to date avoided the rapid increase in HIV infection among injectors that has occurred in many parts of the world. The same period saw the continuation of high prevalence levels in New York and many European cities, and the explosive spread of HIV in many countries in south-east Asia. This paper acknowledges the difficulties is proving links between social interventions and epidemic prevention. It argues that there is prima facie evidence for the success of public health prevention, that the collection of intervention approaches in the U.K. had a significant impact on IDUs behaviour, and that this has helped prevent an epidemic of HIV infection among IDUs. The U.K. experience adds to the growing evidence of the significance of early interventions in encouraging behaviour change and in limiting the spread of HIV infection.
... Dr. Kidd recalls that some societal unease about methadone did remain: local community pressure groups in Glasgow canvassed the local health board in an attempt to prevent the introduction of methadone prescribing. Nonetheless, funding for drug services increased from £5.235 million to £8.239 million per year between 1987 and 1993 and funding for care targeting HIV positive people who used drugs increased from £1.132 million per year to £16.132 million in the same period
(Stimson 1995)
. There was also a lack of constraint placed upon the form of drug treatment services by the government which facilitated reorientation around the harm reduction approach (Stimson 1995). ...
... Nonetheless, funding for drug services increased from £5.235 million to £8.239 million per year between 1987 and 1993 and funding for care targeting HIV positive people who used drugs increased from £1.132 million per year to £16.132 million in the same period (Stimson 1995). There was also a lack of constraint placed upon the form of drug treatment services by the government which facilitated reorientation around the harm reduction approach
(Stimson 1995)
. ...
... The approach was broad-based, and included the provision and expansion of opiate substitution treatment, needle exchange and education regarding safer injecting techniques. Needle and syringe sharing causing HIV transmission in people who inject drugs in Edinburgh peaked in 1980-1982(Robertson 2005 and dropped from peak levels of 55% to 20% by 1993
(Stimson 1995)
. The UK avoided the rapid rise in HIV seen in other countries. ...
Treatment and Intervention for Opiate Dependence in the United Kingdom: Lessons from Triumph and Failure
Article
Jun 2018
Eur J Crim Pol Res
Nicola Kalk
J. Roy Robertson
Brian Kidd
John Strang
The history of opiate treatment in the United Kingdom (UK) since the early 1980s is a rich source of learning about the benefits and pitfalls of drug treatment policy. We present five possible lessons to be learnt about how factors outside the clinic, including government, charities and researchers can influence treatment and outcomes. First, do not let a crisis go to waste. The philosophical shift from abstinence to harm reduction in the 1980s, in response to an HIV outbreak in injecting users, facilitated expansion in addiction services and made a harm reduction approach more acceptable. Second, studies of drug-related deaths can lead to advances in care. By elucidating the pattern of mortality, and designing interventions to address the causes, researchers have improved patient safety in certain contexts, though significant investment in Scotland has not arrested rising mortality. Third, collection of longitudinal data and its use to inform clinical guidelines, as pursued from the mid-1990s, can form an enduring evidence base and shape policy, sometimes in unintended ways. Fourth, beware of the presentation of harm reduction and recovery as in conflict. At the least, this reduces patient choice, and at worst, it has caused some services to be redesigned in a manner that jeopardises patient safety. Fifth, the relationship between the third and state sectors must be carefully nurtured. In the UK, early collaboration has been replaced by competition, driven by changes in funding, to the detriment of service provision.
... Después de lo sucedido en Merseyside (Inglaterra) en 1985, se introdujeron las pruebas de anticuerpos contra el VIH en varios países de Europa, lo que condujo al descubrimiento de altas tasas de infección en numerosas ciudades entre las personas que se inyectan drogas
(Stimson, 1995)
. ...
... En este año, el Informe Coona al Parlamento Europeo 426 había abogado por el uso de programas de intercambio de agujas y tratamiento con metadona (Coona, 1992). Esto fue evidencia de un enfoque pragmático cada vez mayor en Europa basado en los principios de reducción de daños, que refleja un cambio de opinión significativo entre 1985 y principios de la década de 1990, muy influenciado por la conciencia sobre el VIH/SIDA y sus vínculos con el consumo de drogas inyectables
(Stimson, 1995)
. Sin embargo, el Parlamento Europeo en ese momento no adoptó estas recomendaciones. ...
Sujetos, consumos y aportes para la prevención y atención de adicciones
May 2021
Carlos Arturo Robledo
Victor Cano
Ana María Quiceno Vásquez
Andrés Cristancho-Duarte
El consumo de sustancias psicoactivas se ha convertido en una problemática de las sociedades del presente siglo, lo que supone un gran reto alrededor del cual es necesario generar reflexiones, análisis y estudios científicos interdisciplinares. Es preciso un diálogo de saberes donde sociología, antropología, economía, derecho, demografía, psicología, medicina, psiquiatría, epidemiología, medicina, salud pública e incluso arquitectura y planeación urbana tengan un punto de encuentro que permita trascender el dominio de su propia disciplina hacia la convergencia de teorías, perspectivas, programas, métodos y autores, para así propiciar un debate abierto que lleve a la mejor comprensión de un fenómeno tan complejo y multidimensional como este. Este libro que presentamos bajo el título de Sujetos, consumos y aportes para la prevención y atención de adicciones tiene como propósito promover la gestión de conocimiento sobre la realidad del problemático consumo de sustancias psicoactivas en la contemporaneidad, teniendo en cuenta sus múltiples dimensiones, para el fácil acceso y consulta de académicos, centros de investigación, organizaciones privadas, entidades estatales y público en general. Para ello, la Escuela Contra la Drogadicción ha convocado a universidades, grupos de investigación y organizaciones de la sociedad civil del país para que presenten sus resultados de investigación, trayectoria académica, tendencias investigativas y aprendizajes al respecto, pero sobre todo, para que contribuyan a generar nuevos interrogantes que abran de líneas de conocimiento futuras y puedan llevar a respuesta frente a las necesidades diferenciales de un país como Colombia. Bajo esta premisa, el presente libro está estructurado bajo cinco categorías que se entretejen entre sí: 1. consumo de sustancias psicoactivas y conductas adictivas, donde se evidencia como la brecha de consumo por edad es cada vez más corta; 2. prevención e intervención en el uso de sustancias psicoactivas, la cual resalta la importancia de conocer la historia, sus antecedentes, los programas existentes y los retos que supone su abordaje; 3. sujetos de consumo y experiencia institucional, categoría que da a conocer de primera mano la voz de los actores, ya sea como consumidores directos o instituciones que luchan en contra de este flagelo; 4. sustancias legales consumidas: alcohol, pone de manifiesto la importancia de generar debate en torno a las sustancias legales y su impacto en la calidad de vida de las personas y, finalmente, 5. perspectiva de reducción del daño, donde se insta a la minimización de las consecuencias adversas en el consumo a partir de políticas públicas, programas y enfoques diversos para la calidad de vida de la población.
... This anxiety related to a concern that the growing drug-addicted population might contaminate the nonaddicted population through sexual activity. This event has been described as a ''catalytic moment for drugs policy'' (Seddon, 2010, p. 86) in that it encouraged a transformation from a system emphasizing expert responsibility over irrational individuals to a more pragmatic public health approach concerned with promoting self-regulation and the reduction of harm
(Stimson, 1995)
. This new approach was underpinned by the view that drug-related harms posed a greater threat to the health of the population than the drugs themselves (Stimson, 1995). ...
... This event has been described as a ''catalytic moment for drugs policy'' (Seddon, 2010, p. 86) in that it encouraged a transformation from a system emphasizing expert responsibility over irrational individuals to a more pragmatic public health approach concerned with promoting self-regulation and the reduction of harm (Stimson, 1995). This new approach was underpinned by the view that drug-related harms posed a greater threat to the health of the population than the drugs themselves
(Stimson, 1995)
. This required a reconceptualization of the narrowly defined psychological and physical harms of the clinic system to public health, social, and legal harms (Lart, 1998). ...
Coming Off Drugs: A Critical History of the Withdrawing Body
Sep 2016
Contemp Drug Probl
Ian Walmsley
Heroin withdrawal is perhaps one of the most taken-for-granted components of the addiction framework. Heroin users as well as researchers, policy makers, and practitioners have become dependent on it for thinking about and acting upon the process of heroin leaving the body. It is thought to be among the most challenging aspects of the recovery journey and has been linked to a range of public health, legal, and social problems. The taken-for-granted nature of heroin withdrawal has arguably limited its scrutiny in sociological and historical analyses. This article offers an alternative and critical perspective that draws attention to the heterogeneity of historical events and strategies that have left their mark on the withdrawing body of the heroin user. It maps changes in the discourse from the 18th century to the present and closes with developments in the neuroscience of addiction, which have relocated withdrawal from the body to the neurocircuitry of the brain and reframed it as a negative emotional state. This new language suggests the future of the discourse of withdrawal might be relatively short. The analysis moves beyond existing understandings of withdrawal as the simple absence of drugs from the body.
... It appears that the 'philosophy' o f'harm minimisation' has had an impact on drug misuse, in terms of a move by drug misusers from injecting to oral use of opiates, a fall in the numbers of misusers sharing injecting equipment and a reduction in the rates of HIV among drug misusers, over time (Robertson et al, 1994;Greenwood 1996). Britain has maintained one of the lowest HIV seroprevalence rates among injecting drug misusers globally
(Stimson, 1995)
, and appears to have contained the 'epidemic' of HIV. Despite the success of the HIV prevention strategies, of concern remains the high incidence and prevalence of Hepatitis B and C among drug misusers (Stimson, 1995;van Beek et al, 1998). ...
... Britain has maintained one of the lowest HIV seroprevalence rates among injecting drug misusers globally (Stimson, 1995), and appears to have contained the 'epidemic' of HIV. Despite the success of the HIV prevention strategies, of concern remains the high incidence and prevalence of Hepatitis B and C among drug misusers
(Stimson, 1995;
van Beek et al, 1998). ...
Drug users and their general practitioners : a survey of the views of drug users; training of general practitioners in the management of drug use
Thesis
Jan 2000
C Hindler
Objectives
1. To determine drug misusers' views about their primary health care and their relationship with
general practitioners.
2. To undertake a controlled evaluation of small group education of general practitioners in the
management of drug misusers.
Method
1. Drug misusers attending five treatment services in north east London - a general practice with a
special interest in managing drug misuse; a private drug clinic; a community drug team; a drug
dependence unit and a street agency - were interviewed using a semi-structured interview and
the Social Functioning Questionnaire.
2. All general practitioners who practised within the former North East Thames Regional Health
Authority were approached to take part in small group teaching about drug misuse. This was
conducted over two consecutive afternoons in a general practice, with four follow-up seminars.
The trained doctors were compared with two groups of untrained general practitioners. Outcome
measures included: Drug Training Questionnaire responses at the outset and 9 months after
training; evaluation of the training appraised on a ten point Likert scale; Home Office Addicts Index
and North Thames Regional Drug Misuse Database figures for notification of newly presenting
subjects, for each of the three groups of general practitioners, 8 months prior to training and 8 and
16 months after training.
Results
Ninety percent of the drug misusers were registered with a non-specialist general practitioner and
88% of these doctors were aware of their patients' drug use. Half of the non-specialist general practitioners aware of their patient's drug use were reported as prescribing substitute medication.
Sixty percent of misusers attending the non-specialist doctors perceived their general practitioners
to hold negative or neutral views about them. Doctors in the specialist general practice were more
likely to prescribe, compared to the other four centres, and 97% of their patients believed these
doctors had a positive view of drug misusers. The specialist general practice was more active in
providing counselling and/or education about drug misuse.
2. Forty doctors attended the teaching programme. Twenty-eight doctors comprised comparison
group one (interested but unable to attend the teaching) and 30 formed comparison group two(not interested in training but completed questionnaires). The about to be trained group were seeing and treating more drug misusers compared to the comparison groups. The overall ratings for the teaching programme were high (7.9 for usefulness and 8.0 for interest - maximum score 10).
Doctors in the trained group were found to be notifying significantly more drug misusers to the
Home Office and prescribing methadone more frequent1y 16 months after the teaching, than
doctors in the comparison groups. Over 9 months, the Drug Training Questionnaires
demonstrated no significant changes. The cost of the course per doctor was £127.
Conclusions
1. The majority of drug misusers attending treatment centres are registered with general practitioners
and regarded them as an important health resource in managing both their drug use and wider
medical issues, despite the reluctance of non-specialist general practitioners to be involved in
prescribing and a high prevalence of unfavourable attitudes towards drug misusers.
2. The participating doctors assessed the teaching programme positively and it was relatively cheap
to run. The self-report questionnaires as a single determinant of outcome revealed no significant
change in attitudes, knowledge or behaviour but when assessed by more objective means,
demonstrated a rise in notification rates and methadone prescribing by the trained doctors.
... One of the most unsettling is the potential spread of HIV through drug user networks and eventually to the general public. Between 1983 and
1995, there
were no recorded cases of HIV/AIDS among PWID in the country (Hacker et al., 2005;Miguez et al., 1997). The Colombian Ministry of Health first confirmed cases of HIV among PWID in 1999 (Ross, 2002), and the WHO-II Study reported a 1% HIV prevalence rate among PWID who injected cocaine, alcohol, and heroin in Bogotá (Mejía Motta, 2003). ...
... Thus the timely introduction of harm reduction interventions could prevent an explosion in HIV prevalence, as has occurred in other countries (Mathers et al., 2008). Preventing a widespread epidemic among PWID has been accomplished in many locations, including Australia and parts of the United Kingdom, where interventions were implemented before or at an early stage of viral diffusion (Iversen, Wand, Topp, Kaldor, & Maher, 2014;
Stimson, 1995
Stimson, , 1996Wodak & Maher, 2010). These examples illustrate that early prevention can be effective in both keeping HIV prevalence low among PWID and preventing the rapid spread of HIV within injection networks. ...
Consumption of injecting heroin in Colombia and risk behaviors
Article
Full-text available
Jan 2013
Dedsy Berbesi
Angela María Segura Cardona
Liliana Montoya-Velez
Pedro Mateu-Gelabert
Objective: To determine socio-demographic characteristics, prevalence of HIV and risk behaviors in injecting drug users (IDU). Methods: A cross-sectional study using sampling generated by the respondent was performed. The samples consisted of 540 participants (Pereira: n=300; Medellín: n=240) over 18 years of age. The interview was conducted by an HIV and sexually transmitted diseases expert. Ethical requirements were met. RDSAT (version 6.01) software and SPSS (version 8.0) software were used. Results: There are extensive networks of injecting drug users in both cities. The population was mostly men between 18 and 24 years of age with secondary education. Data suggest a recent introduction of HIV into networks and a high degree of risk behavior, including the use of syringes received from third parties during the past six months. Conclusions: Data indicate a high-risk situation for a possible HIV spreading among injecting networks in Colombia. The foregoing originates due to the introduction of HIV into such groups and to the lack of information regarding the injection as a risk practice associated with HIV.
... Other scholars have also claimed that a Western and colonial conceptualization of rationality is inherent in harm reduction discourses. For example, before the AIDS pandemic of the early/mid-1980s, in keeping with wider Western conceptions of illicit drug use as disruptive of rationality (Keane, 2003), drug policy and practice discourses inscribed drug-using service users as "enslaved by pharmacology and therefore incapable of rational decision-making" (Moore & Fraser, 2006;
Stimson, 1995)
. Western colonial perspectives also created oppressive pathologized subjectivities for people who use drugs. ...
Understanding Substance Use and Addiction from a Queer Perspective: Towards Mobilizing a Queer-Oriented Harm Reduction Approach
Chapter
Full-text available
Feb 2023
Fritz Pino
Rusty Souleymanov
... While HIV prevalence has fluctuated over time, it has remained relatively low at around 1.0%, despite those participating in the UAM Survey having had a long duration of injection risk exposure. The prompt introduction and high coverage of harm reduction measures, such as needle and syringe programmes (NSPs) and opioid substitution therapy, early on in the epidemic dramatically limited the transmission of HIV among people who inject drugs [11,
12]
. The diversification of new diagnoses among people who inject drugs, with a higher proportion of older people and those born outside of the UK being diagnosed over time, is likely reflective of changes in the underlying injecting population (e.g. ...
Epidemiology of HIV infection and associated behaviours among people who inject drugs in England, Wales, and Northern Ireland: Nearly 40 years on
Article
Full-text available
Mar 2022
Sara Croxford
Eva Emanuel
Ammi Shah
Emily Phipps
Introduction:
People who inject drugs are at high risk of blood-borne infections. We describe the epidemiology of HIV among people who inject drugs in England, Wales, and Northern Ireland (EW&NI) since 1981.
Methods:
National HIV surveillance data were used to describe trends in diagnoses (1981-2019), prevalence (1990-2019), and behaviours (1990-2019) among people who inject drugs aged ≥15 years in EW&NI. HIV care and treatment uptake were assessed among those attending in 2019.
Results:
Over the past four decades, the prevalence of HIV among people who inject drugs in EW&NI remained low (range: 0.64%-1.81%). Overall, 4978 people who inject drugs were diagnosed with HIV (3.2% of cases). Diagnoses peaked at 234 in 1987, decreasing to 78 in 2019; the majority were among white men born in the UK/Europe (90%), though the epidemic diversified over time. Late diagnosis (CD4 <350 cells/µl) was common (2010-2019: 52% [429/832]). Of those who last attended for HIV care in 2019, 97% (1503/1550) were receiving HIV treatment and 90% (1375/1520) had a suppressed viral load (<200 copies/ml). HIV testing uptake has steadily increased among people who inject drugs (32% since 1990). However, in 2019, 18% (246/1404) of those currently injecting reported never testing. The proportion of people currently injecting reporting sharing needles/syringes decreased from 1999 to 2012, before increasing to 20% (288/1426) in 2019, with sharing of any injecting equipment at 37% (523/1429).
Conclusion:
The HIV epidemic among people who inject drugs in EW&NI has remained relatively contained compared with in other countries, most likely because of the prompt implementation of an effective national harm reduction programme. However, risk behaviours and varied access to preventive interventions among people who inject drugs indicate the potential for HIV outbreaks.
... However, they became widely accepted as their important role in reducing blood borne virus transmission was recognised.
6
Arguments that overdose prevention centres condone drug use are comparable to objections to needle and syringe programmes, which are no longer considered credible, while harm reduction approaches generally are promoted by the highest coordination forum of the UN. 7 Thirdly, regarding the claim that a range of offences would be committed by overdose prevention centre providers; the liability of providers is subject to debate, in the UK at least. ...
Overdose prevention centres in the UK
Mar 2022
Adam Holland
Magdalena Harris
Matthew Hickman
Maggie Rae
... Researches mainly concentrated on the prevention and treatment, assessment methods and models, and epidemiology. 5 HIV/AIDS is the most controversial research topic, including its prevention and treatment, [6]
[7]
[8][9][10] epidemiology and pathogenesis, 11 and interventions. 10,[12][13][14][15][16][17] Other epidemics also caused much attention, such as dengue epidemics, 18 hepatitis C, 19,20 and influenza. ...
System dynamics modeling of public health services provided by China CDC to control infectious and endemic diseases in China
Full-text available
Mar 2019
Meina Li
Wenya Yu
Wei Tian
Lulu Zhang
Background:
Infectious and endemic diseases are a serious public health concern worldwide, and their prevention and treatment are globally controversial. This study aimed to establish an system dynamics (SD) model to analyze the factors influencing public health services provided by the Chinese Centers for Disease Control and Prevention (China CDC) to implement infectious and endemic disease control in China, by establishing more effective interventions to provide public health services and thus achieving the goal of controlling infectious and endemic diseases.
Materials and methods:
An SD model was constructed using the Vensim DSS program. Intervention experiments were performed using the SD model, which reflected the influences on disease control by adjusting the governmental investment and compensation level for public health products.
Results:
The experimental results showed that increasing the governmental investment in China CDC and compensation level for public health products will significantly increase the public health product rate provided by China CDC.
Discussion:
Problems with infectious and endemic disease prevention and treatment are the result of the system's incomplete functioning and limited health resources. To address the current problems and improve the system, the government should increase its investment in the public health service system and improve the compensation system to ensure smooth implementation of infectious and endemic disease prevention and treatment and, ultimately, improve public health in China.
... This epidemic was closely linked to similar ones in Dundee and Dublin [3], but few HIV cases were seen among PWID in Glasgow at the time [7]. Rapid introduction in the United Kingdom of needle exchange in 1986, followed by other harm reduction measures
[8]
, dramatically decreased spread of HIV within this population. Since the mid-1990s, HIV diagnoses among PWID in Glasgow have averaged 10 per year [9]. ...
Recent and Rapid Transmission of HIV Among People Who Inject Drugs in Scotland Revealed Through Phylogenetic Analysis
Article
Mar 2018
J INFECT DIS
Manon Ragonnet-Cronin
Celia Jackson
Amanda Jane Bradley-Stewart
Andrew J. Leigh Brown
Background:
Harm reduction has dramatically reduced HIV incidence among people who inject drugs (PWID). In Glasgow, Scotland, <10 infections/year have been diagnosed among PWID since the mid-1990s. However, in 2015 a sharp rise in diagnoses was noted among PWID; many were subtype C with 2 identical drug-resistant mutations and some displayed low avidity, suggesting the infections were linked and recent.
Methods:
We collected Scottish pol sequences and identified closely related sequences from public databases. Genetic linkage was ascertained among 228 Scottish, 1820 UK, and 524 global sequences. The outbreak cluster was extracted to estimate epidemic parameters.
Results:
All 104 outbreak sequences originated from Scotland and contained E138A and V179E. Mean genetic distance was <1% and mean time between transmissions was 6.7 months. The average number of onward transmissions consistently exceeded 1, indicating that spread was ongoing.
Conclusions:
In contrast to other recent HIV outbreaks among PWID, harm reduction services were not clearly reduced in Scotland. Nonetheless, the high proportion of individuals with a history of homelessness (45%) suggests that services were inadequate for those in precarious living situations. The high prevalence of hepatitis C (>90%) is indicative of sharing of injecting equipment. Monitoring the epidemic phylogenetically in real time may accelerate public health action.
... There is now over fifteen years of experience showing that these programs can prevent HIV epidemics among IDUs. There are a number of cities and countries such as the United Kingdom
(Stimson, 1995)
and Australia (Wodak and Lurie, 1996) where HIV infection has been limited to less than 5 percent of the IDU population and the rates of new HIV infections are less than 1 percent per year. These examples share three common characteristics : prevention efforts were begun early, while HIV prevalence was 5 percent or less; trusted communication was established between health workers and the local community of IDUs (often through outreach efforts); and, IDUs had very good access to sterile injection equipment (through syringe exchange or pharmacy sales without much police interference of IDUs access to and use of the sterile injection equipment). ...
Epidemiology of Drug Abuse
As the drug abuse epidemic evolves, so do the tools needed to understand and treat it. Accordingly, Epidemiology of Drug Abuse takes the long view, cogently outlining what the book calls "the natural history of drug abuse" and redefining its complex phenomena to reflect our present-day knowledge. Twenty-six eminent contributors discuss the state and future of the field, balancing the practical concerns involved in gathering drug abuse data with the ethics of using the information. - Current thinking on pathways and etiology, as well as medical, psychological, and social sequelae of drug abuse - Proven, up-to-date methodologies for assessment - Challenges of gathering data from high-risk and other user populations - Sampling and application issues - Uses, sources, and limitations of treatment data - Analytical papers applying the methodologies to specific and global studies - The role of epidemiology studies in developing prevention strategies With this multifaceted approach to the subject, Epidemiology of Drug Abuse provides researchers and educators with a reference that sheds significant light on infrequently covered areas. In addition, its breadth and accessibility of coverage make it a teaching text suitable to courses in epidemiology, public health, and drug abuse. © 2005 Springer Science+Business Media, Inc. All rights reserved.
... If effective prevention programs are implemented prior to outbreaks of HIV among PWIDs then it is possible to avert HIV epidemics. Australia [24] and the United Kingdom
[25]
are notable examples of countries that implemented large-scale effective HIV prevention programs early and never experienced national epidemics of HIV among PWIDs. ...
HIV infection among persons who inject drugs: ending old epidemics and addressing new outbreaks
... Numerosos estudios ya han demostrado que los UDIs son capaces de modificar sus conductas de riesgo asociadas al consumo inyectado de drogas para reducir estos riesgos (Watters, Estilo, Kral y cols.,1994;Watters, Estilo, Clark y Lorvick, J.,1994;Stimson y Power, 1992;
Stimson, 1995)
. En resumen, tanto la mayoría de los estudios publicados como nuestros propios resultados vienen a demostrar que los programas de mantenimiento con metadona y los PIJs suelen disminuir sustancialmente el número y frecuencias de conductas de riesgo asociadas al consumo inyectado de drogas: consumo de drogas ilegales, inyección de drogas. ...
Cognición, actitud y conducta: cambio en UDIs hacia la reducción de los riesgos asociados al uso de drogas
Article
Apr 2002
Adicciones
P. Insúa
Objetivo: El objetivo es evaluar 15 Talleres disenados para la reduccion de los riesgos asociados a la inyeccion de drogas. Material y Metodo: La muestra incluye 229 hombres y mujeres con una edad promedio de 34 anos, policonsumidores de drogas por la via parenteral. Los sujetos fueron evaluados en pretest, postest y seguimiento utilizando un cuestionario autoaplicado sobre conductas de riesgo asociadas a la inyeccion y variables mediadoras en estas conductas. Resultados: Los Talleres de Consumo de Menor Riesgo estan asociados a una disminucion en las conductas de riesgo y a un aumento en las conductas de proteccion en la inyeccion de drogas. Tambien estan asociados a un aumento en los conocimientos sobre los riesgos asociados a la inyeccion de drogas y sobre la transmision del VIH / SIDA, a una mayor autoeficacia de afrontamiento ante situaciones de riesgo y a un mantenimiento de la motivacion para reducir estos riesgos. Adicionalmente, la satisfaccion de los usuarios de estos Talleres es muy elevada. Conclusion: Estos resultados proporcionan apoyo a la eficacia de estos Talleres de Consumo de Menor Riesgo, e indirectamente en favor del Programa de Formacion en redes para profesionales sanitarios para el diseno, implementacion y evaluacion de los Talleres para la reduccion de riesgos asociados al uso de drogas.
... No obstante, diversas investigaciones indican que esta tendencia a adoptar conductas preventivas no se produce en las relaciones sexuales íntimas, y de forma particular con la pareja estable, y que los cambios en la conducta sexual (en caso de producirse) se dan de forma marcadamente más lenta que los cambios en la conducta de inyección y son menos estables y duraderos. Datos aportados por distintos autores (Battjes et al., 1995;Pavia et al., 1997;Menoyo et al., 1998) sugieren que la seguridad sexual no es considerada como una alta prioridad para los UDIs y sus parejas sexuales y si bien las normas cotidianas del grupo han comenzado a enfatizar el "uso seguro de drogas" , enfatizan las prácticas sexuales inseguras Numerosos estudios ya han demostrado que los UDIs son capaces de modificar sus conductas de riesgo en el uso inyectado de drogas de cara a reducirlos (Watters, Estilo, Kral et al..,1994;Watters, Estilo, Clark y Lorvick, 1994;Stimson y Power,1992;
Stimson, 1995)
. Sin embargo, los resultados de los estudios de evaluación sobre la prevención de la transmisión sexual del VIH/SIDA han sido menos prometedores (Dolezal et al., 1999) y han mostrado que las conductas sexuales de riesgo parecen ser más resistentes al cambio que las conductas de autoadministración de drogas. ...
Estrategias de reducción de riesgos con usuarios de drogas inyectadas: talleres de sexo más seguro
Adicciones
... Thus the timely introduction of harm reduction interventions could prevent an explosion in HIV prevalence, as has occurred in other countries (Mathers et al., 2008). Preventing a widespread epidemic among PWID has been accomplished in many locations, including Australia and parts of the United Kingdom, where interventions were implemented before or at an early stage of viral diffusion (Iversen, Wand, Topp, Kaldor, & Maher, 2014;
Stimson, 1995
Stimson, , 1996Wodak & Maher, 2010). These examples illustrate that early prevention can be effective in both keeping HIV prevalence low among PWID and preventing the rapid spread of HIV within injection networks. ...
Heroin Use and Injection Risk Behaviors in Colombia: Implications for HIV/AIDS Prevention
SUBST USE MISUSE
Background:
Heroin production in Colombia has increased dramatically in recent decades, and some studies point to an increase in local heroin use since the mid-1990s. Despite this rapid increase, little is known about the effects of these activities on heroin injection within Colombia. One of the biggest concerns surrounding heroin injection is the potential spread of HIV through drug user networks.
Objectives:
This article examines injection risk behaviors among heroin injectors in the Colombian cities of Medellín and Pereira to explore the implications for possible increased HIV transmission within this group.
Methods:
A cross-sectional study used respondent-driving sampling to recruit a sample of 540 people who inject drugs (PWID) over 18 years of age (Medellín: n = 242, Pereira: n = 298). Structured interviews with each participant were conducted using the World Health Organization Drug Injection Study Phase II Survey. An HIV test was also administered.
Results:
Information regarding the socio-demographics, injection drug use, HIV risk and transmission behaviors, injection risk management, and HIV knowledge and prevalence of participants are reported. The study identified many young, newly initiated injectors who engage in risky injection practices. The study also found that HIV prevalence is fairly low among participants (2.7%). Conclusions/Importance: Findings indicate a potential risk for the spread of HIV among PWID in Colombia given their widespread sharing practices, high rate of new injector initiation, and unsafe syringe cleaning practices. Colombia has a possibly time-limited opportunity to prevent an HIV epidemic by implementing harm reduction interventions among young, newly initiated PWID.
... There is now over fifteen years of experience showing that these programs can prevent HIV epidemics among IDUs. There are a number of cities and countries such as the United Kingdom
(Stimson, 1995)
and Australia (Wodak and Lurie, 1996) where HIV infection has been limited to less than 5 percent of the IDU population and the rates of new HIV infections are less than 1 percent per year. These examples share three common characteristics : prevention efforts were begun early, while HIV prevalence was 5 percent or less; trusted communication was established between health workers and the local community of IDUs (often through outreach efforts); and, IDUs had very good access to sterile injection equipment (through syringe exchange or pharmacy sales without much police interference of IDUs access to and use of the sterile injection equipment). ...
Drug abuse and the spread of infection: HIV and AIDS as an example
... The findings reported from the NSE evaluation, rather than in themselves leading to policy change, legitimised a decision that had already been taken. Carefully presented, they confirmed the wisdom that NSE had a role to play
(Stimson 1995)
. And beyond supporting the initial policy shift within UK, this study would later be cited to support claims for the effectiveness of harm reduction internationally, arguing that the British approach had been crucial in warding off an HIV epidemic. ...
The Impact of Research on Policy in the Drugs Field
Article
Full-text available
The article uses examples of UK drugs research (1980–2010) to illustrate the complex relationship between research, policy and politics. It draws on literature, documentary analysis, interviews and participant observation. ‘Drugs' is a contested issue and values compete with evidence to influence decisions. Research provides only one form of evidence. Sociological research became less influential in these years, reflecting the neo-liberal climate. The absence of research was also influential in shaping policy. However social research made significant contributions. It impacted initially by helping to understand a new problem; then through the construction of the ‘harm reduction approach’; and then by contributing to ‘the criminalisation of drugs policy’. Research helped by gathering intelligence, accumulating findings, raising questions and encouraging a culture of objectivity. Cases described indicate the role of filters as evidence percolated into or was rejected by policy-making circles. As government advisors, researchers risked being captured by politicians. But engaging in public debate could be challenging as researchers might lose control over how their findings were interpreted. The media were dominant influences in public debate and the simplification of discourse at this level was a hindrance. It is concluded that research has had impact where it linked directly to the policy market. Networks, think-tanks and policy entrepreneurs played key roles. An appropriate packaging of findings was important. Impact happened where there was a receptive audience and a window of opportunity opened, raising the issue on policy agendas. To intervene effectively, researchers had to ensure that reports were timely, to act quickly and work in alliances. Researchers who had impact often had a specific commitment to the drugs field. Beyond this, there remains a need for humanities and social science scholars to engage in public dialogue on this issue.
... The potential for epidemic spread of blood-borne viruses through sharing of contaminated needles, syringes and other injecting equipment is high. Since sharing or use of contaminated syringes and needles is a very efficient way of spreading HIV, it can spread very rapidly amongst injecting drug users (Des Jarlais, Friedman, Woods, & Milliken, 1992;
Stimson, 1995)
. ...
National Guidelines for Medication-Assisted Treatment of Opioid Dependence
None available
Child sexual exploitation and the adoption of public health approaches to prevention: critical reflections on evolving processes and practices
Full-text available
Jun 2023
Crime Prev Community Saf Int J
Gabe Mythen
Samantha Weston
In recent years, the use of public health approaches to address complex social problems has gained popularity. In England and Wales, the rise in low-volume, high-harm crime has accelerated this shift, with calls for public health interventions to tackle knife-crime, extremism and sexual violence made by politicians, policy-makers, welfare workers and the police service. Notwithstanding such appeals, how public health approaches are both operationalised and impact remain largely unknown. Drawing on findings from a qualitative study focused on the implementation of a specific initiative in the UK designed to reduce the risk of Child Sexual Exploitation (CSE) amongst young people, this article attempts to address tangible gaps in these two key areas of knowledge. Although generally supportive of a public health approach to CSE, an analysis of in-depth interviews with members of a multi-agency team reveals a number of quandaries and thorny issues when implemented within a specific policing and criminal justice context.
Bibliography
Chapter
Full-text available
May 2015
Natasha Du Rose
Bibliography
Chapter
Full-text available
May 2015
Natasha Du Rose
Mapping as a Method for Analysing Policy Response in the Management of Health Services
Article
Nov 2001
Lisa Luger
Jane Carrier
Robert Power
Health services are susceptible to changes in health need, resource allocation, public-health debates and health policies. Service mapping is considered a useful tool for analysing complex issues, monitoring changes over time and facilitating change. It also enables one to describe pathways of care and the relationships between services. This article centres on two projects — a London-wide project ‘Service networks for HIV Care’ and a local survey ‘Mapping of HIV-related services for illicit drug users’ — and demonstrates the usefulness of mapping for both studies. Mapping of service networks allowed exploration of a variety of connections between treatment centres, and led to recommendations for a model of HIV service networks across London. The mapping of HIV-related services for illicit drug users confirmed that the service provision was balanced in time, space and target groups, but also identified gaps showing that services were not very successful in attracting women and members of ethnic minority groups. It is clear from both studies that mapping provides an overview of existing services, describing details of services, their target groups or links. It can assist to monitor changes over time, to reconfigure services according to need, and to target resources where need becomes apparent. Mapping exercises also can be useful in identifying new areas for collaboration and interagency work.
2. Politiques britanniques de la drogue (1985-1997) : un succès pour la sociologie ?
Chapter
Jun 2017
Herve Hudebine
Opioids: heroin, methadone, and buprenorphine
Chapter
Feb 2012
Soraya Mayet
Adam R. Winstock
John Strang
Opioid dependence is a chronic relapsing and remitting disorder affecting a large proportion of people throughout the world with severe physical, psychological, and social consequences. Opioid overdose and spread of blood borne viruses are major causes of morbidity and mortality. Assessment of opioid use and dependence should be systematic and confirmation of dependence is of paramount importance before initiating treatment. The prescription of substitute opioids should be managed carefully to prevent harm, diversion to others and improve safety. Management of opioid dependence can greatly improve outcomes and may be based on opioid maintenance stabilization or detoxification combined with psychosocial interventions.
Working with and Negotiating ‘Risk’: Examining the Effects of Awareness Raising Interventions Designed to Prevent Child Sexual Exploitation
Article
Jul 2019
Samantha Weston
Gabe Mythen
This article considers the effects of an educational intervention with young people designed to reduce the risk of child sexual exploitation (CSE). Drawing on findings from a qualitative study, we consider processes of engagement with the initiative, the relevance of the strategy adopted by the delivery team and the impacts on the perspectives of young people targeted. Focusing on mutually constitutive problems of context sensitivity, recognition of ambiguity and the silencing of alternative narratives, we raise several critical caveats that should be considered in the design and implementation of future CSE awareness raising initiatives. Overall, we aver that an unstinting focus on individual behaviour management unduly responsibilizes young people and draws inflexible demarcation lines between appropriate and inappropriate sexual conduct.
Elimination of HIV transmission through novel and established prevention strategies among people who inject drugs
Article
Dec 2018
Hudson Reddon
Brandon D. L. Marshall
M-J Milloy
Despite the effectiveness of existing HIV prevention strategies for people who inject drugs (PWID), uncontrolled outbreaks of HIV among this group are common and occur around the world. In this Review, we summarise recent evidence for novel and established HIV prevention approaches to eliminate HIV transmission among PWID. Effective HIV prevention strategies include mobile needle and syringe programmes, pre-exposure prophylaxis, supervised injection facilities, and, to a lesser extent, some behavioural interventions. Studies have also shown the cost-effectiveness of long-standing HIV prevention strategies including needle and syringe programmes, opioid agonist therapy, and antiretroviral therapy for prevention. Although each individual intervention can reduce the risk of HIV acquisition among PWID, there is a consensus that a combination of approaches is required to achieve substantial and durable reductions in HIV transmission. Unfortunately, in many settings, the implementation of these interventions is often limited by public and political opposition that manifests as structural barriers to HIV prevention, such as the criminalisation of drug use. Given that there is ample evidence showing the effectiveness of several HIV prevention methods, social and political advocacy will be needed to overcome these barriers and integrate innovative HIV prevention approaches with addiction science to create effective drug policies.
Step Two: Recognise the Primary Importance of Addressing the Harm That Stems From and is Associated With Drug Use and Drug Control Policies
Chapter
May 2018
Caroline Chatwin
This chapter documents the rise of alternative strategies of drug control which aim to reduce drug related harm, rather than drug use per se. It explores the concept of harm reduction, its evolution over time, and its limitations, recommending that harm reduction strategies should also seek to address the harm that is caused by inequality and human rights abuses related harm. The final section address the extent to which harm reduction strategies have already become embedded in global drug policy practice, and suggests that it remains very much of secondary status.
UK Drug Policy
Chapter
Jul 2017
Susanne MacGregor
This chapter gives an overview of the development of UK drugs policy since the MDA 1971. After noting changes in the social context, three phases are identified: the turn to harm reduction; the drugs-crime agenda; and the move to recovery. Continuities and changes are noted in the perception of the ‘problem’ (HIV/AIDS, acquisitive crime and welfare dependence) and solutions proposed (expansion of treatment, partnership, localism and recovery). Current issues are highlighted including the effects of stop and search, imprisonment and the impact of austerity budgets.
Evidence and Policy
Chapter
Jul 2017
Susanne MacGregor
Where ideas and values clash, the question then often turns to ‘what does the evidence say?’ This chapter demonstrates the growth in information and evidence on drugs in recent years and its wider availability. The institutions within which evidence is located are illustrated, as is the role of networks and collaborations in creating a standard body of information and shared understandings. The ways in which evidence is linked to policy are discussed, looking at the role of experts and the special function of the Report. Examples are given of reports which have or have not influenced policy. The over-riding impact of moral frames and politicians’ preferences is indicated.
The Prevention and Treatment of the Abuse of Illicit Drugs
Chapter
Jun 2017
John Joshua
This chapter discusses the prevention and treatment of the abuse of illicit drugs and begins with a description of programs such as the methadone maintenance treatment program, the heroin maintenance program, and harm minimization programs. It is argued that such programs should include vocational counselling as part of the rehabilitation programs. The creation of special drug courts may be seen as an alternative to the more common present criminal justice system to enable the integration of the judicial and criminal justice system together with the treatment of drug abuse and rehabilitation. The chapter then concludes with a discussion of an effective scientifically oriented drug policy. It is argued that a viable drug policy should be based on scientific and empirical evidence.
HIV and Injection Drug Abuse in Countries of the Eastern Mediterranean Region of the World Health Organization
Conference Paper
Full-text available
Aug 1999
Jihane Tawilah
Ahmad Mohit
Drs. Jihane Tawilah and Ahmad Mohit described the HIV and injection drug use trends in the Eastern Mediterranean region. Although HIV transmission among IDUs accounts for approximately 4 percent of all AIDS cases reported annually, with the majority originating from heterosexual contact, almost all countries in this region have reported HIV cases among IDUs. Although injection drug use has existed for some time in this region, the number of IDUs remains relatively low and is estimated to account for 10 to 17 percent of all users of illicit drugs in the region. Many countries are experiencing outbreaks among subgroups of sexually transmitted disease (STD) patients and IDUs. Since 1996, Iran also has experienced major outbreaks of HIV among IDUs in prisons. Overall, this area is experiencing a low-level epidemic, although IDUs are clearly leading other subgroups in terms of high HIV rates and have the potential for explosive outbreaks. The countries in this region serve as either producers (for example, Afghanistan) or as transit routes and consumers for a wide variety of substances, including an increase in heroin use. Data of the United Nations International Drug Control Programme (UNDCP) indicate that injectable forms of drugs are becoming increasingly available in this region, and that many of the drug injectors are young.
References
Chapter
Mar 2008
Tom Waller
Daphne Rumball
My time with the International Journal of Drug Policy
Jan 2017
INT J DRUG POLICY
Gerry V. Stimson
Prophylaxis after occupational exposure to HIV
Feb 1998
Veerakathy Harindra
J M Tobin
J R Willcox
M. T Reynolds
EDITOR—Easterbrook and Ippolito discuss prophylaxis after occupational exposure to HIV.1 Ignorance about this problem among the medical profession is still considerable. Although the risk of occupational exposure to HIV is rare, every hospital should have a written policy on how to manage healthcare workers after needlestick injury or exposure to body fluids.
In Portsmouth, many years ago, a healthcare worker acquired HIV infection after a needlestick injury despite receiving zidovudine. Since then the department of genitourinary medicine has developed an efficient service, providing a 24 hour hotline for all healthcare workers employed by the trust and community and also for members of the general public who have sustained needlestick injuries. The hotline is staffed by nurse specialists experienced in HIV infection, who are overseen by the genitourinary physicians. This enables the person who sustained the injury to access care immediately and to discuss with experienced counsellors not only HIV infection but also infection with hepatitis B and hepatitis C viruses, in a confidential manner. Appropriate treatment can also be started by the nurse specialist without delay. Since all patients with HIV infection in Portsmouth are treated by the genitourinary physicians, the nurse specialists are fully aware of their antiretroviral treatment and the stage of their disease. The consultants hold weekly updates about all the patients and also discuss all new developments in the field of HIV infection with the nurse specialists.
This model of care is superior to the one described in the editorial, which suggests that the assessment and treatment should be initiated in the accident and emergency department. There is a rapid turnover of junior medical staff in accident and emergency departments, who will find it difficult to keep up to date with all the advances in antiretroviral treatment. Though a written protocol gives an overall prescription …
Within and between: Understanding and treating addiction problems in diverse clinical settings
Feb 2016
Paul Davis
Ryan Kemp
Luke Mitcheson
Trend of HIV Incidence Rates Among Drug Users in an HIV Epicenter in Northern Thailand (1989-1997)
Jan 1999
Pathom Sawanpanyalert
Somsak Supawitkul
Hideki Yanai
Surachai Piyaworawong
Objectives: to determine trends and associated risk factors of HIV incidence (1989-1997) in a drug abuse treatment clinic in northern Thailand where HIV is epidemic
Design: retrospective cohort study
Methods: Nine-years (1989-1997) of data (excluding names) from the logbook of drug abusers seeking treatments in Mae Chan Hospital in Chiangrai Thailand, were transcribed and doubleentered into separate computer files which were later validated against each other. For each patient, the dates of the first HIV negative, the last HIV negative, and the first HIV positive were determined. A retrospective cohort of drug users who were initially HIV-negative and treated for more than once was constructed. HIV seroconversion was assumed to follow a uniform distribution between the last negative and the first positive HIV tests. The incidence rates and their 95% confidence intervals (CI) were calculated.
Results: Of the 378 repeat patients, 16 (4.2%) HIV seroconverted. This is equivalent to 5.11 per 100 person-years of observation (PYO) (95%C1=3.13-8.35). The incidence remained relatively stable over the study period while the prevalence was on the decline. The younger, Thai lowlanders, drug injectors had higher incidence rates than the older, ethnic minorities and drug smokers, respectively.
Conclusion: Prevalence can give illusional results. It is necessary to know baseline HIV incidence to monitor and evaluate an HIV intervention program.
J Epidemiol, 1999 ; 9 : 114-120
A tale of two epidemics: drugs harm reduction and tobacco harm reduction in the United Kingdom
Article
Sep 2016
Gerry V. Stimson
Purpose
The purpose of this paper is to compare the response to HIV/AIDS and drug use (drugs harm reduction) with tobacco harm reduction.
Design/methodology/approach
Analysis of historical and contemporary sources, combined with personal knowledge of key stakeholders in the history and development of both fields.
Findings
Both drugs harm reduction and tobacco harm reduction share a similar objective – to reduce health risks for people who are unwilling or unable to stop using their drug of choice. Both also share a broader public health aim of helping people to make healthier decisions. Drugs harm reduction – as a response to HIV/AIDS – included the adoption of a wide range of radical harm reduction interventions and was a public health success. It became an established part of the professional Public Health agenda. In contrast the Public Health response to e-cigarettes and tobacco harm reduction has ranged from the negative to the cautious. A recent Public Health England report is exceptional for its endorsement of e-cigarettes.
Originality/value
Highlights contradictions in Public Health responses to drugs and tobacco; and that public health interventions can be implemented without and despite the contribution of professional Public Health.
Politics, practice and research into treatment of heroin addiction
Chapter
Mar 2009
James Bell
Science, Ideology, and Needle Exchange Programs
Jul 2002
Martin T Schechter
Needle exchange programs (NEPs) to prevent HIV transmission among injection drug users are accepted in many countries but remain at the center of heated debate in the United States. In 1997, the author published a study of injection drug users in Vancouver showing an explosive outbreak or HIV An incidental finding was higher HIV rates among frequent attendees of the local NEP While this was expected because NEPs attract users at highest risk, opponents of needle exchange applied an unsupportable causal interpretation to this finding. If frequent NEP attendees had higher HIV rates, so the interpretation went, NEPs must be responsible for promoting the spread of HIV. Despite the author's admonitions against this misinterpretation of the data, it was used as part of a successful campaign to oppose U.S. federal funding of needle exchange. Regrettably, biased or even misleading interpretations often occur in the volatile interface of imperfect science and ideological debate.
HIV infection among persons who inject drugs
Feb 2016
Thomas Kerr
Patrizia Carrieri
Kamyar Arasteh
Don C Des Jarlais
AIDS among persons who inject drugs, first identified in December 1981, has become a global epidemic. Injecting drug use has been reported in 148 countries and HIV infection has been seen among persons who inject drugs in 61 countries. Many locations have experienced outbreaks of HIV infection among persons who inject drugs, under specific conditions that promote very rapid spread of the virus. In response to these HIV outbreaks, specific interventions for persons who inject drugs include needle/syringe exchange programs, medicated assisted treatment (with methadone or buprenorphine) and antiretroviral therapy. Through a "combined prevention" approach, these interventions significantly reduced new HIV infections among persons who inject drugs in several locations including New York City, Vancouver and France. The efforts effectively ended the local HIV epidemic among persons who inject drugs in those locations. This review examines possible processes through which combined prevention programs may lead to ending HIV epidemics. However, notable outbreaks of HIV among persons who inject drugs have recently occurred in several countries, including in Athens, Greece, Tel-Aviv, Israel, Dublin Ireland, as well as in Scott County, Indiana USA. This review also considers different factors that may have led to these outbreaks. We conclude with addressing the remaining challenges for reducing HIV infection among persons who inject drugs. Copyright (C) 2016 Wolters Kluwer Health, Inc.
Illegal drug problems and their treatment
Feb 2003
PSYCHOLOGIST
L. Mitcheson
Michael Gossop
Epidemiology of HIV in Intravenous Drug Users and Public Health Policy in Germany
Jan 1997
J DRUG ISSUES
Anand Pant
Renate Soellner
The paper assesses AIDS and drug policy development in Germany between 1982 and 1996 and relates it to the development of epidemiological research in HIV among injecting drug users (IDUs). In a historical review, this paper outlines how results of epidemiological HIV surveillance studies among IDUs and public health responses were mutually dependent. The authors argue that a specific development in HIV policy encouraged a confounding of basic methodological concepts (validity and precision) in epidemiological research, which in turn led to misinterpretation of available data on seroprevalence trends in Germany. In order to overcome methodological shortcomings under given legal and practical restrictions, pragmatic approaches to increase validity of seroprevalence and risk factor estimations are discussed.
Opioid Substitution: Critical Issues and Future Directions
Dec 1998
J DRUG ISSUES
| https://www.researchgate.net/publication/15697205_AIDS_and_injecting_drug_use_in_the_United_Kingdom_1987-1993_the_policy_response_and_the_prevention_of_the_epidemic |
A Study to Evaluate Androgen-Deprivation Therapy and Radiation Therapy in Treating Patients With Prostate Cancer - Mayo Clinic
Clinical Trials
A Study to Evaluate Androgen-Deprivation Therapy and Radiation Therapy in Treating Patients With Prostate Cancer
Overview
Tab Title Description
Study type
Interventional
Observational study — observes people and measures outcomes without affecting results.
Interventional study (clinical trial) — studies new tests, treatments, drugs, surgical procedures or devices.
Medical records research — uses historical information collected from medical records of large groups of people to study how diseases progress and which treatments and surgeries work best.
Study phase
3
During the early phases (phases 1 and 2), researchers assess safety, side effects, optimal dosages and risks/benefits. In the later phase (phase 3), researchers study whether the treatment works better than the current standard therapy. They also compare the safety of the new treatment with that of current treatments. Phase 3 trials include large numbers of people to make sure that the result is valid. There are also less common very early (phase 0) and later (phase 4) phases. Phase 0 trials are small trials that help researchers decide if a new agent should be tested in a phase 1 trial. Phase 4 trials look at long-term safety and effectiveness, after a new treatment has been approved and is on the market.
Study IDs
Site IRB
Eau Claire, Wisconsin: 12-004274
NCT ID: NCT01368588
Sponsor Protocol Number: RTOG-0924
About this study
The purpose of this study is to evaluate androgen-deprivation therapy and radiation therapy in treating patients with prostate cancer. Androgens can cause the growth of prostate cancer cells. Androgen deprivation therapy may stop the adrenal glands from making androgens. Radiation therapy uses high-energy x-rays to kill tumor cells.
Participation eligibility
Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.
Eligibility Criteria:
DISEASE CHARACTERISTICS
Pathologically (histologically or cytologically) proven diagnosis of prostatic adenocarcinoma within 180 days of registration at moderate-to high-risk for recurrence as determined by one of the following combinations:
Gleason score 7-10 + T1c-T2b (palpation) + prostate-specific antigen (PSA) < 50 ng/mL (includes intermediate- and high-risk patients);
Gleason score 6 + T2c-T4 (palpation) + PSA < 50 ng/mL; OR
Gleason score 6 + >= 50% (positive) biopsies + PSA < 50 ng/ml;
History and/or physical examination (to include at a minimum digital rectal examination of the prostate and examination of the skeletal system and abdomen) within 90 days prior to registration
Clinically negative lymph nodes as established by imaging (pelvic and/or abdominal CT or MR), (but not by nodal sampling, or dissection) within 90 days prior to registration.
Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are ≤ 1.5 cm.
Patients status post a negative lymph node dissection are not eligible.
No evidence of bone metastases (M0) on bone scan within 120 days prior to registration (Na F PET/CT is an acceptable substitute),
Equivocal bone scan findings are allowed if plain films (or CT or MRI) are negative for metastasis.
Baseline serum PSA value performed with an FDA-approved assay (e.g., Abbott, Hybritech) within 120 days prior to registration.
Study entry PSA should not be obtained during the following time frames:
Ten-day period following prostate biopsy;
Following initiation of hormonal therapy;
Within 30 days after discontinuation of finasteride;
Within 90 days after discontinuation of dutasteride.
PATIENT CHARACTERISTICS
Zubrod performance status 0-1.
Absolute neutrophil count (ANC) ≥ 1,500/mm³.
Platelet count ≥ 100,000/mm³.
Hemoglobin (Hgb) ≥ 8.0 g/dL (transfusion or other intervention to achieve Hgb ≥ 8.0 g/dL is acceptable).
No prior invasive (except non-melanoma skin cancer) malignancy unless disease-free for a minimum of 3 years (1,095 days) and not in the pelvis; e.g., carcinoma in situ of the oral cavity is permissible. However, patients with prior history of bladder cancer are not allowed.
No prior hematological (e.g., leukemia, lymphoma, or myeloma) malignancy.
No previous radical surgery (prostatectomy) or cryosurgery for prostate cancer.
No previous pelvic irradiation, prostate brachytherapy or bilateral orchiectomy.
No previous hormonal therapy, such as LHRH agonists (e.g., leuprolide, goserelin, buserelin, triptorelin) or LHRH antagonist (e.g., degarelix), anti-androgens (e.g., flutamide, bicalutamide, cyproterone acetate), estrogens (e.g., DES), or surgical castration (orchiectomy),
No severe, active co-morbidity, defined as any of the following:
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months;
Transmural myocardial infarction within the last 6 months;
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration;
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects or severe liver dysfunction;
Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition.
Protocol-specific requirements may also exclude immuno-compromised patients.
HIV testing is not required for entry into this protocol.
No patients who are sexually active and not willing/able to use medically acceptable forms of contraception.
No prior allergic reaction to the hormones involved in this protocol.
PRIOR CONCURRENT THERAPY
No prior radical surgery (prostatectomy) or cryosurgery for prostate cancer.
No prior pelvic irradiation, prostate brachytherapy, or bilateral orchiectomy.
No prior hormonal therapy, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., leuprolide, goserelin, buserelin, triptorelin) or LHRH antagonist (e.g., degarelix), anti-androgens (e.g., flutamide, bicalutamide, cyproterone acetate), estrogens (e.g., diethylstilbestrol (DES) ), or surgical castration (orchiectomy).
No prior pharmacologic androgen ablation for prostate cancer unless the onset of androgen ablation is ≤ 45 days prior to the date of registration.
No finasteride within 30 days prior to registration.
No dutasteride or dutasteride/tamsulosin (Jalyn) within 90 days prior to registration.
No prior or concurrent cytotoxic chemotherapy for prostate cancer.
Prior chemotherapy for a different cancer is allowable.
No prior radiotherapy, including brachytherapy, to the region of the study cancer that would result in overlap of radiation therapy fields.
Participating Mayo Clinic locations
Mayo Clinic Location Status Contact Eau Claire, Wis.Mayo Clinic principal investigatorEyad Al-Hattab, M.D. Contact information:Cancer Center Clinical Trials Referral Office(855) 776-0015Closed for enrollment
Publications
Publications are currently not available
| https://www.mayo.edu/research/clinical-trials/cls-20470675 |
Predictors of inaccurate coronary arterial stenosis assessment by CT angiography
Yan RT, Miller JM, Rochitte CE, Dewey M, Niinuma H, Clouse ME, Vavere AL, Brinker J, Lima JA, Arbab-Zadeh A. Predictors of inaccurate coronary arterial stenosis assessment by CT angiography. JACC Cardiovasc Imaging. 2013 Sep;6(9):963-72. doi: 10.1016/j.jcmg.2013.02.011. Epub 2013 Aug 8.
Predictors of inaccurate coronary arterial stenosis assessment by CT angiography
Raymond T Yan, Julie M Miller, Carlos E Rochitte, Marc Dewey, Hiroyuki Niinuma, Melvin E Clouse, Andrea L Vavere, Jeffrey Brinker, Joăo A C Lima, Armin Arbab-Zadeh, Raymond T Yan, Julie M Miller, Carlos E Rochitte, Marc Dewey, Hiroyuki Niinuma, Melvin E Clouse, Andrea L Vavere, Jeffrey Brinker, Joăo A C Lima, Armin Arbab-Zadeh
Abstract
Objectives:This study sought to investigate the clinical and imaging characteristics associated with diagnostic inaccuracy of computed tomography angiography (CTA) for detecting obstructive coronary artery disease (CAD) defined by quantitative coronary angiography (QCA).
Background:Although diagnostic performance metrics of CTA have been reported, there are sparse data on predictors of diagnostic inaccuracy by CTA.
Methods:The clinical characteristics of 291 patients (mean age: 59 ± 10 years; female: 25.8%) enrolled in the multicenter CorE-64 (Coronary Artery Evaluation Using 64-Row Multi-detector Computed Tomography Angiography) study were examined. Pre-defined CTA segment-level characteristics of all true-positive (N = 237), false-positive (N = 115), false-negative (FN) (N = 159), and a random subset of true-negative segments (N = 511) for ≥50% stenosis with QCA as the reference standard were blindly abstracted in a central core laboratory. Factors independently associated with corresponding levels of CTA diagnostic inaccuracies on a patient level and coronary artery segment level were determined using multivariable logistic regression models and generalized estimating equations, respectively.
Results:An Agatston calcium score of ≥1 per patient (odds ratio [OR]: 5.2; 95% confidence interval [CI]: 1.1 to 24.6) and the presence of within-segment calcification (OR: 10.2; 95% CI: 5.2 to 19.8) predicted false-positive diagnoses. Conversely, absence of within-segment calcification was an independent predictor of an FN diagnosis (OR: 2.0; 95% CI: 1.2 to 3.5). Prior percutaneous revascularization was independently associated with patient-level misdiagnosis of obstructive CAD (OR: 4.2; 95% CI: 1.6 to 11.2). Specific segment characteristics on CTA, notably segment tortuosity (OR: 3.5; 95% CI: 2.4 to 5.1), smaller luminal caliber (OR: 0.48; 95% CI: 0.36 to 0.63 per 1-mm increment), and juxta-arterial vein conspicuity (OR: 2.1; 95% CI: 1.4 to 3.2), were independently associated with segment-level misdiagnoses. Attaining greater intraluminal contrast enhancement independently lowered the risk of an FN diagnosis (OR: 0.96; 95% CI: 0.94 to 0.99 per 10-Hounsfield unit increment).
Conclusions:We identified clinical and readily discernible imaging characteristics on CTA predicting inaccurate CTA diagnosis of obstructive CAD defined by QCA. Knowledge and appropriate considerations of these features may improve the diagnostic accuracy in clinical CTA interpretation. (Diagnostic Accuracy of Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors [CORE-64];NCT00738218).
Keywords:BMI; CAD; CI; CTA; FN; FP; OR; QCA; TN; TP; accuracy; body mass index; computed tomography angiography; confidence interval; coronary artery disease; false-negative; false-positive; odds ratio; quantitative coronary angiography; true-negative; true-positive.
Figures
<here is a image 1d429f19ecadea1d-ba871def00798863>
Figure 1
Panel A. An example of false-positive diagnoses by CT angiography at the mid left-anterior-descending artery (arrows) with focal tortuosity, motion and coronary calcification (proximal site) as well as poor contrast opacification in the distal portion.. Panel B. Corresponding conventional angiography without significant stenoses.
<here is a image 738b817922ee170f-6cbcf8da926ccbe3>
Figure 2
An example of conspicuous adjacent cardiac venous structure confounding coronary arterial interpretation. Panel A. Partial volume averaging effect by CT with adjacent cardiac vein mimicking focal non-calcified stenosis (first arrow) leading to false positive diagnosis. The distal arrow marks a false-negative diagnosis (CTA=15%, QCA=74% stenosis) masked by an adjacent cardiac vein. Panel B. Conventional angiography correlation revealing no stenosis at the proximal site but significant lesion at the distal site.
<here is a image 5f45bd94a9c3c997-1f34d1d0e00959b0>
Figure 3
An example of poor contrast opacification leading to ambiguous lumen evaluation by CT. Panel A. Poor contrast filling of a proximal right coronary artery (arrow) does not allow visualization of a subtotal occlusion. Panel B. Corresponding invasive angiogram reveals severe lumen narrowing in the proximal right coronary artery (arrow).
<here is a image 23df9b3184540609-86d5550c73efee1e>
Figure 4
Effect of cardiac motion on CT interpretation. A minor motion artifact leads to slightly smaller lumen appearance by CT (arrow, Panel A) compared to conventional angiography (arrow, Panel B) resulting in a false positive diagnosis of obstructive coronary artery disease.
Source:PubMed
| https://ichgcp.net/clinical-trials-registry/publications/172721-predictors-of-inaccurate-coronary-arterial-stenosis-assessment-by-ct-angiography |
Network Working Group G. Armitage
Request for Comments: 2191 Lucent Technologies
Category: Informational September 1997
VENUS - Very Extensive Non-Unicast Service
Status of this Memo
This memo provides information for the Internet community. This memo
does not specify an Internet standard of any kind. Distribution of
this memo is unlimited.
Abstract
The MARS model (RFC2022) provides a solution to intra-LIS IP
multicasting over ATM, establishing and managing the use of ATM pt-
mpt SVCs for IP multicast packet forwarding. Inter-LIS multicast
forwarding is achieved using Mrouters, in a similar manner to which
the "Classical IP over ATM" model uses Routers to inter-connect LISes
for unicast traffic. The development of unicast IP shortcut
mechanisms (e.g. NHRP) has led some people to request the
development of a Multicast equivalent. There are a number of
different approaches. This document focuses exclusively on the
problems associated with extending the MARS model to cover multiple
clusters or clusters spanning more than one subnet. It describes a
hypothetical solution, dubbed "Very Extensive NonUnicast Service"
(VENUS), and shows how complex such a service would be. It is also
noted that VENUS ultimately has the look and feel of a single, large
cluster using a distributed MARS. This document is being issued to
help focus ION efforts towards alternative solutions for establishing
ATM level multicast connections between LISes.
1. Introduction
The classical model of the Internet running over an ATM cloud
consists of multiple Logical IP Subnets (LISs) interconnected by IP
Routers [1]. The evolving IP Multicast over ATM solution (the "MARS
model" [2]) retains the classical model. The LIS becomes a "MARS
Cluster", and Clusters are interconnected by conventional IP
Multicast routers (Mrouters).
The development of NHRP [3], a protocol for discovering and managing
unicast forwarding paths that bypass IP routers, has led to some
calls for an IP multicast equivalent. Unfortunately, the IP
multicast service is a rather different beast to the IP unicast
service. This document aims to explain how much of what has been
learned during the development of NHRP must be carefully scrutinized
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before being re-applied to the multicast scenario. Indeed, the
service provided by the MARS and MARS Clients in [2] are almost
orthogonal to the IP unicast service over ATM.
For the sake of discussion, let's call this hypothetical multicast
shortcut discovery protocol the "Very Extensive Non-Unicast Service"
(VENUS). A "VENUS Domain" is defined as the set of hosts from two or
more participating Logical IP Subnets (LISs). A multicast shortcut
connection is a point to multipoint SVC whose leaf nodes are
scattered around the VENUS Domain. (It will be noted in section 2
that a VENUS Domain might consist of a single MARS Cluster spanning
multiple LISs, or multiple MARS Clusters.)
VENUS faces a number of fundamental problems. The first is exploding
the scope over which individual IP/ATM interfaces must track and
react to IP multicast group membership changes. Under the classical
IP routing model Mrouters act as aggregation points for multicast
traffic flows in and out of Clusters [4]. They also act as
aggregators of group membership change information - only the IP/ATM
interfaces within each Cluster need to know the specific identities
of their local (intra-cluster) group members at any given time.
However, once you have sources within a VENUS Domain establishing
shortcut connections the data and signaling plane aggregation of
Mrouters is lost. In order for all possible sources throughout a
VENUS Domain to manage their outgoing pt-mpt SVCs they must be kept
aware of MARS_JOINs and MARS_LEAVEs occuring in every MARS Cluster
that makes up a VENUS Domain. The nett effect is that a VENUS domain
looks very similar to a single, large distributed MARS Cluster.
A second problem is the impact that shortcut connections will have on
IP level Inter Domain Multicast Routing (IDMR) protocols. Multicast
groups have many sources and many destinations scattered amongst the
participating Clusters. IDMR protocols assume that they can calculate
efficient inter-Cluster multicast trees by aggregating individual
sources or group members in any given Cluster (subnet) behind the
Mrouter serving that Cluster. If sources are able to simply bypass an
Mrouter we introduce a requirement that the existence of each and
every shortcut connection be propagated into the IDMR decision making
processes. The IDMR protocols may need to adapt when a source's
traffic bypasses its local Mrouter(s) and is injected into Mrouters
at more distant points on the IP-level multicast distribution tree.
(This issue has been looked at in [7], focussing on building
forwarding trees within networks where the termination points are
small in number and sparsely distributed. VENUS introduces tougher
requirements by assuming that multicast group membership may be dense
across the region of interest.)
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This document will focus primarily on the internal problems of a
VENUS Domain, and leave the IDMR interactions for future analysis.
2. What does it mean to "shortcut" ?
Before going further it is worth considering both the definition of
the Cluster, and two possible definitions of "shortcut".
2.1 What is a Cluster?
In [2] a MARS Cluster is defined as the set of IP/ATM interfaces that
are willing to engage in direct, ATM level pt-mpt SVCs to perform IP
multicast packet forwarding. Each IP/ATM interface (a MARS Client)
must keep state information regarding the ATM addresses of each leaf
node (recipient) of each pt-mpt SVC it has open. In addition, each
MARS Client receives MARS_JOIN and MARS_LEAVE messages from the MARS
whenever there is a requirement that Clients around the Cluster need
to update their pt-mpt SVCs for a given IP multicast group.
It is worth noting that no MARS Client has any concept of how big its
local cluster is - this knowledge is kept only by the MARS that a
given Client is registered with.
Fundamentally the Cluster (and the MARS model as a whole) is a
response to the requirement that any multicast IP/ATM interface using
pt-mpt SVCs must, as group membership changes, add and drop leaf
nodes itself. This means that some mechanism, spanning all possible
group members within the scopes of these pt-mpt SVCs, is required to
collect group membership information and distribute it in a timely
fashion to those interfaces. This is the MARS Cluster, with certain
scaling limits described in [4].
2.2 LIS/Cluster boundary "shortcut"
The currently popular definition of "shortcut" is based on the
existence of unicast LIS boundaries. It is tied to the notion that
LIS boundaries have physical routers, and cutting through a LIS
boundary means bypassing a router. Intelligently bypassing routers
that sit at the edges of LISs has been the goal of NHRP. Discovering
the ATM level identity of an IP endpoint in a different LIS allows a
direct SVC to be established, thus shortcutting the logical IP
topology (and very real routers) along the unicast path from source
to destination.
For simplicity of early adoption RFC2022 recommends that a Cluster's
scope be made equivalent to that of a LIS. Under these circumstances
the "Classical IP" routing model places Mrouters at LIS/Cluster
boundaries, and multicast shortcutting must involve bypassing the
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same physical routing entities as unicast shortcutting. Each MARS
Cluster would be independent and contain only those IP/ATM interfaces
that had been assigned to the same LIS.
As a consequence, a VENUS Domain covering the hosts in a number of
LIS/Clusters would have to co-ordinate each individual MARS from each
LIS/Cluster (to ensure group membership updates from around the VENUS
Domain were propagated correctly).
2.3 Big Cluster, LIS boundary "shortcut"
The MARS model's fundamental definition of a Cluster was deliberately
created to be independent of unicast terminology. Although not
currently well understood, it is possible to build a single MARS
Cluster that encompasses the members of multiple LISs. As expected,
inter-LIS unicast traffic would pass through (or bypass, if using
NHRP) routers on the LIS boundaries. Also as expected, each IP/ATM
interface, acting as a MARS Client, would forward their IP multicast
packets directly to intra-cluster group members. However, because the
direct intra-cluster SVCs would exist between hosts from the
different LISs making up the cluster, this could be considered a
"shortcut" of the unicast LIS boundaries.
This approach immediately brings up the problem of how the IDMR
protocols will react. Mrouters only need to exist at the edges of
Clusters. In the case of a single Cluster spanning multiple LISs,
each LIS becomes hidden behind the Mrouter at the Cluster's edge.
This is arguably not a big problem if the Cluster is a stub on an
IDMR protocol's multicast distribution tree, and if there is only a
single Mrouter in or out of the Cluster. Problems arise when two or
more Mrouters are attached to the edges of the Cluster, and the
Cluster is used for transit multicast traffic. Each Mrouter's
interface is assigned a unicast identity (e.g. that of the unicast
router containing the Mrouter). IDMR protocols that filter packets
based on the correctness of the upstream source may be confused at
receiving IP multicast packets directly from another Mrouter in the
same cluster but notionally "belonging" to an LIS multiple unicast IP
hops away.
Adjusting the packet filtering algorithms of Mrouters is something
that needs to be addressed by any multicast shortcut scheme. It has
been noted before and a solution proposed in [7]. For the sake of
argument this document will assume the problem solvable. (However, it
is important that any solution scales well under general topologies
and group membership densities.)
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A multi-LIS MARS Cluster can be considered a simple VENUS Domain.
Since it is a single Cluster it can be scaled using the distributed
MARS solutions currently being developed within the IETF [5,6].
3. So what must VENUS look like?
A number of functions that occur in the MARS model are fundamental to
the problem of managing root controlled, pt-mpt SVCs. The initial
setup of the forwarding SVC by any one MARS Client requires a
query/response exchange with the Client's local MARS, establishing
who the current group members are (i.e. what leaf nodes should be on
the SVC). Following SVC establishment comes the management phase -
MARS Clients need to be kept informed of group membership changes
within the scopes of their SVCs, so that leaf nodes may be added or
dropped as appropriate.
For intra-cluster multicasting the current MARS approach is our
solution for these two phases.
For the rest of this document we will focus on what VENUS would look
like when a VENUS Domain spans multiple MARS Clusters. Under such
circumstances VENUS is a mechanism co-ordinating the MARS entities of
each participating cluster. Each MARS is kept up to date with
sufficient domain-wide information to support both phases of client
operation (SVC establishment and SVC management) when the SVC's
endpoints are outside the immediate scope of a client's local MARS.
Inside a VENUS Domain a MARS Client is supplied information on group
members from all participating clusters.
The following subsections look at the problems associated with both
of these phases independently. To a first approximation the problems
identified are independent of the possible inter-MARS mechanisms. The
reader may assume the MARS in any cluster has some undefined
mechanism for communicating with the MARSs of clusters immediately
adjacent to its own cluster (i.e. connected by a single Mrouter hop).
3.1 SVC establishment - answering a MARS_REQUEST.
The SVC establishment phase contains a number of inter-related
problems.
First, the target of a MARS_REQUEST (an IP multicast group) is an
abstract entity. Let us assume that VENUS does not require every MARS
to know the entire list of group members across the participating
clusters. In this case each time a MARS_REQUEST is received by a
MARS from a local client, the MARS must construct a sequence of
MARS_MULTIs based on locally held information (on intra-cluster
members) and remotely solicited information.
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So how does it solicit this information? Unlike the unicast
situation, there is no definite, single direction to route a
MARS_REQUEST across the participating clusters. The only "right"
approach is to send the MARS_REQUEST to all clusters, since group
members may exist anywhere and everywhere. Let us allow one obvious
optimization - the MARS_REQUEST is propagated along the IP multicast
forwarding tree that has been established for the target group by
whatever IDMR protocol is running at the time.
As noted in [4] there are various reasons why a Cluster's scope be
kept limited. Some of these (MARS Client or ATM NIC limitations)
imply that the VENUS discovery process not return more group members
in the MARS_MULTIs that the requesting MARS Client can handle. This
provides VENUS with an interesting problem of propagating out the
original MARS_REQUEST, but curtailing the MARS_REQUESTs propagation
when a sufficient number of group members have been identified.
Viewed from a different perspective, this means that the scope of
shortcut achievable by any given MARS Client may depend greatly on
the shape of the IP forwarding tree away from its location (and the
density of group members within clusters along the tree) at the time
the request was issued.
How might we limit the number of group members returned to a given
MARS Client? Adding a limit TLV to the MARS_REQUEST itself is
trivial. At first glance it might appear that when the limit is being
reached we could summarize the next cluster along the tree by the ATM
address of the Mrouter into that cluster. The nett effect would be
that the MARS Client establishes a shortcut to many hosts that are
inside closer clusters, and passes its traffic to more distant
clusters through the distant Mrouter. However, this approach only
works passably well for a very simplistic multicast topology (e.g. a
linear concatenation of clusters).
In a more general topology the IP multicast forwarding tree away from
the requesting MARS Client will branch a number of times, requiring
the MARS_REQUEST to be replicated along each branch. Ensuring that
the total number of returned group members does not exceed the
client's limit becomes rather more difficult to do efficiently.
(VENUS could simply halve the limit value each time it split a
MARS_REQUEST, but this might cause group member discovery on one
branch to end prematurely while all the group members along another
branch are discovered without reaching the subdivided limit.)
Now consider this decision making process scattered across all the
clients in all participating clusters. Clients may have different
limits on how many group members they can handle - leading to
situations where different sources can shortcut to different
(sub)sets of the group members scattered across the participating
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RFC 2191 VENUS September 1997
clusters (because the IP multicast forwarding trees from senders in
different clusters may result in different discovery paths being
taken by their MARS_REQUESTs.)
Finally, when the MARS_REQUEST passes a cluster where the target
group is MCS supported, VENUS must ensure the ATM address of the MCS
is collected rather than the addresses of the actual group members.
(To do otherwise would violate the remote cluster's intra-cluster
decision to use an MCS. The shortcut in this case must be content to
directly reach the remote cluster's MCS.)
(A solution to part of this problem would be to ensure that a VENUS
Domain never has more MARS Clients throughout than the clients are
capable of adding as leaf nodes. This may or may not appeal to
people's desire for generality of a VENUS solution. It also would
appear to beg the question of why the problem of multiple-LIS
multicasting isn't solved simply by creating a single big MARS
Cluster.)
3.2 SVC management - tracking group membership changes.
Once a client's pt-mpt SVC is established, it must be kept up to
date. The consequence of this is simple, and potentially
devastating: The MARS_JOINs and MARS_LEAVEs from every MARS Client in
every participating cluster must be propagated to every possible
sender in every participating cluster (this applies to groups that
are VC Mesh supported - groups that are MCS supported in some or all
participating clusters introduce complications described below).
Unfortunately, the consequential signaling load (as all the
participating MARSs start broadcasting their MARS_JOIN/LEAVE
activity) is not localized to clusters containing MARS Clients who
have established shortcut SVCs. Since the IP multicast model is Any
to Multipoint, and you can never know where there may be source MARS
Clients, the JOINs and LEAVEs must be propagated everywhere, always,
just in case. (This is simply a larger scale version of sending JOINs
and LEAVEs to every cluster member over ClusterControlVC, and for
exactly the same reason.)
The use of MCSs in some clusters instead of VC Meshes significantly
complicates the situation, as does the initial scoping of a client's
shortcut during the SVC establishment phase (described in the
preceding section).
In Clusters where MCSs are supporting certain groups, MARS_JOINs or
MARS_LEAVEs are only propagated to MARS Clients when an MCS comes or
goes. However, it is not clear how to effectively accommodate the
current MARS_MIGRATE functionality (that allows a previously VC Mesh
based group to be shifted to an MCS within the scope of a single
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cluster). If an MCS starts up within a single Cluster, it is possible
to shift all the intra-cluster senders to the MCS using MARS_MIGRATE
as currently described in the MARS model. However, MARS Clients in
remote clusters that have shortcut SVCs into the local cluster also
need some signal to shift (otherwise they will continue to send their
packets directly to the group members in the local cluster).
This is a non-trivial requirement, since we only want to force the
remote MARS Clients to drop some of their leaf nodes (the ones to
clients within the Cluster that now has an MCS), add the new MCS as a
leaf node, and leave all their other leaf nodes untouched (the cut-
through connections to other clusters). Simply broadcasting the
MARS_MIGRATE around all participating clusters would certainly not
work. VENUS needs a new control message with semantics of "replaced
leaf nodes {x, y, z} with leaf node {a}, and leave the rest alone".
Such a message is easy to define, but harder to use.
Another issue for SVC management is that the scope over which a MARS
Client needs to receive JOINs and LEAVEs needs to respect the
Client's limited capacity for handling leaf nodes on its SVC. If the
MARS Client initially issued a MARS_REQUEST and indicated it could
handle 1000 leaf nodes, it is not clear how to ensure that subsequent
joins of new members wont exceed that limit. Furthermore, if the SVC
establishment phase decided that the SVC would stop at a particular
Mrouter (due to leaf node limits being reached), the Client probably
should not be receiving direct MARS_JOIN or MARS_LEAVE messages
pertaining to activity in the cluster "behind" this Mrouter. (To do
otherwise could lead to multiple copies of the source client's
packets reaching group members inside the remote cluster - one
version through the Mrouter, and another on the direct SVC connection
that the source client would establish after receiving a subsequent,
global MARS_JOIN regarding a host inside the remote cluster.)
Another scenario involves the density of group members along the IDMR
multicast tree increasing with time after the initial MARS_REQUEST is
answered. Subsequent JOINs from Cluster members may dictate that a
"closer" Mrouter be used to aggregate the source's outbound traffic
(so as not to exceed the source's leaf node limitations). How to
dynamically shift between terminating on hosts within a Cluster, and
terminating on a cluster's edge Mrouter, is an open question.
To complicate matters further, this scoping of the VENUS domain-wide
propagation of MARS_JOINs and MARS_LEAVEs needs to be on a per-
source- cluster basis, at least. If MARS Clients within the same
cluster have different leaf node limits, the problem worsens. Under
such circumstances, one client may have been able to establish a
shortcut SVC directly into a remote cluster while a second client -
in the same source cluster - may have been forced to terminate its
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shortcut on the remote cluster's Mrouter. The first client obviously
needs to know about group membership changes in the remote cluster,
whilst the second client does not. Propagating these JOIN/LEAVE
messages on ClusterControlVC in the source cluster will not work -
the MARS for the source cluster will need to explicitly send copies
of the JOIN/LEAVE messages only to those MARS Clients whose prior SVC
establishment phase indicates they need them. Propagation of messages
to indicate a VC Mesh to MCS transition within clusters may also need
to take account of the leaf node limitations of MARS Clients. The
scaling characteristics of this problem are left to the readers
imagination.
It was noted in the previous section that a VENUS domain could be
limited to ensure there are never more MARS Clients than any one
client's leaf node limit. This would certainly avoid the need to for
complicated MARS_JOIN/LEAVE propagation mechanisms. However, it begs
the question of how different the VENUS domain then becomes from a
single, large MARS Cluster.
4. What is the value in bypassing Mrouters?
This is a good question, since the whole aim of developing a shortcut
connection mechanism is predicated on the assumption that bypassing
IP level entities is always a "win". However, this is arguably not
true for multicast.
The most important observation that should be made about shortcut
connection scenarios is that they increase the exposure of any given
IP/ATM interface to externally generated SVCs. If there are a
potential 1000 senders in a VENUS Domain, then you (as a group
member) open yourself up to a potential demand for 1000 instances of
your re-assembly engine (and 1000 distinct incoming SVCs, when you
get added as a leaf node to each sender's pt-mpt SVC, which your
local switch port must be able to support).
It should be no surprise that the ATM level scaling limits applicable
to a single MARS Cluster [4] will also apply to a VENUS Domain. Again
we're up against the question of why you'd bypass an Mrouter. As
noted in [4] Mrouters perform a useful function of data path
aggregation - 100 senders in one cluster become 1 pt-mpt SVC out of
the Mrouter into the next cluster along the tree. They also hide MARS
signaling activity - individual group membership changes in one
cluster are hidden from IP/ATM interfaces in surrounding clusters.
The loss of these benefits must be factored into any network designed
to utilize multicast shortcut connections.
Armitage Informational [Page 9]
RFC 2191 VENUS September 1997
(For the sake of completeness, it must be noted that extremely poor
mismatches of IP and ATM topologies may make Mrouter bypass
attractive if it improves the use of the underlying ATM cloud. There
may also be benefits in removing the additional re-
assembly/segmentation latencies of having packets pass through an
Mrouter. However, a VENUS Domain ascertained to be small enough to
avoid the scaling limits in [4] might just as well be constructed as
a single large MARS Cluster. A large cluster also avoids a
topological mismatch between IP Mrouters and ATM switches.)
5. Relationship to Distributed MARS protocols.
The ION working group is looking closely at the development of
distributed MARS architectures. An outline of some issues is provided
in [5,6]. As noted earlier in this document the problem space looks
very similar that faced by our hypothetical VENUS Domain. For
example, in the load-sharing distributed MARS model:
- The Cluster is partitioned into sub-clusters.
- Each Active MARS is assigned a particular sub-cluster, and uses
its own sub-ClusterControlVC to propagate JOIN/LEAVE messages to
members of its sub-cluster.
- The MARS_REQUEST from any sub-cluster member must return
information from all the sub-clusters, so as to ensure that all a
group's members across the cluster are identified.
- Group membership changes in any one sub-cluster must be
immediately propagated to all the other sub-clusters.
There is a clear analogy to be made between a distributed MARS
Cluster, and a VENUS Domain made up of multiple single-MARS Clusters.
The information that must be shared between sub-clusters in a
distributed MARS scenario is similar to the information that must be
shared between Clusters in a VENUS Domain.
The distributed MARS problem is slightly simpler than that faced by
VENUS:
- There are no Mrouters (IDMR nodes) within the scope of the
distributed Cluster.
- In a distributed MARS Cluster an MCS supported group uses the
same MCS across all the sub-clusters (unlike the VENUS Domain,
where complete generality makes it necessary to cope with mixtures
of MCS and VC Mesh based Clusters).
Armitage Informational [Page 10]
RFC 2191 VENUS September 1997
6. Conclusion.
This document has described a hypothetical multicast shortcut
connection scheme, dubbed "Very Extensive NonUnicast Service"
(VENUS). The two phases of multicast support - SVC establishment,
and SVC management - are shown to be essential whether the scope is a
Cluster or a wider VENUS Domain. It has been shown that once the
potential scope of a pt-mpt SVC at establishment phase has been
expanded, the scope of the SVC management mechanism must similarly be
expanded. This means timely tracking and propagation of group
membership changes across the entire scope of a VENUS Domain.
It has also been noted that there is little difference in result
between a VENUS Domain and a large MARS Cluster. Both suffer from the
same fundamental scaling limitations, and both can be arranged to
provide shortcut of unicast routing boundaries. However, a completely
general multi-cluster VENUS solution ends up being more complex. It
needs to deal with bypassed Mrouter boundaries, and dynamically
changing group membership densities along multicast distribution
trees established by the IDMR protocols in use.
No solutions have been presented. This document's role is to provide
context for future developments.
Acknowledgment
This document was prepared while the author was with the
Internetworking Research group at Bellcore.
Security Considerations
This memo addresses specific scaling issues associated with the
extension of the MARS architecture beyond that described in RFC 2022.
It is an Informational memo, and does not mandate any additional
protocol behaviors beyond those described in RFC 2022. As such, the
security implications are no greater or less than the implications
inherent in RFC 2022. Should enhancements to security be required,
they would need to be added as an extension to the base architecture
in RFC 2022.
Armitage Informational [Page 11]
RFC 2191 VENUS September 1997
Author's Address
Grenville Armitage
Bell Labs, Lucent Technologies.
101 Crawfords Corner Rd,
Holmdel, NJ, 07733
USA
EMail: [email protected]
References
[1] Laubach, M., "Classical IP and ARP over ATM", RFC 1577, Hewlett-
Packard Laboratories, December 1993.
[2] Armitage, G., "Support for Multicast over UNI 3.0/3.1 based ATM
Networks.", Bellcore, RFC 2022, November 1996.
[3] Luciani, J., et al, "NBMA Next Hop Resolution Protocol (NHRP)",
Work in Progress, February 1997.
[4] Armitage, G., "Issues affecting MARS Cluster Size", Bellcore, RFC
2121, March 1997.
[5] Armitage, G., "Redundant MARS architectures and SCSP", Bellcore,
Work in Progress, November 1996.
[6] Luciani, J., G. Armitage, J. Jalpern, "Server Cache
Synchronization Protocol (SCSP) - NBMA", Work in Progress, March 1997.
[7] Rekhter, Y., D. Farinacci, " Support for Sparse Mode PIM over
ATM", Cisco Systems, Work in Progress, April 1996.
Armitage Informational [Page 12]
| http://www.fifi.org/doc/RFC/informational/rfc2191.txt.gz |
(PDF) Photonic crystal fiber-based plasmonic biosensor with external sensing approach
PDF | We propose a simple photonic crystal fiber (PCF) biosensor based on the surface plasmon resonance effect. The sensing properties are characterized... | Find, read and cite all the research you need on ResearchGate
June 2017 Journal of Nanophotonics
12(1):012503
DOI: 10.1117/1.JNP.12.012503
Authors:
Rifat Ahmmed Aoni
University of Southern California
Md Rabiul Hasan
UiT The Arctic University of Norway
Rajib Ahmed
Rajib Ahmed
This person is not on ResearchGate, or hasn't claimed this research yet.
Haider Butt
Khalifa University
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Citations (92)
References (45)
Figures (6)
Abstract and Figures
We propose a simple photonic crystal fiber (PCF) biosensor based on the surface plasmon resonance effect. The sensing properties are characterized using the finite element method. Chemically stable gold material is deposited on the outer surface of the PCF to realize the practical sensing approach. The performance of the modeled biosensor is investigated in terms of wavelength sensitivity, amplitude sensitivity, sensor resolution, and linearity of the resonant wavelength with the variation of structural parameters. In the sensing range of 1.33 to 1.37, maximum sensitivities of 4000 nm∕RIU and 478 RIU−1 are achieved with the high sensor resolutions of 2.5×10−5 and 2.1×10−5 RIU using wavelength and amplitude interrogation methods, respectively. The designed biosensor will reduce fabrication complexity due to its simple and realistic hexagonal lattice structure. It is anticipated that the proposed biosensor may find possible applications for unknown biological and biochemical analyte detections with a high degree of accuracy.
a) Cross-section view of the stacked preform of the proposed PCF. (b) Cross-section view of the computational model of the proposed biosensor in the xy plane.
…
Comparison among the properties of the proposed fiber with previously reported sensors.
…
Loss spectrum of the proposed PCF biosensor for different n a with the variation of wavelength. Linear curve fitting of resonant wavelength is shown in the inset.
…
Amplitude sensitivity of the proposed PCF biosensor as a function of wavelength with different n a .
…
+1
a) Loss spectrum of the proposed PCF biosensor for the variation of gold layer thickness with n a ¼ 1.33 and 1.34. (b) Amplitude sensitivity as a function of wavelength with varying t g at n a ¼ 1.33.
…
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Photonic crystal fiber-based
plasmonic biosensor with external
sensing approach
Ahmmed A. Rifat
Md. Rabiul Hasan
Rajib Ahmed
Haider Butt
Ahmmed A. Rifat, Md. Rabiul Hasan, Rajib Ahmed, Haider Butt, “ Photonic cryst al fiber-based plasmonic
biosensor with external sensing approach, ” J. Nanophoton. 12 (1), 012503 (2017),
doi: 10.1117/1.JNP
.12.012503.
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.org/journals/Journal-of-Nanophotonics on 8/23/2017 T
erms of Use: https://spiedigitallibrary.spie.org/ss/T
ermsOfUse.aspx
Photonic crystal fiber-based plasmonic biosensor with
external sensing approach
Ahmmed A. Rifat, a,b, * Md. Rabiul Hasan, c Rajib Ahmed, d and
Haider Butt d
a Australian National University, Nonlinear Physics Centre, Research School of Physics and
Engineering, Canberra, Australia
b University of Malaya, Integrated Lightwave Research Group, Department of Electrical
Engineering, Kuala Lumpur, Malaysia
c Rajshahi University of Engineering and Technology , Department of Electronics and
Telecommunication Engineering, Rajshahi, Bangladesh
d University of Birmingham, Nanotechnology Laboratory, School of Engineering, Birmingham,
United Kingdom
Abstract. We propose a simple photonic crystal fiber (PCF) biosensor based on the surface
plasmon resonance effect. The sensing properties are characterized
using the finite element
method. Chemically stable gold material is deposited on the outer surface of the PCF to realize
the practical sensing approach. The performance of the modeled biosensor is investigated in
terms of wavelength sensitivity, amplitude sensitivity
, sensor resolution, and linearity of the res-
onant wavelength with the variation of structural parameters. In the sensing range of 1.33 to 1.37,
maximum sensitivities of 4000 nm ∕ RIU and 478 RIU − 1 are achieved with the high sensor res-
olutions of 2.5 × 10 − 5 and 2.1 × 10 − 5 RIU using wavelength and amplitude interrogation meth-
ods, respectively. The designed biosensor will reduce fabrication complexity due to its simple
and realistic hexagonal lattice structure. It is anticipated that the proposed biosensor may find
possible applications for unknown biological and biochemical analyte detections with a high
degree of accuracy. © 2017 Society of Photo-Optical Instrumentation Engineers (SPIE) [DOI: 10
.1117/1.JNP
.12.012503 ]
Keywords: surface plasmon resonance; photonic crystal fiber; fiber optic sensor; biosensor;
sensitivity; resolution.
Paper 17034SS received Mar. 24, 2017; accepted for publication Jun.
5, 2017; published online
Jun. 19, 2017; corrected Aug. 17, 2017.
1 Introduction
Over the last decades, photonic biosensors have attracted intense attention due
to their promising
applications in several fields including medical diagnostics,
biomolecules detection, biochem-
icals detection, environment monitoring, etc. 1 – 3 Several sensing approaches such as fiber Bragg
grating, microring resonator, resonant mirror, multimode interference, and surface plasmon res-
onance (SPR) have been widely explored. 4 Among them, SPR-based sensors have gained maxi-
mum interest as they offer high sensitivity and better detection accuracy of unknown analytes.
The earlier SPR biosensors were mostly based on the Kretschmann set-up
configuration, where
a prism and active metal layer were used. Since pris
m-coupling SPR sensors are bulky and
consist of moving optical and mechanical
parts, they are not suitable for remote-s
ensing
applications. 4 The use of fiber optic can greatly reduce the major challenges of prism-based
biosensors. Photonic crystal fiber (PCF) is more convenient compared with the regular fiber
in SPR sensing. In PCF-based SPR sensing, an evanescent field is the focal parameter to enhance
the sensor performance. Conventional optical fiber consists of core and cladding having different
materials. The index contrast between core and cladding is relatively smaller, which limits the
*Address all correspondence to: Ahmmed A. Rifat, E-mail: rifat.ahmmed@osamem ber.org
1934-2608/2017/$25.00 © 2017 SPIE
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efficient control of the evanescent field. However
, PCFs offer wider design space by taking ad-
vantage of large index contrast between core and cladding. By varying the structural parameters
such as air-hole diameter, pitch, and crystal arrangement, the evanescent field can be easily tail-
ored. As a result, PCFs have been widely used instead of conventional optical fiber. 5 – 7 In PCFs,
SPR phenomena can be easily observed, and performance of the sensor can be controlled by
varying the fiber ’ s design parameters (air-hole radius, pitch size, etc.). The structures of PCF-
based biosensors can be realized using existing fabrication technologies. In addition, PCF-based
SPR biosensors allow reduction of sensor size and permit easy manipulation of the guided
electromagnetic field. To create the SPR effect, a metal coating is required to be deposited either
in the inner air holes of the PCF or on the outer surface of the PCF
. Several plasmonic materials
including silver, gold, and copper have been widely studied for SPR sensors. 6 , 7 Although silver
material offers a sharp resonance peak, it is chemically
unstable and very susceptible to
oxi-
dization, which reduces the sensing performance. 7 To prevent oxidization, an effective approach
is to deposit nanoscale graphene layers on the top of the plasmonic material. 8 – 10 However, main-
taining a uniform thickness of this additional layer is difficult, and it also increases the overall
manufacturing cost. On the other hand, gold is chemically stable and provides a high resonance
peak. Unlike copper, gold material does not suffer from oxidization. 7 In PCF SPR biosensor, an
evanescent field propagating toward the cladding region strikes the plasmonic metal interface
that excites the free electrons. When the frequency of the oscillating surface electrons and inci-
dent photons are matched, a sharp loss-peak is
observed. Mathematical
ly, SPR phenomenon
happens when the real refractive index (RI) ( n eff ) of the guide mode and the real n eff of the
surface plasmon polariton (SPP) mode are equal. Under this con
dition, maximum mode
power transfers from the core-guided mode to the SPP mode.
To date, se
veral distinct PCFs biosensors based on the SPR phenomenon have been
proposed. 5 , 6 , 11 – 13 Internally, metal film-coated PCF biosensors have been reported in
Refs. 13 – 15 . In such PCFs, several micron-scale air holes are selectively coated with plasmonic
metal as well as selectively infiltrated with liquids. Although these types of biosensors
(inside
sensing) offer high sensitivity, they
are difficult to realize from the fabrication point of view
.
Maintaining an accurate coating inside the air holes to deposit several metal layers is also a
challenging task. To eliminate the shortcomings of these biosensors, externally metal-coated
PCF SPR sensors have been introduced. The D-shaped PCF SPR sensors have been reported
in Refs. 12 , 16 – 19 , showing the improved sensing performances. Tian et al. reported a D-shaped
PCF-based SPR sensor where silver was used as the plasm
onic material. 18 However, silver is not
chemically stable and prone to
oxidize easily. It achieved the maximum sensor resolution of
7300 nm ∕ RIU at analyte RI 1.38. However, such D-shaped PCFs require additional ef fort to
polish the predefined section of the PCF, which increases the fabrication difficulties. T
o date,
several improved PCF SPR sensors have been reported where a plasmonic metal layer is placed
outside the PCF structure. 6 , 20 – 23 However, these PCFs contain elliptical air-holes 22 and different
sized air-holes, 7 , 21 and some of the PCF outer structures are slotted, 6 , 22 which are difficult to
control during fabrication. Additionally, most of the reported external sensor approaches
used a small central air hole to facilitate penetr
ation of the evanescent field. Practically, achieving
such PCF structures are challenging. Recently, metallic nanowire-based plasmonic sensors have
been reported using silver nanowires. 24 , 25 Based on the plasmonic resonance, ultrathin metallic
nanolayer plasmonic tapered fiber sensors have also been explored in the literature. 26 , 27
In this paper, we propose a simple solid-core PCF-based SPR biosensor. Unlike the existing
biosensors, the proposed sensor has minimum irregular design parameter
s, which reduces the
fabrication complexity. Chemically stable gold material is coated on the outer surface of the PCF
structure, which is more straightforward for practical fabricati
on. The proposed biosensor also
allows a simple detection approach since unknown analyte can be detected by flowing it through
the outer gold surface.
2
Design and Simulation Methodology
Figure 1(a) shows the cross-section of the proposed PCF preform structure during the stacking
process. As illustrated in the figure, the central core and four missing air holes in the second ring
Rifat
et
al.:
Photonic
crystal
fiber-based plasmonic
biosensor. . .
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can be created by inserting solid rods. In contrast to others, thick wall capillaries are used for
smaller air holes, and the larger air holes can be created using thin wall capillaries. Figure 1(b)
shows the cross-section of the proposed PCF SPR biosensor, where the PCF consists of a two-
ring hexagonal lattice design. The center-to-center distance between air
holes is Λ ¼ 2 μ m , and
the core diameter is 1.4 × Λ . The diameter of air holes in the first and second rings is d ¼ 0.6 × Λ
and d 1 ¼ 0.8 × Λ , respectively . The total size of the PCF is 10 μ m , and the outer diameter of the
fused silica [perfectly matched layer (PML) thickness] is 1.5 μ m . The analyte layer thickness is
1.2 μ m . Unlike other PCF sensors, 7 , 17 , 20 this PCF is comparatively simple in the sense that it has
fewer design parameters. The missing central air hole also facilitates the fabrication process. In
this design, fused silica was used
as the background material
.
The RI of fused silica
was obtained using
the following Sellmeier equation: 28
EQ-TARGET;temp:intralink-;e001;116;441 n 2 ð λ Þ¼ 1 þ B 1 λ 2
λ 2 − C 1
þ B 2 λ 2
λ 2 − C 2
þ B 3 λ 2
λ 2 − C 3
; (1)
where n is the wavelength-dependent RI of fused silica and λ is the wavelength in μ m . B 1 , B 2 , B 3 ,
C 1 , C 2 , and C 3 are the Sellmeier constants. For fused silica, the constants are 0.69616300,
0.407942600, 0.897479400, 0.00467914826, 0.0135120631, and 97.9340025, respec
tively
.
A thin gold layer with a thickness of t g ¼ 30 nm is deposited in the outer layer of the PCF. It
is a challenging task to maintain a uniform thickness of the outer thin gold
layer coated on a
circular surface of the PCF. There are several techniques such as radio frequency sputtering, 29
thermal evaporation, 30 and wet-chemistry deposition 31 that can be used to deposit this outer met-
allic layer. However
, these metal-coating techniques suffer from extreme surface roughness. In
this context, chemical vapour deposition 32 is an efficient method that permits uniform nanola yer
coating with minimal surface roughness. In addition, the newly reported gold atomic layer dep-
osition method, 33 which can deposit a more unifo rm gold coating on the curve fiber surface,
could be used. The dielectric constant of gold can be obtai
ned from the Drude – Lorentz model 34
EQ-TARGET;temp:intralink-;e002;116;251 ε Au ¼ ε ∞ − ω 2
D
ω ð ω þ j γ D Þ − Δ ε Ω 2
L
ð ω 2 − Ω 2
L Þþ j Γ L ω ; (2)
where ε Au is the permittivity of gold, ε ∞ is the permittivity at a high frequency with the value of
5.9673, ω is the angular frequency, which is given by ω ¼ 2 π c ∕ λ , c is the velocity of light in
vacuum, ω D is the plasma frequency , and γ D is the damping frequency. Here, ω D ∕ 2 π ¼
2113.6 THz , γ D ∕ 2 π ¼ 15.92 THz , and the weighting factor Δ ε ¼ 1.09 . The spectral width
and oscillator strength of the Lorentz
oscillators are given by Γ L ∕ 2 π ¼ 104.86 THz and
Ω L ∕ 2 π ¼ 650.07 THz , respectively.
The finite element method-based state-of-the-art COMSOL v 5.0 has been used to design and
simulate the proposed structure. We imposed circular PML and scattering boundary conditions
that absorb outgoing waves from the surface of the PCF.
The convergence test was performed to
confirm the simulation accuracy. The total computation domain took 30,150 triangular elements
to represent the structure. The thickness of the PML and analyte layer was about 14% and 12% of
the fiber diameter, respectively
.
(a) (b)
Fig. 1 (a) Cross-section view of the stacked preform of the proposed PCF. (b) Cross-section view
of the computational model of the proposed biosensor in the xy
plane.
Rifat
et
al.:
Photonic
crystal
fiber-based
plasmonic
biosensor. . .
Journal of Nanophotonics
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3
Results and Discussions
The fundamental mode field profiles of the core-guided mode and SPP mode for x - and y -polar-
izations are shown in Figs. 2(a) – 2(d) , respectively. As seen from the figure, in y -polarization
mode more of the evanescent field reaches the metal layer
in comparison with the x -polarization
mode. As a result, the core-guided mode of y -polarization can easily excite the metal electrons to
create the SPR effect. Therefore, in the rest of the discussions, we only consider the y
-polari-
zation mode because of higher loss depth. Although the y -polarized mode showed the higher
evanescent field compared with the x -polarized mode, it is not significant enough to produce a
larger amount of propagation loss. More evanescent field interaction with the sample means
more propagation loss. Increase of the propagation loss will lead to the higher signal-to-noise
ratio; however, if
propagation loss is increased, then the sensor lengt
h will be reduced to generate
the measureable signal. As a result, practical
realization will be difficult. For instance, SPR
λ = 620nm, n a =1.33
spp mode, x -pol.
(b)
0
-2
-4 -6 24 6
λ = 620nm, n a =1.33
Core mode, x -pol.
0
0
–2
–4
–6
–2
–4
–6
2
4
6
24 6
(a)
(d)
0
–2
–4
–6 24 6
0
–2
–4
–6 24 6
(c)
X ( µ m) X ( µ m)
X (
µ m) X ( µ m)
)
m
µ
( Y
0
–2
–4
–6
2
4
6
)
m
µ
( Y
1.444
1.446
1.448
1.45
1.452
1.454
1.456
0
5
10
15
20
25
540 580 620 660 700
Effective index (real)
Loss (dB/cm)
Wavelength (nm)
y-pol. core mode
y-pol. core mode
y-pol. spp mode
(e)
λ = 620nm, n a =1.33
Core mode, y -pol.
λ = 620nm, n a =1.33
spp mode, y -pol.
1.0
0.0
1.0
0.0
1.0
0.0
1.0
0.0
0
–2
–4
–6
2
4
6
)
m
µ
( Y
0
–2
–4
–6
2
4
6
)
m
µ
( Y
Fig. 2 Mode field distribution of the proposed sensor. (a) and (b) x -polarized fundamental core-
guided mode and spp mode, respectively; (c) and (d) y -polarized fundamental core-guided mode
and spp mode, respectively; and (e) dispersion relation between core-guided mode and SPP
mode while analyte RI 1.33.
Rifat
et
al.:
Photonic
crystal
fiber-based plasmonic
biosensor. . .
Journal of Nanophotonics
012503-4
Jan – Mar 2018 • Vol. 12(1)
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sensors are more sensitive compared with other
optical sensors, 6 – 8 , 13 , 15 , 20 and smaller evanescent
field interaction with the sample is able to detect the unknown sample. 6 , 7 , 35 Figure 2(e) represents
the relationship between the confinement loss and n eff of the core mode and the SPP mode for
analyte RI ( n a ) of 1.33. It is evident that, at a wavelength ( λ ) of 620 nm, the n eff of the core-
guided mode and SPP is equal, which satisfies the required resonance condition. At the resonant
wavelength, a sharp loss peak occurs that indicates the maximum power transfer from the core-
guided mode to the SPP mode. The unknown analyte can be detected from the resona
nt wave-
length shifts or the amplitude variation of the loss peaks. The confinement loss can be obtained
by 5 , 12 , 13
EQ-TARGET;temp:i ntralink-;e003;116;628 α ð dB ∕ cm Þ¼ 8.686 × k 0 Im ð n eff Þ × 10 4 ; (3)
where Im ð n eff Þ is the imaginary part of the effective mode index and k 0 is the wave number.
A small change of the analyte RI has a significant impact on the loss depth. Loss spectrum of
the proposed PCF biosensor with different n a is shown in Fig. 3 . It can be observed that increas-
ing n a results in shifting the loss peak toward longer wavelengths (also known as redshift) with
an increasing of loss depth. The highest loss depth is 60 dB ∕ cm for n a ¼ 1.37 . The higher loss
depth indicates stronger power interchange between the core and SPP modes, which results in
a
narrow resonant spectrum. Linear curve fitting of the resonant wavelength is also shown in the
inset of Fig. 3 . The calculated linearity R 2 value is 0.9868, which shows a good linear fitting
characteristic. Therefore, the proposed biosensor can be utilized for
practical biosensing
applications.
The sensitivity of a biosensor can be measured by wavelength interrogation and amplit
ude
interrogation methods. In the wavelength interrogation method, the sensitivity of a biosensor can
be calculated from S λ ð λ Þ¼ Δ λ peak ∕ Δ n a , 17 where Δ λ peak is the difference between two resona nt
wavelengths and Δ n a is the analyte RI difference. Using the wavelength interrogation met hod,
the proposed sensor shows sensitivity of 2000, 3000, 3000, and 4000 nm ∕ RIU for n a of 1.33,
1.34, 1.35, an
d 1.36, respec
tively
. When
the analyte RI is changed fr
om 1.33 to 1.34
, 1.34 to 1.35,
1.35 to 1.36, and 1.
36 to 1.37, the calculat
ed Δ λ peak are 20, 30, 30 , and 40 nm, respec tively . The
resolution of th
e sensor is anothe
r important param
eter that descri
bes how a small var
iation of the
analyte RI ca
n be detected by
the sensor
. Resolution ( R ) of the proposed sens or can be given as 5
EQ-TARGET;temp:intralink-;e004;116;368 R ¼ Δ n a × Δ λ min ∕ Δ λ peak RIU ; (4)
where Δ n a is the v ariation of analyt e RI, Δ λ peak is the minimum spectr al resolution , and Δ λ peak is
the maximum reso
nant wavelen
gth peak shift. Assu
ming that Δ n a ¼ 0.01 , Δ λ min ¼ 0.1 ,
Δ λ peak ¼ 40 nm ,a n d n a ¼ 1.36 , the calcul ated maximum sens or resolution is 2.5 × 10 − 5 RIU .
This resoluti
on is comparable wi
th the results report
ed in Refs. 12 , 20 ,a n d 23 . Using t he amplitu de
interrogat
ion method, the ampl
itude sensiti
vity can be obtain
ed from 15
0
10
20
30
40
50
60
540 590 640 690 740 790 840 890 940 990
Loss (dB/cm)
Wavelength (nm)
n a = 1.33
n a = 1.34
n a
= 1.35
n a = 1.36
n a = 1.37
y = 3000
x –3376
R ² = 0.9868
15
30
45
60
75
550
590
630
670
710
750
1.32 1.34 1.36 1.38
Loss (dB/cm)
Res. Wav. (nm)
Refractive index (RIU)
Resonant wavelength
Peak loss
Linear fit of Res. Wave.
Fig. 3 Loss spectrum of the proposed PCF biosensor for different n a with the variation of wave-
length. Linear curve fitting of resonant wavelength is shown in the inset.
Rifat
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Photonic
crystal
fiber-based
plasmonic
biosensor. . .
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EQ-TARGET;temp:intralink-;e005;116;528 S A ð RIU − 1 Þ¼ − 1
α ð λ ;n
a Þ
∂ α ð λ ;n
a Þ
∂ n a
; (5)
where α ð λ ;n
a Þ is the overall pr opagation loss at th e RI of n a and ∂ α ð λ ;n
a Þ is the loss diffe rence
between two loss spec
tra.
Figure 4 shows the S A as a function of wavelength for different n a . As observed from the
figure, the proposed sensor shows a maximum amplitude sensitivity of 478 RIU − 1 when
n a ¼ 1.36 . This value is higher than most of the previously reported results. 7 , 13 , 15 , 20 , 23 The ampli-
tude sensitivities for n a of 1.33, 1.34, and 1.35 are 190, 277, and 397 RIU − 1 , respectively . In the
case of maximum sensitivity, i.e., 478 RIU − 1 , the calculated sensor resolution is about
2.1 × 10 − 5 RIU taking into consideration that a minimum 1% of transmitted intensity can be
detected accurately.
The thickness of the gold layer has a dominant effect on the performance of the proposed
biosensor. The effect of changing t g for n a ¼ 1.33 and 1.34 is shown in Fig. 5(a) . Due to the
increase of t g , loss depth reduces significantly, which is shown in the inset of Fig. 5(a) . When t g
is varied from 30 to 50 nm, the corresponding peak loss reduces from 27 to 6d B ∕ cm for
n a ¼ 1.34 . This indicates that, with the increase of t g thickness, the evanescent field interaction
with the analyte decreases significantly. The physical reason is the higher damping loss of gold
due to the increasing of t g . Moreover, it can be found that increasing t g causes loss peak shifting
toward a longer wavelength. In addition, amplitude sensitivity also shows the same scenario. By
increasing the gold thickness from 30 to 50 nm, amplitude sensitivity decreases dramatically,
with the values being 190, 155, and 141 RIU − 1 , respectively [shown in Fig. 5(b) ]. In addition,
the resonant wavelength shifted from 650 to 670 nm (redshift).
–550
–400
–
250
–100
50
200
540 590 640 690 740 790
Amplitude sensitivity (1/RIU)
Wavelength (nm)
n a = 1.33
n a = 1.34
n a = 1.35
n a
= 1.36
Fig. 4 Amplitude sensitivity of the proposed PCF biosensor as a function of wavelength with differ-
ent n a .
0
5
10
15
20
25
30
540 590 640 690 740 790 840
)
m
c
/
B
d
(
s
s
o
L
Wavelength (nm)
30 nm, n
a
=1.33
30 nm, n
a
=1.34
40 nm, n
a
=1.33
40 nm, n
a
=1.34
50 nm, n
a
=1.33
50 nm, n
a
=1.34
0
10
20
30
25 35 45 55
Loss (dB/cm)
Gold thicknes (nm)
n
a
=1.33
n
a
=1.34
–210
–160
–110
–60
–10
40
90
540 580 620 660 700
Amp. sensitivity (1/RIU)
Wavelength (nm)
t
g
= 30 nm
t
g
= 40 nm
t
g
= 50 nm
(a) (b)
Fig. 5 (a) Loss spectrum of the proposed PCF biosensor for the variation of gold layer thickness
with n a ¼ 1 . 33 and 1.34. (b) Amplitude sensitivity as a function of wavelength with varying t g at
n a ¼ 1 . 33 .
Rifat
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Photonic
crystal
fiber-based plasmonic
biosensor. . .
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The effect of changing the air-hole diameter d on the surface plasmon waves is shown in
Fig. 6(a) .A s d is increased from 0.5 Λ to 0.7 Λ , the amplitude of peak loss gradual ly increases
with redshifting of the resonant wavelength for a constant n a of 1.33. When d is increased, it
results in a decreasing of the index contrast between core and cladding. As a result, peak loss
increases, which indicates strong coupling between the guided mode and the SPP
mode. In addi-
tion, the effect of changing pitch Λ on the loss spectrum is shown in Fig. 6(b)
. Unlike the results
obtained from increasing d , when the value of Λ is increased, the amplitude of the loss peak
decreases slowly. Although increasing the value of d shows large redshift, in this case incre asing
Λ results in small blueshift, i.e., changing the resonant peak toward a shorter wavelength.
Considering the strength of the coupling between the core and SPP mode, we have selected
the optimized values of d and Λ , which are 0.6 × Λ and 2 μ m , respectively.
Table 1 sho ws the comparison among the properties of the proposed SPR sensor with existing
structures in the literature. The performance comparison has
taken into accou
nt structure type,
sensing approach, RI range, wavelength sensitivity, amplitude sensitivity
, and sensor resolution.
As clearly evident from the table, the proposed SPR PCF sensor shows better performance in
terms of amplitude sensitivity, wavelength sensiti
vity, and sensor resolution.
0
5
10
15
20
25
30
520 560 600 640 680
Loss (dB/cm)
Wavelength (nm)
Λ =1.90 µ m
Λ =2.00 µ m
Λ =2.10 µ m
Λ =2.20 µ m
(b)
(a)
0
5
10
15
20
25
520 560 600 640 680
)
m
c
/
B
d
(
s
s
o
L
Wavelength (nm)
d =0.5 Λ
d =0.6 Λ
d =0.7 Λ
Fig. 6 Loss spectrum of the proposed PCF biosensor for the variation of (a) air-hole dimension
and (b) pitch for n a ¼ 1 . 33 .
Table 1 Comparison among the properties of the proposed fiber with previously reported
sensors.
References
Structure type
Sensing
approach
RI range
Wavelength
sensitivity
(nm/RIU)
Amplitude
sensitivity
(RIU − 1
)
Resolution
(wavelength
inter.) RIU
6
Multichannel PCF
sensor
External metal
coating
1.33 to 1.34
2400 ——
7
Selectively ITO-coated
PCF sensor
Internal metal
coating
1.33 to 1.35
2000
80 5 × 10 − 5
8
D-shaped PCF sensor
Internal metal
coating
1.33 to 1.35
2520
44 3 . 97 × 10 − 5
13
Multihole PCF sensor
Internal metal
coating
1.33 to 1.35
2000
370 —
15 Silver-graphene-based
PCF sensor
Internal metal
coating
1.46 to 1.49
3000
418 3 . 33 × 10 − 5
20
Two-ring hexagonal
PCF sensor
External metal
coating
1.33 to 1.37
4000
320 2 . 5 × 10 − 5
21
Birefringent PCF
sensor
External metal
coating
1.33 to 1.35
2000
317 5 × 10 − 5
This work
Gold-coated PCF
sensor
External metal
coating
1.33 to 1.37
4000
478 2 . 5 × 10 − 5
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et
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Photonic
crystal
fiber-based
plasmonic
biosensor. . .
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At this stage, we would like to explore the fabrication feasibility of the proposed PCF-based
sensor. It is already known that hexagonal lattice PCF can be realized using the most versatile
stack-and-draw method. 36 , 37 As seen in Fig. 1(b) , the designed PCF has h exagonal lattice with
two air-hole rings. Therefore, the standard stack-and-draw method can be a viable way to realize
this PCF in practical form. It should be pointed out that the pitch size is 2 μ m , yielding a total
fiber diameter of around 10 μ m . The diameter of the conventional PCF is about 125 μ m . In this
case, the proposed PCF could be realized by either stacking
the extra solid-rod or two or three
times jacketing of the
outer layer. Regarding this designed structure, a solid sil
ica surface will be
formed in the outside of the cladding (similarly demonstrated in
Ref. 38 ), which can be polished
to realize the proposed PCF. Moreov
er, the proposed PCF can also be realized using a tapered
technique. 39 In practical sensing applicati ons, generally a white light source/supercont inuum
(SC) light source can be used in the visible range to illuminate light into a single
mode fiber
(SMF). 40 – 42 A splicing technique or free-space alignment can be used to connect the SMF with
the proposed PCF sensor. On the top of the gold surface [according to Fig. 1(b) ], a sample ana-
lyte channel can be
maintai
ned through a pump. The
effective RI of the SPP mode will be
changed because of the interaction of sample analyte with the ligand; thereby, either blue-
or redshift will occur. The optical spectrum analyzer (OSA) or photodetector can be used to
measure the transmittance light. The output of the OSA or photodetector
can be used for further
analysis in the computer.
4 Conclusion
In summary, we numerically investigated
a relati
vely simple and realistic PCF SPR biosensor
based on the SPR effect. Chemically stable gold is used as the plasmonic material as it offers
simultaneously a narrow resonance
spectrum and large wavelength shift. The proposed biosensor
shows a maximum wavelength sensitivity of 4000 nm ∕ RIU and a maximum amplitude sensi-
tivity of 478 RIU − 1 within the sensing range of 1.33 to 1.37. High sensor resolution of 2.5 ×
10 − 5 RIU and good linear fitting characteristics are obtained for the optimum design parameters.
Due to structural simplicity and excellent sensing proper
ties, the proposed PCF can be regarded
as a good biosensor.
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et
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Photonic
crystal
fiber-based
plasmonic
biosensor. . .
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Ahmmed A. Rifat is a PhD student at Australian National University, Canberra, Australia. He
received his MEngSc degree in electrical engineering from
the University of Malaya, Malaysia,
in January 2016. He also worked as a research assistant at the Integrated Lightwave Research
Group, University of Malaya, Kuala Lumpur, Malaysia. His research interests include surface
plasmon resonance, dielectric metasurfaces, photonic crystal
fiber, optical sensors, and optical
devices. He has published over 20 peer-reviewed journal articles.
Md. Rabiul Hasan received his MSc engineering degree in electrical and electronic engineering
from Rajshahi University of Engineering and Technology (RUET), Rajshahi, Bangladesh, in
2016. He received his BSc Eng degree in electronics and telecommunication engine
ering
(ETE) from RUET
, in 2012. Currently, he is working as an assistant professor in the ETE
Department, RUET
. His current research interests include photonic cryst
al fibers, terahertz
wave propagation, and surface plasmon resonance biosensor.
Rajib Ahmed is a PhD student at the School of Engineering, University of Birmingham, United
Kingdom. His research focuses on photonic devices based on nanostructures,
including laser-
based nanofabrication, carbon nanotubes (CNTs), waveguide, microring resonator, photonic
crystals, and graphene-based photonic devices modeling and implementation.
Haider Butt is a lecturer (assistant professor) at the Sc hool of Engineering, University of
Birmingham, United Kingdom.
Previously, he was a Henslow research fellow at the
University
of Cambridge, United Kingdom, from where he received his PhD in 2012. His research focuses
on photonic devices based on nanostructures such as CNT, graphene, and plasmonic nanostruc-
tures. He has published over 50 peer-reviewed journal articles and has secured se
veral presti-
gious research awards.
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Photonic
crystal
fiber-based plasmonic
biosensor. . .
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Citations (92) References (45)
... Optimum evanescent fields and desirable peak resonance are both easily derived from it [23]. It is kept in the note that PCF-based SPR sensor provides high sensor resolution [23, 24]
. ...
... The base material of the suggested sensor is fused silica, and its refractive index is varied by wavelength and some other constants. The Sellmeier's empirical equation is described as
[24,
25], Here, the constant terms used for fused silica are described as the Sellmeier's constants which are with respect to 0.69616, 0.407942, 0.897479, 0.0046914826 m 2 , 0.0135120631 m 2 and 97.9340025 ...
Novel Detection of Diesel Adulteration using Silver coated Surface Plasmon Resonance Sensor Preprint Full-text available
Apr 2021
Md. Asaduzzaman Jabin Md. Juwel Rana F.A. Al-Zahrani Francis M. Bui
In this study, we propose a silver-coated (SPR-surface plasmon resonance) based biosensor for the detection of diesel adulteration for the first time in the field of bio-sensing. Here, the numerical analysis is done by COMSOL Multiphysics V-5.1 and fully simulation software MATLAB-V16 on 30190 mesh elements, 2792 boundary elements, and 206593 degrees of freedom using finite element method (FEM) at 250C (298 K) for different concentration level. Moreover, the entire experiment on SPR-PCF is done for the major optical parameters for instance- Birefringence ( B i ), Coupling-length ( L c ), Power-fraction ( P f ), Confinement-loss ( α c ), Amplitudesensitivity ( S a ), Wavelength-sensitivity ( S w ), Resolution ( R l ), Transmittance ( T x ), Transmittance variance ( T v ), Relative-sensitivity ( S r ), Figure-of-merit (FOM) and Resonance ( R 2 ) etc which are respectively to their corresponding maximum performance profiles of 2.5 🞩 10 ⁻³ , 1300 μm, 99.93%, 1200 –1600 dB/cm , -7950 RIU -1 , 49941.169 nm/RIU , 6.319 🞩 10 ⁻⁴ RIU , -180 dB , 170 dB/RIU , 97.25%, 980, and 0.98312 at operating wavelength 0.5–2 μm. Therefore, it is noticed that the proposed sensor can be able to establish itself as one of the toughest candidates in fiber sensing. Also, diesel adulteration sensing including the entire working procedure using a SPR platform will be regarded as a novel procedure for diesel sensing in the history of photonics.
View Show abstract
... Typically, the resonance wavelength shifts towards a higher value as the RI increases. Wavelength sensitivity can be calculated using the wavelength interrogation method, which can be quantified using the following equation
[58]
: ...
Numerical Analysis of Highly Sensitive Twin-Core, Gold-Coated, D-Shaped Photonic Crystal Fiber Based on Surface Plasmon Resonance Sensor Article Full-text available
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Mohammad Faisal Md.Ranju Sardar
This research article proposes and numerically investigates a photonic crystal fiber (PCF) based on a surface plasmon resonance (SPR) sensor for the detecting refractive index (RI) of unknown analytes. The plasmonic material (gold) layer is placed outside of the PCF by removing two air holes from the main structure, and a D-shaped PCF-SPR sensor is formed. The purpose of using a plasmonic material (gold) layer in a PCF structure is to introduce an SPR phenomenon. The structure of the PCF is likely enclosed by the analyte to be detected, and an external sensing system is used to measure changes in the SPR signal. Moreover, a perfectly matched layer (PML) is also placed outside of the PCF to absorb unwanted light signals towards the surface. The numerical investigation of all guiding properties of the PCF-SPR sensor is completed using a fully vectorial-based finite element method (FEM) to achieve the finest sensing performance. The design of the PCF-SPR sensor is completed using COMSOL Multiphysics software, version 1.4.50. According to the simulation results, the proposed PCF-SPR sensor has a maximum wavelength sensitivity of 9000 nm/RIU, an amplitude sensitivity of 3746 RIU−1, a sensor resolution of 1 × 10−5 RIU, and a figure of merit (FOM) of 900 RIU−1 in the x-polarized direction light signal. The miniaturized structure and high sensitivity of the proposed PCF-SPR sensor make it a promising candidate for detecting RI of analytes ranging from 1.28 to 1.42.
View Show abstract
... The analyte is used to fill the air hole in the internal sensing or nanowire-based sensing, and a metal layer is coated around the core. Placing the plasmonic material externally is another approach to external sensing medium, such as microchannel sensors, slit sensors, and D-shape 14
. ...
Photonic Crystal Fiber Pollution Sensor Based on the Surface Plasmon Resonance Technology Article Full-text available
Apr 2023
Fatima Fadhil Abbas Soudad S. Ahmed
Photonic Crystal Fiber (PCF) based on the Surface Plasmon Resonance (SPR) effect has been proposed to detect polluted water samples. The sensing characteristics are illustrated using the finite element method. The right hole of the right side of PCF core has been coated with chemically stable gold material to achieve the practical sensing approach. The performance parameter of the proposed sensor is investigated in terms of wavelength sensitivity, amplitude sensitivity, sensor resolution, and linearity of the resonant wavelength with the variation of refractive index of analyte. In the sensing range of 1.33 to 1.3624, maximum sensitivities of 1360.2 nm ∕ RIU and 184 RIU−1 are achieved with the high sensor resolutions of 7 ×10-5 RIU and 5.4× 10−5 RIU using wavelength and amplitude interrogation methods, respectively. The proposed sensor could be established to detect various refractive index (RI) of pollutions in water.
View Show abstract
... In comparison to Conventional Optical Fibres (COFs), PCFs have larger refractive indices between the cladding and the core. Hence, the evanescent field can be easily controlled in PCFs
[3]
. PCFs have evolved over the years taking many shapes and sizes in terms of their cladding and core designs depending on the requirements. ...
HIGH-PERFORMANCE MICROSTRUCTURE CORE PHOTONIC CRYSTAL FIBRE-BASED BIOSENSOR FOR ALCOHOL DETECTION Article
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Ang Chuan Shi Abdul Mu’iz Maidi Nianyu Zou Feroza Begum
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Design and Characterization of Photonic Crystal Fiber Based Surface Plasmon Resonance Refractive Index Sensor Conference Paper
Dec 2022
Sayda Fahmida Kayser Md. Arif Uddin
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Modelling a simple arc shaped gold coated PCF-based SPR sensor
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Feb 2023
Melwin Gnanasekaran K. Senthilnathan
In this paper, we investigate a simple arc shaped Au coated photonic crystal fiber-based refractive index sensor that works on principle of surface plasmon resonance. We analyze the performance of the proposed sensor using the finite element method. Further, we analyze the effect of the arc shaped metal coating on different orientations of air holes in the cladding region. For the sensing range of 1.32–1.37, the proposed PCF sensor structure exhibits a maximum wavelength sensitivity of 14,100 nm/RIU with the resolution of 7.09 × 10–6 RIU. Also, this sensor exhibits a maximum amplitude sensitivity of 109 RIU−1 with a resolution of 9.17 × 10–6 RIU. Further, from the linearity of the proposed sensor, R2, is 0.96181 for the refractive index ranging between 1.32 and 1.37. Furthermore, we carry out perturbation analysis to ensure that the proposed sensor withstands the fabrication tolerance. Therefore, the proposed sensor holds good for a potential contender for sensing in chemical and biological applications.
View Show abstract
Design and analysis of highly sensitive solid core gold-coated hexagonal photonic crystal fiber sensor based on surface plasmon resonance Preprint Full-text available
Apr 2021
Monika Kiroriwal Poonam Singal
In this article, a surface plasmon-based hexagonal photonic crystal fiber sensor is numerically computed and studied. Metallic layer thickness and lattice period are optimized to 30 nm and 1.75 µm respectively to enhance the sensor performance. Sensor sensitivity is obtained by employing the finite element method by enclosing the structure with a perfectly matched layer. This studied sensor uncovers the wavelength sensitivity of 8000nm/RIU, amplitude sensitivity of 3959 /RIU, and minimum detection ability of 1.25x10 − 5 RIU for the analyte refractive index range from 1.36 to 1.40. The simulated results’ variations are also analyzed by altering the metallic layer thickness, lattice period, and air hole diameter. The computed PCF sensor might be a promising aspirant in the area of chemical sensing, bio-molecule detection, and biological sample recognition.
View Show abstract
Optical biosensors: a decade in review
Article
Mar 2023
Amit Kumar Singh Shweta Mittal
Mangal Das Manish Tiwari
Miniaturized, specific, rapid response and economical biosensors are finding applications in biotechnology, environmental studies, agriculture, food inspection and safety, disease diagnosis and medical utilities. Of the many categories of biosensors, optical biosensors have brought about an extra edge in sensing applications due to their selective, rapid and extremely sensitive measurements. Biosensors are analytical tools used to detect specific analytes such as cholesterol, urea, etc. having biomolecules such as nucleic acids, proteins, carbohydrates as key element for detecting these analytes along with a transducer and a data analysis and visualization tool. In case of optical biosensors the analyte is detected using light with either label based or label free techniques. In this paper some of the marked advances in the last decade in the field of optical biosensors have been reviewed with an emphasis on their fabrication approaches and growing application areas. Along with some of the carefully selected article on new developments in optical biosensors through the last decade, a brief historical review of optical biosensors since the breakthrough in optical biosensors in 1970s has also been presented. Another focus of the current review is the classification of biosensors, typical structures along with emerging developments in optical biosensing that are likely to impact the current decade. Major application areas and emerging applications through the last decade have been outlined to present a clear picture on the versatility of optical biosensors. Finally, the review also considers the challenges and future of emerging optical biosensing technologies in the current decade.
View Show abstract
Advances in Photonic Crystal Fiber-Based Sensor for Detection of Physical and Biochemical Parameters—A Review Article
Jan 2022 IEEE SENS J
Vijay Shanker Chaudhary Dr. Dharmendra Kumar Bramha P Pandey
Santosh Kumar
The promising properties of photonic crystal fibers (PCFs) have sparked the interest of a number of research organizations. Due to the PCF’s air holes, liquid or gas samples can be inserted into them. This permits a well-controlled interaction between confined light and sensing samples, enabling the development of novel sensing applications. That was never conceivable with conventional optical fiber. PCF applications in sensing fields can be divided into physical sensors and biochemical sensors based on the parameter being measured. Physical sensors measure pressure, temperature, refractive index (RI), curvature, vibration, torsion, electric field, and displacement, among other physical characteristics. Biochemical sensors can detect chemical and biological (such as antibody, cell, bacteria, enzyme, virus, nucleic acid, etc.) substances. The measurement of the chemical RI is a crucial component of biochemical sensors. Due to their close relationship with biosensors, chemical sensors are commonly referred to as biochemical sensors. This paper covers the detecting capabilities of SPR-based PCF biochemical and physical sensors in addition to a variety of ways to enhance their sensing capacities.
View Show abstract
Surface Plasmon Resonance Voltage SensorBased on Liquid Crystal-Infiltrated Hollow Fiber Article
Nov 2022
Md. Shofiqul Islam Md Aslam Mollah
Abdulhameed Fouad Alkhateeb Sami Alghamdi
We propose an electric field tunable nematic liquid crystal (NLC) infiltrated single-hole hollow fiber sensor for voltage measurement. Due to only an air hole, the proposed sensor got a straightforward structure, and the liquid-filling process will be uncomplicated. The addition of the gold wire successfully incorporated the surface plasmon resonance (SPR) phenomenon as a sensing methodology in the proposed sensor. Besides that, the use of metal wire instead of the metal film will reduce the complicacy associated with the acquisition of uniform film thickness. The sensor characterization and performance evaluation have been done using the finite element method (FEM) for a wide voltage range from 200V to 400V. The sensor exhibits wavelength sensitivity (WS) and linearity as high as 5 nm/V and 0.9935, respectively. In addition, maximum amplitude sensitivity (AS) and wavelength resolution ( R ) is attained of −353.46 RIU ⁻¹ and 0.02V, respectively. Due to its excellent performance with a wide sensing range, and a simple and compact structure, the proposed sensor can be used for voltage measurement in a sophisticated place.
View Show abstract
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A Highly Sensitive Gold-Coated Photonic Crystal Fiber Biosensor Based on Surface Plasmon Resonance Article Full-text available Mar 2017 Md Rabiul Hasan Sanjida Akter Rifat Ahmmed Aoni Sharafat Ali In this paper, we numerically demonstrate a two-layer circular lattice photonic crystal
fiber (PCF) biosensor based on the principle of surface plasmon resonance (SPR). The finite element
method (FEM) with circular perfectly matched layer (PML) boundary condition is applied to evaluate
the performance of the proposed sensor. A thin gold layer is deposited outside the PCF structure,
which acts as the plasmonic material for this design. The sensing layer (analyte) is implemented
in the outermost layer, which permits easy and more practical fabrication process compared to
analyte is put inside the air holes. It is demonstrated that, at gold layer thickness of 40 nm, the
proposed sensor shows maximum sensitivity of 2200 nm/RIU using the wavelength interrogation
method in the sensing range between 1.33–1.36. Besides, using an amplitude interrogation method, a
maximum sensitivity of 266 RIU−1 and a maximum sensor resolution of 3.75 × 10−5 RIU are obtained.
We also discuss how phase matching points are varied with different fiber parameters. Owing to high
sensitivity and simple design, the proposed sensor may find important applications in biochemical
and biological analyte detection. View Show abstract Highly Sensitive Surface Plasmon Resonance Based D-Shaped Photonic Crystal Fiber Refractive Index Sensor Article Full-text available Oct 2017 PLASMONICS Rahul Kumar Gangwar Vinod Kumar Singh In this article, a D-shaped photonic crystal fiber based surface plasmon resonance sensor is proposed for refractive index sensing. Surface plasmon resonance effect between surface plasmon polariton modes and fiber core modes of the designed D-shaped photonic crystal fiber is used to measure the refractive index of the analyte. By using finite element method, the sensing properties of the proposed sensor are investigated, and a very high average sensitivity of 7700 nm/RIU with the resolution of 1.30 × 10−5 RIU is obtained for the analyte of different refractive indices varies from 1.43 to 1.46. In the proposed sensor, the analyte and coating of gold are placed on the plane surface of the photonic crystal fiber, hence there is no necessity of the filling of voids, thus it is gentle to apply and easy to use. View Show abstract A simple photonic crystal fiber based plasmonic biosensor Conference Paper Full-text available Sep 2016 Rifat Ahmmed Aoni Rajib Ahmed A simple photonic crystal fiber based surface plasmon resonance sensor is proposed for refractive index sensing. Chemically stable novel material gold is used as a plasmonic material. Finite element method (FEM) is used to investigate the sensing performance. Proposed sensor shows the maximum wavelength and amplitude sensitivity of 4,000 nm/RIU and 478 RIU-1 , respectively. Simple sensor structure with promising results will pave the practical realization of proposed sensor which will find the potential application in biomolecules detection.
OCIS codes: (240.6680) Surface plasmons; (060.5295) Photonic crystal fibers; (280.4788) Optical sensing and sensors. View Show abstract Analysis of Graphene-Based Photonic Crystal Fiber Sensor Using Birefringence and Surface Plasmon Resonance Article Full-text available Apr 2017 PLASMONICS Xianchao Yang Ying Lu Baolin Liu J. Q. Yao We present and numerically characterize a photonic crystal fiber (PCF)-based surface plasmon resonance (SPR) sensor. By adjusting the air hole sizes of the PCF, the effective refractive index (RI) of core-guided mode can be tuned effectively and the sensor exhibits strong birefringence. Alternate holes coated with graphene-Ag bimetallic layers in the second layer are used as analyte channels, which can avoid adjacent interference and improve the signal to noise ratio (SNR). The graphene’s good features can not only solve the problem of silver oxidation but also increase the absorption of molecules. We theoretically analyze the influence of the air hole sizes of the PCF and the thicknesses of graphene layer and Ag layer on the performance of the designed sensor using wavelength and amplitude interrogations. The wavelength sensitivity we obtained is as high as 2520 nm/RIU with the resolution of 3.97 × 10−5 RIU, which can provide a reference for developing a high-sensitivity, real-time, fast-response, and distributed SPR sensor. View Show abstract Multichannel photonic crystal fiber surface plasmon resonance based sensor Article Full-text available Jan 2016 OPT QUANT ELECTRON Shaimaa Azzam M.F.O. Hameed Rania Eid A. Shehata S. S. Obayya A novel design of multichannel biosensor based on surface plasmon resonance photonic crystal fiber is proposed and analysed using full vectorial finite element method. The analyte detection can be performed using four modes, \({\text{H}}_{11}^{\text{x}}\), \({\text{H}}_{11}^{\text{y}}\), \({\text{H}}_{12}^{\text{x}}\), and \({\text{H}}_{12}^{\text{y}}\), which offers the possibility of multi-channel/multi-analyte sensing with high accuracy. The sensor geometrical parameters are studied to achieve high sensitivity for the four studied modes. The reported sensor has relatively high sensitivities up to 2200, 2400, 2200, and 2400 nm/RIU according to the \({\text{H}}_{11}^{\text{x}}\), \({\text{H}}_{11}^{\text{y}}\), \({\text{H}}_{12}^{\text{x}}\), and \({\text{H}}_{12}^{\text{y}}\) modes, respectively. Additionally, the structure of the suggested sensor is easy for fabrication with standard PCF fabrication technologies. View Show abstract Highly Sensitive D-Shaped Photonic Crystal Fiber Based Plasmonic Biosensor in Visible to Near-IR Article Mar 2017 IEEE SENS J Rifat Ahmmed Aoni Rajib Ahmed Ghafour Amouzad Mahdiraji F. R. Mahamd Adikan View Characteristics of D-shaped photonic crystal fiber surface plasmon resonance sensors with different side-polished lengths Article Feb 2017 Qingli Xie Yuzhi Chen Xuejin Li Xueming Hong Sensing characteristics of D-shaped photonic crystal fiber surface plasmon resonance sensors are investigated in this paper. The finite element method is used to study the influences of side-polished depths and sensing layer thicknesses on our sensors. The results show that the sensitivity increases with the increase of the sensing layer thickness but decreases a little with the increase of the side-polished depth in a certain range. The influences of the side-polished lengths on our sensors are studied experimentally. It is revealed that a short side-polished length is conducive to improving the performance of our sensors. The highest sensitivity of our sensors is obtained to be 7381.0 nm/RIU in the refractive index environment of 1.40-1.42, when the side-polished length is controlled at 10 mm. The novel D-shaped photonic crystal fiber surface plasmon resonance sensors will bring new vitality to the application of biochemistry. View Show abstract Plasmonic structure: Fiber grating formed by gold nanorods on a tapered fiber Article Dec 2016 Joshua O. Trevisanutto A. Linhananta Gautam Das The authors demonstrated the fabrication of a fiber Bragg grating-like plasmonic nanostructure on the surface of a tapered optical fiber using gold nanorods (GNRs). A multimode optical fiber with core and cladding diameters of 105 and 125 μm, respectively, was used to make a tapered fiber using a dynamic etching process. The tip diameter was ∼100 nm. Light from a laser was coupled to the untapered end of the fiber, which produced a strong evanescent field around the tapered section of the fiber. The gradient force due to the evanescent field trapped the GNRs on the surface of the tapered fiber. The authors explored possible causes of the GNR distribution. The plasmonic structure will be a good candidate for sensing based on surface enhanced Raman scattering. View Show abstract Photonic Crystal Fiber Based Plasmonic Sensors Article Nov 2016 SENSOR ACTUAT B-CHEM Rifat Ahmmed Aoni Rajib Ahmed Ali K. Yetisen F. R. Mahamd Adikan The development of highly-sensitive miniaturized sensors that allow real-time quantification of analytes is desirable for application in medical diagnostics, veterinary testing, food safety, and environmental monitoring. Photonic Crystal Fiber Surface Plasmon Resonance (PCF SPR) has emerged as a highly-sensitive portable sensing technology for testing chemical and biological analytes. PCF SPR sensing combines the advantages of PCF technology and plasmonics to accurately control the evanescent field and light propagation properties in single or multimode configurations. This review discusses fundamentals and fabrication of fiber optic technologies incorporating plasmonic coatings to rationally design, optimize and construct PCF SPR sensors as compared to conventional SPR sensing. It describes PCF SPR sensors with selective metal coatings of fibers, silver nanowires, slotted patterns, and D-shaped structures for internal and external microfluidic flows. This review also includes potential applications of PCF SPR sensors, identifies perceived limitations, challenges to scaling up, and provides future directions for their commercial realization. View Show abstract Numerical analysis of a photonic crystal fiber based on a surface plasmon resonance sensor with an annular analyte channel Article Jan 2017 OPT COMMUN Chao Liu Lin Yang Weiquan Su Paul K. Chu A sensing structure is designed with a photonic crystal fiber based on a surface plasmon resonance (PCF-SPR) sensor using gold as the sensitive material. The benefit of the structure is to reduce the difficulty in gold deposition, because the Au film is deposited on the outside of the fiber core instead of on the holes filled with analyte inside the core. The properties of the sensor are numerically calculated by the finite element method. The results show that the thickness of the gold film, refractive index of the analyte, and radius of the central hole affect the sensing performance of the PCF-SPR. By optimizing the model, an extra graphene layer with the thickness of 20 nm is deposited on the gold film in the model. The maximum spectral sensitivity can be as high as 7500 nm/RIU for the sensor with the gold-graphene composite film as the sensitive material. View Show abstract Show more
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Discover more about: Biosensors
Conference Paper
Side-core holey fiber based plasmonic sensor
October 2013
· Proceedings of SPIE - The International Society for Optical Engineering
Deming Liu Ya Han Li Xia
We proposed a closed-form all-in-fiber SCHF-SPR sensor. Using the dual-core directional microstructure for reference, we add a metal layer in the left core to directly enhance the overlapping area of the core mode and plasmonic mode. A theoretical analysis is carried out to simulate the resonant wavelength shift corresponding to RI. An average sensitivity of 2390.91nm/RIU in the RI range
... [Show full abstract]
1.33-1.43, and 9294.55nm/RIU in 1.44-1.54 with high linearity and sensitivity is achieved. This SCHF-SPR sensor has a good sensing performance on RI among the existing RI sensors.
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November 2012
· Optics Express
Binbin Shuai Li Xia Deming Liu
We present and numerically characterize a liquid-core photonic crystal fiber based plasmonic sensor. The coupling properties and sensing performance are investigated by the finite element method. It is found that not only the plasmonic mode dispersion relation but also the fundamental mode dispersion relation is rather sensitive to the analyte refractive index (RI). The positive and negative RI
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crystal fiber (PCF) is analyzed by the finite element method. The
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Article Full-text available
A High Refractive Index Plasmonic Sensor Based on D-Shaped Photonic Crystal Fiber With Laterally Acc...
October 2018
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Nannan Luan Lei Zhao Yudong Lian Shuqin Lou
A unique surface plasmon resonance (SPR) sensor based on photonic crystal fiber (PCF) is proposed in this paper, which consists of a D-shaped profile where a gold film is coated on its flat surface and a laterally accessible hollow core in which the analyte is infiltrated. The spectral sensitivity and the amplitude sensitivity of the proposed sensor are investigated by the finite element method ... [Show full abstract]
when it is completely and partly immersed into the analyte solution. Simulation results indicate that the proposed sensor can detect the refractive index of the analyte higher than that of the PCF background, and shows higher sensitivity when its core portion is immersed into the analyte. In this way, this sensor can provide the ability of anti-interference from the metal coating. The proposed sensor can be conveniently coated with metal films and provides a possibility for real time sensing, which are not possible with traditional PCF-based SPR sensors.
View full-text
Last Updated: 26 Mar 2023
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Plants | Free Full-Text | Root-Shoot Nutrient Dynamics of Huanglongbing-Affected Grapefruit Trees
With huanglongbing (HLB) causing a reduction in fine root mass early in disease progression, HLB-affected trees have lower nutrient uptake capability. Questions regarding the uptake efficiency of certain fertilizer application methods have been raised. Therefore, the goals of this study are to determine if nutrient management methods impact nutrient translocation and identify where in the tree nutrients are translocated. Destructive nutrient and biomass analysis were conducted on field grown HLB-affected grapefruit trees (Citrus × paradisi) grafted on ‘sour orange’ (Citrus × aurantium) rootstock under different fertilizer application methods. Fertilizer was applied in the form of either 100% soluble granular fertilizer, controlled release fertilizer (CRF), or liquid fertilizer. After three years, the entire tree was removed from the grove, dissected into eight different components (feeder roots, lateral roots, structural roots, trunk, primary branches, secondary branches, twigs, and leaves), weighed, and then analyzed for nutrient contents. Overall, application methods showed differences in nutrient allocation in leaf, twig, and feeder root; however, no consistent pattern was observed. Additionally, leaf, twig, and feeder roots had higher amount of nutrients compared to the other tree components. This study showed that fertilization methods do impact nutrient contents in different components of HLB-affected trees. Further research should be conducted on the impact of different fertilizer application methods and rates on HLB-affected trees.
Root-Shoot Nutrient Dynamics of Huanglongbing-Affected Grapefruit Trees
Indian River Research and Education Center, Horticultural Sciences Department, Institute of Food and Agricultural Sciences, University of Florida, Fort Pierce, FL 34945, USA
2
Citrus Research and Education Center, Soil, Water and Ecosystem Sciences Department, Institute of Food and Agricultural Sciences, University of Florida, Lake Alfred, FL 33850, USA
3
Indian River Research and Education Center, Soil, Water and Ecosystem Sciences Department, Institute of Food and Agricultural Sciences, University of Florida, Fort Pierce, FL 34945, USA
*
Author to whom correspondence should be addressed.
Plants 2022 , 11 (23), 3226; https://doi.org/10.3390/plants11233226
Received: 30 October 2022 / Revised: 16 November 2022 / Accepted: 24 November 2022 / Published: 24 November 2022
(This article belongs to the Special Issue Advances in Ecophysiology of Root Systems-Environment Interaction )
Abstract
With huanglongbing (HLB) causing a reduction in fine root mass early in disease progression, HLB-affected trees have lower nutrient uptake capability. Questions regarding the uptake efficiency of certain fertilizer application methods have been raised. Therefore, the goals of this study are to determine if nutrient management methods impact nutrient translocation and identify where in the tree nutrients are translocated. Destructive nutrient and biomass analysis were conducted on field grown HLB-affected grapefruit trees (
Citrus × paradisi
) grafted on ‘sour orange’ (
Citrus × aurantium
) rootstock under different fertilizer application methods. Fertilizer was applied in the form of either 100% soluble granular fertilizer, controlled release fertilizer (CRF), or liquid fertilizer. After three years, the entire tree was removed from the grove, dissected into eight different components (feeder roots, lateral roots, structural roots, trunk, primary branches, secondary branches, twigs, and leaves), weighed, and then analyzed for nutrient contents. Overall, application methods showed differences in nutrient allocation in leaf, twig, and feeder root; however, no consistent pattern was observed. Additionally, leaf, twig, and feeder roots had higher amount of nutrients compared to the other tree components. This study showed that fertilization methods do impact nutrient contents in different components of HLB-affected trees. Further research should be conducted on the impact of different fertilizer application methods and rates on HLB-affected trees.
Keywords:
citrus greening
;
Citrus paradisi
;
destructive analysis
;
nutrient translocation
;
fertilizer application methods
1. Introduction
Proper nutrient management is integral to increase both the operational profitability and environmental sustainability of Florida’s citrus industry. Citrus trees require 17 elements for optimum growth and production [ 1 ]; of which, nitrogen (N), phosphorus (P), potassium (K), magnesium (Mg), calcium (Ca), sulfur (S), iron (Fe), zinc (Zn), manganese (Mn), copper (Cu), and boron (B) are commonly supplied via inorganic fertilizers. If any essential element is deficient, tree growth, development, and yield is reduced [ 2 , 3 , 4 ]. Although fertilization is commonplace, supplying the optimum levels of nutrients can be challenging due to several factors such as edaphic conditions, environmental issues, and disease pressure [ 5 , 6 ].
Oftentimes sandy soils in citrus growing regions, such as those found in Florida, are low in natural fertility, resulting in required higher and more frequent fertilizer inputs [ 7 , 8 , 9 ]. This management method is not without risk since the over application of fertilizers can result in toxicity effects on the plants and nutrient leaching into groundwater [ 10 , 11 ].
Huanglongbing (HLB; Citrus greening) impacts nutrient uptake and translocation. This disease is caused by the phloem limited bacteria Candidatus Liberibacter asiaticus ( C Las) and vectored by the Asian citrus Psyllid Diaphorina citri ; moreover, it is commonly associated with root and canopy dieback, poor fruit yield and quality, and tree death [ 12 , 13 ]. Research has also shown that HLB alters nutrient contents within affected trees [ 14 , 15 ]. For example, a study by da Silva et al. [ 16 ] found that HLB-affected sweet orange ( Citrus × aurantium ) trees had lower levels of N, Mg, and S in leaves and sap extracts. Similarly, a study by Shahzad et al. [ 17 ] found that HLB-affected sweet orange trees had lower leaf Ca, Mg, and S compared to healthy trees.
The studies described above clearly demonstrate that HLB changes how nutrients are taken up by and translocated within affected trees. Although much research has been focused on how different nutrient rates impact HLB-affected tree health [ 18 , 19 , 20 , 21 ], there is a lack of understanding regarding where in the trees these nutrients are translocated. For example, a previous study conducted by [ 22 ] analyzed nutrient contents on different components of sweet orange trees, but this was done with non HLB-affected trees.
In addition to applying the correct rate of fertilizers, the method in which fertilizers are applied can be equally important. In the Florida citrus industry, both liquid and solid granular fertilizers are readily available and commonly used [ 23 ]. Granular fertilizers can be formulated as 100% soluble or controlled release fertilizers (CRF). The nutrients in CRF have polymer coatings which better control nutrient release timing and rate compared to 100% soluble granular fertilizers [ 24 , 25 ]. Liquid fertilization is also popular since it can be integrated into existing irrigation systems. This integration allows for more precise control over fertilizer rate, timing, and location. The use of liquid fertilization has been shown to reduce nutrient leaching, increase tree growth rates, and increase yield [ 23 , 26 ]. Very few studies exist that compare the use of 100% soluble granular fertilizers, CRF, and liquid fertilization on HLB-affected grapefruits ( Citrus × paradisi ) grown on flatwood soils; furthermore, none of the existing studies conducted a full tree destructive biomass and nutrient content analysis.
As HLB continues to hinder Florida’s citrus industry, it is necessary to create more accurate nutrient application guidelines to improve both HLB-affected tree health and profitability. Although nutrient application methods such as CRF and liquid treatments are likely to lead to higher nutrient uptake compared to 100% soluble granular fertilizers, there is a lack of published literature on nutrient dynamics in HLB-affected grapefruit. Therefore, the goal of this study was to determine if nutrient management methods impact nutrient translocation and to identify where nutrients are translocated within the tree.
2. Results
2.1. Macronutrient Concentration
Differences in leaf macronutrients were observed between application methods ( Figure 1 A). The CRF treatment led to 12.1% higher leaf N compared to the LW treatment, higher leaf Ca compared to both the L (27.5%) and LW (25.0%) treatment, and higher S compared to the L (18.25%) and LW (26.43%) treatments. Additionally, 23.8% higher leaf K was observed in the L treatment compared to the control.
Figure 1. Macronutrient concentration (%) in leaf ( A ), twig ( B ), secondary branch ( C ), and primary branch ( D ). Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Treatments were applied three times a year (control and CRF), biweekly (L), or weekly (LW), for three years. A one-way variance (ANOVA) with a Tukey’s honestly significant difference (HSD) test was used to determine significant differences between means. Lowercase letters (a, b, c) indicate statistically significant differences ( p ≤ 0.05). Data represents means ( n = 4) ± standard error.
In the twigs, the only difference observed was in Mg levels, where the L treatment led to 37.5% higher Mg compared to the control and 45.2% higher Mg compared to the CRF treatment ( Figure 1 B).
No differences were observed in macronutrient allocation between treatments in the secondary branches ( Figure 1 C); however, in the primary branches, K levels were 33.3% higher in the L treatment compared to the control treatment ( Figure 1 D). In the trunk, the L treatment had 29.0% higher N compared to the LW treatment.
In the structural roots, differences in N and Ca levels were observed between treatments (
Figure 2
B). The L treatment led to 20% more N compared to the LW treatment. However, the control resulted in 23.1% more Ca compared to the L treatment and 18.8% more Ca compared to the LW treatment. No differences in macronutrients were observed between any of the treatments in the lateral roots (
Figure 2
C). In the feeder roots, the only difference between macronutrient concentrations was observed in P (
Figure 2
D). The control led to 19.4% more P compared to the CRF and LW treatments and 34.5% more P compared to the L treatment.
Figure 2. Macronutrient concentration (%) in trunk ( A ), structural root ( B ), lateral root ( C ), and feeder root ( D ). Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Treatments were applied three times a year (control and CRF), biweekly (L), or weekly (LW), for three years. A one-way analysis of variance (ANOVA) with a Tukey’s honestly significant difference (HSD) test was used to determine significant differences between means. Lowercase letters (a, b) indicate statistically significant differences ( p ≤ 0.05). Data represents means ( n = 4) ± standard error.
2.2. Micronutrient Concentration
In the leaves, B was 50.7% higher in the CRF treatment compared to the L treatment and 42.2% higher compared to the LW treatment ( Figure 3 A). No differences in micronutrient concentrations were detected between treatments in the twigs ( Figure 3 B), secondary branches ( Figure 3 C), primary branches ( Figure 3 D), trunk ( Figure 4 A), structural roots ( Figure 4 B), or the lateral roots ( Figure 4 C). Like the leaves, B in the feeder roots was 19.8% and 22.2% higher in the CRF treatment compared to the control and LW treatment, respectively ( Figure 4 D).
Figure 3. Micronutrient concentration (ppm) in leaf ( A ), twig ( B ), secondary branch ( C ), and primary branch ( D ). Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Treatments were applied three times a year (control and CRF), biweekly (L), or weekly (LW), for three years. A one-way variance (ANOVA) with a Tukey’s honestly significant difference (HSD) test was used to determine significant differences between means. Lowercase letters (a, b) indicate statistically significant differences ( p ≤ 0.05). Data represents means ( n = 4) ± standard error.
Figure 4. Micronutrient concentration (ppm) in trunk ( A ), structural root ( B ), lateral root ( C ), and feeder root ( D ). Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Treatments were applied three times a year (control and CRF), biweekly (L), or weekly (LW), for three years. A one-way variance (ANOVA) with a Tukey’s honestly significant difference (HSD) test was used to determine significant differences between means. Lowercase letters (a, b) indicate statistically significant differences ( p ≤ 0.05). Data represents means ( n = 4) ± standard error.
2.3. Total Tree Nutrient Content and Biomass
No differences in individual tree component ( Figure 5 ) and total N, P, K, Mg, Ca, and S content were observed between any of the treatments ( Table 1 and Table 2 ). Additionally, no differences were observed in total plant N, P, K, Mg, Ca, and S between any of the treatments. Differences in macronutrient levels were observed between different plant components. The greatest amount of total N, P, K, Mg, Ca, and S tended to be found in the leaves, secondary branches, primary branches, and structural roots in all treatments ( Table 1 and Table 2 ).
Figure 5. Dry weight (kg) of each tree component. Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Treatments were applied three times a year (control and CRF), biweekly (L), or weekly (LW), for three years. Data represents means ( n = 4) ± standard error.
Table 1. Nitrogen (N), phosphorus (P), and potassium (K) contents per individual tree components and tree total. Six-year-old Huanglongbing -affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). A Kruskal–Wallis test was used in combination with a Tukey’s honestly significant difference (HSD) test to identify and test significant differences in total nutrients in individual tree components (differences signified by letters). Data represents means ( n = 4) ± standard error.
Table 2. Magnesium (Mg), calcium (Ca), and potassium (S) contents per individual components and tree total. Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). A Kruskal–Wallis test was used in combination with a Tukey’s honestly significant difference (HSD) test to identify and test significant differences in total nutrients in individual tree components (differences signified by letters). Data represents means ( n = 4) ± standard error.
Total B, Zn, Mn, and Fe contents per individual tree components were consistent across all treatments except for Mn in the lateral roots ( Table 3 ). The CRF trees had significantly more Mn in the lateral roots compared to the F treatment; however, no differences were observed in total tree micronutrients regardless of treatment ( Table 3 and Table 4 ).
Table 3. Boron (B), zinc (Zn), and manganese (Mn) contents per individual components and tree total. Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). A Kruskal–Wallis test was used in combination with a Tukey’s honestly significant difference (HSD)test to identify and test significant differences in total nutrients in individual tree components (differences signified by letters). A one-way analysis of variance (ANOVA) with a Tukey HSD test was used to determine significant differences between the means of between different fertilizer application methods (differences signified by *). Data represents means ( n = 4) ± standard error.
Table 4. Iron (Fe) and copper (Cu) contents per individual components and tree total. Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). A Kruskal–Wallis test was used in combination with a Tukey’s honestly significant difference (HSD) test to identify and test significant differences in total nutrients in individual tree components (differences signified by letters). Data represents means ( n = 4) ± standard error.
Differences were observed in total micronutrient contents between plant components. Twigs consistently contained the largest amounts of Zn (61–72% of total plant Zn), Mn (69–79% of total Mn), and Fe (67–71% of total Fe) compared to all other plant components ( Table 3 and Table 4 ). Additionally, the leaves contained between 24–39% of the total tree B in all treatments, making the leaves the greatest pool of B in the entire tree ( Table 3 ). Finally, no differences were observed in total tree dry weight between any treatments ( Table 5 ).
Table 5. Total mean dry weight (DW) per treatment. Six-year-old HLB-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Data represents means ± standard error.
3. Discussion
Overall, the application methods showed differences in uptake and translocation, particularly in the leaves and feeder roots. Regardless of the treatment, leaves and feeder roots contained higher concentrations of N and K compared to the other tree components sampled. The leaves also contained higher B concentration compared to any other organ. All other nutrient concentrations were consistent across components.
The CRF treatment had higher N, Ca, S, and B in the leaves compared to the other treatments, and these increases in leaf nutrient concentrations are consistent with the current literature. It is well established that CRF’s outperform conventional granular fertilizers in nutrient uptake and fruit production [ 27 , 28 , 29 ]. In HLB-affected sweet orange trees, [ 30 ] found that CRF formulations resulted in exceptionally high yields. Although no differences in biomass were reported between any of the treatments, the higher macronutrient concentrations in the leaves of the CRF treatment supports the increased effectiveness of CRF’s over conventional fertilizers. Research by [ 3 ] did show that a CRF led to higher plant biomass compared to fertigation and water soluble granular treatments; however, the study was conducted on 32-month-old sweet orange trees. The lack of differences observed in total biomass between treatments could be a result of the three-year time frame of this study. This may not have been long enough to detect changes due to fertilizer treatments.
The lower levels of N, Ca, S, and B found in the leaves of the LW treatment compared to the other treatments is important to note. The LW method was chosen as a treatment due to grower reports that supplying nutrients in smaller doses but at shorter intervals led to higher uptake [
31
]; however, this was not observed. Our results were consistent with those of [
32
,
33
] which found that increased fertilizer frequency led to no differences in growth parameters or leaf nutrient concentration of sweet orange trees. The lower uptake of leaf macronutrients in the LW treatment could be due to increased leaching compared to the other treatments. Liquid treatments can lead to a better response compared to granular fertilizers; however, if the grove experiences high rainfall and/or irrigation management is poor, leaching can occur [
34
]. Additionally, the trees used in the study were severely HLB- affected and had a depleted root system. Logically, a depleted root system will intercept less nutrients and thus the benefits of more frequent fertilization may not be realized.
Higher nutrient contents in the leaves and feeder roots were expected. This was similar to research conducted by [ 22 ], which showed that the leaves of 32-month old sweet orange trees had the highest content of total N compared to other tree components. Plants require large amounts of N due to its roles in amino acids, sugars, and proteins [ 7 , 35 ]. In citrus trees, large amounts of N are found in young tender tissues such as leaves [ 7 ]. Levels of K are often higher in the leaves due to its role in regulation of stomatal opening and closing [ 36 ]. Additionally, citrus fruits utilize large amount of K [ 3 ]. Although this study did not sample any fruits due to fruit drop before analysis, the higher contents of K observed in the leaves compared to other plant components could indicate that leaves are a reservoir for K export into fruit. Lastly, the higher levels of B in the leaves compared to other components are likely due to its role in photosynthesis and carbohydrate metabolism [ 37 ].
When considering the biomass of each component in relation to nutrient percentage, the leaves, twigs, and secondary branches contained most of the total macronutrients in the trees. Similar findings were reported by [
38
,
39
], which showed higher percentages of N in newer organs of citrus trees. The root system, particularly the feeder and lateral roots, contained the lowest macronutrient content. Although the feeder root nutrient samples tend to have higher levels of all nutrients compared to nutrient samples taken from the woody sections of the trees (trunk, branches, lateral and structural roots), the feeder root biomass is much lower compared to the other components. As a result, feeder roots often constitute the lowest amount of nutrients, particularly macronutrients, to the overall nutrient total of the trees.
No other investigators have conducted a destructive study coupled with nutrient analysis of field-grown HLB-affected grapefruit trees. Furthermore, the trees were sub sectioned into 8 different components: five above ground and three below ground components. This level of detail is challenging to obtain due to the inaccessibility of fruit bearing citrus trees that can be removed from the ground and dissected. This provides a greater amount of detailed data on the nutrient uptake and translocation inside the different components and the tree as a whole. Although the aforementioned peculiarities of our study represents strengths, some limitations also need to be acknowledged: (i) the lack of timepoints to compare different seasons and (ii) the method used to remove the trees from the field. Obtaining seasonal timepoints would have required much more resources and available trees to be excavated and dissected over time. This data would have allowed for better inferences regarding the impact of seasonality on nutrient dynamics in HLB-affected citrus trees. On the other hand, the method by which trees were extracted from the field allowed for a greater number of replications to be analyzed but may have resulted in a loss of fine roots. The utilization of a better and more gentle excavation method would have limited fine root loss at the expense of time and resources.
4. Materials and Methods
4.1. Site Description
A 3-year nutrition trial was conducted at the University of Florida, Institute of Food and Agricultural Sciences (UF/IFAS), Indian River Research and Education Center (IRREC) located in Fort Pierce, Florida, USA. Tree material consisted of 6-year-old field grown ‘Ruby Red’ grapefruit trees ( Citrus × paradisi ) grafted on ‘sour orange’ ( Citrus × aurantium ) rootstock ( Figure 6 ). All trees examined were HLB-affected, confirmed by both Ct values and visual analysis.
Figure 6. Satellite image of the area in which the study was conducted. The experimental grove from which the grapefruit trees were excavated is highlighted in red. The grapefruit grove is located at the University of Florida, Institute of Food and Agricultural Sciences (UF/IFAS), Indian River Research and Education Center (IRREC) located in Fort Pierce, Florida, USA. Image was acquired from Google Maps on 16 November 2022.
The trees were grown on 1-m-high raised beds for drainage purposes and irrigated with 39.7 L per hour microjet sprinklers (Maxijet, Dundee, FL, USA). The grove soils were sandy Alfisols classified as loamy, siliceous, active, hyperthermic Arenic Glossaqualfs with less than 1% organic matter. Soil pH was 5.8 and cation exchange capacity (C.E.C.) was 3.5 cmol kg −1 [ 40 ].
Treatments consisted of four different fertilizer application methods (Control, controlled release fertilizer (CRF), liquid (L) and liquid weekly (LW). The control treatment was an industry standard 100% soluble dry granular fertilizer applied three times throughout the growing season. The CRF treatment was a granular fertilizer with 50% solubility and contained polymer coated nutrients. Like the control treatment, the CRF treatment was applied three times throughout the growing season. The L and LW were both liquid treatments applied at a rate of 11.36 L per tree using a ~1100-L single axle admire mobile spray tank (Chemical Containers, Inc., Lake Wales, FL, USA). The L treatment was applied bi-weekly throughout the growing season while the LW treatment was applied weekly. The same yearly amount of nutrients were applied to all treatments regardless of application method. These amounts were calculated using the current UF/IFAS recommendations [
41
].
4.2. Tree Excavation and Dissection
Trees were excavated in September 2021 using a John Deere 7030 tractor and root rake implement. The base of the tree trunk was securely grasped by the rake and slowly lifted from the soil. During the lifting process, the trees were gently shaken to assist in removal of sand from the root mass. Once removed from the soil, the entire tree was moved to a covered location for dissection.
Each tree was divided into eight different components: leaf, twig, secondary branch, primary branch, trunk, structural root, lateral root, and feeder root (
Figure 7
). All leaves, including both immature and fully expanded leaves, were collected by hand. Twigs were defined as the woody portions connected to the leaves. Secondary branches were defined as those directly connected to the twigs but not directly connected to the main trunk. The primary branches were those that connected directly to the main trunk and supported the secondary branches. The main trunk was defined as the central woody structure connecting the root mass to the branches.
Figure 7. Schematic representation of a six-year-old grapefruit tree divided into eight different components: leaf, twig, secondary branch, primary branch, trunk, structural root, lateral root, and feeder root.
Roots were divided into structural, lateral, and feeder roots. The structural roots were directly connected to the trunk and ranged from 10 mm to 20 mm. Lateral roots connected the primary roots to the feeder roots and ranged from 2 mm to 10 mm. Feeder roots were defined as the non-woody roots less than 2 mm in diameter protruding from the lateral roots.
The different components were removed from one another using Felco 2 pruners (Les Geneveys-sur-Coffrane, Switzerland), Fiskars 28″ loppers (Helsinki, Finland), and a Ryobi 40V HP Brushless 14in. battery operated chainsaw (Fuchu, Hiroshima, Japan). Once the components were removed from the tree and separated from each other, the total weight of each component, as well as nutrient analysis, was conducted.
4.3. Tree Biomass and Mineral Analysis
The entire fresh weight of each component was collected and weighed using a digital field scale (Ohaus Corporation, Parsippany, NJ, USA). Subsamples were then collected from each component and weighed. The subsamples were then dried at 60 °C for 3 to 15 days depending on the component size. Once dried, the subsample dry weight was collected using an analytical scale (Sartorius AG, Göttingen, Germany). Dried subsamples were then ground to pass through 1.0 mm mesh screen and 5 mL of nitric acid (HNO 3 ) was added. Samples were then heated to 95 °C for 90 min and 4 mL of 30% Hydrogen Peroxide (H 2 O 2 ) was added. After 20 min of cooling, 50 mL of deionized water was added to each sample. Analysis of N, P, K, Mg, Ca, S, B, Zn, Mn, and Fe concentration was conducted using inductively coupled argon plasma emission (ICP-MS) spectrophotometer (Spectro Ciros CCD, Fitzburg, MA, USA) [ 42 ].
4.4. Experimental Design and Statistical Analysis
The experiment was organized into a completely randomized design with split plot arrangement. Each treatment was replicated 4 times and each replicant consisted of 10 trees. One tree from each replication was randomly selected to be excavated and dissected. A one-way Analysis of Variance (ANOVA) was used to determine significant differences between fertilizer treatments. When differences were detected ( p < 0.05), a Tukey’s honestly significant difference (HSD) test was conducted. A Kruskal–Wallis test was used in combination with a Tukey’s HSD test to identify and test significant differences in total nutrients in individual tree components. All statistical analyses were conducted using the software R with ‘agricolae’ package [ 43 ]. Figures were generated using the software Minitab 17 (Minitab, LCC, State College, PA, USA).
5. Conclusions
Although nutrient use has been extensively studied in citrus, the uptake and distribution of nutrients in field grown HLB-affected grapefruit trees is less understood. This was the first study to conduct destructive nutrient analysis on field grown HLB-affected grapefruit trees. The research above shows where in the trees nutrients are stored and how much of each given nutrient are present in the entire tree. Additionally, this study showed that fertilization methods do impact nutrient contents in different components of HLB-affected trees. With these results in mind, further research should be conducted on how foliar nutrient application methods impact nutrient allocation within HLB-affected trees. Future studies should include internal movements of nutrients and tree destructive analysis at multiple time points throughout the year to account for seasonal variations. These continued evaluations of nutrient uptake and allocation could improve the efficiency of nutrient management programs in the age of HLB.
Author Contributions
Conceptualization, L.R. and D.M.K.; methodology, D.M.K., L.R. and A.L.W.; statistical analysis, L.M.H.; resources, L.R. and D.M.K.; writing—original draft preparation, L.M.H.; writing—review and editing, L.M.H., D.M.K., J.-P.F., L.R. and A.L.W.; data visualization, L.R. and L.M.H.; supervision, L.R.; funding acquisition, L.R. and D.M.K. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by the Citrus Research and Development Foundation project #18-042C “Development of Root Nutrient and Fertilization Guidelines for Huanglongbing (HLB)-Affected Orange and Grapefruit”. This work was also supported by the U.S. Department of Agriculture National Institute of Food and Agriculture, Hatch project #FLA-IRC-005743.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Raw data will be available by requesting them via email to [email protected] .
Acknowledgments
The authors are grateful to Jacob Lang, Felix Palencia and Laura Muschweck for assistance in treatment application and data collection. Lastly, the authors would like to thank H. Thomas James, III and Randy G. Burton for their management of the UF/IFAS Indian River Research and Education Center experimental citrus grove.
Conflicts of Interest
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
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Figure 1. Macronutrient concentration (%) in leaf ( A ), twig ( B ), secondary branch ( C ), and primary branch ( D ). Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Treatments were applied three times a year (control and CRF), biweekly (L), or weekly (LW), for three years. A one-way variance (ANOVA) with a Tukey’s honestly significant difference (HSD) test was used to determine significant differences between means. Lowercase letters (a, b, c) indicate statistically significant differences ( p ≤ 0.05). Data represents means ( n = 4) ± standard error.
Figure 2. Macronutrient concentration (%) in trunk ( A ), structural root ( B ), lateral root ( C ), and feeder root ( D ). Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Treatments were applied three times a year (control and CRF), biweekly (L), or weekly (LW), for three years. A one-way analysis of variance (ANOVA) with a Tukey’s honestly significant difference (HSD) test was used to determine significant differences between means. Lowercase letters (a, b) indicate statistically significant differences ( p ≤ 0.05). Data represents means ( n = 4) ± standard error.
Figure 3. Micronutrient concentration (ppm) in leaf ( A ), twig ( B ), secondary branch ( C ), and primary branch ( D ). Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Treatments were applied three times a year (control and CRF), biweekly (L), or weekly (LW), for three years. A one-way variance (ANOVA) with a Tukey’s honestly significant difference (HSD) test was used to determine significant differences between means. Lowercase letters (a, b) indicate statistically significant differences ( p ≤ 0.05). Data represents means ( n = 4) ± standard error.
Figure 4. Micronutrient concentration (ppm) in trunk ( A ), structural root ( B ), lateral root ( C ), and feeder root ( D ). Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Treatments were applied three times a year (control and CRF), biweekly (L), or weekly (LW), for three years. A one-way variance (ANOVA) with a Tukey’s honestly significant difference (HSD) test was used to determine significant differences between means. Lowercase letters (a, b) indicate statistically significant differences ( p ≤ 0.05). Data represents means ( n = 4) ± standard error.
Figure 5. Dry weight (kg) of each tree component. Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). Treatments were applied three times a year (control and CRF), biweekly (L), or weekly (LW), for three years. Data represents means ( n = 4) ± standard error.
Figure 6. Satellite image of the area in which the study was conducted. The experimental grove from which the grapefruit trees were excavated is highlighted in red. The grapefruit grove is located at the University of Florida, Institute of Food and Agricultural Sciences (UF/IFAS), Indian River Research and Education Center (IRREC) located in Fort Pierce, Florida, USA. Image was acquired from Google Maps on 16 November 2022.
Figure 7. Schematic representation of a six-year-old grapefruit tree divided into eight different components: leaf, twig, secondary branch, primary branch, trunk, structural root, lateral root, and feeder root.
Table 1. Nitrogen (N), phosphorus (P), and potassium (K) contents per individual tree components and tree total. Six-year-old Huanglongbing -affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). A Kruskal–Wallis test was used in combination with a Tukey’s honestly significant difference (HSD) test to identify and test significant differences in total nutrients in individual tree components (differences signified by letters). Data represents means ( n = 4) ± standard error.
N g tree −1 Tree component Control CRF L LW Leaf 40.64 ± 7.14 abc 67.51 ± 14.9 a 66.42 ± 13.31 a 45.35 ± 10.88 abc Twig 26.81 ± 7.11 abcd 50.75 ± 15.27 abc 39.4 ± 4.89 ab 40.89 ± 13.86 abc Secondary Branch 46.67 ± 13.03 ab 59.59 ± 12.84 ab 51.57 ± 8.57 a 56.72 ± 7.17 a Primary Branch 47.43 ± 12.17 a 48.55 ± 9.36 abc 54.07 ± 8.53 a 48.38 ± 14.41 ab Trunk 12.34 ± 1.51 bcd 14.34 ± 2.16 bc 12.67 ± 1.33 bc 12.40 ± 1.99 bc Structural Root 38.31 ± 4.22 abc 46.38 ± 15.56 abc 50.68 ± 3.46 a 55.69 ± 6.78 a Lateral Root 10.68 ± 2.22 cd 11.30 ± 2.22 bc 10.50 ± 2.87 bc 12.40 ± 4.37 bc Feeder Root 2.15 ± 0.84 d 2.19 ± 0.76 c 2.88 ± 0.65 c 3.9 ± 0.24 c Total 225.07 ± 1.81 300.64 ± 5.55 288.22 ± 5.17 275.77 ± 4.60 P g tree −1 Tree component Control CRF L LW Leaf 2.6 ± 0.40 ab 4.00 ± 0.87 a 4.11 ± 0.97 a 3.0 ± 0.76 a Twig 1.34 ± 0.31 abc 2.78 ± 0.91 ab 2.2 ± 0.41 ab 1.98 ± 0.65 abc Secondary Branch 2.83 ± 0.68 ab 3.87 1.18 a 2.95 ± 0.58 ab 3.91 ± 0.31 a Primary Branch 3.14 ± 0.77 a 2.96 ± 0.62 ab 4.00 ± 1.09 a 2.94 ± 0.72 ab Trunk 0.93 ± 0.16 bc 0.91 ± 0.15 ab 0.98± 0.24 b 0.81± 0.11 bc Structural Root 1.64 ± 0.28 abc 1.90 ± 0.82 ab 1.88 ± 0.44 ab 2.02 ± 0.40 abc Lateral Root 0.46 ± 0.09 c 0.42 ± 0.10 b 0.45 ± 0.20 b 0.47 ± 0.13 c Feeder Root 0.2 ± 0.08 c 0.16 ± 0.05 b 0.18 ± 0.04 b 0.31 ± 0.03 c Total 13.19 ± 0.23 17.03 ± 1.50 16.78 ± 1.45 15.53 ± 3.38 K g tree −1 Tree component Control CRF L Leaf 16.33 ± 2.55 a 26.19 ± 5.58 a 33.91 ± 8.82 a Twig 7.59 ± 2.23 bcd 19.17 ± 6.31 abc 19.4 ± 4.48 abc Secondary Branch 13.88 ± 1.90 ab 21.04 ± 4.92 ab 18.96 ± 3.55 ab Primary Branch 13.64 ± 2.67 abc 22.52 ± 5.22 ab 23.63 ± 5.69 abc Trunk 5.52 ± 0.95 cd 5.83 ± 1.06 bc 6.18 ± 1.16 bc Structural Root 9.05 ± 1.16 abcd 10.04 ± 3.64 abc 13.36 ± 1.63 bc Lateral Root 3.29 ± 0.66 d 3.33 ± 0.70 bc 3.59 ± 1.22 bc Feeder Root 0.83 ± 0.32 d 0.78 ± 0.25 c 1.17 ± 0.29 c Total 70.17 ± 0.58 108.96 ± 3.93 120.25 ± 4.01
Table 2. Magnesium (Mg), calcium (Ca), and potassium (S) contents per individual components and tree total. Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). A Kruskal–Wallis test was used in combination with a Tukey’s honestly significant difference (HSD) test to identify and test significant differences in total nutrients in individual tree components (differences signified by letters). Data represents means ( n = 4) ± standard error.
Mg g tree −1 Tree component Control CRF L LW Leaf 3.09 ± 0.50 a 5.17 ± 1.22 a 4.98 ± 0.97 a 3.43 ± 0.78 a Twig 1.89 ± 0.59 abc 3.5 ± 0.91 abc 4.33 ± 0.68 a 3.59 ± 1.03 a Secondary Branch 2.97 ± 0.71 ab 5.19 ± 1.07 a 2.79 ± 0.44 a 3.93 ± 0.87 a Primary Branch 3.33 ± 0.60 a 3.66 ± 0.51 ab 3.65 ± 0.47 a 3.02 ± 0.67 ab Trunk 0.57 ± 0.22 c 0.82 ± 0.30 bc 0.67 ± 0.16 bc 0.49 ± 0.19 b Primary Root 0.90 ± 0.12 bc 1.10 ± 0.41 bc 1.19 ± 0.22 bc 1.24 ± 0.32 ab Secondary Root 0.27 ± 0.04 c 0.31 ± 0.06 c 0.31 ± 0.11 c 0.31 ± 0.07 b Feeder Root 0.22 ± 0.09 c 0.22 ± 0.07 c 0.23 ± 0.05 c 0.35 ± 0.03 b Total 13.268 ± 0.33 20.01 ± 1.96 18.17 ± 1.90 16.40 ± 1.67 Ca g tree −1 Tree component Control CRF L LW Leaf 49.71 ± 9.34 abc 83.65 ± 18.45 abc 63.39 ± 12.60 bc 47.77 ± 9.53 bcd Twig 36.42 ± 9.76 bc 71.09 ± 24.22 abcd 49.9 ± 7.06 bcd 54.23 ± 15.39 abcd Secondary Branch 85.05 ± 14.59 a 138.67 ± 23.22 a 87.72 ± 17.63 ab 118.75 ± 25.01 a Primary Branch 97.40 ± 19.79 a 103.83 ± 13.01 ab 122.57 ± 22.45 a 106.77 ± 23.41 ab Trunk 30.46 ± 3.73 bc 32.32 ± 5.41 bcd 27.63 ± 3.29 cd 27.69 ± 5.44 cd Structural Root 60.93 ± 4.34 ab 72.91 ± 24.80 abcd 62.56 ± 7.43 bc 85.98 ± 9.17 abc Lateral Root 16.99 ± 3.68 bc 18.38 ± 4.14 cd 15.64 ± 5.04 cd 21.44 ± 7.05 cd Feeder Root 3.54 ± 1.46 c 3.15 ± 1.06 d 3.34 ± 0.65 d 5.59 ± 0.61 d Total 380.53 ± 1.24 524.05 ± 8.08 432.79 ± 7.60 468.24 ± 7.57 S g tree −1 Tree component Control CRF L LW Leaf 4.78 ± 0.87 a 7.96 ± 1.90 ab 6.59 ± 1.39 ab 4.64 ± 1.01 ab Twig 4.92 ± 1.52 a 9.69 ± 2.31 a 7.42 ± 1.19 a 6.19 ± 1.72 a Secondary Branch 3.63 ± 0.89 ab 5.05 ± 1.09 abc 3.67 ± 0.57 bc 4.39 ± 0.76 abc Primary Branch 3.49 ± 0.87 ab 3.54 ± 0.44 bc 4.73 ± 1.02 ab 3.55 ± 1.05 abc Trunk 0.93 ± 0.13 b 1.03 ± 0.17 c 0.81 ± 0.09 c 0.82 ± 0.15 bc Structural Root 2.71 ± 0.27 ab 3.43 ± 1.19 bc 3.37 ± 0.34 bc 3.87 ± 0.63 abc Lateral Root 0.92 ± 0.16 b 1.07 ± 0.20 c 0.88 ± 0.27 c 1.03 ± 0.30 abc Feeder Root 0.22 ± 0.07 b 0.24 ± 0.08 c 0.27 ± 0.06 c 0.36 ± 0.04 c Total 21.63 ± 0.53 32.04 ± 2.50 27.78 ± 2.12 24.89 ± 1.63
Table 3. Boron (B), zinc (Zn), and manganese (Mn) contents per individual components and tree total. Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). A Kruskal–Wallis test was used in combination with a Tukey’s honestly significant difference (HSD)test to identify and test significant differences in total nutrients in individual tree components (differences signified by letters). A one-way analysis of variance (ANOVA) with a Tukey HSD test was used to determine significant differences between the means of between different fertilizer application methods (differences signified by *). Data represents means ( n = 4) ± standard error.
B mg kg −1 Tree component Control CRF L LW Leaf 99.77 ± 20.85 a 199.19 ± 58.39 a 115.65 ± 24.16 a 92.58 ± 20.11 a Twig 29.16 ± 9.14 bc 52.38 ± 17.25 b 35.68 ± 3.57 bcd 41.02 ± 12.78 abc Secondary Branch 52.70 ± 8.74 b 85.73 ± 18.14 b 61.16 ± 9.01 bc 74.04 ± 17.64 ab Primary Branch 55.58 ± 13.56 ab 77.05 ± 14.13 b 81.80 ± 14.40 ab 70.92 ± 26.73 abc Trunk 14.00 ± 2.14 bc 13.77 ± 2.40 b 10.28 ± 1.43 d 13.69 ± 2.10 bc Structural Root 40.42 ± 3.32 bc 56.37 ± 20.04 b 48.99 ± 5.16 bcd 66.23 ± 9.86 abc Lateral Root 13.67 ± 2.58 bc 15.54 ± 3.43 b 12.51 ± 3.65 cd 17.44 ± 5.42 bc Feeder Root 2.35 ± 0.82 c 3.09 ± 1.15 b 3.22 ± 0.73 d 4.43 ± 0.35 c Total 307.70 ± 1.77 503.17 ± 9.18 369.32 ± 6.85 380.40 ± 5.79 Zn mg kg −1 Tree component Control CRF L LW Leaf 62.45 ± 8.47 b 109.01 ± 29.73 b 93.43 ± 23.72 b 71.35 ± 20.47 b Twig 756.91 ± 254.33 a 1467.75 ± 403.15 a 815.33 ± 128.33 a 870.69 ± 342.09 a Secondary Branch 92.43 ± 15.89 b 142.7 6± 30 31 b 96.53 ± 13.51 b 127.33 12.56 b Primary Branch 113.91 ± 27.63 b 102.58 ± 11.14 b 169.62 ± 54.63 b 86.82 ± 24.17 b Trunk 37.67 ± 9.94 b 36.44 ± 17.89 b 15.70 ± 3.66 b 21.72 ± 6.13 b Structural Root 70.97 ± 9.83 b 127.51 ± 45.64 b 119.87 ± 14.28 b 131.17 ± 21.74 b Lateral Root 34.87 ±c4.05 b 49.10 ± 7.81 b 28.78 ± 6.13 b 43.17 ± 10.13 b Feeder Root 4.46 ± 1.39 b 5.05 ± 1.93 b 5.39 ± 1.13 b 7.08 ± 0.65 b Total 1173.31 ± 7.36 2040.23 ± 31.68 1344.69 ± 21.45 1359.36 ± 22.08 Mn mg kg −1 Tree component Control CRF L LW Leaf 73.07 ± 11.10 b 121.10 ± 34.10 b 104.64 ± 22.53 b 80.04 ± 19.03 b Twig 453.87 ± 157.22 a 931.26 ± 265.62 a 843.84 ± 157.15 a 686.03 ± 246.98 a Secondary Branch 32.95 ± 11.28 b 35.23 ± 4.32 b 32.16 ± 7.24 b 39.76 ± 3.60 b Primary Branch 38.26 ± 10.90 b 32.56 ± 1.24 b 79.98 ± 44.31 b 29.90 ± 9.83 b Trunk 27.62 ± 13.46 b 12.91 ± 6.97 b 4.82 ± 1.13 b 11.43 ± 2.36 b Structural Root 18.95 ± 5.85 b 23.25 ± 11.78 b 61.36 ± 36.51 b 23.47 ± 4.25 b Lateral Root * 9.60 ± 2.30 b 16.26 ± 3.50 b 4.67 ± 0.69 b 9.98 ± 1.15 b Feeder Root 1.26 ± 0.33 b 1.67 ± 0.66 b 1.75 ± 0.32 b 1.89 ± 0.17 b Total 655.63 ± 6.34 1174.27 ± 29.55 1133.25 ± 26.47 882.53 ± 24.53
Table 4. Iron (Fe) and copper (Cu) contents per individual components and tree total. Six-year-old Huanglongbing-affected ‘Ruby Red’ grapefruit trees grafted on sour orange rootstock were used. Treatments consisted of two liquid (L and LW) and two granular fertilizers (Control and controlled-release fertilizer (CRF)). A Kruskal–Wallis test was used in combination with a Tukey’s honestly significant difference (HSD) test to identify and test significant differences in total nutrients in individual tree components (differences signified by letters). Data represents means ( n = 4) ± standard error.
Fe mg kg −1 Tree component Control CRF L LW Leaf 144.04 ± 21.07 b 251.31 ± 59.80 b 215.68 ± 40.79 b 218.14 ± 73.26 b Twig 2060 ± 863.63 a 3305.2 ± 1182.37 a 2827.4 ± 507.11 a 2380.39 ± 818.77 a Secondary Branch 140.61 ± 22.13 b 197.23 ± 33.46 b 149.03 ± 28.58 b 170.09 ± 25.40 b Primary Branch 151.01 ± 28.07 b 204.10 ± 67.91 b 197.80 ± 35.09 b 137.59 ± 25.97 b Trunk 122.70 ± 29.65 b 98.34 ± 24.10 b 74.21 ± 10.74 b 87.74 ±17.99 b Structural Root 304.55 ± 77.35 b 473.65 ± 202.92 b 403.70 ± 57.21 b 342.15 ± 31.18 b Lateral Root 115.10 ± 24.12 b 123.89 ± 14.00 b 88.32 ± 18.88 b 104.99 ± 29.36 b Feeder Root 6.22 ± 2.07 b 7.34 ± 2.68 b 7.31 ± 1.53 b 11.49 ± 0.86 b Total 3044.27 ± 16.42 4661.09 ± 47.00 3963.51 ± 43.75 3452.63 ± 39.62 Cu mg kg −1 Tree component Control CRF L LW Leaf 551.08 ± 77.48 a 908.36 ± 310.29 a 880.74 ± 249.09 a 660.71 ± 194.10 ab Twig 260.7 ± 69.64 ab 425.37 ± 149.26 abc 377.82 ± 52.99 ab 377.4 ± 94.32 ab Secondary Branch 574.28 ± 109.89 a 1000.56 ± 127.06 a 653.89 ± 114.90 ab 859.96 ± 102.49 a Primary Branch 570.21 ± 131.41 a 663.72 ± 81.37 ab 1113.84 ± 346.38 a 790.24 ± 325.53 a Trunk 123.32 ± 41.76 b 86.529 ± 44.81 bc 25.97 ± 11.06 b 98.32 ± 62.54 b Structural Root 58.39 ± 32.95 b 42.88 ± 16.66 bc 35.77 ± 8.15 b 40.88 ± 3.62 b Lateral Root 9.49 ± 1.34 b 17.98 ± 4.28 c 9.83 ± 3.34 b 13.64 ± 3.90 b Feeder Root 22.64 ± 6.00 b 33.97 ± 14.97 c 35.89 ± 8.29 b 49.85 ± 7.69 b Total 2170.15 ± 198.15 3179.4 ± 1649.66 3133.80 ± 1735.76 2891.04 ± 1520.87
Treatment Total (DW) kg Control 18.61 ± 1.81 CRF 26.47 ± 4.88 L 18.45 ± 2.74 LW 20.98 ± 3.99
| https://www.mdpi.com/2223-7747/11/23/3226/html |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
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Type
Report
Themes
Assistive & Accessible Technology
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Vicki Austin,Dilisha Patel,Jamie Danemayer,Kate Mattick,Anna Landre,Marketa Smitova,Maryam Bandukda, Aoife Healy, Nachiappan Chockalingam,Diane Bell,Cathy Holloway
This report was prepared by Global Disability Innovation (GDI) Hub for the Disability Unit in the Cabinet Office His Majesty’s Government (HMG). The report presents findings from a Country Capacity Assessment (CCA) of AT access in England. Findings illustrate a complex state of AT in England. While delivery systems tend to provide quality products that have a strong, positive impact on people’s lives, processes are often slow and stressful for users and providers alike. Startlingly, there is also an AT access gap of 31% of disabled people not having the assistive products they need to flourish, thrive, or even participate in daily life.
The Cabinet Office; 2023
Abstract
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
The aim of this research was to undertake a Country Capacity Assessment (CCA) to inform a more integrated approach to Assistive Technology (AT) provision in England. The results aim to support policymakers in identifying actions to strengthen service delivery to better meet disabled people’s needs, improving outcomes for AT users and reducing inefficiencies in the current approach.
The research was undertaken from November 2022 to March 2023 and led by the Global Disability Innovation (GDI) Hub, which is the World Health Organization (WHO) Global Collaborating Centre on AT access, using WHO tools in the Assistive Technology Assessment (ATA) suite.
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Suggested Citation: Austin, V, Patel, D, Danemayer, J, Mattick, K, Landre, A, Smitova, M, Bandukda, M, Healy, A, Chockalingam, N, Bell D, and Holloway, C; Assistive Technology Changes Lives: an assessment of AT need and capacity in England; Cabinet Office, HMG; 2023
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
<here is a image a4b21d12b83a54d7-54e7ea9035f65c57>
Type
Workshop
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Sahan Bulathwela, María Pérez-Ortiz,Catherine Holloway, John Shawe-Taylor
This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies.
Workshop on Machine Learning for the Developing World (ML4D) at the Conference on Neural Information Processing Systems 2021; 2021
Abstract
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Artificial Intelligence (AI) in Education has been said to have the potential for building more personalised curricula, as well as democratising education worldwide and creating a Renaissance of new ways of teaching and learning. Millions of students are already starting to benefit from the use of these technologies, but millions more around the world are not. If this trend continues, the first delivery of AI in Education could be greater educational inequality, along with a global misallocation of educational resources motivated by the current technological determinism narrative. In this paper, we focus on speculating and posing questions around the future of AI in Education, with the aim of starting the pressing conversation that would set the right foundations for the new generation of education that is permeated by technology. This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies. Finally, we ask what would it take for this educational revolution to provide egalitarian and empowering access to education, beyond any political, cultural, language, geographical and learning ability barriers.
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
<here is a image bed0040d68070c54-de0c3a2c6262948d>
Type
Workshop
Themes
Assistive & Accessible Technology
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Tabish Ahmed, Sahan Bulathwela
The informational needs of people are highly contextual and can depend on many different factors such as their current knowledge state, interests and goals [1, 2, 3]. However, an effective information retrieval companion should minimise the human effort required in i) expressing a human information need and ii) navigating a lengthy result set. Using topical representations of the user history (e.g. [4]) can immensely help formulating zero shot queries and refining short user queries that enable proactive information retrieval (IR). While the world has digital textual information in abundance, it can often be noisy (e.g. extracted through Automatic Speech Recognition (ASR), PDF text extraction etc.), leading to state-of-the-art neural models being highly sensitive to the noise producing sub-optimal results [5]. This demands denoising steps to refine both query and document representation. In this paper, we argue that Wikipedia, an openly available encyclopedia, can be a humanly intuitive knowledge base [6] that has the potential to provide the world view many noisy information Retrieval systems need.
Published at the First Workshop on Proactive and Agent-Supported Information Retrieval at CIKM 2022; 2022
Abstract
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Extracting useful information from the user history to clearly understand informational needs is a crucial feature of a proactive information retrieval system. Regarding understanding information and relevance, Wikipedia can provide the background knowledge that an intelligent system needs. This work explores how exploiting the context of a query using Wikipedia concepts can improve proactive information retrieval on noisy text. We formulate two models that use entity linking to associate Wikipedia topics with the relevance model. Our experiments around a podcast segment retrieval task demonstrate that there is a clear signal of relevance in Wikipedia concepts while a ranking model can improve precision by incorporating them. We also find Wikifying the background context of a query can help disambiguate the meaning of the query, further helping proactive information retrieval.
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
<here is a image 03afd8993ddd7e2f-562efde35f46bbad>
Type
Article
Themes
Assistive & Accessible Technology
These tools help visually impaired scientists read data and journals
Alla Katsnelson
This article was featured in Nature and discusses tools that help visually impaired scientists read data and Journals. Innovation Manager, Daniel Hajas, was interviewed as part of this piece and highlights the need for an ecosystem approach, and access to data / visualisations for blind members of the research and science community.
Nature; 2023
These tools help visually impaired scientists read data and journals
<here is a image b2d78ba3ce8ab7a7-889d3f69e10c4bbe>
Type
Toolkit
Innovate Now Toolkit
As an entrepreneur, learning how to solve problems by creating and experimenting with different strategies is a core pillar of the entrepreneurial mindset you need to succeed. However, there’s rarely a single correct way to solve problems as an entrepreneur, so you need to learn how to create and compare different solutions.
The open entrepreneurship toolkit is a set of learning materials that can help you and your team do just that. Covering the domains of user, product, market and business development, the set of cards have been designed to be used by two or more group members to actively experiment with different solutions.
Innovate Now
<here is a image 9fb3548128563dfe-2feef8cecfbebcc4>
Type
Workshop
Themes
Assistive & Accessible Technology
Culture and Participation
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
Maryam Bandukda, Aneesha Singh,Catherine Holloway,Nadia Berthouze, Emeline Brulé, Ana Tajadura-Jiménez, Oussama Metatla, Ana Javornik, and Anja Thieme
The emerging possibilities of multisensory interactions provide an exciting space for disability and open up opportunities to explore new experiences for perceiving one's own body, it's interactions with the environment and also to explore the environment itself. In addition, dynamic aspects of living with disability, life transitions, including ageing, psychological distress, long-term conditions such as chronic pain and new conditions such as long-COVID further affect people's abilities. Interactions with this diversity of embodiments can be enriched, empowered and augmented through using multisensory and cross-sensory modalities to create more inclusive technologies and experiences. To explore this, in this workshop we will explore three related sub-domains: immersive multi-sensory experiences, embodied experiences, and disability interactions and design.
CHI EA '21: Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems
Abstract
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
The emerging possibilities of multisensory interactions provide an exciting space for disability and open up opportunities to explore new experiences for perceiving one's own body, it's interactions with the environment and also to explore the environment itself. In addition, dynamic aspects of living with disability, life transitions, including ageing, psychological distress, long-term conditions such as chronic pain and new conditions such as long-COVID further affect people's abilities. Interactions with this diversity of embodiments can be enriched, empowered and augmented through using multisensory and cross-sensory modalities to create more inclusive technologies and experiences. To explore this, in this workshop we will explore three related sub-domains: immersive multi-sensory experiences, embodied experiences, and disability interactions and design. The aim is to better understand how we can re-think the senses in technology design for disability interactions and the dynamic self, constructed through continuously changing sensing capabilities either because of changing ability or because of the empowering technology. This workshop will: (i) bring together HCI researchers from different areas, (ii) discuss tools, frameworks and methods, and (iii) form a multidisciplinary community to build synergies for further collaboration.
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
Maryam Bandukda, Aneesha Singh, Catherine Holloway, Nadia Berthouze, Emeline Brulé, Ana Tajadura-Jiménez, Oussama Metatla, Ana Javornik, and Anja Thieme. 2021. Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions. Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems. Association for Computing Machinery, New York, NY, USA, Article 118, 1–5. DOI:https://doi.org/10.1145/341176...
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
| https://www.disabilityinnovation.com/publications?subject=dementia+mobility&type=toolkit+report+article+workshop |
Zip code 46368 Indiana Demographics and census data 46405 and 46403
Zip code 46368 Indiana Demographics data with population from census for research with charts, graphs, and local map 46405 and 46403
ZIP code 46368 Population Charts
According to the most recent ZIP code 46368 Indiana demographics data available from the 2022 Census Bureau released in the American Community Survey in November of 2022,
Figure 1
ZIP code 46368 shows it has a Population 2021 of 39,599 which is the largest of all zip codes in the greater ZIP code 46368 region.
Figure 3
uses the ZIP code 46368 population data for a comparison of the population growth/population change estimates from the years 2010 to 2021 and
46368
Indiana depicts an increase of 908 (2%).
The total ZIP code 46368 Indiana greater area population percent change for all areas for the years from 2010 to 2021 is shown in
Figure 4
and for
46368
Looking at the ZIP code 46368 population density (measured as people per square mile) and providing comparisons to both the national and state average population density in
Figure 5
,
46368
Indiana depicts it has 1,511 people per square mile which is the second most of all the zip codes in the metro area. The next lower population density is
46405
about 8.4% smaller with population density of 1,393. The zip code with the highest population density in the area is
46402
which depicts a people per square mile of 1,604 (6.1% larger).
Figure 6
provides ZIP code 46368 demographics for the overall median age for all people in the region and
46368
depicts it has a Median Age of 37.1 which is less than most other zip codes in the metro area. The zip code with the highest overall median age of all people in the area is
46393
which depicts an age of 56.4 (52.0% larger). The ZIP code 46368 Indiana population data for median age broken out by gender for both men versus the median age of women is shown in
Figure 7
.
46368
Indiana depicts a median age of men only about 5.3% smaller as the median age of women.
The next demographic analysis (
Figure 8
Indiana has one of the largest proportions of people less than 20 years of age at 14.8% of the total and is ranked #3. Only #2
46393
(15.2%), and #1
46405
(16.4%) are larger.
Figure 9
illustrates the overall diversity breakdown for ZIP code 46368 population and ethnicity groups in the area. (note: Hispanic/Latino is broken out separately in the next diagram and also the group denoted as Native ethnicity includes Native American, and Hawaiian and Other Pacific Islander.)
46368
Indiana has one of the largest proportions of White population at 8.9% of the total and is ranked #3. Only #2
46403
(62.2%), and #1
46402
(88.3%) are larger.
Figure 10
shows the ZIP code 46368 Indiana Hispanic (including non Hispanic whites) population household ethnicity in the region and
46368
depicts it has a Hispanic or Latino of 19.8% which is the second most Hispanic Population of all the zip codes in the greater ZIP code 46368 region.
Figure 11
compares the ratio of the amount of men to the amount of women and depicts total male population about 6.1% smaller as the total female population.
ZIP code 46368 Marital Status and Families Charts
Figure 12
(18%), and #1
46403
(18%) are larger. Third, it has less than most other zip codes in the area in order of percent divorced at 6% of the total.
Figure 14
compares the average household size using the average number of people in a family for ZIP code 46368 households.
46368
depicts it has a Family Size of 3.2 which is in the mid range of other zip codes in the greater region. The zip code with the highest average family size in the area is
46402
which depicts an average family size of 3.7 (14.0% larger).
Figure 15
shows the overall ratio of ZIP code 46368 households for families to the total number of ZIP code 46368 households and that
46368
shows it has a Families of 67% which is the third most of all other zip codes in the metro area. The zip code with the highest percent of people who are in a family in the area is
46405
which depicts a families percent of 69% (only about 2.9% larger).
Looking at ZIP code 46368 households that are headed by a husband and wife as a percent of all families in
Figure 16
,
46368
shows it has a Married-couple family of 69% which is in the center range of other zip codes in the area. The zip code with the highest percent of people in a husband and wife family in the area is
46304
shows ZIP code 46368 demographics for the head of household for each place using a breakdown of married-couple, male-headed alone, and female-headed alone.
46368
Indiana has the percentage of households the second smallest in order of percent of families in husband and wife household of all the other zip codes in the surrounding region at 7.6% of the total.
ZIP code 46368 Mothers and Children Charts
The next section of charts provide a detailed look at mothers and baby births that occurred over the past 12 months.
Figure 18
shows the rate of women aged 15 to 50 years old who have given birth.
46368
depicts it has a Birth Rate of 3.8% which is less than most other zip codes in the greater region. The zip code with the highest percent of women who gave birth in the area is
46403
which depicts a birth rate of 13.8% (approximately 3.6 times bigger).
Figure 19
shows the breakdown of the mother's age for all baby births that occurred in the last 12 months and has the percentage of percent of births to mothers aged 15 to 19 less than most other zip codes in the local area at 20% of the total. Second, it has the largest proportion of percent of births to mothers aged 20 to 24 at 46% of the total and is ranked #1.
In
Figure 21
, the percentage of all births in the last 12 months to mothers that were unmarried is shown (unwed mothers.)
46368
shows it has a Unwed Births of 10% which is the second smallest when ranked by percent of unwed women who have given birth of all the other zip codes in the greater region. The zip code with the highest percent of unwed women who have given birth in the area is
46405
which indicates an unwed mother birth rate of 68% ( very much bigger).
The next chart,
Figure 22
, shows the percentage of unwed mothers who are also on public assistance.
46368
depicts it has a Unwed birth and on public assistance of 25.7% which is at the top of all other zip codes in the greater ZIP code 46368 region.
Unwed mothers who have given birth in the last 12 months are also shown broken down by age group in
Figure 24
.
46368
Indiana has the largest proportion of unwed mothers aged 15 to 19 at 100.0% of the total and is ranked #1.
Figure 26
shows unwed mothers in poverty (based on median household income definition) who have given birth in the last 12 months.
46368
Indiana has the largest proportion of unwed births and living between 100% and 199% of poverty level at 74.3% of the total and is ranked #1.
For all births to unwed mothers,
Figure 27
breaks down the education level of the mother by less than high school through college and post graduate attainment has the percentage of percent of unwed mothers with less than high school education in the center range of other zip codes in the greater region at 26% of the total. Second, it has the largest proportion of percent of unwed mothers who are a high school graduate or equivalent at 74% of the total and is ranked #1.
ZIP code 46368 Marital Status Charts
The next set of demographic data looks at the marital status for ZIP code 46368 households which is useful for internet research.
Figure 28
compares the total number of single people in each area.
46368
shows it has a Total Single People of 52% which is less than most other zip codes in the local area. The zip code with the highest percent of people who are single for any reason in the area is
46402
which shows a percent single of 78% (50.5% larger). Comparing percent of people who are single for any reason to the
United States
average of 50%, ZIP code 46368 is only about 2.9% larger. Also, in comparison with the state of
Indiana
, percent of people who are single for any reason of 50%, ZIP code 46368 is only about 3.6% larger.
Figure 30
compares the single people in each area broken down by never married, divorced, and widowed.
46368
Indiana has one of the largest proportions of percent never married at 13% of the total and is ranked #3. Only #2
46405
(18%), and #1
46403
(18%) are larger. Second, it has less than most other zip codes in the metropolitan area in terms of percent divorced at 6% of the total.
Figure 31
shows the demographics for the number of single men adults in each area broken out by never married, divorced and widowed.
46368
Indiana has the percentage of men who are divorced the second smallest in terms of percent of men who have never been married of all the other zip codes in the greater region at 3% of the total.
Figure 32
shows the number of single women adults in each area broken out by never married, divorced and widowed.
46368
Indiana has one of the largest proportions of women who have never been married at 16% of the total and is ranked #2. The only larger zip code being
46403
with 21%. Second, it has less than most other zip codes in the area as measured by women who are divorced at 8% of the total.
Figure 33
shows the ZIP code 46368 demographics for the ratio of the number of single men between the age of 18 and 65, in each area, broken down by age group for the ZIP code 46368 metro area.
46368
Indiana has one of the largest proportions of single men 18 to 24 at 16% of the total and is ranked #2. The only larger zip code being
46393
with 17%. Second, it has less than most other zip codes in the metro area when sorted by single men 45 to 49 at 19% of the total.
Figure 34
shows the ZIP code 46368 population data for the ratio of the number of single women between the age of 18 and 65, in each area, broken down by age group for the ZIP code 46368 metro area.
46368
Indiana has the percentage of single women 18 to 24 in the center range of other zip codes in the metro area at 12% of the total. Second, it has one of the largest proportions of single women 25 to 29 at 11% of the total and is ranked #2. The only larger zip code being
46403
with 11%. Third, it has one of the largest proportions of single women 30 to 34 at 11% of the total and is ranked #3. Only #2
46342
(13%), and #1
46402
(14%) are larger. Also, it has one of the largest proportions of single women 40 to 44 at 10% of the total and is ranked #2. The only larger zip code being
46403
with 11%.
ZIP code 46368 Citizenship Demographics Charts
In
Figure 37
, the demographic percentage of ZIP code 46368 residents who were not born in the United States is shown (i.e. percent foreign born.)
46368
depicts it has a Percent Foreign Born of 3.8% which is the third most of all other zip codes in the metro area. The zip code with the highest percent of population who was born in another country in the area is
46405
which shows a percent born outside United States of 5.2% (36.1% larger). Comparing percent of population who was born in another country to the
United States
average of 13.6%, ZIP code 46368 is approximately a third the size. Also, measured against the state of
Indiana
, percent of population who was born in another country of 5.4%, ZIP code 46368 is approximately three-fourths the size.
Figure 39
provides a detailed analysis of non citizens by breaking them into two age groups: Under 18 and over the age of 18.
46368
Indiana shows a percent of non citizens under 18 years old only about 4.5% the size as the percent of non citizens over 18 years old.
Figure 40
provides further information for non citizen age by showing a comparison of the median age for all non citizens immigrants. it has a Non Citizen Median Age of 44.2 which is the second most median age of non citizens of all the zip codes in the greater ZIP code 46368 region. The zip code with the highest median age of non citizens in the area is
46342
which shows a median age of 44.5 ( about the same size). The next diagram (
Figure 41
) shows the year of entry that non citizens entered the United States. The year of entry can show the rate of flow at various points of time in the past for when they entered the U.S. it has the largest proportion of non citizens who entered the US between 2000 to 2009 at 46% of the total and is ranked #1. Second, it has in the mid range of other zip codes in the area as measured by non citizens who entered the US before 1990 at 4% of the total.
For all foreign born people who have gone through naturalization (the process of becoming a legal U.S. resident citizen),
Figure 42
shows the year when they became fully naturalized U.S. citizens. has the percentage of people naturalized 2015 or later less than most other zip codes in the greater region at 3% of the total. Second, it has the largest proportion of people naturalized 2010 to 2014 at 14% of the total and is ranked #1. Third, it has less than most other zip codes in the local area in order of people naturalized 2005 to 2009 at 11% of the total. Also, it has the largest proportion of people naturalized 2000 to 2004 at 9% of the total and is ranked #1. In addition, it has one of the largest proportions of people naturalized 1990 to 1994 at 18% of the total and is ranked #2. The only larger zip code being
46403
with 30%. Furthermore, it has one of the largest proportions of people naturalized before 1990 at 43% of the total and is ranked #2. The only larger zip code being
46402
with 83%.
ZIP code 46368 Birthplace Demographic Charts
Figure 43
displays a map of the globe and shows ZIP code 46368 demographic information for large regions of the world that people from this place originally came from.
46368
Indiana has one of the largest proportions of from Asia at 20% of the total and is ranked #2. The only larger zip code being
46304
with 39%. Second, it has one of the largest proportions of from Africa at 4% of the total and is ranked #3. Only #2
46402
(25%), and #1
46403
(48%) are larger. Third, it has one of the largest proportions of from the Americas at 56% of the total and is ranked #3. Only #2
46402
(75%), and #1
46405
(79%) are larger.
Figure 44
categorizes the location for where foreign born people originally come from based on very large continental geographic areas.
46368
Indiana has one of the largest proportions of from Asia at 4% of the total and is ranked #3. Only #2
46402
(25%), and #1
46403
(48%) are larger. Second, it has one of the largest proportions of from Oceania at 56% of the total and is ranked #3. Only #2
46402
(75%), and #1
46405
(79%) are larger.
Figure 45
is a table that breaks out all the people who were foreign born by which large geographic region where they were born.
46368
Indiana has the largest proportion of people who were born in South Central Asia at 11.0% of the total and is ranked #1.
Zip code 46368, Indiana Demographics Data
Demographics
Population
Marital Status and Families
Mothers and Children
Marital Status
Citizenship Demographics
Birthplace Demographic
Housing
Economy
Education
Healthcare
Figure 1: 46368, IN and Area 2021 Population Data Figure 2: Map of 46368, IN and Area 0 20,000 40,000 46393 46402 46403 46405 46304 46342 46368 Place Population 2021 46393 217 46402 6,105 46403 11,337 46405 12,101 46304 26,476 46342 31,707 46368 39,599 ...
Figure 3: 46368, IN Population Change 2010 to 2021 Figure 4: 46368, IN 2010 to 2021 Population Percent Change Population… Population… 46368 0 10,000 20,000 30,000 40,000 Place Population 2010 Population 2021 46368 38,691 39,599 Population 2021… -50% 0% 50% 46393 46403 46402 46342 46368 46405 46304 Place Population Change 46393 -45.6% 46403 -10% 46402 -9.2% 46342 1.5% 46368 2.3% 46405 3% 46304 9.4% ...
Figure 5: 46368, IN Population Density Figure 6: Median Age in 46368, IN 0 1,000 2,000 United States 46393 Indiana South Bend-Elkhart- Mishawaka 46304 46342 46403 46405 46368 46402 Place Population Density United States 93 46393 145 Indiana 188 South Bend-Elkhart-Mishawaka 335 46304 493 46342 900 46403 1,370 46405 1,393 46368 1,511 46402 1,604 Mishawaka 20 40 60 46402 46405 46368 Indiana United States South Bend-Elkhart- Mishawaka 46304 46342 46403 46393 Place Median Age 46402 33.4 46405 36.3 46368 37.1 Indiana 37.9 United States 38.4 South Bend-Elkhart-Mishawaka 38.5 46304 39.2 46342 39.8 46403 42.8 46393 56.4 Mishawaka
Figure 7: Median Age by Gender in 46368, IN Male Age Female Age 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart-Mis… 30 40 50 60 Place Male Age Female Age 46368 36.1 38 46405 38 32.7 46403 41.1 43.1 46393 56 59.6 46342 38.3 41.1 46304 38.9 39.4 46402 31.7 36 United States 37.3 39.5 Indiana 36.8 38.9 South Bend-Elkhart-Mishawaka 37.4 39.5 Female Age
Figure 8: 46368, IN and Area Age by Generation <20 20s 30s 40s 50s 60s 70+ 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart-Mis… 0% 50% 100% Place <20 20s 30s 40s 50s 60s 70+ 46368 25% 14.8% 14.2% 11.1% 13.5% 12.6% 8.8% 46405 25.7% 16.4% 12.5% 9.5% 14.8% 14.4% 6.8% 46403 25.7% 10% 11.1% 13.1% 13.5% 14.8% 11.8% 46393 0% 15.2% 8.8% 7.4% 31.3% 30% 7.4% 46342 23.5% 11.6% 15.2% 13.3% 12.6% 13.8% 10% 46304 24.3% 11.2% 15.8% 12.3% 13.2% 12.8% 10.4% 46402 34.8% 12.4% 10.9% 8.2% 10.5% 12.2% 11% United States 25.2% 13.5% 13.5% 12.5% 13% 11.7% 10.7% Indiana 26.4% 13.5% 12.8% 12.2% 12.9% 11.7% 10.3% South Bend-Elkhart-Mishawaka 27.1% 13% 11.9% 11.9% 12.6% 12.4% 11.1% 70+
Figure 9: 46368, IN and Area Ethnicity Makeup White Black or African American Asian Native Other Race 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart-Mis… 0% 50% 100% Place White Black or African American Asian Native Other Race 46368 80.9% 8.9% 1.3% 0.2% 8.7% 46405 73.1% 5% 0.3% 0.4% 21.2% 46403 27.3% 62.2% 0.1% 0.1% 10.3% 46393 94.5% 0% 0% 5.5% 0% 46342 80.9% 7.4% 1.2% 0.2% 10.2% 46304 90.2% 1.9% 1.8% 0% 6.1% 46402 4.9% 88.3% 1% 0.1% 5.7% United States 68.2% 12.6% 5.7% 1% 12.6% Indiana 81.2% 9.4% 2.4% 0.2% 6.7% South Bend-Elkhart-Mishawaka 81% 8.7% 1.6% 0.4% 8.3% Other Race
Figure 10: 46368, IN Hispanic Population Figure 11: Male vs. Female Population 0% 20% 40% 46402 Indiana 46304 South Bend-Elkhart- Mishawaka 46403 46342 United States 46368 46405 Place Hispanic or Latino 46402 3.5% Indiana 7.3% 46304 8.7% South Bend-Elkhart-Mishawaka 10.1% 46403 11.7% 46342 17.7% United States 18.4% 46368 19.8% 46405 28% Mishawaka 0% 50% 100% 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart- Mishawaka Place Male Ratio Female Ratio 46368 48.5% 51.5% 46405 50.5% 49.5% 46403 49.1% 50.9% 46393 60.4% 39.6% 46342 48.2% 51.8% 46304 50% 50% 46402 46.8% 53.2% United States 49.5% 50.5% Indiana 49.5% 50.5% South Bend-Elkhart-Mishawaka 49.5% 50.5% Mishawaka
Figure 12: 46368, IN Marriage Status Figure 13: Advertisement 0% 50% 100% 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart- Mishawaka Place Total Married Never Married Divorced Widowed 46368 48% 33% 13% 6% 46405 36% 41% 18% 5% 46403 36% 40% 18% 7% 46393 46% 42% 0% 12% 46342 50% 31% 12% 8% 46304 54% 29% 12% 5% 46402 22% 54% 12% 11% United States 50% 34% 11% 6% Indiana 50% 32% 12% 6% South Bend-Elkhart-Mishawaka 51% 32% 12% 6% Mishawaka
Figure 14: 46368, IN Average Family Size in Household Figure 15: Families as % of All Households 2 3 4 46393 46304 46403 Indiana 46368 46342 South Bend-Elkhart- Mishawaka United States 46405 46402 Place Family Size 46393 2.5 46304 3 46403 3.1 Indiana 3.2 46368 3.2 46342 3.3 South Bend-Elkhart-Mishawaka 3.3 United States 3.3 46405 3.5 46402 3.7 Mishawaka 50% 60% 70% 46402 46403 46393 46342 Indiana United States South Bend-Elkhart- Mishawaka 46368 46304 46405 Place Families 46402 54% 46403 57% 46393 61% 46342 63% Indiana 64% United States 65% South Bend-Elkhart-Mishawaka 65% 46368 67% 46304 67% 46405 69% Mishawaka
Figure 16: Married Couples as Percent of All Families Figure 17: 46368, IN Head of Household 0% 50% 100% 46402 46405 46403 46368 46342 46393 United States South Bend-Elkhart- Mishawaka Indiana 46304 Place Married-couple family 46402 26% 46405 52% 46403 52% 46368 69% 46342 72% 46393 73% United States 74% South Bend-Elkhart-Mishawaka 74% Indiana 75% 46304 79% Mishawaka 0% 50% 100% 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart- Mishawaka Place Married-couple family Male Head Alone Female Head Alone 46368 68.8% 7.6% 23.6% 46405 51.7% 18.6% 29.8% 46403 52.1% 16.3% 31.6% 46393 72.9% 27.1% 0% 46342 71.8% 11% 17.2% 46304 78.9% 5.1% 16% 46402 25.5% 15.6% 58.9% United States 73.5% 7.6% 18.9% Indiana 74.5% 7.7% 17.8% South Bend-Elkhart-Mishawaka 74.3% 7.3% 18.4% Mishawaka
Figure 18: 46368, IN Birth Rate (Last 12 months) Figure 19: All Births Age of Mother 0% 10% 20% 46342 46368 46304 46402 United States Indiana South Bend-Elkhart- Mishawaka 46405 46403 Place Birth Rate 46342 3.4% 46368 3.8% 46304 4.6% 46402 4.8% United States 5.1% Indiana 5.3% South Bend-Elkhart-Mishawaka 5.4% 46405 5.5% 46403 13.8% Mishawaka Aged 25 to 29 Aged 30 to 34 Aged 20 to 24 Aged 35 to 39 45.7% 19.9% 29.9% Place 46368 Aged 25 to 29 0.457 Aged 30 to 34 0.299 Aged 20 to 24 0.199 Aged 35 to 39 0.044 Aged 35 to 39
Figure 20: 46368, IN Teenager Birth Rate Figure 21: 46368, IN Unwed Mothers as % of All Births 0% 50% 100% United States Indiana South Bend-Elkhart- Mishawaka 46405 46402 46403 Place Teenager Birth Rate United States 3% Indiana 3% South Bend-Elkhart-Mishawaka 4% 46405 6% 46402 8% 46403 42% Mishawaka 0% 50% 100% 46368 United States 46403 Indiana South Bend-Elkhart- Mishawaka 46304 46342 46402 46405 Place Unwed Births 46368 10% United States 32% 46403 34% Indiana 36% South Bend-Elkhart-Mishawaka 38% 46304 66% 46342 67% 46402 67% 46405 68% Mishawaka
Figure 22: 46368, IN Unwed and On Public Assitance Figure 23: Advertisement 0% 20% 40% Indiana South Bend-Elkhart- Mishawaka United States 46402 46368 Place Unwed birth and on public assistance Indiana 5.3% South Bend-Elkhart-Mishawaka 7.1% United States 8.5% 46402 14.3% 46368 25.7% Mishawaka
Figure 24: 46368, IN Unwed Mother Births By Age Group Unwed Births-15 to 19 year olds Unwed Births-20 to 34 year olds Unwed Births-35 to 50 year olds 46368 46405 46403 46342 46304 46402 United States Indiana South Bend-Elkhart-Mis… 0% 50% 100% Place Unwed Births-15 to 19 year olds Unwed Births-20 to 34 year olds Unwed Births-35 to 50 year olds 46368 0% 100% 0% 46405 8.7% 91.3% 0% 46403 0% 100% 0% 46342 0% 100% 0% 46304 0% 100% 0% 46402 11.9% 73.8% 14.3% United States 7.3% 76.8% 16% Indiana 7.3% 81.9% 10.8% South Bend-Elkhart-Mishawaka 9.4% 81.3% 9.3% Unwed Births-35 to 50 year olds
Figure 25: 46368, IN Unwed Mother Birth Rate By Race White unwed birth rate Black unwed birth rate Hispanic unwed birth rate Asian unwed birth rate Native Hawaiian unwed birth rate American Indian unwed birth rate 46368 0% 5% 10% 15% Place White unwed birth rate Black unwed birth rate Hispanic unwed birth rate Asian unwed birth rate Native Hawaiian unwed birth rate American Indian unwed birth rate 46368 11% 0% 0% 0% 0% 0% American Indian unwed birth rate
Figure 26: 46368, IN Unwed Mother Births By Poverty Level Figure 27: Unwed Births and Education Level 0% 50% 100% 46368 46405 46403 46342 46304 46402 United States Indiana South Bend-Elkhart- Mishawaka Place Unwed Births-Below poverty level Unwed Births-100 to 199% of poverty level Unwed Births-200% or more of poverty level 46368 25.7% 0% 74.3% 46405 34.6% 29.8% 35.6% 46403 55.4% 44.6% 0% 46342 56.1% 43.9% 0% 46304 91.8% 5.6% 2.6% 46402 100% 0% 0% United States 43.2% 24.5% 32.2% Indiana 48% 24.5% 27.5% South Bend-Elkhart-Mishawaka 49.4% 21% 29.6% Mishawaka Some college or associates degree High school graduate or equivalent 25.7% 74.3% Place 46368 Some college or associates degree 0.743 High school graduate or equivalent 0.257 equivalent
Figure 28: Total Single People Figure 29: Advertisement 0% 50% 100% 46304 South Bend-Elkhart- Mishawaka Indiana United States 46342 46368 46393 46405 46403 46402 Place Total Single People 46304 46% South Bend-Elkhart-Mishawaka 50% Indiana 50% United States 50% 46342 50% 46368 52% 46393 54% 46405 64% 46403 65% 46402 78% Mishawaka
Figure 30: 46368, IN Single People Broken Down By Reason Never Married Divorced Widowed 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart-Mis… 0% 50% 100% Place Never Married Divorced Widowed 46368 33% 13% 6% 46405 41% 18% 5% 46403 40% 18% 7% 46393 42% 0% 12% 46342 31% 12% 8% 46304 29% 12% 5% 46402 54% 12% 11% United States 34% 11% 6% Indiana 32% 12% 6% South Bend-Elkhart-Mishawaka 32% 12% 6% Widowed
Figure 31: 46368, IN Single Men in Area Figure 32: 46368, IN Single Women in Area 0% 50% 100% 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart- Mishawaka Place Men-Never Married Men-Divorced Men-Widowed 46368 38% 10% 3% 46405 44% 20% 2% 46403 43% 14% 5% 46393 54% 0% 5% 46342 37% 11% 4% 46304 30% 11% 3% 46402 58% 13% 7% United States 37% 10% 3% Indiana 35% 11% 3% South Bend-Elkhart-Mishawaka 34% 11% 3% Mishawaka 0% 50% 100% 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart- Mishawaka Place Women-Never Married Women-Divorced Women-Widowed 46368 28% 16% 9% 46405 39% 15% 8% 46403 36% 21% 9% 46393 24% 0% 22% 46342 26% 13% 11% 46304 27% 14% 7% 46402 51% 12% 16% United States 31% 12% 8% Indiana 29% 13% 9% South Bend-Elkhart-Mishawaka 29% 13% 8% Mishawaka
Figure 33: Single Men by Age Group Single Men 18 to 24 Single Men 25 to 29 Single Men 30 to 34 Single Men 35 to 39 Single Men 40 to 44 Single Men 45 to 49 Single Men 50 to 60 Single Men 60 to 65 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart-Mis… 0% 50% 100% Place Single Men 18 to 24 Single Men 25 to 29 Single Men 30 to 34 Single Men 35 to 39 Single Men 40 to 44 Single Men 45 to 49 Single Men 50 to 60 Single Men 60 to 65 46368 26% 16% 11% 11% 5% 6% 19% 6% 46405 20% 11% 9% 8% 12% 3% 23% 14% 46403 13% 16% 3% 19% 10% 9% 24% 7% 46393 0% 17% 27% 0% 0% 0% 56% 0% 46342 25% 10% 15% 13% 10% 6% 15% 7% 46304 23% 15% 13% 9% 9% 12% 15% 4% 46402 30% 14% 6% 11% 10% 2% 19% 9% United States 29% 17% 12% 9% 7% 7% 14% 6% Indiana 31% 15% 10% 8% 7% 7% 15% 7% South Bend-Elkhart-Mishawaka 30% 16% 10% 8% 7% 7% 14% 8% Single Men 60 to 65
Figure 34: Single Women by Age Group Single Women 18 to 24 Single Women 25 to 29 Single Women 30 to 34 Single Women 35 to 39 Single Women 40 to 44 Single Women 45 to 49 Single Women 50 to 60 Single Women 60 to 65 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart-Mis… 0% 50% 100% Place Single Women 18 to 24 Single Women 25 to 29 Single Women 30 to 34 Single Women 35 to 39 Single Women 40 to 44 Single Women 45 to 49 Single Women 50 to 60 Single Women 60 to 65 46368 29% 12% 11% 11% 7% 10% 12% 9% 46405 37% 16% 10% 9% 6% 5% 12% 6% 46403 14% 8% 11% 9% 14% 11% 25% 8% 46393 0% 53% 0% 0% 0% 0% 0% 48% 46342 27% 11% 10% 13% 12% 3% 16% 7% 46304 27% 21% 7% 8% 3% 10% 15% 10% 46402 26% 7% 7% 14% 16% 7% 17% 6% United States 28% 15% 10% 8% 7% 7% 16% 9% Indiana 30% 14% 9% 8% 7% 7% 16% 9% South Bend-Elkhart-Mishawaka 31% 13% 9% 7% 7% 7% 16% 10% Single Women 60 to 65
Figure 35: 46368, IN Citizenship Status Figure 36: Citizen Place of Birth for 46368, IN 0% 50% 100% 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart- Mishawaka Place Citizen Born In US Citizen by Naturalization Not a Citizen 46368 96% 2% 2% 46405 95% 2% 3% 46403 97% 1% 2% 46393 100% 0% 0% 46342 96% 3% 1% 46304 96% 4% 1% 46402 99% 1% 0% United States 86% 7% 7% Indiana 95% 2% 3% South Bend-Elkhart-Mishawaka 94% 3% 4% Mishawaka Birthplace-this State Birthplace- Midwest Birthplace- South Birthplace- West Birthplace- Northeast Birthplace- Outside US 16.5% 70% Place 46368 Birthplace-this State 0.7 Birthplace-Midwest 0.165 Birthplace-South 0.069 Birthplace-West 0.034 Birthplace-Northeast 0.02 Birthplace-Outside US 0.012 Outside US
Figure 37: 46368, IN Percent of Population Foreign Born Figure 38: Advertisement 0% 10% 20% 46402 46403 46342 46368 46304 46405 Indiana South Bend-Elkhart- Mishawaka United States Place Percent Foreign Born 46402 1% 46403 2.7% 46342 3.7% 46368 3.8% 46304 4.4% 46405 5.2% Indiana 5.4% South Bend-Elkhart-Mishawaka 6% United States 13.6% Mishawaka
Figure 39: 46368, IN Non Citizen Age Breakout Figure 40: Non Citizen Median Age 0% 50% 100% 46368 46405 46403 46342 46304 46402 United States Indiana South Bend-Elkhart- Mishawaka Place Non Citizens Under 18 Non Citizens Over 18 46368 4% 96% 46405 11% 89% 46403 35% 66% 46342 2% 99% 46304 9% 91% 46402 0% 100% United States 9% 91% Indiana 10% 90% South Bend-Elkhart-Mishawaka 9% 91% Mishawaka 0 25 50 46403 Indiana South Bend-Elkhart- Mishawaka 46304 United States 46405 46368 46342 Place Non Citizen Median Age 46403 32.4 Indiana 35.4 South Bend-Elkhart-Mishawaka 37.2 46304 37.9 United States 39.3 46405 40.5 46368 44.2 46342 44.5 Mishawaka
Figure 41: % Non Citizen Year of Entry into USA Figure 42: Year of Naturalization Entered 2000 to 2009 Entered US after 2010 Entered 1990 to 1999 Entered before 1990 46.2% 17.1% 33% Year of Entry 46368 Entered 2000 to 2009 0.462 Entered US after 2010 0.33 Entered 1990 to 1999 0.171 Entered before 1990 0.036 1990 Naturalized before 1990 Naturalized 1990 to 1994 Naturalized 2010 to 2014 Naturalized 2005 to 2009 Naturalized 2000 to 2004 Naturalized 2015 or later Naturalized 1995 to 1999 42.7% 9.4% 11.4% 13.6% 18% Year of Naturalization 46368 Naturalized before 1990 0.427 Naturalized 1990 to 1994 0.18 Naturalized 2010 to 2014 0.136 Naturalized 2005 to 2009 0.114 Naturalized 2000 to 2004 0.094 Naturalized 2015 or later 0.028 Naturalized 1995 to 1999 0.022 1995 to 1999
Figure 43: 46368, IN Foreign Born People are From What Region
Figure 44: 46368, IN Foreign-Born World Region of Birth Europe Asia Africa Oceania Americas 46368 46405 46403 46342 46304 46402 United States Indiana South Bend-Elkhart-Mis… 0% 50% 100% Place Europe Asia Africa Oceania Americas 46368 21% 20% 4% 0% 56% 46405 17% 4% 0% 0% 79% 46403 8% 5% 48% 0% 40% 46342 29% 19% 3% 8% 42% 46304 40% 39% 2% 0% 19% 46402 0% 0% 25% 0% 75% United States 11% 31% 6% 1% 52% Indiana 11% 36% 10% 0% 44% South Bend-Elkhart-Mishawaka 12% 24% 7% 1% 57% Americas
Figure 45: 46368, IN Foreign-Born Sub-Region of Birth Sub-Region 46368 46405 46403 46393 46342 46304 46402 United States Indiana South Bend-Elkhart-Mishawaka Americas-Central America 52.7% 79.1% 36.9% 0% 38.4% 9.7% 65.1% 32.2% 34% 44.0% Europe-East 18.6% 11.6% 0% 0% 16.2% 34.8% 0% 4.9% 5% 5.0% Asia-South Central 11% 0% 0% 0% 0% 10.2% 0% 9.4% 10.9% 7.3% Asia-South East 6.4% 0% 4.6% 0% 12.4% 8.9% 0% 9.6% 12.4% 7.4% Africa-West 3.6% 0% 0% 0% 1.2% 0% 25.4% 2.1% 4.9% 1.9% Asia-East 2.1% 0% 0% 0% 6.8% 14.3% 0% 9.4% 10% 7.7% Europe-Western 1.8% 0% 3.6% 0% 2.4% 1.5% 0% 2.1% 2.5% 3.6% Americas-North America 1.5% 0% 0% 0% 0% 6.7% 0% 1.8% 2.2% 2.9% Americas-Caribbean 0.9% 0% 2.6% 0% 1.1% 0.9% 9.5% 10% 2.9% 2.8% Americas-South America 0.6% 0% 0% 0% 2.2% 1.4% 0% 7.8% 4.4% 7.3% 1 2
Figure 46: Foreign-Born Country of People Living in 46368, IN Figure 47: Foreign-Born Country for all people in the United States Country 46368 Mexico 48.4% Other Eastern Europe 17.1% India 10.6% Philippines 4.3% Nigeria 3.6% El Salvador 3.4% Canada 1.5% Vietnam 1.3% France 1.3% China-excluding Hong Kong and Taiwan 1.1% 1 2 3 Country United States Mexico 24.2% Other Eastern Europe 0.3% India 6.0% Philippines 4.4% Nigeria 0.9% El Salvador 3.1% Canada 1.8% Vietnam 3.0% France 0.4% China-excluding Hong Kong and Taiwan 4.9% 1 2 10 13
Cities marked with an asterisk ("*") should resemble a city or town but do not have their own government (i.e. Mayor, City Council, etc.) These places should be recognizable by the local community but their boundaries have no legal status. Technically these include both Census Designated Places (CDP) and Census County Divisions (CCD) which are defined by the Census Bureau along with local authorities. (For more information, see: Census Designated Place or "CDP") and Census County Division "CCD".) For comparison purposes, the US national average and the state average value are provided. Additionally, the "Combined Statistical Area" or CSA is shown that is closest to the city, county, or zip code shown. A CSA is a large grouping of adjacent metropolitan areas that identified by the Census Bureau based on social and economic ties. (See: Combined Statistical Area ) Data sources - Mouse over icon in upper right corner of each chart for information.
| https://www.towncharts.com/Indiana/Demographics/46368-Zipcode-IN-Demographics-data.html |
Zoo Announces Another Seven Adorable Cheetah Cubs Are Born | At the Smithsonian| Smithsonian Magazine
With wild populations threatened, emerging and new techniques in the breeding science is growing ever more critical
Zoo Announces Another Seven Adorable Cheetah Cubs Are Born
The science behind the uptick in cheetah births includes a new fecal hormone method to determine pregnancy in the animals. National Zoo/SCBI
Seven cheetah cubs, coated with smokey gray hair and about the size of an American football, were born at the National Zoo’s Smithsonian Conservation Biology Institute (SCBI) in Front Royal, Virginia on July 9. The cubs are a first for parents Erin and Rico, yet, the litter itself was the 12th SCBI has seen since 2010, bringing the grand total to 53.
“It is really exciting to have such a large and healthy litter of cubs, especially from first-time parents,” said Adrienne Crosier, a biologist and manager of SCBI’s cheetah reproductive and research program. “A global self-sustaining cheetah population in human care is becoming even more important with the continued decrease of animal numbers in the wild.”
Population estimates for wild cheetahs is currently about7,100 . Due to habitat loss, human conflict and illegal trade, the cheetah’s habitat range isconfined to east and southern areas of Sub-Saharan Africa and a small portion of northeastern Iran, justnine percent of its historic area. To make matters worse, the infant mortality rate for cubs born in captivity is about30 percent and up to90 percent in the wild.
One of the main issues contributing to the decline in global cheetah population is the lack of genetic diversity. About10,000 years ago, cheetahs experienced a population bottleneck following the last ice-age. The surviving cheetahs repopulated, but had limited genetic diversity in their offspring. The effect: susceptibility to disease, low-fertility, genetic mutations and physical homogeneity.
The low-levels of genetic variation have been particularly troubling for breeding cheetah populations in captivity. Since 2012, a group of organizations—SCBI included—have created theBreeding Centers Coalition to address these genetic challenges and produce more cubs with higher genetic diversity.
This litter is particularly important to the population of cheetahs living in zoos because the mother, Erin’s, genes are not well represented in cheetahs living under human care in North America. Almost all the cheetahs in the United States descend fromtwo cheetah subspecies , one from South Africa and the other from Namibia. Additionally, the cubs’ father, Rico, was specifically brought in at the ripe age of nine to mate with Erin.
“We want to make the best matches possible,” Crosier said. “We need these populations to survive long into the future.”
Across nine different breeding centers, researchers have a catalog of approximately 360 cheetahs. With full knowledge of their ancestry, scientists are able to determine the best mates for breeding genetically diverse litters, according to Crosier.
To further counter population decline in the wild and in captivity, SCBI researchers are using anew fecal hormone method to determine pregnancy in cheetahs. Cheetah pregnancies typically last three months and, usually, it is extremely difficult for researchers to determine whether a female is pregnant until at least 55 days into the pregnancy, in part because cheetahs frequently experience pseudopregnancy, a condition where non-pregnant females exhibit behavior conducive to pregnancy after mating.
Because, pregnancy diagnosis is a crucial element in the rehabilitation of small populations of threatened animals, SCBI has identified a protein, immunoglobulin J (IGJ), that is more abundant in the feces of pregnant cheetahs during the first month of gestation to help identify pregnancy. Fecal samples from Erin will contribute to creating a non-invasive pregnancy test to help researchers make critical decisions about preparing for birth and/or allowing them to rematch female cheetahs with new mates.
The seven cubs will likely move to other zoos or facilities accredited by the A ssociation of Zoo and Aquariums once they are mature. But, for now, the cubs are under tight watch from their new mother, who only leaves the cubs for 10 or 15 minutes max.
“Every mother is different, but I would say Erin is on the protective side,” Crosier said. “She gave birth to a litter twice the size of an average litter, she’s got a lot on her plate.”
| https://www.smithsonianmag.com/smithsonian-institution/zoo-announces-another-seven-adorable-cheetah-cubs-are-born-180969732/ |
NATO - Opinion: Joint press point with NATO Secretary General Jens Stoltenberg and the President of the Republic of Poland, Andrzej Duda, 04-Jun.-2019
(As delivered)
Joint press point
with NATO Secretary General Jens Stoltenberg and the President of the Republic of Poland, Andrzej Duda
(As delivered)
Oana Lungescu [NATO Spokesperson]:Good evening. The Secretary General and the President will make short introductory remarks and then we have time for one or two questions. Secretary General?
Jens Stoltenberg [NATO Secretary General]:President Duda, my friend Andrzej, it's a great pleasure to see you once again and to meet you here at the NATO Headquarters and we last met in Warsaw a few months ago; then we marked the 70 thanniversary of NATO, but also the 20 thanniversary since Poland joined the Alliance. And it's always a great pleasure to meet with you and I thank you for your strong personal commitment to our Alliance and our friendship, which we have developed over several years. Poland makes major contributions to our shared security, including forces as part of NATO’s forward presence in Latvia and Romania, regular contributions to NATO air policing; and trainers in our missions in Afghanistan and Iraq.
Poland leads by example on defence spending, investing 2% of GDP to defence and investing well over 20% of its defence spending in major new capabilities. And Poland hosts key NATO facilities, including our Multinational Corps Northeast and a site for our ballistic missile defence. So NATO is very present in Poland. In fact, NATO’s presence has grown in your country, with a multinational battlegroup as part of our Enhanced Forward Presence in the region and a rotational US armoured brigade. Earlier this spring, NATO agreed to invest $260million in a major project to store and maintain US military equipment pre-positioned in central Poland. This is NATO’s biggest investment in military infrastructure in more than 30 years and it takes place in Poland. It shows also the commitment of NATO to Poland. NATO has also stepped up its presence in the Baltic Sea and we conduct regular training and exercises in Poland. As we speak, Exercise Noble Jump is testing the deployment of NATO's Very High Readiness Joint Task Force.
All of this shows that Poland is strongly committed to NATO and that NATO is strongly committed to Poland’s security. This is important as we continue to adapt to the most unpredictable security environment in a generation. This includes Russia’s ongoing violation of the INF Treaty. I urge Russia to show the political will to save the Treaty by returning to compliance. So, President Duda and I, we just discussed our preparations for the Summit of the NATO leaders in London this December. It will be an opportunity to reflect on how much we have achieved and the work which lies ahead. We are determined to ensure our Alliance remains the ultimate insurance policy for almost one billion people. We also discussed NATO’s relations with Ukraine; the NATO-Ukraine Commission just met with President Zelenskyy. The President’s visit to NATO Headquarters on his first trip abroad shows Ukraine’s continuous commitment to Euro-Atlantic integration. And I thank you for the support Poland is providing to Ukraine, including by providing experts to NATO’s representation in Ukraine and contributions to the NATO-Ukraine trust funds. So, President Duda, thank you once again for your leadership and for Poland's deeply valued contributions to NATO. So, once again, welcome. It's great to see you again.
Andrzej Duda [President of Poland] [Translated]:Thank you very much, Mr Secretary General. Ladies and Gentlemen, first and foremost I would like to thank Mr Secretary General for inviting me here to NATO Headquarters in Europe. I would like to thank Mr Secretary General for the meeting that we had just a few minutes ago. And I came here to share with Mr Secretary General information connected with our talks that we are holding with the United States, with Mr Donald Trump Administration, in connection with the plans to increase US military presence in our country and in our part of Europe. These conversations between Poland and the United States, which I have informed Mr Secretary General on several occasions, have been ongoing for some time now. We are willing to make sure that this hopefully increased US military presence is part of the creation of security in our region.
But, first and foremost, that it makes part of the NATO activities conducted and implemented under the auspices of the North Atlantic Alliance, of which we are all members. This presence is important to me and I informed Mr Secretary General about that just a moment ago because I have got this feeling that I can only see, in a very clear way, that the military activity which is happening in Poland, through the trainings and exercises going on there, through the presence, be it the US rotational presence or through the component which is deployed there as part of Enhanced Forward Presence, the Allied component which is deployed to our country, throughout that the feeling of security is growing also on the part of our Baltic Allies. Please believe me, you can see it very clearly that it is important to them that this is not only the presence of battalion battlegroups in their territories, but also in Poland, in a big country which is their neighbour, and they feel that there is this background there with more and more serious troops being deployed there, especially US troops. I'm not only talking about the numbers of soldiers, but also about the infrastructure and everything which is indispensable to make sure that, in case, we are able to repel aggression in an efficient way.
This is of huge importance and this is going to be one of the topics I will tackle during my conversation with President Donald Trump. I do hope that, in a sense, our top level discussions will be a complement to the talks, which have been going on at the level of the cabinet, at the level of minsters, so far. And I hope that we will be able to reach initial agreements by us and the United States. And let me reiterate once again, what is very important to me is that this is part of the NATO presence in our territory. In other words, that we can also discuss that during the December NATO Summit, as an element of meeting all the obligations which we took upon ourselves as Allies, in Wales, the obligations which we later discussed in 2016 during Warsaw NATO Summit and during that next consecutive NATO Summits which were held here in Brussels. Mr Secretary General shared with me also his remarks and observations concerning the ongoing NATO related matters and security related matters, not only in our part of Europe, but also in other places around the globe.
We are going to discuss also that. I will try to raise these topics also during my talks with President Donald Trump. We also tackled Ukraine; we spoke about the security, Ukraine is very important indeed, Ukraine is still aspiring to NATO. I will meet today President Volodymyr Zelenskyy and I will talk to him as well. This is going to be our first direct conversation. Before, we had an opportunity to briefly talk on the phone, when I congratulated Mr President on his election. And I would like to assure the President of Ukraine that Poland is a loyal Ally of Ukraine and that we are not only supporting Ukraine in all the possible international forums, that we are also ready to support Ukraine still and we hope that it will finally regain the territories which it lost, because these territories today are occupied by Russia. So, we would like international law to be respected again and we want borders not to be shifted by force. And we are going to go to lengths to make sure that we reinstate the state of normality/normalcy which was there before the Russian aggression.
Oana Lungescu [NATO Spokesperson]:Time pressures, I'm afraid we only have time for one question, the Polish news agency, please, PAP.
Question [PAP]:Christopher Sheshenko, Polish Press Agency. Secretary General, a question for you. The President informed you about his trip to US and the plans increasing US presence in Poland. What's the stance of NATO on that? Are there any controversial regarding to that?
Question [PAP] [Translated]:You said about completing the talks which have been going on at the level of cabinets. What can we expect from the visit to the United States concretely? Are you going to sign any kind of agreement/political declaration? Thank you very much.
Jens Stoltenberg [NATO Secretary General]:I welcome the strong commitment of the United States to European security and we see that also now expressed by the fact that the United States is increasing their military presence in Europe. We have seen that over the last years, for instance with the new armoured brigade, which is also rotating through Poland, which is also present in Poland, and of course also we see increased US presence in Poland also through the US led NATO battlegroup, which is already present in Poland, and we have a NATO ballistic missile defence site which we now are in the process of establishing in Poland. We have some command and control. We have more exercises and more NATO and US presence in Europe and in Poland in different ways. We have seen that over the last years.
And then I mentioned also the fact that actually NATO will now invest US$260million in a major project to support US forces in Powidz, central Poland, which is a big and significant investment of NATO, to enable more US prepositioned equipment in Poland. So, it just shows that US presence and NATO presence in Poland is very much interlinked. We welcome the fact that Poland has briefed NATO Allies and President Duda has briefed me several times on the bilateral consultations, the bilateral dialogue between Poland and United States on further increase in US presence. That is a bilateral arrangement, but of course it will be part of the broader presence of NATO Allies in Europe, and especially then the broader presence of US in Europe, and this is part of the strengthened US presence in Europe.
Andrzej Duda [President of Poland] [Translated]:Well, my answer to your question is the following: my contact with President Donald Trump, as for standards of contacts with the President of the United States, are very intensive indeed. We have met very frequently indeed. We have had many conversations before. Every time, we talk about security of both Poland and our part of Europe. Let me stress also the Baltic States in this context, because every time this is mentioned in our conversation, but we are also talking about the security to the south and to the east, in terms of Ukraine. But we are also looking to the south. I am thinking about Bulgaria and Romania.
In Romania, we have got also Polish soldiers deployed as part of tailored Forward Presence. And they are fulfilling their mission as part of NATO. So, we are tackling all those topics. Talking about supplementing the current talks, I'm thinking that the real US presence that we have had in Poland for two years now, this presence has been a stage and I have treated this as a kind of US reconnaissance. They wanted to see how Poland looks, how you can function in Poland, what possibilities we are offering for having the military presence, what conditions there are, and I think that this reconnaissance has been positive. And we can say that this first stage, I would like this first stage to be closed during our meeting and I would like us to open another stage.
Whenever I'm talking about closing something, then I mean that we are closing one stage and we are opening another stage, in terms of our military cooperation. And that means that this presence is a presence which is well founded, well rooted. This is positive because it demonstrates to our allies that the United States looks at us in a serious way and it looks seriously at the security in our part of Europe, just like the entire NATO. And this is the most important element. And of course, apart from that, we are also going to discuss energy cooperation in different fields, so that economic topics will also be a very serious element of our meeting.
Oana Lungescu [NATO Spokesperson]:Thank you.
Jens Stoltenberg [NATO Secretary General]:Thank you.
Audio
ORIGINAL - Joint press point by NATO Secretary General Jens Stoltenberg and the President of Poland Andrzej Duda
ENGLISH - Joint press point by NATO Secretary General Jens Stoltenberg and the President of Poland Andrzej Duda
FRENCH - Joint press point by NATO Secretary General Jens Stoltenberg and the President of Poland Andrzej Duda
RUSSIAN - Joint press point by NATO Secretary General Jens Stoltenberg and the President of Poland Andrzej Duda
| https://www.nato.int/cps/en/SID-B5035C3A-CAACDB0B/natolive/opinions_166564.htm?selectedLocale=en |
Construction Materials BRIC (Brazil, Russia, India, China) Industry Guide - Market Summary, Competitive Analysis and Forecast to 2025
Construction Materials BRIC (Brazil, Russia, India, China) Industry Guide - Market Summary, Competitive Analysis and Forecast to 2025 Construction Materials BRIC (Brazil, Russia, India, China) - Market research report and industry analysis - 30037979
Construction Materials BRIC (Brazil, Russia, India, China) Industry Guide - Market Summary, Competitive Analysis and Forecast to 2025
Best Price Guarantee Price from $995 Length 100 Pages Publisher MarketLine Published Date July, 2021 SKU MTLN16752006
Table of Contents
Description
Construction Materials BRIC (Brazil, Russia, India, China) Industry Guide - Market Summary, Competitive Analysis and Forecast to 2025 SummaryThe BRIC Construction Materials industry profile provides top-line qualitative and quantitative summary information including: market size (value 2016-20, and forecast to 2025). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Key Highlights
Brazil, Russian Federation, India and China (BRIC) are the emerging and fast growing countries within the construction materials industry and had a total market value of $634,752.3 million in 2020. China was the fastest growing country with a CAGR of 5.1% over the 2016-20 period.
Within the construction materials industry, China is the leading country among the BRIC nations with market revenues of $537,887.9 million in 2020. This was followed by India, Russia and Brazil with a value of $69,774.5, $15,888.1, and $11,201.8 million, respectively.
China is expected to lead the construction materials industry in the BRIC nations with a value of $797,015.2 million in 2025, followed by India, Russia, Brazil with expected values of $119,634.1, $22,062.3 and $13,399.5 million, respectively.
Scope
Save time carrying out entry-level research by identifying the size, growth, major segments, and leading players in the BRIC construction materials market
Use the Five Forces analysis to determine the competitive intensity and therefore attractiveness of the BRIC construction materials market
Leading company profiles reveal details of key construction materials market players’ BRIC operations and financial performance
Add weight to presentations and pitches by understanding the future growth prospects of the BRIC construction materials market with five year forecasts
Compares data from Brazil, Russia, India, and China, alongside individual chapters on each country
Reasons to Buy
What was the size of the BRIC construction materials market by value in 2020?
What will be the size of the BRIC construction materials market in 2025?
What factors are affecting the strength of competition in the BRIC construction materials market?
How has the market performed over the last five years?
What are the main segments that make up the BRIC construction materials market?
1 Introduction
1.1. What is this report about?
1.2. Who is the target reader?
1.3. How to use this report
1.4. Definitions
2 Construction Materials in Brazil
2.1. Market Overview
2.2. Market Data
2.3. Market Segmentation
2.4. Market outlook
2.5. Five forces analysis
2.6. Macroeconomic Indicators
3 Construction Materials in China
3.1. Market Overview
3.2. Market Data
3.3. Market Segmentation
3.4. Market outlook
3.5. Five forces analysis
3.6. Macroeconomic Indicators
4.1. Market Overview
4.2. Market Data
4.3. Market Segmentation
4.4. Market outlook
4.5. Five forces analysis
4.6. Macroeconomic Indicators
5 Construction Materials in Russia
5.1. Market Overview
5.2. Market Data
5.3. Market Segmentation
5.4. Market outlook
5.5. Five forces analysis
5.6. Macroeconomic Indicators
6 Company Profiles
6.1. Votorantim SA
6.2. Anhui Conch Cement Co Ltd
6.3. Taiwan Cement Corp
6.4. BBMG Corp
6.5. China National Building Material Co Ltd
6.6. LafargeHolcim Ltd.
6.7. UltraTech Cement Ltd
6.8. India Cements Capital Ltd
6.10. Eurocement Group
7 Appendix
7.1. Methodology
7.2. About MarketLine
List of Tables
Table 1: Brazil construction materials market value: $ million, 2016-20
Table 2: Brazil construction materials market category segmentation: $ million, 2020
Table 3: Brazil construction materials market geography segmentation: $ million, 2020
Table 4: Brazil construction materials market value forecast: $ million, 2020-25
Table 5: Brazil size of population (million), 2016-20
Table 6: Brazil gdp (constant 2005 prices, $ billion), 2016-20
Table 7: Brazil gdp (current prices, $ billion), 2016-20
Table 8: Brazil inflation, 2016-20
Table 9: Brazil consumer price index (absolute), 2016-20
Table 10: Brazil exchange rate, 2016-20
Table 11: China construction materials market value: $ million, 2016-20
Table 12: China construction materials market category segmentation: $ million, 2020
Table 13: China construction materials market geography segmentation: $ million, 2020
Table 14: China construction materials market value forecast: $ million, 2020-25
Table 15: China size of population (million), 2016-20
Table 16: China gdp (constant 2005 prices, $ billion), 2016-20
Table 17: China gdp (current prices, $ billion), 2016-20
Table 18: China inflation, 2016-20
Table 19: China consumer price index (absolute), 2016-20
Table 20: China exchange rate, 2016-20
Table 21: India construction materials market value: $ million, 2016-20
Table 22: India construction materials market category segmentation: $ million, 2020
Table 23: India construction materials market geography segmentation: $ million, 2020
Table 24: India construction materials market value forecast: $ million, 2020-25
Table 25: India size of population (million), 2016-20
Table 26: India gdp (constant 2005 prices, $ billion), 2016-20
Table 27: India gdp (current prices, $ billion), 2016-20
Table 28: India inflation, 2016-20
Table 29: India consumer price index (absolute), 2016-20
Table 30: India exchange rate, 2016-20
Table 31: Russia construction materials market value: $ million, 2016-20
Table 32: Russia construction materials market category segmentation: $ million, 2020
Table 33: Russia construction materials market geography segmentation: $ million, 2020
Table 34: Russia construction materials market value forecast: $ million, 2020-25
Table 35: Russia size of population (million), 2016-20
Table 36: Russia gdp (constant 2005 prices, $ billion), 2016-20
Table 37: Russia gdp (current prices, $ billion), 2016-20
Table 38: Russia inflation, 2016-20
Table 39: Russia consumer price index (absolute), 2016-20
Table 40: Russia exchange rate, 2016-20
Table 41: Votorantim SA: key facts
Table 42: Votorantim SA: Key Employees
Table 43: Anhui Conch Cement Co Ltd: key facts
Table 44: Anhui Conch Cement Co Ltd: Annual Financial Ratios
Table 45: Anhui Conch Cement Co Ltd: Key Employees
Table 46: Taiwan Cement Corp: key facts
Table 47: Taiwan Cement Corp: Annual Financial Ratios
Table 48: Taiwan Cement Corp: Key Employees
Table 49: BBMG Corp: key facts
Table 50: BBMG Corp: Annual Financial Ratios
Table 51: BBMG Corp: Annual Financial Ratios (Continued)
Table 52: BBMG Corp: Key Employees
Table 53: China National Building Material Co Ltd: key facts
Table 54: China National Building Material Co Ltd: Annual Financial Ratios
Table 55: China National Building Material Co Ltd: Key Employees
Table 56: China National Building Material Co Ltd: Key Employees Continued
Table 57: LafargeHolcim Ltd.: key facts
Table 58: LafargeHolcim Ltd.: Annual Financial Ratios
Table 59: LafargeHolcim Ltd.: Key Employees
Table 60: UltraTech Cement Ltd: key facts
Table 61: UltraTech Cement Ltd: Annual Financial Ratios
Table 62: UltraTech Cement Ltd: Key Employees
Table 63: India Cements Capital Ltd: key facts
Table 64: India Cements Capital Ltd: Annual Financial Ratios
Table 65: India Cements Capital Ltd: Key Employees
List of Figures
Figure 1: Brazil construction materials market value: $ million, 2016-20
Figure 2: Brazil construction materials market category segmentation: % share, by value, 2020
Figure 3: Brazil construction materials market geography segmentation: % share, by value, 2020
Figure 4: Brazil construction materials market value forecast: $ million, 2020-25
Figure 5: Forces driving competition in the construction materials market in Brazil, 2020
Figure 6: Drivers of buyer power in the construction materials market in Brazil, 2020
Figure 7: Drivers of supplier power in the construction materials market in Brazil, 2020
Figure 8: Factors influencing the likelihood of new entrants in the construction materials market in Brazil, 2020
Figure 9: Factors influencing the threat of substitutes in the construction materials market in Brazil, 2020
Figure 10: Drivers of degree of rivalry in the construction materials market in Brazil, 2020
Figure 11: China construction materials market value: $ million, 2016-20
Figure 12: China construction materials market category segmentation: % share, by value, 2020
Figure 13: China construction materials market geography segmentation: % share, by value, 2020
Figure 14: China construction materials market value forecast: $ million, 2020-25
Figure 15: Forces driving competition in the construction materials market in China, 2020
Figure 16: Drivers of buyer power in the construction materials market in China, 2020
Figure 17: Drivers of supplier power in the construction materials market in China, 2020
Figure 18: Factors influencing the likelihood of new entrants in the construction materials market in China, 2020
Figure 19: Factors influencing the threat of substitutes in the construction materials market in China, 2020
Figure 20: Drivers of degree of rivalry in the construction materials market in China, 2020
Figure 21: India construction materials market value: $ million, 2016-20
Figure 22: India construction materials market category segmentation: % share, by value, 2020
Figure 23: India construction materials market geography segmentation: % share, by value, 2020
Figure 24: India construction materials market value forecast: $ million, 2020-25
Figure 25: Forces driving competition in the construction materials market in India, 2020
Figure 26: Drivers of buyer power in the construction materials market in India, 2020
Figure 27: Drivers of supplier power in the construction materials market in India, 2020
Figure 28: Factors influencing the likelihood of new entrants in the construction materials market in India, 2020
Figure 29: Factors influencing the threat of substitutes in the construction materials market in India, 2020
Figure 30: Drivers of degree of rivalry in the construction materials market in India, 2020
Figure 31: Russia construction materials market value: $ million, 2016-20
Figure 32: Russia construction materials market category segmentation: % share, by value, 2020
Figure 33: Russia construction materials market geography segmentation: % share, by value, 2020
Figure 34: Russia construction materials market value forecast: $ million, 2020-25
Figure 35: Forces driving competition in the construction materials market in Russia, 2020
Figure 36: Drivers of buyer power in the construction materials market in Russia, 2020
Figure 37: Drivers of supplier power in the construction materials market in Russia, 2020
Figure 38: Factors influencing the likelihood of new entrants in the construction materials market in Russia, 2020
Figure 39: Factors influencing the threat of substitutes in the construction materials market in Russia, 2020
Figure 40: Drivers of degree of rivalry in the construction materials market in Russia, 2020
Residential Construction BRIC (Brazil, Russia, India, China) Industry Guide - Market Summary, Competitive Analysis and Forecast to 2025
Non-Residential Construction BRIC (Brazil, Russia, India, China) Industry Guide - Market Summary, Competitive Analysis and Forecast to 2025
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People ex rel. Mather v. Marshall Field & Co., 9743. - Illinois - Case Law - VLEX 893455509
0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object]. 4: [object Object]. 5: [object Object]
People ex rel. Mather v. Marshall Field & Co., 9743.
Court Supreme Court of Illinois Writing for the Court CARTER Citation 107 N.E. 864,266 Ill. 609 Decision Date 17 February 1915 Docket Number No. 9743.,9743. Parties PEOPLE ex rel. MATHER v. MARSHALL FIELD & CO. et al.
266 Ill. 609 107 N.E. 864
PEOPLE ex rel. MATHER v. MARSHALL FIELD & CO. et al.
No. 9743.
Supreme Court of Illinois.
Feb. 17, 1915.
Appeal from Circuit Court, Cook County; John P. McGoorty, Judge.
[266 Ill. 610]Maclay, Hoyne, State's Atty., and George P. Merrick, both of Chicago, for appellant.
Wm. H. Sexton, Corp. Counsel, and Joseph F. Grossman, both of Chicago, for appellee City of Chicago.
Tolman & Redfield, of Chicago (John P. Wilson and Edgar B. Tolman, both of Chicago, of counsel), for Marshall Field & Co.
CARTER, J.
This is an appeal from a decree of the circuit court of Cook county dismissing for want of equity an information brought in the name of the people by Maclay Hoyne, state's attorney, upon the relation of Stephen T. Mather, to enjoin the use and occupation of certain passageways or tunnels under Washington street, in the city of Chicago, by Marshall Field & Co., and to restrain the city of Chicago from permitting the subsurface of Washington street to be so used, and to have a certain ordinance granting such use declared null and void. The trial court certified that, the validity of a municipal ordinance being involved, the public interests required an appeal directly to this court.
The ordinance in question was passed by the city council of Chicago on November 18, 1912. It provides, among other things, as follows:
‘Section 1. That for the purpose of connecting the basements of the building now standing
[107 N.E. 865]
or hereafter to be [266 Ill. 611]erected upon block thirteen (13) in Fort Dearborn addition to Chicago, with the basement of the building now standing or hereafter to be erected upon lots one (1), two (2) and three (3) in block fourteen (14), Fort Dearborn addition to Chicago, and under the east half of Holden court, adjoining said lots one (1), two (2) and three (3), permission and authority be and the same are hereby given and granted to Marshall Field & Co., a corporation, its successors and assigns, (hereafter designated as the grantee,) to excavate, use and occupy a tunnel or passageway under the surface of Washington street, extending from the north to the south curb line thereof, the center line of which tunnel or passageway shall be midway between the west line of Wabash avenue and the east line of Holden court. Said tunnel or passageway shall not exceed eighty (80) feet in width nor fifteen (15) feet in depth below the grade of the street there. That for the purpose of connecting the subbasements of the buildings now erected or hereafter to be erected on the aforementioned premises, permission and authority are also given and granted to said grantee to excavate, use and occupy a tunnel or passageway under the surface of Washington street from the north to the south curb line thereof, the center line of which tunnel or passageway shall be ten (10) feet east of the center line of Holden court extended across said Washington street. Said tunnel or passageway shall not exceed twenty (20) feet in width nor fourteen (14) feet in height and shall not extend more than twenty-seven (27) feet below the level of the street there. The depth of said passageways shall be computed exclusive of the thickness of the pavement: Provided, however, that said tunnels or passageways shall not be used at any time for the sale of any goods or merchandise whatsoever.
‘Sec. 2. The permission and authority herein granted shall cease and determine twenty (20) years from and after the date of the passage of this ordinance, or may be revoked[266 Ill. 612]at any time prior thereto by the mayor, in his discretion, without the consent of the grantee herein named. This ordinance shall also be subject to amendment, modification or repeal at any time without the consent of the said grantee, and in case of such repeal all the privileges herein granted shall thereupon cease and determine. In the event of the termination, revocation, amendment or modification of the authority or privileges hereby granted, by lapse of time, the exercise of the mayor's discretion or the exercise by the city council of the powers above reserved, the grantee, by the filing of the written acceptance hereinafter provided for, shall be understood as consenting that the city shall retain all money it shall have previously received from said grantee under the provisions of this ordinance, said money to be treated and considered as compensation for the authority, permission and privileges enjoyed from the date of the passage of this ordinance until such repeal.’
Section 3 provides that the city of Chicago shall be paid a certain compensation by Marshall Field & Co. for the first 10 years of said period, and for the last 10 years such compensation as may be determined by the city council of said city.
Section 4 provides that the work of putting in such tunnel shall be done in accordance with the plans signed by the building commissioner, commissioner of public works, and the fire marshal of said city, and under the supervision of the latter two of said officials.
Section 5 reads:
‘Sec 5. At the termination of the privileges herein granted, whether by lapse of time, revocation by the mayor or by amendment, modification or repeal by the city council, said grantee shall immediately vacate said Washington street and immediately remove therefrom all construction installed, under authority of this ordinance, below the surface of said street (including the filling up of the space beneath the street), and shall place the surface of the street [266 Ill. 613]in condition for use by the public at its own expense, without cost of any kind whatsoever to the city of Chicago; and in the event of the failure, neglect or refusal on the part of said grantee to comply with the provisions of this section of this ordinance the city of Chicago may proceed to remove the same and fill the space and charge the expense thereof to said grantee. Said grantee shall never set up any claim against the city of Chicago which would operate to extend its right to use said space beyond the date of termination of the privileges herein granted by lapse of time, revocation by the mayor or by amendment, modification or repeal by the city council.’
Section 6 provides that Marshall Field & Co. shall give a bond of $100,000 to the city of Chicago to secure the faithful performance by said company of the contract and to indemnify said city against all loss, damage, or expense of any kind under it.
Section 7 provides that before putting in the tunnel Marshall Field & Co. shall provide for the care and adjustment, under the direction of the commissioner of public works and to his satisfaction, of the sewers, water pipes, electric light conduits, and other public utilities in that portion of Washington street covered by the ordinance, at the expense of said company.
And section 8 provides that Marshall Field & Co. shall not prevent or delay any revocation of said ordinance by the mayor or city council by any action at law or in chancery.
The cause was heard by the chancellor on amended bill and answers. From the pleadings and proof introduced, it appears that the title to Washington street is in the city; that the subsurface of the street at the point in question is now, and has been for years, used for public utilities, including sewers, water pipes, gas mains, gas pipes, electric light wires, and conduits; that some 52,800 cubic feet of space are taken for said tunnels and they occupy under said street 4,800 square feet of superficial area; that the tunnels, at the time of the hearing below, were practically completed[266 Ill. 614]at a cost of about $70,000 and were then being used and occupied in accordance with the provisions of the ordinance; that the upper tunnel, situated halfway between Wabash avenue and Holden court, was 80 feet in width and 9 feet and 2 inches in height, the bottom being 15 feet below the surface of the ground; that the lower or subbasement tunnel, located substantially under the east half of Holden court if extended across Washington street, was 20 feet in width and 14 feet in depth the bottom being 27 feet below the surface of the street; that while said tunnels were being constructed, or thereafter, the grantee at its own expense, under the direction of
[107 N.E. 866]
the city officials and working with the officials of the various public utility companies affected, had changed the gas mains, gas pipe, electric light wires, telephone wires, conduits, etc., and placed them above the upper tunnel but below the surface of the street. It further appears from the record that under the supervision of the city authorities Marshall Field & Co. had changed the six-inch water pipe in the street, which theretofore was laid at grade about six feet below the surface at this point, so that it ran down one side of the upper tunnel and under and then up the other side, so that the water would run through the bend somewhat on the principle of a siphon. It further appears that, before these tunnels were constructed, Holden court at this point, where it crossed Washington street, was the summit of a sewer in that street, so that the sewage in the sewer east of Holden court would run towards Wabash avenue and the sewage in the sewer west of Holden court would run west to State street; that the grade, however, of the sewer at Holden court in either direction was very slight; that in constructing the upper tunnel Marshall Field & Co., under the supervision of the city, cut out the section of the sewer from Holden court to the east side of said upper tunnel and blocked or stopped the end of the sewer west of Holden court and the...
17 practice notes
Yale University v. City of New Haven United States Connecticut Supreme Court July 3, 1926 ...to an owner upon both sides of the highway to build a structure across it depends upon what is reasonable (People ex rel. v. Field & Co., 266 Ill. 609 , 618, 107 N.E. 864, L.R.A. 1915F, 937, Ann.Cas. 1916B, 743), and that is to be tested by the standard of every age, as Justice Baldwin said,......
Yale Univ. v. City of New Haven United States Supreme Court of Connecticut July 3, 1926 ...to an owner upon both sides of the highway to build a structure across it depends upon what is reasonable (People ex rel. v. Field & Co., 266 Ill. 609 , 618, 107 N. E. 864, L. R. A. 1915F, 937, Ann. Cas. 1916B, 743), and that is to be tested by the standard of every age, as Justice Baldwin s......
Gerstley v. Globe Wernicke Co. , No. 19539. United States Supreme Court of Illinois October 8, 1930 ...in question. There is no showing that the five bridges promote in any way the public interest. The case of People v. Marshall Field & Co., 266 Ill. 609 , 107 N. E. 864, L. R. A. 1915F, 937, Ann. Cas. 1916B, 743, involving an [340 Ill. 278]ordinance which permitted a subway across Washington ......
State ex rel. York v. Board of Com'rs of Walla Walla County, 30196. United States United States State Supreme Court of Washington September 16, 1947 ...151 Cal. 425, 90 P. 1053, 13 L.R.A.,N.S., 904 (private irrigation pipe under street); People ex rel. Mather v. Marshall Field & Co., 266 Ill. 609 , 107 N.E. 864, L.R.A.1915F, 937, Ann.Cas.1916B, 743 (tunnel under street); and (4) with the exemption of corporations and other associations, not......
17 cases
Yale University v. City of New Haven United States Connecticut Supreme Court July 3, 1926 ...to an owner upon both sides of the highway to build a structure across it depends upon what is reasonable (People ex rel. v. Field & Co., 266 Ill. 609 , 618, 107 N.E. 864, L.R.A. 1915F, 937, Ann.Cas. 1916B, 743), and that is to be tested by the standard of every age, as Justice Baldwin said,......
Yale Univ. v. City of New Haven United States Supreme Court of Connecticut July 3, 1926 ...to an owner upon both sides of the highway to build a structure across it depends upon what is reasonable (People ex rel. v. Field & Co., 266 Ill. 609 , 618, 107 N. E. 864, L. R. A. 1915F, 937, Ann. Cas. 1916B, 743), and that is to be tested by the standard of every age, as Justice Baldwin s......
Gerstley v. Globe Wernicke Co. , No. 19539. United States Supreme Court of Illinois October 8, 1930 ...in question. There is no showing that the five bridges promote in any way the public interest. The case of People v. Marshall Field & Co., 266 Ill. 609 , 107 N. E. 864, L. R. A. 1915F, 937, Ann. Cas. 1916B, 743, involving an [340 Ill. 278]ordinance which permitted a subway across Washington ......
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(PDF) Relative genus bounds in indefinite four-manifolds
PDF | Given a closed four-manifold $X$ with an indefinite intersection form, we consider smoothly embedded surfaces in $X \setminus $int$(B^4)$, with... | Find, read and cite all the research you need on ResearchGate
Relative genus bounds in indefinite four-manifolds
Abstract and Figures
Given a closed four-manifold $X$ with an indefinite intersection form, we consider smoothly embedded surfaces in $X \setminus $int$(B^4)$, with boundary a knot $K \subset S^3$. We give several methods to bound the genus of such surfaces in a fixed homology class. Our techniques include adjunction inequalities and the $10/8 + 4$ theorem. In particular, we present obstructions to a knot being H-slice (that is, bounding a null-homologous disk) in a four-manifold and show that the set of H-slice knots can detect exotic smooth structures on closed $4$-manifolds.
The figure shows the effect of adding a negative full twist along k strands. …
The closure of the braid above is the topologically slice knot from [11, Figure 3]. The number within each box indicates the number of full twists performed there. The fractional number + 8 9 indicates 8 ninths of positive full twist, assuming that the strands locally lie on a cylinder, equally spaced from each other. …
RELA TIVE GENUS BOUNDS IN INDEFINITE FOUR-MANIFOLDS
CIPRIAN MANOLESCU, MARCO MARENGON, AND LISA PICCIRILLO
Abstract. Given a closed four-manifold X with an indefinite intersection form, w e consider
smoothly embedded surfaces in X \ ˚
B 4 , with boundary a knot K ⊂ S 3 . W e give several
methods to bound the genus of such surfaces in a fixed homology class. Our techniques include
adjunction inequalities and the 10 / 8 + 4 theorem. In particular, we present obstructions to
a knot being H-slice (that is, bounding a null-homologous disk) in a four-manifold and show
that the set of H-slice knots can detect exotic smooth structures on closed 4-manifolds.
1. Introduction
A fundamental problem in four-dimensional topology is to find the minimal genus of embed-
ded surfaces in a four-manifold, in a given homology class. F or example, the Thom conjecture
[35] and the symplectic Thom conjecture [46] were problems of this type; their solutions rank
among the major successes of gauge theory. A relative version of the same problem concerns
bounding the genus of properly embedded surfaces Σ in a four-manifold W with boundary,
when ∂ Σ is a given knot K ⊂ ∂W and the relative homology class of Σ is fixed.
W e will focus on the case where the four-manifold has boundary S 3 . W e let X be a
closed, connected, oriented, smooth four-manifold, and consider properly embedded surfaces
in X ◦ := X \ ˚
B 4 , with boundary a classical knot K ⊂ S 3 . One problem of interest is whether
K bounds a null-homologous disk in X ◦ ; if so, we say that K is H-slic e in X .
When X = S 4 , the problem reduces to the well-known question of finding the four-ball
genus of knots, and in particular of determining which knots are slice. More generally , when
X has definite intersection form, many of the gauge theoretic techniques for bounding the
genus of embedded surfaces still apply; see [48, 36, 24]. When X = # n CP 2 or # n CP 2 , there
are also bounds from Khovano v homology [39].
Less is known about relative genus bounds in more complicated, indefinite four-manifolds,
such as the K3 surface or complex surfaces of general type. Classical methods produce top o-
logical constraints (that apply equally well for surfaces em bedded in a lo cally flat way in a
topological four-manifold). We will review these in Section 3. They include constraints from
the Arf inv ariant [56, 14, 32], from the T ristram-Levine signatures [10], and from a theorem
of Rokhlin [57].
The main purpose of this paper is to use gauge theory and Heegaard Flo er homology to
develop new techniques for bounding the genus of smoothly embedded surfaces with boundary ,
in indefinite four-manifolds.
Inside 4-manifolds with non-trivial Seiberg-Witten (or Ozsv´ ath-Szab´ o) inv ariants, the genus
of closed surfaces can be bounded using the adjunction inequalities from [35], [41], [46], [51].
This can be leveraged to bound the genus of surfaces Σ ⊂ X ◦ with boundary a knot K : by
capping off Σ with a smooth surface F in some manifold Z with ∂ Z ⊃ S 3 and ∂ F = K (the
LP was supported by NSF postdoctoral fellowship DMS-1902735 and the Max Planck Institute for
Mathematics.
1
2 CIPRIAN MANOLESCU, MARCO MARENGON, AND LISA PICCIRILLO
mirror of K ), we can apply the adjunction inequality in X ◦ ∪ Z to the resulting closed surface
Σ ∪ F .
The simplest way to do this is to tak e Z = B 4 and F a surface in B 4 with boundary K .
This gives an inequality of the follo wing form, involving the slice genus g 4 ( K ) of the knot:
(1) h c 1 ( s ) , [Σ] i + [Σ] 2 ≤ 2 g (Σ) − 2+2 g 4 ( K ) .
A stronger bound can be obtained by taking Z to be the cob ordism associated to some
surgery on K , and letting F be the core of the 2-handle. This improves the inequality (1)
to one involving the concordance in varian t ν + from knot Floer homology [26]. W e obtain
the following relative adjunction inequalit y (see Section 4 for an introduction to Φ X, s and
manifolds of Ozsv´ ath–Szab´ o simple t ype):
Theorem 1.1. Let X b e a closed 4-manifold, with b +
2 ( X ) > 1 . Let Σ ⊂ X ◦ b e a prop erly
embe dded surfac e with g (Σ) > 0 and ∂ Σ = K , and let K denote the mirror of K . Suppose that
either [Σ] 2 ≥ 2 ν + ( K ) or X is of Ozsv´ ath-Szab´ o simple type. Then, for every spin c structure
s ∈ Spin c ( X ) for which the mixed invariant Φ X, s is non-zer o, we have
h c 1 ( s ) , [Σ] i + [Σ] 2 ≤ 2 g (Σ) − 2+2 ν + ( K ) .
Remark 1.2 . A differen t relative adjunction inequality , in terms of the concordance inv ariant
τ , was prov ed by Ozsv´ ath and Szab´ o [48, Theorem 1.1]. Theirs applies to surfaces in negative
definite 4-manifolds, whereas ours is for 4-manifolds with b +
2 ( X ) > 1.
Remark 1.3 . Y et another relative adjunction inequalit y , in terms of invarian ts from contact
geometry , was prov ed by Mrowk a and Rollin [42].
Theorem 1.1 gives non-trivial obstructions for surfaces Σ of positive genus and with [Σ] 6 = 0,
but does not say anything about H-sliceness in X . Instead, we can get constrain ts on H-
sliceness by filling X ◦ with suitable symplectic manifolds, and using adjunction inequalities
based on the Bauer-F uruta inv ariants:
Theorem 1.4. Let X and X 0 b e closed symple ctic 4 -manifolds satisfying b +
2 ( X ) ≡ b +
2 ( X 0 ) ≡ 3
(mod 4) . Supp ose that a knot K ⊂ S 3 is such that the mirr or K bounds a smo oth, prop erly
embe dded disk ∆ ⊂ X ◦ with [∆] 2 ≥ 0 and [∆] 6 = 0 . Then K is not H-slice in X 0 .
F rom here we obtain the following application.
Corollary 1.5. There exist smo oth, homeomorphic four-manifolds X and X 0 and a knot
K ⊂ S 3 that is H-slice in X but not in X 0 . For example, one c an take
X = #3 CP 2 #20 CP 2 , X 0 = K 3# CP 2 ,
and K to be the right-hande d trefoil.
This result sheds some light on the following w ell-known strategy to disprov e the smooth
4-dimensional Poincar´ e conjecture: find a knot K that is H-slice (or equivalen tly slice) in a
homotopy 4-sphere but not in S 4 ; see for example [13]. Corollary 1.5 gives the first example
showing that indeed there are closed 4-manifolds for which the set of H-slice knots can detect
exotic smooth structures. (W e note that the literature already contains examples of exotic
4-manifold pairs, where the boundary Y is not S 3 , such that some knot in Y bounds a null-
homologous smooth disk in one manifold and not in the other; this is the case, for instance,
with Akbulut’s corks [1]).
W e also observe that Corollary 1.5 gives an example of a knot that is topologically but not
smoothly H-slice in an indefinite 4-manifold; under the homeomorphism X → X 0 , the image
RELATIVE GENUS BOUNDS IN INDEFINITE F OUR-MANIFOLDS 3
of the smooth H-slice disk for the right hand trefoil in X is a topological H-slice disk for the
right-handed trefoil in X 0 . Since the right-handed trefoil does not bound a topological disk
in S 3 × [0 , 1], Corollary 1.5 demonstrates that this disparity between smooth and topological
sliceness is inherent to X 0 rather than inherited from the well-kno wn disparity between smooth
and topological sliceness in B 4 .
In a different direction, F uruta’s celebrated 10 / 8-theorem [16] gives constraints on the
intersection forms of smooth spin 4-manifolds. Donald and V afaee [11] used the 10 / 8-theorem
to derive a new sliceness obstruction (in the four-ball). Their result was strengthened b y
T ruong in [65], by applying a refinement of F uruta’s theorem (called the 10 / 8 + 4 theorem)
due to Hopkins-Lin-Shi-Xu [27].
The same techniques can be used to obstruct H-sliceness in other 4-manifolds. We obtain:
Theorem 1.6. Let K ⊂ S 3 be an H -slic e knot in a closed spin 4-manifold X , and let W b e
a spin 2-handlebody with ∂W = S 3
0 ( K ) . If b 2 ( X ) + b 2 ( W ) 6 = 1 , 3 , 23 , then
b 2 ( X ) + b 2 ( W ) ≥ 10
8 · | σ ( X ) − σ ( W ) | + 5 .
In [11, Section 3.2], Donald and Vafaee applied their methods to show that a certain
topologically slice knot, which we call K DV and reproduce in Figure 5, is not smoothly slice.
Theorem 1.6 implies the following.
Corollary 1.7. The topologic ally slice knot K DV is not H -slic e in the K3 surface.
Note that this example is qualitatively different from that of the trefoil in X 0 = K 3# CP 2 ,
because K DV bounds a locally flat disk in a neighborho od of the b oundary , i.e., in S 3 × [0 , 1].
In the terminology of [34], K DV is topologically shallow slice in the K3 surface, whereas the
trefoil is topologically deep slice in X 0 .
Remark 1.8 . In unpublished w ork, Anthony Conw ay and Oliver Singh used the same technique
to investigate topological versus smooth H-sliceness in # n ( S 2 × S 2 ).
1.1. Organization of the paper. In Section 2 we discuss the notions of slice and H-slice
knots in four-manifolds, and give some examples. In Section 3 we review several topological
constraints on the existence of surfaces with boundary inside four-manifolds. In Section 4
we prov e the relative adjunction inequality , Theorem 1.1, along with Theorem 1.4 and Corol-
lary 1.5. In Section 5 we present the relative Donald-V afaee obstruction, Theorem 1.6, and
prove Corollary 1.7. Finally, in Section 6 we list a few open problems.
1.2. Acknowledgmen ts. W e are grateful to Matt Hedden, Michael Klug, Maggie Miller,
Benjamin Ruppik, and Ian Zemke for helpful conv ersations.
2. Slice and H-slice knots
Let X be a closed, connected, oriented, smooth four-manifold, and consider prop erly em-
bedded surfaces in X ◦ := X \ ˚
B 4 .
Definition 2.1. (a) W e say that a knot K in S 3 ∼
= ∂X ◦ is slice in X if it bounds a smo othly ,
properly embedded disk ∆ ⊂ X ◦ .
(b) If K is slice in X and the disk ∆ can be taken so that [∆] = 0 ∈ H 2 ( X ◦ , ∂ X ◦ ) ∼
= H 2 ( X ) ,
we say that K is H -slic e in X .
As a simple observation, w e note that a knot K is slice (resp. H-slice) in X if and only if
its mirror image K is slice (resp. H-slice) in X .
4 CIPRIAN MANOLESCU, MARCO MARENGON, AND LISA PICCIRILLO
+1
∂
=
γ
Figure 1. There is a cobordism in CP 2 \ ( ˚
B 4 t ˚
B 4 ) from LHT to the unknot.
W e denote by S ( X ), resp. S H ( X ), the set of knots that are slice, resp. H-slice, in X . In
particular, we write S = S ( S 4 ) = S H ( S 4 ) for the usual set of slice knots. W e also write K for
the set of all knots. Note that for every X we hav e
(2) S ⊆ S H ( X ) ⊆ S ( X ) ⊆ K .
In a topological 4-manifold X , we also have related notions of top ologic ally slice , and topo-
logic ally H-slice knots in X , referring to the existence of disks that are embedded in a locally
flat way .
Let us mention a few results about sliceness and H-sliceness in some particular four-
manifolds: Norman [45] and Suzuki [60] proved that every knot is slice in CP 2 # CP 2 and
S 2 × S 2 . F urther, Schneiderman [59] show ed that every knot of Arf inv ariant zero is H-slice
in # n ( S 2 × S 2 ) for some n ≥ 0. At the opposite end, for manifolds such as X = S 1 × S 3
or T 4 , we have S ( X ) = S H ( X ) = S . A more interesting example is CP 2 , for which all the
inclusions in (2) are strict. Indeed, there exist knots that are not slice in CP 2 , such as T 2 , − 15 ,
cf. Y asuhara [69, 70]; there are also knots that are slice in CP 2 but not H-slice in CP 2 , such
as the left-handed trefoil; and knots that are H-slice in CP 2 but not slice in S 4 , such as the
right-handed trefoil. (See Examples 2.2–2.4 below.) Sliceness and related notions in # n CP 2
(or its reverse) were further in vestigated in [7], [8], [54].
Inv ariants from Floer homology and Khov anov homology can be used to obstruct H-sliceness
in definite four-manifolds [48, 36, 39, 24].
Example 2.2 . The left hand trefoil (LHT) is not H-slice in CP 2 , for example by the adjunction
inequality for τ or s [51, 39].
Example 2.3 . On the other hand, the right handed trefoil (RHT) is H-slice in CP 2 . One way
to see this is to consider the standard handle diagram for CP 2 . After we remov e the 0-handle
and the 4-handle, we get a cobordism CP 2 \ ( ˚
B 4 t ˚
B 4 ) from S 3 to S 3 . Observe that there is a
null-homologous annulus in CP 2 \ ( ˚
B 4 t ˚
B 4 ) from LHT in ∂ − ( CP 2 \ ( ˚
B 4 t ˚
B 4 )) to the curve γ
in ∂ + ( CP 2 \ ( ˚
B 4 t ˚
B 4 )) shown in the left frame of Figure 1. The annulus is null-homologous
because γ has vanishing linking num ber with the 2-handle. Now observe that when we iden tify
∂ + ( CP 2 \ ( ˚
B 4 t ˚
B 4 )) with the standard diagram of S 3 , as in the right of Figure 1, we can
identify γ as the unknot. Since the unknot bounds a disk in the 4-handle, we have found a
nullhomologous disk in CP 2 \ ˚
B 4 with boundary LHT in ∂ − ( CP 2 \ ˚
B 4 ). Adjusting for the
standard outward-normal-first orien tation on boundaries, the claim follows.
Example 2.4 . Note that the red +1 framed unknot in Figure 1 encircles a crossing of LHT,
with linking number 0. If we had instead considered a − 1 framed unknot encircling a crossing
of LHT, with linking number 2, then we could argue exactly as in Example 2.3 that there is
a cobordism in CP 2 \ ( ˚
B 4 t ˚
B 4 ) from LHT to the unknot, hence proving that RHT bounds a
RELATIVE GENUS BOUNDS IN INDEFINITE F OUR-MANIFOLDS 5
0
− 1 − 1
Figure 2. The handle diagram of the K3 surface from [23, Section 8.3]. All
circles except the right handed trefoil hav e framing − 2.
disk in CP 2 . Howev er in this setting the disk is in homology class 2 H , where H is a generator
of H 2 ( CP 2 ; Z ). After a global change of orien tation, we see that LHT bounds a disk in CP 2
with homology class 2 H , where H is a generator of H 2 ( CP 2 ; Z ).
W e now give some examples of slice and H-slice knots in the K3 surface. W e chose the
K3 surface because it is a symplectic 4-manifold with a rather simple description, but it is
not definite, nor is it homeomorphic to a sum of CP 2 , CP 2 , or S 2 × S 2 . The K3 surface can
be given a handle decomposition with a 0-handle, twent y-two 2-handles, and a 4-handle, as
explained in [23, Section 8.3]. See Figure 2 for such a handle diagram.
Example 2.5 . The left handed trefoil LHT bounds a disk ∆ ⊂ K3 \ ˚
B 4 with [∆] 2 = 0 and
[∆] 6 = 0. T o see this, as in Example 2.3, we locate RHT in ∂ − of the standard handle diagram
of K3 with the 0-handle removed. The core of the trefoil-shaped 2-handle in Figure 2 is a disk
in K3 with boundary this RHT. Thus after correcting for outward normal first orien tation we
see that LHT bounds the desired disk in K3.
The next lemma implies that the family S (K3) of knots that are slice in K3 is quite large.
W e start by giving a definition.
Definition 2.6. We sa y that a knot K 2 is obtained from a knot K 1 by adding a negative
twist along k strands if K 1 and K 2 admit knot diagrams that agree everywhere except in a
small region where they appear as shown in Figure 3.
Lemma 2.7. Let K 0 , K 1 , and K 2 be knots such that K i is obtaine d from K i +1 by adding
a negative full twist along k i strands, and supp ose that k i ≤ 5 . Then, there exists a smo oth,
conne cted, pr operly emb edde d surfac e Σ ⊂ K3 \ ˚
B 4 with ∂ Σ = K 2 and
g (Σ) ≤ g 4 ( K 0 ) .
Pro of. Let X be a closed four-manifold with a handle diagram with no 1-handles, and let
W = X \ ( ˚
B 4 t ˚
B 4 ), seen as a cobordism from S 3 to S 3 . We first observ e that if any T k, − k
torus link appears as a sublink of such a handle diagram (where we make no assumption on
the framings of the components), and the knot J is obtained from K by adding a negative
twist along k strands, then there is an embedded annulus in W from J ⊂ ∂ − W to K ⊂ ∂ + W .
Such an annulus is sho wn in Figure 4.
6 CIPRIAN MANOLESCU, MARCO MARENGON, AND LISA PICCIRILLO
...
k
− 1
...
...
− →
{
Figure 3. The figure sho ws the effect of adding a negative full twist along k strands.
... − 1
...
...
− →
− 1
...
Figure 4. F or a 4-manifold W as in the proof of Lemma 2.7, the red curves
on the left represent some 2-handles of W arranged as a T k, − k torus link. If we
slide k parallel strands of a knot K ⊂ ∂ + W over the 2-handles as sho wn in the
figure, the resulting knot J ⊂ ∂ − W is obtained from K by adding a negative
full twist along k strands.
Now observe that the handle diagram of K3 in Figure 2 con tains two disjoin t copies of T 5 , − 5 ,
namely the 5 outermost components of the left bundle and the 5 innermost components of the
right bundle. Thus, there is an embedded annulus A in W = K3 \ ( ˚
B 4 t ˚
B 4 ) from K 0 to K 2 .
T o get the surface Σ, we attach a minimal genus surface for K 0 in a B 4 glued to ∂ − W .
Corollary 2.8. Any knot K with unknotting number u ( K ) ≤ 2 is slice in K3 .
Pro of. Suppose that the knots K 0 = U (the unknot), K 1 , and K 2 = K are such that K i is
obtained from K i +1 by a crossing change. Note that any crossing change can be realized by
adding a negative full twist along 2 strands. By applying Lemma 2.7, we obtain a slice disk
Σ for K .
Example 2.9 . F rom Corollary 2.8 we see that both trefoils are slice in K3. (See also Example
2.5.) However, note that neither trefoil is H-slice in K3; see Example 3.3 below.
The following lemma illustrates a wa y to construct H-slice knots in a general 4-manifold.
Lemma 2.10. Let X b e a 4-manifold and let K be a knot in S 3 which b ounds a surface Σ of
genus g in X ◦ . Then Wh ±
− [Σ] 2 ( K ) bounds a homolo gically trivial embe dded surfac e Wh ±
− [Σ] 2 (Σ)
of genus 2 g in X ◦ .
Pro of. T ake tw o copies Σ 1 and Σ 2 of Σ with opposite orientations, with boundary the un-
twisted cable C 2 , 0 ( K ), where the two components ha ve opposite orientations. Note that
RELATIVE GENUS BOUNDS IN INDEFINITE F OUR-MANIFOLDS 7
Σ 1 · Σ 2 = − [Σ] 2 . W e can cancel the double points b y bringing them to the boundary, where
they contribute to the linking num ber. Thus, we get a 2-component embedded surface with
boundary C 2 , − 2[Σ] 2 ( K ), i.e. so that the linking number of the two components is equal to [Σ] 2 .
By adding a twisted band to connect the tw o components we get a null-homologous embedded
surface Wh ±
− [Σ] 2 (Σ) with boundary Wh ±
− [Σ] 2 ( K ).
Example 2.11 . By Lemma 2.10 applied to Example 2.5, we see that Wh ±
0 (LHT) is H-slice in
K3.
3. Topological obstructions
W e review here some constraints on the homology classes of surfaces embedded in topolog-
ical four-manifolds.
3.1. The Arf inv ariant. The Kirby-Siebenmann inv ariant ks( X ) ∈ H 4 ( X ; Z / 2) is an ob-
struction to smoothing topological manifolds; see [31]. When X is a closed oriented topological
4-manifold, then ks( X ) is valued in Z / 2 and giv en by the formula
ks( X ) = 1
8 ( σ ( X ) − [Σ] 2 ) − Arf ( X, Σ) (mo d 2) ,
where Σ is any characteristic surface in X ; see [32, Corollary 9.3]. In particular, when X is
smooth, we have ks( X ) = 0 and we obtain:
(3) σ ( X ) − [Σ] 2
8 ≡ Arf ( X, Σ) (mo d 2) .
This result is due to Rokhlin [58]; see [14], [40] for different proofs. There is also a relative
version of (3), as follows.
Theorem 3.1. Let X be a smo oth, closed, c onnecte d, oriented 4 -manifold. If Σ ⊂ X ◦ is a
prop erly embe dded, lo c al ly flat characteristic surfac e with boundary a knot K , then
(4) σ ( X ) − [Σ] 2
8 ≡ Arf ( K ) + Arf ( X, Σ) (mo d 2) .
This appears (with minor modifications) as Corollary 6 on [30, p. 69], and also as Theorem
2.2 in [71]. See [33, Theorem 2] for a generalization of Theorem 3.1 to the case of 4-manifolds
with boundary a homology sphere.
When X is spin and Σ is a null-homologous disk, we hav e σ ( X ) ≡ 0 (mo d 16) and Arf ( X, Σ) =
0. From (4), w e recover an old result of Robertello [56, p. 1-2]:
Theorem 3.2 (Robertello [56]) . If a knot K is topolo gically H-slice in a spin smo oth 4 -
manifold, then Arf ( K ) = 0 .
Example 3.3 . Recall that the Arf inv ariant of a knot can be read from the determinant
D = | ∆ K ( − 1) | : we have Arf = 0 ⇐ ⇒ D ≡ ± 1 (mod 8) . For example, the torus knot
T 2 , 2 k +1 has D = 2 k + 1 and therefore Arf = 0 ⇐ ⇒ k ≡ 0 or 3 (mod 4). Thus, torus knots
of the form T 2 , 8 k +3 and T 2 , 8 k +5 are not H-slice in smooth spin 4-manifolds.
3.2. Levine-T ristram signatures. Giv en a knot K ⊂ S 3 and a value ω ∈ S 1 , the Levine-
T ristram signature σ K ( ω ) is defined as the signature of (1 − ω ) A + (1 − ω ) A T , where A is a
Seifert matrix for K ; see [64], [37], or [9].
F ollowing [43], we denote by S 1
! the set of unit complex numbers that are not zeros of
any integral Lauren t polynomial p with p (1) = 1. Note that S 1
! includes, for example, roots
8 CIPRIAN MANOLESCU, MARCO MARENGON, AND LISA PICCIRILLO
of unity of order a prime power. The ev aluations σ K ( ω ) for ω ∈ S 1
! are knot concordance
inv ariants; see [43]. In particular, for ω = − 1, we obtain the usual knot signature
σ ( K ) := σ K ( − 1) .
The following result is a special case of Theorem 3.8 in [10].
Theorem 3.4 (Conwa y-Nagel [10]) . Let X b e a closed top ologic al 4 -manifold with H 1 ( X ; Z ) =
0 and signature σ ( X ) . If the knot K ⊂ S 3 bounds a lo cally flat, properly emb edde d, null-
homologous surfac e in X ◦ of genus g , then
(5) | σ K ( ω ) + σ ( X ) | ≤ b 2 ( X )+2 g,
for every ω ∈ S 1
! .
Note that we can re-write the constraint (5) as
σ K ( ω ) ∈ [ − 2 b + ( X ) − 2 g, 2 b − ( X )+2 g ] .
One case of interest is when g = 0:
Corollary 3.5 (Corollary 4.7 in [34]) . If K is topolo gically H-slice in X , and ω ∈ S 1
! , then
σ K ( ω ) ∈ [ − 2 b + ( X ) , 2 b − ( X )] .
As an application of this, Klug and Ruppik showed in [34, Theorem 4.4] that for every
closed oriented 4-manifold X , there exists a knot K ⊂ S 3 that is not topologically H-slice in
X .
3.3. Relative Rokhlin-type inequalities. Rokhlin [57] gave constraints on the homology
classes of closed embedded surfaces inside 4-manifolds, provided these homology classes are
divisible by a prime. (Note that this includes the null-homologous case.) Rokhlin’s results
were used by Y asuhara in [69, 70] to pro ve the existence of non-slice knots in CP 2 . Rokhlin’s
results were also used by Klug and Ruppik in [34] to sho w that every closed 2-handlebody
X 6 = S 4 admits knots that are slice in X but not slice in S 4 .
Rokhlin’s constraints were generalized to surfaces with boundary a knot K in the work of
Viro [66] and Gilmer [22, Theorem 4.1 and Remark (a) on p.371]. Note that while Rokhlin,
Viro and Gilmer all worked in the smooth category , the main ingredient in their proofs is the
G -signature theorem [3], which also works in the topological category when applied to tame,
semi-free actions (such as, in our case, the action of deck transformations on a cyclic branched
cover); see [67, Theorem 14B.2]. We will phrase the relative result in the topological category .
Theorem 3.6 (Viro [66], Gilmer [22]) . Let X b e a topolo gical close d oriented 4 -manifold with
H 1 ( X ; Z ) = 0 . Let Σ ⊂ X ◦ b e a loc ally flat, prop erly embe dded surfac e of genus g , with
boundary a knot K ⊂ S 3 . If the homology class [Σ] ∈ H 2 ( X ◦ , ∂X ◦ ) ∼
= H 2 ( X ) is divisible by a
prime power m = p k , then
(6)
σ K ( e 2 πri/m ) + σ ( X ) − 2 r ( m − r ) · [Σ] 2
m 2
≤ b 2 ( X )+2 g,
for every r = 1 , . . . , m − 1 .
Remark 3.7 . When [Σ] is 2-divisible, taking m = 2 in Theorem 3.6 we get:
(7)
σ ( K ) + σ ( X ) − [Σ] 2
2
≤ b 2 ( X )+2 g.
Remark 3.8 . Suppose K is the unknot. After capping K with a disk in B 4 , the inequality (6)
for r = b m/ 2 c gives Rokhlin’s main theorem from [57].
RELATIVE GENUS BOUNDS IN INDEFINITE F OUR-MANIFOLDS 9
Remark 3.9 . When Σ is n ull-homologous, Theorem 3.6 reduces to the Conway-Nagel result
(Theorem 3.4) for ω = e 2 πri/m .
4. Adjunction inequalities
4.1. The adjunction inequality for closed surfaces in closed 4 -manifolds. W e start
by reviewing the adjunction inequality from Seiberg-Witten theory , which gives gen us bounds
on smoothly embedded surfaces in 4-manifolds.
Let X be a closed 4-manifold with b +
2 ( X ) > 1. Recall that X is called of Seiber g-Witten
simple type if the Seiberg-Witten inv ariants SW X, s vanish whenever the expected dimension
of the Seiberg-Witten moduli space,
d ( s ) = c 1 ( s ) 2 − (2 χ ( X )+3 σ ( X ))
4 ,
is nonzero. It is known that complex pro jective surfaces and, more generally, symplectic
4-manifolds are of simple type; cf. [62], [63].
Theorem 4.1 ([35], [41], [46]) . Let X b e a closed 4 -manifold with b +
2 ( X ) > 1 . Let Σ ⊂ X b e
a smoothly emb edde d surface of genus g (Σ) > 0 . Suppose that either
(a) [Σ] 2 ≥ 0 ; or
(b) X is of Seiber g-Witten simple type.
Then, for each spin c structur e s ∈ Spin c ( X ) for which SW X, s 6 = 0 , we have
(8) h c 1 ( s ) , [Σ] i + [Σ] 2 ≤ 2 g (Σ) − 2 .
In Heegaard Floer theory, the analogues of the Seiberg-Witten inv ariants are the Ozsv´ ath-
Szab´ o mixed invariants Φ X, s defined in [51]. The invarian ts Φ X, s are conjecturally equal to the
Seiberg-Witten invarian ts, and have similar properties. W e recall their definition in Section
4.2.
W e say that X is of Ozsv´ ath-Szab´ o simple type if Φ X, s = 0 whenever d ( s ) 6 = 0. It is expected
that symplectic 4-manifolds are of Ozsv´ ath-Szab´ o simple type; see [28, Conjecture 1.3]. In
any case, we kno w that the K3 surface is of Ozsv´ ath-Szab´ o simple type by the calculation in
[50, Section 4]; see [28] for other examples.
Theorem 4.2 (Ozsv´ ath-Szab´ o [51, 50]) . Let X b e a closed 4 -manifold with b +
2 ( X ) > 1 . Let
Σ ⊂ X be a smo othly embe dded surfac e of genus g (Σ) > 0 . Suppose that either
(a) [Σ] 2 ≥ 0 ; or
(b) X is of Ozsv´ ath-Szab´ o simple type.
Then, for each spin c structur e s ∈ Spin c ( X ) for which Φ X, s 6 = 0 , we have
(9) h c 1 ( s ) , [Σ] i + [Σ] 2 ≤ 2 g (Σ) − 2 .
Under the hypothesis (a), this result is [51, Theorem 1.5]. An alternativ e proof was given
by Zemke [72, Theorem 1.6]. Under the hypotheses (b), it is a consequence of the adjunction
relation in [50, Theorem 3.1]. It is also a particular case of Theorem 4.7, which we will prov e
below.
In Seiberg-Witten theory, there is also an adjunction inequalit y for embedded spheres:
Theorem 4.3 (Fintushel-Stern [12]) . L et X be a close d 4 -manifold with b +
2 ( X ) > 1 . Suppose
that there exists a spin c structur e s with SW X, s 6 = 0 . Then, ther e exist no smoothly emb edde d
spheres Σ ⊂ X such that [Σ] 2 ≥ 0 and [Σ] 6 = 0 .
10 CIPRIAN MANOLESCU, MARCO MARENGON, AND LISA PICCIRILLO
Remark 4.4 . The proof of Theorem 4.3 inv olves the blow-up formula and the finiteness of basic
classes. Since the same results also hold in the Heegaard Floer setting (cf. [51, Theorems
1.4 and 3.3]), the adjunction inequality for spheres also holds if we replace the condition
SW X , s 6 = 0 with Φ X, s 6 = 0.
F or future reference, we will need a refinement of Theorem 4.3, based on the Bauer-F uruta
inv ariants instead of the Seiberg-Witten inv ariants. The Bauer-F uruta invarian t takes v alues
in an (equivarian t) stable homotopy group of spheres, and is defined from the Seiberg-Witten
map by using finite dimensional approximation. F or simplicity , we will only consider the
nonequivarian t Bauer-F uruta invarian t, with values in the ordinary stable homotopy groups
of spheres:
BF X, s ∈ π st
d ( s )+1 ( S 0 ) .
Intuitively , via the Pon tryagin-Thom construction, this captures the framed cobordism class
of the Seiberg-Witten moduli space. Unlike the Seiberg-Witten invarian t, it can be nonzero
even when b +
2 ( X ) is even. See [5], [4] for more details.
Theorem 4.5. Let X b e a closed 4 -manifold with b +
2 ( X ) > 1 . Suppose that ther e exists a
spin c structure with BF X, s 6 = 0 . Then, there exist no smoothly emb edde d spheres Σ ⊂ X such
that [Σ] 2 ≥ 0 and [Σ] 6 = 0 .
Pro of. In the case [Σ] 2 = 0, we claim that the arguments given b y Fintushel and Stern in their
proof of Theorem 4.3 in [12, Lemma 5.1] also hold in our case. Indeed, their pro of uses three
ingredients: Theorem 4.1 under the hypothesis (a), the blow-up form ula, and the finiteness
of basic classes.
With regard to Theorem 4.1 (a), its proof (see [35, Lemma 9]) is based on studying the
Seiberg-Witten equations when the metric on X is deformed by inserting a “long neck” around
the surface. Thus, for its hypothesis, instead of asking for SW X ,s 6 = 0, w e could ask that the
Seiberg-Witten equations for ( X, s ) admit a solution for all p ossible metrics and perturbations.
This is automatically guaranteed if BF X, s 6 = 0. (In fact, adjunction inequalities using the
Bauer-F uruta inv ariants were already discussed in a restricted context in [19], [18].)
With regard to the blow-up formula, what w e need is a relation between the Bauer-F uruta
inv ariants of ( X, s ) and ( X # CP 2 , s # s E ), where s E is the spin c structure on CP 2 with c 1 ( s E )
being a generator of H 2 ( CP 2 ; Z ) ∼
= Z . Since CP 2 is negative definite and has H 1 = 0, its
Bauer-F uruta inv ariant is the identity map; see [5, p.17]. W e can then apply the connected
sum formula from [4, Theorem 1.1] to deduce that
(10) BF X, s = BF X # CP 2 , s # s E ,
as in [4, Corollary 4.2].
W e also need that there are only finitely many spin c structures s on X with BF X, s 6 = 0.
Indeed, the proof of finiteness for basic classes in [68] relies on curvature inequalities for
solutions to the Seiberg-Witten equations, and shows that there are only finitely many s such
that such solutions exist.
With these three ingredients in place, the arguments in [12, Lemma 5.1] go through in our
setting, for [Σ] 2 = 0. The case [Σ] 2 > 0 can be deduced from that with [Σ] 2 = 0 using the
blow-up formula.
4.2. The adjunction inequality for closed surfaces in 4-manifolds with boundary.
An inequality of this form was pro ved by Zemk e [72, Theorem 1.6], assuming the map on
CFL − is nonzero. Here we will prove a similar inequalit y involving mixed in variants.
RELATIVE GENUS BOUNDS IN INDEFINITE F OUR-MANIFOLDS 11
The mixed inv ariant for a 4-manifold X with boundary Y and b +
2 > 1 is defined in [51,
Section 8] as follows: We c hoose an admissible cut N that splits X as X 1 ∪ N X 2 , with ∂ X 1 = N
and ∂X 2 = N t Y . For a spin c structure s ∈ Spin c ( X ), we com bine the minus map on X 1 with
the plus map on X 2 and the identification HF +
red ( N ) ∼
= HF −
red ( N ) in the middle, to obtain a
mixed map
HF − ( S 3 ) → HF + ( Y, s | Y ) .
By incorporating the action of A ( X ) = Λ ∗ ( H 1 ( X ; Z ) / Tors)[ U ], w e get a map
Φ X, s : A ( X ) ⊗ Z [ U ] HF − ( S 3 ) → HF + ( Y , s | Y ) ,
which we call the Ozsv´ ath–Szab´ o mixed invariant . W e remark that we consider all the Hee-
gaard Floer modules over F 2 [ U ], where F 2 is the field with two elements (see [29] for a
discussion of the coefficient ring).
F or a cobordism W b etween non-empt y manifolds Y 0 and Y 1 , together with a spin c structure
s which is torsion on Y 0 and Y 1 , we define the quan tity
D( W, s ) = c 2
1 ( s ) − (2 χ ( W )+3 σ ( W ))
4 ,
which is additive under composition of spin c cobordisms.
Note that for a closed 4-manifold X with a spin c structure s , we hav e d ( s ) = D( W, s ) − 1,
where W is X \ ( ˚
B 4 t ˚
B 4 ) seen as a cobordism from S 3 to S 3 . Analogously, for a 4-manifold
X with one boundary component Y and a spin c structure s which is torsion on Y , we define
d ( s ) = D( W, s | W ) − 1 = c 1 ( s ) 2 − (2 χ ( X )+3 σ ( X ))
4 − 1
2 ,
where W = X \ ˚
B 4 seen as a cobordism from S 3 to Y .
Definition 4.6. Let X b e a smooth 4-manifold X with ∂ X = Y and b +
2 ( X ) > 1. W e say that
X is of relative Ozsv´ ath–Szab´ o simple type if Y is a rational homology sphere and Φ X, s = 0
whenever d ( s ) 6 = d ( Y, s | Y ).
Note that when X is closed, then X being of Ozsv´ ath–Szab´ o simple type (in the usual sense)
is equivalen t to X ◦ = X \ ˚
B 4 being of relative Ozsv´ ath–Szab´ o simple type as in Definition 4.6.
Theorem 4.7. Let X be a smo oth 4 -manifold (possibly with b oundary) and b +
2 ( X ) > 1 . Let
Σ ⊂ Int( X ) b e a smoothly emb edde d closed c onnecte d surface of genus g (Σ) > 0 . Suppose that
either
(a) [Σ] 2 ≥ 0 ; or
(b) X is of relative Ozsv´ ath-Szab´ o simple type.
Then, for each spin c structur e s ∈ Spin c ( X ) for which Φ X, s 6 = 0 , we have
(11) h c 1 ( s ) , [Σ] i + [Σ] 2 ≤ 2 g (Σ) − 2 .
Pro of. In case (a) we follow Ozsv´ ath–Szab´ o’s proof of [51, Theorem 1.5]. Split X as X 1 ∪ N X 2
with N an admissible cut. W e first reduce to the case [Σ] 2 = 0 by repeatedly blowing up:
the mixed inv ariant map is still non-v anishing. The surface Σ is replaced by the connected
sum of itself with the exceptional divisor, and the spin c structure on CP 2 is chosen so that
h c 1 ( s ) , [Σ] i + [Σ] 2 does not change.
Since b +
2 ( X ) > 1, there exists a homology class α ∈ H 2 ( X ; Z ) with α 2 > 0 and α · [Σ] = 0.
W e represent α by a smoothly embedded surface T transverse to Σ. By adding tub es on
T to cancel intersections with Σ, we can also assume that T and Σ are disjoint (note that
12 CIPRIAN MANOLESCU, MARCO MARENGON, AND LISA PICCIRILLO
[ T ] = α does not change while doing so). Let N ( T ) be a tubular neighborhoo d of T . Then
N = ∂ N ( T ) is an admissible cut of X , and we can assume that Σ ⊂ X 2 . Since [Σ] 2 = 0, the
cobordism map
F +
X 2 , s : HF + ( N, s ) → HF + ( Y , s )
factors through HF + ( Y #( S 1 × Σ) , s ), which v anishes by [49, Theorem 7.1] unless
|h c 1 ( s ) , [Σ] i| ≤ 2 g (Σ) − 2 .
This concludes the proof of case (a), since the vanishing of HF + ( Y #( S 1 × Σ) , s ) implies that
of Φ X, s too.
W e now turn to case (b). Assume by contradiction that the inequalit y (11) does not hold.
By blowing up appropriately we can repeatedly reduce the quantit y h c 1 ( s ) , [Σ] i + [Σ] 2 by 2
until
h c 1 ( s ) , [Σ] i + [Σ] 2 = 2 g (Σ) ,
while keeping Φ X, s 6 = 0. (Recall that the left hand side of the previous equation is always
even because c 1 ( s ) is characteristic.)
As before, we find an admissible cut of X with Σ ⊂ X 2 . Then, by [72, Theorem 1.5] applied
to Σ, with Σ w being a disk and Σ z = Σ \ Σ w , we ha ve
F +
X 2 , s ( − ) = F +
X 2 , s + P D ([Σ]) ( ι ∗ ( ξ (Σ z )) ⊗ − ) .
Thus, on the mixed inv ariant lev el, we get that
Φ X, s + P D ([Σ]) ( ι ∗ ( ξ (Σ z )) ⊗ − )=Φ X, s ( − ) 6 = 0 ,
showing that Φ X, s + P D ([Σ]) 6 = 0.
Note that s and s + P D ([Σ]) restrict to the same spin c structure on ∂ X : this is because the
condition Σ ⊂ Int( X ) implies that P D ([Σ]) ∈ H 2 ( X ) maps to 0 ∈ H 2 ( ∂X ) under the map
induced by restriction, hence P D ([Σ]) acts trivially on Spin c ( ∂X ).
By arguing as in [46, Corollary 1.7] we get a contradiction with the relativ e Ozsv´ ath–Szab´ o
simple type assumption, since
d ( s + P D ([Σ])) = ( c 1 ( s ) 2 + 4 h c 1 ( s ) , [Σ] i + 4[Σ] 2 ) − (2 χ ( X )+3 σ ( X ))
4 − 1
2
= d ( s ) + h c 1 ( s ) , [Σ] i + [Σ] 2 = d ( s )+2 g (Σ) > d ( s ) .
4.3. Relative adjunction inequalities. We will be interested in surfaces with boundary in
4-manifolds of the form X ◦ = X \ ˚
B 4 , where X is closed. The adjunction inequality for closed
surfaces (Theorem 4.2) has the following immediate consequence.
Theorem 4.8. Let Σ ⊂ X ◦ b e a prop erly embe dded surfac e with g (Σ) + g 4 ( K ) > 0 , where X
is a closed 4-manifold with b +
2 ( X ) > 1 . Suppose that either
(a) [Σ] 2 ≥ 0 ; or
(b) X is of Ozsv´ ath–Szab´ o simple type.
Then, for each spin c structur e s ∈ Spin c ( X ) for which Φ X, s 6 = 0 , we have
(12) h c 1 ( s ) , [Σ] i + [Σ] 2 ≤ 2 g (Σ) − 2+2 g 4 ( K ) .
Pro of. Choose a surface S ⊂ B 4 with boundary K and genus g 4 ( K ). By gluing Σ and S
together we get a closed surface in X , to which w e can apply Theorem 4.2.
RELATIVE GENUS BOUNDS IN INDEFINITE F OUR-MANIFOLDS 13
W e will refine this using the inv ariant ν + constructed by Hom and W u in [26]. Let
CFK ∞ ( K ) denote the ( Z ⊕ Z )-filtered knot Floer complex of a knot K in S 3 , and let i
and j denote the two filtration indices. Following [25], we define A −
s = C { max { j − s, i } ≤ 0 }
and B − = C { i ≤ 0 } . The inclusion map v −
s : A −
s → B − induces a map v −
s, ∗ in homology , and
we define
V s ( K ) := rank F 2 (coker v −
s, ∗ ) .
The numbers V s ( K ) are concordance inv ariants. They are non-negative, non-increasing in s ,
and they vanish for s 0. They were originally defined b y Rasmussen [55], although the
notation V s ( K ) was introduced in [53, Section 8]. The inv ariant ν + is defined as
ν + ( K ) := min { s ≥ 0 | V s ( K )=0 } .
(Strictly speaking, this is the definition of ν − ( K ), but ν − ( K ) = ν + ( K ) by [52, Proposition
2.13].)
Theorem 1.1. Let X b e a closed 4-manifold, with b +
2 ( X ) > 1 . Let Σ ⊂ X ◦ b e a prop erly
embe dded surfac e with g (Σ) > 0 and ∂ Σ = K , and let K denote the mirror of K . Suppose that
either [Σ] 2 ≥ 2 ν + ( K ) or X is of Ozsv´ ath-Szab´ o simple type. Then, for every spin c structure
s ∈ Spin c ( X ) for which the mixed invariant Φ X, s is non-zer o, we have
(13) h c 1 ( s ) , [Σ] i + [Σ] 2 ≤ 2 g (Σ) − 2+2 ν + ( K ) .
Pro of. W e begin by setting up some objects and notation: Let n ≥ 0. Attac h a ( − n )-
framed 2-handle along K to X ◦ . We denote the tr ace of the surgery by X − n ( K ), and we call
ˆ
X − n = X ◦ ∪ S 3 X − n ( K ). Let ˆ
Σ − n denote the surface obtained by capping off Σ with the core
of the 2-handle.
Let ˆ
s be a spin c structure on ˆ
X − n . If H denotes the homology class given by the core of
the 2-handle, for i ∈ Z let s i denote the spin c structure on the positive trace X n ( K ) with
h c 1 ( s i ) , H i = n + 2 i . We denote by t i its restriction of S 3
n ( K ); note that t i = t n + i . F ollowing
usual conven tions, we let s i denote also the corresponding spin c structure on its orientation
reversal X − n ( K ), which has h c 1 ( s i ) , H i = − n − 2 i .
(14) h c 1 ( ˆ
s ) , [ ˆ
Σ − n ] i + [ ˆ
Σ − n ] 2 ≤ 2 g ( ˆ
Σ − n ) − 2
whenever we are in the setting
• [ ˆ
Σ − n ] 2 = [Σ] 2 − n ≥ 0 or ˆ
X − n is of Ozsv´ ath–Szab´ o simple type;
• g ( ˆ
Σ − n ) = g (Σ) > 0; and
• the map
(15) F + : HF + ( S 3 ) → HF + ( S 3
− n ( K ) , ˆ
s | S 3
− n ( K ) )
is nonzero on the bottom element.
W e now chec k that we can choose n and ˆ
s so that these conditions are satisfied. W e will
first assume that either [Σ] 2 > 0 or X is of Ozsv´ ath–Szab´ o simple type. We will deal with the
special case [Σ] 2 = 0 at the end. Notice that the second bullet point is satisfied by hypothesis
and when X is not of Ozsv´ ath–Szab´ o simple type we can satisfy the first half of the first bullet
When X is of Ozsv´ ath–Szab´ o simple type, we will now argue that ˆ
X − n is of relative
Ozsv´ ath–Szab´ o simple type for all n > 0. Supp ose that Φ ˆ
X − n , ˆ
s 6 = 0 for some ˆ
s = s # s i . Since
Φ ˆ
X − n , ˆ
s = F + ◦ Φ X, s , we have that Φ X, s 6 = 0. Since d ( s ) = 0 (b y the simple type assumption)
14 CIPRIAN MANOLESCU, MARCO MARENGON, AND LISA PICCIRILLO
and since the action of Λ k ( H 1 ( X ; Z ) / T ors) lowers the degree b y k , by grading considerations
we hav e
Φ X, s ( h ⊗ ξ ) = 0
whenever h ∈ L k ≥ 1 Λ k ( H 1 ( X ; Z ) / T ors) ⊂ A ( X ) or ξ ∈ U · HF − ( S 3 ) ⊂ HF − ( S 3 ). Th us, the
fact that Φ X, s 6 = 0 implies that the following relation holds:
Φ X, s (1 A ( X ) ⊗ 1 HF − ( S 3 ) )=1 HF + ( S 3 ) .
Thus, the fact that Φ ˆ
X − n , ˆ
s 6 = 0 implies that F + (1 HF + ( S 3 ) ) 6 = 0. Because the map induced by
X − n ( K ) on HF ∞ is nontrivial for n > 0 and for all spin c structures [47, Proposition 9.4], F +
must map 1 HF + ( S 3 ) nontrivially to the to wer of HF + ( Y, t i ). Then, the U -equivariance forces
F + to send 1 HF + ( S 3 ) to the bottom element x of such a tow er. Thus, we can compute
− n ( K ) , t i ) − d ( S 3 ) = d ( S 3
− n ( K ) , t i ) .
Finally , we compute
d ( ˆ
s ) = D( ˆ
X − n \ ˚
B 4 , ˆ
s ) − 1
= (D( X \ ˚
B 4 , s ) − 1) + D( X − n ( K ) , s i )
= d ( s ) + gr ( F + )
= d ( S 3
− n ( K ) , t i )
proving that ˆ
X − n is of relative Ozsv´ ath–Szab´ o simple type.
Now, to chec k when condition (15) is satisfied, we consider the map induced by X − n ( K )
on HF ∞ , which is nontrivial for n > 0 and for all spin c structures [47, Proposition 9.4].
Under our assumption that n > 0 there is a single tower in both the source and the target
of F + . Thus, F + is nonzero on the bottom element if and only if its grading shift gr ( F + )
coincides with d ( S 3
− n ( K ) , ˆ
s | S 3
If we choose the spin c structure s − i on X − n ( K ), we compute
gr ( F + ) = c 1 ( s − i ) 2 − 2 χ − 3 σ
4 = − ( − n +2 i ) 2
n − 2 · 1 − 3 · ( − 1)
4 = n − ( n − 2 i ) 2
4 n .
On the other hand, using S 3
− n ( K ) = − S 3
n ( K ) and d ( − Y, t ) = − d ( Y , t ), we get d ( S 3
− n ( K ) , t − i ) =
− d ( S 3
n ( K ) , t − i ), and by Ni-W u’s formula [44, Proposition 1.6 and Remark 2.10], which holds
for n > 0, we get
d ( S 3
− n ( K ) , t − i ) = n − ( n − 2[ − i ]) 2
4 n + max V [ − i ] ( K ) , V n − [ − i ] ( K ) ,
where [ − i ] ∈ { 0 , 1 , . . . , n − 1 } denotes the reduction of − i (mo d n ).
By imposing gr ( F + ) = d ( S 3
− n ( K ) , t − i ), we get
(16) ( n − 2[ − i ]) 2
4 n = ( n − 2 i ) 2
4 n + max V [ − i ] ( K ) , V n − [ − i ] ( K ) .
Since the V k ’s are non-negative, for i < 0 or i>n the right hand side of Equation (16) is
stricly bigger the the left hand side, so the equality cannot hold. For 0 ≤ i ≤ n , the terms
( n − 2[ − i ]) 2
4 n and ( n − 2 i ) 2
4 n coincide, so Equation (16) reduces to
max { V n − i ( K ) , V n − ( n − i ) ( K ) } = 0 .
Since the V k ’s are non-increasing, we can rewrite it as
V min { i,n − i } ( K )=0 .
RELATIVE GENUS BOUNDS IN INDEFINITE F OUR-MANIFOLDS 15
This is possible if and only if ν + ( K ) ≤ n/ 2. So we can satisfy the third bullet point by
choosing n ≥ 2 ν + ( K ). When X is simple type, we can choose any n ≥ max 1 , 2 ν + ( K ) .
The other case was [Σ] 2 > 0: recall that in such a case we previously chose 0 < n ≤ [Σ] 2 , so
we understand the necessity of our h ypothesis 2 ν + ( K ) ≤ [Σ] 2 .
F or any such an n , we will try to maximize the left hand side of equation (14). T ow ards
that aim, choose ˆ
s = s # s − i on ˆ
X − n , then
h c 1 ( ˆ
s ) , [ ˆ
Σ − n ] i = h c 1 ( s ) , [Σ] i + h c 1 ( s − i ) , H i = h c 1 ( s ) , [Σ] i + ( − n + 2 i ) .
Therefore, Equation (14) becomes
(17) h c 1 ( s ) , [Σ] i + [Σ] 2 − 2 n + 2 i ≤ 2 g (Σ) − 2 .
T o maximize the left hand side of equation 17 we should choose i = n − ν + ( K ), which
yields precisely the inequality (13).
W e now consider the case when [Σ] 2 = 0 (and when X is not of Ozsv´ ath–Szab´ o simple type).
In such a case, our hypothesis [Σ] 2 ≥ 2 ν + ( K ) forces ν + ( K ) = 0, and therefore V 0 ( K ) = 0 too.
Let X 0 ( K ) be the trace of the 0-surgery, endow ed with the spin structure s 0 , characterised
by c 1 ( s 0 ) 2 = 0, and let t 0 denote the restriction of s 0 to S 3
0 ( K ). By [21, Proposition 22],
HF + ( S 3
0 ( K ) , t 0 ) = T +
− 1
2 +2 V 0 ( K ) ⊕ T +
1
2 − 2 V 0 ( K ) ⊕ HF red ( S 3
0 ( K ) , t 0 ) .
Since U decreases the Maslov grading by 2, the homogeneous elements of T +
− 1
2 +2 V 0 ( K ) have
Maslov grading in 2 Z − 1
2 , while those of T +
1
2 − 2 V 0 ( K ) have Maslo v grading in 2 Z + 1
2 .
By [47, Proposition 9.3], the map
F +
s 0 : HF + ( S 3 ) → HF + ( S 3
0 ( K ) , t 0 )
is non-trivial, so its image must be one of the two to wers. Since the grading shift is
gr ( F +
s 0 ) = c 2
1 ( s 0 ) − 2 χ ( X 0 ( K )) − 3 σ ( X 0 ( K ))
4 = − 1
2 ∈ 2 Z − 1
2 ,
we deduce that im( F +
s 0 ) = T +
− 1
2 +2 V 0 ( K ) . Then, the condition V 0 ( K ) = 0 and the fact that
gr ( F +
s 0 ) = − 1
2 guarantee that the bottom element of HF + ( S 3 ) is sent to the bottom element
of T +
− 1
2 +2 V 0 ( K ) = T +
− 1
2
. Thus, condition (15) is satisfied.
Hom and W u proved in [26] that
0 ≤ ν + ( K ) ≤ g 4 ( K ) ,
so the inequality (13) is stronger than (12). On the other hand, the inequality (13) says
nothing about null-homologous surfaces, because ν + ( K ) ≥ 0 is already automatic.
Remark 4.9 . Theorem 1.1 should be compared to another relative adjunction inequalit y, due
to Hedden and Raoux [24]. They proved that, if X be a smooth, oriented four-manifold with
boundary Y and Σ ⊂ X a properly smo othly embedded surface such that the relative element
F X, s ∈ d
H F ( Y ) is non trivial, then
2 τ ( K ) + h c 1 ( s ) , [Σ] i + [Σ] 2 ≤ 2 g (Σ) .
When Y = S 3 , the hypotheses are only satisfied for negative definite 4-manifolds, and we get
the inequality
2 τ ( K ) + k [Σ] k L 1 + [Σ] 2 ≤ 2 g (Σ) ,
which was previously pro ved by Ozsv´ ath and Szab´ o [48].
16 CIPRIAN MANOLESCU, MARCO MARENGON, AND LISA PICCIRILLO
Remark 4.10 . In [42], Mro wka and Rollin prov ed a genus bound for surfaces in four-manifolds
with contact boundary . Sp ecializing to the case when the boundary is S 3 (with its standard
tight contact structure ξ ), their result says that if X ◦ has non-trivial Seiberg-Witten inv ariant
in the spin c structure s , relative to ξ , and Σ ⊂ X ◦ is a smo othly, properly embedded surface,
then
(18) h c 1 ( s ) , [Σ] i + [Σ] 2 ≤ 2 g (Σ) − 1 − sl ( K ) ,
where sl ( K ) is the maximal self-linking number of transverse knots in the isotopy class of
K . In some cases, the inequality (18) is stronger than our bound (13): for example, this
happens for strongly quasipositive quasialternating knots with σ ≤ − 4 (such as the positive
torus knots T 2 , 2 k +1 with k ≥ 2, for which ν + ( T 2 , − (2 k +1) ) = 0 and sl ( T 2 , 2 k +1 ) > 0). In other
situations, however, our bound is stronger: for example, this happens for any knot with
sl ( K ) ≤ 1 − 2 g 4 ( K ) (such as the negative torus knots T 2 , − (2 k +1) , for which g 4 ( T 2 , − (2 k +1) ) =
ν + ( T 2 , 2 k +1 ) = k and sl ( T 2 , − (2 k +1) ) = − 2 k − 1).
W e note that the work in [42] was preceded b y genus bounds in Stein manifolds [2, 38].
Another related result is a version of the symplectic Thom conjecture for manifolds with
boundary, whic h was proved in [6, Theorem 7.2.3] and [20, Theorem 1.2]: If X is a symplectic
four-manifold with convex boundary , and Σ ⊂ X is a symplectic surface with boundary a
transverse knot K ⊂ ∂X , then Σ is genus minimizing in its relative homology class.
4.4. Applications. The K3 surface has one basic class, namely the spin c structure satisfying
c 1 ( s ) = 0. Thus, we can apply the inequality (13) to this case. More generally , we ha ve the
following result.
Corollary 4.11. If ν + ( K ) = 0 , then the knot K does not bound a p ositive self-intersection
surface with genus g (Σ) ≤ 1 in any spin symple ctic manifold X with b +
2 ( X ) > 1 .
Pro of. F rom [50] we know that the canonical class k is a basic class. Since X is also spin,
c 1 ( T X ) = w 2 ( T X ) = 0, so c 1 ( k ) = 0 as w ell, since the canonical bundle is det( T ∗ X ). Thus,
if g (Σ) = 1, we can apply (13) to this case. If g (Σ) = 0, we stabilize Σ once before applying
(13).
Example 4.12 . By Theorem 4.8, if K is one of the trefoils or the figure-eight knot, then K
does not bound a disk ∆ with [∆] 2 > 0 in the K3 surface or in any spin symplectic manifold
with b +
2 > 1, because g 4 ( K ) = 1.
Since the left-handed trefoil and the figure-eight knots hav e ν + = 0, we get better bounds
from Theorem 1.1. Indeed, by Corollary 4.11, the right-handed trefoil or the figure-eight knot
do not even bound a genus-1 surface Σ with [Σ] 2 > 0 in any spin symplectic manifold with
b +
2 > 1.
More generally , by Theorem 4.8 we see that for p, q > 0 and coprime, if the torus knot
T p,q bounds a surface Σ of genus g in a spin symplectic manifold with b +
2 > 1, then [Σ] 2 ≤
2 g − 2+( p − 1)( q − 1). However, by Theorem 1.1 w e get a better bound, namely [Σ] 2 ≤ 2 g − 2
(provided g > 0).
4.5. An application using the Bauer-F uruta inv ariants.
Proposition 4.13. Let X be a smo oth closed 4 -manifold with b +
2 ( X ) ≡ 3 (mo d 4) , admitting
a spin c structure s such that d ( s ) = 0 and S W X, s odd. Let X 0 b e another 4 -manifold with the
same prop erties. Suppose that a knot K ⊂ S 3 is such that the mirr or K b ounds a smooth,
prop erly embe dded disk ∆ ⊂ X ◦ with [∆] 2 ≥ 0 and [∆] 6 = 0 . Then K is not H-slice in X 0 .
RELATIVE GENUS BOUNDS IN INDEFINITE F OUR-MANIFOLDS 17
Pro of. Since d ( s ) = 0 and b +
2 ( X ) ≡ 3 (mo d 4), the Bauer-F uruta inv ariant
BF X, s ∈ π st
1 ( S 0 ) ∼
= Z / 2
is the mod 2 reduction of the Seiberg-Witten invariant; see [4, proof of Proposition 4.4]. By
our assumption SW X , s is odd, so BF X, s is the nontrivial element η (the Hopf map) in π st
1 ( S 0 ).
The same is true for BF X 0 , s 0 . Applying the connected sum formula ([4, Theorem 1.1]), we
obtain
(19) BF X # X 0 , s # s 0 = η 2 6 = 0 ∈ π st
2 ( S 0 ) ∼
= Z / 2 .
Suppose that K bounds an H-slice disk ∆ 0 in ( X 0 ) ◦ . By gluing ∆ to ∆ 0 we obtain a smoothly
embedded sphere S ⊂ X # X 0 with [ S ] 2 ≥ 0 and [ S ] 6 = 0. F rom (19) and Theorem 4.5, we
derive a contradiction.
Theorem 1.4. Let X and X 0 b e closed symple ctic 4 -manifolds satisfying b +
2 ( X ) ≡ b +
2 ( X 0 ) ≡ 3
(mod 4) . Suppose that a knot K ⊂ S 3 is such that the mirr or K bounds a smo oth, prop erly
embe dded disk ∆ ⊂ X ◦ with [∆] 2 ≥ 0 and [∆] 6 = 0 . Then K is not H-slice in X 0 .
Pro of. This follows from Proposition 4.13, using the facts that the canonical class k of a
symplectic manifold satisfies d ( k ) = 0 and S W X, k = ± 1; cf. [61].
Corollary 1.5. There exist smo oth, homeomorphic four-manifolds X and X 0 and a knot
K ⊂ S 3 that is H-slice in X but not in X 0 . For example, one c an take
X = #3 CP 2 #20 CP 2 , X 0 = K 3# CP 2 ,
and K to be the right-hande d trefoil.
Pro of. Note that X = #3 CP 2 #20 CP 2 and X 0 = K 3# CP 2 are simply connected smooth four-
manifolds with the same intersection form, so they are homeomorphic by F reedman’s theorem
[15].
Let K be the right handed trefoil. Then K is H-slice in X b ecause it is already H-slice in
CP 2 ; see Example 2.3.
Recall from Example 2.5 that the left-handed trefoil K bounds a slice disk ∆ in K3 with
[∆] 2 = 0 and [∆] 6 = 0. Since both K3 and its blow-up X 0 = K 3# CP 2 are complex pro jective
surfaces (hence symplectic), we can apply Theorem 1.4 to deduce that K is not H-slice in
X 0 .
5. Relative Donald-V afaee obstr uctions
The following theorem is a generalization of [11] and [65] to spin 4-manifolds.
Theorem 1.6. Let K ⊂ S 3 be an H -slic e knot in a closed spin 4-manifold X , and let W b e
a spin 2-handlebody with ∂W = S 3
0 ( K ) . If b 2 ( X ) + b 2 ( W ) 6 = 1 , 3 , 23 , then
b 2 ( X ) + b 2 ( W ) ≥ 10
8 · | σ ( X ) − σ ( W ) | + 5 .
Pro of. The proof is analogous to [11]. A neighborhoo d of the slice disk Σ in X ◦ together with
the removed ˚
B 4 gives an embedding of X 0 ( K ), the trace of the 0-surgery on K , inside X .
Thus, we ha ve a splitting X = X 0 ( K ) ∪ V . The manifold V is spin (by restricting the spin
structure on X ). We will sho w in the next paragraph that the map
H 1 ( V ; F 2 ) → H 1 ( ∂V ; F 2 )
is surjective, which implies that both spin structures on S 3
0 ( K ) extend to V .
18 CIPRIAN MANOLESCU, MARCO MARENGON, AND LISA PICCIRILLO
+ 8
9
− 1
− 1
− 1
− 1
− 1
Figure 5. The closure of the braid abov e is the topologically slice knot from
[11, Figure 3]. The number within each box indicates the n umber of full twists
performed there. The fractional number + 8
9 indicates 8 ninths of positive full
twist, assuming that the strands locally lie on a cylinder, equally spaced from
each other.
Consider the following portion of the Mayer–Vietoris long exact sequence in homology
associated to X = X 0 ( K ) ∪ V , with F 2 coefficients:
H 2 ( X ) f
− → H 1 ( S 3
0 ( K )) g
− → H 1 ( X 0 ( K )) ⊕ H 1 ( V ) .
Since H 1 ( S 3
0 ( K )) is 1-dimensional, generated by the meridian µ , and H 1 ( X 0 ( K )) = 0, we get
H 2 ( X ) f
− → F 2 h µ i g
− → H 1 ( V ) .
If F is a closed surface in X ◦ ⊂ X transverse to Σ, then F ∩ S 3
0 ( K ) consists of copies of the
meridian µ , and each copy of µ corresponds to an intersection point F ∩ Σ. Thus, f ([ F ]) =
([ F ] · [Σ]) µ (mod 2). Since [Σ] = 0 (with Z coefficients, and hence with F 2 coefficients), the
map f is vanishing, and b y exactness
g : H 1 ( S 3
0 ( K ); F 2 ) → H 1 ( V ; F 2 )
is injective. By taking duals, the restriction map
H 1 ( V ; F 2 ) → H 1 ( ∂V ; F 2 )
is surjective. Thus, both spin structures on S 3
0 ( K ) extend to V .
W e now consider Z = ( − V ) ∪ W . The spin structure on W extends to a spin structure on
Z . Moreover, May er-Vietoris shows that b 2 ( Z ) = b 2 ( V ) + b 2 ( W ) − 1 = b 2 ( X ) + b 2 ( W ) − 1.
By Noviko v’s additivity theorem σ ( Z ) = − σ ( V ) + σ ( W ) = − σ ( X ) + σ ( W ). Thus, by [27], w e
get
b 2 ( X ) + b 2 ( W ) ≥ 10
8 · | σ ( X ) − σ ( W ) | + 5 .
Remark 5.1 . A v ersion of Theorem 1.6 still holds if we allow W to be any spin 4-manifold
with ∂W = S 3
0 ( K ) instead of a 2-handlebody. In that case, we obtain the weak er inequality
b 2 ( X ) + b 2 ( W ) ≥ 10
8 · | σ ( X ) − σ ( W ) | + 4 .
Indeed, the same proof applies, except that b +
2 ( Z ) can now be either b +
2 ( V ) + b +
2 ( W ) or
b +
2 ( V ) + b +
2 ( W ) − 1.
Corollary 1.7. Let K DV be the top ologic ally slice knot in [11, Figure 3] , which is the closur e
of the braid in Figur e 5. Then K DV is not H -slice in the K3 surfac e.
RELATIVE GENUS BOUNDS IN INDEFINITE F OUR-MANIFOLDS 19
Pro of. It is shown in [11, Example 3.4] that S 3
0 ( K DV ) bounds a 2-handleb ody W with b 2 ( W ) =
21 and σ ( W ) = 16. Since b 2 (K3) = 22 and σ (K3) = − 16, if the knot were H -slice in K3 we
would get
22 + 21 ≥ 10
8 · 32 + 5 ,
which is false.
Remark 5.2 . What is really needed for Corollary 1.7 is the non-existence of a smooth, closed,
simply connected 4-manifold with intersection form 4( − E 8 ) ⊕ 5 ( 0 1
1 0 ). This do es not quite
follow from F uruta’s 10 / 8 + 2 theorem [16], but it was known before the general 10 / 8+4
theorem from [27]. Indeed, it is due to Furuta, Kametani and Matsue [17].
6. Open problems
Theorems 3.2, 3.4, 1.4 and 1.6 provide obstructions for a knot to be H-slice in an indefinite
4-manifold. For example, H-slice knots K in the K3 surface must satisfy Arf( K ) = 0 and
σ K ( ω ) ∈ [ − 6 , 38] for all ω ∈ S 1
! . Theorems 3.1, 3.6 and 1.1 give additional constraints on
the homology class of a slice disk in such a four-manifold. One can ask whether, by these
and other methods, one can rule out all homology classes for a slice disk for a knot K in an
indefinite 4-manifold, in the spirit of Y asuhara’s proof that T 2 , − 15 is not slice in CP 2 [69]. In
particular, we raise the following:
Question 6.1. Is there a knot that is not slic e in the K3 surface?
Also, we can ask whether the analogue of Corollary 1.5 holds for slice knots (instead of
H-slice knots).
Question 6.2. Can the set of slice knots dete ct exotic smooth structur es? In other words, do
there exist smo oth, homeomorphic four-manifolds X and X 0 and a knot K ⊂ S 3 that is slic e
in X but not in X 0 ?
Finally , in view of Corollaries 1.5 and 1.7, we propose the following problem.
Question 6.3. Is it true that for every closed 4 -manifold X , there is a knot K that is top o-
logic ally but not smoothly H-slice in X ?
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The Levine-Tristram signature associates to each oriented link L in S³ a function σL: S¹ → \( {\mathbb{z}} \). This invariant can be defined in a variety of ways, and its numerous applications include the study of unlinking numbers and link concordance. In this survey, we recall the three and four dimensional definitions of σL, list its main properties and applications, and give comprehensive references for the proofs of these statements.
Using the 10/8+4 theorem of Hopkins, Lin, Shi, and Xu, we derive a smooth slicing obstruction for knots in the three-sphere using a spin 4-manifold whose boundary is 0–surgery on a knot. This improves upon the slicing obstruction bound by Vafaee and Donald that relies on Furuta’s 10/8 theorem. We give an example where our obstruction is able to detect the smooth non-sliceness of a knot by using a spin 4-manifold for which the Donald-Vafaee slice obstruction fails.
| https://www.researchgate.net/publication/347797321_Relative_genus_bounds_in_indefinite_four-manifolds |
Four Counties Water Users Association v. Middle Park Water Conservancy District | Supreme Court of Colorado | 01-23-1967 | www.anylaw.com
Research the case of Four Counties Water Users Association v. Middle Park Water Conservancy District, from the Supreme Court of Colorado, 01-23-1967. AnyLaw is the FREE and Friendly legal research service that gives you unlimited access to massive amounts of valuable legal data.
Four Counties Water Users Association v. Middle Park Water Conservancy District
This writ of error is from a supplemental adjudication of water rights held by the district court of Grand County for Water District 50. Involved are conditional decrees awarded to claimants Middle Park Water Conservancy District in cooperation with the Colorado River Water Conservation District, defendants in error. They will be referred to as Middle Park, and the District, respectively.
The challenge to the decrees relates to priority dates claimed and allowed in connection with what has been denominated as the Rabbit Ears and Troublesome Projects. The protest and objection to the Rabbit Ears decree is asserted by plaintiff in error, Four Counties Water Users Association, hereinafter referred to as Four Counties.
The controversy concerning the decree granted Middle Park and the District for the Troublesome Project affects the prior adjudicated rights of the defendant in error, Lynn A. Matheson, to whom we will refer by name. The decrees will be discussed as follows:
THE RABBIT EARS PROJECT
Middle Park made a statement of claim for water in connection with the Rabbit Ears Project and requested a priority date of August 18, 1959 based on a survey which it had undertaken as of that date with the cooperation of the District. This work resulted in the filing of a map and statement of claims for the project with the state engineer a few months thereafter. Claim was filed and an adjudication therein held November 2,
1959 resulting in a conditional decree for the project being granted as prayed for with the priority date of August 18, 1959. There is no objection to this original adjudication. Middle Park later filed an amendment to its statement of claim for this project and claimed a different and earlier date for its priority based upon reconnaissance investigation undertaken on the Rabbit Ears Project by the Bureau of Reclamation of the United States starting on September 15, 1950.
At the supplemental hearing on this amended statement, Four Counties appeared and objected and excepted to it, asserting that it would be adversely affected because of claiming a priority of June 2, 1958 for the same waters as claimed by Middle Park.
After hearing held June 13, 1962 Middle Park's amended claim was allowed by the court and a new decree was awarded to it relating back to the 1950 date.
There are other factors, however, which are asserted as making out a stronger case for relation back to the initial Bureau reconnaissance respecting the Rabbit Ears Project. These are that this particular project was specifically identified in the Upper Colorado River Storage Project Act, 43 USC § 620a, passed by the United States Congress in 1956. That legislation directed the Secretary
of the Interior to give priority to the planning of the Rabbit Ears Project and to a report of such planning as well. Testimony was presented that as a result of the identification of the Rabbit Ears Project in such legislation, the Colorado Water Conservation Board had scheduled 1964 or 1965 as the time when such planning would actually begin. As has been stated, Middle Park and the District joined together in 1959 in the making of surveys of the project which resulted in the filing of maps and a statement of claim for water with the state engineer.
The only difference in the factual situation between this case and Four Counties Water v. Colo. River, supra is that the Rabbit Ears Project was specifically named for planning in the 1956 act. The question is whether the inclusion of the Rabbit Ears Project among those having special preference for planning evidenced an intent to appropriate different from what was shown in Four Counties Water v. Colo. River, supra. We conclude that although the interest of the United States in the development of the project might be argued to have become more definite, it still lacked the fixed purpose and intent to effect a diversion of water that would be required to initiate an actual appropriation under Colorado water law. (See discussion in Four Counties Water v. Colo. River, supra.)
This conclusion is compelled by the testimony in the record as to the nature of the planning report to which the act directed the secretary to give priority. It follows:
"Q. All right. I will reframe the question. Explain to the Court the nature of planning reports and what its purpose is. The planning reports, I mean, mentioned in Public Law 485.
"A. Planning reports are very little different than the report I mentioned here (referring to surveys that had been done on the projects) except that it is done in greater detail. For instance, in a planning report it is required that land classification be performed in the field on a map drawn to scale, one inch to four hundred
feet, whereas maps used in this study here are on a scale of one inch to one thousand feet. All of the studies are carried out in greater detail and to such refinement that the Bureau of Reclamation is willing to go to the Congress and recommend authorization, that they found the projects to be fully feasible and justified and that they recommend this construction.
"Q. Then in the ordinary course of Reclamation procedure then is the completion of the planning report necessary before the project can be authorized?
"A. It is necessary, absolutely necessary." (Emphasis supplied.)
It is clear from the above that the United States at no time had made a determination to pursue the Rabbit Ears Project with a definite intent to actually go ahead with the same and thereby appropriate the waters of this state. The first such intention manifested by anyone was that of Middle Park and the District when they commenced, on August 18, 1959, the surveys which led to the filings with the state engineer. As of the first claim and the adjudication obtained, both were of the view that that was the proper date upon which the appropriation had been initiated. The idea to claim the earlier date was an afterthought based on an erroneous premise. For the court to have awarded a priority date earlier than August 18, 1959 on the Rabbit Ears Project was erroneous.
THE TROUBLESOME PROJECT
We now turn to a discussion of the controversy in the instant case involving the Troublesome Project and the defendant in error, Lynn A. Matheson. The evidence regarding the Troublesome Project is similar to that in the Rabbit Ears Project. An August 5, 1959 priority date was originally requested by the claimants based on the commencement of survey work it had done preparatory to the filings with the state engineer. Later an amendment of the statement of claim was made and an amended decree was sought with a September
15, 1950 priority date based on the same kind of work as was done about the same time on the Rabbit Ears Project. Like the Rabbit Ears Project, the Troublesome was named for priority in connection with the completion of planning reports in the 1956 Congressional legislation, 43 USC § 620a. The statement of claimants in their answer brief pretty well sums up the evidence in the record on the Troublesome Project: "The history and development of the Troublesome Project is almost identical to the Rabbit Ears Project."
Our determination that this project falls squarely within the reasoning and the holding in Four Counties Water v. Colo. River, supra would dispose of the matter except for the fact that Middle Park and the District claim right to the earlier 1950 priority date by default. Apparently no objections or exceptions were filed below to Middle Park's amended claim on the Troublesome. Matheson, who was adversely affected by Middle Park's claim thereon as amended, did not protest because of a lack of notice. There is nothing in the record to show to whom or in what manner notice was given of the amended claim, but it appears from a transcript of the record that no notice was given. Counsel for Middle Park stated to the court at one stage of the hearing:
"The court will note that in connection with the Troublesome Project, knowing there would be no formal protest, I have not filed an amended statement of claim but rather have filed amendments of statement of claim, amending certain paragraphs * * *."
This statement was borne out by the record which shows that Paragraph No. 5 of the original statement of claim was stricken and a new paragraph added giving the date of September 15, 1950, and that paragraph No. 7 of the original claim was stricken and a new paragraph substituted. Counsel, it seems, did not treat the matter as a new claim for priority and did not commence anew, giving the requisite notices to those who would be adversely affected.
We find, however, that Matheson was before the court before the conditional decrees were made a final judgment of the court. Cognizant of the fact that Matheson's position was identical with Four Counties and that the amended claim of the Troublesome Project was identical with that in the Rabbit Ears Project, and that the arguments in connection therewith were also the same, it did not reopen the matter to hear Matheson's objection but rather permitted Matheson to join Four Counties in a motion for new trial. When the motion for new trial was denied and the conditional decrees made final by the court, it was fully cognizant of Matheson's prior claim and of the objections to the Troublesome Project.
In this court, although not here as a plaintiff in error, as he probably should have been, Matheson, nevertheless, is a party to these proceedings. He was designated a defendant in error by Four Counties, even though it now appears that he is not adversely affected by Four Counties' Claim and is actually in the same position as Four Counties. Matheson, as defendant in error, filed cross-error in his answer brief as to the Troublesome Project, adopting all of Four Counties' arguments.
We find that there was no appropriation sufficient to satisfy the law by the Bureau of Reclamation in 1950 on the Troublesome Project and that the correct priority date on the Troublesome Project is as originally requested, to-wit: August 5, 1959.
The judgments are reversed and the cause remanded to the trial court with directions to modify the conditional decrees by striking the priority date of September 15, 1950 and substituting therefore the date of November 2, 1959 as to the Rabbit Ears Project, and August 5, 1959 as to the Troublesome Project.
Disposition
| https://www.anylaw.com/case/four-counties-water-users-association-v-middle-park-water-conservancy-district/supreme-court-of-colorado/01-23-1967/cqQ-SGYBTlTomsSBL8Xi |
(PDF) Mutations in the UBIAD1 Gene, Encoding a Potential Prenyltransferase, Are Causal for Schnyder Crystalline Corneal Dystrophy
PDF | Schnyder crystalline corneal dystrophy (SCCD, MIM 121800) is a rare autosomal dominant disease characterized by progressive opacification of the... | Find, read and cite all the research you need on ResearchGate
Mutations in the UBIAD1 Gene, Encoding a Potential Prenyltransferase, Are Causal for Schnyder Crystalline Corneal Dystrophy
DOI: 10.1371/journal.pone.0000685
CC BY 4.0
Authors:
Université de Montréal
Alberta Health Services
Haiyan Jiang
Abstract and Figures
Schnyder crystalline corneal dystrophy (SCCD, MIM 121800) is a rare autosomal dominant disease characterized by progressive opacification of the cornea resulting from the local accumulation of lipids, and associated in some cases with systemic dyslipidemia. Although previous studies of the genetics of SCCD have localized the defective gene to a 1.58 Mbp interval on chromosome 1p, exhaustive sequencing of positional candidate genes has thus far failed to reveal causal mutations. We have ascertained a large multigenerational family in Nova Scotia affected with SCCD in which we have confirmed linkage to the same general area of chromosome 1. Intensive fine mapping in our family revealed a 1.3 Mbp candidate interval overlapping that previously reported. Sequencing of genes in our interval led to the identification of five putative causal mutations in gene UBIAD1, in our family as well as in four other small families of various geographic origins. UBIAD1 encodes a potential prenyltransferase, and is reported to interact physically with apolipoprotein E. UBIAD1 may play a direct role in intracellular cholesterol biochemistry, or may prenylate other proteins regulating cholesterol transport and storage.
Slit lamp image of the right cornea from a 50-year old affected member of family 105, demonstrating a ''bull's eye'' morphology of central and peripheral corneal clouding associated with a relatively spared mid-peripheral zone. Central subepithelial crystalline deposits and prominent corneal arcus are also present. doi:10.1371/journal.pone.0000685.g001 …
SCCD pedigrees. a) Family F105, showing affection status (filled symbols) and phased haplotypes generated by Simwalk for selected markers in the linked chromosomal region. Flanking recombinants in markers 10_55 and 11_752 are indicated. Genders are anonymized to preserve patient confidentiality. b) Family F115, showing affection status (filled symbols). doi:10.1371/journal.pone.0000685.g002 …
ClustalW alignment of vertebrate and invertebrate UBIAD1 putative orthologs. The five familial mutations are highlighted in yellow above the mutated residue. doi:10.1371/journal.pone.0000685.g004 …
Central subepithelial crystalline deposits and prominent corneal arcus are also present. …
a) Family F105, showing affection status (filled symbols) and phased haplotypes generated by Simwalk for selected markers in the linked chromosomal region. Flanking recombinants in markers 10_55 and 11_752 are indicated. Genders are anonymized to preserve patient confidentiality. b) Family F115, showing affection status (filled symbols). …
Mutations in the UBIAD1 Gene, Encodin g a Potential
Prenyltransferas e, Are Cau sal for Schnyder Crystalline
Corneal Dystrophy
Andrew Orr
1,2
, Marie-Pierre Dube
´
3
, Julien Marcadier
4
, Haiyan Jiang
2
, Antonio Federico
5
, Stanley George
1
, Christopher Seamone
1
, David
Andrews
1
, Paul Dubord
6
, Simon Holland
6
, Sylvie Provost
3
, Vanessa Mongrain
4
, Susan Evans
4
, Brent Higgins
7
, Sharen Bowman
7
, Duane
Guernsey
2
, Mark Samuels
2,8¤
*
1 Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada, 2 Department of Pathology, Dalhousie
University, Halifax, Nova Scotia, Canada, 3 Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada, 4 Faculty of Medicine,
Dalhousie University, Halifax, Nova Scotia, Canada, 5 Dipartimento di Scienze Neurologiche e del Comportamento, Universita
`
degli Studi di Siena,
Siena, Italy, 6 Department of Ophthalmology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada, 7 Genome
Atlantic, National Research Council of Canada Institute of Marine Biology, Halifax, Nova Scotia, Canada, 8 Department of Medicine, University of
Montreal, Montreal, Quebec, Canada
Schnyder crystalline corneal dystrophy (SCCD, MIM 121800) is a rare autosomal dominant disease characterized by progressive
opacification of the cornea resulting from the local accumulation of lipids, and associated in some cases with systemic
dyslipidemia. Although previous studies of the genetics of SCCD have localized the defective gene to a 1.58 Mbp interval on
chromosome 1p, exhaustive sequencing of positional candidate genes has thus far failed to reveal causal mutations. We have
ascertained a large multigenerational family in Nova Scotia affected with SCCD in which we have confirmed linkage to the
same general area of chromosome 1. Intensive fine mapping in our family revealed a 1.3 Mbp candidate interval overlapping
that previously reported. Sequencing of genes in our interval led to the identification of five putative causal mutations in gene
UBIAD1, in our family as well as in four other small families of various geographic origins. UBIAD1 encodes a potential
prenyltransferase, and is reported to interact physically with apolipoprotein E. UBIAD1 may play a direct role in intracellular
cholesterol biochemistry, or may prenylate other proteins regulating cholesterol transport and storage.
Citation: Orr A, Dube
´
M-P, Marcadier J, Jiang H, Federico A, et al (2007) Mutations in the UBIAD1 Gene, Encoding a Potential Prenyltransferase, Are
Causal for Schnyder Crystalline Corneal Dystrophy. PLoS ONE 2(8): e685. doi:10.1371/journal.pone.0000685
INTRODUCTION
Schnyder crystalline corneal dystrophy (SCCD, MIM 121800) is
an inherited disorder whose most prominent feature is progressive,
symmetrical opacification of the central cornea, the transparent
anterior face of the eye (Fig. 1). Described first in 1924 by van
Went and Wibaut[1], and later in more detail by Schnyder[2],
SCCD is very rare. Until recently, the world literature contained
fewer than 100 cases[3]. SCCD affects both sexes equally, and is
found in multiple ethnic groups around the globe.
SCCD can become manifest as early as in the first few years of
life, although it more common ly presen ts in the second decade.
Thereaf ter, the clini cal course is somewh at variab le, although
surprisi ngly good vision can be retained long-term despite
signif icant corneal cloudi ng[4]. Eventually however, reduced visual
acuity and glare often mandat e interv ention. While photother-
apeutic keratectom y (remova l of superfi cial corne al layers via
excimer laser ablation) can provide temporary relief in selecte d
cases[5], the definitive treatme nt is surgical rep laceme nt of the
central cornea (pene trating kerato plasty ) with cadaveric donor
tissue. SCCD can recur in the corneal graft postoperati vely [4].
Pathophysiologically, SCCD appears to result from an abnor-
mality in lipid metabolism in the cells of the cornea[6–14].
Examination of corneal tissue removed from affected patients
during transplantation surgery has revealed a tenfold increase in
mainly unesterified cholesterol levels, and a five- to ninefold
increase in phospholipids[11,12]. Immunohistochemical analysis
of the same tissue is consistent with an underlying defect in HDL
metabolism[11]. Although not a constant finding[7], SCCD has
been associated in some patients with systemic dyslipidemia[9,15–
18] and thus possibly to an elevated risk of cardiovascular events
such as myocardial infarction (heart attack) and stroke[9].
SCCD is inherited as an autosomal dominant trait with age-
dependent penetrance, in which it is possible to assign affection
status unambiguously by 40 years of age[19]. Although strongly
genetic, identification of a causal gene has been elusive. Shearman
et al. performed linkage analysis on a large family originally of
Swedish/Finnish ancestry, localizing the defective gene to the
short arm of chromosome 1, at 1p34–36[20,21]. Theendakara et
al. further refined the SCCD locus using families of multiple
ethnicities, reducing the candidate region to a 2.32 Mbp (million
base pair) interval lying between genetic markers D1S1160 and
Academic Editor: Florian Kronenbe rg, Inns bruck Medical Unive rsity, Austria
Received April 23, 2007; Accept ed June 13, 2007; Published August 1, 2007
Copyright: ß 2007 Orr et al. This is an open-access article distributed under the
terms of the Creative Commons Attribu tion License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author
and source are credited.
Funding: AO was supported by the Queen Elizabeth II Health Science Centre
Research Fund. MES was supporte d by Dalhousie University, the IWK Health
Centre, the Dalhousie Medical Research Foundation, the Capital District Health
Authority, Genome Atlantic and Genomic Canada. SB was supported by Genome
Canada/Genome Atlantic. MPD was supported by the Fonds de Recherche en
Sante
´
du Que
´
bec (FRSQ).
Competing Interests: The authors have declared that no competing interests
exist.
* To whom correspondence should be addressed. E-mail: mark.e.samuels@
umontreal.ca
¤ Current addr ess: Department of Medicine, Unive rsity of Montreal, Montreal,
Quebec, Canada
PLoS ONE | www.plosone.org 1 August 2007 | Issue 8 | e685
D1S1635, or possibly a smaller 1.58 Mbp interval between
D1S503 and D1S1635[22]. Recently Aldave et al. and Oleynikov
et al. have reported sequencing of all annotated genes within the
larger interval, finding no pathogenic mutations and tentatively
excluding them as causing SCCD[23,24], a finding proposed to
result from locus heterogeneity, mutations within promoter or
untranslated regions, or the presence of an unannotated gene.
RESULTS
Confirmation of linkage to chromosome 1p
Initial microsatellite genotyping using selected markers from the
published linkage interval[22] on chromosome 1 were consistent
with linkage in family F105 and F115 (see Materials and Methods
and Fig. 2 for ascertainment and descriptions of families
segregating SCCD). The two families together generated a multi-
point sumLOD score of 8.7 using the 90% penetrance trans-
mission model, with family F105 providing essentially all the
statistical power (Fig. 3).
Fine mapping the SCCD locus
We then performed extensive fine mapping utilizing 45 additional
microsatellite markers from published databases or novel markers
developed in our laboratory. All affected individuals segregated
a shared haplotype in family F105 (simplified haplotype shown in
Fig. 2). Recombinant haplotypes in affected individuals 1433 and
1347 (and inherited in each case by an affected child) defined
a likely interval from marker 10_55 to 11_752 (corresponding to
physical map locations of 10.55 Mbp and 11.752 Mbp, re-
spectively) containing the causal gene. The haplotype shared de
facto by the two affected individuals in F115 did not further reduce
this interval, which comprises approximately 1.3 Mbp according
to build 36, and contains 20 annotated genes in public databases.
Although there is no known genealogical relationship between
the families F105 and F115, the affected haplotypes in the two
families shared a small region of three consecutive markers (10_59,
10_70, 10_89) identical by state. These markers defined
a potentially shared interval of 361 Kbp containing three genes
(3 9 end of PEX14, CASZ1, SRG [not currently annotated by
RefSeq]).
Mutation detection of SCCD
Mutation detection by direct DNA sequencing was initiated in the
small potentially shared interval between these two families.
However, no obviously causal mutations were identified in any of
the three genes; moreover several SNPs were detected which
segregated differently in the two families, suggesting that the
microsatellite allele sharing by state was coincidental and not
reflective of identity by descent. Therefore we extended sequenc-
ing of coding exons across the entire 1.3 Mbp interval defined in
family F105.
Following tentative prioritization based on known or predicted
biological function, all or part of 6 additional genes (C1ORF127,
KIAA1337, MASP2, ANGPTL7, FRAP1 and UBIAD1) were
sequenced. Approximately 125 distinct coding exons were
sequenced in total, when potentially causal variants were detected
in both families in gene UBIAD1. In family F105, a heterozygous
missense variant c.355A . G (p. Arg119Gly) was identified (see
Figure S1 for all sequence traces), which segregated to all 18
affected individuals in the pedigree consistently with being on the
affected haplotype. In family F115, a heterozygous missense
variant c.524C . T (p.Thr175Ile) was identified, which segregated
to the two affected individuals in the pedigree. Neither variant was
detected in any sampled unaffected individuals in the pedigrees,
with the possible exception of individual 1443 whose phenotypic
status is uncertain (see Materials and Methods), nor in 144 control
samples (288 chromosomes) collected from the general Nova
Scotia population, nor in 59 unrelated Caucasian CEPH HapMap
DNA samples (118 chromosomes), nor in 89 unrelated Asian
HapMap DNA samples (178 chromosomes). Neither variant
occurs in dbSNP.
Sequencing of UBIAD1 for affected patients from the three
remaining families detected additional heterozygous missense
variants in each of these pedigrees, c.695A . G (p.Asn232Ser) in
F118, c.335A . G (p.Asp112Gly) in F122, and c.305A . G
(p.Asn102Ser) in F123, likewise in residues identical across
vertebrates and invertebrates (Fig. 4). None of the variants was
detected in the Nova Scotia or HapMap control DNA samples or
in dbSNP. Three Nova Scotia and four Caucasian CEPH
HapMap control samples contained a heterozygous missense
variant, c.224C . T (p.Ser75Phe), which appears to be a moder-
ately common (approximately 3%) polymorphism in Caucasian
populations. The identification of five different segregating, rare
missense variants in an extremely conserved gene, strongly
supports the identification of UBIAD1 as the causal gene for
Schnyder crystalline corneal dystrophy. The data suggest limited if
any genetic heterogeneity for this phenotype.
Public databases report three UBIAD1 transcripts of 1.5, 3.1
and 3.5 kb. The 1.5 kb transcript is attributable to the 1520 bp
UBIAD1 reference sequence in NCBI (NM_013319.1, or
CCDS129.1) and Ensembl (Build 38) coding for a 338 amino
acid protein. The 3.1 kb Ensembl (Build 38) gene prediction
corresponds to ENST00000240179 and NCBI cDNA clone
AK074890. The 3.5 kb transcript corresponds to the Ensembl
(Build 38) gene prediction ENST00000376810. These transcript
variants all encode the same 338 amino acid protein product that
was screened by our sequence analysis. There is a rare isoform
variant that is predicted to splice out the UBIAD1 second exon
and add three additional amino acids to the 3 9 end of exon 1
(Ensembl ENST00000376804; Expasy Q9Y5Z9-2). These addi-
tional 3 amino acids are derived from a putative ubiguitin-
conjugating enzyme E2 variant 2 (UBE2V2) pseudogene that is
approximately 8.6 kb from the 3 9 UBIAD1 second exon (NCBI
Accession AL031291), suggesting that this derives from an
aberrantly spliced message.
Figure 1. Slit lamp image of the right cornea from a 50-year old
affected membe r of fam ily 105, dem onstrating a ‘‘bull ’s eye’’
morphology of central and peripheral corneal clouding associated
with a relatively spared mid-peripheral zone. Central subepithelial
crystalline deposits and prominent corneal arcus are also present.
doi:10.1371/journal.pone.0000685.g00 1
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Bioinformatics analysis of UBIAD1
UBIAD1 is a highly conserved gene, almost 100% identical across
much of its length in vertebrate genomes and with extensive
homology in insects. All five putative causal variants detected in
families with SCCD occur at amino acid residues which are
identical in mammalian, avian, fish, and insect putative orthologs
(Fig. 4).
InterPro, Pfam and ProSite all predict that UBIAD1 contains
a prenyltransferase domain from residues 58-333, for which the
archetype is bacterial protein UbiA (hence the name, UBIAD1).
All five detected familial mutations occur in this domain (Fig. 5).
PSORTII predicts 7 transmembrane domains and an integral
membrane localization. No signal peptide or cleavage signal is
predicted by SignalP. No prenylation sites were predicted by
PrePS.
Three tools, SIFT, PANTHER and POLYPHEN were
employed to judge the potential pathogenicity of the five familial
plus one control missense variant. The results of prediction are
shown in Table 1. The familial variants are predicted to have
pathogenic consequences on the protein whereas the control
variant p.Ser75Phe is predicted to be benign. All three methods
predicted the familial mutations p.Asp112Gly and p.Thr175Ile
have deleterious effects on protein function. Two out of three
methods predicted other three familial variants p.Asn102Ser,
p.Arg119Gly, p.Asn232Ser have damaging effects.
The evolutionary conservation score for each residue of
UBIAD1 was calculated and mapped to a predicted 3-dimensional
protein structure by ConSurf (Fig. 6). The scores for the 5 residues
with familial missense mutations, p.Asn102Ser, p.Asp112Gly,
p.Arg119Gly, p.Thr175Ile, and p.Asn232Ser are 9, 9, 7, 9, and 9,
respectively. The score for control polymorphism p.Ser75Phe is 1.
Figure 2. SCCD pedigrees. a) Family F105, showing affection status (filled symbols) and phased haplotypes generated by Simwalk for selected
markers in the linked chromosomal region. Flanking recombinants in markers 10_55 and 11_752 are indicated. Genders are anonymized to preserve
patient confidentiality. b) Family F115, showing affection status (filled symbols).
doi:10.1371/journal.pone.0000685.g00 2
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The familial variants also lie close to each other in contrast to the
control variant on the predicted protein structure model.
Structurally and functionally important regions in the protein
typically appear as patches of evolutionarily conserved residues
that are spatially close to each other[25]. The evolutionary
conservation and the physical proximities of the five familial
variants support that the variants are in a functional region of
UBIAD1 protein.
DISCUSSION
We have identified the putative causal gene for Schnyder
crystalline corneal dystrophy (SCCD) through a positional candi-
date strategy. We ascertained a large Nova Scotia family, as well as
four small families, segregating SCCD in a dominant transmission
pattern. Within the large family we were able to confirm linkage to
the published locus at chromosome 1p36.2–36.3 with high
statistical significance (maxLOD = 8.7), and we defined a minimal
recombinant interval containing 20 annotated genes. Direct DNA
resequencing of coding exons in the region identified five different
10
02468 1 0 1 2 1 4
cM
LOD
D1S2667
LOD = 8.7
ped 1
ped 115
Simwalk2 multipoint linkage: Chomosome 1
Figure 3. Multipoint linkage analysis using Simwalk for Family F105
(ped 1 in the figure) and F115 (ped 115 in the figure), across the
linked chromosomal interval. In this analysis individual 1443 of family
105 was set as phenotype unaffected; the maxLOD increased slightly to
9.5 when 1443 was set to phenotype unknown. A maxLOD = 6.6 was
obtained using an affecteds-only model.
doi:10.1371/journal.pone.0000685.g00 3
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PLoS ONE | www.plosone.org 4 August 2007 | Issue 8 | e685
Figure 4. ClustalW alignment of vertebrate and invertebrate UBIAD1 putative orthologs. The five familial mutations are highlighted in yellow
above the mutated residue.
doi:10.1371/journal.pone.0000685.g00 4
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PLoS ONE | www.plosone.org 5 August 2007 | Issue 8 | e685
is intriguing to speculate that UBIAD1 may play a role in
cardiovascular disease, or may be a potential novel target for
modulation of circulating or intracellular HDL cholesterol levels.
As a significant caveat to our interpretation, biochemical studies
will be required to verify the predicted prenyl binding and/or
prenylation activities of UBIAD1. Measurements of circulating
lipid particles (including HDL subtypes) and perhaps particle flux
in affected individuals would also be informative, although these
have not yet been attempted in our patients. Direct studies of HDL
particle assembly in cell culture models may also clarify the role of
UBIAD1.
Unexpectedly, UBIAD1 also has a proposed role in cancer. The
gene was detected in gene expression studies in transient bladder
carcinoma cells, and named TERE1[27,31]. It is upregulated in
particular cancer types. Clearly a directed study of intracellular
cholesterol transport in the relevant cancers may clarify the role of
TERE1/UBIAD1. Since cell growth is strongly dependent on
synthesis of novel membrane components, pharmaceutical in-
hibition of UBIAD1 could potentially lead to reduction of
unrestricted cell growth.
Mutations are known in the putative Drosophila UBIAD1
ortholog heixuedian ( heix )[32]. These exhibit an array of cellular and
developmental phenotypes including abnormal imaginal disc
growth, hemocyte overgrowth and melanotic tumors, and wing
abnormalities. Other than P-element insertions, the molecular
bases of heix alleles have not been reported, nor have subcellular
histological examinations been reported. It will be interesting to
examine heix mutants in the light of our results, to determine
whether abnormal lipid transport or intracellular cholesterol
deposition underlie the developmental defects.
Figure 5. Conserved amino acid residues in three regions of UBIAD1 containing familial mutations (CS1, CS2, CS3). Also shown are two regions
aligning with putative bacterial UbiA active sites (AS1, AS2), which are overlapped with CS1 and CS3, respectively. Familial mutations plus the control
variant detected in this study are highlighted in yellow above each consensus plot. The sequence logo was generated with the multiple sequence
alignment of distant orthologs selected from Eukaryota, Bacteria, and Archaea. The pairwise alignment of human UBIAD1 and E.coli UbiA peptide
sequences aligned by ClustalW was used to annotate the regions of putative active sites.
doi:10.1371/journal.pone.0000685.g00 5
Table 1. Effects of mutations predicted by SIFT, PANTHER and
PolyPhen.
............... ........................ ....................... ........
Variants Method
SIFT PANTHER PolyPhen
p.Ser75Phe 22 2
p.Asn102Ser ++ 2
p.Asp112Gly ++ +
p. Arg119Gly + 2 +
p.Thr175Ile ++ +
p.Asn232Ser + 2 +
Sequence homology for SIFT prediction was calculated with the alignment of
orthologs selected from Eukaryota. ‘ 2 ’a n d‘ + ’ indicate the predicted benign
and deleterious effects of the mutations, respectively.
doi:10.1371/journal.pone.0000685.t001
.............. ....................... .................
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MATERIALS AND METHODS
Ethical approval for this study was obtained from the Research
Ethics Board of the Queen Elizabeth II Health Sciences Centre.
Clinical Assessment
We ascertained a large family from Nova Scotia known on
a longstanding basis to local corneal specialists. The family, F105,
unilineally segregates SCCD in 18 living affecteds and offered an
excellent opportunity to discover the identity of the defective gene
responsible for this disorder (Fig. 2a). This family is of uncertain,
but possibly Spanish ancestry. Concurrently, we identified another
nuclear family with SCCD, originally from Scotland, that had
recently immigrated to Nova Scotia (F115, two affecteds, Fig. 2b).
Subsequently, two further families were recruited from the clinical
practices of Canadian corneal specialists: family F118, previously
described elsewhere[12], containing two affected members of
unknown ancestry, and family F122, of East Indian descent, with
A
B
Figure 6. Predicted UBIA prenyltransferase domain-containing protein 1 structure from ModBase mapped with evolutionary conservation
scores calculated by ConSurf. Five familial mutations plus one control variant detected in this study are indicated. The color scale ranging from blue
to red represents the conservation score of residue varies from 9 (most conserved) to 1 (most variable). a, Front view; b, Rear view.
doi:10.1371/journal.pone.0000685.g00 6
UBIAD1 Gene
PLoS ONE | www.plosone.org 7 August 2007 | Issue 8 | e685
one known affected member. Lastly, family F123 with two
available affected members, also previously described else-
where[7], was recruited from colleagues in Italy.
Affection status of participants was determined in the following
manner. Individuals were regarded as affected if typical corneal
features of SCCD were present on slit lamp examination, or in
documentary slit lamp images, or if corneal transplantation had
been performed with SCCD as the underlying diagnosis.
Individuals were regarded as unaffected if, by the age of forty,
no features of SCCD were found. To facilitate phase determina-
tion during subsequent haplotype analysis, we collected DNA
specimens from as many family members as possible. In the case of
participants residing outside of Nova Scotia, in whom direct
examination was not possible, individuals older than forty years of
age without a definite diagnosis of SCCD and a history of normal
routine eye examinations were considered to be probably
unaffected. One individual, 1443 in family 105, is also of uncertain
phenotype; visual exam did not indicate status as affected, however
full slit-lamp examination could not be conducted due to local
circumstances.
Control DNA samples were obtained from a randomized
collection of apparently healthy individuals in the local Nova
Scotia population, biased toward Caucasian ancestry. Additional
controls were derived from the set of generally available HapMap
DNA samples, specifically the 60 CEPH Caucasian parents and 90
East Asian unrelated individuals. Affection status of controls was
unknown, but the possibility that any would be affected by SCCD
seems remote, given its rarity and the likelihood in the case of the
local population controls that they would have come to the
attention of clinicians in the academic hospital system associated
with Dalhousie University.
Following written informed consent, saliva or venous blood
samples were obtained from all ascertained subjects, from which
DNA was extracted according to standard protocols. We used the
Oragene kits from DNA Genotek (Ottawa, Canada) for self-
collection of salivary DNA (particularly in situations where it was
desirable for samples to be collected via mail), with excellent DNA
yields and performance during microsatellite genotyping and
direct sequencing.
Genotyping and Linkage Analysis
Microsatellite genotyping was performed using fluorescent pri-
mers. 5 9 tags were added to the reverse, unlabelled primer in each
case to reduce variable non-templated nucleotide addition[33,34].
Products were resolved on ABI 377 electrophoresis instruments
and genotype chromatograms were interpreted using the Gene-
Marker program from SoftGenetics, Inc.[35] See Table S1 for
details of custom marker primers.
Pedigree files and genotype data were imported into Progeny
Lab software version (6.6.01). Mendelian inconsistencies were
identified with Pedcheck version 1.1[36]. Allele calls for in-
consistent markers were set to 0 in the offending nuclear families
involved in the inconsistencies. Genetic positions from the Decode
map were used when available[37]. To calculate genetic position
for markers not on the Decode map, linear interpolation was used
between the two closest common markers flanking the markers to
position, using physical distances provided by human genome
assembly, build 36.
Statistical analyses were conducted with two models.
1. An affected only model in which all individuals not known to
be affected except spouses were set to unknown and using
penetrance set to 0.99, phenocopy rate set to 0.001 for
a dominant disease with allele frequency of 0.001.
2. Penetrance set to 0.90 with a phenocopy rate of 0.001 and
a dominant disease allele frequency of 0.001.
Marker allele frequencies were estimated by maximum likelihood
using Merlin version 1.0.1 (option –fm)[38]. As Merlin can not
handle large pedigrees, pedigree 105 was divided into three
smaller families (branch 2/3, 74/75 and 100/103/101) for this
stage of the analysis. Allelic frequencies from Merlin were
manually incorporated into dat files.
Two-point linkage was carried out using the MLINK routine of
FASTLINK v4.1P on Linux. LOD scores were compiled by
extracting results from the final.out output file using MLINK_-
LODS v2. Multipoint linkage analysis and haplotyping were
carried out using SIMWALK version 2.90 on Linux[39]. The
input files were converted to SIMWALK format using Mega2 v3.0
R4. The haplotype routine converged on the first run for both
pedigrees.
Mutation Detection
Predicted protein coding regions of all examined genes were
amplified using primers designed with Primer3[40] (http://frodo.
wi.mit.edu/) (see Table S2 for sequences) from two affected
individuals from family F105 and one affected individual from
family F115. Coding exons of gene UBIAD1 were subsequently
sequenced in samples from additional affected individuals in all
five families, and from controls. PCR products were sequenced
using ABI 377 or 3700 electrophoresis instruments at the Genome
Atlantic and Institute for Marine Biology TAGC or at the McGill
University and Genome Quebec Centre for Innovation. Sequence
chromatograms were interpreted using the MutationSurveyor
program from SoftGenetics, Inc., with gene annotations from
GenBank[35].
Bioinformatics Analysis
InterPro, Pfam, ProSite, PSORTII, SignalP, and PrePS were run
via the Expasy web site (http://us.expasy.org/tools/ ). The effects
of amino acid substitutions on protein function were predicted
with SIFT[41–43], PolyPhen[44–46], and PANTHER[47,48].
Homologous peptide sequences of human UBIAD1 gene in
Eukaryota, Archaea and Bacteria were retrieved through NCBI
web site using protein-protein BLAST (blastp) against the nr
database. Multiple sequence alignments were computed by
ClustalW and displayed with BoxShade. The sequences of
distantly related orthologs were aligned by MUSCLE[49]. The
sequence logo in Fig. 5 was created by WebLogo[50]. The
evolutionary conservation of amino acid sites with mutations was
analyzed using ConSurf[25,51,52], based on alignments shown in
Fig. S2 and S3. The predicted protein structure from Mod-
Base[53] for the UbiA prenyltransferase domain-containing pro-
tein 1 was used to build a 3D model. Figure 6 was generated using
PyMOL[54].
SUPPORTING INFORMATION
Table S1 Custom microsatellite genotyping marker primer data.
Found at: doi:10.1371/journal.pone.0000685.s001 (0.17 MB
DOC)
Table S2 Primer sequences for mutation detection amplification
of UBIAD1 coding exons (two amplicons for each exon).
Found at: doi:10.1371/journal.pone.0000685.s002 (0.03 MB
DOC)
Figure S1 Mutation detection sequencing traces for affected
patients from each of the five families with SCCD, following
UBIAD1 Gene
PLoS ONE | www.plosone.org 8 August 2007 | Issue 8 | e685
fluorescent sequencing on ABI 377 or 3700 electrophoresis
instruments and alignment to annotated genomic sequences
containing the UBIAD1 gene using MutationSurveyor. Each
panel has 7 lines generated by the software: from top to bottom are
the amino acid translations of consensus and predicted mutation
sequences, forward direction virtual reference trace, forward
direction patient sequence trace, forward direction mutation call,
reverse direction mutation call, reverse direction patient sequence
trace, reverse direction virtual reference trace. a, Family F105; b,
Family F115; c, Family F118; d, Family F122; e, Family F123.
Found at: doi:10.1371/journal.pone.0000685.s003 (0.33 MB TIF)
Figure S2 Multiple sequence alignment of the Eukaryota
orthologs of Human UBIAD1 peptide sequence. The alignment
was used to study the sequence conservation and predict the effects
of mutations.
Found at: doi:10.1371/journal.pone.0000685.s004 (3.89 MB TIF)
Figure S3 Multiple sequence alignment of distant orthologs of
Human UBIAD1 peptide sequence selected from Eukaryota,
Bacteria, and Archaea. The alignment was used to study the
sequence conservation and generate the sequence logo.
Found at: doi:10.1371/journal.pone.0000685.s005 (4.73 MB TIF)
ACKNOWLEDGMENTS
We are grateful to the families who generously contributed their time and
materials for this research.
Author Contributions
Conceive d and de signed the expe riments: MS AO. Perf ormed the
experiments: JM VM SE BH SB DG. Analyzed the data: MS AO MD
JM HJ SP VM SE BH DG. Contributed reagents/materials/analysis tools:
AO AF SG CS DA PD SH. Wrote the paper: MS AO MD DG. Other:
Supervi sed molec ular genetic s exper iments: DG SB. Seni or cli ni cal
investigator: AC. Senior investigator overseeing all molecular genetic
aspects of project: MS.
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| https://www.researchgate.net/publication/6171385_Mutations_in_the_UBIAD1_Gene_Encoding_a_Potential_Prenyltransferase_Are_Causal_for_Schnyder_Crystalline_Corneal_Dystrophy |
JoF | Free Full-Text | EUCAST Ibrexafungerp MICs and Wild-Type Upper Limits for Contemporary Danish Yeast Isolates
Ibrexafungerp is a novel triterpenoid antifungal that inhibits glucan synthase and thus fungal cell wall synthesis. We examined the in vitro activity against contemporary clinical yeast, investigated inter-laboratory and intra-laboratory variability, suggested wild-type upper-limit values (WT-UL), and compared in vitro activity of ibrexafungerp to five licensed antifungals. Susceptibility to ibrexafungerp and comparators was investigated prospectively for 1965 isolates (11,790 MICs) and repetitively for three QC strains (1764 MICs) following the EUCAST E.Def 7.3.2 method. Elevated ibrexafungerp/echinocandin MICs prompted FKS sequencing. Published ibrexafungerp EUCAST MIC-distributions were retrieved and aggregated for WT-UL determinations following EUCAST principles. Ibrexafungerp MICs were & le;2 mg/L except against C. pararugosa, Cryptococcus and some rare yeasts. Modal MICs (mg/L) were 0.06/0.125/0.25/0.5/0.5/0.5/0.5/1/2 for C. albicans/C. dubliniensis/C. glabrata/C. krusei/C. parapsilosis/C. tropicalis/S. cerevisiae/C. guilliermondii/C. lusitaniae and aligned within & plusmn;1 dilution with published values. The MIC ranges for QC strains were: 0.06& ndash;0.25/0.5& ndash;1/0.125& ndash;0.5 for CNM-CL-F8555/ATCC6258/ATCC22019. The WT-UL (mg/L) were: 0.25/0.5/1/1/2 for C. albicans/C. glabrata/C. krusei/C. parapsilosis/C. tropicalis. Adopting these, non-wild-type rates were 0.3%/0.6%/0%/8%/3% for C. albicans/C. glabrata/C. krusei/C. parapsilosis/C. tropicalis and overall lower than for comparators except amphotericin B. Five/six non-wild-type C. albicans/C. glabrata were echinocandin and Fks non-wild-type (F641S, F659del or F659L). Eight C. parapsilosis and three C. tropicalis non-wild-type isolates were echinocandin and Fks wild-type. Partial inhibition near 50% in the supra-MIC range may explain variable MICs. Ibrexafungerp EUCAST MIC testing is robust, although the significance of paradoxical growth for some species requires further investigation. The spectrum is broad and will provide an oral option for the growing population with azole refractory infection.
EUCAST Ibrexafungerp MICs and Wild-Type Upper Limits for Contemporary Danish Yeast Isolates
by Karin M. Jørgensen 1 , Karen M. T. Astvad 1 , Rasmus K. Hare 1 and Maiken C. Arendrup 1,2,3,*
1
Unit of Mycology, Statens Serum Institut, DK-2300 Copenhagen, Denmark
2
Department of Clinical Microbiology, Rigshospitalet, DK-2100 Copenhagen, Denmark
3
Department of Clinical Medicine, University of Copenhagen, DK-2100 Copenhagen, Denmark
*
Author to whom correspondence should be addressed.
J. Fungi 2022 , 8 (10), 1106; https://doi.org/10.3390/jof8101106
Received: 7 September 2022 / Revised: 7 October 2022 / Accepted: 11 October 2022 / Published: 20 October 2022
Abstract
Ibrexafungerp is a novel triterpenoid antifungal that inhibits glucan synthase and thus fungal cell wall synthesis. We examined the in vitro activity against contemporary clinical yeast, investigated inter-laboratory and intra-laboratory variability, suggested wild-type upper-limit values (WT-UL), and compared in vitro activity of ibrexafungerp to five licensed antifungals. Susceptibility to ibrexafungerp and comparators was investigated prospectively for 1965 isolates (11,790 MICs) and repetitively for three QC strains (1764 MICs) following the EUCAST E.Def 7.3.2 method. Elevated ibrexafungerp/echinocandin MICs prompted
FKS
sequencing. Published ibrexafungerp EUCAST MIC-distributions were retrieved and aggregated for WT-UL determinations following EUCAST principles. Ibrexafungerp MICs were ≤2 mg/L except against
C. pararugosa, Cryptococcus
and some rare yeasts. Modal MICs (mg/L) were 0.06/0.125/0.25/0.5/0.5/0.5/0.5/1/2 for
C. albicans
/
C. dubliniensis
/
C. glabrata
/
C. krusei
/
C. parapsilosis
/
C. tropicalis
/
S. cerevisiae
/
C. guilliermondii
/
C. lusitaniae
and aligned within ±1 dilution with published values. The MIC ranges for QC strains were: 0.06–0.25/0.5–1/0.125–0.5 for CNM-CL-F8555/ATCC6258/ATCC22019. The WT-UL (mg/L) were: 0.25/0.5/1/1/2 for
C. albicans
/
C. glabrata
/
C. krusei
/
C. parapsilosis
/
C. tropicalis
. Adopting these, non-wild-type rates were 0.3%/0.6%/0%/8%/3% for
C. albicans
/
C. glabrata
/
C. krusei
/
C. parapsilosis
/
C. tropicalis
and overall lower than for comparators except amphotericin B. Five/six non-wild-type
C. albicans
/
C. glabrata
were echinocandin and Fks non-wild-type (F641S, F659del or F659L). Eight
C. parapsilosis
and three
C. tropicalis
non-wild-type isolates were echinocandin and Fks wild-type. Partial inhibition near 50% in the supra-MIC range may explain variable MICs. Ibrexafungerp EUCAST MIC testing is robust, although the significance of paradoxical growth for some species requires further investigation. The spectrum is broad and will provide an oral option for the growing population with azole refractory infection.
Keywords:
Candida
;
echinocandins
;
ECOFF
;
WT-UL
1. Introduction
Ibrexafungerp (formerly SCY-078) is a novel triterpenoid antifungal that interferes with the fungal cell wall synthesis through inhibition of glucan synthase [ 1 ]. It has fungicidal activity against Candida , including the often multidrug-resistant species Candida auris and fungistatic activity against Aspergillus [ 2 , 3 , 4 , 5 ]. Moreover, ibrexafungerp has activity against the ascus form of Pneumocystis jirovecii and has displayed activity in a murine prophylaxis model of pneumocystosis [ 6 ]. Ibrexafungerp is available in oral formulations and was approved in 2021 by the FDA for treatment of Candida vaginitis. A liposomal intravenous formulation is under development and ibrexafungerp is currently in clinical studies for treatment of refractory or intolerant fungal diseases, for C. auris infections, for treatment of invasive pulmonary aspergillosis in combination therapy with voriconazole, and for recurrent vulvovaginal candidiasis. The mode of action is comparable to that of the echinocandins. The binding site is different from, but overlapping with that of the echinocandins leading to cross-resistance to some but not all FKS mutations in Candida spp. [ 3 , 7 ].
Clinical breakpoints have not yet been set for ibrexafungerp against Candida spp. An obligatory ingredient in breakpoint setting is analysis of MIC distributions from multiple sources and determination of epidemiological cut off values (ECOFF in EUCAST terminology and ECV in CLSI terminology). These are defined as the highest MIC value for isolates devoid of phenotypically detectable acquired resistance mechanisms, also called wild-type isolates [ 8 ]. The ECOFFs do not inform on clinical susceptibility because they only reflect the inherent susceptibility of the species, but they inform on the likelihood of presence of acquired resistance mechanisms that may or may not affect outcome depending on the drug exposure during therapy. Microbroth susceptibility testing is associated with technical variation related to differences between products from different manufacturers (such as brand of microtitre plates, medium and characteristics of the antifungal agent), method used for serial dilution, differences in how materials are made or handled, differences between how different individuals perform the same test, differences in cell density in the inoculum, differences in temperature stability of incubators, differences in atmospheres in incubators, etc. [ 8 , 9 , 10 , 11 ]. To encompass this variation, EUCAST requires at least 100 MICs from at least five independent sources, each consisting of at least 15 isolates and for which the modal MIC may not deviate more than one two-fold dilution from the most common mode for dataset used for EUCAST ECOFF setting [ 8 ]. So far, three studies have reported single or multicentre MICs [ 12 , 13 , 14 ]. The objectives of this study were to examine the in vitro activity of ibrexafungerp against a nationwide and representative sample of contemporary clinical yeast isolates of Candida , to compare the MICs obtained with those recently reported and set preliminary wild-type upper limits (WT-UL), and to compare the activity of ibrexafungerp to that of other agents licensed for the therapy of candidiasis.
2. Materials and Methods
Isolates.
All unique yeast isolates received at the Statens Serum Institut (SSI) as pure cultures or cultured from clinical samples during 2020 and 2021 were included. Same patient same species isolates were regarded as unique if obtained >21 days apart or with a different susceptibility pattern.
Susceptibility testing and target gene sequencing.
EUCAST E.Def 7.3.2 MIC determination was performed for ibrexafungerp and five comparators with
Candida krusei
ATCC 6258,
Candida parapsilosis
ATCC 22019 and
Candida albicans
CNM CL-F8555 as QC strains [
15
]. The MIC determination was performed prospectively during 2020–2021 using multiple batches of in-house prepared trays. Cell culture treated (Nunc™ MicroWell™ 96-Well Microplates, ThermoFisher Scientific cat. no. 167008/161093) were used throughout. Microtitre plates with 2-fold dilutions were prepared using serial dilution and two pipette tip changes and frozen at −80 °C for at least 24 h prior to use [
10
]. Ibrexafungerp (SCY-078, Scynexis Inc., Jersey City, NJ, USA) pure substance was stored in aliquots at −80 °C and stock solutions prepared in DMSO (Sigma-Aldrich, Brøndby, Denmark, 5000 mg/L). The final drug concentration range studied was 0.008–8 mg/L. The following comparator compounds were also investigated (source of compound and final concentration range in parentheses). Anidulafungin (Pfizer A/S, Ballerup, Denmark, 0.004–4 mg/L), micafungin (Astellas Pharma Inc., Tokyo, Japan until August 2021, then from Molcan corporation, Toronto, Canada, 0.004–4 mg/L), amphotericin B (Sigma-Aldrich, 0.004–4 mg/L), fluconazole (Sigma-Aldrich, either 0.06–64 mg/L), and voriconazole (Pfizer A/S, Ballerup, Denmark, 0.004–4 mg/L). The following quality control (QC) strains (number of repetitions) were included:
C. albicans
CNM-CL-F8555 (n = 79),
C. krusei
ATCC 6258 (n = 116) and
C. parapsilosis
ATCC 22019 (n = 99) as quality controls for the comparators and to generate QC MIC data for Ibrexafungerp (1764 MICs for QC strains in total).
FKS sequencing was performed for echinocandin-resistant isolates as previously described [ 16 ].
Data management.
The MIC ranges, modal MIC (the most common MIC), and MIC
50
and MIC
90
(the MIC value that includes 50% and 90% of the isolates, respectively) values were determined for ibrexafungerp and comparators (anidulafungin, micafungin, amphotericin B, fluconazole and voriconazole). Published EUCAST MIC distributions were retrieved and inspected for agreement with data from this study according to the EUCAST SOP 10.2 [
8
]. Ibrexafungerp WT-UL values, defined as the upper MIC value where the wild-type distribution ends, were determined visually and statistically using the EUCAST ECOFFinder programme and inclusion of 97.5% to 99.9% of the predicted wild-type population for species-specific MIC distributions with ≥15 isolates [
17
]. However, as the values reported here are not formally accepted EUCAST ibrexafungerp ECOFFs, we used the term “WT-UL” to avoid confusion.
3. Results
Ibrexafungerp activity against clinical isolates.
In total, 1965 yeast isolates (hereof 1893
Candida
spp. isolates) were included and tested prospectively in parallel with repetitive testing of three quality control strains during 2020 and 2021 using multiple batches of in-house-prepared microdilution EUCAST plates. The number of clinical isolates per year was comparable with 967 isolates, including 540 from blood cultures, from 794 patients in 2020, and 1001 isolates, including 561 blood isolates, from 824 patients in 2021, respectively. The modal MICs were identical comparing MIC distributions from 2020 and 2021 for all species represented with at least 10 isolates (
C. albicans
,
C. dubliniensis
,
C. glabrata
,
C. krusei
,
C. parapsilosis
,
C. tropicalis
,
C. guilliermondii
,
C. lusitaniae
and
S. cerevisiae
) and hence the data from the two years were compiled (
Table 1
). As expected for Gaussian distributions, the modal MIC and MIC
50
values were identical for each species:
C. albicans
: 0.06 mg/L,
C. dubliniensis
0.125 mg/L,
C. glabrata
0.25 mg/L and for
C. krusei
,
C. parapsilosis, C. tropicalis
and
S. cerevisiae
all 0.5 mg/L.
C. guilliermondii, C. lusitaniae
and
C. pararugosa
were less susceptible (modal MIC/MIC
50
values of 1, 2 and 8 mg/L, respectively). Among the rare yeast, ibrexafungerp MICs ≤ 2 mg/L were found for
Arxula adeninivorans
(n = 1),
Lodderomyces elongisporus
(n = 1),
Pichia manshurica
(n = 1),
Wickerhamomyces anomalus
(
Candida pelliculosa
) (n = 2),
Wickerhamomyces onychis
(n = 1),
Yarrowia lipolytica
(
Candida lusitaniae
)(n = 1),
Kodamaea ohmeri
(n = 1) and
Wickerhamomyces
species (n = 1) whereas the majority of the MICs against the remaining rare yeast species were ≥4 mg/L (
Supplementary Table S1
).
Table 1. Ibrexafungerp MICs (mg/L) for 1965 yeast isolates (incl. 1893 Candida spp. isolates) and three other species isolates from Denmark collected in 2020 and 2021 combined.
Activity against quality control strains.
The MIC ranges for ibrexafungerp against all three QC strains spanned two to three two-fold dilutions both years (
Table 2
). The ibrexafungerp modal MICs (mg/L) in 2020, 2021 and combined were:
C. albicans
CNM-CL F8555: 0.125; 0.125 and 0.125,
C. krusei
ATCC 6258: 0.5; 1 and 0.5 and
C. parapsilosis
ATCC 22019: 0.25; 0.25 and 0.25. In comparison, the MIC ranges for the comparators spanned two to four two-fold dilutions for amphotericin B, three to four dilutions for anidulafungin, two to four dilutions for micafungin, three dilutions for fluconazole and three to four dilutions for voriconazole. At least 95% of the MICs for comparators fell within the established MIC ranges for the three QC strains for amphotericin B, anidulafungin and voriconazole but fewer 79% for micafungin against
C. krusei
ATCC 6258 in 2020 and 31–46% for fluconazole against
C. albicans
CNM-CL F8555 in 2020 and 2021, specifically.
Table 2. MIC values for ibrexafungerp and comparators against three QC strains that were tested repetitively throughout the 2-year study period in parallel with the clinical isolates.
Inter-laboratory agreement for ibrexafungerp MIC testing . Next, the ibrexafungerp MIC distributions were compared to those from three recent publications ( Table 3 ) [ 12 , 13 , 14 ]. All MIC distributions were unimodal with the exception of a bimodal MIC distribution for C. albicans (modes 0.03 and 0.125 mg/L) reported in the multicentre study by Quindos et al. [ 14 ], and which therefore was excluded from the WT-UL determination for the aggregated data. The species-specific modal MICs all fell within ± 1 two-fold dilution from the most common species-specific modal MIC. The modal MICs for the aggregated dataset were for all species identical to the ones obtained in this study: C. albicans : 0.06 mg/L, C. glabrata: 0.25 mg/L, C. krusei : 0.5 mg/L, C. parapsilosis : 0.5 mg/L and C. tropicalis 0.5 mg/L.
Table 3. Ibrexafungerp MICs for the five most common Candida species isolates (3146 in total) from this study (n = 1705) and from three additional studies (two single-centre studies [ 12 , 13 ] and a multicentre study [ 14 ]). The Pfaller et al. study [ 13 ] included isolates selected to include wild-type and fluconazole and echinocandin-resistant strains, whereas the two other studies included unselected clinical isolates. The modal MIC is highlighted in underlined font. The consensus WT-UL is indicated by a dashed vertical line ( Table 4 ).
Table 4. Statistical and visual wild-type upper limit values (WT-UL, mg/L) for the five most common Candida spp. determined using the aggregated distributions presented in Table 3 , single-centre data for C. dubliniensis and 97.5–99.9% of the modelled MIC distributions.
WT-UL determination and wild-type non-wild-type classification. WT-ULs were determined statistically including 97.5%, 99%, 99.5% and 99.9% of the modelled aggregated wild-type distributions, and visually. The best agreement between the statistical and visual values was found for the WT-UL including 99.5%, which was chosen for wild-type versus non-wild-type classification. A single-centre WT-UL was also determined for C. dubliniensis MICs from this study following the same criteria ( Table 4 ).
Applying the consensus WT-UL to the Danish isolates, three C. albicans , one C. dubliniensis , three C. glabrata , eight C. parapsilosis and three C. tropicalis were classified as non-wild-type isolates ( Table 1 and Table 3 ). The MIC and Fks information for these isolates are detailed in Table 5 , together with isolates that were found wild-type for ibrexafungerp but anidulafungin- and micafungin-resistant. Among C. albicans isolates with ibrexafungerp MIC 1–2 mg/L, two of three were resistant to anidulafungin and micafungin, and both harboured an F641S alteration in Fks1. The third isolate was anidulafungin, micafungin and FKS wild-type. Among C. albicans isolates with ibrexafungerp MIC 0.25 mg/L and wild-type to ibrexafungerp, two of ten were resistant to anidulafungin and micafungin. Both isolates were FKS -sequenced and harboured alterations known to confer echinocandin resistance (S645P and R1361H, respectively), whereas the remaining eight were anidulafungin and micafungin wild-type and not FKS -sequenced. For C. glabrata with ibrexafungerp MICs 1-2 mg/L, three of three isolates were resistant to anidulafungin or micafungin, and all three harboured alterations involving F659 in Fks2. Eleven C. glabrata isolates were ibrexafungerp wild-type (MIC 0.25–0.5 mg/L) but were resistant to anidulafungin or micafungin. Among these, two harboured an F659Y alteration (ibrexafungerp MIC 0.25 and 0.5 mg/L, respectively), eight isolates harboured alterations involving codons further downstream in Fks1 or Fks2 hot spot regions ( Table 5 ) and one isolate had alteration (K1323E)17 amino acids prior to Fks1 hot spot two. For the remaining species with MICs above the WT-ULs, one of one C. dubliniensis , eight of eight C. parapsilosis and three of three C. tropicalis isolates were anidulafungin- and micafungin- susceptible. Seven of these were FKS -sequenced and confirmed without mutations in the echinocandin hotspots or regions upstream thereof ( Table 5 ).
Table 5. MIC and Fks protein details for isolates with elevated MICs to either ibrexafungerp or echinocandin.
Two additional isolates were found non-wild-type to echinocandins. One was a C. krusei wild-type for ibrexafungerp but with a micafungin MIC of 2 mg/L and an S659P alteration. The other was a C. auris isolate with anidulafungin and micafungin resistance and an Fks1 F635Y alteration [ 18 ]. The ibrexafungerp MIC of this isolate was 1 mg/L, and thus only one two-fold dilution higher than the modal MIC determined in our study of ibrexafungerp EUCAST susceptibility of C. auris [ 3 ].
Growth patterns for ibrexafungerp non-wild-type but echinocandin-susceptible isolates. A total of 13 isolates (one C. albicans , one C. dubliniensis , eight C. parapsilosis and three C. tropicalis ) were deemed ibrexafungerp non-wild-type but anidulafungin- and micafungin-susceptible and FKS wild-type if sequenced. The growth curves of these isolates were inspected and compared to those for selected wild-type isolates ( Supplementary Figure S1a–h ). The growth curves for repeated testing of the C. albicans isolate were characterised by complete inhibition in the presence of 8 and 4 mg/L ibrexafungerp, by partial inhibition close to 50% in the 2–0.25 mg/L concentration range, and by decreasing inhibition with decreasing concentrations thereafter ( Figure S1a ). This led to inconsistent MIC determination in three runs: 0.25 mg/L, 2 mg/L and 4 mg/L, respectively, depending on where the curve intersected the 50% endpoint in the range of partial inhibition. For comparison, the growth curves for five C. albicans isolates without partial inhibition but with differential susceptibility are shown in Figure S1b . The C. dubliniensis isolate displayed a steadily rising growth curve with decreasing concentrations on repeat testing ( Figure S1c ). Three randomly selected C. dubliniensis with MIC 0.125 mg/L are shown in Figure S1d and show a characteristic paradoxical growth in supra MIC concentrations 1–4 mg/L but that does not exceed the 50% cut-off line. Growth curves for the eight C. parapsilosis isolates with MICs 4–8 mg/L when applying a 50% endpoint are shown in Figure S1e and compared to repetitive testing of the C. parapsilosis QC strain ATCC 22019 in Figure S1f . Complete inhibition is seen in the presence of 8 mg/L, partial inhibition in the 0.5–4 mg/L range and loss of activity in the following decreasing concentrations. The level of growth in the partial inhibition area was variable on repeated testing and again led to random MICs depending on if the level exceeded the 50% cut-off line or not. Finally, the three C. tropicalis isolates were compared to three selected isolates where the growth curve intersected the 50% growth line several times complicating endpoint reading, and three randomly chosen isolates displaying paradoxical growth at supra MIC concentrations but not above the 50% ( Figure S1g,h ).
Susceptibility to comparators.
Amphotericin B was the agent with the broadest activity, as resistance was only found against four
Trichosporon
spp. isolates out of the thirty-four rare yeast (
Table 6
). Fluconazole resistance was found among all
Candida
species except
C. kefyr
and
C. lusitaniae
and with acquired resistance ranging from 2.6% in
C. albicans
,
C. dubliniensis
and
C. tropicalis
to over 6.4% in
C. parapsilosis
to 10.1% in
C. glabrata
. A notable number of
Candida
isolates were resistant to voriconazole with rates varying from 0.9% in
C. dubliniensis
to 6.4 and 6.6% in
C. parapsilosis
and
C. glabrata
, respectively. Finally, acquired resistance to anidulafungin/micafungin was found in
C. albicans
1.0/1.8%,
C. glabrata
2.3/3.6%,
C. krusei
0.9/0.9% and
C. parapsilosis
0/2.6%.
Table 6. Susceptibility characteristics given as MIC 50 and MIC range (both mg/L) and percentage of isolates classified as I (susceptible, increased exposure) a and R (resistant) for 1965 Danish yeast isolates collected 2020–2021 to five licensed antifungal agents.
4. Discussion
The main findings in this study were (1) that ibrexafungerp susceptibility testing during 2 years of routine testing conditions was robust, and that inter-laboratory agreement was high when compared to published data, (2) that WT-ULs could be set and adopted for classification into wild-type and non-wild-type phenotypes until formal EUCAST ECOFFs and clinical breakpoints have been established, (3) that ibrexafungerp displays broad activity against all the included
Candida
spp. except
C. pararugosa
, (4) that ibrexafungerp retains activity against most
FKS
mutant isolates found in our laboratory during 2020–2021, and (5) that only amphotericin B displayed a lower resistance rate in agreement with the almost universal activity of this agent. However, the study also identified some technical challenges that may lead to random classification of isolates, particularly for
C. dubliniensis
,
C. parapsilosis
and
C. tropicalis
due to partial growth inhibition in a supra-MIC range for EUCAST testing.
The ibrexafungerp MIC testing was robust as documented by narrow and comparable MIC distributions for QC strains and identical modal MICs for clinical isolates across the two years. This suggests a stable and robust intra-laboratory performance of the EUCAST method. The modal MICs obtained in this study were identical to or one dilution from the modal MIC both for the two QC strains also repeatedly tested by Mesquida et al. [ 12 ], and for the common Candida species included in recent single and multicentre studies of ibrexafungerp EUCAST susceptibility [ 12 , 13 , 14 ]. These observations suggest a good inter-laboratory agreement. Of note however, a bimodal MIC distribution was noted in the multicentre study for C. albicans specifically, with a first peak at 0.03 mg/L and another at 0.125 mg/L suggesting that some optimisation may be warranted, which will be facilitated once QC MIC target and ranges have been established [ 14 ].
The activity of ibrexafungerp was broad and more uniform than for echinocandins against
Candida
spp. with
C. pararugosa
being the only clearly ibrexafungerp-resistant
Candida
species in our study. The activity included the rarer species
S. cerevisiae, A. adeninivorans
,
L
.
elongisporus
,
P. manshurica
,
W. anomalus
(
C. pelliculosa
),
W. onychis
and
Y. lipolytica
(
C
.
lipolytica
), which were susceptible at concentrations up to 2 mg/L. The inherent echinocandin susceptibility of
C. parapsilosis
is notably different compared to that for other
Candida
species (e.g., eight two-fold dilutions for anidulafungin MICs in this study).
In contrast, the ibrexafungerp MICs are more discretely elevated for C. parapsilosis compared to C. albicans (three dilutions) and comparable to those against C. tropicalis and C. krusei . C. parapsilosis harbours an intrinsic amino acid substitution, alanine A660, at the last position of the hot spot region in Fks1 in contrast to proline in the other Candida species (P649 in C. albicans ). This aligns with the fact that the binding site for ibrexafungerp is earlier compared to that for echinocandins and hence not affected by alterations in the mid and last parts of the hotspot region [ 19 ].
Adopting the WT-UL values based upon the aggregated data from this study and three others [ 12 , 13 , 14 ], we found 18 isolates among the common species with non-wild-type MIC. Five of six were C. albicans or C. glabrata with alterations at the first codon in hot spot one of Fks 1 or Fks2 ( C. albicans F641S (n = 2), C. glabrata F659del (n = 2) and F659L (n = 1)), previously associated with ibrexafungerp echinocandin cross-resistance [ 7 , 20 ]. However, we also found two C. glabrata and one C. auris with F659Y and F635Y alterations, respectively, which were echinocandin-resistant but ibrexafungerp wild-type. Pfaller et al. found elevated ibrexafungerp MICs for C. albicans isolates harbouring F641I, F641Y and F641S in Fks1, C. glabrata harbouring F625S, but not F625Y, in Fks1, and F659V in Fks2 and in 2/3 C. tropicalis isolates harbouring the F641S alteration in Fks1 [ 13 ]. Mesquida et al. found three isolates with non-wild-type MICs of which the C. glabrata isolates had a F659S alteration but the C. albicans and C. tropicalis isolates did not harbour Fks alterations among their blood stream isolates [ 12 , 20 ]. These data support that alterations at the phenylalanine (F) codon can cause echinocandin and/or ibrexafungerp resistance but not universally and that some resistant isolates do not harbour Fks alterations. Obviously, this will complicate a translation of molecular data to phenotypic susceptibility pattern. None of our 12 C. dubliniensis , C. parapsilosis or C. tropicalis isolates with elevated ibrexafungerp MICs harboured Fks alterations or displayed resistance to the echinocandins. For a number of these, we believe that a paradoxical growth in the 0.5 to 4 mg/L range led to a random wild-type versus non-wild-type classification depending on if the growth curve intersected the 50% inhibition line or not. Of note, this was not observed for the highest concentration tested (8 mg/L), which is somewhat in contrast to the paradoxical effect described for echinocandins [ 21 ]. We also hypothesise that this is not only an issue in our laboratory, as wide MIC distributions for C. parapsilosis and C. tropicalis were also reported by Quindos et al. [ 14 ]. Obviously, further studies are warranted to explore whether this is solely a technical issue or has potential clinical aspects.
As expected for a new drug class, non-wild-type isolates were less common than for echinocandins and azoles. This is indeed promising, with currently no oral alternatives for azole-resistant infections, and at a time where fluconazole resistance is emerging in both C. glabrata and C. parapsilosis [ 22 , 23 , 24 , 25 ].
5. Conclusions
Ibrexafungerp displayed broad activity against Danish isolates including most FKS mutant Candida isolates and species with inherent or acquired resistance to fluconazole. This is a promising prospect for many patients for whom we today have no oral options. WT-ULs were set and MICs for QC strains presented, which will allow for comparison and interpretation until formal values have been set by EUCAST. A partial inhibition pattern was observed against some isolates, particularly those of C. parapsilosis but also C. dubliniensis and C. tropicalis , which complicated MIC determination. Whether this reflects different clinical susceptibility or a technical issue related to in vitro testing warrants further investigation.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jof8101106/s1 , Figure S1: Growth curve examples for isolates defined as ibrexafungerp wild-type and non-wild-type adopting the WT-UL 97.5%; Table S1: Ibrexafungerp EUCAST MICs of rare yeast.
Author Contributions
Conceptualization, M.C.A.; methodology, M.C.A. and R.K.H.; validation, M.C.A., K.M.J., K.M.T.A. and R.K.H.; formal analysis, K.M.J. and M.C.A.; resources, M.C.A.; data curation, K.M.J., M.C.A.; writing—original draft preparation, M.C.A.; writing—review and editing, M.C.A., K.M.J., K.M.T.A., R.K.H.; visualization, M.C.A. and K.M.J.; supervision, M.C.A.; project administration, K.M.J.; funding acquisition, M.C.A. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by an unrestricted grant from Scynexis, Inc. The funder approved the study design and reviewed the manuscript, but had no influence on the analysis of the results or the interpretation hereof.
Data Availability Statement
Not applicable.
Acknowledgments
We thank research technicians Birgit Brandt, Désiré Mageme Nahimana and Nissrine Abou-Chakra for excellent technical assistance.
Conflicts of Interest
Outside this work the authors have the following potential conflicts to declare: MaCA has, over the past 5 years, received research grants/contract work (paid to the SSI) from Amplyx, Basilea, Cidara, F2G, Gilead, Novabiotics and Scynexis, and speaker honoraria (personal fee) from Astellas, Chiesi, Gilead, MSD and SEGES. She is the current chairman of the EUCAST-AFST. KMJ has received a meeting grant from MSD and travel grants from F2G and Amplyx. RKH has received meeting grants from MSD, Pfizer, Gilead and Astellas and unrestricted research grants from Gilead. KMTA has, over the past 5 years, received speaker honoraria (personal fee) from Gilead and Pfizer.
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Table 1. Ibrexafungerp MICs (mg/L) for 1965 yeast isolates (incl. 1893 Candida spp. isolates) and three other species isolates from Denmark collected in 2020 and 2021 combined.
Species N MIC (mg/L) MIC 50 MIC 90 MIC Range % NWT 0.016 0.03 0.06 0.125 0.25 0.5 1 2 4 8 >8 Candida C. albicans 896 5 91 574 213 10 2 ^ 1 0.06 0.125 0.016–2 0.3 C. dubliniensis 117 15 64 33 4 1 0.125 0.25 0.06–2 0.9 C. glabrata 475 5 319 148 2 ^ 1 ^ 0.25 0.5 0.125–2 0.6 C. krusei 110 14 74 22 0.5 1 0.25–1 0 C. parapsilosis 78 1 23 44 2 1 6 1 0.5 2 0.125–8 10.3 C. tropicalis 146 8 44 75 16 2 1 0.5 1 0.125–8 2.1 C. guilliermondii 12 1 10 1 1 NA 0.5–2 NA C. kefyr 8 1 5 2 0.25 NA 0.125–0.5 NA C. lusitaniae 19 7 11 1 2 2 1–4 0 Other Candida # 33 2 16 4 10 1 NA NA 0.125–8 NA Other yeast S. cerevisiae 30 1 10 19 0.5 0.5 0.125–0.5 NA Cryptococcus spp. 7 5 2 2 NA 2–4 NA Rare yeast * 34 1 3 3 3 2 3 13 6 NA NA 0.03–>8 NA In total 1965 5 92 589 295 477 374 74 23 14 16 6 NA
Modal MICs are underlined; non-wild-type (NWT) MIC defined as MICs above the consensus WT-UL (see WT-UL determination section below) are highlighted using bold font. ^ indicates ibrexafungerp non-wild-type isolates that harbour Fks amino acid (AA) alterations: C. albicans : both isolates F641S, C. glabrata : two isolates with F659del and one with F659L. # Other Candida included the following species with ibrexafungerp MIC in the 0.125–0.5 range: C. metapsilosis (one), C. orthopsilosis (eight), C. lambica (one), C. norvegensis (six), C. pelliculosa (two), C. utilis (one); the following species with ibrexafungerp MIC in the 0.5–2 range: C. intermedia (one), C. stellimalicola (one) C. auris (two), C. fermentati (four), C. inconspicua (one), C. lipolytica (one), C. melibiosica (one), C. pulcherrima (one), C. sorbosivorans (one); and finally one C. pararugosa with an MIC of 8 mg/L. * Rare yeast included the following species with ibrexafungerp MIC ≤ 0.5 range: Arxula adeninivorans (one), Lodderomyces elongisporus (one), Pichia manshurica (one), Wickerhamomyces anomalus (two), Wickerhamomyces onychis (one) and Yarrowia lipolytica (one); the following species with ibrexafungerp MIC in the 0.5–2 range: Wickerhamomyces species (one); and finally the following species that included isolates with the majority of MICs being 4 mg/L or greater: Magnusiomyces capitatus (five), Trichosporon asahii (four), Geotrichum candidum (five), Rhodotorula mucilaginosa (three), Exophiala dermatitidis (one), Lachancea thermotolerans (one), Trichosporon dermatis (two), Geotrichum capitatum (two), Geotrichum species (two) and Geotrichum silvicola (one). NA: Not applicable, MIC 50 values were determined for all species-specific MIC distributions. MIC 90 values for species with ≥15 isolates.
Table 2. MIC values for ibrexafungerp and comparators against three QC strains that were tested repetitively throughout the 2-year study period in parallel with the clinical isolates.
Compound MIC (mg/L) % within Range QC Strain, Year (N. of Repetitions) ≤0.004 0.008 0.016 0.03 0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 Ibrexafungerp C. albicans CNM-CL F8555, 2020 (37) 16 20 1 C. albicans CNM-CL F8555, 2021 (42) 16 25 1 C. krusei ATCC 6258, 2020 (68) 43 25 C. krusei ATCC 6258, 2021 (48) 23 25 C. parapsilosis ATCC 22019, 2020 (55) 4 32 19 C. parapsilosis ATCC 22019, 2021 (44) 31 13 Amphotericin B C. albicans CNM-CL F8555, 2020 (37) 10 23 4 100% C. albicans CNM-CL F8555, 2021 (42) 12 30 100% C. krusei ATCC 6258, 2020 (68) 0 36 32 100% C. krusei ATCC 6258, 2021 (48) 5 38 5 100% C. parapsilosis ATCC 22019, 2020 (55) 3 16 33 3 100% C. parapsilosis ATCC 22019, 2021 (44) 1 23 19 1 100% Anidulafungin C. albicans CNM-CL F8555, 2020 (37) 21 16 C. albicans CNM-CL F8555, 2021 (42) 37 5 C. krusei ATCC 6258, 2020 (68) 6 57 5 100% C. krusei ATCC 6258, 2021 (48) 9 39 100% C. parapsilosis ATCC 22019, 2020 (55) 1 5 42 7 98% C. parapsilosis ATCC 22019, 2021 (44) 7 35 2 100% Micafungin C. albicans CNM-CL F8555, 2020 (37) 15 22 C. albicans CNM-CL F8555, 2021 (42) 31 11 C. krusei ATCC 6258, 2020 (68) 0 54 14 79% C. krusei ATCC 6258, 2021 (48) 0 47 1 98% C. parapsilosis ATCC 22019, 2020 (55) 1 6 43 5 98% C. parapsilosis ATCC 22019, 2021 (44) 2 36 6 100% Fluconazole C. albicans CNM-CL F8555, 2020 (37) 20 17 0 46% C. albicans CNM-CL F8555, 2021 (42) 29 12 1 31% C. krusei ATCC 6258, 2020 (68) 5 59 4 100% C. krusei ATCC 6258, 2021 (48) 1 42 5 100% C. parapsilosis ATCC 22019, 2020 (55) 14 38 3 95% C. parapsilosis ATCC 22019, 2021 (44) 14 28 2 95% Voriconazole C. albicans CNM-CL F8555, 2020 (37) 2 33 2 95% C. albicans CNM-CL F8555, 2021 (42) 4 36 1 1 90% C. krusei ATCC 6258, 2020 (68) 1 10 57 100% C. krusei ATCC 6258, 2021 (48) 0 4 42 2 96% C. parapsilosis ATCC 22019, 2020 (55) 8 43 4 100% C. parapsilosis ATCC 22019, 2021 (44) 1 29 14 100%
The concentration range tested varied by agent. Grey colour indicates concentrations not tested. The modal MICs for the MICs obtained in this study are highlighted in bold font. The recommended EUCAST MIC range and target MIC for the QC strains are indicated in green shading and underlined font, respectively, as summarised in “The European Committee on Antimicrobial Susceptibility Testing. Routine and extended internal quality control for MIC determination and agar dilution for yeasts, moulds and dermatophytes as recommended by EUCAST. Version 6.0, 2022. http://www.eucast.org ”.
Table 3. Ibrexafungerp MICs for the five most common Candida species isolates (3146 in total) from this study (n = 1705) and from three additional studies (two single-centre studies [ 12 , 13 ] and a multicentre study [ 14 ]). The Pfaller et al. study [ 13 ] included isolates selected to include wild-type and fluconazole and echinocandin-resistant strains, whereas the two other studies included unselected clinical isolates. The modal MIC is highlighted in underlined font. The consensus WT-UL is indicated by a dashed vertical line ( Table 4 ).
Species N 0.016 0.03 0.06 0.125 0.25 0.5 1 2 4 8 >8 nwt % Reference C. albicans 896 5 91 574 213 10 2 1 3 0.3 This study C. albicans 462 5 101 245 107 3 1 1 0.2 [ 12 ] C. albicans 29 3 12 7 1 2 3 1 6 20.7 [ 13 ] C. albicans 163 7 50 48 50 6 2 2 1.2 [ 14 ] Aggregated excl. [ 14 ] 1387 10 195 831 327 14 3 5 2 10 0.7 C. glabrata 475 5 319 148 2 1 3 0.6 This study C. glabrata 120 3 54 59 3 1 4 3.3 [ 12 ] C. glabrata 29 15 12 3 1 4 13.8 [ 13 ] C. glabrata 60 2 1 10 22 16 5 1 2 1 9 15.0 [ 14 ] Aggregated 684 2 1 18 410 235 13 4 2 1 20 2.9 C. krusei 110 14 74 22 0 0.0 This study C. krusei 24 2 10 10 2 2 8.3 [ 12 ] C. krusei 19 3 121 4 0 0.0 [ 13 ] C. krusei 29 1 2 10 16 0 0.0 [ 14 ] Aggregated 182 1 21 215 52 2 2 1.1 C. parapsilosis 78 1 23 44 2 1 6 1 8 10.3 This study C. parapsilosis 249 1 22 127 92 7 0 0.0 [ 12 ] C. parapsilosis 15 1 11 3 0 0.0 [ 13 ] C. parapsilosis 108 6 1 3 10 38 24 15 6 5 26 24.1 [ 14 ] Aggregated 450 6 2 27 171 177 33 16 12 6 34 7.6 C. tropicalis 146 8 44 75 16 2 1 3 2.1 This study C. tropicalis 73 1 3 36 24 8 1 1 1.4 [ 12 ] C. tropicalis 21 1 3 10 3 2 2 0 0.0 [ 13 ] C. tropicalis 40 2 3 9 12 8 5 1 1 2.5 [ 14 ] Aggregated 280 1 3 17 99 114 34 7 3 1 1 5 1.8 C. dubliniensis 117 15 64 33 4 1 1 0.9 This study
nwt: non-wild-type.
Table 4. Statistical and visual wild-type upper limit values (WT-UL, mg/L) for the five most common Candida spp. determined using the aggregated distributions presented in Table 3 , single-centre data for C. dubliniensis and 97.5–99.9% of the modelled MIC distributions.
Statistical WT-UL Values Visual WT-UL Consensus WT-UL 97.5% 99.0% 99.5% 99.9% C. albicans 0.125 0.125 0.25 0.25 0.25 0.25 C. glabrata 0.5 0.5 0.5 1 1 0.5 C. krusei 1 1 1 1 1 1 C. parapsilosis 1 1 1 2 2 1 C. tropicalis 1 2 2 2 2 2 C. dubliniensis 0.25 0.5 0.5 0.5 0.5 0.5
Table 5. MIC and Fks protein details for isolates with elevated MICs to either ibrexafungerp or echinocandin.
Species MIC (mg/L) * Fks Amino Acid Alterations IBX ANF MFG AMB FLZ VRZ C. albicans 2 0.008 0.03 0.125 0.125 0.004 WT C. albicans 1 0.06 0.25 0.25 0.5 0.016 F641S C. albicans 1 0.125 0.5 0.25 0.125 0.004 F641S C. albicans 0.25 0.25 1 0.125 0.125 0.008 R1361H C. albicans 0.25 0.008 0.03 0.25 0.25 0.008 C. albicans 0.25 0.008 0.03 0.25 0.125 ≤0.004 C. albicans 0.25 0.004 0.016 0.25 0.25 0.008 C. albicans 0.25 0.008 0.016 0.25 0.5 0.008 C. albicans 0.25 0.25 2 0.25 0.25 0.008 S645P C. albicans 0.25 0.004 0.016 0.25 0.25 0.008 C. albicans 0.25 0.008 0.03 0.5 0.25 0.008 C. albicans 0.25 0.008 0.016 0.125 0.125 ≤0.004 C. albicans 0.25 ≤0.004 0.016 0.5 0.5 0.008 C. albicans 0.125 0.03 0.06 0.25 0.25 0.008 R1361H C. albicans 0.06 0.06 0.125 0.25 0.125 ≤0.004 R1361S C. albicans 0.06 0.125 0.25 0.25 0.25 ≤0.004 R1361S C. albicans 0.06 0.016 0.06 0.25 0.125 0.004 S645P C. dubliniensis 2 0.016 0.03 0.06 0.5 0.016 WT C. dubliniensis 0.5 0.016 0.03 0.06 0.5 0.016 C. dubliniensis 0.5 0.03 0.06 0.25 0.5 0.016 C. dubliniensis 0.5 0.016 0.03 0.25 0.5 0.016 C. dubliniensis 0.5 0.008 0.016 0.06 0.25 0.016 C. glabrata 2 0.5 0.5 0.25 2 0.03 F659del (Fks2) C. glabrata 1 1 2 0.25 32 0.5 F659del (Fks2) C. glabrata 1 0.03 0.06 0.25 2 0.06 F659L (Fks2) C. glabrata 0.5 0.06 0.06 0.25 16 0.5 S629P (Fks1) C. glabrata 0.5 0.06 0.06 0.125 4 0.06 L662F (Fks2) C. glabrata 0.5 0.125 0.06 0.25 8 0.125 F659Y (Fks2) C. glabrata 0.5 0.125 0.125 0.25 32 1 P667I (Fks2) C. glabrata 0.5 1 1 0.25 4 0.125 S663P (Fks2) C. glabrata 0.5 1 1 0.5 >64 4 S663P (Fks2) C. glabrata 0.5 0.125 0.125 0.5 64 2 L662W (Fks2) C. glabrata 0.5 2 2 0.25 4 0.06 S629P (Fks1)/L640X (Fks2) C. glabrata 0.25 0.06 0.25 0.25 4 0.125 R665G (Fks2) C. glabrata 0.25 0.125 0.06 0.25 2 0.06 F659Y (Fks2) C. glabrata 0.25 0.03 0.06 0.25 2 0.06 K1323E 17 AA prior to Fks1 HS-2 C. krusei 1 0.125 2 0.5 32 0.5 S659P/L701M C. parapsilosis 8 2 4 1 >16 >4 WT C. parapsilosis 4 1 2 1 64 1 C. parapsilosis 4 2 2 0.5 64 2 C. parapsilosis 4 0.5 1 0.5 1 0.016 C. parapsilosis 4 1 2 0.5 0.5 0.008 C. parapsilosis 4 0.5 2 0.5 0.25 0.008 C. parapsilosis 4 0.5 1 0.5 0.25 0.016 C. parapsilosis 2 2 4 1 1 0.016 WT C. tropicalis 8 0.016 0.03 0.5 0.5 0.03 WT C. tropicalis 4 0.016 0.03 0.5 2 0.125 WT C. tropicalis 4 0.016 0.016 0.125 0.5 0.03 WT C. tropicalis 1 0.03 0.06 0.5 4 0.125 WT C. auris 1 2 >4 1 >64 1 F635Y
* MICs that are categorised as non-wild-type for ibrexafungerp with all four WT-UL values and for the echinocandins adopting the EUCAST ECOFFs are indicated in red . Blue is used for Fks alterations at the first codon in hot spot one of the target genes, which has been associated with ibrexafungerp cross-resistance. Empty fields indicate that FKS sequencing has not been done.
Table 6. Susceptibility characteristics given as MIC 50 and MIC range (both mg/L) and percentage of isolates classified as I (susceptible, increased exposure) a and R (resistant) for 1965 Danish yeast isolates collected 2020–2021 to five licensed antifungal agents.
Anidulafungin Micafungin Amphotericin B Fluconazole Voriconazole Species ( N ) MIC 50 MIC Range %R/nwt MIC 50 MIC Range %R/nwt MIC 50 MIC Range %R/nwt MIC 50 MIC Range %I %R MIC 50 MIC Range %R/nwt Candida spp. C. albicans (896) ≤0.004 ≤0.004–0.5 1.0 0.016 ≤0.004–2 1.8 0.25 0.06–1 0 0.25 ≤0.06–>64 0.3 2.7 0.008 ≤0.004–>4 3.0 C. dubliniensis (117) 0.016 ≤0.004–0.03 0 0.03 0.008–0.06 0 0.06 0.016–0.25 0 0.25 0.125–>64 0.0 2.6 0.008 ≤0.004–>4 0.9 C. glabrata (475) 0.016 0.008–2 2.3 0.03 ≤0.004–2 3.6 0.25 0.03–1 0 4 1–>64 89.9 10.1 0.06 0.016–>4 6.7 C. krusei (110) 0.03 0.016–0.125 0.9 0.125 0.06–2 0.9 0.5 0.125–1 0 32 16–>64 0 100.0 0.5 0.125–>4 4.5 C. parapsilosis (78) 1 0.25–2 0 1 0.5–4 2.6 0.5 0.125–1 0 1 0.25–64 2.6 6.4 0.016 0.008–>4 6.4 C. tropicalis (146) 0.016 ≤0.004–0.03 0 0.03 0.008–6 0 0.5 0.125–1 0 0.5 0.125–32 5.5 2.7 0.03 0.008–1 5.5 C. guilliermondii (12) 0.5 0.25–1 NA b 0.25 0.25–0.5 NA 0.125 0.125–0.25 0 8 2–>64 18.2 72.7 0.25 0.06–4 NA C. kefyr (8) 0.03 0.016–0.125 NA 0.06 0.06–0.25 NA 0.5 0.25–1 0 0.5 0.25–1 0.0 0.0 0.008 0.008–0.03 NA C. lusitaniae (19) 0.03 0.016–0.06 NA 0.06 0.06–0.125 NA 0.125 0.06–0.25 0 0.5 0.125–1 0.0 0.0 0.008 ≤0.004–0.016 NA Other spp. (34) 0.125 0.008–>4 NA 0.125 0.03–>4 NA 0.5 0.016–1 0 4 0.125–>64 11.8 44.1 0.125 ≤0.004–>4 NA Other yeast S. cerevisiae (30) 0.06 0.03–0.125 NA 0.25 0.125–0.25 NA 0.25 0.06–0.5 0 8 2–32 20.0 76.7 0.125 0.06–1 NA Cryptococcus spp. (7) >4 >4 NA >4 >4 NA 0.5 0.25–1 0 4 2–16 NA NA 0.125 0.03–0.25 0 Rare yeast (34) >4 0.008–>4 NA >4 0.03–>4 NA 0.5 0.125–>4 11.8 16 0.25–>64 NA NA 0.25 ≤0.004–>4 NA
a No isolates are classified as I to anidulafungin, micafungin, amphotericin B or voriconazole; hence, columns for the I-category are omitted for these agents. b NA: not applicable (EUCAST breakpoints or ECOFFs are not established). nwt: non-wild-type.
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P-V Diagrams: Definition & Applications | Sciencing
When trying to understand and interpret thermodynamic processes, a P-V diagram is useful. P-V diagrams are pressure-volume diagrams that illustrate thermodynamic processes. They are graphs with pressure on the y-axis and volume on the x-axis so that pressure is plotted as a function of volume.
P-V Diagrams: Definition & Applications
When trying to understand and interpret thermodynamic processes, a P-V diagram, which plots the pressure of a system as a function of volume, is useful in illustrating process details.
Ideal Gas
A sample of gas is typically made up of an incredibly large number of molecules. Each of these molecules is free to move, and the gas can be thought of as a bunch of microscopic rubber balls all jiggling around and bouncing off of each other.
As you are likely familiar, analyzing the interactions of just two objects undergoing collisions in three dimensions can be cumbersome. Can you imagine trying to keep track of 100 or 1,000,000 or even more? This is precisely the challenge physicists face when trying to understand gases. In fact, it’s nearly impossible to understand a gas by looking at each molecule and all of the collisions between the molecules. Because of this, some simplifications are necessary, and gases are generally understood in terms of macroscopic variables such as pressure and temperature instead.
An ideal gas is a hypothetical gas whose particles interact with perfectly elastic collisions, and are very far apart from each other. By making these simplifying assumptions, the gas can be modeled in terms of macroscopic state variables related to each other relatively simply.
Ideal Gas Law
The ideal gas law relates the pressure, temperature and volume of an ideal gas. It is given by the formula:
P V = n R T PV = nRT P V = n RT
Where P is pressure, V is volume, n is the number of moles of the gas and the gas constant R = 8.314 J/mol K. This law is also sometimes written as:
P V = N k T PV = NkT P V = N k T
Where
N
is the number of molecules and the Boltzmann constant
k
= 1.38065
× 10
-23
J/K.
These relationships follow from the ideal gas law:
At constant temperature, pressure and volume are inversely related. (Decreasing volume increases temperature, and vice versa.)
At constant pressure, volume and temperature are directly proportional. (Increasing the temperature increases the volume.)
At constant volume, pressure and temperature are directly proportional. (Increasing the temperature increases the pressure.)
P-V Diagrams
P-V diagrams are pressure-volume diagrams that illustrate thermodynamic processes. They are graphs with pressure on the y-axis and volume on the x-axis so that pressure is plotted as a function of volume.
Since work is equal to the product of force and displacement, and pressure is force per unit area, then pressure × change in volume = force/area × volume = force × displacement. Hence thermodynamic work is equal to the integral of PdV, which is the area under the P-V curve.
Thermodynamic Processes
There are many different thermodynamic processes. In fact, if you pick two points on a P-V graph, you can create any number of paths to connect them – which means any number of thermodynamic processes can take you between those two states. By studying certain idealized processes, however, you can gain a better understanding for thermodynamics in general.
One type of idealized process is an isothermal process. In such a process, temperature remains constant. Because of this, P is inversely proportional to V, and an isothermal P-V graph between two points will look like a 1/V curve. In order to be truly isothermal, such a process would have to take place over an infinite time period in order for perfect thermal equilibrium to be maintained. This is why it is considered an idealized process. You can get close to it in principle, but never achieve it in reality.
An isochoric process (sometimes also called isovolumetric) is one in which volume remains constant. This is achieved by not allowing the container holding the gas to expand or contract or otherwise change shape in any way. On a P-V diagram, such a process looks like a vertical line.
An isobaric process is one of constant pressure. For constant pressure to be achieved, the volume of the container must be free to expand and contract such as to maintain pressure equilibrium with the external environment. This type of process is represented by a horizontal line on the P-V diagram.
An
adiabatic
process is one in which there is no heat exchange between the system and the surroundings. In order for that to occur, the process would need to take place instantaneously so that heat has no time to transfer. This is because there is no such thing as a perfect insulator, so some degree of heat exchange will always happen. However, while we can’t achieve a perfectly adiabatic process in practice, we can get close and use it as an approximation. In such a process, pressure is inversely proportional to volume to a power
γ
where
γ
= 5/3 for a monatomic gas and
γ
= 7/5 for a diatomic gas.
First Law of Thermodynamics
The first law of thermodynamics states that the change in internal energy = heat added to the system minus work done by the system. Or as an equation:
Δ U = Q − W \Delta U = Q - W Δ U = Q − W
Recall that internal energy is directly proportional to the temperature of a gas.
In an isothermal process, since the temperature does not change, then the internal energy also cannot change. Hence you get the relationship ΔU = 0, which implies that Q = W, or the heat added to the system is equal to the work done by the system.
In an isochoric process, since volume does not change, then no work is done. This combined with the first law of thermodynamics tells us that ΔU = Q, or the change in internal energy is equal to the heat added to the system.
In an isobaric process, the work done can be calculated without invoking calculus. Since it is the area under the P-V curve, and the curve for such a process is simply a horizontal line, you get that W = PΔV. Note that the ideal gas law makes it possible to determine the temperature at any particular point on a P-V graph, so knowledge of the end points of an isobaric process will allow for calculation of internal energy and change in internal energy throughout the process. From this and the simple calculation for W, Q can be found.
In an adiabatic process, no heat exchange implies that Q = 0. Because of this, ΔU = W. The change in internal energy equals the work done by the system.
Heat Engines
Heat engines are engines that use thermodynamic processes to do work in a cyclic manner. The processes occurring in a heat engine will form some sort of closed loop on a P-V diagram, with the system ending up in the same state in which it began after exchanging energy and doing work.
Because a heat engine cycle creates a closed loop in a P-V diagram, the net work done by a heat engine cycle will equal the area contained within that loop.
By computing the change in internal energy for each leg of the cycle, you can also determine the heat exchanged during each process. The efficiency of a heat engine, which is a measure of how good it is at turning heat energy into work, is calculated as the ratio of the work done to the heat added. No heat engine can be 100 percent efficient. The maximum possible efficiency is the efficiency of a Carnot cycle, which is made of reversible processes.
P-V Diagram Applied to a Heat Engine Cycle
Consider the following heat engine model setup. A glass syringe with diameter of 2.5 cm is held vertically with the plunger end on top. The tip of the syringe is connected via plastic tubing to a small Erlenmeyer flask. The volume of the flask and tubing combined is 150 cm 3. The flask, tubing and syringe are filled with a fixed quantity of air. Assume atmospheric pressure is P atm= 101,325 pascals. This setup does work as a heat engine via the following steps:
At the start, the flask in a cold bath (a tub of cold water) and the plunger in the syringe is at a height of 4 cm.
A 100-g mass is placed on the plunger, causing the syringe to compress to a height of 3.33 cm.
The flask is then placed into a heat bath (a tub of hot water), which causes the air in the system to expand, and the plunger of the syringe slides up to a height of 6 cm.
The mass is then removed from the plunger, and the plunger rises to a height of 6.72 cm.
The flask is returned to the cold reservoir, and the plunger lowers back to its starting position of 4 cm.
Here, the useful work done by this heat engine is the lifting of the mass against gravity. But let's analyze each step in more detail from a thermodynamic point of view.
To determine the starting state, you need to determine the pressure, volume and internal energy. The initial pressure is simply P 1= 101,325 Pa. The initial volume is the volume of the flask and tubing plus the volume of the syringe:
V 1 = 1 5 0 c m 3 + π ( 2 . 5 c m 2 ) 2 × 4 c m = 1 6 9 . 6 c m 3 = 1 . 6 9 6 × 1 0 − 4 m 3 V_1=150\text{ cm}^3+\pi\Big(\frac{2.5\text{ cm}}{2}\Big)^2\times4\text{ cm} = 169.6 \text{ cm}^3 = 1.696\times 10^{-4}\text{ m}^3 V 1 = 150 cm 3 + π ( 2 2.5 cm ) 2 × 4 cm = 169.6 cm 3 = 1.696 × 1 0 − 4 m 3
The internal energy can be found from the relationship U = 3/2 PV = 25.78 J.
Here the pressure is the sum of the atmospheric pressure plus the pressure of the mass on the plunger:
P 2 = P a t m + m g A = 1 0 3 , 3 2 1 P a P_2 = P_{atm} + \frac{mg}{A} = 103,321 \text{ Pa} P 2 = P a t m + A m g = 103 , 321 Pa
The volume is found again by adding the flask + tubing volume to the syringe volume, which gives 1.663 × 10 -4m 3. Internal energy = 3/2 PV = 25.78 J.
Note that in moving from Step 1 to Step 2, the temperature remained constant, which means this was an isothermal process. This is why the internal energy did not change.
Since no additional pressure was added and the plunger was free to move, the pressure at this step is P 3= 103,321 Pa still. The volume is now 1.795 × 10 -4m 3, and the internal energy = 3/2 PV = 27.81 J.
Moving from Step 2 to Step 3 was an isobaric process, which is a nice horizontal line on a P-V diagram.
Here the mass is removed, so the pressure falls to what it was originally P 4= 101,325 Pa, and the volume becomes 1.8299 × 10 -4m 3. Internal energy is 3/2 PV = 27.81 J. Moving from Step 3 to Step 4 was another isothermal process, hence ΔU = 0.
Pressure remains unchanged, so P 5= 101,325 Pa. The volume reduces to 1.696 × 10 -4m 3. The internal energy is 3/2 PV = 25.78 J in this final isobaric process.
On a P-V diagram, this process begins at the point (1.696 × 10 -4, 101,325) in the lower left corner. It then follows an isotherm (a 1/V line) up and to the left to the point (1.663 × 10 -4, 103,321). For Step 3, it moves to the right as a horizontal line to the point (1.795 × 10 -4, 103,321). Step 4 follows another isotherm down and to the right to the point (1.8299 × 10 -4, 101,325). The final step moves along a horizontal line to the left, back to the original starting point.
How to Calculate the Temperature Drop Due to a Pressure...
| https://sciencing.com/p-v-diagrams-definition-applications-13722764.html |
In-bed sulfur removal during the fluidized bed combustion of coal impregnated with calcium magnesium acetate | Request PDF
Request PDF | In-bed sulfur removal during the fluidized bed combustion of coal impregnated with calcium magnesium acetate | Sulfur removal during the fluidized bed combustion of coal has been carried out at temperatures of 960–1140 K. Coal impregnated with calcium... | Find, read and cite all the research you need on ResearchGate
In-bed sulfur removal during the fluidized bed combustion of coal impregnated with calcium magnesium acetate
October 1992
Resources Conservation and Recycling 7(1-3):69-82
DOI: 10.1016/0921-3449(92)90007-O
Abstract
Sulfur removal during the fluidized bed combustion of coal has been carried out at temperatures of 960–1140 K. Coal impregnated with calcium magnesium acetate (CMA) is used as a sulfur sorbent. The amount of CMA actually loaded is larger for brown coal with a higher ion-exchange capacity. CMA shows no significant effect on the burn-off irrespective of the coal type and temperature. However, calcium impregnation is effective for in-bed sulfur removal. The efficiency depends on the coal type, probably the type of sulfur in the coal; a high sulfur retention is attained for Illinois No. 6 coal with a large proportion of pyritic sulfur in spite of low Ca/S ratios of around 0.5. In the coprocessing of bituminous coal with impregnated low-sulfur brown coal, the highly dispersed calcium in the brown coal captures effectively the sulfur evolved during the combustion of the bituminous coal.
Simultaneous reduction of NOx and SO2 emissions from coal combustion by calcium magnesium acetate
Article
Jan 2004
FUEL
William Nimmo
A. A. Patsias
E. Hampartsoumian
P.T. Williams
The potential of calcium magnesium acetate (CMA) as a medium for the simultaneous control of NOx and SOx emissions has been investigated using a pulverized coal combustion rig operating at 80 kW. A US and a UK coal of significantly different sulphur contents were used as primary fuel and CMA was injected in solution form into the combustion gases by horizontally opposed twin-fluid atomisers at temperatures of 1100–1200 °C. SO2 reductions typically greater than 80 and 70% were found for initial SO2 levels of 1000 and 1500 ppm, respectively, at Ca/S ratios greater than 2.5. There did not appear to be significant limitation on sulphation by pore blockage using CMA due to the open structure formed during calcination and there is clear potential for zero SO2 emissions at higher Ca/S ratios. The Ca content of the CMA in the form of CaO, via a droplet drying/particle calcination process, absorbs SO2 by sulphation processes by penetration into the open pore structure of these particles. The effect of primary zone stoichiometry (λ1=1.05, 1.15 and 1.4) on NOx reduction was investigated for a range of CMA feed rates up to a coal equivalent of 24% of the total thermal input. NOx reductions of 80, 50 and 30% were achieved at a primary zone stoichiometry of λ1=1.05, 1.15 and 1.4, respectively, for a reburn zone residence time of 0.8 s. At lower equivalent reburn fuel fractions, coal gave greater NOx reductions than CMA but similar levels were achieved above Rff=18%. The mechanism for NOx reduction involves the organic fraction of CMA which pyrolyses into hydrocarbon fragments (CHi), but to a lesser degree than coal, which may then react with NOx in a manner similar to a conventional ‘reburn’ mechanism where NOx is partly converted to N2 depending on the availability of oxygen.
View
Phase Diagram of Ternary Calcium Acetate—Magnesium Acetate—Water System at 298 K, 313 K and 323 K
Article
Jun 2007
J PHASE EQUILIB DIFF
Hong-Kun Zhao
Dao-Sen Zhang
Cao Tang
Shi-Hai Yuan
The solubility data of the calcium acetate-magnesium acetate-water system at 298, 313, and 323 K were measured using the Schreinemaker’s
wet residue method, the corresponding phase diagram for the system were constructed. The solid phase in the system at different
temperatures was confirmed by the Schreinemaker’s wet residue method, which correspond to Mg(CH3COO)2·4H2O and Ca(CH3COO)2·2H2O. At the studied temperature, no double salt was formed. The crystalline region of Ca(CH3COO)2·2H2O is larger than that of Mg(CH3COO)2·4H2O. The solubility of Mg(CH3COO)2 increases with the increasing of the temperature, while the solubility of Ca(CH3COO)2 decreases with the increasing of the temperature.
New technology for control of NOx, SO2 and HCI emissions from large scale combustion plant using calcium magnesium acetate
Article
Jun 2006
William Nimmo
A. A. Patsias
Bernard M. Gibbs
P.T. Williams
Calcium magnesium acetate (CMA) combines the essential properties for NOx control by reburning and in furnace acid gas capture by calcium in one reducing agent. The organic content behaves like a fuel in the reburn zone of a furnace and the Ca content calcines in the furnace principally to CaO for acid gas capture. The technique can be modified for advanced reburning by the addition of urea to the CMA solution so that the selective non-catalytic reduction (SNCR) agent enters the reburn zone at the point of CMA injection. The performance of this novel technique has been assessed for NOx, SO2 and HCl control at the pilot scale, in a combustor operating at 80 kW. Simultaneous reduction of all three pollutants was obtained and a synergy between SO2 and HCl capture was identified. Comparison of the performance of calcium magnesium acetate with a suite of five other carboxylic salts has been performed. NOx reduction has been correlated to volatile organic content and the decomposition rates of the carboxylic salts, as determined by thermogravimetric analysis.
Phase Diagram of Ternary Magnesium Acetate-Acetic Acid-Water System at 298.1 and 333.1 K
Article
Feb 2008
J PHASE EQUILIB DIFF
Hong-Kun Zhao
Dao-Sen Zhang
Rong-Rong Li
Cao Tang
In this investigation, the mutual solubilities for the ternary Mg(CH3COO)2-CH3COOH-H2O system were determined at 298.1 and 333.1K. Two partial isothermal phase diagrams for this ternary system were constructed
on the basis of the measured solubilities, one at 298.1K and the other at 333.1K. At 298.1K, two solid phases were formed
and confirmed by the Schreinemaker’s wet residue method, and the two were identified as 2Mg(CH3COO)2·3CH3COOH·3H2O and Mg(CH3COO)2·4H2O. However, only one solid phase, Mg(CH3COO)2·4H2O was formed in the ternary Mg(CH3COO)2-CH3COOH·H2O system at 333.1K. The solubilities of Mg(CH3COO)2 in water-CH3COOH solutions increased with increasing temperature.
Sulfur removal at high temperature during coal combustion in furnaces: A review
Article
Dec 2003
PROG ENERG COMBUST
Jun Cheng
Junhu Zhou
Jianzhong Liu
Kefa Cen
This paper focuses on sulfur removal technologies in industrial grate furnaces (IGF) and pulverized coal fired boilers (PCFB) with high flame temperature of 1200–1600 °C. The SO2 reduction without sorbents during coal combustion, thermal stabilities of sulfation products, kinetics of sulfur retention reactions of sorbents, desulfurization processes, and sulfur removal under unconventional atmospheres at high temperature are reviewed. It is proposed that some powdered minerals or industrial wastes with effective metal components may be used as sorbents for sulfur removal to promote cost effectiveness. Because the main reason that results in low desulfurization efficiencies in IGF and PCFB is the thermal decomposition of the conventional sulfation product CaSO4 above 1200 °C, it is key to explore new sulfation products that are thermally stable at high temperatures. It is also necessary to study the kinetic catalysis of alkali and transitional metal compounds on sulfation reactions under the combustion conditions of IGF and PCFB. The two-stage desulfurization process, in which SO2 is captured by sorbents both in the coal bed and the combustion gas, is promising for IGF, especially with the humidification of flue gas in a water-film dust catcher. The staged desulfurization process combined with air-staged combustion, in which sorbents are injected into the primary air field and upper furnace to capture SO2 under reducing and oxidizing atmospheres, is promising for PCFB. Flue gas recirculation is also an effective desulfurization process under O2/CO2 conditions and can give a high desulfurization efficiency of about 80% in furnaces.
| https://www.researchgate.net/publication/229180469_In-bed_sulfur_removal_during_the_fluidized_bed_combustion_of_coal_impregnated_with_calcium_magnesium_acetate |
Kingsbury Dental Practice - Care Quality Commission
Dentist
Archived: Kingsbury Dental Practice
529 Kingsbury Road, Kingsbury, London, NW9 9EG (020) 8204 8966
Overview
Latest inspection summary
Latest inspection summary
On this page
Background to this inspection
Overall inspection
Background to this inspection
We carried out this inspection under Section 60 of the Health and Social Care Act 2008 as part of our regulatory functions. This inspection was planned to check whether the practice was meeting the legal requirements and regulations associated with the Health and Social Care Act 2008.
We carried out an announced, comprehensive inspection on 12 August 2016. The inspection was carried out by a CQC inspector and a dental specialist advisor. Prior to the inspection we reviewed information submitted by the provider.
During our inspection visit, we reviewed policy documents and staff records. We spoke with seven members of staff, which included the principal dentist, two associate dentists, two dental nurses, a trainee dental nurse and the receptionist. We conducted a tour of the practice and looked at the storage arrangements for emergency medicines and equipment. We reviewed the practice’s decontamination procedures of dental instruments and also observed staff interacting with patients in the waiting area.
To get to the heart of patients’ experiences of care and treatment, we always ask the following five questions:
Is it safe?
Is it effective?
Is it caring?
Is it responsive to people’s needs?
Is it well-led?
These questions therefore formed the framework for the areas we looked at during the inspection.
Overall inspection
We carried out an announced comprehensive inspection on 12 August 2016 to ask the practice the following key questions; Are services safe, effective, caring, responsive and well-led?
Our findings were:
Are services safe?
We found that this practice was providing safe care in accordance with the relevant regulations.
Are services effective?
We found that this practice was providing effective care in accordance with the relevant regulations.
Are services caring?
We found that this practice was providing caring services in accordance with the relevant regulations.
Are services responsive?
We found that this practice was providing responsive care in accordance with the relevant regulations.
Are services well-led?
We found that this practice was providing well-led care in accordance with the relevant regulations.
Background
Kingsbury Dental Practice is located in the London Borough of Brent and provides NHS and private dental treatment to both adults and children. The premises are on the first floor above retail premises and consist of three treatment rooms, a reception area and a dedicated decontamination room. The practice is open Monday to Friday 9:00am – 6:00pm.
The staff consists of the principal dentist, two associate dentists, three dental nurses, a trainee dental nurse and two receptionists.
The principal dentist is registered with the Care Quality Commission (CQC) as an individual ‘registered person’. Registered persons have legal responsibility for meeting the requirements in the Health and Social Care Act 2008 and associated Regulations about how the practice is run.
We reviewed 17 CQC comment cards, the practice patient satisfaction survey and the NHS Friends and Family test. Patients were positive about the service. They were complimentary about the friendly and caring attitude of the staff.
The inspection took place over one day and was carried out by a CQC inspector and a dental specialist advisor.
Our key findings were:
Patients’ needs were assessed and care was planned in line with current guidance such as from the National Institute for Health and Care Excellence (NICE).
We found the dentists regularly assessed each patient’s gum health and took X-rays at appropriate intervals.
Patients were involved in their care and treatment planning so they could make informed decisions.
There were effective processes in place to reduce and minimise the risk and spread of infection.
The practice had effective safeguarding processes in place and staff understood their responsibilities for safeguarding adults and child protection.
Equipment, such as the autoclave (steriliser), fire extinguishers, and X-ray equipment had all been checked for effectiveness and had been regularly serviced.
Patients were treated with dignity and respect and confidentiality was maintained.
The practice had implemented clear procedures for managing comments, concerns or complaints.
Patients indicated that they found the team to be efficient, professional, caring and reassuring.
Patients had good access to appointments, including emergency appointments, which were available on the same day.
Leadership structures were clear and there were processes in place for dissemination of information and feedback to staff.
There were areas where the provider could make improvements and should:
Review availability of medicines and equipment to manage medical emergencies giving due regard to guidelines issued by the Resuscitation Council (UK), and the General Dental Council (GDC) standards for the dental team.
Review the training, learning and development needs of individual staff members and have an effective process established for the on-going assessment and supervision of all staff.
| https://www.cqc.org.uk/location/1-220444698/inspection-summary |
Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms in: Endocrine-Related Cancer Volume 18 Issue S1 (2011)
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are composed of cells with a neuroendocrine phenotype. The old and the new WHO classifications distinguish between well-differentiated and poorly differentiated neoplasms. All well-differentiated neoplasms, regardless of whether they behave benignly or develop metastases, will be called neuroendocrine tumours (NETs), and graded G1 (Ki67 20%). To stratify the GEP-NETs and GEP-NECs regarding their prognosis, they are now further classified according to TNM-stage systems that were recently proposed by the European Neuroendocrine Tumour Society (ENETS) and the AJCC/UICC. In the light of these criteria the pathology and biology of the various NETs and NECs of the gastrointestinal tract (including the oesophagus) and the pancreas are reviewed.
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are composed of cells with a neuroendocrine phenotype. The old and the new WHO classifications distinguish between well-differentiated and poorly differentiated neoplasms. All well-differentiated neoplasms, regardless of whether they behave benignly or develop metastases, will be called neuroendocrine tumours (NETs), and graded G1 (Ki67 < 2%) or G2 (Ki67 2–20%). All poorly differentiated neoplasms will be termed neuroendocrine carcinomas (NECs) and graded G3 (Ki67 > 20%). To stratify the GEP-NETs and GEP-NECs regarding their prognosis, they are now further classified according to TNM-stage systems that were recently proposed by the European Neuroendocrine Tumour Society (ENETS) and the AJCC/UICC. In the light of these criteria the pathology and biology of the various NETs and NECs of the gastrointestinal tract (including the oesophagus) and the pancreas are reviewed.
Introduction
Endocrine neoplasms can be divided according to the chemical nature of their secretion products into two groups. Neoplasms that produce and secrete (glyco)peptide hormones and biogenic amines comprise the first group. The second group includes the tumours that generate steroid hormones. The tumours of the first group are called neuroendocrine neoplasms (NENs) because of the marker proteins that they share with the neural cell system. These markers are synaptophysin and neuron-specific enolase. Other markers that also recognise the neuroendocrine phenotype are the chromogranins A, B and C and the proprotein convertases PC2 and PC3 (Lloyd 2003,Klöppelet al. 2007). The neural cell adhesion molecule CD56 is positive in many NENs, but is not specific for these tumours (Klöppelet al. 2009). Under the electron microscope the NENs show typical neurosecretory granules.
This review deals with the classification of the gastroenteropancreatic NENs (GEP-NENs) and discusses briefly the pathology and biology of the various GEP-NEN entities that are observed in the foregut, midgut and hindgut regions.
Classification
The NENs arise from the neuroendocrine cell system that forms organoid cell aggregations or consists of disseminated cells in various organs of the body. In the gastrointestinal tract and pancreas, there are 15 different cell types defined by the hormonal products (Rindi & Klöppel 2004). Only eight of the 15 hormones that were identified in the cells of the gastrointestinal tract have so far been recognised in GEP-NENs. Many of these hormones give rise to hormonal syndromes, if they are produced and secreted by the majority of the tumour cells. The GEP-NENs that are associated with hormonal syndromes are then called insulinomas, glucagonomas, gastrinomas and seretoninomas. In addition, there are GEP-NENs that produce hormones that are ectopic to the GEP system such as vasoactive intestinal polypeptide (VIP), ACTH or GH-releasing factor. GEP-NENs that are non-functioning (i.e. not associated with a hormonal syndrome), but immunohistochemically are found to be composed predominantly of – for instance – glucagon-expressing cells, may be called glucagon-producing NENs.
It seems that all GEP-NENs are potentially malignant neoplasms. However, the various entities that are recognised in the gastrointestinal tract and the pancreas differ considerably in their metastasising capacity (i.e. their behaviour). In addition, they differ in their hormonal cell composition and consequently in the associated hormonal syndromes. The reason for this biological complexity of the GEP-NENs is probably the functional diversity and nonrandom distribution of the various neuroendocrine cell types in the gut and pancreas, from which the tumours derive. It has therefore always been difficult to classify the GEP-NENs.Williams & Sandler (1963)classified the GEP-NENs by embryological origin as foregut (stomach, duodenum, upper jejunum and pancreas), midgut (lower jejunum, ileum, appendix and caecum) and hindgut (colon and rectum) tumours and found considerable clinicopathological differences among the three groups. However, with the recognition of many new GEP-NEN entities in the last two decades, especially among the foregut tumours, the usefulness of this classification in practical diagnostic work is more and more limited.
The WHO classification that appeared in 2000 for the NENs of the gastrointestinal tract (Solciaet al. 2000), and in 2004 for the NENs of the pancreas (Heitzet al. 2004), followed a new approach that attempted to predict the biological behaviour of GEP-NENs (Capellaet al. 1995). As a first step, it distinguished between pure endocrine tumours and mixed endocrine–exocrine tumours. In a second step, a uniform scheme of classification was applied to all pure GEP-NENs, identifying three tumour categories, irrespective of their site of origin (seeTable 1): 1) well-differentiated endocrine tumours (WDETs) with probably benign behaviour, 2) WDETs with uncertain behaviour and well-differentiated endocrine carcinomas with low-grade malignant behaviour and 3) poorly differentiated endocrine carcinomas with high-grade malignant behaviour.
Table 1
Comparison of the 2010 WHO classification for gastroenteropancreatic neuroendocrine neoplasms with previous WHO classifications
WHO 1980WHO 2000WHO 2010
I. Carcinoid1. Well-differentiated endocrine tumour (WDET)a1. Neuroendocrine tumour (NET) G1 (carcinoid) G2a
2. Well-differentiated endocrine carcinoma (WDEC)a
3. Poorly differentiated endocrine carcinoma/small cell carcinoma (PDEC)2. Neuroendocrine carcinoma (NEC) G3 large cell or small cell type
4. Mixed exocrine–endocrine carcinoma (MEEC)3. Mixed adenoneuroendocrine carcinoma (MANEC)
II. Pseudotumour lesions5. Tumour-like lesions (TLL)4. Hyperplastic and preneoplastic lesions
G, grade (for definition, see text).
aIn case that the Ki67 proliferation rate exceeds 20%, this NET may be graded G3.
In a third step, the well-differentiated, low-grade-proliferative GEP-NENs (Fig. 1a) which are also called carcinoids in the gastrointestinal tract (Oberndorfer 1907) or islet cell tumours in the pancreas, were distinguished on the basis of their site of origin (stomach, duodenum, jejunum, ileum, appendix, colon and rectum and pancreas), size, gross and/or microscopic tumour extension, angioinvasion, proliferative activity (Ki67 index) and their syndromatic features (Solciaet al. 2000,Heitzet al. 2004). They were characterised by their immunostaining for synaptophysin and usually also for chromogranin A. Poorly differentiated NECs that were composed of highly proliferative cells formed a separate group because of their invariable high-grade malignancy (Fig. 1b). They were characterised by their diffuse immunostaining for synaptophysin, and only infrequent and sparse immunostaining for chromogranin A (Klöppelet al. 2009).
Figure 1
(a) Well-differentiated neuroendocrine tumour. (b) Poorly differentiated neuroendocrine carcinoma.
Citation: Endocrine-Related Cancer 18, S1;10.1530/ERC-11-0013
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Figure 1
(a) Well-differentiated neuroendocrine tumour. (b) Poorly differentiated neuroendocrine carcinoma.
Citation: Endocrine-Related Cancer 18, S1;10.1530/ERC-11-0013
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Figure 1
(a) Well-differentiated neuroendocrine tumour. (b) Poorly differentiated neuroendocrine carcinoma.
Citation: Endocrine-Related Cancer 18, S1;10.1530/ERC-11-0013
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In recent years, it was felt that the WHO classification should be supplemented by criteria that may refine the prognostic stratification of GEP-NENs to allow a better stage-adjusted treatment of the patients. Therefore, the European Neuroendocrine Tumour Society (ENETS) developed guidelines for the diagnosis and treatment of GEP-NENs that contained site-specific TNM-classifications (Rindiet al. 2006,2007). In addition, a three-tiered grading system of GEP-NENs based on mitotic count and Ki67 index (Rindiet al. 2006,2007) and a standardised diagnostic procedure were suggested (Klöppelet al. 2009). Both grade 1 (Ki67 index < 2%) and grade 2 (Ki67 index 2–20%) NENs are considered well-differentiated tumours, whereas grade 3 (Ki67 index > 20%) characterises the poorly differentiated tumours. Both the staging proposal and the grading system were recently validated for foregut and particularly pancreatic NENs (PanNENs) by several studies and their biological relevance and power to discriminate among prognostic groups was largely confirmed (Ekebladet al. 2008,Fischeret al. 2008,Papeet al. 2008,La Rosaet al. 2009,Scarpaet al. 2010).
Unfortunately, the recently published seventh edition of the AJCC/UICC (Sobinet al. 2009) contains a TNM classification of well-differentiated neuroendocrine tumours (NETs; carcinoids) of the gastrointestinal tract and the pancreas that differs in a number of criteria from the ENETS-TNM system (Klöppelet al. 2010). It does not apply to high-grade (large and small cells) neuroendocrine carcinomas (NECs) and does not exactly follow the ENETS classifications for some of the anatomic sites (seeTable 2for the pancreas). No data are presented to justify the use of different staging parameters. The result is that there now exist two parallel systems, each of which uses identical TNM terminology but may refer to different types and extents of disease for certain GEP-NENs. This discrepancy will lead to much confusion among clinicians and will likely limit the ability to compare research (Klöppelet al. 2010).
Table 2
Comparison of the criteria for the T category in the ENETS and UICC TNM classifications of pancreatic neuroendocrine tumours
ENETS TNMUICC TNM
T1Confined to pancreas, < 2 cmConfined to pancreas, < 2 cm
T2Confined to pancreas, 2–4 cmConfined to pancreas, 2–4 cm
T3Confined to pancreas, > 4 cm, or invasion of duodenum or bile ductPeripancreatic spread, but without vascular invasion
T4Peripancreatic spread with invasion of large vessels or adjacent organsVascular invasion (truncus coeliacus, superior mesenteric artery)
In the second half of 2010, a revised version of the WHO classification of GEP-NENs appeared (Rindiet al. 2010). This new classification introduced several changes. First, the label ‘neuroendocrine’ was now officially adopted to indicate neoplastic cells expressing neural markers such as synaptophysin. Secondly, the term ‘NEN’ encompasses all well and poorly differentiated tumours of the neuroendocrine cells. Thirdly, the pure NENs of the gastrointestinal tract and pancreas are stratified into two groups (Table 1): 1) the well-differentiated NETs and 2) the poorly differentiated NECs. The NETs are then separated by their proliferative activity into either G1 (equivalent to carcinoids) or G2 NETs. The NECs, that are G3 tumours, are subtyped into small cell and large cell neoplasms (seeTable 1). TNM-staging of tumour extension according to tumour site leads to a further stratification of NETs and NECs. The neoplasms that show in addition to neuroendocrine cells (exceeding at least 30% of all tumour cells) non-endocrine components (usually adenocarcinoma structures) are distinguished from the pure NENs and called mixed adenoneuroendocrine carcinomas (Table 1).
Pathology
Origin, distribution and relative frequency
The cells that give rise to GEP-NENs derive from gastrointestinal stem cells that are able to differentiate into neuroendocrine cells. It is likely that the well and the poorly differentiated NENs come from different types of tumour stem cells. Analysing the development of NENs of the pancreas and duodenum in multiple endocrine neoplasia type 1 (MEN1) it was found that a hyperplastic preprogrammed (i.e. hormonally differentiated) neuroendocrine cell that carries the germ line mutation of theMEN1gene gives rise to well-differentiated low-grade malignant neoplasms by allelic loss of the 11q13 region of the chromosome 11 (Anlaufet al. 2007a,b,Perrenet al. 2007). In contrast, in poorly differentiated NENs, which are on the other end of the differentiation spectrum of NENs, the cell of origin is most likely close to the intestinal stem cell. If this cell is tackled by mutational hits, multiple profound genetic alterations are initiated, such as p53 mutations, that lead to the development of high-grade malignant, poorly differentiated NENs.
GEP-NENs can occur anywhere in the GEP neuroendocrine cell system. However, they are not equally distributed, but concentrate at certain sites such as the gastric fundus–corpus, the proximal duodenum, the papilla of Vater, the terminal ileum, the tip of the appendix, the lower rectum and the pancreas. In the past NENs of the ileum and appendix were the most common GEP-NENs. Recent studies, however, revealed that probably the gastric NENs outnumber all other GEP-NENs (Klöppelet al. 2007,Niederleet al. 2010).
In general, the well-differentiated NENs are much more common (by a rate of ∼10:0.5) than the poorly differentiated NENs. However, at certain locations such as the oesophagus or the colon the poorly differentiated NENs are more frequent than their well-differentiated counterparts.
Oesophagus
NENs of the oesophagus are extremely rare and therefore something special. Usually they present as large ulcerated poorly differentiated NECs in the lower third of the oesophagus and may, in addition, contain exocrine elements (Capellaet al. 2000,Maruet al. 2008).
Stomach
The stomach gives origin to three distinct types of well-differentiated NETs (Rindiet al. 1993) and also, but only rarely, to poorly differentiated NECs (Klöppel & Clemens 1996,Capellaet al. 2000). The type 1 comprises 70–80% of all cases and occurs mainly in women at the age of 50–60 (Rindiet al. 1993,Scherüblet al. 2010). It is characterised by the occurrence of multiple small polypoid tumours (0.3–1 cm;Fig. 2a), which are composed of enterochromaffin-like (ECL) histamine-producing cells and are always associated with autoimmune chronic atrophic gastritis of the oxyntic mucosa. This disease leads to the disappearance of the specific glands of the oxyntic mucosa harbouring the parietal cells. The consequences of the loss of parietal cells are insufficient production of intrinsic factor triggering pernicious anaemia via the decreased resorption of vitamin B12 and deficient production of gastric acid that stimulates the antral G cells to persistent hypersecretion of gastrin. It is thought that the hypergastrinaemia promotes the growth of the ECL cells of the oxyntic mucosa so that diffuse to micronodular ECL cell hyperplasia develops (Fig. 2b) and is followed by multiple ECL neoplasms after a latent period of many years (Bordiet al. 1998). The prognosis of these tumours is excellent, because they are usually G1 – NETs and so small when detected that they can be completely removed endoscopically. Metastasising type 1 gastric NETs may occasionally be observed, if the tumours are larger than 2 cm in size, infiltrate the muscularis propria, are angioinvasive and/or show G2 grade (Rappelet al. 1995).
Figure 2
Well-differentiated neuroendocrine neoplasms of the stomach: (a) multiple small polypoid tumours in the corpus region of the stomach associated with chronic atrophic gastritis of the oxyntic mucosa (type 1 gastric NET). (b) ECL cell hyperplasia in the oxyntic mucosa with microtumours. (c) ECL cell hyperplasia in patients with MEN1. (d) Type 3 NEN of the stomach with infiltration of muscular wall.
Citation: Endocrine-Related Cancer 18, S1;10.1530/ERC-11-0013
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Figure 2
Well-differentiated neuroendocrine neoplasms of the stomach: (a) multiple small polypoid tumours in the corpus region of the stomach associated with chronic atrophic gastritis of the oxyntic mucosa (type 1 gastric NET). (b) ECL cell hyperplasia in the oxyntic mucosa with microtumours. (c) ECL cell hyperplasia in patients with MEN1. (d) Type 3 NEN of the stomach with infiltration of muscular wall.
Citation: Endocrine-Related Cancer 18, S1;10.1530/ERC-11-0013
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Figure 2
Well-differentiated neuroendocrine neoplasms of the stomach: (a) multiple small polypoid tumours in the corpus region of the stomach associated with chronic atrophic gastritis of the oxyntic mucosa (type 1 gastric NET). (b) ECL cell hyperplasia in the oxyntic mucosa with microtumours. (c) ECL cell hyperplasia in patients with MEN1. (d) Type 3 NEN of the stomach with infiltration of muscular wall.
Citation: Endocrine-Related Cancer 18, S1;10.1530/ERC-11-0013
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Type 2 gastric NETs are very similar to type 1 NETs regarding cellular composition (ECL-tumours) and multifocality, but occur in the setting of MEN1, that is associated with a Zollinger–Ellison syndrome (ZES). They affect men and women equally (Scherüblet al. 2010). As patients with ZES but without MEN1 usually do not develop type 2 gastric NETs, the genetic changes associated with MEN1 are probably needed for tumour development (Debelenkoet al. 1997). The tumour-free oxyntic mucosa shows ECL cell hyperplasia, but is not atrophic as in type 1 gastric NETs (Fig. 2c). Lymph node metastases are found more often than in type 1 NETs, since type 2 NETs are often more advanced in terms of size, muscular wall infiltration and angioinvasion than type 1 gastric NETs (Solciaet al. 1989).
Type 3 gastric NETs are solitary tumours that develop unrelated to chronic atrophic gastritis or MEN1. They occur mainly in men, at a mean age of 55 years (Scherüblet al. 2010). In most cases type 3 NETs are composed of ECL cells, while EC (serotonin) cell or gastrin cell tumours are extremely rare (Klöppel & Clemens 1996). Histologically, they are well differentiated, show a trabecular to solid pattern and in at least one-third of the patients, the tumour is already larger than 2 cm at the time of diagnosis (Fig. 2d), has invaded the muscular layer, shows angioinvasion, and/or has a proliferation rate exceeding 2–5%. In those type 3 NETs metastases are very likely to be present (Rappelet al. 1995). In rare cases type 3 tumours may be associated with a so-called atypical carcinoid syndrome, characterised by cutaneous flushing in the absence of diarrhoea, usually coupled with liver metastases and production of histamine and 5-hydroxytryptophan (Scherüblet al. 2010).
Poorly differentiated NECs of the stomach (type 4 gastric NENs) are more common in men than in women, aged between 60 and 70 years (Scherübl 2010). They present as a large ulcerated lump with symptoms similar to those of adenocarcinomas. Occasionally they harbour an adenocarcinoma component. Hormones cannot be demonstrated and there is no relationships to chronic atrophic gastritis, but in exceptional cases are associated with MEN1 (Bordiet al. 1997). At the time of diagnosis most of the tumours are already in an advanced stage (tumour diameter more than 4 cm) and show extensive metastasis (Bordiet al. 1997).
Recently, multiple large (up to 1.3 cm) ECL cell tumours were found in a background of ECL cell hyperplasia and parietal cell hyperplasia in patients with hypergastrinaemia, but without ZES (Ooiet al. 1995,Abrahamet al. 2005). It was suggested that the development of these NETs is associated with an intrinsic acid secretion abnormality of the parietal cells.
Duodenum and upper jejunum
On the basis of their clinical, morphological, hormonal and genetic features several types have to be distinguished in the upper small testine: gastrin-producing NETs with ZES (i.e. gastrinomas), gastrin-producing NETs without ZES, somatostatin-producing tumours with or without neurofibromatosis type 1 (NF1), serotonin- or calcitonin-producing NETs, gangliocytic paragangliomas and poorly differentiated NECs (Burkeet al. 1990,Capellaet al. 1995,Solciaet al. 2000,Jensenet al. 2006a,b,Klöppelet al. 2007;Fig. 3). These duodenal NENs can be divided into non-functioning and functioning neoplasms.
Figure 3
Relative ratios of neuroendocrine tumours of the duodenum defined by their hormone expression. Neuroendocrine tumour archives of the Department of Pathology, University of Kiel, 1970 and 2006. Reproduced with kind permission from Springer Science+Media:Virchows Archiv, Site-specific biology and pathology of gastroenteropancreatic neuroendocrine tumors, volume 451 supplement 1, ppS9–S27,Klöppelet al. (2007).
Citation: Endocrine-Related Cancer 18, S1;10.1530/ERC-11-0013
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IJERPH | Free Full-Text | Indoor Air Quality Prior to and Following School Building Renovation in a Mid-Atlantic School District
Children spend the majority of their time indoors, and a substantial portion of this time in the school environment. Air pollution has been shown to adversely impact lung development and has effects that extend beyond respiratory health. The goal of this study was to evaluate the indoor environment in public schools in the context of an ongoing urban renovation program to investigate the impact of school building renovation and replacement on indoor air quality. Indoor air quality (CO2, PM2.5, CO, and temperature) was assessed for two weeks during fall, winter, and spring seasons in 29 urban public schools between December 2015 and March 2020. Seven schools had pre- and post-renovation data available. Linear mixed models were used to examine changes in air quality outcomes by renovation status in the seven schools with pre- and post-renovation data. Prior to renovation, indoor CO measurements were within World Health Organization (WHO) guidelines, and indoor PM2.5 measurements rarely exceeded them. Within the seven schools with pre- and post-renovation data, over 30% of indoor CO2 measurements and over 50% of indoor temperatures exceeded recommended guidelines from the American Society of Heating, Refrigerating, and Air Conditioning Engineers. Following renovation, 10% of indoor CO2 measurements and 28% of indoor temperatures fell outside of the recommended ranges. Linear mixed models showed significant improvement in CO2, indoor PM2.5, and CO following school renovation. Even among schools that generally met recommendations on key guidelines, school renovation improved the indoor air quality. Our findings suggest that school renovation may benefit communities of children, particularly those in low-income areas with aging school infrastructure, through improvements in the indoor environment.
Indoor Air Quality Prior to and Following School Building Renovation in a Mid-Atlantic School District
Kirsten Koehler 3 ,
Michelle N. Eakin 2 ,
Christopher Wohn 4 ,
Ike Diibor 4 ,
Thomas Eckmann 2 ,
Tianshi David Wu 5,6 ,
Dorothy Clemons-Erby 3 ,
Christine E. Gummerson 7 ,
Timothy Green 3 ,
Megan Wood 3 ,
Ehsan Majd 8 ,
Marc L. Stein 9,10 ,
Ana Rule 3 ,
Meghan F. Davis 3,11 and
Meredith C. McCormack 2,*
1
Division of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
2
Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
3
Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21287, USA
4
Baltimore City Public Schools, Baltimore, MD 21287, USA
5
Division of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA
6
Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
7
Division of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA
8
Division of Mobile Source Control, California Air Resources Board, Sacramento, CA 95817, USA
9
Johns Hopkins School of Education, Baltimore, MD 21287, USA
10
Baltimore Education Research Consortium, Baltimore, MD 21287, USA
11
Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2021 , 18 (22), 12149; https://doi.org/10.3390/ijerph182212149
Received: 17 October 2021 / Revised: 12 November 2021 / Accepted: 16 November 2021 / Published: 19 November 2021
Abstract
Children spend the majority of their time indoors, and a substantial portion of this time in the school environment. Air pollution has been shown to adversely impact lung development and has effects that extend beyond respiratory health. The goal of this study was to evaluate the indoor environment in public schools in the context of an ongoing urban renovation program to investigate the impact of school building renovation and replacement on indoor air quality. Indoor air quality (CO
2
, PM
2.5
, CO, and temperature) was assessed for two weeks during fall, winter, and spring seasons in 29 urban public schools between December 2015 and March 2020. Seven schools had pre- and post-renovation data available. Linear mixed models were used to examine changes in air quality outcomes by renovation status in the seven schools with pre- and post-renovation data. Prior to renovation, indoor CO measurements were within World Health Organization (WHO) guidelines, and indoor PM
2.5
measurements rarely exceeded them. Within the seven schools with pre- and post-renovation data, over 30% of indoor CO
2
measurements and over 50% of indoor temperatures exceeded recommended guidelines from the American Society of Heating, Refrigerating, and Air Conditioning Engineers. Following renovation, 10% of indoor CO
2
measurements and 28% of indoor temperatures fell outside of the recommended ranges. Linear mixed models showed significant improvement in CO
2
, indoor PM
2.5
, and CO following school renovation. Even among schools that generally met recommendations on key guidelines, school renovation improved the indoor air quality. Our findings suggest that school renovation may benefit communities of children, particularly those in low-income areas with aging school infrastructure, through improvements in the indoor environment.
Keywords:
schools
;
indoor air quality
renovation
1. Introduction
Americans spend about 90% of their time indoors, and for children, a substantial portion of this time is spent in the school setting [ 1 ]. Indoor air quality is particularly relevant for children. Air pollution has been shown to impact lung growth and contribute to the risk of asthma exacerbation [ 2 ], a leading reason for school absences. Studies have linked air quality and thermal comfort to student performance [ 3 , 4 , 5 ].
The indoor environment is modifiable and studies have focused on interventions in the home setting as a means to improve the health of children and other household members [ 6 , 7 , 8 ]. Interventions in the school environment provide a means to positively impact children at a community level and to benefit many children by interventions focused on shared, common spaces.
As school infrastructure in the United States ages, school buildings require increased maintenance, and school environmental conditions may be less conducive to optimal health and learning. In 2017, nationwide infrastructure reports showed that almost a quarter of public schools with permanent buildings in the United States were rated as being in “fair” or “poor” condition [
9
]. There are significant disparities in funding for improvement and maintenance of facilities, with prior evidence showing that capital funds for school facility improvement often fail to reach schools with children from low income communities [
10
].
Prior research from our group has shown that worse school infrastructure is associated with worse student achievement [ 11 ]. Additionally, building characteristics within schools such as physical defects (i.e., leaks in roof, broken windows, damaged walls) are associated with increased indoor air pollution (higher indoor NO 2 and indoor CO levels) [ 12 ]. Poor air quality can also be a concern during the process of school renovation due to the release of toxic materials during demolition, dust and fumes from construction, and designs that interfere with ventilation [ 13 ]. Few studies have directly assessed school environmental conditions and very few have measured the impact of renovation or improvement of school facilities after renovation has been completed [ 14 ]. An ongoing school renovation program in an urban environment within the mid-Atlantic region (including the states of Delaware, Maryland, New Jersey, and Pennsylvania) provided the opportunity to apply a natural experimental study design to assess the impact of renovation on indoor air quality. The urban renovation program was launched in 2010 with the aim of addressing the city’s aging school buildings and infrastructure [ 15 ].
Our aim was to evaluate environmental conditions in schools that were included in the urban renovation program to investigate the impact of school building renovation and replacement on indoor air quality. We hypothesized that school building renovation would lead to improved indoor air quality. We performed a detailed assessment of indoor air quality measures that have been shown to have an impact on health and performance (including CO 2 , PM 2.5 , CO, and temperature) [ 16 , 17 , 18 , 19 , 20 ].
2. Methods
2.1. School Characterization
To guide prioritization of schools for renovation, a districtwide facility condition assessment was initially performed by an independent engineering firm (Jacobs Engineering Group, Dallas, TX, USA) [ 21 ]. The facility condition index (FCI), a national standard for the overall condition of a building, was calculated for every school [ 22 ]. The FCI is derived as a ratio of the cost to repair a given school to the cost of constructing a theoretical school with similar characteristics. FCI ≤ 10% is good condition; 11–30% is average; 31–50% is poor; 51–74% is very poor; ≥75% is a candidate for replacement [ 21 ].
Twenty-nine schools in the ongoing school renovation program were enrolled between December 2015 and March 2020. Institutional review board (IRB) approvals were obtained from the Johns Hopkins School of Public Health IRB and the IRB of the participating school district. Three schools entered the study after renovation had been completed and contributed only post-renovation data, seven schools contributed data pre- and post-renovation, and the remaining nineteen schools contributed only pre-renovation data. Within this study, our analysis focuses on the seven schools with both pre- and post-renovation data. Air quality measurements were stopped in March of 2020 due to the COVID-19 pandemic.
2.2. Renovation
The renovations performed on each school within the urban renovation program were heterogeneous and tailored to the needs of the individual school. Of the eleven schools in which post-renovation data was assessed, nine schools had additions and substantial renovations performed (including new heating, ventilation, and air conditioning, or HVAC systems, and window replacement) and two schools were replaced [ 23 ]. For replacement schools, entirely new school buildings were constructed. One school was constructed at the same site and the other replacement school was constructed behind the existing school. Within the seven schools with pre- and post-renovation data, six schools had renovations performed and one school was replaced. All seven schools had new HVAC systems installed.
2.3. Procedures for Air Quality Monitoring within Schools
Within each school, indoor air quality was assessed at three time points within a given academic year. Over 1400 school days of monitoring were performed throughout the study. For most schools, this included a visit in the fall (September to November), winter (December to February), and spring (March to May). Within each season school visit, two weeks of monitoring was performed, with five consecutive days (Monday-Friday) in each week (mean indoor visit length: 89.7 ± 16.7 h). In the first week, one classroom and one common area were monitored, and in the second week, a different classroom and common space were monitored. Common spaces included areas such as the gymnasium, cafeteria, or library. Environmental equipment was placed on a portable table provided by the study team in a protective wire cage/frame with signs that explained the purpose of the equipment. CO
2,
indoor PM
2.5
, CO, and indoor temperature were measured at the same location.
Within monitoring locations, particulate matter with an aerodynamic diameter smaller than 2.5 μm (PM
2.5
) was measured using a Personal DataRam (pDR) monitor, model pDR-1200 (Thermo Electron, Franklin, MA, USA), with 0.001–400 mg/m
3
concentration measurement range and a 5-min logging resolution. The pDR was connected to a BGI model 400 s personal sampling pump (BGI INC., Waltham, MA, USA) operating at the air flow of 4 L/min, and a BGI model GK 2.05 (Mesa Labs, Butler, NJ, USA) inlet cyclone with a 50% cut point of 2.5 μm. Filter samples collected downstream of the pDR nephelometer were collected on 37-mm, 2.0 μm pore-size PTFE membrane filters and were used to correct concentrations from the pDR for gravimetric time-weighted average (TWA) concentrations. pDR concentrations were also humidity corrected using standard approaches [
24
]. Filters were preconditioned for 24 h in a humidity and temperature controlled room prior to being weighed in the same room. Indoor PM samples included at least 10% blanks and duplicates and all reported concentrations were blank corrected.
CO
2
and CO were measured at 1-min intervals using a direct-reading Advanced Sense Pro indoor air quality (IAQ) meter (GrayWolf Sensing Solutions LLC, Shelton, CT, USA). A dual-wave NDIR IR-Infrared sensor was used to measure CO
2
while an electromechanical sensor was used to detect CO. The IAQ meter was factory calibrated annually and checked for quality control weekly using a calibration kit provided by the manufacturer for a one point calibration with zero air starting in April 2018. Prior to that only annual calibrations were used. Within each monitoring location, the IAQ meter was placed on a table approximately 1 m away from the ground and away from air vents, windows, and doors, as possible. Indoor temperature measurements were obtained using HOBO data loggers (HOBO U12 Data Logger, Onset Computer Corporation, Bourne MA, USA).
Outside of each school, samplers were placed on the roof to assess the contribution of outdoor air to indoor air quality. Outdoor sampling at each school occurred throughout both weeks of indoor air quality monitoring (including the weekend between the two indoor sampling weeks) (mean outdoor visit length: 240.5 ± 48.9 h). A SKC Personal Environmental Monitor (PEM) for PM
2.5
with the same type of filter used for the pDR was connected to an Allegro model 9805 diaphragm sampling pump (Allegro Industries, Piedmont, SC, USA), operating at the air flow of 4 L/min. A battery powered iButton data logger (iButtonLink, Whitewater, WI, USA) was used to measure outdoor temperature at 10-min intervals.
2.4. Statistical Analysis
For each monitored location, CO
2
and CO were monitored at 1-min resolution and indoor PM
2.5
was monitored at 5-min resolution. For indoor temperature, data were first measured at 10-min intervals and then averaged at the hour level, taking the mean of each hour’s six measurements. School day mean values (8 AM to 4 PM) of CO
2
, PM
2.5
, CO, and indoor temperature were calculated. During data quality control assessments, CO
2
data was filtered to remove values >4000 ppm and <250 ppm as a school day mean (3.9% of days). The limit of detection was 1 µg/m
3
for the PM
2.5
; for school day mean values below the LOD, a value of
LOD / √ 2 LOD / √ 2
(0.7 µg/m
3
) was imputed (4.6% of days). CO data was reported at intervals of 1 ppm and was filtered to remove values for which 0 ppm was reported for more than 90% of the school day (27.3% of days).
For each monitored location, outdoor PM
2.5
and temperature were monitored. There was one outdoor sample collected for PM
2.5
over the two week period per school, resulting in one value for approximately 12 days of sampling. Outdoor temperature data was measured at 10-min intervals and then averaged at the hour level, taking the mean of each hour’s six measurements. School day mean values (8 AM to 4 PM) of outdoor temperature were calculated.
Descriptive statistics (median and interquartile range, IQR) were calculated for all air quality measures prior to and post-renovation. CO 2 was compared to an indoor concentration of 1000 ppm as recommended by the American Society of Heating, Refrigerating, and Air Conditioning Engineers (ASHRAE) [ 25 ]. PM 2.5 and CO values were compared to corresponding indoor WHO guidelines (25 µg/m 3 for PM 2.5 and 7 mg/m 3 [~6.1 ppm at 25 °C for CO] as a 24 h average) [ 26 ].
For indoor temperature, in addition to describing the average school day value, the proportion of respective temperature measurements taken at 10 min resolution at each site during the school day that were outside of the recommended value/range based on standards from ASHRAE were calculated prior to and following renovation. For indoor temperature, recommended seasonal temperatures from ASHRAE assume slow air moment and 40% indoor relative humidity. The recommended indoor temperature ranges are 68–75 °F or 20–23.9 °C in fall/winter and 73–80 °F or 22.8–26.7 °C in spring/summer [
27
,
28
]. Temperature measurements were designated as being in range if they were within recommended ASHRAE guidelines based on season of assessment. Temperatures were considered to be too cold or too warm if they were below or above the limit of the ASHRAE recommended range for the season by 4 °C or less. Extreme values were defined as values that were more than 4 °C outside of the ASHRAE recommended range (too warm or too cold). The sum of temperature measurements that were assigned as extremely too cold, too cold, too warm, and extremely too warm divided by the total number of temperatures measurements were determined to be the proportion out of range for each school, location, and season.
Within the seven schools with pre- and post-renovation data, we assessed four indoor environmental parameters (CO
2
, PM
2.5
, CO, and proportion of temperature out of range) and two outdoor environmental parameters (PM
2.5
and average school daily temperature) using six separate linear mixed models. Given that we had multiple time points of data measurement nested within each school, and to account for missing data, we used maximum likelihood estimates. Linear mixed models were used to account for intra-cluster variance of observations within schools. A mean school daily value of CO
2
, indoor PM
2.5
, CO, and a total proportion of temperature out of range from each of the four locations within each school during each visit was included in the model. A mean school daily value of outdoor temperature and a two-week value of outdoor PM
2.5
within one location outside of each school was included in the model. CO
2
, indoor and outdoor PM
2.5
, and CO school daily mean values were log-transformed. Each model was controlled for renovation status of the school and season (fall, winter, spring). The results of a similar analysis incorporating all schools within our sample are included in the Online Supplement.
3. Results
Prior to renovation, IAQ measures (CO
2
, PM
2.5
, and CO) and temperature were measured in 26 schools and post-renovation IAQ measures and temperature were measured in 11 schools. Schools had a median Facility Condition Index (FCI) of 70.6 (IQR: 59.3–91.75), which corresponded to the very poor category. The majority of students were non-white (median 98.8%; IQR: 92.7–99.1%) with 93.7% (IQR: 89.5–96.1%) of free and reduced lunch meals (FARMS) provided in the 2014–2015 school year. The median year of school construction was 1958, with the oldest school constructed in 1910 and the most recent in 1981. Within the seven schools that had pre- and post-renovation data, the median FCI was 76.4 (IQR: 65.1–96.5), and the median year of construction was 1944 (
Table 1
).
Table 1. Characteristics of schools.
3.1. Indoor Air Quality Measures
Within the seven schools that had pre- and post-renovation data, the median average school daily CO
2
was 774.0 ppm (IQR: 626.3–1073.2 ppm), with over 30% of average school daily CO
2
measurements exceeding ASHRAE guidelines. Following renovation, the median average school daily CO
2
was 542.4 ppm (IQR: 460.3–679.4 ppm), with over 10% of average school daily CO
2
measurements exceeding ASHRAE guidelines (
Table 2
). Prior to renovation, the median average school daily PM
2.5
was 5.9 µg/m
3
(IQR: 3.8–9.5 µg/m
3
) with average school daily PM
2.5
exceeding WHO guidelines 2% of the time. Following renovation, the median average school daily PM
2.5
was 2.7 µg/m
3
(IQR: 1.4–5.2 µg/m
3
) with all average school daily PM
2.5
measurements below WHO guidelines. Prior to renovation, the median school daily CO was 0.4 ppm (IQR: 0.3–0.6 ppm) and all values were within indoor air quality guidelines from the WHO. Following renovation, median average school daily CO was 0.3 ppm (IQR: 0.1–0.6 ppm). Indoor air quality metrics within the overall sample of 29 schools were similar to the seven schools with pre- and post-renovation data and are shown in Online
Supplement Table S1
.
Table 2. Characteristics of indoor and outdoor air quality and performance outcomes by renovation status in 7 schools with pre- and post-renovation data.
Box plots of school daily indoor air quality data for schools prior to and post-renovation within the seven schools with pre- and post-renovation data, compared to recommended indoor air quality levels, are shown in Figure 1 .
Figure 1.
Indoor air quality measures by school renovation status in seven schools with pre- and post-renovation data. The boxes demonstrate the interquartile range (IQR) of the indoor air quality measure. Whiskers represent closest value within 1.5× the IQR of the indoor air quality measure. Blue dots represent individual values that extend beyond the whisker value. The red line in (
B
) represents the indoor concentration of 1000 ppm recommended by ASHRAE. The red line in (
C
) represents the indoor WHO guidelines of 25 µg/m
3
. All CO values were below the recommended WHO guideline of 7 mg/m
3
(6.1 ppm at 25 °C). All school daily measurements included were taken between 8:00 a.m. and 4:00 p.m. (
A
) Indoor school daily CO by school renovation status; (
B
) Indoor school daily CO
2
by school renovation status; (
C
) Indoor school daily PM
2.5
by school renovation status.
The results of the linear mixed models for indoor air quality within the seven schools with pre- and post-renovation data, shown in Table 3 , show significant reductions in CO 2 , indoor PM 2.5 , and CO by renovation status after controlling for season. Linear mixed models of indoor air quality within the full sample of 26 pre-renovation and 11 post-renovation schools show similar results (Online Supplement Table S2 ).
Table 3. Linear mixed models comparing indoor air quality within seven schools with pre- and post-renovation monitoring data.
3.2. Indoor Air Temperature and Temperature out of Range
Within the seven schools with pre- and post-renovation data, there was decreased temperature variability across seasons following renovation ( Table 2 , Figure 2 ). The results of the linear mixed model, in Table 3 , show a reduction of proportion of temperature out of range by 21% following renovation after controlling for season. Results of the linear mixed model including all schools in the sample were similar, with a significant reduction in proportion of temperature out of range by 19% (Online Supplement Table S2 ).
Figure 2. Indoor school daily temperature by school renovation status and season in seven schools with pre- and post-renovation data. The boxes demonstrate the IQR of average indoor daily temperature. Whiskers represent closest value within 1.5× the IQR of the average indoor daily temperature. Blue dots represent individual values that extend beyond the whisker values. Red lines indicate recommended indoor temperature guidelines from ASHRAE: 68–75 °F (20–23.9 °C) in fall/winter and 73–80 °F (22.8–26.7 °C) in the spring/summer. Indoor school daily temperatures were measured between 8:00 a.m. and 4:00 p.m.
The proportion of indoor air temperatures out of range, by season, prior to and following renovation is shown in
Figure 3
(temperature measured every 10 min). Temperatures were more frequently within the recommended range following renovation (72.0%) than prior to renovation (49.4%). Prior to renovation, temperatures were too warm 39.6% of the time in the fall, 27.9% of the time in the winter, and 9.3% of the time in the spring. Additionally prior to renovation, temperatures were extremely too warm 6.8% of the time in the fall, 1.9% of the time in the winter, and 0.2% of the time in the spring. Following renovation, 21.3% of temperatures were too warm in the fall, 10.5% were too warm in the winter, and 0.6% were too warm in the spring. Following renovation, there was improvement in indoor temperature such that no temperatures were extremely too warm in the fall or spring and only 0.5% of temperatures were extremely too warm in the winter.
Figure 3.
Proportion of indoor temperatures within and outside of range in seven schools with pre- and post-renovation monitoring data. In range indoor air temperatures were determined according to ASHRAE guidelines by season: 68–75 °F (20–23.9 °C) in fall/winter and 73–80 °F (22.8–26.7 °C) in the spring/summer. Temperatures were considered to be too cold or too warm if they were below or above the limit of the ASHRAE recommended range for the season by 4 °C or less. Extreme values were defined as values that were more than 4 °C outside of the ASHRAE recommended range. All indoor temperatures included were taken during the school day, between 8:00 a.m. and 4:00 p.m.
Prior to renovation, temperatures were too cold 9.6% of the time in the fall, 14.1% of the time in the winter, and 35.3% of the time in the spring. Additionally prior to renovation, temperatures were extremely too cold 1.4% of the time in the winter and 7.8% of the time in the spring. Following renovation, 3.7% of temperatures were too cold in the fall, 3.4% were too cold in the winter, and 46.6% were too cold in the spring. Also, following renovation, there was improvement such that no temperatures were extremely too cold in the fall, winter, or spring. The proportion of indoor air temperatures out of range by season in the complete sample of 29 schools can be seen in Online
Supplement Figure S1
.
3.3. Outdoor Air Quality Measures
Prior to renovation, the two week average outdoor PM 2.5 was 8.0 µg/m 3 (IQR: 7.3–14.3 µg/m 3 ) and following renovation, it was 6.7 µg/m 3 (IQR: 5.2–7.5 µg/m 3 ). Prior to renovation, median school daily temperature was 20.9 °C (IQR: 18.3–23.2 °C) in the fall, 8.5 °C (IQR: 4.2–14.2 °C) in the winter, and 16.3 °C (IQR: 11.6–23.3 °C) in the spring. Following renovation, median school daily temperature was 20.2 °C (IQR: 14.9–26.7 °C) in the fall, 4.9 °C (IQR: 2.8–8.1 °C) in the winter, and 20.1 °C (IQR: 12.5–25.3 °C) in the spring ( Table 2 ).
The results of the linear mixed models for outdoor air quality ( Table 3 ) showed no difference in outdoor PM 2.5 by renovation status after controlling for season, and significantly warmer temperatures following renovation compared to prior to renovation.
4. Discussion
A school renovation program in an urban, mid-Atlantic school district provided the opportunity to apply a natural experimental design to study the impact of building renovation or replacement on indoor air quality. Prior to renovation, within the seven schools in our sample that had pre- and post-renovation data, nearly one third of indoor CO
2
measurements exceeded recommended guidelines, and over half of indoor temperature measurements were outside of the recommended range, typically too warm even when temperatures were cool outside. All CO and most PM
2.5
levels fell within recommended guidelines prior to renovation. Following school renovation, there were improvements in indoor air quality with a significant decrease in CO
2
, indoor PM
2.5
, and CO levels, in addition to an improvement in indoor temperature more frequently within the recommended range for thermal comfort.
The study addresses a recognized research gap by intensively characterizing school indoor air quality with direct assessment at multiple times across different seasons. The unique design provided the opportunity to quantify the impact of an intervention—school renovation or replacement—on indoor air quality. The study was based in an urban school district that serves predominantly low-income, Black children who are disproportionately affected by challenges of aging school infrastructure in urban areas across the United States [
31
]. The 2011 survey that informed the school renovation program upon which this study was based reported that nearly a quarter of schools were constructed before 1946 (23%), and that the majority (122 out of 145) were rated in poor or worse condition. Only 1 of the 145 schools surveyed was rated in good condition [
21
]. It is also notable that the schools that were slated to undergo renovation first were those in the worst condition and thus are the schools included in the present study.
Our data shows substantial post-renovation improvement in ventilation, which refers to the exchange of indoor air for clean outdoor air in order to dilute air pollution or contaminants that come from indoor sources and the crowding of people. Notably, among our larger sample of 26 schools that had pre-renovation measurements, more than one-quarter had median CO 2 values that exceeded the ASHRAE recommended threshold, and this was substantially improved among schools that underwent renovation. Most schools and buildings have HVAC systems with filters on them to maintain good indoor air quality and to provide thermal comfort. In general, the greater number of people in an indoor space, the greater need for ventilation, and thus CO 2 is used as a surrogate for adequacy of ventilation per occupant. Elevated CO 2 has been associated with reduced student performance in several states and many countries [ 19 , 32 , 33 , 34 , 35 ], and also associated with an increase in student absences in the US [ 36 ]. Marked improvement in ventilation after renovation demonstrates the benefit of investment in school infrastructure with improvement in ventilation, which has the potential to improve standardized test scores and academic performance [ 34 , 35 ], reduce respiratory health effects, and reduce student absences [ 34 ]. Of note, in the context of the current SARS-CoV-2 pandemic, there has been increased attention to ventilation characteristics of school buildings. In devising plans to allow children to return to school safely, improving ventilation is one strategy that is being promoted to mitigate airborne viral transmission as well as to improve indoor air quality.
Within the seven schools with pre- and post-renovation data, the majority of baseline average indoor PM 2.5 concentrations (median 5.9 µg/m 3 , IQR: 3.8–9.5 µg/m 3 ) were below the recommended limits for indoor air and consistent with the few other studies that have assessed indoor PM in school environments [ 37 ]. PM 2.5 measured in schools was much lower than PM 2.5 that have been measured in homes of children in an urban environment in several other research studies [ 7 , 38 , 39 , 40 ]. One contributing factor to lower PM 2.5 levels in schools may be the lack of secondhand smoke (SHS), which is a prominent contributor to household PM 2 .5. SHS was initially assessed within this study but was discontinued, as it was found to be routinely below the limit of detection (90% of collected samples below the limit of detection). School policies ban smoking on campus and study staff did not observe any evidence of smoking on campus over the study period.
While there were improvements in indoor PM
2.5
concentrations with renovation, there was no change in concurrently measured outdoor PM
2.5
concentrations over time, suggesting that improvements in indoor PM
2.5
were not due to changes in outdoor levels. Despite low baseline PM
2.5
values, school renovation still resulted in reductions of PM
2.5
concentrations. This is notable due to evidence suggesting that reduction of PM
2.5,
even at lower concentrations, may have amplified health benefits, and that there is no evidence of a threshold value, meaning that lower PM is better and there is no safe level of exposure below which there is not the potential for adverse health effects [
41
,
42
]. This may be especially relevant for children who have higher respiratory rates and are developing physically (e.g., lung growth, neurocognition) [
43
].
Thermal comfort was assessed and baseline findings were striking and mirrored the experiences of the study staff regarding the proportion of time that temperature was beyond that in the range for thermal comfort. The extreme values measured were informative. For example, within schools with pre and post renovation data, temperatures were too warm or extremely too warm 46.4% and 29.8% of the time during the fall and winter prior to renovation. There were no extremely too warm values measured post-renovation. It is logical that such thermal conditions may not be conducive to optimal learning. Prior data has shown that indoor temperatures impact student achievement with classroom temperature reduced to the lower end of the comfortable range being associated with increased student work rate, reduced errors, and higher performance scores [
20
,
44
]. Higher classroom temperatures have also been shown to be associated with higher daytime attacks of breathlessness [
33
]. Our findings suggest that renovation greatly improves temperature control with over 20% improvement in the number of days within recommended ranges following school renovation. Perhaps surprisingly, the temperatures were still out of range 28% of the time following renovation, with more temperatures out of range being too cold rather than too warm. This could be due to incomplete benefit of the renovation on the goal of achieving climate control or, alternately, may be due to factors such as the scheduled programming of thermostats that are not responsive to real time weather changes (e.g., heat is turned off in the spring overnight or not turned back on during unexpected cold weather events).
There were several limitations to this study. Given that this study occurred within a natural experiment of an ongoing urban school renovation project and schools were selected based on poor condition, we were unable to randomly assign renovation status to schools within the district or control the extent of renovation performed. The planned renovation timeline for schools extends beyond our study window and thus we sampled more schools pre-renovation than post-renovation. As the renovation project was based in urban schools with low income and minority students, findings may be representative of similar low income communities throughout the country, but are not generalizable to all schools. However, the improvement of indoor school air quality for this vulnerable group of students is particularly important due to known disparities in health and education among low-income communities. Additionally, individual consent from students, teachers, and staff was not a feature of this study. This was intentional in order to reduce burden on the schools and in order to build a working relationship to foster future collaboration. Thus, we were unable to measure individual benefits for these groups. As cost is a significant consideration of school renovation and replacement, cost analysis is also of great interest but is beyond the scope of this study. Measurements of indoor air quality were measured using electrochemical (CO) and NDIR (CO
2
) sensors. These sensors were selected to provide high temporal resolution data enabling an assessment of concentrations during school hours only. However, these sensors can be less accurate and precise than cumulative methods and can be subject to bias based on environmental conditions. Finally, classroom occupancy, which would contribute to ventilation, was not directly measured in this study. As classroom occupancy rates are mandated by school district, occupancy was likely stable prior to and following school renovation.
Due to a history of underinvestment, low income communities have aging school infrastructure that is in significant need of renovation [
45
]. There is a need to prioritize renovation and replacement of schools within these communities to help address disparities. Our findings show significant improvement in indoor air quality, including CO
2
, indoor PM
2.5
, and CO, as well as an increase in the proportion of indoor temperatures within recommended ranges following school renovation. These findings underscore the need for investment in school renovation to improve building infrastructure and indoor air quality, which may lead to health and academic benefits for students and teachers. Future studies should consider measuring the impact of school renovation and improvements in indoor air quality on student health and performance outcomes.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/ijerph182212149/s1 , Figure S1: Proportion of indoor temperatures within and outside of range prior to and post-renovation in 29 schools, Table S1: Characteristics of indoor and outdoor air quality and performance outcomes by renovation status in 29 schools, Table S2: Six linear mixed models showing indoor and outdoor air quality prior to and following school renovation in 29 schools.
Author Contributions
Conceptualization, K.K., M.F.D. and M.C.M.; Methodology, S.E.Z., M.N.E., T.E. and M.C.M.; Software: K.K., T.G. and M.W.; Validation, K.K., T.G and M.W.; Formal Analysis, S.E.Z., T.E., M.N.E. and M.W.; Data Curation, S.E.Z., K.K., M.W. and T.E.; Writing—Original Draft Preparation, S.E.Z.; Writing—Review & Editing, S.E.Z., K.K., M.N.E., C.W., I.D., T.D.W., D.C.-E., C.E.G., T.G., E.M., M.L.S., A.R., M.F.D. and M.C.M.; Visualization, K.K., C.W., I.D., M.F.D. and M.C.M.; Supervision, M.N.E., K.K., M.C.M.; Project Administration, D.C.-E.; Funding Acquisition, K.K., M.F.D. and M.C.M. All authors have read and agreed to the published version of the manuscript.
Funding
This publication was developed under Assistance Agreement No 83563901 and 83615201 awarded by the U.S. Environmental Protection Agency (EPA) to Meredith McCormack. Research reported in this publication was supported by National Institute of Environmental Health Sciences of the National Institutes of Health (NIH) under award number P50ES018176. Portions of this work were supported by a Johns Hopkins Spark Award (Ex-SP-09-19003) from the Bloomberg American Health Initiative. MFD was supported by the NIH/Office of the Director (K01OD019918). TDW is supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Center for Innovations in Quality, Effectiveness, and Safety (CIN 13-413). SZ was supported by NIH F32HL149195-01 and NIH T32HL007534-6. This publication has not been formally reviewed by EPA or the US Department of Veterans Affairs. The views expressed in this document are solely those of the authors and do not necessarily reflect those of the EPA or the US Department of Veterans Affairs. EPA does not endorse any products or commercial services mentioned in this publication.
Institutional Review Board Statement
Institutional review board (IRB) approvals were obtained from the Johns Hopkins School of Public Health IRB and the IRB of the participating school district.
Informed Consent Statement
Not applicable.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to potential identification.
Conflicts of Interest
The authors declare that they have no actual or potential competing interest.
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Figure 1. Indoor air quality measures by school renovation status in seven schools with pre- and post-renovation data. The boxes demonstrate the interquartile range (IQR) of the indoor air quality measure. Whiskers represent closest value within 1.5× the IQR of the indoor air quality measure. Blue dots represent individual values that extend beyond the whisker value. The red line in ( B ) represents the indoor concentration of 1000 ppm recommended by ASHRAE. The red line in ( C ) represents the indoor WHO guidelines of 25 µg/m 3 . All CO values were below the recommended WHO guideline of 7 mg/m 3 (6.1 ppm at 25 °C). All school daily measurements included were taken between 8:00 a.m. and 4:00 p.m. ( A ) Indoor school daily CO by school renovation status; ( B ) Indoor school daily CO 2 by school renovation status; ( C ) Indoor school daily PM 2.5 by school renovation status.
Figure 2. Indoor school daily temperature by school renovation status and season in seven schools with pre- and post-renovation data. The boxes demonstrate the IQR of average indoor daily temperature. Whiskers represent closest value within 1.5× the IQR of the average indoor daily temperature. Blue dots represent individual values that extend beyond the whisker values. Red lines indicate recommended indoor temperature guidelines from ASHRAE: 68–75 °F (20–23.9 °C) in fall/winter and 73–80 °F (22.8–26.7 °C) in the spring/summer. Indoor school daily temperatures were measured between 8:00 a.m. and 4:00 p.m.
Figure 3. Proportion of indoor temperatures within and outside of range in seven schools with pre- and post-renovation monitoring data. In range indoor air temperatures were determined according to ASHRAE guidelines by season: 68–75 °F (20–23.9 °C) in fall/winter and 73–80 °F (22.8–26.7 °C) in the spring/summer. Temperatures were considered to be too cold or too warm if they were below or above the limit of the ASHRAE recommended range for the season by 4 °C or less. Extreme values were defined as values that were more than 4 °C outside of the ASHRAE recommended range. All indoor temperatures included were taken during the school day, between 8:00 a.m. and 4:00 p.m.
Table 1. Characteristics of schools.
School Statistics School Variable No. (% of 29 Total Schools) No. (% of 7 Schools with Pre- and Post- Renovation Data) School type Elementary school only (K-5) 10 (34.5) 1 (14.3) Elementary/Middle school (K-8) 15 (51.7) 3 (42.9) Middle/High school 1 (3.4) 1 (14.3) High school only 3 (10.3) 2 (28.6) School renovation status Renovated 9 (31) 5 (71.4) Replaced 2 (6.8) 2 (28.6) Stage of renovation that data was collected Pre-renovation only 19 (65.5) 0 Pre-renovation and Post-renovation 7 (24.1) 7 (100) Post-renovation only 3 (10.3) 0 Median (IQR) Median (IQR) School characteristics Facility condition index a 70.6 (59.3–91.75) 76.4 (65.1–96.5) Year of construction 1958 (Min: 1910/Max: 1981) 1944 (Min: 1926/Max: 1971) % Non-white students b 98.8 (92.7–99.1) 99.1 (85.3–99.8) % Free and reduced lunch c 93.7 (89.5–96.1) 91.3 (85.2–94.6)
a Facility Condition Index (FCI) is an industry standard to evaluate building conditions: ≤10% is good condition; 11–30% is average; 31–50% is poor; 51–74% is very poor; ≥75% is a candidate for replacement. FCI was measured in all schools within the Jacobs Report [ 21 ]. b % Non-white students is the percentage of non-white students within the school during the year of entry in the study [ 29 ]. c % Free and Reduced Lunch Meals (FARMS) is the percentage of free and reduced meals provided within the school during the 2014–2015 school year. Baltimore City started offering free and reduced meals to all public school students in June 2015 [ 30 ].
Table 2. Characteristics of indoor and outdoor air quality and performance outcomes by renovation status in 7 schools with pre- and post-renovation data.
Pre-Renovation Post-Renovation Indoor Exposures Season N1 N2 Median (IQR) Min, Max Season N1 N2 Median (IQR) Min, Max School daily CO 2 (ppm) 7 230 774.0 (626.3–1073.2) 354.1, 2157.1 7 232 542.4 (460.3–679.4) 332.2, 2444 School daily PM 2.5 (µg/m 3 ) 7 204 5.9 (3.8–9.5) 1.0, 25.5 7 252 2.7 (1.4–5.2) 0.7, 17.9 School daily CO (ppm) 7 209 0.4 (0.3–0.6) 0, 1.4 7 179 0.3 (0.1–0.6) 0, 3.1 School daily temperature (°C) Fall 4 41 23.5 (21.9–25.5) 18.1, 28.0 Fall 6 95 22.5 (21.4–23.5) 18.4, 26.5 Winter 6 67 22.2 (20.9–24.8) 14.7, 27.4 Winter 6 78 22.2 (21.3–22.9) 18.9, 25.5 Spring 7 94 23.3 (21.9–24.9) 15.0, 28.0 Spring 6 54 23.4 (22.4–23.9) 20.6, 24.8 Outdoor Exposures Two week average PM 2.5 (µg/m 3 ) 7 18 8.0 (7.3–14.3) 6.7, 56.1 3 8 6.7 (5.2–7.5) 4.0, 8.5 School daily temperature (°C) Fall 4 37 20.9 (18.4–23.2) 7.3, 33.6 Fall 4 44 20.2 (14.9–26.7) 1, 37.4 Winter 5 58 8.5 (4.2–14.2) −6.1, 23.6 Winter 3 29 4.9 (2.8–8.1) −4.0, 17.0 Spring 6 67 16.3 (11.6–23.3) 4.4, 30.7 Spring 4 30 20.1 (12.5–25.3) 8.5, 38.3
N1 = Number of schools monitored. N2 = Number of days monitored (indoor CO, indoor CO 2, indoor PM 2.5, indoor temperature, outdoor temperature) or number of two week measurements (outdoor PM 2.5 ). All school daily measurements were taken between 8:00 a.m. and to 4:00 p.m.
Table 3. Linear mixed models comparing indoor air quality within seven schools with pre- and post-renovation monitoring data.
Note: PM 2.5 , CO, and CO 2 have been log transformed. This model controls for season and renovation status. Coefficient values are comparing post-renovation to pre-renovation status, resulting in negative values for the environmental measures that suggest improvement. School daily exposure measurements were taken between 8:00 a.m. and 4:00 p.m. The abbreviation NS stands for not significant.
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JoF | Free Full-Text | Burden of Serious Fungal Infections in Argentina
The number of fungal infections at any given time in Argentina is not known. Here we estimate the burden of serious fungal infections in Argentina for the first time. Specific population statistics were searched from multiple sources, local literature was identified, and estimates made. Some additional data were sourced from the Ministry of Health, the Global Initiative for Asthma (GINA) program, and national haematology and transplant societies. Argentina has a population of 43.8 million, with 25% of this total being children under 15 years. The predicted candidemia annual incidence is 2193 cases, with 50% occurring in the ICU. At a 6% prevalence rate, an estimated 593,695 women suffer from recurrent vulvovaginal candidiasis. Invasive aspergillosis is relatively common because of high smoking and chronic obstructive pulmonary disease (COPD) rates, with 268 cases in immunocompromised patients and another 1938 in the 168,000 COPD patients admitted to hospital. Asthma is also common, affecting 14% of adults, and so allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) are major problems. An estimated 432 cases of cryptococcal meningitis (CM)—90% of them in AIDS patients—and 1177 cases of Pneumocystis pneumonia (PCP) occur each year. The estimated annual case number of disseminated histoplasmosis is 404 in AIDS patients, almost as frequent as CM. Paracoccidioidomycosis annual incidence is estimated at 219, and coccidioidomycosis at 16 cases. At least 881,023 people (& gt;2.01%) in Argentina are affected by a serious fungal disease annually, with considerable morbidity and mortality.
Burden of Serious Fungal Infections in Argentina
by Fernando O. Riera 1,* , Juan P. Caeiro 2,* and David W. Denning 3,*
1
Infectology Department, Sanatorio Allende Córdoba, Av Hipólito Yirgoyen 384, Córdoba, Argentina
2
Infectious Diseases Section, Hospital Privado Universitario de Córdoba, Av. Naciones Unidas 346, Córdoba, Argentina
3
The Natonal Aspergillosis Centre, Wythenshawe Hospital, Manchester Academic Health Science Centre, and The University of Manchester, Manchester M23 9LT, UK
Authors to whom correspondence should be addressed.
Received: 14 February 2018 / Revised: 9 April 2018 / Accepted: 13 April 2018 / Published: 24 April 2018
(This article belongs to the Special Issue Fungal Burden in Different Countries )
Abstract
:
The number of fungal infections at any given time in Argentina is not known. Here we estimate the burden of serious fungal infections in Argentina for the first time. Specific population statistics were searched from multiple sources, local literature was identified, and estimates made. Some additional data were sourced from the Ministry of Health, the Global Initiative for Asthma (GINA) program, and national haematology and transplant societies. Argentina has a population of 43.8 million, with 25% of this total being children under 15 years. The predicted candidemia annual incidence is 2193 cases, with 50% occurring in the ICU. At a 6% prevalence rate, an estimated 593,695 women suffer from recurrent vulvovaginal candidiasis. Invasive aspergillosis is relatively common because of high smoking and chronic obstructive pulmonary disease (COPD) rates, with 268 cases in immunocompromised patients and another 1938 in the 168,000 COPD patients admitted to hospital. Asthma is also common, affecting 14% of adults, and so allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) are major problems. An estimated 432 cases of cryptococcal meningitis (CM)—90% of them in AIDS patients—and 1177 cases of
Pneumocystis
pneumonia (PCP) occur each year. The estimated annual case number of disseminated histoplasmosis is 404 in AIDS patients, almost as frequent as CM. Paracoccidioidomycosis annual incidence is estimated at 219, and coccidioidomycosis at 16 cases. At least 881,023 people (>2.01%) in Argentina are affected by a serious fungal disease annually, with considerable morbidity and mortality.
Keywords:
mycoses
;
epidemiology
;
aspergillosis
;
candidemia
;
fungal infections
1. Introduction
Argentina is the eighth-largest country in the world and the second-largest country in Latin America. It has a wide range of climates and several endemic fungal diseases are present. The Gross Domestic Product per capita is $ 12,000, and the average life expectancy is 77.1 years [ 1 ].
As fungal diseases are not reportable, exact data are not available and the current number of fungal infections occurring each year in Argentina is not known. In addition, in Argentina there are few published papers on the incidence and prevalence of some life-threatening fungal disease entities. However, it is desirable to integrate new data to provide an overall estimate on the total population affected by fungal diseases in healthcare for the purposes of future research and healthcare planning. Diagnostic treatment gaps are also highlighted by comparing local data with those of other neighboring countries where estimates have been published, such as Brazil, Chile, Peru, and Ecuador [ 2 , 3 , 4 , 5 , 6 ].
The aim of this study was to estimate the total population in Argentina affected by serious fungal disease. By using the available epidemiological data, we have calculated the incidence and prevalence; for those diseases with no existing local data, we have used published data from neighboring countries, or international sources. We have applied calculations based on national, regional, and international cohort studies; clinical trials; and rates of infections already documented in similar groups of patients, as others have reported [ 2 , 3 , 4 , 5 , 6 ].
2. Materials and Methods
In order to elucidate the serious fungal burden in Argentina, we performed an exhaustive search of epidemiological reports. To estimate the fungal burden, data were retrieved from the National Institute of Statistics and Census (INDEC), the Annual Report of HIV and AIDS, National Administration of Laboratory and Health Institutes (ANLIS), and from the Ministry of Health publications. We also searched the bibliography for Argentinian data on mycotic diseases, asthma, Chronic Obstructive Pulmonary Diseases (COPD), cancer, and transplant patients. The incidence and prevalence for each fungal disease were estimated in specific populations at risk. When no data existed, risk populations were used to estimate frequencies of fungal infections, using the previously described methodology by Leading International Fungal Education (LIFE) [
7
].
The number of patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) was obtained from epidemiological surveillance of AIDS in Argentina published in the Joint United Nations Programme on HIV/AIDS (UNAIDS) [
8
] and from the Argentina Annual Report of HIV and AIDS [
9
,
10
]. Similarly, the proportions of AIDS patients presenting with
Pneumocystis
pneumonia (PCP),
Candida
esophagitis, or cryptococcal meningitis in 2017 were calculated using estimates based on a literature review of manuscripts addressing the incidence rates of infections for a specific set of patients. PCP is most commonly associated with the initial presentation of AIDS in 25% of cases [
11
].
In a recent study, the prevalence of cryptococcal antigenemia in Argentina was 8.1% in those with CD4 counts of <100 × 10 6 /mL, and cryptococcal meningitis affected 4.87% of patients with AIDS in this series [ 12 ]. Furthermore, of 2041 patients with cryptococcosis, 98% of the cases were associated with AIDS and meningitis was seen in 90% of the patients [ 13 ].
In most populations, it is assumed that 90% of patients with late-stage HIV who are not being treated with highly active antiretroviral therapy (HAART) will develop oral candidiasis [ 14 , 15 ]. Earlier data from a US cohort study showed that oral candidiasis may occur in 16% of cases with HIV/AIDS treated with HAART [ 16 ]. Esophageal candidiasis was based on the assumption that 20% of HIV patients with CD4 counts under 200 × 10 6 /mL who are not on antiretroviral therapy are affected by this condition, as well as 5% of those on therapy [ 17 , 18 ].
Cases of candidemia in hospitalized patients were based on the prevalence rates documented between November 2008 and October 2010 in three tertiary care hospitals in Argentina as part of a multicenter study in Latin America [ 19 ]. The incidence of candidemia per 1000 admissions was 1.95 (range 1.26–2.98) and the incidence per 1000 patient-days was 0.24 (range 0.13–0.19). We assumed that 50% of candidemia episodes occur in the intensive care unit (ICU) and that the rate of Candida peritonitis is ~50% of the ICU candidemia rate [ 20 , 21 , 22 , 23 ].
The number of tuberculosis (TB) cases was taken from the epidemiological surveillance registry in the Ministry of Health of Argentina [ 24 ]. It is assumed that 22% of patients with lung cavities and 2% of those without cavities following pulmonary tuberculosis (PTB) will develop chronic pulmonary aspergillosis (CPA) [ 25 ]. Patients with PTB are expected to represent ~20% of the total number of CPA cases annually, so the total prevalence of CPA from any cause is estimated using the national PTB figures [ 26 ].
Asthma rates in Argentina were obtained from the first prevalence study by the Ministry of Health of Argentina. In 2015, 5.98% of the adult population were estimated to have asthma [ 27 ]. The risk of allergic bronchopulmonary aspergillosis (ABPA) was estimated at 2.5% based on previous studies from other countries [ 28 ]. The rate of severe asthma with fungal sensitization (SAFS) was estimated for the most severe 10% of cases of the total asthma population; out of that, 33% were assumed to have fungal sensitization [ 29 , 30 , 31 ].
An estimated 2.3 million people in Argentina are living with a diagnosis of COPD, a prevalence of 14.5% in those >40 years old. We assumed that 7% of these patients are admitted to hospital each year [ 32 ].
Argentina’s cancer data were reported by the International Agency for Research on Cancer through the Globocan Project in 2012, showing an estimated incidence of crude rates for leukemia at 5.1/100,000; acute myeloid leukemia (AML) is the most common type of leukemia in adults [ 33 ]. Overall, there were 2372 cases of leukemia reported, and 11,244 people were diagnosed with lung cancer in 2012.
It is assumed that non-acute myeloid leukemia hematological conditions in total represent the same population incidence of invasive aspergillosis (IA) as do AML patients—an incidence of approximately 10% [ 34 ]. Furthermore, it is assumed that the incidence of IA in allogeneic hematopoietic stem cell transplants is 8% [ 35 ].
IA is also associated with solid organ transplantation, although the reported incidence varies by both dataset and anatomical site. The Transplant-Associated Infection Surveillance Network data found the 1 year cumulative incidence of documented IA to be 0.5% of renal, 2.0% of heart, 0.9% of liver, and 9.1% of lung transplants [
36
]. Given the size of this dataset, it provides the most precise disease rates and we have adopted these values. Argentinian transplant data were obtained from the 2016 Instituto Nacional Central Único Coordinador de Ablación e Implante (INCUCAI) report on organ transplant and organ donation registry. In Argentina in 2016, 1687 solid organ transplants were performed [
34
]. Of the total 1687 transplants, 1121 were renal (740 with deceased donor and 381 with living donor), 349 were livers (312 with deceased donors and 37 with living donors), 109 were hearts, and 33 were lungs. In addition, 937 corneal transplants were performed [
37
]. We have assumed that the rate of IA in lung cancer patients was 2.6%, as described by Yan et al (2009) [
38
].
Recurrent Candida vaginitis (more than 4 episodes per year) was included in the context of serious infections due to its impact on quality of life as well [ 39 ]. For recurrent Candida vaginitis, the number of cases was based on 6% expected prevalence among women of ages 15 to 50 years old [ 7 , 40 ]. According to the INDEC, the population of this age group of women in Argentina is ~9,894,900.
Mucormycosis was estimated using data forma population studies in which incidence was 1.7 million inhabitants and data from Transplant-Associated Infection Surveillance Network (TRANSNET) [ 41 , 42 ].
In 2004, the National Network of Mycology Laboratories of Argentina (ANLIS) reported the results of a retrospective nationwide survey on mycoses diagnosed between January and December, 2004. The study included data provided by 72 laboratories located in 19 provinces of Argentina. A total of 23,600 mycoses cases were diagnosed, of which 1663 patients (7%) presented with deep mycoses. Although the survey is based on laboratory data only, we used these data to estimate the incidence per 100,000 patients according to the population of that year (38,730,000) and we apply that indicator to the current population [
43
].
3. Results
Argentina has a population of approximately 43.8 million, with 25% of these being children under 15 years old and 16% being women >60 years old. The average life expectancy is 77.1 years [ 1 ]. Demographic data of the Argentinian population are presented in Table 1 , including the main at-risk categories for fungal diseases. The gross domestic product was USD $ 12,450 per capita in 2016.
3.1. Infections in HIV-Infected Patients
In Argentina there are 120,000 people living with HIV/AIDS and 6500 new cases are notified annually; 27.5% of these people are diagnosed late, so they often have or are at immediate risk of acquiring an opportunistic infection [ 10 ].
The annual incidence of cryptococcosis is difficult to establish because cryptococcosis is not a reportable disease in Argentina. In a study of HIV-positive patients ≥18 years of age with advanced immunosuppression, CrAg-positivity was 8.1% [
10
,
11
]. The estimated incidence is 0.85/100,000 cases or a total of 372 cases in AIDS, with another 60 cases in non-HIV patients. Microbiologic confirmation of PCP diagnosis is rarely accomplished in most developing countries. PCP prevalence among adult HIV-infected patients ranges widely, from 5% to 60%, due to use of different diagnostic techniques. The estimated incidence is 2.68/100,000, a total of 877 in AIDS, with another 300 cases in non-HIV patients. The estimated number of oral and oesophageal candidiasis cases in patients with HIV is 7200 cases (
Table 2
).
3.2. Histoplasmosis
In 1945, the Argentinian mycologist Dr. Pablo Negroni published the first case of histoplasmosis in South America [ 44 ]. Histoplasmosis is the most frequent endemic mycosis in Argentina—30–40% of apparently healthy adult inhabitants of endemic areas have been infected by H. capsulatum [ 45 ]. Most of the reported cases correspond to the region known as Pampa Húmeda that includes the provinces of Buenos Aires, Entre Ríos, Santa Fe, Córdoba and La Pampa. A large part of the country’s population is concentrated in this area. Several outbreaks have also been described in the country [ 45 , 46 ]. AIDS patients account for about 90% of documented cases. Disseminated histoplasmosis has been reported in 5.3–6% of advanced HIV infection patients in Argentina with frequent skin involvement, followed by pulmonary disease [ 47 ]. Radiological findings include miliary patterns, interstitial infiltrates, and focal infiltrates [ 48 ]. The estimated incidence based in laboratory data is 0.45/100,000 assuming that this represents only 50% of the diagnoses [ 43 , 49 ]. We estimated 404 cases annually. No estimate is provided for subacute or chronic forms of histoplasmosis.
3.3. Endemic Fungal Infections Other Than Histoplasmosis
Paracoccidioidomycosis (PCM) has a restricted geographic distribution. It is endemic in humid subtropical areas of Latin America, from Mexico to Argentina [ 45 ]. In Argentina, there are two endemic areas—one in the northeast and one in the northwest [ 50 ]. In endemic areas, a population prevalence of 7.16% has been reported [ 51 ]. In recent years, the frequency of cases of PCM has increased, but with different epidemiological characteristics to those historically reported, with more patients presenting with the juvenile clinical form [ 52 ]. The estimated incidence is 0.5/100,000—an estimated 219 cases annually.
Coccidioidomycosis was reported for the first time in Argentina in 1892 by Posadas and Wernicke [ 53 ]. Clinical cases of coccidioidomycosis are rare in Argentina and are generally found in the large arid precordilleran area of the country [ 54 ]. The incidence rate is estimated at only 2/100,000 inhabitants in the endemic area (Catamarca, La Rioja, and San Luis provinces), with an estimated 16 cases [ 51 ].
3.4. Candida Infections Other Than Those Seen in HIV-Infected Patients
The incidence of bloodstream infections per 100,000 in Latin America varies annually between 1.2 and 5.3. Data from hospitals in Argentina showed an incidence rate of 1.95/100,000 admissions and 0.24/1000 patients in hospital [ 19 ]. Candida albicans was the most common species (52.2%), followed by C. parapsilosis (30.4%) and C. tropicalis (10.9%) [ 23 ]. The estimated number of cases of candidemia was 2193 and 548 of Candida peritonitis.
In a review of oral fungal infections in patients receiving cancer therapy, for all cancer treatments, the weighted prevalences of clinical oral fungal infections were found to be 7.5% pretreatment, 39.1% during treatment, and 32.6% after the end of cancer therapy [
33
]. These rates may differ each year but may be used as an estimate for current calculations. Each year, 55,000 new cancer cases (including hematological cancers) are recorded. Assuming that the majority of cancer patients (>90%) receive anti-cancer treatment, oral candidiasis episodes were calculated, resulting in a total of 23,375 episodes and 632 oesophageal cases each year.
It was assumed that 6% of women have recurrent vaginal candidiasis (four or more episodes per year), which correlates with 593,695 Argentinian women with recurrent vaginal thrush in any one year.
3.5. Chronic, Allergic, and Invasive Aspergillosis
Of the 10,423 cases of TB in 2016, mostly in HIV-negative people, 8891 (85.3%) had pulmonary tuberculosis. There were 757 deaths and we have assumed that all of them were pulmonary TB cases, leaving 8134 survivors. Using the approach taken by Denning et al. which assumed a 22% cavitation rate following therapy, with a 22% rate of CPA in this group and a 2% in the remainder, we estimate that annually at least 469 patients develop CPA following pulmonary TB, which gives a 5 year period prevalence of 1938, assuming a 15% annual mortality and surgical resection rate. It was assumed that TB was the underlying diagnosis of CPA in 20% of cases and so the total CPA prevalence is 7750 patients [
24
,
25
,
26
].
Estimates of asthma prevalence in adults were around 6% [
27
]. Assuming that 2.5% of asthmatics have ABPA, there will be 114,709 Argentinian adults with ABPA (261/100,000) [
28
,
29
]. In fact, there are no reports of ABPA from Argentina or Latin America, so this estimate is uncertain. Severe asthma is also an increasing problem in Argentina, and fungal allergy has been documented in Brazil, although not in Argentina. Nonetheless, we have assumed that 10% of adults have severe asthma and 33% of these people have fungal sensitization, so we would expect about 151,416 (345/100,000) to have severe asthma with fungal sensitization (SAFS) [
30
]. There may be some duplication between these prevalence figures, as some patients with ABPA have severe asthma.
According to the Ministry of Public Health of Argentina, 2.3 million people have chronic obstructive pulmonary disease (COPD), and it is assumed that 7% of these patients are admitted to hospital [
32
]. Given that 1.3–3.9% of these patients develop invasive aspergillosis, we anticipate at least 1934 such cases annually, although many are not currently diagnosed. Recently, over 10% of patients with COPD were found to be sensitized to
A. fumigatus
and this was associated with worse pulmonary function; therefore, we expect 230,000 patients with COPD to have allergic or chronic aspergillosis, although the therapeutic implications of this are not clear [
32
].
The most important risk factor for IA has historically been neutropenia, and we estimate 480 cases of IA in leukemia patients. According to the INCUCAI data in Argentina, there were 1687 transplants. We estimate the incidences of IA in 22 cases after allogeneic hematopoietic stem cell transplant and in 13 cases after solid organ transplantation. In addition, IA causes complications in patients with lung cancer. A retrospective study reported a frequency of 2.6% [ 38 ]; we estimate 268 cases of IA complicating lung cancer. The total IA incidence is estimated at 2536.
We estimated 75 cases of mucormycosis, most in immunocompromised patients.
Overall, it is estimated that ~881,023 people in Argentina (2.01% of the total population) are affected by a serious fungal infection. We were not able to estimate the burden of other serious fungal diseases such as, mycetoma, chromoblastomycosis, sporotrichosis, fungal keratitis, or tinea capitis.
4. Discussion
This is the first attempt to summarize epidemiological data on the prevalence of serious fungal diseases in Argentina and has used a basic deterministic model. There are few epidemiology papers that have directly reported incidence, prevalence, or fungal infection rates, so every estimate is based on previously published data. As George Box [
55
] wrote in a statistics workshop proceedings paper published in 1979, “All models are wrong but some are useful” and “Now it would be very remarkable if any system existing in the real world could be exactly represented by any simple model. However, cunningly chosen parsimonious models often do provide remarkably useful approximations.” This has been our aim.
Our overall estimate of 2.01% of the total population affected by a serious fungal infection is similar to others reported for American countries such as Brazil, Dominican Republic, Jamaica, Mexico, Trinidad, Tobago, Peru, and Ecuador ranging from 1.9% to 2.4% [ 35 , 56 ]. It is similar to the rates reported for some European developed countries, such as Denmark and Belgium (1.7% and 2.1%, respectively), and for African countries such as Senegal and Tanzania (1.6% and 2.3%) [ 56 ]. The estimated rate for Argentina is also lower than the ones reported from Spain and Germany (3 and 3.6%) [ 56 ].
Recurrent
Candida
vaginitis is the most frequent infection and usually affects women without known underlying diseases; it is the most frequent indication for using antifungals and is therefore, a potential source for colonization by azole-resistant
Candida
strains.
We believe that the 2.01% figure is an underestimation of the real burden of serious fungal diseases in Argentina, with no true explanation for cause, other than missing data. First, mycotic diseases are underdiagnosed due to inadequate access to health services, the limited sensitivity of available diagnostic tests, and an inadequate level of clinical suspicion of fungal diseases explained by inadequate training of health personnel. This is a common problem across the world. These reasons could explain the small number of endemic mycoses diagnosed in Argentina, even though one-third of the territory has conditions for acquisition of them. The perception of a small burden is one reason why flucytosine, a critically important and WHO Essential Medicine, has not been available for more than two decades in Argentina, as in most Latin American countries.
The second reason for believing that we have an underestimated burden is that reporting of fungal diseases is not mandatory and there is no surveillance system for any mycotic disease.
Third, the lack of data available to estimate the size of populations at risk drove us to use conservative figures.
This first estimation of the fungal burden in Argentina needs to be refined, improving measures of fungal diseases and of populations at risk. We acknowledge that using this data representing the country as a whole, and using data not locally produced, has the potential for introducing substantial levels of inaccuracy. The use of better data will produce better estimations and allow trend analyses. However, our results create awareness on fungal diseases that are a public health priority.
Author Contributions
David W. Denning designed the initial study format and conducted modelling for the study; and Fernando O. Riera conducted modelling for a part of the study. The three authors wrote and edited the study all through the preparation period of the manuscript. Three authors, Fernando O. Riera, Juan P. Caeiro and David W. Denning, contributed equally to the writing of the manuscript.
Conflicts of Interest
Fernando O. Riera in the last year, he has been paid for talks on behalf Merck. Currently is president of the commission of fungal infections of the Pan American Association of Infectious Diseases (API) and member of and of the executive committee of the Argentine Society of Infectious Diseases (SADI). He is editor of the manual of fungal infections of the Panamerican Association of Infectious Diseases. David W. Denning and family hold Founder shares in F2G Ltd., a University of Manchester spin-out antifungal discovery company. He acts or has recently acted as a consultant to Scynexis, Cidara, Biosergen, Quintiles, Pulmatrix, Pulmocide, Zambon and Fujifilm. In the last 3 years, he has been paid for talks on behalf of Astellas, Dynamiker, Gilead, Merck, Mylan and Pfizer. He is a longstanding member of the Infectious Disease Society of America Aspergillosis Guidelines group, the European Society for Clinical Microbiology and Infectious Diseases Aspergillosis Guidelines group and the British Society for Medical Mycology Standards of Care committee. Juan P. Caeiro in the last year, he has been paid for talks on behalf Merck and Pfizer. He is member of Argentine Society of infectious Diseases (SADI).
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Table 1. Demographic data for the calculation of fungal-related diseases in Argentina.
Table 1. Demographic data for the calculation of fungal-related diseases in Argentina.
Population estimates in July 2016 43,886,748 HIV and AIDS estimates People living with HIV 2016 120,000 New HIV infections 6500 AIDS-related death 2400 HIV + on highly active antiretroviral therapy (HAART) 75,400 Patients at risk (CD4 count <200 and who developed AIDS) 1105 % Late diagnosis (AIDS symptoms and <200 CD4) at risk of opportunistic infection (OI) 2275 (35%) Leukemia, transplant, and other immunocompromised patients Leukemia 1369 All cancers excl. non-melanoma skin cancer 54,953 Solid organ transplant 2016 year 1687 Renal 1121 Liver 349 Heart 109 Pancreas 46 Lung 33 Liver–renal 17 Intestinal 4 Heart–renal 4 Pancreatic–liver 2 Liver pulmonary 1 Heart–hepatic 1 Pulmonary diseases Tuberculosis total 10,525 Pulmonary tuberculosis (PTB) 9605 Annual incidence 26,3/100,000 HIV-positive TB patients 525 Lung cancer 7690 Chronic obstructive pulmonary disease 2,300,000 Prevalence (for patients over 40 years old) 14.5% Chronic obstructive pulmonary disease admissions to hospital per year 168,000 Asthma In adults >40 years old 4,588,360 Cystic fibrosis Total registered 156 Critical care and surgery cases (2013 year) Critical care beds 9116
Table 2. Burden of serious fungal infection in Argentina.
Table 2. Burden of serious fungal infection in Argentina.
Rate/100,000 Burden Serious Fungal Infection Totals No Underlying Disease HIV/AIDS Respiratory Disease Cancer + immuno-Compromised Critical Care + Surgery Cryptococcal meningitis 1.0 I 432 372 60 Pneumocystis pneumonia 2.68 I 1177 877 300 Invasive aspergillosis 5.8 I 2536 268 334 1934 Chronic pulmonary aspergillosis post TB 1.1 I 615 615 Chronic pulmonary aspergillosis post TB 4.0 P 1938 1938 Chronic pulmonary aspergillosis—all 19.9 P 7750 7750 Allergic bronchopulmonary aspergillosis (ABPA) 261 P 114,709 114,709 Severe asthma with fungal sensitisation (SAFS) 345 P 151,416 65,172 Candidaemia 5.0 I 2193 1096 1097 Candida peritonitis 1.25 I 548 Oesophageal candidiasis 13.1 I 5743 5111 632 Recurrent Candida vaginitis (≥4×/year) 2706 P 593,695 593,695 Mucormycosis 0.17 I 75 13 62 Disseminated histoplasmosis 0.91 I 404 37 367 40 Coccidioidomycosis 0.03 I 14 14 Paracoccidioidomycosis 0.56 I 246 246 Total serious fungal infection burden 881,023 2.01%
I: incidence, P: prevalence.
MDPI and ACS Style
Riera, F.O.; Caeiro, J.P.; Denning, D.W. Burden of Serious Fungal Infections in Argentina. J. Fungi 2018, 4, 51.
https://doi.org/10.3390/jof4020051
AMA Style
Riera FO, Caeiro JP, Denning DW. Burden of Serious Fungal Infections in Argentina. Journal of Fungi. 2018; 4(2):51.
https://doi.org/10.3390/jof4020051
Chicago/Turabian Style
Riera, Fernando O., Juan P. Caeiro, and David W. Denning. 2018. "Burden of Serious Fungal Infections in Argentina" Journal of Fungi4, no. 2: 51.
https://doi.org/10.3390/jof4020051
Article Metrics
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(PDF) The Effect of Services Marketing Mix Elements on Customer-Based Brand Equity: An Empirical Study on Mobile Telecom Service Recipients in Jordan
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The Effect of Services Marketing Mix Elements on Customer-Based Brand Equity: An Empirical Study on Mobile Telecom Service Recipients in Jordan
May 2013
International Journal of Business and Management 8(11):13-26
DOI: 10.5539/ijbm.v8n11p13
Abstract and Figures
The purpose of this research is to study the effect of services marketing mix elements on customer-based brand equity through empirical study of mobile telecommunication service recipients. It also aims to determine the influence of such elements on customer-based brand equity and to reveal which is the most influential. We employed a questionnaire-based survey consisting of 56 questions and distributed to 1,930 respondents in the three largest governorates in Jordan: Amman, Irbid, and Al-Zarqa. In total, 1,492 questionnaires were returned, corresponding to a response rate of 77%. In order to analyze the data obtained from questionnaires, quantitative methods were employed, and reveal that there is a significant effect of services marketing mix elements upon customer-based brand equity. The study suggests that customer-based brand equity is a valuable asset for any services sector, especially for marketing managers to assess the results of their efforts by getting feedback from customers to diagnose any problem that can appear in the provided service. In addition, customer-based brand equity provides a clear approach which can be employed by managers for the design and creation of branding strategy. This should enable managers to minimise problems that could arise from limited resources.
The model of this study …
. The population and the sample size …
. Coefficient of the Multiple Regression Model/ perceived quality …
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International Journal of Business a nd Management; V ol. 8, No. 11; 2013
ISSN 1833-3850 E-ISSN 1833-8119
Published by Canadian Center of Science and Education
13
The Effect of Services Marketin g Mix Elements on Customer-Based
Brand Equity: An Empirical Stud y on Mobile Telecom Service
Recipients in Jordan
Hani Al-Dmour 1 , Zu’bi M. F. Al-Zu’bi 1 & Dana Kakeesh 1
1 Business School, University of Jorda n, Amman, Jordan
Correspondence: Zu’bi M. F. Al-Zu’bi, University of Jordan, P.O. Box 13413, Amman, 11942, Jordan. Tel:
962-79-562-939. E-mail: [email protected]
Received: December 18, 2012 Accepted: Ja nuary 11, 2013 On line Published: May 16, 2013
doi:10.5539/ijbm.v8n11p13 URL: http://dx.doi.org/10.5539/ijbm.v8n11p13
Abstract
The purpose of this research is to study the effect of services marketing mix elemen ts on customer-based brand
equity through empirical study of mobile telecommunicat ion service recipients. It also aims to determine the
influence of such elements on customer-based bra nd e quity and to reveal which is the most influential.
We employed a questionnaire-based survey consisting of 56 questi ons and distributed to 1, 930 respondents in the
three largest governorates in Jordan: Amman, Irbid, and Al-Zarqa. In total, 1,492 questionnaires were returned,
corresponding to a response rate of 77%. In order to analyze the data obtai ned fr om questionnaires, quantitative
methods were employed, and reveal that there is a significant ef fect of services marketing mix el ements upon
customer-based brand equity.
The study suggests that customer-based brand equity is a valuable asset fo r any services sector, especially for
marketing managers to assess the results of their ef forts by getting feedback from customers to diagnose any
problem that can appear in the provided se rvice. In addition, customer-based bran d equity provides a clear
approach which can be employed by managers for the design and c reation of branding strategy. T his should enable
managers to minimise problem s that could arise from limited resou rces.
Keywords: service marketing, customer-based brand e quity, Jordan
1. Introduction
Service in Jordan is considered to be most prominent amongst economic sectors, comprising 67% of the GDP. The
large contribution of the service sect or to GDP compared with the small contribution of the industrial and
agricultural sectors results in a service-oriented econ omy (Statistical Ye arbook, 20 09). Recent years have seen
rapid changes in the service sector and the increased competition between firms, which has increased the
importance of services brand management. All these cond it ions have increased pressure upon the most dynam ic
member on the service sector: the mobile telecommunication s ector. Managers in this sect or find themselves face d
with increasing demands from customers, a nd face new challenges to achieve what they want and provide clients
with superior services in light of the existence of higher co mpetition in the marketplace.
This issue is essential in the design and development of the company’s service offering s because the ultimate goal
of any company is to have valuable b rand equity. This means that the manager must give more attention and care
to the company-marketing program by developing effect ive services m arketing mix (SMM) elements that can
increase brand equity over competitors. Thus, this research investigates the influence of services marketing mix
on customer-based brand equity, and serves as an empirical study of mobile services recipients. The literature
review reveals a large amount of research related to service marketing (Langeard et al. , 1981; Zeithaml et al. ,
1985; Onkvisit and Shaw, 1989; Bitner, 1990, 1992; Gron roos, 1994). Many of the stud ies criticise the traditional
concept of marketing mix that was introduced fo r the first time by Borden in 1948 (Shostack 1977; 1976; Kent,
1986). Booms and Bitner (1981) introduced the “3 P’s” of service marketing mix-people, physical evidence, and
process-to figure out services problem by having more comprehensive model specified for service product.
On the other hand, the definition and quantification of brand equity is of con siderable interest to many researchers
(Aaker, 1991;1996; Keller, 1993; Lasse r, 1995) because of the necessity in today’s marketplace to develop and
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14
utilize product branding to ensure that companies ca n enjoy co mpetitive advantage (Pitt and McCarthy, 2008). It
is now appreciated that brands are intangible assets, wh ich has been reflected by an increased em phasis in the
literature on the ways in which brand equity can be developed, maintained and measured (Keller, 2008; 2003). In
general, brand equity is viewed from one of three perspectives, dis tinguished by being customer-base d,
company-based or financially-based (Aaker, 1996; Keller and Lehmman, 2003b). This research uses the
customer-based brand equity (CBBE) approach. At the same time, many academics were attem pting to develop
various models to measure the brand equit y (Aaker 1993; 1996; and Lasser, 199 5) depending mainly on Keller
(1993) CBBE dimensions.
1.1 Problem Statement
Since the Jordanian services market is rapidly changing, and servi ce companies experiencing increased
competition, the management of service brands has gained gr eater significance. It is not straightforward to assess
customer-based brand equity. As a largely intangible and com plex concept, it is difficult f or a customer to contrast
the offerings of various service companies on the market. Consequently, this research aims to investigate out the
effect of services marketing m ix on customer-based bra nd equity: an empirical study on mobile telecom service
recipients, and to answer the following research questions:
1) How much do marketing mix elements of mobile tel ecommunication service effect on the cost umer–based
brand equity?
2) Within SMM, which elements have greatest influence on CBBE?
1.2 Significance
Despite the considerable progress of pre vious research in explaining the link bet ween SMM and CBBE this study
adds further insight to understand of this link. In add ition, this research has the following important aspects:
1) The mobile service providers (MSP) a re amongst the fastest growing com panies in the service sector in
Jordan. This rapid growth ha s been accompanied by other dram atic changes that have begun to exert
significant pressures on MSPs to raise the value of their brands and to provide bette r services than what the
other competitors in the market place do.
2) The scarcity of Jordanian studies on the CBBE gave the advantage of this research in helping the Jordanian
managers to start thinking about their m obile telecom service recipients and organizi ng their marketing
efforts in order to raise their CBBE.
3) It is an empirical study applied on the main MSPs in Jordan (Zain, Orange, and Umniah) which m eans that
the results of this study will be ve ry important to each company in orde r to increase or to maintain their
competitive advantages in the market place.
1.3 Study Conceptual Framework
Rathmell (1966) defined services as acts, d eeds, performances, or efforts. Zeithaml, et al. , (1985) described
services similarly to Rathmell’s definition as deeds, pr ocesses, and performances delivered from one entity or
individual to another entity or individual. Service is mainly intangible product tran sfer the benefit from one party
to another without trans ferring the ownership of this kind of product (Kotle r et al. , 2005). Lovelock and Writz
(2007, p.15) stated services as “an economic activities offered by one party to another, most commonly employing
time-based performances to bring about desired results in recipients themselves or in objects or other assets for
which purchasers have responsibility.” Services are often de scribed in contrast to goods. A good is a tangible ite m
that can be produced, sold, and then consum ed later, while a service is intangible and perishable. It is sold,
produced, and then consumed. T his study builds on Rathmell' s (1966) definition.
Keller (1993) defines CBBE as “the differential effect of brand knowledge on consumer response to the marketing
of the brand.” Keller includes three main concepts in his definition. The first one is the “differential effect” and
this can be determined by comparing the customer’s respon se toward the marketing of a brand with the response to
the marketing of other brand from the same category. The second one is “brand kn owledge” and comprises two
principal components: brand a wareness–the extent to which customers are aware about a bran d, and brand image,
which reflects the association customers hold in their mi nd regar ding a brand. The final conce pt is “consumer
response” this can be described as the consum er perceptions, preferences, and behavior t oward the marketing
activities. A brand has positive CBBE when a customer’s reaction is considered to be positive toward the brand
and vice-versa.
Aaker (1991; 1996) incorporates both perceptual and the behavioral dimensi ons. He lists ten sets of measures
divided into five categories. The first four categories— perception of quality, loyalty to a brand, awareness of a
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brand, and brand association—are c oncerned with the customer. The last one, other propriety assets, is rela ted to
the market wherein the firm is oper ating. Aaker contents that brand loyalty reflects the level of commitment
exhibited by a consumer for a particular brand. Brand aware ness is related to the potentia l for a customer to
identify a brand among competitors’ pr oducts in the marketplace. Brand association de scribes any memory or
perception that a customer may have in connection to the brand. Proprietary brand assets refer to special issues
like the patents and trademarks. The stronger these dimensions are, the higher the res ulting brand equity.
In contrast to Aaker’s (1991) focus on th e five brand equity dimensions discussed above, Keller’s (1993) approac h
is to either indirectly or directly measure CBBE from the point of view of just two construct s: brand image and
brand awareness. The indirect approach involves identification of possible so urces of CBBE such as channels of
distribution, the efficacy of communicati ng about the marketing, and the success of strategies to extend the brand
by, for example, measuring brand a war eness and exploring the mechanisms of brand associations. The direct
approach, on the other hand, primaril y involves studies of how consumers respo nd to various aspects of the
marketing strategy of the company (Keller, 2003).
Lasser et al. (1995), modify the previous scales used b y practitioners. Their main modifications concentrate on
four main aspects. First they repl ace the quality dimension with performan ce, and then they use the social
dimension instead of the image di mension. Third, they try to clearly distinguish between the feeling com mitment
and the action commitment. Finally, they constitute a specif ic definitio n for both value and trustworthiness as a
part from brand equity. Brand knowledge c an be considered to comprise primari ly of brand awareness and brand
image. This construct has been use d in the CBBE framework proposed by Keller (1993).
Yoo et al. (200 0) adopt three of the dimensions from the Aaker (1991) model: brand loyalt y, brand association and
perceived quality. The authors also extend the model by adding antecedents of brand equity, which they identify
as price, price deals, distribution intensity, store image and advertising expenditure. Their study reveals that these
dimensions have a significant effect on brand e quity. Prasad and Dev (2000) and Low and L amb Jr (2000) both
adopt four of Aaker’s (1991) compone nts: brand awareness, brand association, perceived quality, and brand
loyalty.
For the purpose of this study , four dimensions explor ed, comprised of three perceptua l dimensions-perceived
quality, brand image and brand awarene ss, brand image, and one behavioural dimension-brand loyalty. Brand
image is used interchangeably with brand association. According to Keller (2003), brand image relates to the
associations related to the brand that exist within the minds of customers, and comprises all expectations and
knowledge relating to a particular product or service.
Empirical studies which focused on SMM were identif ied using the scholarly Internet search engine
scholar.google.com, in addition to various online databases encompassing leading journ als in a range of fields
including marketing service and brand equi ty. A number of studies related to SMM can be found in various
marketing journals and magazines. However, many of them are conceptual or non-empiri cal studies using either a
qualitative or quantitative approach. For example, a study by Kayaman and Arsalai (2007) aimed to identify the
relationship among four dime nsions of brand equity: brand im age, brand awareness, brand loy alty and perceived
quality. In this work they propose a conceptual framework to describe hotel brand equ ity. This study examines
five-star hotels in northern Cyprus. The model was developed by considering perceived quality as in dependent
variable and the other three brand equity dimensions as a dependent variables. The concl usions of the study are
that that awareness has only minim al effect on brand equity, but at the same time brand image, brand loyalty and
perceived quality are important factors in building brand eq uity in the hotel sector. Finally, this stud y recommends
that executive managers pay m ore attention to these variables for t heir significant importance in desi gning and
providing services.
Akroush and Al-Dmour (2006) st udy seventeen commercial banks to investigate the relationship bet ween
branding benefits and brand-building factors within comme rcial banks opera ting in Jordan. This study adopts a
model that consists of corporate culture, internal marke ting, service delivery process, atmosphe rics, distinctive
banking product, marketing communication, and cross f unctiona l team as independent variables, while the
building brand benefits whic h encompass overall benefits , fi nancial benefits, and non-fi nancial benefits as
dependent variables. The study found a strong and positiv e correlation between the brand building factors and the
overall brand benefits; financial and non-financial. The important finding is that service deli very process,
atmosphere, and marketing com munication and non-financial benefi ts (i.e. brand image) are related. Akroush and
Al-Dmour recommend that the m anagers focus on providing disti nctive banking products, in orde r to build
customer-oriented corporate culture, and to pay more attent ion to the employees in front offices. T hey also suggest
to focus also on marketing communications, atmospherics, and service delivery activities in order to enhance
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building a desirable image in the m arketplace. In another study, Akro ush, et al. (2006) aimed to study how SMM
elements affect customer satisfaction relating to comprehensive motor insurance. The study identifies significant
and positive relationship between the summated SMM com ponents and customer satisfaction. This pape r also
reports a significant positive correlation between the new 3P marketing mix (processes, people and physical
evidence) on the satisfaction enjoyed by customers. They also mentio ned that the 3P’s effect on customer
satisfaction is stronger than the effect of the traditional marketing mix components.
Rajh & Dosen (2009) explore how various marketing mix el ements affect service brand equity. This work has
greatest value in its reports of how different elements have different effects on service brand e quity, and by
showing how essential it is to devel op approaching the development of s ervice brand in a strategic m anner. In
addition, the findings draw conclusions relating to th e necessity for concerted ef forts regarding e mployees,
advertising, price level, interior appearance and servic e operation, as each of th ese factors positively affects
service brand equity. The results indicate how important it is to build service brands strategically, with a primary
long-term goal to establish service brand equity.
Faircloth et al. (2001) investigates how brand image and attitude affect brand equity. The authors perform an
empirical study of a conceptual model derived fro m work by Aaker (1991) and Keller (1993). The results suggest
the manipulation of brand equit y through communication of specifi c signals or brand associations to consum ers,
which will influence attitudes and images of customers to these brands, hence affecting brand equity. The
researcher also suggests a focus on specific constructs that have greatest influe nce on brand equity, rather than
attempting to quantify total monetary performance.
Yoo et al. (2000) explore how brand equity can be created by certain marketing mix elements. The paper o utlines
a conceptual framework describing the relat ionship between various dimensi ons of brand equity and marketing
elements. Specifically, these dimensions are brand lo yalty, perceived quality, brand associations and brand
awareness. The research hypotheses were tested empirica lly using str uctured equation modeling, which f ound that
price deals and other price prom otions give rise to low brand eq uity while increased spending on advertising,
higher prices, greater intensity of distribution and improv ed store image have a significant positive relation ship to
high brand equity.
Cobb-Walgren et al. (1995) perform ed a study using a perception-based m easure of brand equity from the
perspective of the customer. The study uses the Aaker (1991) conceptualization as adopted by Keller (1993) –
brand association, brand awareness and perceived qu ality. Specifically, the work investigated hotel and
househould cleanser used in the service sector t o explore the effect of brand equity o n consumer’s preference and
purchase intention. The results show that brand equity increases bot h consumer’s preference and purc hase
intention.
2. Methods
2.1 The Study's Model
Figure 1. The model of this s tudy
Our theoretical research model arises from our review of the literature and the aforementioned study objectives.
Figure 1 presents the research model developed for the purposes of this research. It consists one dependent
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variable-customer-based brand e quity (CBBE) and one indepe ndent variable-the service m arketing mix elements.
This is affected by the independe nt variables, the serv ice marketing m ix elements. These elements were derived
from previous research, where all were independently found to be related to increased levels of CBBE. However,
they had not been combined and t ested in the same study. The research pr oposes four dependent varia bles: brand
image, brand awarenes s, brand locality and perceived quality).
2.2 Operational Definitions
Independent Variable (Services Marketing Mix) is def ined as “the set of tools availabl e to an organization to
shape the nature of its offer to customers”. These elements are:
1) Service elements are defined as the intangible activities and performance designed by interactive process in
order to satisfy customer needs and expectat ions, and convince them, this process could be done by using
tangible products. Table 1 shows the five items used to operationalise this construct.
2) Price elements are defined as the value of items which are needed for the acquisition of a product. Tab le 1
shows the four items were used to operationalise this construct.
3) Distribution/Place refers to th e personnel and firms involved in t he development of a product from producer
to user. Table 1 shows the six items were used to operationalise this construct.
4) Promotion includes all of the tools available to the marketer to transform their message about the product
strategy to the target market; moreover, this consists of communication mix. Table 1 shows the six items
were used to operationalise this construct.
5) People consist of staff with the require d attitude, service knowledge and relational skills to ensure that the
consumers will receive the service fo r which they are paying. Table 1 shows the five items were us ed to
operationalise this construct.
6) Physical Evidence is the environment in which the service is delivered and any tangible goods that facilitate
the performance and communication of the service. Customers look for clues to the likely quality of a service
also by inspecting the tangible evidence. Table 1 shows the four items were used to operationalise this
construct.
7) Process means procedures, mechanism and flow of activ ities by which a service is acquired. Process
decisions radically affect how a service is delivered to customers. Table 1 shows the six items were used to
operationalise this construct.
Dependent Variables, Cust omer-Based Brand Equity:
Brand equity is the “added value” with which a gi ven brand endows a product (Farquha r, 1989, p. 7). Aaker
(1991, p. 38) defines brand equity as “a set of brand a ssets and liabilities linked to a brand, its name and symbol
that add to or subtract from the val ue provided by a product or servi ce to a firm and/or to that firm’s custom ers.”
Keller (1993, p. 8) defines CBBE as the differential eff ect of brand knowledge on ho w a co nsumer will respond to
brand marketing.
1) Brand Awareness: how well a potential buyer is able to observe and remember that a brand lies within a
particular class of products (Aaker, 1991). Table 1 shows the three items used to operationalise this
construct.
2) Brand Image: is a consumer’s perception abo ut the brand as reflected by the brand associations hel d in his or
her mind (Keller, 2008). Table 1 shows the six items were used t o operationalise this construct.
3) Perceived Quality: “The consumer' s judgment about a product's overall exce llence or superiority” (Zeithaml,
4) Brand Loyalty: defined by Aaker ( 1991) as the affection felt by a customer to a pa rticular brand. Table 1
shows the three items that were used to operationalise this construct.
5) Overall Brand Equity: table 1 shows the four items were used to operationalise this construct.
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Table 1. The scales of measuring the study items
No. Services Marketing Mix Elements Source(s)
The Services nature Akroush et al. (2006)
1. My mobile service provider pr ovides me with distinctive after sale services.
2. My mobile service provider cares about my opinion in the development of new services.
3. I deal with a mobile service provider th at has a distinctive brand in the market.
4. My mobile service provider pr ovides me with updates about deve loped service products.
5. My mobile service provider provide s m e with a variety of services
The Price Yoo et al. (2000)
6. My mobile service provider provides me with more than one paying facility/ option.
7. My mobile service provider’ s prices are appropriate to me.
8. The prices a re appropriate compared to the quality of services provided.
9. The prices a re competitive compared to the other mobile service providers.
The Distribution/Place Yoo et al. (2000)
10. My mobile service provider has many br anches within m y region of residence.
11. The number of outlets that deal with my mob ile services provider are more than those of its
competing brands.
13. The website essential base for dealing with my mobile service provider (paying the bills, detailed
bill on your e -mail…. etc.) is satisfactory.
14. My mobile service provide r website is well-organized.
15. Signs of my mobile service pr ovider’s location are available.
The Promotion Yoo et al. (2000)
16. The advertising campaigns seem very creative, compared to campaigns for competing brands .
17. The advertisements are frequently seen th rough media such as TV, radio and billboards.
18. In general, I can feel that there is a credibility in the advertisements.
19. My mobile service provider gives me special offe rs from time to time (i.e .: free hours, sms,
mms, … etc.) .
20. My mobile service provider cares about cu ltural activities and program sponsorship (i.e.:
independent day festival, social events, sp ort games, …etc.).
21. When I decide to purchase a sp ecific service, I take into c onsideration the spoken word of
mouth from friends and relatives.
People Akroush et al. (2006)
22. The staff is able to provide the required services quickly.
23. Most of the time the staff is able to answer my inquiries.
24. The staff is well-trained and know how to deal with customers.
25. The staff treats me as a special and valued customer.
26. The staff is always willing and ready to deliver the service to me.
Physical Evidence Akroush et al. (2006)
27. The staff appears in attractive uniforms.
comfortable and attractive.
29. My mobile service provider uses modern and sophisticated equipments.
30. The overall atmosphere is comfortable.
Processes Akroush et al. (2006)
31. The procedures to get the required services are easy, quick and immediate.
32. My mobile service provider delivers services as promised.
33. My mobile service provider provides services to customers free of errors.
34. My mobile service provider deals with the clients in confidentiality and privacy.
35. My mobile service provider handl es seriously with my complaints.
36. My mobile service provider is committed to all of the conditions offered to clients in the purchase
policy.
Brand Awareness Yoo et al. (2000)
37. It’s easy to recognize my mobile service provider’s name among ot her competing brands.
38. I am familiar with the ot her mobile service providers.
39. Some characteristics of my mobile service provider come to my mind quickly.
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Brand Image Aaker and Álvarez del
Blanco(1995);
Lassar et al. (1995);
and
Yoo et al. (2000)
41. I respect and admire the other customers who deal with my mobile service provider.
42. My mobile service provider has a di fferentiated image from other companies.
43. My mobile service provider provides a high value in relation to the price I must pay.
44. I like and trust my mobile service provider’s offers.
45. My familiarity of the Company’s Origin Country affects the way I look at my mobile service
provider.
Perceived Quality Yoo et al. (2000)
46. My mobile service provider has the best qualit y in providing the services compared to the
other co mpeting brands.
47. I can feel that there is a consistency in the level of quality provided.
48. There is an obvious reliability in providing service.
49. My mobile service provider always delivers superior services.
Brand Loyalty Anderson and Sullivan
(1993); Fornell et al.
(1996); Hallowell
(1996); Oliver (1999);
Kim, Park, and Jeong
(2004)
50. I would buy from my mobile service provider again in the future.
51. I would recommend my mobile service provider to other people ( i.e.: my friends and relatives )
to make their purch ases in the future.
52. I would endorse and defend my mobile service provider's image in front of other customers.
Overall Brand Equity Yoo et al. (2000)
53. It makes sense to deal with my mobile service provider instead of any other provider, even if they
are the same.
54. If other mobile service providers are not diffe rent from mine, I deal with my mobile service
provider in any way, since it seems smarter to purchase.
55. Even if there is another brand as good as my mob ile service provider’s brand, I prefer to keep with
my current provider.
56. My mobile service provider is more than a service to me.
2.3 Research Hypotheses
Based on the previous model use d, a number of hypotheses were form ulated to investigate the research pr oblem
and to fulfill its goal. Three main null-hypotheses were tested in this research. The hypotheses are as listed below.
1) H 0.1 : Services marketing mix elements do not have a significant effect on bra nd awareness.
2) H 0.2 : Services marketing mix elements do not have a significant effect on brand image.
3) H 0.3 : Services marketing mix elements do not have a significant effect on perceived quality.
4) H 0.4 : Services marketing mix elements do not have a significant effect on bra nd loyalty.
2.4 Research Design
This section demonstrates the research design an d clarifies data collection and analysis methods.
1) Research Type: This research uses two research scientific approaches, the descriptive analysis is
undertaken to describe the characteristics of the variables. Empirical investigation is used to test the research
hypotheses, and to explain the nature of variables relationships.
2) Population and Sampling Design: The population in this study-the group of interest–is all the mobile
telecom service recipients in Jordan; this means all the clie nts of MSPs which are licensed as
telecommunication companies at Tel ecommunication Regulatory C ommission (TRC). The type of the
sample has been decided to be a convenience sample of 2,000 responde nts in order to assure an acceptable
confidence in our parameters estimation. Table 2 sh ows how resp ondents vary according to the type of
service provider and the city.
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Table 2. The population and the sample size
MSP
Total Market
Share % 1, 2
MSP’s
Number of
Governorates
Governorates’
respondents
1
Governorates’
Number of
Respondents
Allocation of
Unallocated #
from MSP’s
respondents
The actual
number of
distributed
questionnaire
Number of
Returned
Questionnaire
Return Rate
1 Zain 0.45 900 Amman 55.25 497 4 3 501 403 0.80
Irbid 12.40 112 1 113 78 0.69
Al-Zarka 31.40 283 3 286 221 0.77
Unallocated #
from MSP’
respondents
82 - -
Total 99.50 900 8 900 702 0.78
2 Orange 0.32 640 Amman 12.58 81 22 103 77 0.72
Irbid 28.10 180 50 230 163 0.69
Al-Zarka 31.50 202 56 258 205 0.77
Other 204 - -
Total 72.18 640 147 591 445 0.76
3 Umniah 0.22 440 Amman 17.92 79 5 84 77 0.92
Irbid 35.8 158 9 167 132 0.79
Al-Zarka 40.40 178 10 188 136 0.72
Other 25 - -
Total 94.12 440 24 439 345 0.79
Total 0.99 1,980 - - 1,743 179 1,930 1,492 4 0.77
1 Source: Ipsos state Jordan.
2 calculated as 900-(479+112+283).
3 calculated by 8 x 55.25%.
4 1,949-1,553=396 questionnaires; 273 questionnai res unreturned and 123 questionnair es invalid.
2.5 Research Validity and Reliability
Validity test: To ascertain the validity of the study instruments, the questionnaire was presented to a group of
specialized people on the related subject s, to identify their views, and the ap propriateness of all the questions to
the main study objectives . They proposed some adjustme nts and suggested some necessary corrections to ensure
improvement and validity of the instruments. The questio nnaires were modified accor ding with the notes and
instructions that were taken from t hese people. The researchers then excluded irreleva nt questions and changed
unclear or difficult terminologies into simple ones.
Reliability test: Consistency-how well items fit as a set-and stab ility of data are both measures of reliability
(Sekaran, 2003, page 307). Cronbach's alpha, in partic u lar, is a measure of reliability, and reports mean
inter-correlations between the item s which measure a concept. A Cronbach's al pha of close to 1 indicates a high
the internal consistency of the study tool. (Se karan, 2003, p. 307). The Cronbach's Alpha values, and was (0.941)
which is considered to be good because it is greater than accepted perce nt (0.60). These results mean that the
internal consistency reliability was high and acceptable and can be considered to be highly reliable to reach the
research purpose.
3. Results
3.1 Hypotheses Testing
Multiple linear regression analysis was employed in this work to investigate the research main and sub-hypotheses
of this study. Multiple regressions enables researcher s to examine the effect of many different factors
(independent variables) on a certain outcome (dependent variable) at the sam e time. The general goals behind
using the multiple regression method were to learn more about the relationship between several independent
variables and a dependent variable, and also to investigate the functional relationshi ps between independent and
dependent variables in order to u nderstand what might be causing the variation in the dependent variabl e. This
section presents the main result of the research hypotheses.
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3.1.1 Testing the first hypothesis
H 0.1 : Services marketing mix elements do not ha ve a significant effect on brand awareness.
To test this hypothesis the multiple regression test is us ed, and according to the SPSS analysis, it is found that F
calculated = 116.492 is greater than F tabulated = 2.01. According to the decision rule, this null-hypothesis H 0 is
rejected, meaning; SMM elements have a positive significant effect on brand image. R square value exhibits the
capability of the independent variable in predicting the dependent variable; ind icating that only 35.5% of the
variation in brand image is expl ained by SMM elements Table 3.
Table 3. The result of multiple regression analysis for th e effect of SMM elements t ogether on brand awareness
F calculated F tabulated F Sig R R 2 Testing Result
106.845 2.01 000 .579 .335 Rejected
Table 4 below exhibits the results of each component of SMM taken separately The result showed that the
promotion element is the most influential element on br and awareness followed by processes, physical evidence,
the service nature, and people in order this finding is consistent with other researchers’ findings (Yoo et al. ,
2000; Cobb-walgren et al. , 1995). Unexpectedly, the results showed that both the price and the distribution
element do not have effect on brand awareness. These may indicate that creation of brand awareness is the
primary goal of promotion neither the price nor the distri bution, in addition to that brand awareness refers to
how aware customers and potential customers are of company.
Table 4. Coefficient of the multiple regression model/ brand awareness
Model Unstandardized Coefficients Standardized Coefficients T Sig.
B Std. Error Beta
1 (Constant) 1.839 .093 19.842 .000
Service
Nature .069 .023 .077 3.002 .003
Price .003 .016 .004 .178 .858
Distribution .024 .020 .030 1.184 .237
Promotion .230 .023 .271 9.822 .000
People .070 .021 .094 3.344 . 001
Physical
Evidence .079 .021 .101 3.792 .000
Processes .145 .024 .176 6.013 .000
a Dependent Variable: brand awareness.
3.1.2 Testing the Second Hypothesis
H 0.2 : Services marketing mix elements do not have a significant effect on brand image.
To test this hypothesis the multiple regression test is us ed, and according to the SPSS analysis, it is found that F
calculated=116.492 is greater than F tabulated=2.01. According to the decision rule, this null-hypothesis H 0 is
rejected, meaning; SMM elements have a positive significant effect on brand image. R square value exhibits the
capability of the independent variable in predicting the dependent variable; ind icating that only 35.5% of the
variation in brand image is explained by SMM elements (Table 5).
Table 5. The Result of Multiple Regression Analysis for the effect of SMM elements together on brand image
F calculated F tabulated F Sig R R 2 Testing Result
116.492 2.01 000 .596 .355 Rejected
Table 6 exhibits the results of each co mponent of SMM, taken separately. Th e result shows that all SMM elements
except people element have a positive significant effect on brand image; this finding is consistent with other
researchers’ findings (Al-Dmour and Ay esh, 2005; Berry, 2000; Yoo, et al. , 2000; Hogg, et al. , 1998;
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Cobb-walgren, et al. , 1995; Gronroos, 1994; Bitner, 1992; Zeitha ml, et al. , 1985). Processes el ement was the most
influential element on brand image followed by the price, the service nature, the promotion, physical evidence,
and distribution in order. This surprisin g result contradi cts with previous researches results which states that
people strongly affect on brand image. This result may be attributed to the narrow eff ect of MSP’s staff on image.
Therefore, company should give more attention to their staff.
Table 6. Coefficient of the multiple regression model/brand image
Coefficients a
Model Unstandardized Coefficients Standardized Coefficients T Sig.
B Std. Error Beta
1 (Constant) -.143 .140 -1.023 .306
Service Nature .158 .035 .115 4.553 .000
Price .236 .024 .236 9.905 .000
Distribution .079 .030 .066 2.621 .009
Promotion .131 .035 .101 3.719 .000
People -.035 .032 -.031 -1.098 .272
Physical Evidence .109 .031 .091 3.482 .001
Processes .307 .036 .243 8.409 .000
a Dependent Variable: Brand Image
3.1.3 Testing the Third Hypothesis
H 0.3 : Services marketing mix elements do not have significant effect on perceived quality.
The multiple regression test is used to test this hypoth esis, and according to the SPSS analysis, it is found that F
calculated=154.128 is greater than F tabulated=2.01. According to the decision rule, this hypothesis H 0 is rejected,
meaning; SMM elements have a positive significant eff ect on perceived quality. R square value exhibits the
capability of the independent variable in predicting the dependent variable; indicating that 42.1% of the variation
in perceived quality is explained by SMM elements Table 7.
Table 7. The Result of multiple regression analysis for th e effect of smm elements together on perceived quality
F calculated F tabulated F Sig R R 2 Testing Result
154.128 2.01 000 .649 .421 Rejected
Table 7 exhibits the results of each compone nt of SMM, taken separately. The result shows t hat the SMM
elements except the distribution have a positive significant effect on perceived quality; this finding is consistent
with other researchers’ findings ( Yoo, et al, 2000; Cobb-walgren, et al.1995) Pr ocesses element was the most
influential element on perceived quality followed by the promotion, the services nature, people, the price, and
physical evidence in order. This may be due to the fact th at perceived quality is the consumer’s quality perception
of the brand when he compares it with other product in the same category so it could be inferred that there is no
effect of distribution process on customers’ perceived quality.
The researcher found that SMM elements together have a positive significant effect on CBBE dimensions equal
0.553, which is strong relation .This finding is consis tent with other researchers’ findings (Simon and Sullivan,
1993; Cobb-Walgren, et al. , 1995; Akroush and Al-Dmour, 2006; Akroush, et al. , 2006).
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Table 8. Coefficient of the Multiple Regression Model/ perceived quality
Coefficients a
Model Unstandardized Coefficients Standardized Coefficients t Sig.
B Std. Error Beta
1 (Constant) .005 .121 .042 .967
Service Nature .176 .030 .141 5.870 .000
Price .054 .021 .059 2.634 .009
Distribution .037 .026 .034 1.408 .159
Promotion .242 .031 .204 7.937 .000
People .100 .027 .096 3.654 .000
Physical
Evidence .055 .027 .051 2.050 .041
Processes .321 .032 .278 10.176 .000
a Dependent Variable: Perceived Quality
3.1.4 Testing the Fourth Hypothesis
H 0.4 : Services marketing mix elements do not have a significant effect on bran d loyalty.
To test this hypothesis the multiple regression test is us ed, and according to the SPSS analysis, it is found that F
calculated=122.171 is greater than F tabulated=2.01. According to the decision rule, this hypothesis H 0 is
rejected, meaning; SMM elements have a positive significant effect on brand loyalty. R square value exhibits the
capability of the independent variable in predicting the dependent variable; ind icating that only 36.6% of the
variation in brand loyalty is explained by SMM. (Table 9).
Table 9. The Result of Multiple Regression Analysis for the effect of SMM elements together on brand loyalty
F calculated F tabulated F Sig R R 2 Testing Result
122.171 2.01 000 .605 .366 Rejected
Table 10 exhibits the results of eac h component of SMM . The results show that all the SMM elements have a
positive significant effect on brand loyalty. Processes elem ent was the most influential element on brand loyalty
followed by the price, the promoti on, the services nature, the distribution, peo ple, and physical evidence. This
finding is consistent with othe r researchers’ findings (Yoo et al. , 2000).
Table 10. Coefficient of the multiple regression model/brand loyalty
Coefficients a
Model Unstandardized Coefficients Standardized Coefficients t Sig.
B Std. Error Beta
1 (Constant) -.223 .147 -1.518 .129
Service Nature .133 .036 .092 3.658 .000
Price .209 .025 .197 8.362 .000
Distribution .095 .032 .075 3.015 .003
Promotion .239 .037 .174 6.458 .000
People .082 .033 .067 2.443 .015
Physical Evidence .067 .033 .053 2.032 .042
Processes .248 .038 .185 6.486 .000
a Dependent Variable: Brand Loyalty.
4. Conclusions
A summary of the main research resu lts and findings are presented below:
1) Research findings indicate that there is a statis tical significant relationship between SMM and brand
awareness and the result showed that the promotion element was the most influential on brand awareness
followed by process, physical evidence, the service name and people respectively.
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2) They also indicate that there is a relationship between SM M and brand image and it showed that process
element was the most influential one on brand image fo llowed by price, the service itself, the promotion,
physical evidence and distribution in order, however, the people element was was found insignificant.
3) Findings also indicate that there is a statistical signi ficant relationship between SMM and brand quality and
the process element was the most important one on perceived quality followed by the promotion, serviced,
people, the price, and physical evidence respectivel y, however, the distribution element was found
insignificant.
4) The results also showed that there is a statistical significant relationship between SMM and brand locality,
and the process was the most influential one on brand lo cality followed by price, the promotion, the service,
the distribution, people and physical evidence.
4.1 Marketing Implications and Recommenda tions
The marketing implications of the study results and recommendations can be summarized as follows:
1) The brand awareness is considered to be an impor tant dimension in CBBE, this dimension could be
supported mainly, through the pr omotion efforts by sending m essages to customer‘s mind about the ser vices;
as a result this might increase the service qua lity, loyalty, and affect positively on brand image.
2) The brand image and perceived quality are two other important dimensions in CBBE, an image created by
customers consisting of the knowledge and expectations associated with the service results which showed
that both brand image and perceived quality should be supported mainly through the processes.
3) Consumer's commitment to repu rchase or otherwise continue using t he brand can be demonstrated mainly
through the processe s that take place within the company.
4) CBBE is a valuable asset for any services sector especially for the marketing managers to assess the results of
their efforts by getting the feedback from customers to diagnose any problem that can appeare in the
provided service.
5) In addition, CBBE gives the managers structured approach for designing and creating the branding strateg y,
because it is a model when you know the appropriate componen ts then it becomes a routinely way that could
be then modified according to any situational issue. Based on that the managers will be able to solve the
problems that could be aroused from t he limited resources they have, because they gain suf ficient knowledge
about how to utilize and employ resources in an efficient way.
6) Many problems aroused from the characteristics of the service; insepara bility, heterogeneity, and
perishability. However, the most crucial for marketin g managers is intangibility. Of course focusing on
Tangible cues, using personal sources more than n onpersonal sources, also emphasizing on the importance
of word-of-mouth communications and finally build strong image could affect positively on CBBE.
7) These four problems should be given enough attention because if these problems are not carefu lly managed,
they will usually have a negative effect on the percei ved quality and the image of the company and this will
reduce the customer’s retention and loyalty.
8) Finding and winning cust omers these days is not an easy job, but keeping them i s more important, because
when the firm is capable of keeping its customer then they necessarily become loyal for it. Moreover, when
it reaches this point this means that it has a good SMM combination, as a result the cu stomers will talk about
its services positively. And this would be reflected on the brand image.
9) People could have a magnificence role on CBBE. The quality of a service can vary from service providers;
this lack of homogeneity in services can be solved by the well-trained e mployees, as services are delivered
through contact between customers and employees, and attention to the beh avior and attitudes of service
providers can therefore greatly influe nce customers’ views and loyalties.
4.2 Future Research Areas
The researchers suggest the following future studies:
1) Apply this study on other services sect ors in order to generalize and validat e the results of this study.
2) The distinctions between CBBE dim ensions and marketing could be tested by performing a comparative
study of the industrial sector and service sector.
3) Apply this study on other Ara b countries in order to gain more validation and generalized fin dings.
4) Measure the brand equity from the company's point of view or t hrough financial measurement s.
www.ccsenet.or g/ijbm International Journal of Bu siness and Management V ol. 8, No. 11; 2013
25
5) Investigate CBBE more by us ing other brand equity dim ensions.
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[17]
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(PDF) Into the Andes: three new introductions of Lissachatina fulica (Gastropoda, Achatinidae) and its potential distribution in South America
PDF | Tentacle No. 17—January 2009 6 important – such as squid, common hake, croaker and shrimp – the ecosystem's global significance resides in the... | Find, read and cite all the research you need on ResearchGate
PDF Available
Into the Andes: three new introductions of Lissachatina fulica (Gastropoda, Achatinidae) and its potential distribution in South America
<here is a image 198fa674c9e2c8db-93980cf497d68507>
United States Department of Agriculture
<here is a image 313c15b335d54b6c-9ca5396005d35db2>
Bram Breure
Naturalis Biodiversity Center
<here is a image 72742d83a75a6424-7e87bf2f99809d8d>
Carl C. Christensen
Bernice Pauahi Bishop Museum
<here is a image c79a5af602e099af-1c181f37a66543c2>
Modesto Correoso
Universidad de las Fuerzas Armadas-ESPE
Abstract and Figures
Tentacle No. 17—January 2009 6 important – such as squid, common hake, croaker and shrimp – the ecosystem's global significance resides in the fact that it provides a feeding ground for migratory birds, fish, turtles and sea mammals. As for invertebrates, there are 900 species of molluscs alone, some of which are only found in the Patagonian Sea. The report contains a chapter on the diversity of molluscs, and some of the threats, especially the impact of trawling on the fauna within the region. ―The international goal is to have 10 percent of the world's oceans under some form of protection by 2012‖, Campagna said. But for the Patagonian Sea, that target seems far away. Nonetheless, the Forum ―does not share the simplistic view that the solution to the Patagonian Sea's conservation problems lies solely in the establishment of protected areas where all forms of economic activities are banned‖, he said. ―The Forum has detected some areas where greater protection would be justified. But it deems that it is possible to achieve a form of ecosystem management that will promote economic activities without affecting biodiversity or the natural course of ecological processes‖, he added. [For more information, see The giant African land snail, Lissachatina fulica (Bowdich, 1822), has been considered one of the most widely introduced and invasive land snail species in the world (Lowe et al., 2000; Raut & Barker, 2002). It has been introduced into many island countries in the Pacific and the Caribbean, into many Asian countries, as well as to Brasil (Thiengo et al., 2007). Fontanilla (2007) investigated phylogenetic relationships within the Achatinidae, concluding that the family is monophyletic and that the subgenus Lissachatina should be given generic rank, to distinguish it from Achatina species (Bequaert, 1950; Mead, 1995; Fontanilla, personal communication). Lissachatina fulica has been introduced primarily by two main pathways: as ―un-invited‖ cargo through the shipping and transportation industries (Robinson, 1999); and purposely as a pet, potential food item, ornamental snail, or as a source of ―baba de caracol‖ (snail mucus) (Correoso, 2006). While L. fulica is mainly a vegetarian and has been identified as a major agricultural pest (Cowie, 2000), there is recent evidence that it can also act as a predator of other snails (Meyer et al., 2008).
<here is a image d17d7b71df55a644-3336a5c9fde24441>
Lissachatina fulica in Mindo, Ecuador. (Photo: F. Borrero, March 2008) …
<here is a image aca8682cb9c23567-7c4b2a2f7fc37d97>
Maxent model of potential distribution of L. fulica, given as logistic values. White squares are actual records of L. fulica (from the references cited in the text). Areas coloured green to red represent logistic values, showing increasingly better conditions for the occurrence of the species. Values of 0.23 and above are considered risky for further spread. White and purple squares denote, respectively, the localities used for training and testing of the Maxent model. …
Figures - uploaded by
Carl C. Christensen
Content uploaded by Carl C. Christensen
6
important –such as squid, common hake, croaker and shrimp
– the ecosystem‘s global significance resides in the fact that it
provides a feeding ground for migratory birds, fish, turtles and
sea mammals. As for invertebrates, there are 900 species of
molluscs alone, some of which are only found in the
Patagonian Sea. The report contains a chapter on the diversity
of molluscs, and some of the threats, especially the impact of
trawling on the fauna within the region.
―The international goal is to have 10 percent of the world‘s
oceans under some form of protection by 2012 ‖,Campagna
said. But for the Patagonian Sea, that target seems far away.
Nonetheless, the Forum ―does not share the simplistic view
that the solution to the Patagonian Sea‘s conservation
problems lies solely in the establishment of protected areas
where all forms of economic activities are banned ‖,he said.
― The Forum has detected some areas where greater protection
would be justified. But it deems that it is possible to achieve a
form of ecosystem management that will promote economic
activities without affecting biodiversity or the natural course of
ecological processes ‖,he added.
Ed.]
INTO THE A NDES: THREE NEW
INTRODUCTIONS OF LISSACHATINA
FULICA (GASTROPODA, ACHATINIDAE)
AND ITS POTENTIAL DISTRIBUTION IN
SOUTH AMERICA
By Francisco J. Borrero, Abraham S.H. Breure,Carl C.
Christensen, Modesto Correoso& Valentín Mogollón Avila
The giant African land snail, Lissachatina fulica(Bowdich,
1822) , has been considered one of the most widely introduced
and invasive land snail species in the world (Lowe et al., 2000;
Raut & Barker, 2002). Ithas been introduced into many island
countries in the Pacific and the Caribbean, into many Asian
countries, as well as to Brasil (Thiengo et al., 2007).
Fontanilla (2007) investigated phylogenetic relationships
within the Achatinidae ,concluding that the family is
monophyletic and that the subgenus Lissachatinashould be
given generic rank, to distinguish it from Achatinaspecies
(Bequaert, 1950; Mead, 1995; Fontanilla, personal
communication).
Lissachatina fulica has been introduced primarily by two main
pathways: as ―un -invited‖ cargo through the shipping and
transportation industries (Robinson, 1999); and purposely as a
pet, potential food item, ornamental snail, or as asource of
―baba de caracol‖ (snail mucus) (Correoso, 2006). While L.
fulica is mainly a vegetarian and has been identified as a major
agricultural pest (Cowie, 2000), there is recent evidence that it
can also act as a predator of other snails (Meyer et al., 2008).
It was by accident that one of us (FB) photographed two live
specimens of Lissachatina fulicawhile on a land snail survey
near Mindo, Province of Pichincha, Ecuador, in March 2008.
The animals were kept by a young lady as pets and as her
family was unwilling to part with them, onlythe pictures are
available (Fig. 1). Initially, we were in doubt about their
identity as we knew of no reports of achatinids from Andean
countries, and some species of Sultana(Orthalicidae) known
from Ecuador show a similar colour pattern. After one of the
photographs had been posted in a blog (Breure, 2008) andthe
photographs shown to others, the correct identification was
received from independent sources. In fact, the presence of the
giant African snail in Ecuador had been mentioned on two
earlier occasions and a preliminary control strategy had been
formulated (Correoso, 2006). However, since the context of
these reports was not biological, they remained unnoticed.
Fig. 1. Lissachatina fulicainMindo, Ecuador.
(Photo: F. Borrero, March 2008)
First, we discovered a mention of L. fulicaon the website of
CORPEI, a private non-profit organization that is recognized
by the Ecuadorian Government as the official body for the
promotion of exports and investments in the country. Snail
farms were introduced some 10 years ago and some valleys in
the Ecuadorian highlands offer an ideal temperature between
17 o and 25 oC, with long periods of sunlight and an adequate
pH to grow snails (CORPEI, 2008). According to this source,
only Helix aspersaMüller, 1774 and Lissachatina fulicaare
reared, the latter called ―Chinese Escargot‖.
Later we found a second bit of information in the online
newsletter of a tourist information service (Kreykenbohm,
2005). In this note, resulting from a newspaper interview with
one of us (MC), it was stated that slime of the giant African
snail was used to produce a cream ―to receive a spotl essly
clean skin‖, at the same time mentioning that th e snail could
destroy the ecosystem of the whole country. According to the
note, ―the Ministry of the Environment is concerned‖. Thus,
we have to conclude that in 2005, the officials knew of the
occurrence of Lissachatina fulicaand the danger it posed(see
also Anonymous, 2005). The snails, ―which can be bought for
one dollar a piece, are sold in Esmeraldas for example as
domestic species‖ (Kreykenbohm, 2005; Correoso, 2006).
ISSN 0958- 5079 TentacleNo. 17 —January 2009
7
From other sources (Anonymous 2001, 2008a) we know that
in 2001 there were at least 1300 snail farms in Ecuador. These
are mainly located in the mountainous central part of the
country (the provinces of Cañar, Chimborazo, Cotopaxi,
Imbabura and Pichincha have been mentioned, but see below).
However, it is not clear how many of these snail farms actually
use Lissachatina fulica.
Conclusively, there is strong evidence that Lissachatina fulica
has been purposely introduced for economic reasons in
Ecuador. We do not know to what extent it may have escaped
from snail farms. Clearly, the extent of this economic activity,
the species used and the localities of the snail farms need
further investigation in all countries concerned. This is
especially urgent once snail farming becomes more popular or
is even promoted for commercial reasons. Thus, the risk of
accidental spread is great and this may lead to an economic
disaster a ndserious environmental risk in the region, as has
already been the case in Brasil (Thiengo et al., 2007).A n
eradication program for this invasive species was initiated in
Ecuador in 2006, although it was not officially announced.
Despite these efforts, L. fulicais still present in Mindo, with
recent reports (by MC) from Santo Domingo Tsáchilas (where
it was found in bananas) and Guayaquil (escaped from a snail
farm outside the city). It is thus probable that these populations
are at low levels, making future outbreaks possible.
A similar situation seems to occur in Colombia. So far, L.
fulica has not been reported for the malacofauna of this
country, but it has turned up in a rural area near Fusagasugá,
close to Bogotá (Clara Inés Medina, personal communication).
An escape from a snail farm is the probable cause again, as
snail rearing has also become popular in this country (Alvis,
2006). Finally, the occurrence of the species in yet another
Andean country was confirmed by the finding of live
specimens in Ayabaca, Piura Department, northern Peru (VM,
voucher in Leiden museum). The animals were purchased from
a dealer, who said they originated from Pucallpa, Ucayali
Department, in eastern Peru.
In South America, Lissachatina fulicahas been introduced to
Brasil and is spreading rapidly (Thiengo et al., 2007).
Martinez & Martinez (1997) reported an incidental
introduction in Venezuela, but recently the species has been
reported as a pest from two other localities in that country
(Anonymous, 2007, 2008b). Since the introduction of the
species onthe western side of the Andes opens up a new area,
we would like to know the potential for the further spread of
Lissachatina fulica in South America. We used Maxent
software (Phillips et al., 2006) with the occurrences from the
known distribution in Brasil (Thiengo et al., 2007), the
Caribbean (Anonymous, 2004) and Venezuela (Anonymous
2007, 2008b), and the recent findings in Ecuador, Colombia
and Peru. The resulting model showing the potential
distribution is presented in Fig. 2. From this figure it isclear
that several areas in the Neotropics may be vulnerable to the
potential spread of this species. Further details are beyond the
scope of this note, and will be given elsewhere (Breure &
Borrero, 2008). Lissachatina fulicais said to exhibit wide
environmental tolerances (Raut & Barker, 2002). Yet we
found in the model that annual cloud cover is the most
Fig. 2. Maxent model of potential distribution of L. fulica ,given as
logistic values. White squares are actual records of L. fulica(from the
re ferences cited in the text). Areas coloured green to red represent
logistic values, showing increasing lybetter conditions for the
occurrence of the species. Values of0.23 and above are considered
risky for further spread. White and purple squares denote,
respectively, the localities used for training and testing of the Maxent
model.
important factor in determining its potential distribution,
followed by annual precipitation. This could be explained by
the preference of this species for relative lyhigh humidity.
Takeda & Ozaki (1986) reported activity of L. fulicaonly
when relative humidity is more than 50 %.
From Fig. 2 it may be concluded that several areas in western
Brasil and southeastern Peru are at risk if L. fulicareach es
them. Also French Guiana, Surinam and to some extent
Guyana are vulnerable to colonization and establishment .
Finally, given reported observations by Kreykenbohm (2005)
and the records in Ecuador so far, the western part of the
country is where the spread of L .fulicaseems almost
inevitable. It is possible that the low minimum temperatures in
the Sierra (central region of Ecuador) may prevent its
establishment there (see also Budha & Naggs, 2008); also, the
high altitude of Ayabaca (2650 m) makes it unlikelythat the
species will survive there if it should escape or be deliberately
released. A very serious danger is its potential introduction
into the Galápagos, which are part of Ecuador. As Cowie &
Robinson (2003) indicated, one of the common pathways for
invasive species to be introduced is assosciated with cargo ,
either via sea or air. Guayaquil, where the species has also
been reported, is both the main harbor and airport forshipment
ISSN 0958- 5079 TentacleNo. 17 —January 2009
8
of goods to the Galápagos. It has been estimated that more
than a third of the endemic species of Orthalicidae in the
Galapagos ha vebecome extinct during the last half century, in
part due to the introduction of alien species (Coppois, 1995;
see also Parent & Smith, 2006). From a conservation
viewpoint, the presence of Lissachatina fulicain western
Ecuador may be considered a major threat to ―Darwin‘s
Laboratory‖.
Alvis, A. 2006. Helicicultura en Colombia.
http://www.monografias.com/trabajos37/helicicultura-
colombia/helicicultura-colombia.shtml accessed 31 October 2008.
Anonymo us 2001. A gourmand‘s delight: f rom Ecuador to your
table…and still fresh .
http://www.internationalreports.net/theamericas/ecuador/2001/ago
urmands.html accessed 4 July 2008.
Anonymous, 2004. Giant African snails: a foreign threat to U.S.
Agriculture. http://www.aphis.usda.gov/lpa/pubs/pa_phgas.pdf
accessed 6 July 2008.
Anonymous, 2005. El caracol gigante, un nuevo peligro.
http://www.elcomercio.com/solo_texto.asp?id_noticia=2258
accessed 7 July 2008.
Anonymous, 2007. African snail attacks local flora.
http://www.tierramerica.info/nota.php?lang=eng&idnews=eco&nr
o=239&olt=239 accessed 6 July 2008.
Anonymous 2008a. Caracoles.
http://www.ecuadorexporta.org/productos_down/perfil_producto_
caracoles546.pdf accessed 4 July 2008 [but no longer accesible].
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http://www.elsoldemargarita.com.ve/Noticias.aspx?NoticiaId=827
5&Seccion=22 accessed 6 July 2008.
Bequaert, J.C. 1950. Studies on the Achatinidae, a group of African
land snails. Bulletin of the Museum of Comparative Zoology105:
1- 216.
Breure, A.S.H. 2008. AchatinainEcuador.
http://www.ashbreure.nl/snailblog/snailblog.html accessed 2 July
2008 .
Breure, A.S.H. & Borrero, F.J. 2008. An annotated checklist of the
land snail family Orthalicidae (Gastropoda: Pulmonata:
Orthalicoidea) in Ecuador, with notes on the distribution of the
mainland species. Zootaxa1768: 1- 40.
Budha, P.B. & Naggs, F. 2008. The Giant African land snail
Lissachatina fulica (Bowdich) in Nepal.
http://www.malacsoc.org.uk/The_Malacologist/BULL50/Budha.ht
m accessed 7 July 2008.
Coppois, G., 1995. Vanishing Galapagos malacofauna. In:
Biodiversity and Conservation of the Mollusca (eds. van Bruggen,
A.C., Wells, S.M. & Kemperman, T.C.M.), p. 205- 209 .Backhuys
Publishing, Oe stgeest/Leid en.
CORPEI 2008. Snail.
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7_2 accessed 30 June 2008 [but nolonger accessible].
Correoso, M., 2006. Estrategia preliminar para evaluar y erradicar
Achatina fulica (Gastropoda: Achatineaceae) en Ecuador.Boletin
Técnico IASA, Serie Zoológica 2:45- 52.
Cowie, R.H. 2000. Non-indigenous landand freshwater molluscs in
the islands of the Pacific: conservation impacts and threats. In:
Invasive species in the Pacific - A Technical Review and Draft
Regional Strategy (ed. Sherley, G. ),p. 143 -172 .SouthPacific
Regional Environmental Programme, Apia.
Cowie, R.H. & Robinson, D.G. 2003. Pathways of introduction of
nonindigenous land and freshwater snails and slugs. In: Invasive
Species: Vectors and Management Strategies (eds. Ruiz, G. &
Carlton, J.T.) .p. 93 -122 .Island Press, Washington DC.
Fontanilla, I.K. 2007. Achatina fulica, its molecular phylogeny and
genetic variations in global populations. The Malacologist48: 1.
[Modified version with different authorship and text available at
http://www.malacsoc.org.uk/The_Malacologist/BULL48/forum48.
htm accessed 30 June 2008].
Kreykenbohm, B. 2005. False promises and African snails.
http://ecuadorline.com/ecuador/newsletter/Newsletter200511.htm#
a2221 accessed 3 July 2008.
Lowe, S., Browne, M., &Boudjelas, S. 2000. 100 of the World’s
Worst Invasive Alien Species. A selection from the Global Invasive
Species Database . Invasive Species Specialist Group, IUCN,
Auckland. 12 p. http://www.issg.org/booklet.pdfaccessed 6 July
2008 .
Martinez, R. & Martinez, E. 1997. Nota acerca de la Achatina
( Lissachatina) fulica (Bowdich, 1822) [sic]. Peligroso caracol
africano (Pulmonata, Achatinidae) introducido en Venezuela. Acta
Biologica Venezuelica 17: 37- 40.
Mead, A.R. 1995. Anatomy, phylogeny, and zoogeography in the
African land snail family Achatinidae. In: Abstracts. 12th
International Malacological Congress (eds. Guerra, A. Rolán, E.
& Roca, F.), p. 422 - 423.Instituto de Investigaciones Marinas, on
behalf of Unitas Malacologica, Vigo.
Meyer, W.M., Hayes, K.A. & Meyer, A.L. 2008. Giant African snail,
Achatina fulica , as a snail predator.AmericanMalacological
Bulletin 24: 117- 119.
Parent, C.E. & Smith, R.P. 2006. Galápagos bulimulids: status report
on a devastated fauna. Tentacle14: 25- 27.
Phillips, S.J., Anderson, R.P. &Schapire, R.E. 2006. Maximum
entropy modeling of species geographic distributions. Ecological
Modeling 190: 231- 259.
Raut, S.K. & Barker, G.M. 2002. Achatina fulicaBowdich and other
Achatinidae as pests in tropical agriculture. In: Molluscs as crop
pests (ed. Barker G.M.). p. 55-114. CABI Publishing, Wallingford.
Robinson, D.G. 1999. Alien invasions: the effect of the global
economy on non-marine gastropod introductions into the United
States. Malacologia41:413-438.
Takeda, N. & Ozaki, T. 1986. Induction of locomotor behaviour in
the giant African snail, Achatina fulica . Comparative Biochemistry
and Physiology 83A: 77- 82.
Thiengo, S.C., Faraco, F.A., Salgado, N.C., Cowie, R.H. &
Fernandez, M.A. 2007. Rapid spread of an invasive snail in South
America: the giant African snail, Achatina fulica, in Brasil.
Biological Invasions 9: 693- 702.
Francisco J. Borrero, Cincinnati Museum Center, Cincinnati, Ohio
45203, USA. [email protected]
Abraham S.H. Breure, National Museum of Natural History, Leiden,
the Netherlands. [email protected]
Carl C. Christensen, William S. Richardson School of Law ,
University of Hawaii, Honolulu, Hawaii 96822; and Bishop Museum,
Honolulu, Hawaii 96817, USA. [email protected]
Modesto Correoso, Escuela Politécnica del Ejército, Quito,Ecuador.
Valentín Mogollón Avila, Universidad Nacional Federico Villareal,
Facultad de Oceanografía, Pesquería y Ciencias Alimentárias, Lima,
Peru.
RARE NEW ZEALAND SNAILS UNDER
DEBATE
By Kath J. Walker
The Rhytidae (Mollusca: Gastropoda: Pulmonata) are a group
of large carnivorous land snails distributed in the southern
hemisphere, with a particularly rich fauna in NewZealand.
The genus Powelliphanta, endemic to New Zealand, consists
of at least 10 species and many more recognised subspecies,
most of which are restricted to the western margin of South
... Currently, annual cloudiness, annual precipitation, altitude, mean annual temperature, seasonality of temperature, and temperature of the coldest quarter are assumed to influence the establishment of L. fulica. Although L. fulica tolerates a wide range of precipitation (from near zero to over 4000 mm) ) and temperature (from 0 to 38 °C) , distribution models for the Neotropical region do not propose equatorial rainforests as areas of high susceptibility; instead, they propose the Cerrado region, recognized for its rainfall regime concentrated in five months of the year, as susceptible
(Borrero et al. 2009;
Mondaini 2019). These results contrast with those found in India, whose central region shows low susceptibility to L. fulica establishment due to high temperatures and low rainfall . ...
... Although the first introductions occurred at the end of the 20th century, dispersal and establishment were identified only in the first decade of the 21st century. For these reasons, the Maxent models constructed by 66
Borrero et al. (2009)
and, although identifying a large part of climatically suitable areas, did not establish the species in the entire region. The climatically suitable areas described inBorrero et al. (2009) coincided considerably with the areas predicted by Model 5; those described in coincided substantially with Models 6 and 7. ...
... For these reasons, the Maxent models constructed by 66Borrero et al. (2009) and, although identifying a large part of climatically suitable areas, did not establish the species in the entire region. The climatically suitable areas described in
Borrero et al. (2009)
coincided considerably with the areas predicted by Model 5; those described in coincided substantially with Models 6 and 7. The current Neotropical distribution of L. fulica is better explained by Models 6 and 7, indicating that the species is established in localities with native and Indo-Malayan climatic conditions. ...
Resposta do caracol gigante africano (Lissachatina fulica, Bowdich 1822) à variação climática global, regional, local e de recursos
Thesis
Full-text available
Feb 2023
<here is a image 3bbc81625641da8c-8c06f080017c9005> Angie Patiño Montoya
Nonnative populations of an invasive species must face obstacles during their transport, introduction, establishment, and dispersal. Climate and resource availability represent some of these obstacles. The response of nonnative populations to climate will depend on the realized climatic niche of the species. Regarding resource availability, the response will depend on how the life history attributes of the organisms react to resource variations. The giant African snail Lissachatina fulica (Bowdich 1822) is a mollusk native to East Africa and classified as invasive. Nonnative populations of L. fulica occur throughout the tropical region of the world and are recognized for their wide climatic tolerance and association with humans. This thesis aims the response of the giant African snail (L. fulica) to global, regional, local climate, and resource variation. In the first chapter, through a systematic literature review, we identified the attributes that define the invasive potential of L. fulica and the characteristics of the sites where it occurs. In the second chapter, by means of potential distribution modeling and environmental PCA, we evaluated the expansion of the climatic niche of L. fulica as a function of its dispersal around the world. In the third chapter, through multivariate ordination analysis, we evaluate the population density of L. fulica under different climatic conditions and anthropic interventions in the Neotropical region. In the fourth chapter, through fieldwork, we characterize the nonnative population of L. fulica located in the Federal District (DF), associate its population density and percentages of dead, egg-bearing, and hermaphrodite individuals, and describe how it responds to small variations in climate and the presence or absence of resources. In the fifth chapter, through the morphometric evaluation of L. fulica growth in the laboratory, we proposed a new method for the identification of hermaphroditic individuals. The systematic review carried out showed a fragmented knowledge about the attributes of L. fulica and almost none about the places where it occurs. The most studied information was associated with abundance, with little consensus in the literature on the relationship of population density with impact. In addition, there is no consensus in the literature on age classes, where shell length appears to differ between males and hermaphrodites. Potential distribution modeling and environmental PCA showed that the realized climatic niche of L. fulica has widened since its dispersal from Africa, in part by its trajectory along different biogeographic regions. According to the models, when the mollusk left Africa, it was first able to establish itself in areas with similar climates to its native range in the Indo-Malaya region. By the time of introduction into the Neotropical region, the mollusk was already associated with humans in slightly different climates. Multivariate ordination analysis showed that the population density of L. fulica in the Neotropics responds to specific combinations of temperature and precipitation but not to human intervention. Low population densities under wide climatic conditions are an alarm signal not to ignore these localities in the control. Fieldwork with the L. fulica population in DF showed three things. First, the nonnative population in DF has almost half of the individuals with egg-laying potential and population densities of less than 1 ind/m2. Second, the percentage of egg-bearing individuals correlates with the percentage of hermaphrodite individuals and in part with population density. Third, regarding climate, the percentages of dead and egg-bearing individuals respond to maximum temperature and minimum relative humidity. Regarding resources, the results obtained in the field show that population density responds to the presence of soil and that the percentage of hermaphrodites responds to the percentage of built-up area. The morphometric evaluation of the shell of L. fulica pointed to a length range where the transition to hermaphrodites probably takes place and suggests two morphological indices that aim to identify individuals who have already gone through this transition. In conclusion, there are still many gaps and little consensus on the knowledge of the attributes that characterize the invasive potential of L. fulica and the characteristics of the sites where it occurs. The lack of knowledge and consensus produces flaws in management, since it is difficult to know if the species is truly in an environment similar to the native area if the densities recorded represent any significant impact or when recolonization may occur. This thesis attempts to fill some of these gaps. Therefore, these results generate subsidies for the development of multiple lines of knowledge generation about the nonnative populations of L. fulica and possibly to optimize management strategies.
... As in Brazil, this was for commercial purposes. Snail farms were built in some valleys of the Ecuadorian highlands, which offered an ideal temperature between 17 °C and 25 °C
[65]
. However, their breeding did not provide the expected economic returns, inevitably, most of the farms were abandoned and the snails were released into the environment. ...
In the Dawn of an Early Invasion: No Genetic Diversity of Angiostrongylus cantonensis in Ecuador?
Preprint
Full-text available
Mar 2023
<here is a image e056d4f0b2d15778-fd4a5427d6fa2a5d> Luis Solorzano
César Humberto Bedoya-Pilozo
Hilda Hernández-Álvarez
<here is a image 991d8126458167e1-5125ed4feda6be8f> Roberto Do Val Vilela
The nematode Angiostrongylus cantonensis has been reported worldwide, however, some basic questions remain unanswered about the presence of A. cantonensis in Ecua-dor: 1) Was the invasion of A. cantonensis in Ecuador unique, or did it occur in different waves? 2) Was this invasion as recent as historical records suggest? 3) Did this inva-sion come from other regions of South America or elsewhere? To address these issues, we assessed the genetic diversity of MT-CO1 gene sequences from isolates obtained in eleven of Ecuador's 24 provinces. Our Bayesian inference phylogenetic tree recovered A. cantonensis as a well-supported monophyletic group. All eleven sequences from Ec-uador were identical and identified as AC17a. The haplotype AC17a, found in Ecuador and the USA, formed a cluster with AC17b (USA); AC13 (Thailand); and AC12a-b (Cambodia). It is notable that all the samples, obtained in different geographic and climatic regions of different Ecuadorian provinces, had no genetic difference between them. Despite the lack of genetic information on A. cantonensis in Latin America, ex-cept in Brazil, our finding differs from previous studies by its absence of genetic diver-sity in Ecuador. We concluded that the invasion of A. cantonensis in Ecuador may have occurred: 1) as a one-time event, 2) recently, and 3) from Asia via the USA. Further re-search should include samples from countries neighboring Ecuador to delve deeper in-to this.
... The trade was not successful; instead, the snails spread rapidly, and by 2007, they were distributed in at least 23 of the 26 Brazilian states (Thiengo et al., 2007). Similar spreads have occurred in Peru, Colombia and Ecuador (Anonymous, 2001;
Borrero et al., 2009)
. ...
Control of invasive alien species: The Giant African snail (Lissachatina fulica) a difficult urban public management challenge
Nov 2022
J ENVIRON MANAGE
M. Celis-Ramírez
<here is a image 292e0248088ea926-29a759ba3bc411fc> Mauricio Quintero-Angel
Rubén E Varela-M
In view of the population growth trends and urbanization processes, one of the current challenges is the surveillance and control of invasive alien species within urban settings, particularly of those species that can serve as vectors or reservoirs of diseases with the potential to affect human health. In this regard, the present study evaluated the public management for the surveillance and control of African snails (Lissachatina fulica) in the city of Santiago de Cali in Colombia between 2016 and 2019 and proposed minimum guidelines for their surveillance and effective control in the urban settings of developing countries. The Giant African snails can be intermediate hosts of various microorganisms that have a great impact on urban public health. The latter may include parasitic, viral, bacterial, and fungal diseases, which are transported by the snail to homes or nearby areas exposing humans and animals to contagion. In the Colombian case the most important are Angiostrongylus parasites, which can cause eosinophilic meningoencephalitis, gastrointestinal disorders in humans and pulmonary hemorrhage in dogs. However, it is also possible that the same snails carry other nematodes such as Aleurostrogylus which can affect cats and dogs in urban areas. Comprehensive actions are required to address the problems related to urban invasive species such the African snail in Santiago de Cali as well as to develop environmental public policies and implement through municipal and state public management. We concluded that government action should be supported by reliable data to identify cases in situ, and to determine pest, environmental, and ecoepidemiological variables. Qualitative and quantitative data analyses will contribute to effective decision-making and the development of control protocols designed for each specific urban scenario.
... La presencia del caracol en Ecuador fue reportada por primera vez en el año 2005 (Correoso, 2008). Los criaderos de caracoles que se construyeron, en algunos valles de la sierra ecuatoriana y que ofrecían una temperatura ideal entre 17 ° C y 25 ° C, con largos periodos de luz solar y un pH adecuado para el cultivo de caracoles
(Borrero et al., 2009)
. Sin embargo, los criaderos no proporcionaron los réditos económicos esperados, inevitablemente, la mayoría de los criaderos quedaron abandonados y los caracoles fueron liberados en la naturaleza El resultado fue una infestación generalizada de áreas urbanas y rurales en casi todas las provincias del país (Solorzano Alava et al., 2014) En relación con los hospederos definitivos, se presume que Rattus rattus llegó al Ecuador entre los siglos XVI o XVII en los barcos de los conquistadores españoles (Tirira, 2007). ...
Angiostrongylus cantonensis en Achatina fulica en la provincia del Napo, Ecuador y el riesgo incrementado de angiostrongiliasis
Jan 2022
Luis Solórzano Álava
Cesar Bedoya Pilozo
Francisco Sánchez Amador
Lázara Rojas Rivero
Introducción: Angiostrongylus cantonensis es reconocido como uno de los principales patógenos causantes de la meningoencefalitis eosinofílica, fue identificado en Ecuador por primera vez en 2008. Métodos: se recolectaron 1476 ejemplares de Achatina fulica con el método de captura por unidad de esfuerzo durante 30 minutos, en 3 cantones de la provincia del Napo, con el fin de establecer la prevalencia de infección por A. cantonensis Resultados: el porcentaje total de caracoles infectados fue de 46,5% (687/1476). Conclusiones: Los resultados revelan una amplia distribución de A. fulica infectado con A. cantonensis, lo que, sumado a la gran cantidad de hospederos definitivos presentes, indica que un número considerable de personas tiene riesgo de adquirir angiostrongiliasis. Se necesita intervenciones educativas comunitaria orientadas a formación sanitaria, recalcando el riesgo de adquirir la infección parasitaria, principalmente por el consumo de A. fulica, crudos y/o con cocción inadecuada, principal forma de contagio. Además, se recomienda vigilancia rigurosa y control de los hospedadores involucrados, saneamiento ambiental, haciendo insistencia en factores relacionados con los hábitos biológico del caracol gigante africano, entre ello alimentos (vegetales), suelos y derivados del caracol de uso artesanal; para prevenir la aparición de casos esporádicos y de brotes de la enfermedad.
... Our models in the current scenario for L. fulica matched previous predictions made for South America [19,
67,
68], with susceptible areas identified in Guyana, French Guiana, Suriname, Peru, Venezuela, Ecuador, and Colombia. At the same time, regions in Chile and Uruguay appear least vulnerable to invasion, except for the area of southern Chile. ...
How Will the Distributions of Native and Invasive Species Be Affected by Climate Change? Insights from Giant South American Land Snails
Article
Full-text available
Jun 2022
Diversity
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Wanderson Teles
<here is a image 0dfb7858873a71ee-eb11a97cf04e23d7> Daniel De Paiva Silva
<here is a image 26a4b458550633b9-b1d603c2023279bb> Bruno Vilela
<here is a image 1ccacc5c102685c8-1d5707a3a2eab47c> Marcel Miranda
Climate change and invasive species are critical factors affecting native land snail diversity. In South America, the introduced Giant African Snail (Lissachatina fulica) has spread significantly in recent decades into the habitat of the threatened native giant snails of the genus Megalobu-limus. We applied species distribution modeling (SDM), using the maximum entropy method (Maxent) and environmental niche analysis, to understand the ecological relationships between these species in a climate change scenario. We compiled a dataset of occurrences of L. fulica and 10 Megalobulimus species in South America and predicted the distribution of the species in current and future scenarios (2040-2060). We found that L. fulica has a broader environmental niche and potential distribution than the South American Megalobulimus species. The distribution of six Megalobu-limus species will have their suitable areas decreased, whereas the distribution of the invasive species L. fulica will not change significantly in the near future. A correlation between the spread of L. fulica and the decline of native Megalobulimus species in South America was found due to habitat alteration from climate change, but this relationship does not seem to be related to a robust competitive interaction between the invasive and native species.
... Tiene una gran plasticidad fenotípica y logra desplazar, por su alta competitividad, al resto de los moluscos terrestres del ecosistema que invaden. A esta situación se suma que también puede actuar como un importante depredador de otros caracoles
(Borrero et al., 2009)
o puede contribuir de forma directa o indirecta a la extinción de diferentes especies de moluscos endémicos, como los de la familia Orthalicidae. Puede propagarse rápidamente e incurrir en daños sustanciales en un período corto si no hay una respuesta de gestión oportuna (Radosevich et al., 2007). ...
Invasiones biológicas en agrosistemas de Ecuador continental: nicho ecológico de especies exóticas y cultivos agrícolas bajo riesgo
Full-text available
May 2021
<here is a image 6dc63f298d54d489-1af9331d6bda8bd2> Yarelys Ferrer-Sánchez
Wilmer Raúl Jacho-Saa
<here is a image 52e291368f3763ad-bad6b092f9d5839c> Juan Pablo Urdánigo
Gabriela Veronica Estrella Bravo
En Ecuador las especies exóticas invasoras (EEI) provocan consecuencias negativas en los aspectos ecológicos, económicos y de seguridad alimentaria. Los agroecosistemas hacen parte de los sectores productivos a nivel mundial, pero son vulnerables a sufrir invasiones biológicas por la constante actividad humana y por el traslado de vegetación, tierra y semillas, por lo que deben ser constantemente monitoreados, pues desempeñan un papel importante en la economía al ser fuente de empleo. El objetivo de esta investigación fue evaluar la influencia potencial de las EEI sobre los agroecosistemas de Ecuador continental a través del modelado del nicho ecológico. Se usó como método de modelación el algoritmo de máxima entropía y se emplearon los registros de presencia de seis especies de plantas y cuatro de insectos en sus regiones nativas y en zonas invadidas a nivel mundial. Los registros provienen de Global Biodiversity Information Facility y de Tropicos. Como variables explicativas se emplearon 19 variables bioclimáticas y seis variables de vegetación. Se obtuvieron los mapas de distribución geográfica potencial, las áreas de superposición de la distribución de las especies y la delimitación de las zonas de mayor riesgo. Se determinó que las condiciones ambientales de las regiones Sierra y Amazónica son idóneas para una posible invasión de seis y siete especies. Además, más del 50 % de la cobertura agropecuaria del país podría ser afectada por las especies Wasmannia rochai, Spondias purpurea L., Lissachatina fulica y Conium maculatum L., siendo los cultivos de ciclo corto los más vulnerables a la invasión por estas especies.
Effect of the invasion history of the giant African snail (Lissachatina fulica) on its realized climatic niche
Article
Oct 2022
INVERTEBR BIOL
<here is a image 3bbc81625641da8c-8c06f080017c9005> Angie Patiño Montoya
<here is a image 6d8bce2c4fec5618-4cbde86137060e7e> Alan Giraldo
<here is a image cd727fa383bdac77-0227db8ed1f5d235> Rosana Tidon
There is almost a century of difference among Indo-Malayan, Australasian, and Neotropical regions in establishment of non-native populations of the giant African snail (Lissachatina fulica). Using potential distribution models and environmental principal component analysis (PCA-env), we first tested whether an expansion of the realized climatic niche of L. fulica occurred. The models showed geographical differences between the native and non-native areas, especially in the Neotropical region, where the last introduction of mollusks occurred. Because PCA-env showed a 60% expansion and 40% overlap between the native and global areas, we next investigated whether the expansion of the realized climatic niche of L. fulica was influenced by its geographical spread. Precipitation had the highest contribution in most models, but temperature was the variable that best explained the projected spread from the current Neotropical distribution. The current Neotropical distribution was better explained when the climatic conditions of the Indo-Malayan and Australasian regions from which the species arrived in the Neotropics were included. PCA-env showed 74% expansion between the native and Indo-Malayan–Australasian areas and 97% expansion between the native and Neotropical areas. In conclusion, the spread between biogeographic regions and the existence of similar climatic conditions between the native and non-native distributions would produce the observed climatic niche of L. fulica.
Distribución potencial del caracol gigante africano (Achatina fulica Bowdich 1822) en Colombia
<here is a image 6d8bce2c4fec5618-4cbde86137060e7e> Alan Giraldo
<here is a image 3bbc81625641da8c-8c06f080017c9005> Angie Patiño Montoya
<here is a image 4067ef8a5390dc76-9715a46fa9388cd0> Rodrigo Lozano Osorio
<here is a image 6a745dc2ad0f05bc-24b44761ce9e54bc> Mario Fernando Garcés-Restrepo
Objective: To establish the potential distribution of the invasive species Achatina fulica (giant African snail) in Colombia based on environmental suitability. Scope: To provide researchers and national environmental authorities with elements to strengthen the research efforts and management and control actions of this invasive species in Colombia. Methodology: A potential distribution model for the African giant snail in Colombia was implemented under the MaxEnt algorithm, using the climatic variables of World Clim. Main Results: The variable that contributed the most was the precipitation of the warmest month followed by the maximum temperature of the warmest month. Fifty per cent of the departments in the country presented an occupancy greater than 50%, being the most affected Cordoba and Atlantico with an occupation area above 80%. An environmental suitability of 100% was identified in locations associated with high density of urban centers. Conclusion: Evidence of the association of this invasive species with urban centers of the country was obtained and the risk of invasion by departments was identified.
Land and freshwater molluscs of mainland Ecuador: an illustrated checklist
Feb 2022
<here is a image 313c15b335d54b6c-9ca5396005d35db2> Bram Breure
<here is a image 9639b7b622da2a5f-03f23211d3085cec> Jonathan Ablett
<here is a image e3c4b178ea5cabcb-1ce2345fa8118ec4> Marijn Roosen
This comprehensive checklist of non-marine molluscs from the mainland of Ecuador pre- sents data on 331 species (of which 5 are considered as nomen dubium), compiled from the literature, a subset of museum databases, and some verified observations from the internet. For all taxa the original reference is given and photographs of type specimens are provided if these could be located and obtained from museums. Where these were not available the original figure(s) have been reproduced. In the introduction, a brief history of research in Ecuador (including the Galápagos archipelago) is presented. This checklist may serve as a baseline document for further research. It is not intended to be a revision- ary work, although we have recognised the following new synonyms: Neritina intermedia (var. β) minima K. Miller, 1879 = Clypeolum latissimum (Broderip, 1833); Aperostoma (Aperostoma) olivaceum Bartsch & Morrison, 1942 = Incidostoma quitense (L. Pfeiffer, 1852); Hemisinus pazi Tryon, 1866 = Hemisinus guayaquilensis (Petit de la Saussaye, 1853); Bulimus cuneus L. Pfeiffer, 1854 = Protobeliscus fairmaireanus (Petit de la Saus- saye, 1853); Synapterpes (Zoniferella) riveti Germain, 1907 = Mesembrinus vesperus Jousseaume, 1887 = Zoniferella albobalteata (Dunker, 1882); Synapterpes bicingulatus Fulton, 1908 = Zoniferella bizonalis (Germain, 1907); Thaumastus thompsonoides Ober- wimmer, 1931 = Kara thompsonii (L. Pfeiffer, 1845). The need for further field work is illustrated by the fact that for 60 species, only imprecise localities are known, while for 168 species no modern (i.e. last 50 years) records are available. There are 179 species considered as endemics for the Ecuadorian malacofauna. For both the terrestrial and fresh- water species the ecoregions where they occur are indicated where possible.
Population characterization and parasitological assessment of the giant African snail (Achatina fulica) in urban areas of Cartagena, Colombia
Mar 2021
Eder Cano-Pérez
Jaison Torres-Pacheco
Luis Barraza-Quiroz
Doris Gómez-Camargo
Background: The giant African snail, Achatina fulica , is an invasive species recognized for being a serious agricultural pest and an intermediary vector for diverse parasites that cause diseases in humans. The knowledge of the state of African snail populations in urban areas is of great ecological and public health importance. Therefore, our objective was to characterize the status of giant African snail populations present in the city of Cartagena, Colombia, including the assessment of nematode parasites in the specimens.
Methods. Sites were visited following information from citizens affected by the presence of the African snail. The specimens were collected and transported to the laboratory; subsequently, they were weighed, measured, and classified by size. Dissections of lung tissue and soft organs were performed to search for and identify nematode parasites. Size measurement between the sampled sites was statistically compared and density and biomass indicators were established.
Results . In total, 204 snails were collected distributed among four sites within Cartagena city. Of these, 50% were juvenile specimens (10-40 mm). The size of the specimens showed significant differences between the sampling areas. The calculated density was between 0.0019-0.68 ind/m ² and the biomass between 3.92-48.75 kg/ha. No presence of nematode parasites was observed in these specimens.
Conclusions . Densities and biomasses of A. fulica in Cartagena do not reach levels considered highly harmful. On the other hand, although no parasites were found in these snails, it is relevant to continue with studies on the human health risks that represent the presence of this invasive species in urban areas of Cartagena.
Individuals of Achatina fulica (Bowdich, 1822) were observed preying on veronicellid slugs at two sites on the island of Oahu, Hawaii. As such, the presence of A. fulica may pose a greater threat to terrestrial mollusc conservation than previously imagined. It is our hope that this note provides some impetus for other researchers to explore the possible predation impacts of introduced populations of A. fulica and to consider the possibility that other introduced snails and slugs may be having as yet unforeseen or unnoticed impacts.
| https://www.researchgate.net/publication/270576929_Into_the_Andes_three_new_introductions_of_Lissachatina_fulica_Gastropoda_Achatinidae_and_its_potential_distribution_in_South_America |
The Oxford Oratory
A sanctuary in the midst of the city
The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman.
Congratulations to Livi, baptised on the vigil of Pentecost.
“Therefore, Lord, we pray: graciously accept this oblation of our service, that of your whole family, which we make to you also for those to whom you have been pleased to give the new birth of water and the Holy Spirit, granting them forgiveness of all their sins; order our days in your peace, and command that we be delivered from eternal damnation and counted among the flock of those you have chosen. Through Christ our Lord. Amen.”
Courtesy
I recall how, as a child at school, we were sometimes made to learn poetry. At the time I hated it, and baulked at the idea of having to commit to memory The Ancient Mariner, and in fact, never did. But one poem which did touch me, was Belloc’s Courtesy. It began:
Of Courtesy, it is much lessThan Courage of Heart or Holiness,Yet in my Walks it seems to meThat the Grace of God is in Courtesy.
The poet goes on to tell us how, on one occasion he visited the ‘monks’ at Storrington in Sussex, and that ‘They took me straight into their Hall’where he ‘saw Three Pictures on a wall, And Courtesy was in them all.’
He then tells us the subject of those paintings:
The first the Annunciation;The second the Visitation;The third the Consolation,Of God that was Our Lady’s Son.
The first was of St. Gabriel;On Wings a-flame from Heaven he fell;And as he went upon one kneeHe shone with Heavenly Courtesy.
Our Lady out of Nazareth rode —It was Her month of heavy load;Yet was her face both great and kind,For Courtesy was in Her Mind.
The third it was our Little Lord,Whom all the Kings in arms adored;He was so small you could not seeHis large intent of Courtesy.
Today is the feast of the Visitation, when we celebrate how our Lady made the long and uncomfortable journey to see her older kinswoman, Elizabeth, and her husband Zachariah, who lived in the hill country of Judah. Courtesy seems to me to be a perfect description of what this moment is all about. Imagine the cordial welcome extended to Mary by the older woman, solicitous for her health and how both women were eager to share with one another the joy of the forthcoming births of their sons. Our Lady had herself gone to visit her older cousin, not simply because she wanted to ‘be there’ for her, but because she wanted to share her own good news, which was not hers alone but for her people and, ultimately for the entire world.
This is something Elizabeth seemed to know already! Her enthusiastic greeting is wonderful when she cries out ‘Oh that I should be visited by the Mother of my Lord’. Her unborn son joins in the greeting, kicking and letting his mother know that he too is part of this exciting thing that is happening. Elizabeth’s gracious words: ‘Blessed art thou among women and blessed is the fruit of thy womb’ have been enshrined in our prayer to the Virgin, incorporated with the Angelic Salutation: ‘Hail Mary, full of grace!’
And if today’s feast is about courtesy (so much more than stiff politeness or polished manners, but a warm and real concern for the wellbeing and interest of the other) then it is also about joy. Mary’s presence, together with that of her Divine Son, transformed the home of Elizabeth and Zachariah. ‘Elizabeth was filled with the Holy Spirit’ because of it. St Jose Maria puts it thus: ‘Mary brought joy to her cousin’s home, because she “brought” Christ’. Dame Julian liked to call Jesus ‘our courteous Lord,’ no doubt on account of his gracious dealings with us, flowing from his ‘large intent of Courtesy’!
Julian writes in her Showings:
And this is a supreme friendship of our courteous Lord, that he protects us so tenderly whilst we are in our sins; and furthermore he touches us most secretly, and shows us our sins by the sweet light of mercy and grace. But when we see ourselves so foul, then we believe that God may be angry with us because of our sins. Then we are moved by the Holy Spirit through contrition to prayer, and we desire with all our might an amendment of ourselves to appease God’s anger, until the time that we find rest of soul and ease of conscience. And then we hope that God has forgiven us our sin; and this is true. And then our courteous Lord shows himself to the soul, happily and with the gladdest countenance, welcoming it as a friend, as if it had been in pain and in prison, saying: My dear darling, I am glad that you have come to me in all your woe. I have always been with you, and now you see me loving, and we are made one in bliss.
So sins are forgiven by grace and mercy, and our soul is honourably received in joy, as it will be when it comes into heaven, as often as it comes by the operation of grace of the Holy Spirit and the power of Christ’s Passion.
Even though we have just changed all the light bulbs, our church looks its best when we don’t need to use them.
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The flag goes up on feast days!
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Blessings with St Philip’s relic after Vespers on Thursday.
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Look down from heaven, Holy Father, from the loftiness of that mountain to the lowliness of this valley; from that harbour of quietness and tranquillity to this calamitous sea. And now that the darkness of this world hinders no more those benignant eyes of thine from looking clearly into all things, look down and visit, O most diligent keeper, this vineyard which thy right hand planted with so much labour, anxiety and peril. To thee then we fly; from thee we seek for aid; to thee we give our whole selves unreservedly. Thee we adopt for our patron and defender; undertake the cause of our salvation, protect thy clients. To thee we appeal as our leader; rule thine army fighting against the assaults of the devil. To thee, kindest of pilots, we give up the rudder of our lives; steer this little ship of thine, and, placed as thou art on high, keep us off all the rocks of evil desires, that with thee for our pilot and our guide, we may safely come to the port of eternal bliss.
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Our celebrations for St Philip began with First Vespers last night and continue with Masses today. Here St Philip’s relic and altar are incensed during Vespers.
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Our new longer term temporary digital organ was hoisted up to the gallery this week in time for First Vespers of Our Holy Father St Philip. Catch up on our YouTube channel if you missed it, and join us for the Solemn Mass at 6pm this Friday.
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Vessel of the Holy Spirit
This year the novena in preparation for the feast of Our Holy Father St Philip corresponds almost exactly with the novena of novenas, the first novena, the nine days of prayer between the Ascension and Pentecost when we wait once more with the Apostles for the outpouring of the Holy Spirit. And this is most appropriate, as St Philip was, more than anything else, a man of the Spirit — as we say in his litany, he is the “vessel of the Holy Spirit”. The story of his life, which we read during the novena, really begins with his singular experience of the Spirit on the Vigil of Pentecost 1544 in the catacomb of St Sebastian when the Spirit descended like a ball of fire, entering his mouth and then into his heart. After that experience — Philip’s own Pentecost — his life would never be the same again.
Behind his holiness of life, and his preaching, and his miracles, and his founding of our Institute, there is something fundamental we can learn from St Philip — conveniently for this time in the Church’s liturgical calendar, something about the Holy Spirit. St Philip’s life shows us what happens when we do not simply possess the Holy Spirit, but allow ourselves to be possessed by him. We all have the Holy Spirit dwelling in us — all of us who have been baptised and confirmed. He is in us as much as he was in St Philip Neri, as much as he was in the Apostles at Pentecost. But we are very good at closing ourselves to the Spirit — we, through our sins and our selfishness, our attachments and our self-will, block him out; we ignore his prompting and are deaf to his call, we partition him away into a little forgotten compartment in our souls. Or we make of him a very petty little thing indeed, our God — a God who always agrees with what we say, who wants us to do precisely what we want to do, and makes me right and everyone else wrong.
But this is not the Holy Spirit whom we worship; this is not the awesome power of Almighty God, who hovered over the waters at creation, who raised Jesus from the dead, who came down on the Apostles and Our Lady in the Upper Room, who wonderfully penetrated the heart of St Philip, and who gives power and authority to the Church. The Holy Spirit blows where he wills; his ways are not always our ways; and if we give ourselves to him and allow him to possess us completely — as St Philip did — then we will find that he will do more for us than we ask or even imagine; do more through us and with us. St Philip wanted to be a layman — the Spirit called him to the priesthood; he wanted to be a martyr, the Spirit made him a martyr not of blood, but of charity; Philip wanted to preach the Gospel to the pagans in the Indies, the Holy Spirit had other plans. He wanted to be a humble, hidden servant of the Church, living at San Girolamo and doing what good he could, but the Spirit gave him the gift of preaching and teaching and working miracles and reading men’s hearts and winning souls, and brought him to the Vallicella, and through him founded the Congregation of the Oratory, spread, as it now is, across the world. St Philip loved to be unknown — the Holy Spirit moulded and fashioned and transformed him into one of the most popular saints, the Apostle of Rome. St Philip wanted to reform the hearts and souls of those men and women he met — the Spirit used him to reform the very heart of the Church herself.
It is not enough to have the Holy Spirit — it is not enough even to think we are serving God or doing great things in his honour. We must allow ourselves to be led by the Spirit, formed and transformed by the Spirit. We must be prepared to give up our own desires and plans — even the good ones — and be taken over by the Holy Spirit to be used for his own purposes. If we do this, if we open up to the Spirit who dwells in our hearts, then the life of St Philip Neri, and indeed of all the saints, shows us that the Spirit will do great things for, in, and through us. St Philip, Vessel of the Holy Spirit and Sweetest of Fathers. Pray for us.
A Prayer of Our Holy Father St Philip:
My Lord Jesus, I want to love you but you cannot trust me. If you do not help me, I will never do any good. I do not know you; I look for you but I do not find you. Come to me, O Lord. If I knew you, I would also know myself. If I have never loved you before, I want to love you truly now. I want to do your will alone; putting no trust in myself, I hope in you, O Lord.
The Paschal Candle has been lit for Masses since the Easter Vigil to represent Christ’s presence among us, as with his disciples for forty days. After the Gospel of the Solemn Mass yesterday, it is extinguished to symbolise his ascension into heaven.
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Look up to heaven
On Monday this week some of the Fathers and Brothers spent the day erecting and moving scaffolding — with all due health and safety measures observed — in order to change and improve the lighting on the sanctuary of our church. It is already a great boon for us to see more clearly the beautiful decoration which adorns that focal point of the whole building, as well as being a great help for the priest reading from the missal. Tomorrow as we celebrate the feast of the Ascension, our eyes are directed upwards once more as Our Risen Lord ascends to heaven and for a moment like the Apostles we gaze upwards as he is taken from our sight.
How very much more clearly do we see when we make that effort to lift up our eyes towards the Lord. We not only contemplate his glory but from that vantage point are able to see all things in their fullness, seeing them from the perspective of heaven. Prayer, the lifting of the mind and heart to God, enables us to understand and to see clearly, all those other things of life in which we are otherwise immersed. That daily shifting our focus from the things of this world to the vantage point of heaven is that great encouragement for our daily striving for God, so that where Christ goes we too may follow him.
It is often an effort for us to pull ourselves out of the daily round in order to lift up our heads and our hearts to the things of heaven, but if we are to have the desire for heaven to drive us on, it is essential that we always keep our goal before us. Not only in prayer, but all those things which form the way we see things must have heaven as their vantage point and aim. Monsignor Knox wrote:
In all ages, in all countries, the world acts as a solvent to Catholic piety; breathes an air in which Catholic piety languishes. Man’s intellect always wants to approach things from the human side, from the side from which they can be known by man; shirks and burkes discussion of things from the side of reality, from the side which relates them to God. Man’s art and literary genius is constantly concerned with man at his most human level, his passions, his craven fears, the rebellion of his will against the order in which he lives. All that breathes a poison, for which writers who care about the truth as it is in God have to provide an antidote; they must fight, they must react, but still more they must see things, they must record things, from that higher standpoint which is God’s. You must, sometimes, give the lungs of your soul an airing on these heights, even if the atmosphere of it is more rare, is breathed with more effort, than the other. Or else, the miasma of the modern world will get you down, will weaken your resistance; you will be a prey to the germs of infidelity, to the infection of bad example. And you will forget your Friend.
As the Church invites us then on the Ascension to gaze up towards heaven, to contemplate Our Lord, Risen and Ascended, it is perhaps a good time for us to think on the place we give to the things of heaven in our life each day — not only in terms of the time we give to heaven, but also in terms of what we strive for, on what really all our efforts are in fact based.
And from our gazing upon heaven, we can then go on like the Apostles, down from that mountain and into the world — to teach the Good News and make disciples of all nations, keeping ever in mind that he whom we meet on those heights of prayer is with us always, even to the end of time.
Tuesday 16 May 2023
Q: How many Oratorians does it take to change a lightbulb?A: “Change”?
Actually the real answer turns out to be three, plus one very helpful volunteer and a lot of scaffolding. The sanctuary lighting is all working at full brightness again!
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Monday 15 May 2023
Congratulations to David who was baptised on Saturday!
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Saturday 13 May 2023
One of this month’s relics on display is St Philip’s own copy of Jacapone da Todi’s “Laude”, which St Philip has written his name in. The story of how it was rediscovered in our church — only days before the first Fathers of the Oratory arrived here from Birmingham — is extraordinary. You might find it hard to believe, unless you heard it straight from the priest who found them, who is now the Bishop of Leeds. Read his account from his St Philip’s day sermon on our website:
www.oxfordoratory.org.uk/blog/post/1335-solemnity-of-our-holy-father-saint-philip
The novena to St Philip begins on Tuesday after the evening Mass. You will be able to place your own prayer intentions for the novena in St Philip’s chapel over the weekend.
There will be Solemn Choral Vespers on Thursday 25 May at 6:30pm.
We will welcome Fr Robert Ombres OP from Blackfriars to preach at the Solemn Mass for the feast day itself on Friday 26 May at 6pm.
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Friday 12 May 2023
May Music
Sunday 7 MaySolemn Mass 11:005th Sunday of EasterMissa Simile est regnum caelorum LoboJubilate Deo universa terra PalestrinaCaro mea vere est cibus Guerrero
Sunday 14 MaySolemn Mass 11:006th Sunday of EasterMissa Regina caeli PalestrinaBenedicite gentes PalestrinaPortio mea White
Thursday 18 MaySolemn Mass 18:00The Ascension of the LordMissa Ascendens Christus VictoriaAscendit Deus PhilipsO Rex gloriae Marenzio
Sunday 21 MaySolemn Mass 11:007th Sunday of EasterMissa Jam Christus astra ascenderat PalestrinaViri Galilaei PalestrinaEgo sum panis vivus Palestrina
Thursday 25 MaySolemn Vespers 18:30Our Holy Father St Philip NeriDeus in adjutorium PadillaMagnificat primi toni VictoriaPangamus Nerio SewellO salutaris hostia LalouxTantum ergo WidorAlleluia GabrieliRespice de caelo Sewell
Friday 26 MaySolemn Mass 18:00Our Holy Father St Philip NeriMissa Papae Marcelli PalestrinaIn spiritu humilitatis CroceJubilate Deo a8 G Gabrieli
Sunday 28 MaySolemn Mass 11:00PentecostMissa De la Batalla GuerreroConfirma hoc deus LassusLoquebantur variis linguis Palestrina
Wednesday 10 May 2023
Crowns come in different sizes
One could not have missed the many images of crowns in the past week. On posters and flags, on shop advertisements and on the official emblem of the coronation of His Majesty the King. The whole world, it seems, was caught up in amazement at that moment when St Edward’s crown was placed on the King’s head, the only time it is ever worn, to be replaced by the Imperial State Crown, impressive in its size and its jewels. One could not help but feel a certain sympathy with them — perhaps especially Her Majesty the Queen — as they walked around gingerly with several pounds’ weight of crown on their heads, lest they take a tumble. A crown is a symbol not only of a regal inheritance, but of a sacred anointing and the leadership of a nation. It also shows that one is set apart from the rest, is chosen, is consecrated.
Crowns are a familiar sight even in church. Our Lady’s statue is crowned, there are crowns above the cabinets in the Relic Chapel and they are even to be found, accompanied by palm branches, on the reliquaries placed on the High Altar on feast days. These crowns too stand for those set apart, who are chosen to bear the ultimate witness to the greatest truth.
On Friday we keep the feast of Saints Nereus and Achilleus. Baptised by St Peter himself, these two soldiers having obeyed the cruel orders of their emperor out of fear alone, it is said, came quite suddenly to faith in Christ and in doing so were liberated. They were freed from their obedience to a tyrant to embrace obedience to Christ and in so doing were called to shed their blood in witness to their faith. Theirs is the story of so many brave Christians who saw eternal life as the greatest prize against which everything the world has to offer pales in comparison. St Philip had a great devotion to the saints. Their relics are enshrined at the Roman Oratory and the Venerable Cardinal Baronius was the Cardinal Priest of their ancient church, often frequented by St Philip.
St Philip had a marvellous devotion to the saints and their relics. In his last years we are told he had the lives of the saints read to him daily and took great care to preserve the relics of the saints with devotion at the Vallicella. He saw in the lives of the saints a guide for the rest of us so that where they have gone we might follow.
Earthly crowns fall on the heads of very few men. The crowns on our relic cabinets, on the altar reliquaries and paintings in the church are a reminder to us that there is a lasting crown in store for all of us, a crown of glory that will never fade and is given us by the Lord. It may not be that we have to win it by shedding our blood like Nereus and Achilleus, but rather through the long and arduous path of growing in holiness day by day. We are chosen and set apart, we are consecrated by our baptism to win the crown that is fitted for us. In the eyes of the world it rarely glitters, but it is more lasting than anything the world can dream up. And go for it we must.
And we pray for our King Charles, that the golden crown set on his head a few days ago may always remind him of that crown of glory that awaits him, please God, after a life of service and virtue. May he be helped in seeking that crown by our prayers.
Saturday 6 May 2023
God save the King!
Photo from our Coronation watch party today.
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Friday 5 May 2023
Where will you be watching tomorrow? Preparations are well underway for the Oratory Watch Party tomorrow after the 10:00am Mass. Why not join us? #oxfordoratory
Wednesday 3 May 2023
Praying with words
There is an idea among some people that our prayer is meant to evolve with time. They think that while we all start with vocal prayer (made with words either aloud or silently), we are meant, as we grow up, to use fewer words, to move on to mental prayer or meditation, and eventually move beyond that and learn pure contemplative prayer, where we are silent both without and within. Some authors speak as if the silence of contemplation were the only true prayer. And yet one of the Church’s greatest mystics, St Theresa of Avila, spent her day, in between periods of contemplation, reciting the words of the psalms of the Divine Office with her fellow sisters. Mental and contemplative prayer are certainly forms of prayer we only learn about when we are older, but vocal prayer cannot be something that we are meant to grow out of. When the Apostles asked Our Lord to teach them to pray, he told them: ‘Pray like this: Our Father, who art in heaven…’ (Matthew 6:9) He taught them, in the first place, the wordsof a prayer.
Catholic interest in the Mass (which is certainly a good thing) also seems to have eclipsed our interest in other prayers, so that the only prayer book most people might own is a missal. And many other books of prayers have little space for other devotions, because so much space is given to the text of the Mass.
There haven’t been so many books of prayersprinted in recent decades. When we look back a hundred years, we find a combination of factors led to a golden age of prayer books for ordinary people. I remember inheriting my grandfather’s prayer book from 1959, and feeling that I had discovered a hidden treasure. While freedom in choosing how to pray is essential, sometimes we do need someone to teach us, like Our Lord: ‘Pray like this. Say these prayers.’ And that’s what I found in that prayer book of my grandfather. Many of the prayers inour new prayer book(pretty much the entire collection of night prayers) come straight from that old prayer book. And many other collections have been plundered for their treasures too, together with a handful of newly adapted or translated texts.
But that is only meant to be a starting point. It is a wonderful thing to build up — committing to memory or even to paper — our own collection of favourite prayers: from the scriptures, from the writings of the saints, from the prayers of the Church. Metropolitan Anthony of Sourozh writes in School for Prayer:
Mark these passages that go deep into your heart, that move you deeply, that makes sense, that express something which is already within your experience, either of sin, or of bliss in God, or of struggle. Learn those passages, because one day when you are so completely low, so profoundly desperate that you cannot call out of your soul any spontaneous expression, any spontaneous wording, you will discover that these words come up and offer themselves to you as a gift of God, as a gift of the Church, as a gift of holiness, helping our simple lack of strength. And then you really need the prayers you have learnt and made a part of yourself.
We don’t always find time to think about the words of our prayers as much as we might like. Ideally, we would spend some time thinking about not just what our prayer says to God, but also what it says to us about him and about ourselves in relation to him. St Philip used to teach people to take the Our Father slowly, word by word, phrase by phrase, and draw out all the ideas it contains. We don’t have time to do that every time we say it though. And so when we do rush through it in a few seconds, we mean implicitly whatever it was Christ meant when he gave it to his disciples and asked them to hand it down to us. And we intend to say to God all the ideas that would come to mind, if we did have a bit more time to think about it.
Similarly, when our prayer has been composed by a saint, we can be confident that the thoughts those words express — even if we don’t always have time to explore them — led the author to an even closer union with God.
We might think that we can compose better prayers in our own words than some of these old prayers, and that might even be true. Some part of our time of prayer can and should involve speaking to God in our own words. But there is something special about joining in a prayer that has been in use even from before we were born, that has been sanctified by centuries of use. When we use a prayer that is shared with the rest of the Church, we are reminded that we don’t just pray by ourselves. We imply not only all those ideas we might find in it, but we attach to it also all those intentions that our brothers and sisters in the Church, throughout the world, throughout time, have meant and do mean and ever will mean in their use of the same prayer. And it is a comforting thought to imagine all the saints — past, present and future — praying with us and for us in those same words.
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Survey of Rice Pests, Diseases and Natural Enemies on “Upsus” Program in Karawang District, West Java Province | Effendi | Jurnal Perlindungan Tanaman Indonesia
Survey of Rice Pests, Diseases and Natural Enemies on “Upsus” Program in Karawang District, West Java Province
Survey of Rice Pests, Diseases and Natural Enemies on “Upsus” Program in Karawang District, West Java Province
https://doi.org/10.22146/jpti.50365
Kurniawan Effendi
(1*)
, I Wayan Winasa
(3)
(1) Department of Plant Protection, Faculty of Agriculture, IPB University, Jln. Meranti, Kampus IPB Dramaga, Bogor, West Java 16680
(2) Department of Plant Protection, Faculty of Agriculture, IPB University, Jln. Meranti, Kampus IPB Dramaga, Bogor, West Java 16680
(3) Department of Plant Protection, Faculty of Agriculture, IPB University, Jln. Meranti, Kampus IPB Dramaga, Bogor, West Java 16680
(*) Corresponding Author
Abstract
"Upsus" (Special Efforts) Program is a program to increase crop production and productivity to support the acceleration of food self-sufficiency held by the government. The targets are to increase the planting index (IP) by 0.5 and productivity by 0.3 ton/ha/Harvested Dry Grain (HDG). Increased productivity has not been reached optimally. This research aimed to determine the number/types of the dominant pests and natural enemies, and pests and diseases attack rates in the wetland rice plantation "Upsus" Program in Karawang District. Direct observation was carried out on four stages of plant development, in the nursery stage (10–14 days after sowing) 200–300 m², seedlings stage (10–20 days after planting), vegetative stage (5–6 weeks after planting), and reproductive stage (1–2 weeks after flowering) respectively within an area of 2000 m². Twenty samples were observed in the nursery stage and 50 samples in the following stages. The dominant pests and diseases found were Nilaparvata lugens, Leptocarisa oratorius, Schirpophaga incertulas, Cnaphalocrocis medinalis, Scotinophara coarctata, Mythimna separata, bacterial leaf blight ( Xanthomonas. oryzae pv. oryzae), blast ( Pyricularia grisea) and narrow brown spot ( Cercospora oryzae). The recorded dominant natural enemies were Cyrtorhinussp., Paederussp., Tetragnathasp., and Pardosa pseudoannulata. S. incertulasshowed the highest attack intensity and the highest disease severity was found in bacterial leaf blight. The largest population of dominant pests and natural enemies was found in the generative stage. The high application of pesticides affected the population of pests, natural enemies, and the level of pest and disease attacks.
Keywords
diseases; natural enemies; pests; special effort
Full Text:
PDF
References
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DOI:
| https://jurnal.ugm.ac.id/jpti/article/view/50365 |
Retrovirus Life Cycles and Reverse Transcription | Biology | JoVE
JoVE publishes peer-reviewed scientific video protocols to accelerate biological, medical, chemical and physical research. Watch our scientific video articles.
16.5: Retrovirus Life Cycles
A retrovirus is a single-stranded RNA virus that binds to specific cell surface receptors on a targeted host cell's outer membrane, fuses, and enters via endocytosis to replicate its genetic material in a unique way.
After enter the host's cell, the capsid is uncoated and the enzyme reverse transcriptase or RT binds to the viral RNA, synthesizing complementary DNA and with time, double-stranded DNA the reverse of the usual pattern.
Inside the nucleus of the host cell, the viral DNA is integrated into the host DNA forming a provirus. Thus the viral DNA is actively transcribed whenever the host DNA is transcribed, forming messenger RNA.
This mRNA exits the nucleus, enters the cytoplasm, and is translated to form new viral proteins, which can then assemble into new retroviruses that butt out of the cell and are ready to infect other cells.
16.5: Retrovirus Life Cycles
Retroviruses have a single-stranded RNA genome that undergoes a special form of replication. Once the retrovirus has entered the host cell, an enzyme called reverse transcriptase synthesizes double-stranded DNA from the retroviral RNA genome. This DNA copy of the genome is then integrated into the host’s genome inside the nucleus via an enzyme called integrase. Consequently, the retroviral genome is transcribed into RNA whenever the host’s genome is transcribed, allowing the retrovirus to replicate. New retroviral RNA is transported to the cytoplasm, where it is translated into proteins that assemble new retroviruses.
Antiretroviral Drugs Target Different Stages of the HIV Life Cycle
Particular drugs have been developed to fight retroviral infections. These drugs target specific aspects of the life cycle. One class of antiretroviral drugs, fusion inhibitors, prevents the entry of the retrovirus into the host cell by inhibiting the fusion of the retrovirus with the host cell membrane. Another class of antiretrovirals, reverse transcriptase inhibitors, inhibits the reverse transcriptase enzymes that make DNA copies of the retroviral RNA genome. Reverse transcriptase inhibitors are competitive inhibitors; during the process of reverse transcription, the drug molecules are incorporated into the growing DNA strand instead of the usual DNA bases. Once incorporated, the drug molecules block further progress by the reverse transcriptase enzyme. The third class of drugs, integrase inhibitors, prevents the integrase enzymes from integrating the retroviral genome into the host genome. Finally, protease inhibitors interfere with the enzymatic reactions that are necessary for producing fully functioning retroviral particles.
Combinations (or “cocktails”) of antiretrovirals are used to fight Human Immunodeficiency Virus (HIV). If left untreated, this retrovirus causes AIDS. Cocktails of antiretrovirals are necessary to fight HIV infections because the retrovirus can quickly evolve resistance to any one drug. This capacity for rapid evolution stems from the single-stranded RNA genome of HIV, which accumulates mutations more rapidly than DNA or double-stranded genomes. Some of these mutations confer drug-resistance.
However, by combining drugs that target events at the beginning, middle, and end of the retroviral life cycle, antiretroviral cocktails (called highly active antiretroviral therapy, or HAART) dramatically reduce the HIV population in a patient. The likelihood of multiple mutations that confer resistance to various drugs in the HIV genome is much lower than that of a single resistant mutation, making the HAART strategy much more effective than single-drug therapies. This cocktail strategy has been enormously successful in treating HIV, such that it is now uncommon for treated individuals to develop AIDS.
| https://www.jove.com/science-education/10825/retrovirus-life-cycles |
P0528r0: The Curious Case of Padding Bits, Featuring Atomic Compare-and-Exchange
The Curious Case of Padding Bits, Featuring Atomic Compare-and-Exchange
Published Proposal, 12 November 2016
This version:
http://wg21.link/P0528r0
Authors:
JF Bastien ( Apple )
Michael Spencer ( Sony Playstation )
Audience:
SG1, LEWG, LWG, CWG
Project:
ISO JTC1/SC22/WG21: Programming Language C++
Source:
github.com/jfbastien/papers/blob/master/source/P0528r0.bs
Abstract
I was thinking how nothing lasts—especially a struct’s padding bits—and what a shame that is when used with atomic compare-and-exchange.
Table of Contents
1 Story Time
1.1 The Curious Case of struct
1.2 A union Born in Unusual Circumstances
1.3 Points are Floating, Even
NaN wards
1.4 You Never Know What’s Storing
1.5 Defining the Opportunities We’ll Miss
1.6 Making the Greatest Impression
1.7 Standards Can Only Be Understood Backward, they Must Be Lived Forward
2 Proposed Wording
2.1 Header < type_traits >
synopsis [ meta.type.synop ]
2.2 Type properties [ meta.unary.prop ]
2.3 Requirements for operations on atomic types [
atomics.types.operations.req ]
2.4 Atomic types [ atomics.types.generic ]
2.5 Header < atomic > synopsis [ atomics.syn ]
3 Sample Program
References
Informative References
This issue has been discussed by the authors at every recent Standards meetings,
yet a full solution has been elusive despite helpful proposals. We believe that
this proposal can fix this oft-encountered problem once and for all.
1. Story Time
1.1. The Curious Case of
struct
Using the Standard’s atomic compare-and-exchange on struct
s with padding bits
is fraught with peril: the desired
value is passed by value to all of the
methods, which doesn’t guarantee than any particular bit pattern is preserved in
the bits which don’t participate in the
value representation
. the
padding bits mean that there are multiple
object representations
for
the same value representation.
Indeed:
Object initialization doesn’t guarantee any particular value for padding bits.
Copying an object can change its padding bits, on every copy
.
Whereas using compare-and-exchange acts on the entire
object,
padding bits included. From 29.6.5 Requirements for operations on atomic types
[ atomics.types.operations.req
], ¶24:
[ Note: For example, the effect of
atomic_compare_exchange_strong is
if ( memcmp ( object , expected , sizeof ( * object )) == 0 ) memcpy ( object , & desired , sizeof ( * object ));
else memcpy ( expected , object , sizeof ( * object ));
— end note
]
Compare-and-exchange is specified this way because that’s how hardware works: cmpxchg
or load-linked / store-conditional instuctions must operate on the
entire address range to be atomic.
The interactions between non-atomic and atomic objects which contain padding
bits means that compare-and-exchange is never
guaranteed to
succeed, even if the program only ever uses a single value representation.
We’ve included a §3 Sample Program
which exhibits this behavior.
1.2. A union Born in Unusual Circumstances
Unions can exhibit a similar problem: they can contain padding, but can also
contain bits which don’t participate in their active member’s value
representation.
1.3. Points are Floating, Even
NaN wards
Astute readers will note that value representations with multiple object
representations exist for more than simply struct
and union
. Even with
std :: atomic
's requirement that objects be trivially copyable, it is possible
for boolean, signed integral and floating-point values to suffer from this
problem.
The common example where this happens is when signaling NaN
s are present: some
platforms canonicalize them to quiet a NaN
. This is a similar problem to
padding bits: copying can change the object representation.
1.4. You Never Know What’s Storing
Another surprising case is when atomic store
or exchange
operations are
implemented using compare-and-exchange. This happens when the target
architecture doesn’t have a suitably-sized store
or exchange
instructions,
but has an appropriate
cmpxchg
or load-linked / store-conditional. To
guarantee lock-freedom, implementations rely on compare-and-exchange. This is
transparent to the developer, but can lead to permanent failure to store
or
exchange
if padding bits are present.
The same implementation approach is possible for load
s, but failure to perform
an idempotent compare-and-exchange is the same as a load
, regardless of
padding bits since it yields the previous value.
1.5. Defining the Opportunities We’ll Miss
This problem is valid for union
, some scalar representations, and some
store
/ exchange
implementations. The authors nonetheless believe that it is a
separable from that of padding bits on struct
s. Indeed, all struct
with
padding bits exhibit this problem, whereas only limited scalar values are
affected. The same applies for union
: the issue can only surface when the
widest member isn’t the active member (though
union
s do suffer of the padding
problem). Only some store
/ exchange
implementations are affected, in which
case their struct
s with padding bits are also affected. We don’t believe std :: atomic < bool >
suffers from this problem.
Put another way: compare-and-exchange of a struct
with padding bits is always
wrong, whereas the other similar issues are sometimes
wrong.
This leads us to the following conclusions:
For types with padding bits a simple solution exists using the existing
Standard: developers should explicitly define padding members if they
intend to compare-and-exchange a type. Were an approach such as
[N3986]
adopted, developers could rely on this facility to avoid padding bits more
easily.
Other types which don’t have unique object representations merit another
solution: developers should never compare-and-exchange a value which has
multiple object representations. All other values of that type can be
compare-and-exchanged without issue.
Implementations which rely on compare-and-exchange for the
store
and exchange
functions of certain instantiations of atomic < T >
could apply a
similar solution to that proposed in this paper. The authors are interested
in writing a separate paper to address the issue.
This paper only addresses the first conclusion.
1.6. Making the Greatest Impression
Conclusion 1. above is addressable by developers, but the authors believe that
this Standard should prevent this dangerous usage of compare-and-exchange. This
is better handled as a requirement of the methods than as a QoI warning.
The authors therefore propose using concepts' requires
clause to all the
compare-and-exchange functions, forbidding their usage on a type which has
padding bits. All other
std :: atomic
operations would remain valid, only
compare-and-exchange would become a compilation error if used.
The Standard, if [P0020r3]
is adopted, will specify 4 specializations for std :: atomic
:
std :: atomic < T >
std :: atomic < T *>
std :: atomic < integral >
std :: atomic < floating - point >
Since [P0258r2]
the Standard contains the type trait
has_unique_object_representations
, as defined in 20.15.4.3 Type properties
[ meta.unary.prop
] ¶9. This trait initially seems ideally suited
to our purpose:
The predicate condition for a template specialization
has_unique_object_representations <
T >:: value
shall be satisfied if and only
if:
T is trivially copyable, and
any two objects of type T
with the same value have the same object
representation, where two objects of array or non-union class type are
considered to have the same value if their respective sequences of direct
subobjects have the same values, and two objects of union type are
considered to have the same value if they have the same active member and
the corresponding members have the same value.
The set of scalar types for which this condition holds is
implementation-defined. [ Note:
If a type has padding bits, the
condition does not hold; otherwise, the condition holds true for unsigned
integral types.
— end note
]
We could apply it to the
std :: atomic < T >
variants of compare-and-exchange only,
avoiding the pointer, integral and floating-point specializations. This
unfortunately leaves out what seems like a useful case:
struct T { float a ; float b ;
};
std :: atomic < T > t ;
static_assert ( std :: has_unique_object_representations_v < T > );
This type typically has no padding bits, fits the std :: atomic < T >
specialization, yet on some platforms does not
have a unique
object representation because of its floating-point members. The above type is
often spelled as
std :: atomic < std :: complex < float >>
, which is a very useful
type, even atomically. Naïvely adding requires
has_unique_object_representations_v < T
>
on the compare-and-exchange members of std :: atomic < T >
would—among other things—forbid using compare-and-exchange on
complex numbers. The authors believe this is unacceptable.
1.7. Standards Can Only Be Understood Backward, they Must Be Lived Forward
We find ourselves unable to use
has_unique_object_representations
, which was
intended for future
std :: hash
proposals but was hoped to also be usable for
our present usecase. We thus propose a new type trait, tentatively named
has_padding_bits
.
If this sounds familar, that’s because it is:
[P0258r2]
introduced
has_unique_object_representations
.
[p0258r1]
proposed
is_contiguous_layout
.
[P0029r0]
proposed
is_uniquely_represented
.
[N3980]
proposed
is_contiguously_hashable
.
[N3333]
proposed
is_contiguous_layout
.
[N4130]
discussed the padding bits issue, and wondered whether a has_padding_bits
trait was sensible. It was reviewed by SG1 in the 2014
Redmond meeting. Guidance was sought to also resolve [LWG2334]
as well as
WG14 DR 431 while keeping C compatibility, but no conclusion was reached.
The reader now also understands this paper’s Benjamin Button theme.
2. Proposed Wording
2.1. Header < type_traits >
synopsis [ meta.type.synop ]
Add a new typetrait:
template < class T > struct has_padding_bits ;
and:
template < class T > constexpr bool has_padding_bits_v = has_padding_bits < T >:: value ;
2.2. Type properties [ meta.unary.prop ]
Add to Table — Type property predicates:
Template Condition Preconditions
᠁ ᠁ ᠁
template < class T > struct has_padding_bits ;
For an array type T , the same result as
has_padding_bits < remove_all_extents_t < T >>:: value , otherwise see below
T shall be a complete type, (possibly cv-qualified) void , or an
array of unknown bound.
᠁ ᠁ ᠁
Add the following paragraph:
The predicate condition for a template specialization
has_padding_bits < T >:: value shall be satisfied if and only if:
T is trivially copyable, and
there exists at least one bit in the object representations of an
object of type T which never participates in the value representation.
Or alternatively for the 2nd bullet:
given two objects of type T , for each bit in their object
representations that bit does not participate in their value
representations.
2.3. Requirements for operations on atomic types [
atomics.types.operations.req ]
Precede each of the following functions:
atomic_compare_exchange_weak
atomic_compare_exchange_strong
atomic_compare_exchange_weak_explicit
atomic_compare_exchange_strong_explicit
A :: atomic_compare_exchange_weak
A :: atomic_compare_exchange_strong
With this concept: requires
has_padding_bits_v < C >
.
Update the following paragraph:
Requires:
The failure
argument shall not be memory_order_release
nor memory_order_acq_rel
.
has_padding_bits_v < C > shall be
false .
Update the following note:
[ Note:
The memcpy
and memcmp
semantics of the compare-and-exchange operations may
result in failed comparisons for values that compare equal with operator ==
if the underlying type has
padding bits
bits which don’t
participate in active member’s value representation
, trap bits, or
alternate representations of the same value. Thus,
compare_exchange_strong compare-and-exchange operations
should be used with extreme care.
On the other hand,
compare_exchange_weak should converge rapidly.
— end note
]
2.4. Atomic types [ atomics.types.generic ]
For all functions modified in §2.3 Requirements for operations on atomic types [atomics.types.operations.req]
, add the
same concepts to atomic < T >
's
compare_exchange_weak
and
compare_exchange_strong
and all its specializations.
2.5. Header < atomic > synopsis [ atomics.syn ]
Add the same concept for all overloads of the following free function:
atomic_compare_exchange_weak
atomic_compare_exchange_strong
atomic_compare_exchange_weak_explicit
atomic_compare_exchange_strong_explicit
3. Sample Program
This program uses compare-and-exchange on a struct
which has padding bits. It
may loop infinitely, or not.
#include <atomic>
#include <cstring>
#include <new>
#include <stdio.h>
#include <type_traits>
struct Padded { char c = 0xFF ; // Padding here. int i = 0xFEEDFACE ; Padded () = default ;
};
typedef std :: atomic < Padded > Atomic ;
typedef std :: aligned_storage < sizeof ( Atomic ) >:: type Storage ;
void peek ( const char * what , void * into ) { printf ( "%16s %08x %08x \n " , what , * ( int * ) into , * ( 1 + ( int * ) into ));
}
Storage * create () { auto * storage = new Storage (); std :: memset ( storage , 0xBA , sizeof ( Storage )); asm volatile ( "" ::: "memory" ); peek ( "storage" , storage ); return storage ;
}
Atomic * change ( Storage * storage ) { // As if we used an allocator which reuses memory. auto * atomic = new ( storage ) Atomic ; peek ( "atomic placed" , atomic ); std :: atomic_init ( atomic , Padded ()); // Which bits go in? peek ( "atomic init" , atomic ); return atomic ;
}
Padded infloop_maybe ( Atomic * atomic ) { Padded desired ; // Padding unknown. Padded expected ; // Could be different. peek ( "desired before" , & desired ); peek ( "expected before" , & expected ); peek ( "atomic before" , atomic ); while ( ! atomic -> compare_exchange_strong ( expected , desired // Padding bits added and removed here ˙ ͜ʟ˙ )); peek ( "expected after" , & expected ); peek ( "atomic after" , atomic ); return expected ; // Maybe changed here as well.
}
int main () { auto * storage = create (); auto * atomic = change ( storage ); Padded p = infloop_maybe ( atomic ); peek ( "main" , & p ); return 0 ;
}
References
Informative References
[LWG2334]
Daniel Krügler. atomic's default constructor requires "uninitialized" state even for types with non-trivial default-constructor . SG1. URL:
http://cplusplus.github.io/LWG/lwg-active.html#2334
[N3333]
J. Yasskin, C. Carruth. Hashing User-Defined Types in C++1y
. 13 January 2012. URL:
http://www.open-std.org/jtc1/sc22/wg21/docs/papers/2012/n3333.html
[N3980]
H. Hinnant, V. Falco, J. Byteway.
Types don't know # . 24 May 2014. URL:
http://www.open-std.org/jtc1/sc22/wg21/docs/papers/2014/n3980.html
[N3986]
S. Davalle, D. Gutson, A. Bustamante.
Adding Standard support to avoid padding within structures . 25 April 2014. URL:
http://www.open-std.org/jtc1/sc22/wg21/docs/papers/2014/n3986.pdf
[N4130]
JF Bastien, O. Giroux. Pad Thy Atomics
. 1 September 2014. URL:
http://www.open-std.org/jtc1/sc22/wg21/docs/papers/2014/n4130.pdf
[P0020r3]
H. Carter Edwards, Hans Boehm, Olivier Giroux, JF Bastien, James Reus. Floating Point Atomic View . 14 October 2016. URL:
http://www.open-std.org/jtc1/sc22/wg21/docs/papers/2016/p0020r3.html
[P0029r0]
Geoff Romer, Chandler Carruth.
A Unified Proposal for Composable Hashing
. 21 September 2015. URL:
http://www.open-std.org/jtc1/sc22/wg21/docs/papers/2015/p0029r0.html
[P0258R1]
Michael Spencer.
is_contiguous_layout . 5 March 2016. URL:
http://www.open-std.org/jtc1/sc22/wg21/docs/papers/2016/p0258r1.html
[P0258r2]
Michael Spencer.
has_unique_object_representations - wording . 24 June 2016. URL:
http://www.open-std.org/jtc1/sc22/wg21/docs/papers/2016/p0258r2.html | https://www.open-std.org/JTC1/sc22/WG21/docs/papers/2016/p0528r0.html |
Home Visits, Universal Pre-K, and Trauma-Informed Care… California Dreams Big for Families
With a state budget that invests in families and a Governor committed to California's children, the future looks sunny on the golden coast.
Home Visits, Universal Pre-K, and Trauma-Informed Care… California Dreams Big for Families
At hisinauguration, Governor Newsom exalted the California dream. “So deep does the California dream run in the history and character of our state that it can feel as enduring as our primeval forests or our majestic mountain ranges. But, there’s nothing inevitable about it. Every dream depends on the dreamers, and it’s up to us to renew the California dream for a new generation.”
As though on cue, the next generation of Newsom wandered on to stage and into his father’s arms. The Governor continued on, envisioning a California where every child is loved, fed, and safe, and parents of young children are supported. As his two-year-old son nuzzled into his neck, Newsom remarked, “There’s nothing more important—I hope you can tell—than giving them a good and happy life.”
Newsom’s promise to California’s children and families was signed into reality on June 27, 2019, when the statebudgetwas enacted. The $214.78 billion dollarbudgetincludes $103.4 billion dollars fork-12education programs and roughly$5.5 billionforearly childhood educationand support for families.
Here’s the breakdown:
With the ultimate goal of universal access to high quality education and care, the state will create a new Master Plan for Early Learning and Care. Funded at $5 million, this strategic plan will establish a path to universal pre-K and expand paid family leave, among other goals. An Early Childhood Policy Council will be established to advise the Master Plan, with constituents including parents, providers, and representatives from state agencies. The Early Childhood Policy Council, funded at $2.2 million, will also advise the Legislature’sBlue Ribbon Commission on Early Childhood Education Final Report.
The budget increases access to child care for thousands of families with low-incomes, enabling parents to work or attend classes while their children learn in a safe, caring environment. Through a $143.3 million ongoing investment, partially paid for by an $80.5 million Cannabis Fund and $12.8 million federal Child Care Development Fund, 12,400 more children will receive care through theAlternative Payment Programand the General Child Care Program. TheCalifornia Work Opportunity and Responsibility to Kids(CalWORKs) program, designed to aid working parents with incomes below 85 percent of thestate median income, received $228 million in ongoing funding. This expansion will allow additional work-related activities to ease the burden ofwork requirementsand accommodate the 14,000 children recently accepted into the program.
To move toward universal pre-K, the state invested $31.4 million for the current fiscal year and $124.9 million ongoing into theCalifornia State Preschool Program(CSPP). Though this year’s budget eliminates the work requirements that previously prevented all families from receiving full-day care, children in families who work full-time are prioritized for enrollment. Eligibility was extended for all children living in a school attendance zone where more than 80 percent of children qualify for free and reduced priced lunch. AlthoughCSPPis the largest state-funded pre-K program in the nation, at $932 million, the program earned six out of ten benchmarks for quality in the National Institute for Early Education Research’s 2018 State of Preschool Yearbook, demonstrating a need to improve quality alongside the mission for universal access.
Acknowledging the importance of elevating quality, the budget invests $460 million forfacilityandworkforceimprovements. Of that one-time fund, $245 million along with an additional $18 million transfer from the Child Care Facilities Revolving Loan Fund, will be leveraged over four years. The vast majority of this Early Learning and Infant Care Infrastructure Program will provide grants to child care and pre-K providers to expand facility capacity. Only five percent may be used for renovations and remediation of health and safety concerns.
The remaining quality investments will go to workforce development and data alignment. Over four years, the Early Learning and Care Workforce Development Program will allocate $195 million in grants for professional development and continuing education. The state’s new $20 million Early Learning and Care Data System will integrate statewide provider and recipient information and align seamlessly with the K-12 longitudinaldata system.
A portion of the aforementioned $103.4 billion K-12 funding will serve young children, though elementary schools were not explicitly apportioned in the budget. One early childhood investment that was highlighted was a $300 million one time fund to construct or retrofit facilities to providefull-day kindergartenprograms. Those funds are restricted to districts converting from part-day to full-day kindergarten classes, and are substantially increased from the $100 million investment in the Kindergarten Facilities Expansion Program in2018-2019.
Combating childhood and intergenerationalpovertyare unequivocally critical. The budget expands theEarned Income Tax Creditto provide 3 million working families an additional $1,000 annually for food, rent, and child care. Another $331.5 million of this year’s budget and $441.8 million ongoing will increase the amount of financial support given by Maximum Aid Payments to CalWORKS participants from 38 percent currently up to 52.8 percent of theFederal Poverty Level, depending on local costs. Local child support agencies will receive $19.1 million to increase administrative capacity, which is expected to result in collection of hundreds of millions of dollars from the increase. Students at state colleges with dependent children may take advantage of the $96.7 million put towards CAL Grant Access Awards to earn a $4,000 to $6,000 stipend. Finally, children born in low income families will now have access to $50 million in one-time funding allocated toChild Savings Accounts.
Home visiting programs, in which a health or education professional provides individualized support for families of infants and young children, have been proven to bolsterchild development and school readiness, improvematernal health, and promotepositive parenting practices. California’s new budget expands eligibility for their home visiting programs beyond first-time parents and broadens the range of models to meet families’ unique needs. TheCalWORKs Home Visiting Initiativereceived $89.6 million for the current fiscal year, and $167 million ongoing funds from the state and Temporary Assistance for Needy Families (TANF) block grants. This funding is expected to serve 18,500 additional families. TheCalifornia Home Visiting Programand theBlack Infant Health Programreceived $34.8 million for the current fiscal year and $30.5 million ongoing state funding to support children at risk of trauma and support the health of African Americanmothers and infants.
California is one ofonly five states and D.C.to offer paid family leave. Beginning in July of 2020, families will be able to access eight weeks, rather than the current six weeks, of paid time off to bond with newborns or adopted children, care for an ill relative, or assist during a family member’s military deployment. Wages will be supplemented at 70 percent, with a cap at $1,252 per month. The Governor has expressed the goal of increasing wage supplementation to 90 percent and allowing families three to six months of paid family leave, depending on marital status.
While many of the programs in the budget will benefit young children and their families,criticssuggest that the budget may have not done enough. Though professional development is prioritized, early childhood teachers’ working conditions, adequate salaries, and benefits are not. California’sweak requirementsfor pre-K teachers wereignored, despite the evidence that increased credentials result in higher qualitypre-K learning environments. New questions have also been raised after Newsomvetoeda local tax increase intended to expand access to child care services for working families. The budget is the integral first step, and now thecapable teamNewsom has assembled can turn their attention to the arduouschallengesof sustainability and implementation.
The innumerable ways in which young children’s futures are being protected in California goes far beyond care and education. Their strong funding forenvironmental protections, clean water, and access to affordablehousingwill inevitably improve children’s well-being. With a state budget that heavily invests in families and a Governor committed to California’s children, the future looks sunny on the golden coast.
Related Topics
Other Early Childhood Programs
Birth Through Third Grade Learning
State Funded Pre-K
| https://www.newamerica.org/education-policy/edcentral/home-visits-universal-pre-k-and-trauma-informed-care-california-dreams-big-for-families/ |
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BCM-HGSC | Eric Boerwinkle, Ph.D. | page 6
Associate Director, Baylor College of Medicine Human Genome Sequencing Center Contact information [email protected] Other positions Dean, UTHealth School of Public Health M. David Low Chair in Public Health Kozmetsky Family Chair in Human Genetics Professor, Human Genetics Center and Dept. of Epidemiology Research interests The research interests of Dr. Boerwinkle encompass the
Eric Boerwinkle, Ph.D.
Associate Director, Baylor College of Medicine Human Genome Sequencing Center
Contact information
[email protected] (link sends e-mail)
Other positions
Dean, UTHealth School of Public HealthM. David Low Chair in Public HealthKozmetsky Family Chair in Human GeneticsProfessor, Human Genetics Center and Dept. of Epidemiology
Research interests
The research interests of Dr. Boerwinkle encompass the genetic analysis of the common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes.
Dr. Boerwinkle received his B.S. in Biology from the University of Cincinnati in 1980, an M.A. in Statistics (1984), and M.S. and Ph.D. in Human Genetics (1985) from the University of Michigan, Ann Arbor where he served as Senior Research Associate in the Department of Human Genetics from 1985-1986. He joined the University of Texas-Houston Center for Demographic/ Population Genetics in 1986 as a Research Assistant and became Assistant Professor in the same year. In 1991 he joined the Department of Human Genetics at the School of Public Health, University of Texas-Houston Health Science Center as Associate Professor, in 1996 was promoted to Professor, and in 1997, Director of the Human Genetics Center. He became a faculty member of the Institute of Molecular Medicine in 1996 and became Professor and Director of the Research Center for Human Genetics.
Dr. Boerwinkle is a member of the American Diabetes Association and the American Society of Human Genetics. The research interests of Dr. Boerwinkle encompass the genetic analysis of common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes. This work includes localizing genes which contribute to disease risk, identification of potentially functional mutations within these genes, testing these candidate functional mutations in experimental systems, defining the impact of gene variation on the epidemiology of disease, and determining the extent to which these genes interact with environmental factors to contribute to disease risk. Activities include both statistical analysis and laboratory work. A large part of Dr. Boerwinkle's current research effort consist of localizing genes contributing to disease risk using modern genome-wide mapping methods. Success depends on keeping up with the latest genomic technical advances. The laboratory is set-up and operating as a high through-put sequencing and genotyping facility in which speed, accuracy and efficiency are monitored continuously. However, we are constantly seeking out more efficient methods to collect and manage genetic information.
Dr. Boerwinkle and colleagues have completed the world's first genome-wide analyses for a variety of CAD risk factors, including diabetes and hypertension. These investigations have lead to the identification of novel susceptibility genes in both cases. Dr. Boerwinkle is particularly interested in methods for identifying potentially functional mutations within a gene region. This seemingly simple objective is made difficult because the functional mutations are expected to have small effects and are imbedded in a sea of silent genetic variation. Once nearly all of the variation is catalogued directly by DNA sequencing, individuals are genotyped for each variable site. Both novel and traditional statistical methods are applied to relate the array of genetic information to a wealth of phenotypic data. This algorithm generates "candidate functional mutations" that are then tested in an in vitro or mouse model system. Once a functional mutation has been identified, Dr. Boerwinkle's group evaluates the ability of the variable site to predict the onset of disease (e.g. myocardial infarction or stroke) above and beyond traditional risk factors. This work is carried out as part of multiple prospective studies of cardiovascular disease and its risk factors in tens of thousands of individuals representing the major American ethnic groups.
Finally, he is working on experimental designs for studying genotype by environment interaction in humans. In particular, we are working on the extent to which interindividual variation in lipid lowering and anti-hypertensive medications are influenced by genetic factors. The practical objective of the research is to use genetic information to identify individuals at increase risk of disease and to design more efficacious interventions. Genetic studies are defining, at the molecular level, novel mechanisms of disease risk, onset and progression. Dr. Boerwinkle and collaborators address the localization of genes which contribute to disease risk in cardiovascular diseases, hypertension and diabetes. The methodology used involves screening of families having the disease and linking the presence of disease with known markers of the human genome. In this manner, the genomic region in which relevant mutations are located can be mapped and the relevant DNA sequenced. By assessing the structural change the mutation may have caused in the gene product (protein), it is possible to infer how it may affect biological function. In order to determine experimentally whether a mutation is functional, it is necessary to introduce the mutated gene into an animal, usually a mouse, and assess its biological effects on the animal's phenotype.
Dr. Boerwinkle has participated in multiple notable discoveries since joining the Institute. Only two will be highlighted here. First, Dr. Boerwinkle's group has completed the first ever genome-wide search for genes contributing to inter-individual blood pressure levels. This initial effort has lead to the identification of an important gene (an adrenergic receptor) which influences blood pressure levels and the risk to hypertension. This is the first time that such a genome-wide approach has led to the identification of a susceptibility gene to a major cardiovascular disease risk factor. Second, Dr. Boerwinkle has participated in similar efforts to identify genes contributing to the risk of developing non-insulin dependent (type II) diabetes. In this case, however, there were no genes in the region that were suspects for the disease. A team of collaborating investigators have painstakingly characterized the genetic region and identified the mutated gene (in this case a protease). This is the first time that anyone has ever positionally cloned a gene contributing to any common chronic disease. This work is of obvious potential clinical importance. It may lead to improved prediction of those at increased risk of disease and the design of more efficacious intervention strategies. The technologies and information from the human genome project provide new tools for lessening the burden of ill-health. Dr. Boerwinkle's accomplishments in developing an internationally recognized team of investigators targeting the genetics of cardiovascular disease and its risk factors ensures a productive future and further discoveries.
Publications
2020
Longchamps RJ , Castellani CA , Yang SY , Newcomb CE , Sumpter JA , Lane J , et al. . Evaluation of mitochondrial DNA copy number estimation techniques. PLoS One. 2020;15(1):e0228166. PubMed DOI Google Scholar Tagged
2019
Chen N , Caruso C , Alonso A , Derebail VK , Kshirsagar AV , A Sharrett R , et al. . Association of sickle cell trait with measures of cognitive function and dementia in African Americans. eNeurologicalSci. 2019;16:100201. PubMed DOI Google Scholar Tagged
Kunkle BW , Grenier-Boley B , Sims R , Bis JC , Damotte V , Naj AC , et al. . Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019;51(9):1423-1424. PubMed DOI Google Scholar Tagged
Davies G , Lam M , Harris SE , Trampush JW , Luciano M , W Hill D , et al. . Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun. 2019;10(1):2068. PubMed DOI Google Scholar Tagged
Turcot V , Lu Y , Highland HM , Schurmann C , Justice AE , Fine RS , et al. . Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet. 2019;51(7):1191-1192. PubMed DOI Google Scholar Tagged
He KY , Li X , Kelly TN , Liang J , Cade BE , Assimes TL , et al. . Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data. Hum Genet. 2019;138(2):199-210. PubMed DOI Google Scholar Tagged
Yu B , Flexeder C , McGarrah RW , Wyss A , Morrison AC , North KE , et al. . Metabolomics Identifies Novel Blood Biomarkers of Pulmonary Function and COPD in the General Population. Metabolites. 2019;9(4). PubMed DOI Google Scholar Tagged
Kowalski MH , Qian H , Hou Z , Rosen JD , Tapia AL , Shan Y , et al. . Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations. PLoS Genet. 2019;15(12):e1008500. PubMed DOI Google Scholar Tagged
Noordam R , Bos MM , Wang H , Winkler TW , Bentley AR , Kilpeläinen TO , et al. . Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. Nat Commun. 2019;10(1):5121. PubMed DOI Google Scholar Tagged
Hansen AW , Murugan M , Li H , Khayat MM , Wang L , Rosenfeld J , et al. . A Genocentric Approach to Discovery of Mendelian Disorders. Am J Hum Genet. 2019;105(5):974-986. PubMed DOI Google Scholar Tagged
Liang J , Cade BE , He KY , Wang H , Lee J , Sofer T , et al. . Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level. Am J Hum Genet. 2019;105(5):1057-1068. PubMed DOI Google Scholar Tagged
Sarnowski C , Leong A , Raffield LM , Wu P , de Vries PS , DiCorpo D , et al. . Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. Am J Hum Genet. 2019;105(4):706-718. PubMed DOI Google Scholar Tagged
Yee SWah , Stecula A , Chien H-C , Zou L , Feofanova EV , van Borselen M , et al. . Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies. PLoS Genet. 2019;15(9):e1008208. PubMed DOI Google Scholar Tagged
Chiang T , Liu X , Wu T-J , Hu J , Sedlazeck FJ , White S , et al. . Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel. Genet Med. 2019;21(9):2135-2144. PubMed DOI Google Scholar Tagged
Agha G , Mendelson MM , Ward-Caviness CK , Joehanes R , Huan T , Gondalia R , et al. . Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. Circulation. 2019;140(8):645-657. PubMed DOI Google Scholar Tagged
Sung YJu , Fuentes Lde Las , Winkler TW , Chasman DI , Bentley AR , Kraja AT , et al. . A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure. Hum Mol Genet. 2019;28(15):2615-2633. PubMed DOI Google Scholar Tagged
Pehlivan D , Bayram Y , Gunes N , Akdemir ZCoban , Shukla A , Bierhals T , et al. . The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance. Am J Hum Genet. 2019;105(1):132-150. PubMed DOI Google Scholar Tagged
Wang Z , Zhu C , Nambi V , Morrison AC , Folsom AR , Ballantyne CM , et al. . Metabolomic Pattern Predicts Incident Coronary Heart Disease. Arterioscler Thromb Vasc Biol. 2019;39(7):1475-1482. PubMed DOI Google Scholar Tagged
Tin A , Yu B , Ma J , Masushita K , Daya N , Hoogeveen RC , et al. . Reproducibility and Variability of Protein Analytes Measured Using a Multiplexed Modified Aptamer Assay. J Appl Lab Med. 2019;4(1):30-39. PubMed DOI Google Scholar Tagged
Naj AC , Lin H , Vardarajan BN , White S , Lancour D , Ma Y , et al. . Quality control and integration of genotypes from two calling pipelines for whole genome sequence data in the Alzheimer's disease sequencing project. Genomics. 2019;111(4):808-818. PubMed DOI Google Scholar Tagged
| https://www.hgsc.bcm.edu/people/boerwinkle-e?f%5Bauthor%5D=4183&page=5 |
Disorders of the Peripheral Nervous System | Musculoskeletal Key
Chapter Outline Hereditary Motor and Sensory Neuropathies Congenital and Acquired Analgia Guillain-Barré Syndrome (Acute Polyradiculoneuritis) Sciatic and Peroneal Nerve Palsy Hereditary Motor and Sensory Neuropathies Hereditary motor and sensory neuropathies (HMSNs) are a group of genetically acquired progressive peripheral neuropathies ( Box 38-1 ). The most common of this group is Charcot-Marie-Tooth disease, described by…
Disorders of the Peripheral Nervous System
Chapter Outline
Hereditary Motor and Sensory Neuropathies
Congenital and Acquired Analgia
Guillain-Barré Syndrome (Acute Polyradiculoneuritis)
Sciatic and Peroneal Nerve Palsy
Hereditary Motor and Sensory Neuropathies
Hereditary motor and sensory neuropathies (HMSNs) are a group of genetically acquired progressive peripheral neuropathies (Box 38-1). The most common of this group is Charcot-Marie-Tooth disease, described by the team of Charcot and Marie, and independently by Tooth, in 1886. Dyck and Lambert classified the HMSNs in 1968 (Table 38-1).
Box 38-1
Dyck-Lambert Features of Hereditary Motor Sensory Neuropathies
1.
The predominant involvement is of peripheral motor neurons, with lesser involvement of peripheral sensory and peripheral autonomic neurons.
2.
The disorders are inherited.
3.
The disorders are slowly progressive.
4.
The neurologic signs are symmetric.
5.
The disorders are system degenerations in that several populations of neurons of similar structure and function are affected.
6.
The pathologic features are nonfocal, and nerve fiber degeneration consists of axonal atrophy and degeneration.
From Dyck PJ: Inherited neuronal degeneration and atrophy affecting peripheral motor, sensory, and autonomic neurons. In Dyck PJ, Thomas PK, Lambert EH, et al, editors: Peripheral neuropathy , vol 2, ed 2, Philadelphia, 1984, Saunders, p 1600.
Table 38-1
Classification of Hereditary Motor and Sensory Neuropathies *
Type Example HMSN I Charcot-Marie-Tooth disease (hypertrophic demyelinating type) HMSN II Charcot-Marie-Tooth disease (axonal type) HMSN III Dejerine-Sottas disease HMSN IV Refsum disease HMSN V Spastic paraplegia HMSN VI Similar to type I, with optic atrophy HMSN VII Similar to type I, with retinitis pigmentosa
*Hereditary peripheral neuropathies.
Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease (CMT) has classically been divided into demyelinating and axonal forms. Although types 1A, 1B, and 1C are characterized by demyelination and type 2 by axonal degeneration, studies have established intermediate forms such as type C and X-linked CMT, suggesting a continuum of disease encompassing demyelination and axonal degeneration. Studies have indicated that demyelination renders the axon susceptible to degeneration, which may explain the overlap between what were traditionally considered demyelinating and axonal forms.
Charcot-Marie-Tooth disease type 1 (CMT-1), also known as HSMN I and II, is the most common heritable chronic demyelinating neuropathy. The overall incidence of the various forms of CMT ranges from 1/2500 to 1/5000. The disease is characterized by progressive weakness and atrophy of distal musculature, depressed tendon reflexes, slowed motor nerve conduction velocity, and frequently a family history of the disorder. CMT-1 usually manifests in the second decade of life, but it may become evident earlier in some patients.
Charcot-Marie-Tooth disease type 2 comprises a group of peripheral neuropathies that are inherited as an autosomal dominant or recessive disorder. Although CMT-1 is generally described as a demyelinating process, CMT-2 is characterized by axonal degeneration. It is characterized by older age at onset (usually in the third decade) and normal to only slightly diminished nerve conduction velocities, but severely reduced compound motor action potentials. Deep tendon reflexes are preserved. The prevalence of CMT-2 is approximately one third that of CMT-1.
Although CMT-2 is clinically indistinguishable from CMT-1, it is pathologically and genetically distinct from CMT-1. One form of CMT-2 maps to chromosome 1p36, which encodes for MPZ (CMT-2A), another maps to chromosome 3p (CMT-2B), and another maps to chromosome 7p (CMT-2D) (Table 38-2). Unlike in CMT-1, there is no enlargement of the peripheral nerves, and sensory changes are infrequent. Nerve biopsy does not show hypertrophy; rather, axonal degeneration is seen. The orthopaedic manifestations of the disease are the same as those seen in CMT-1.
Table 38-2
Charcot-Marie-Tooth Disease Subtypes
Type Genes and Loci Features Inheritance
1A PMP22 (peripheral myelin protein); 17p11.2 duplication Most common form (70%); demyelinating Autosomal dominant
1B MPZ or P0 (myelin protein zero); chromosome 1 point deletion Less common (>10% of CMT1) Autosomal dominant
1C SIMPLE gene, 16p13.1-p12.3; early growth response 2 gene Demyelinating Autosomal dominant
2 2a, chromosome 1 2b, chromosome 3 2c, chromosome 7 2d, chromosome 7 2e, chromosome 8 LMNA gene—encodes for lamin A/C Axonal Autosomal dominant and recessive forms
C Chromosome 1p34-p35 Intermediate; axonal and demyelinating features Autosomal dominant
4 Chromosome 5; periaxin gene ( PRX ); SBF2; GDAP1 gene (8q21) Outfolding of myelin sheaths; can be associated with glaucoma; axonal or demyelinating; usually early onset Autosomal recessive
X Connexin32 (CX32) gene X chromosome Second most common form (7%-10%); abnormal gap junction communication; intermediate slowing of nerve conduction velocities; demyelinating and axonal features; boys more severely affected X-linked dominant
Genetics
An explosion in the number of CMT subtypes has occurred as a result of localization of their different genetic abnormalities (seeTable 38-2). There are many described subtypes, including CMT-1 (hypertrophic demyelinating form), CMT-2 (axonal form), and X-linked CMT neuropathy (CMTX). CMT-1 is inherited as an autosomal dominant trait. Genetic loci for CMT-1 have been mapped to chromosome 17 (CMT-1A), chromosome 1 (CMT-1B), and the SIMPLEgene (CMT-1C). CMT-1A is most often associated with a duplication in chromosome 17p11.2-12, an area that codes for the peripheral myelin protein 22 (PMP22), a glycoprotein expressed in the myelin sheath of Schwann cells.
Patients with duplications have three copies of a normal gene, a situation producing disease by what is termed a gene dosage effect—too much of a normal gene. CMT-1B is associated with point mutations in the myelin protein zero ( P0or MPZ) gene. P0 is the major structural membrane protein expressed in Schwann cells of peripheral nerves. CMTX is associated with mutations in the connexin32gene (more recently renamed the gap junction protein beta one gene, GJB1), which codes for connexin, a gap junction protein that enhances conduction across paranodes of the peripheral nerves. Although the specific genetic defects responsible for CMT have become known, there is little correlation between genotype and phenotype, as evidenced by the variability seen in the clinical features among affected family members. The Inherited Peripheral Neuropathies Mutation Database (IPNMDB) provides a comprehensive and updated database of all known mutations. Prenatal diagnosis using molecular genetic techniques is now available but has led to ethical debates regarding the use of prenatal genetic screening for nonlethal diseases.
Clinical Features
The age of onset varies in CMT, with some patients presenting before 5 years of age and others in adulthood. Physical examination in infants and young children with CMT proved by genetic analysis may be normal. Motor milestones are usually achieved at normal ages in those with most forms of CMT. Usually patients present in the second decade of life. Boys and girls are affected in equal numbers, although boys with CMTX are more significantly involved than girls, who may be asymptomatic.
Physical examination reveals diminished to absent deep tendon reflexes, with the ankle reflex disappearing before the knee reflex. Sensory loss occurs in two thirds of affected individuals but is rarely noticed by the patients themselves. There may be palpable enlargement of the peripheral nerves. Motor testing results vary among patients but usually include diminished strength in the anterior tibialis and peroneus brevis. Tibialis anterior weakness can be identified by the inability to stand on the heels. As the patient actively tries to dorsiflex the ankle, the metatarsophalangeal (MTP) joints of the toes extend, and the great toe may dorsiflex to augment the weak anterior tibialis. Some patients have weakness throughout all the distal calf musculature, and those with the most severe involvement have generalized muscle weakness and are unable to walk. Atrophy of the calves can be seen in severely involved individuals, giving a so-called stork’s leg appearance (Fig. 38-1). Foot deformity such as pes cavus, pes cavovarus, or claw toes is very common. Calluses along the lateral border of the foot, particularly over the base of the fifth metatarsal, may be present.
FIGURE 38-1
Father and daughter with Charcot-Marie-Tooth disease type 1. Atrophy of the calves is striking, particularly in the father.
Observation of the gait in patients with early CMT reveals a subtle drop foot in swing phase. As the dorsiflexors become weaker, a steppage gait develops, characterized by plantar flexion of the ankle, hyperflexion of the knee, and hyperflexion of the hip in swing phase. Often the hemipelvis also elevates during swing phase to allow clearance of the foot, and the leg may circumduct. Other characteristics of gait in patients with types I and II CMT include failure of plantar flexion and increased foot supination, hyperextension in stance, excessive external rotation of the hip, and decreased hip adduction in stance (typical of a broad-based gait).
Examination of the hand reveals intrinsic atrophy. The patient may have difficulty grasping a goniometer placed between the fingers.
A careful examination of the spine should be performed. Although CMT is the most common cause of pes cavus, a spinal cord lesion such as a tethered cord or lipomeningocele may manifest initially with pes cavus or cavovarus. The back should be examined for evidence of underlying spinal dysraphism, such as a hairy patch, dimpling, or hemangioma. Scoliosis may be seen in teenagers with CMT but is not seen in young children; therefore, any sign of abnormal curvature in a young child should be further evaluated with magnetic resonance imaging (MRI).
Central nervous system involvement such as sensorineural deafness has been described in a few patients with the X-linked dominant form of the disease. Regardless of the type and severity of CMT, the disorder has been shown to affect the quality of life in childhood negatively, with affected children exhibiting lower physical, psychological, and social well-being than the general pediatric population.
Diagnostic Evaluation
Up to 80% to 90% of all patients with CMT can now be diagnosed only a blood test for the known gene mutations. Patients who are suspected of having CMT should be referred to a neurologist for further diagnostic testing. Electromyography (EMG) and the measurement of nerve conduction velocities can support the diagnosis in questionable cases. In demyelinating forms of CMT, electrophysiologic testing reveals slowing of motor nerve conduction velocities in the upper and lower extremities because of the loss of myelin (Fig. 38-2). Conduction is slowed uniformly from side to side and between different motor nerves. In demyelinating forms of the disease, slowed nerve conduction velocities are present by 3 years of age, although symptoms may not be apparent. EMG may show fibrillation caused by denervation.
FIGURE 38-2
A, Normal median nerve conduction velocity (NCV) of 57 m/sec and amplitude of 12 mV. B, NCV from patient with Charcot-Marie-Tooth (CMT) disease type 1. Because of demyelination, the NCV is significantly diminished (26 m/sec), whereas the amplitude is 8.8 mV (within normal limits). C, NCV from patient with CMT-2. The velocity is 38 m/sec, which is low normal, but the amplitude has significantly diminished to 1.3 m/sec. This result supports an axonal, rather than demyelinating, process.
In occasional patients, the diagnosis remains in question after electrical studies and genetic testing, and a nerve biopsy should be performed for definitive diagnosis. The sural nerve is chosen as the site of biopsy. A 1.5-cm-long segment of nerve is removed in the interval between the posterolateral border of the Achilles tendon and lateral malleolus. The nerve lies together with the lesser saphenous vein, and the two structures should not be confused when the surgeon is obtaining the biopsy specimen. Histopathologic study of sural nerve biopsy specimens from patients with CMT-1 reveals large onion bulb formations resulting from cycles of demyelination and remyelination. The myelin appears folded or uncompacted on ultrastructural examination. There is less demyelination and fewer onion bulbs in CMTX than in classic CMT-1. Muscle biopsy in CMT-1 shows scattered atrophic fibers and neuropathic degeneration.
MRI and computed tomography (CT) of the spine show diffuse enlargement of the cauda equina, nerve roots, and ganglia. A difference in the location of fatty infiltration of muscles on MRI has been identified between CMT-1A and CMT-2A; patients with CMT-1A have selective fatty infiltration primarily in the anterior and lateral compartment (peroneal nerve innervated) musculature, whereas those with CMT-2A have involvement primarily of the superficial posterior compartment muscles.
Medical Treatment
Neuropathic pain is a significant problem for many people with CMT. In one study, 71% of patients who participated stated that they had neuropathic pain, most frequently in the lower back, knees, and feet. The pain may be severe enough to require treatment with medication.
There is no proven medical treatment for the various forms of CMT. Animal models have been developed, and progesterone antagonists and antioxidants, such as vitamin C, coenzyme Q, and lipoic acid, have been under investigation. With further delineation of the molecular genetic defects responsible for CMT, treatment with gene transfer may be feasible in the future.
Orthopaedic Manifestations and Surgical Treatment
Foot
Manifestations.
The most common orthopaedic manifestation of CMT is pes cavovarus. One study has found that patients with bilateral cavovarus feet have a 78% probability of being diagnosed with CMT; a family history of CMT increases the probability to 91%. Patients often present initially to the orthopaedic surgeon for evaluation of pes cavovarus, and the diagnostic workup leads to the diagnosis of CMT. Atrophy and contracture of the intrinsic musculature of the foot occur because of denervation, which leads to collagen replacement of the intrinsic muscles of the foot. There is an increase in the connective tissue within and around the muscle tissue. These pathologic changes produce elevation of the longitudinal arch because of contracture of the plantar fascia, which increases the pressure on the metatarsal heads and leads to painful calluses along the lateral border of the foot and beneath the metatarsal heads (Fig. 38-3). Varus of the hindfoot is caused initially by the plantar flexion of the first ray and forefoot equinus. In addition, the posterior tibialis and peroneus longus remain strong relative to the weak peroneus brevis and anterior tibialis, leading to depression of the first ray and increased varus. It is believed that the peroneus longus remains relatively stronger than the peroneus brevis because it is normally approximately twice as strong as the brevis. Toe deformity results from nonfunctional intrinsic muscles, which normally flex the MTP joints and extend the distal and proximal interphalangeal (IP) joints of the foot. With absent intrinsic function, the long toe flexors create flexion deformities of the IP joints of the toes, and the toes eventually hyperextend through the MTP joints, assuming a dorsally displaced position with metatarsal head prominence on the plantar aspect of the foot.
FIGURE 38-3
Pes cavovarus in a 12-year-old girl with Charcot-Marie-Tooth disease. A, The longitudinal arch of the foot is elevated, and there is clawing of the great toe (hyperextension of the metatarsophalangeal joint and flexion of the interphalangeal joint). B, Hindfoot varus of the right foot is apparent. C, A callus is present over the base of the fifth metatarsal. D, Clawing of the lesser toes is present bilaterally. E, Pressure is abnormally distributed, with excess loading along the lateral border of the foot, on the first metatarsal head, and on the tips of the claw toes.
Standing lateral radiographs of the cavus foot in patients with CMT show an increase in the Meary angle, measured along the longitudinal axis of the talus and first metatarsal. Normal values for the Meary angle range from 0 to 5 degrees, but values average 18 degrees in patients with CMT. Varus is seen as parallelism of the talus and calcaneus on the lateral radiograph. Finally, the lack of hindfoot equinus can be documented by measurement of the calcaneal pitch, which usually reveals dorsiflexion of the calcaneus and the presence of forefoot equinus with the apex of the deformity in the midfoot (Fig. 38-4).
FIGURE 38-4
Standing lateral radiograph of the foot of a 14-year-old girl with Charcot-Marie-Tooth disease and cavovarus deformity. The Meary angle is increased (20 degrees) and there is parallelism of the talus and calcaneus, demonstrated by the ability to “see through” the subtalar joint. The calcaneus is dorsiflexed relative to the tibia.
Azmaipairashvili and colleagues have described the Coleman block lateral radiograph, a mediolateral weight-bearing view for evaluating the flexibility of the hindfoot, rotational correction in the ankle, and degree of correction of forefoot supination. To obtain this view, the patient stands on a 2-inch block of radiolucent material, allowing the first, second, and third rays to drop down on the edge of the block, as in the Coleman block test. The x-ray plate is placed on the lateral side of the foot and the beam is directed from medial to lateral. The authors suggested that this radiographic view may help delineate the need for a midfoot osteotomy versus soft tissue surgery alone to correct a cavovarus foot deformity.
MRI studies have found that the appearance of fatty infiltration differs according to the severity of CMT-1A, ranging from fatty infiltration of only the intrinsic foot muscles to fatty infiltration of the lateral, anterior, and superficial posterior leg muscles; these MRI features correlated with the severity of symptoms.
Treatment.
The treatment of pes cavovarus foot is described in greater detail inChapter 23. The Coleman block test, performed by having the patient stand on a block with the head of the first metatarsal hanging medially off the block, is useful when planning surgical correction of the foot deformity. When hindfoot varus is caused by plantar flexion of the first metatarsal, the heel will evert to neutral as the first metatarsal head drops off the block and is allowed to plantar flex (Fig. 38-5). With time, the varus deformity becomes fixed and does not correct when the block test is performed.
FIGURE 38-5
Coleman block test. The heel of the foot and lateral border are placed on a wooden block, allowing the head of the first metatarsal to drop into plantar flexion. If the hindfoot varus is secondary to the tripod effect of the plantar flexed first ray, the hindfoot will correct to neutral or valgus alignment ( middle ). If the hindfoot varus is rigid, it will not correct ( right ).
The surgical correction of the cavovarus foot in patients with CMT can be divided into two components—deformity correction and rebalancing of deforming muscle forces (Fig. 38-6). When done early in the disease in young patients, soft tissue surgery consisting of plantar fascia release or extensive plantar release, including capsulotomies with tendon transfer, may be sufficient to postpone or avoid triple arthrodesis.*
FIGURE 38-6
Algorithm for treatment of cavus foot deformity in the pediatric patient with Charcot-Marie-Tooth disease. EDL, Extensor digitorum longus; PFR, plantar fascia release.
(Redrawn from Olney B: Treatment of the cavus foot: deformity in the pediatric patient with Charcot-Marie-Tooth, Foot Ankle Clin 5:314, 2000.)
* References .
Dynamic pedobarography has shown that operative treatment, even when the foot deformity is corrected, may not correct abnormal foot pressure patterns, especially increased heel pressure, which was correlated with a decrease in ankle power generation. These residual abnormal pressure patterns may cause persistence of symptoms, and the patient and parent(s) should be informed of this before surgery.
Tendon transfers used in CMT include transfer of the posterior tibialis tendon to the dorsum of the foot and transfer of the peroneus longus to the peroneus brevis to decrease the plantar flexion of the first ray. The anterior tibialis tendon is not transferred because it is usually weak in this disease. Proximal metatarsal osteotomy of the first metatarsal alone or of multiple metatarsals corrects plantar flexion of the forefoot in patients who have flexible varus hindfeet. Care must be taken when performing a proximal first metatarsal osteotomy in a young patient because the open physis is located proximally.
Transfer of the posterior tibialis tendon through the interosseous membrane to the dorsum of the foot may be performed to decrease hindfoot varus and provide ankle dorsiflexion. Weakness of the tibialis anterior leads to a steppage gait and foot drop during swing phase in patients with CMT. Although the posterior tibialis is considered a stance phase muscle, transfer of the posterior tibialis has been performed in this patient population with some success (seePlate 39-1).
When fixed cavovarus deformities are present, bony surgery, such as calcaneal osteotomy, midfoot dorsal closing wedge, or dome osteotomy, is recommended (Figs. 38-7and38-8). Although triple arthrodesis has been discouraged in patients with CMT, it may be preferable to midfoot osteotomy, which can lead to arthrosis because of the need to cross multiple joints with the osteotomy. In severe deformity, a triple arthrodesis may be necessary to restore a plantigrade foot (Fig. 38-9). Careful planning of wedges to be resected during the triple arthrodesis is necessary to correct the complex hindfoot and midfoot deformities because the lack of normal protective sensation may lead to poor results over time if residual deformity persists.
FIGURE 38-7
A to C, Bilateral residual pes cavovarus in a 15-year-old boy with Charcot-Marie-Tooth disease after transfer of the posterior tibialis to the dorsum of the foot, plantar fascia release, and first metatarsal osteotomy. A, Bilateral hindfoot varus is present. B, The longitudinal arch remains elevated, and there is clawing of the second through fifth toes. C, A callus is present on the lateral aspect of the plantar surface of the left foot because of excessive pressure. D to G, Clinical appearance of the foot at 18 years of age, after calcaneal osteotomies and Jones transfers. D, Varus has been improved but is not obliterated. E, The longitudinal arch is restored to normal. F, The toes lie in neutral alignment after Jones transfers and proximal interphalangeal joint fusions. G, Distribution of weight across the sole of the foot has improved.
FIGURE 38-8
A and B, Radiographs of an 11-year-old child with cavovarus feet secondary to Charcot-Marie-Tooth disease. The hindfoot varus was inflexible. C and D, Postoperative radiographic appearance. Surgery consisted of a calcaneal osteotomy, first metatarsal osteotomy, plantar fascia release, and peroneus longus to peroneus brevis transfer.
FIGURE 38-9
A to C, Standing radiographs of a 13-year-old boy with Charcot-Marie-Tooth disease. Severe cavovarus is present bilaterally. D to F, Photographs reveal clawing of the toes, excessive lateral plantar pressure, and elevation of the arch of the foot. G and H, Triple arthrodesis was performed.
Despite frequent residual deformity and poor objective results, patient satisfaction with triple arthrodesis has been reported to be high (85% to 95%) at intermediate and long-term follow-up. Long-term follow-up studies have found deteriorating results, likely because of progressive weakness and degenerative changes in a neighboring joint, especially the ankle joint.
Cavus feet in CMT are difficult to treat because the progressive neuropathy leads to a significant rate of recurrence of deformity after all forms of surgery. A long-term follow-up study (26 years) of 25 adults who were treated for flexible cavovarus deformities with first metatarsal osteotomy and selected muscle transfers has reported that degenerative changes and reoperations were less frequent than after triple arthrodesis, even though almost all patients had recurrence of some hindfoot varus.
Patients with CMT often walk on their toes, and it is tempting to perform an Achilles tendon lengthening procedure in these patients. It is important to note that the forefoot is in equinus in CMT and the calcaneus usually is not, as evidenced by lack of calcaneal plantar flexion or normal calcaneal pitch on standing lateral radiographs of the foot. Therefore, lengthening of the Achilles tendon is not advised. In addition, when a plantar release is performed, a cast is used to maintain dorsiflexion of the forefoot. Manipulating the foot into dorsiflexion in the presence of a surgically lengthened Achilles tendon usually leads to overlengthening of the Achilles tendon and loss of correction of the forefoot equinus.
Weakness in the ankle dorsiflexors also leads to the development of claw toes because the intrinsic muscles are paralyzed and contracted and the toe extensors are recruited to help dorsiflex the ankle. When the condition is symptomatic, a Jones transfer of the extensor tendons of the great and lesser toes can help relieve pain on the dorsum of the toes. The long toe extensors are inserted through bone into the necks of the metatarsals so that they help dorsiflex the ankle rather than clawing the toes. Fusion of the IP joint of the great toe and of the proximal IP joints of the lesser toes helps prevent flexion deformity of the toes and should be done concomitantly with extensor tendon transfer.
Hip
A second orthopaedic problem seen in patients with CMT is hip dysplasia (Fig. 38-10). It has been proposed that subtle weakness in the proximal musculature leads to progressive dysplasia of the hip. Although there are rare cases of hip instability in newborns with CMT, subluxation and acetabular dysplasia are usually asymptomatic until adolescence, when pain and gait abnormalities may occur. Early recognition and appropriate treatment are essential to avoid serious morbidity associated with the condition.
FIGURE 38-10
Radiographic appearance in a 17-year-old girl with Charcot-Marie-Tooth disease and symptomatic left hip dysplasia. A, Preoperative radiograph. B, Postoperative radiograph obtained after a Steel osteotomy and varus derotation osteotomy. C, At 6-month follow-up, the patient was asymptomatic.
Surgical treatment, consisting of varus osteotomy of the femur or an acetabular redirectional osteotomy such as the Steel osteotomy or Bernese periacetabular osteotomy, has been useful in these patients in our practice. The treatment of teenagers with CMT requires correction of the acetabular and femoral components of the dysplasia and is similar to the treatment of adolescent idiopathic hip dysplasia outlined inChapter 16(Fig. 38-11). However, the treatment of the acetabular dysplasia in the CMT population may be associated with a higher rate of major and minor complications.
FIGURE 38-11
A, Anteroposterior radiograph of the pelvis in a 14-year-old boy with Charcot-Marie-Tooth disease type 1A. Left hip dysplasia is evidenced by the break in the Shenton line and a decreased center edge angle. B , The false-profile view shows anterior deficiency. C , A Ganz periacetabular osteotomy was performed.
Spine
Scoliosis is seen in up to 37% of adolescents with CMT. Curves may resemble idiopathic curves in location but usually have increased thoracic kyphosis, unlike idiopathic scoliosis, which is typically lordotic (Fig. 38-12). There is also an increased incidence of left-sided thoracic curves in patients with CMT. Patients at highest risk for scoliosis are girls and those with CMT-1.
FIGURE 38-12
Scoliosis in a 14-year-old with Charcot-Marie-Tooth disease. A, Anteroposterior view. B, Lateral view demonstrates increased thoracic kyphosis.
Orthotic management rarely is successful, and the prescription of a spinal orthosis should be considered in view of the patient’s other orthotic needs and ambulatory abilities. Posterior spinal fusion surgery may be needed if orthotic management fails and the curves are progressive. Spinal cord monitoring of somatosensory evoked potentials is usually impossible because of the peripheral neuropathy, so an intraoperative wake-up test may be necessary in patients with sufficient lower extremity strength. Surgical fusion does not appear to be associated with a high rate of complications in patients with CMT, but a long instrumented posterior fusion usually is necessary. A subset of patients with CMT may have thoracic hyperkyphosis without scoliosis.
Hand
Manifestations.
Hand involvement also occurs in patients with CMT, but intrinsic muscle atrophy and weakness usually become symptomatic later in the course of the disease. The onset of hand symptoms can occur in the first decade or as late as 30 years of age. The appearance of hand involvement may lag behind the appearance of lower extremity symptoms by 8 years. One study, however, has found that hand involvement is present in all children with CMT-1A, even in its earliest stages. A delay in the recognition of hand problems may delay rehabilitation, which becomes more difficult with age because of worsening of day to day problems, such as poor handwriting, weakness, pain, and sensory symptoms. Approximately 75% of children have only mild hand involvement, 20% have hand problems severe enough to require daily rehabilitation, and approximately 5% have problems so severe that independence in activities of daily living (ADLs) is compromised. Patients with significant upper extremity weakness are at risk for weakness of the respiratory muscles as well.
Intrinsic weakness with clawing of the ring and small digits occurs first. Intrinsic paralysis of muscles innervated by ulnar and median nerves is common, whereas muscles innervated by the radial nerve are usually spared. Weakness of the forearm musculature innervated by median and ulnar nerves also occurs.
Treatment.
Reports of treatment to augment upper limb function in patients with CMT have not been widely published. Although nerve conduction velocities are typically slowed, this appears to be a problem intrinsic to the nerve and is not caused by a compressive neuropathy. Thenar muscle wasting and increased median motor and sensory nerve latencies in this diagnosis are not indicative of carpal tunnel syndrome. A carpal tunnel release, therefore, may not relieve symptoms.
The specific functional problems related to the intrinsic weakness of the hands include loss of opposition of the thumb, loss of side to side pinch, and clawing of the fingers (Fig. 38-13). Surgical procedures to augment function are available to take advantage of donor tendons that are unlikely to deteriorate with time or to use bony procedures to correct the deformity. Electrodiagnostic evaluation of potential donor muscles for tendon transfers can help select the best muscle. Opponensplasty using the extensor carpi ulnaris or extensor indicis proprius can greatly increase prehension. Transfers to augment side pinch use the radially innervated extensor pollicis brevis, abductor pollicis longus, or the extensor indicis proprius routed to the first dorsal interosseous or adductor pollicis. Transfers that do not require pulleys are preferred and where a pulley is necessary, it should be static and not another tendon or tendon loop because of the potential for deterioration.
FIGURE 38-13
A, Intrinsic atrophy in a child with Charcot-Marie-Tooth disease. B, There is clawing of the long and ring fingers and wasting of the thenar and hypothenar musculature. C, Functional problems include loss of thumb opposition and pinch.
Arthrodesis of the thumb metacarpophalangeal (MCP) joint or carpometacarpal joint can predictably stabilize one of the unstable motion segments. Intrinsic transfer procedures build in flexion at the MCP joint to help balance the extrinsic metacarpal extensors. Flexor digitorum superficialis looped around the A1 pulley, as described by Zancolli, or metacarpal capsulodesis, restores a more useful posture to the hand.
Performing an upper extremity tendon transfer procedure in a young patient should be considered cautiously. Because hand deformities are likely to progress and because aftercare for the tendon transfers requires protection from excessive abuse, it may be best to wait until the patient reaches an age at which he or she understands the limitations of what can be done and what is expected of him or her afterward.
Hypertrophic Interstitial Neuritis (Dejerine-Sottas Disease)
Dejerine-Sottas disease, also known as HMSN III, is a severe, infantile-onset, demyelinating polyneuropathy. Dejerine and Sottas described this chronic familial polyneuropathy in 1893. It belongs in the family of HMSNs and is related to but more severe than CMT disease.
Dejerine-Sottas disease was traditionally thought to be inherited in an autosomal recessive pattern, but molecular genetic research has shown autosomal dominant inheritance in many patients. Mutations in the genes coding for MPZ on chromosome 1, PMP22on chromosome 17, and periaxinon chromosome 19, as well as in early growth response 2 genes, have been demonstrated in patients with this disease and in patients with CMT. †
† References .
Whereas CMT-1A is caused by a duplication of the
PMP22
gene, Dejerine-Sottas disease can be caused by a point mutation of the same gene.
Pathology
Peripheral nerves are enlarged as a result of the proliferation of perineural and endoneural connective tissue. Classic onion bulb formation is seen on cross section of nerve biopsy specimens because of demyelination and remyelination of the surviving axons, with Schwann cell proliferation. There is a lower density of myelinated fibers. Muscle biopsy reveals atrophy.
Clinical Features
Although the disease can present in the newborn period as respiratory failure, the usual presenting complaint is poor gait in a child younger than 3 years. A history of delayed walking is present. The child is ataxic and unsteady, falls frequently, has difficulty climbing stairs, and cannot run. Sensory disturbances such as paresthesias may occur.
Physical examination reveals weak floppy feet. Deep tendon reflexes are absent or markedly reduced. Sensory loss involves all modalities of sensation and occurs in a stocking-glove pattern. Proprioception is disturbed, and Romberg’s sign is positive. Nystagmus and slurred speech occur in some patients.
The gait is similar to a steppage gait. Muscle weakness is seen distally, and pes cavus occurs at an early age. Paralysis of the intrinsic muscles of the hand appears later. Flexion contractures of the wrist and fingers occur in late childhood. Scoliosis develops in early adolescence.
Diagnosis
The diagnosis is usually made by genetic testing for known mutations. Results of electrodiagnostic studies are notably abnormal because the nerve conduction velocity is markedly prolonged, even more so than in CMT. EMG shows fibrillation in the stimulated muscle caused by denervation.
Cerebrospinal fluid (CSF) shows an elevation in total protein. Blood cell counts are within normal ranges. Laboratory measurements of serum aldolase and creatine phosphokinase levels are normal.
MRI of the spine is performed to rule out an intraspinal tumor. Enlargement of the spinal nerves, cauda equina, and sciatic nerve can be seen in older patients with Dejerine-Sottas disease.
Nerve biopsy and muscle biopsy may be needed to confirm the diagnosis.
Prognosis and Treatment
The disease progresses slowly. In mild cases the neuropathy may plateau and life expectancy may be normal. Many but not all of the patients lose the ability to walk in early adulthood. Death in childhood has been described in severe cases.
There is no specific treatment. Corticosteroids are reported to improve the condition and may be tried in severe cases or during acute exacerbations. Orthopaedic management usually consists of prescribing orthoses to improve gait. Pes cavus may require surgical reconstruction. Carpal tunnel syndrome has been reported in this patient population. Scoliosis may progress and require orthotic management or surgery. Spinal cord and cauda equina compression have been reported in patients with Dejerine-Sottas disease as a result of hypertrophy of the nerve roots.
Refsum Disease
Refsum disease (HMSN IV), also known as heredopathia atactica polyneuritiformis, is a rare disorder of lipid metabolism characterized by peripheral neuropathy, retinitis pigmentosa, cerebellar ataxia, and increased protein in the CSF. Other clinical findings may include cataracts and cardiac arrhythmias. The condition is one of the inherited peroxisomal disorders and is caused by a defect in phytanoyl–coenzyme A (CoA) hydroxylase, the enzyme responsible for the degradation of phytanic acid, a dietary branched-chain fatty acid. This results in an accumulation of phytanic acid in the blood and tissues. The abnormal fatty acids are incorporated into cell membranes and lead to axonal degeneration and demyelination. As is the case with the vast majority of enzyme deficiencies, the disease is inherited in an autosomal recessive pattern. The gene responsible for Refsum disease has been mapped to chromosome 10, and infantile Refsum disease has been linked to the peroxin PEXgene.
There are two clinical presentations of the disease. In the infantile form, hypotonia and developmental delay are first noted. Growth retardation, mental retardation, hepatosplenomegaly, and retinitis pigmentosa then develop. Abnormalities in peroxisomal function are present in the infantile type. Peroxisomes are organelles involved in the metabolism of lipids critical to the functioning of the nervous system.
In the classic form of Refsum disease, symptoms develop between 4 and 7 years of age. The gait becomes unsteady, and the limbs weaken as the distal musculature atrophies. Deep tendon reflexes are absent, and there is no spasticity. The Babinski reflex is absent, but the Romberg sign may be present. Vibration and position sense in the legs may be disturbed. Ophthalmologic changes may be present, and deafness is seen in some patients. Hepatosplenomegaly occurs because of the fatty accumulation.
The skeletal changes in Refsum disease include osteopenia, mild epiphyseal dysplasia (especially in the knees and elbows), and shortening and deformity of the tubular bones in the hands and feet. Pes cavus may result from the peripheral neuropathy.
The diagnosis is made by documenting increased serum phytanic acid levels. Carriers can be detected by a phytol loading test. Nerve biopsy shows onion bulb formation and fatty deposits. Motor nerve conduction velocities are slow. CSF protein levels are increased.
Conditions from which Refsum disease must be distinguished include Friedreich ataxia, the other rare inherited ataxias, and peroneal muscular atrophy. Retinitis pigmentosa is seen only in Refsum disease.
Treatment of both forms of Refsum disease is first dietary, with avoidance of foods that contain phytanic acid. Low phytanic acid intake is achieved by restricting fat while allowing free amounts of fruit and green vegetables. Medical treatment by plasmapheresis can lower the phytanic acid levels, especially during acute attacks. Cascade filtration, a procedure resembling plasmapheresis, similarly lowers the serum phytanic acid level while avoiding loss of albumin and decreasing the loss of immunoglobulins. The main indication for plasma exchange is a severe deterioration in the patient’s clinical condition. A lesser indication is failure of dietary management to reduce the plasma phytanic acid level. Lowering the serum phytanic acid level can improve clinical symptoms of ataxia and weakness.
Congenital and Acquired Analgia
In children, indifference to pain, termed analgia,may be congenital or acquired. Congenital analgia may be one of the following types:
1.
Congenital insensitivity to pain
2.
Familial dysautonomia, also known as Riley-Day syndrome
3.
Congenital sensory neuropathy
4.
Hereditary sensory radicular neuropathy
5.
Congenital insensitivity to pain with anhidrosis
Acquired indifference to pain may be caused by syringomyelia, spinal cord tumor, or diabetes mellitus. The differential diagnosis of absent pain perception in a child is presented in
Table 38-3
.
Table 38-3
Differential Diagnosis of Congenital and Acquired Analgia Syndromes
Parameter Congenital Insensitivity Familial Dysautonomia Congenital Sensory Neuropathy Hereditary Sensory Radicular Neuropathy Familial Sensory Neuropathy With Anhidrosis Acquired Sensory Neuropathy (Toxic, Infectious) Syringomyelia
Heredity None Recessive None, occasionally dominant Dominant Recessive None None
Age at onset Birth Birth Birth Early adolescence Birth Adult Young adult
Physiologic pain reactions Present Absent Absent Absent Absent Absent Absent
Touch perception Normal Normal Lost Lost Normal Normal Normal
Temperature perception Normal Diminished Lost Lost Diminished Normal Normal
Distribution of sensory loss Universal Incomplete Islands of normal sensation Legs and feet, occasionally hands Islands of normal sensation Legs and feet, occasionally hands Arms and hands
Axon reflex Normal Absent Absent Absent Absent Absent Normal
Nerve conduction Normal Normal Sensory absent, motor present Sensory absent, motor present Sensory absent, motor present Motor and sensory abnormal Normal or slightly reduced
Motor strength Normal Normal Normal Normal Normal Weak (atrophied) Weak (atrophied)
Sensory nerve biopsy Normal Absence of fungiform papillae on tongue No myelinated fibers No myelinated fibers Myelinated fibers present Loss of myelinated fibers Normal
Skin biopsy Normal Normal No nerve endings; no cholinesterase — Normal Degeneration of nerve Normal cholinesterase Normal
Brain and other Normal Normal Autonomic nervous system—lack of lacrimation; excessive perspiration; poor temperature control Normal Normal Normal; absence of Lissauer tract and small dorsal root axon Normal Normal
Intelligence Normal Dull to average Dull to average Normal Defective Normal Normal
Adapted from Winkelmann RK, Lambert EH, Hayles AB: Congenital absence of pain: report of a case and experimental studies, Arch Dermatol 85:334, 1965.
Physical examination should assess the different sensory modalities. The physician should assess for temperature sensation with cold and warm items, for light touch sensation, and for deep pain sensation. Deep pain may be tested by applying firm pressure to the bones or muscles and by assessing the response to insertion of needles. It may be difficult to assess small children accurately but if pain is felt, the pulse rate, respiratory rate, and blood pressure will rise, and the pupils will dilate. It is important to try to determine whether a painful stimulus is not felt at all or whether the stimulus is felt but not perceived as painful.
Radiographic evaluation is rarely diagnostic, but MRI of the brain and spinal cord should be done to assess for pathologic processes such as syringomyelia or tumor.
Finally, nerve conduction studies of the motor and sensory nerves should be performed. Often a nerve and muscle biopsy is necessary to confirm the diagnosis. Skin biopsy may be helpful in cases with anhidrosis and to assess for dermal innervation.
Congenital Insensitivity to Pain
This rare disorder is characterized by the absence of subjective and objective responses to noxious stimuli in patients with intact central and peripheral nervous systems. Temperature and touch sensation are preserved. The onset of disease is at or shortly after birth. The cause is unknown. The cutaneous nerve endings in the skin and periosteum are normal in congenital insensitivity to pain. Nerve biopsies in childhood are normal, although it is suspected that the condition may be caused by a sensory neuropathy and that pathologic changes may be seen in adulthood. Substance P, a nociceptive cytokine protein, is absent in the synovial fluid in individuals with congenital insensitivity to pain. One case report has associated congenital indifference to pain with terminal deletion of the long arm of chromosome 10. The disease may be inherited in an autosomal recessive pattern but is usually sporadic.
As soon as the teeth erupt, the condition becomes evident from the child’s biting her or his tongue, lips, and fingers. Burns and bruises do not elicit crying. Corneal damage can be caused by trauma and foreign bodies in the eye. Intelligence is normal.
The orthopaedic manifestations of the disease vary among patients. Traumatic fractures are common and, because of the lack of pain, may go unrecognized for prolonged periods, resulting in malunions or pseudarthroses (Fig. 38-14). Multiple neglected fractures in patients with burns and bruises may lead to confusion of this condition with child abuse. Epiphyseal separations may occur in infancy and may resemble rickets radiographically. Avascular necrosis of the talus, femoral head, or femoral condyles may occur. Recurrent dislocation of the hip that is refractory to cast management has also been described in patients with congenital insensitivity to pain.
FIGURE 38-14
A, Radiographs of a right forearm showing nonunion of fracture in the middle third of the ulna in a 4-year-old with congenital insensitivity to pain. After immobilization in an above-elbow cast for 3 months, there was no evidence of healing. Thus, an open reduction, intramedullary fixation with a Steinmann pin, and onlay bone grafting were performed. B and C, Radiographs of the forearm obtained 3 months after surgery. D and E, Radiographs obtained 1 year later, showing progressive healing of the fracture.
Repetitive trauma to the joints can lead to effusion, hemarthrosis, synovial hypertrophy, and ligamentous laxity. A Charcot joint may be the end result, particularly in weight-bearing joints such as the ankle and knee (Fig. 38-15). Increasing laxity can lead over time to dislocation of the involved joint. Surgical treatment is rarely successful, and conservative treatment with protective orthoses is advised (Fig. 38-16). Septic arthritis is also seen with increased frequency in these patients. Some patients with congenital insensitivity to pain have required amputation for treatment of their Charcot or septic joints. It is important to anticipate and prevent neuropathic joints in these children. Patient and parent education in joint protection and surveillance for injury is the most important component of the treatment plan for these children.
FIGURE 38-15
A, Charcot knees in an 8-year-old boy with congenital insensitivity to pain. Anteroposterior ( B ) and lateral ( C ) radiographs obtained at age 16 years show destruction of joint with multiple loose bodies. D, Charcot changes at the ankle are also present at age 16 years. E, Clinical appearance of the lower extremities. F, Self-inflicted ulcerations of the tongue.
FIGURE 38-16
A and B, Clinical appearance of a 15-year-old boy with congenital insensitivity to pain, bilateral Charcot knees, and insensate wounds on his feet. C, Treatment consisted of a knee-ankle-foot orthosis to protect the knees.
Spinal manifestations of congenital insensitivity to pain include instability caused by the development of Charcot-like changes from neuropathic arthropathy of the spine and scoliosis. Radiographs initially show disk space narrowing, facet arthropathy, and hypertrophic spurs. With time, osteopenia, fragmentation, large osteophytes, and subluxation can be seen. Flexion-extension lateral radiographs can demonstrate instability. Patients may present with neurologic deficits, and surgical fusion (posterior or combined anteroposterior) has been successfully performed in small numbers of patients with congenital insensitivity to pain (Fig. 38-17).
FIGURE 38-17
A, Posteroanterior spine radiograph of an 8-year-old boy with congenital insensitivity to pain. B and C, The patient underwent anteroposterior spinal fusion for treatment of scoliosis. D, At 14 years of age, an amputation of his left great toe was performed because of chronic ulceration and osteomyelitis.
Osteomyelitis is seen more frequently than in the general population, probably as a result of neglected foci of infection, such as dental abscesses and bitten fingers. The most frequent sites are the fingers and toes. Osteomyelitis is usually indolent and chronic rather than acute in presentation. Aspiration for cultures should be undertaken whenever infection is suspected. Wide surgical débridement is usually necessary.
Familial Dysautonomia (Riley-Day Syndrome; Hereditary Sensory and Autonomic Neuropathy Type III)
This disturbance in pain perception is the result of an autosomal recessive trait and is the most common of the hereditary sensory and autonomic neuropathies. It is usually seen in patients of Ashkenazi Jewish descent; the carrier frequency in this population is 1 in 30. The genetic locus has been mapped to chromosome 9q31. It is believed that incomplete maturation of unmyelinated neurons in the sensory, sympathetic, and parasympathetic systems may be responsible for the disease. Infants present with lack of tears (alacrima), excessive perspiration, labile blood pressure, abnormal gastrointestinal motility, and poor temperature control. A characteristic lack of fungiform papillae on the tongue is seen. Speech development is frequently delayed, and the patients usually are of subnormal intelligence. Walking is delayed, and gait is ataxic because of lack of normal proprioception.
Neurologically, patients with familial dysautonomia have diminished temperature and vibration sensation but preserved touch perception. They have a lack of objective response to painful stimuli. Deep tendon reflexes are absent.
Orthopaedic manifestations are the same as in those with congenital insensitivity to pain and include fractures, Charcot joints, and osteomyelitis. In a study of 182 patients with Riley-Day syndrome, 60% had sustained fractures and 11% had one or more neuropathic joints, most commonly the knee. Foot deformity is seen in a subset of the patients.
Limited atlantooccipital and cervical sagittal range of motion has been identified in patients with familial dysautonomia. Scoliosis is seen in up to 90% of children with Riley-Day syndrome and can be extremely difficult to manage (Fig. 38-18). Most patients are diagnosed with scoliosis before 10 years of age. Curves tend to be rigid and may also exhibit significant kyphosis, unlike the deformity seen in idiopathic scoliosis. Left thoracic curves are common in this group of patients. Orthotic management usually fails. In 89% of 65 braced patients with Riley-Day syndrome, orthotic management of their scoliosis failed. When preparing a patient for spinal fusion, a preoperative nutritional evaluation should be performed to rule out malnutrition and reflux with aspiration. Posterior spinal fusion with instrumentation is usually recommended for the treatment of scoliosis in patients with Riley-Day syndrome, but combined anterior and posterior spinal fusion with instrumentation has been advocated for patients with kyphoscoliosis. Fusion should extend to the proximal thoracic spine to decrease the likelihood of junctional kyphosis. Patients are prone to autonomic dysfunction while anesthetized, with wide swings in blood pressure. Intraoperative fatal cardiac arrest has been described in these patients.
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| https://musculoskeletalkey.com/disorders-of-the-peripheral-nervous-system/ |
Idiopathic giant oesophageal ulcer and leucopoenia after renal transplantation | Request PDF
Request PDF | Idiopathic giant oesophageal ulcer and leucopoenia after renal transplantation | A 45-year-old male recipient of a renal allograft was admitted because of a giant oesophageal ulcer coinciding with leucopoenia. An extensive... | Find, read and cite all the research you need on ResearchGate
Article
Idiopathic giant oesophageal ulcer and leucopoenia after renal transplantation
October 2012
The Netherlands Journal of Medicine70(8):370-3
Source
PubMed
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
G A J van Boekel
G A J van Boekel
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
M Volbeda
M Volbeda
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
M W F van den Hoogen
M W F van den Hoogen
<here is a image 02334081f24993f9-4e4edf6c996e28ff>
Luuk B Hilbrands
Radboud University Medical Centre (Radboudumc)
Abstract
A 45-year-old male recipient of a renal allograft was admitted because of a giant oesophageal ulcer coinciding with leucopoenia. An extensive workup revealed no explanation for the ulcer and leucopoenia. Our final diagnosis by exclusion was an idiopathic giant oesophageal ulcer and late-onset neutropenia as consequences of rituximab induction therapy given during the transplant procedure. The patient fully recovered after treatment with prednisone. However, after four months, the ulcer and leucopoenia recurred and again successfully responded to treatment with prednisone.
<here is a image 175d1bd4b7439d95-754927124da715c1>
... It was rst described in association with human immunodeciency virus (HIV) (3,4). Association with kidney transplantation is rare and till date, three such cases have been reported worldwide (5,
6,
7). We present a patient with IgAN related ESKD, who following the transplantation, developed idiopathic GOU. ...
... Since then they have also been described in the setting of organ transplant including hematopoietic stem cell and lung transplant (8,9). Association with kidney transplant is rare and only three cases have been described worldwide (5,
6,
7). We intend to discuss these three cases along with our case so as to derive common pattern. ...
... The second reported case was of a 45 years old male with IgAN related ESKD who developed a 20-millimeter distal oesophageal ulcer six months following the transplant
(6)
. The induction was with rituximab; the maintenance immunosuppression was similar to the rst case. ...
IDIOPATHIC, TREATMENT RESISTANT, GIANT OESOPHAGEAL ULCER IN A KIDNEY TRANSPLANT RECIPIENT
Article
Full-text available
May 2022
Vishal Singh
Chandra Satish
<here is a image f7fc2d70966d99c7-b48947b7baa9309f> Ajay Shankar Prasad
Giant esophageal ulcers (GOU) are variable defined as ulcers larger than 10-20 millimeters. The initial reports were primarily in association with human immunodeficiency virus (HIV). Since then they have been described in the setting of organ transplant including hematopoietic stem cell and lung transplantation. Association with kidney transplantation is rare and only three such cases have been described. The pathophysiology remains an enigma. We report a case of idiopathic, therapy unresponsive, GOU in a young male with Immunoglobulin A nephropathy (IgAN) related end stage kidney disease. Four months following the kidney transplantation he presented with graft dysfunction, reoccurrence of basic disease, odynophagia and weight loss. The endoscopic evaluation showed two GOU in the distal esophagus. The response to therapy was poor; it finally resolved spontaneously. Based on the temporal profile and the review of existing similar case reports, we believe, these GOU represent an extra-renal manifestation of IgAN.
... It was rst described in association with human immunodeciency virus (HIV) (3,4). Association with kidney transplantation is rare and till date, three such cases have been reported worldwide (5,
6,
7). We present a patient with IgAN related ESKD, who following the transplantation, developed idiopathic GOU. ...
... Since then they have also been described in the setting of organ transplant including hematopoietic stem cell and lung transplant (8,9). Association with kidney transplant is rare and only three cases have been described worldwide (5,
6,
7). We intend to discuss these three cases along with our case so as to derive common pattern. ...
... The second reported case was of a 45 years old male with IgAN related ESKD who developed a 20-millimeter distal oesophageal ulcer six months following the transplant
(6)
. The induction was with rituximab; the maintenance immunosuppression was similar to the rst case. ...
IDIOPATHIC, TREATMENT RESISTANT, GIANT OESOPHAGEAL ULCER IN A KIDNEY TRANSPLANT RECIPIENT
Article
Full-text available
Dec 2019
<here is a image 777533013faca4e0-4b07a706b42ba75c> Vishal Singh
Chandra Satish
Giant oesophageal ulcers (GOU) are variable dened as ulcers larger than 10-20 millimeters. The initial reports were primarily in association with human immunodeciency virus (HIV). Since then they have been described in the setting of organ transplant including hematopoietic stem cell and lung transplantation. Association with kidney transplantation is rare and only three such cases have been described. The pathophysiology remains an enigma. We report a case of idiopathic, therapy unresponsive, GOU in a young male with Immunoglobulin A nephropathy (IgAN) related end stage kidney disease. Four months following the kidney transplantation he presented with graft dysfunction, reoccurrence of basic disease, odynophagia and weight loss. The endoscopic evaluation showed two GOU in the distal esophagus. The response to therapy was poor; it nally resolved spontaneously. Based on the temporal prole and the review of existing similar case reports, we believe, these GOU represent an extra-renal manifestation of IgAN.
... However, it can also be detected in esophageal biopsies from patients with Candida, CMV and HSV esophagitis [5] . Our report and other previous cases [7,
8]
provide clinical evidence that idiopathic giant esophageal ulcer can occur in the absence of HIV infection, and favor a defect of immunity rather than a virus etiology in the pathogenesis of idiopathic esophageal ulceration [5] . In our report, although the clinical context of the patient suggested a potential CMV-related ulcer, there was no evidence of viral cytopathology as assessed from routine histological or immunohistochemical studies. ...
Rare cause of odynophagia: Giant esophageal ulcer
Article
Full-text available
Apr 2016
WORLD J GASTROENTERO
<here is a image 3db0440c40ad15d1-0530e970244cae02> Massimiliano Veroux
<here is a image 0aa7523b36f77058-96f3bf815b77c3c9> Giuseppe Aprile
Francesca F Amore
<here is a image 16e85bc451282c03-39f435960ca6926b> Pierfrancesco Veroux
Gastrointestinal complications are a frequent cause of morbidity after transplantation and may affect up to 40% of kidney transplant recipients. Here we report a rare case of idiopathic giant esophageal ulcer in a kidney transplant recipient. A 37-year-old female presented with a one-week history of odynophagia and weight loss. Upon admission, the patient presented cold sores, and a quantitative cytomegalovirus polymerase chain reaction was positive (105 copies/ml). An upper endoscopy demonstrated the presence of a giant ulcer. Serological test and tissue biopsies were unable to demonstrate an infectious origin of the ulcer. Immunosuppression was reduced and everolimus was introduced. An empirical i.v. therapy with acyclovir was started, resulting in a dramatic improvement in symptoms and complete healing of the ulcer. Only two cases of idiopathic giant esophageal ulcer in kidney transplant recipients have been reported in the literature; in both cases, steroid therapy was successful without recurrence of symptoms or endoscopic findings. However, this report suggests that correction of immune imbalance is mandatory to treat such a rare complication.
Rituximab-associated immune myelopathy
Article
Sep 2003
Theodora Papadaki
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Kostas Stamatopoulos
<here is a image fd0971598e646fcc-ba2126fadac99e4b> Achilles Anagnostopoulos
Athanasios Fassas
Rose et al recently reported a case of agranulocytosis following autologous transplantation for diffuse large B-cell lymphoma after in vivo purging with rituximab.[1][1] Agranulocytosis developed on day 122 after transplantation after prompt trilineage engraftment; the bone marrow (BM) was
Lymphocyte subpopulation imbalances, bone marrow hematopoiesis and histopathology in rituximab-treated lymphoma patients with late-onset neutropenia
Article
Aug 2008
LEUKEMIA
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Kostas Stamatopoulos
Theodora Papadaki
C. Pontikoglou
Helen A Papadaki
Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Idiopathic esophageal ulceration in acquired immunodeficiency syndrome: Successful treatment with misoprostol and viscous lidocaine
Article
Nov 1998
Adekunle G. Adeoti
<here is a image b44449b97894d07f-0b7a04df1925551e> Kenneth J Vega
<here is a image 9c68c9f1d4f6783c-877a3512c30a4763> Esam Z Dajani
Patricia C. Kloser
Objective: Esophageal ulceration is a common and important cause of morbidity in patients with acquired immunodeficiency syndrome (AIDS). After known causes are excluded, a subgroup remains with unexplained esophageal ulceration, known as idiopathic esophageal ulceration (IEU). The current therapy of IEU includes corticosteroids or, less frequently, thalidomide, although no placebo-controlled trials have been reported. The aim of this retrospective study was to determine the outcome of treating IEU with misoprostol and viscous lidocaine. Methods: A retrospective review of esophageal ulceration in AIDS identified seven subjects with IEU at our institution. IEU in these subjects was treated successfully with misoprostol, 200 mu g, crushed and suspended in 2% viscous lidocaine, 15 mi, given or ally a.c. and h.s. for 4 wk. Results: All patients reported symptomatic improvement within 2-3 days and complete resolution of their symptoms within 15 days. Healing of esophageal ulcerations was confirmed in five of seven subjects at a repeat endoscopy 8-12 wk later. Conclusions: Misoprostol, an antiulcer drug, has GI cytoprotective properties, and viscous lidocaine, a topical anesthetic, coats mucosal surfaces. We speculate that misoprostol when delivered topically is 3-6 times more effective than when delivered systemically. Considering the rapid resolution of symptoms, healing of ulcers, and lack of side effects, we believe that misoprostol crushed and suspended in viscous lidocaine should be considered for further evaluation in prospective, placebo-controlled trials of IEU. (C) 1998 by Am. Coll. of Gastroenterology.
Idiopathic esophageal ulcers after autologous hemopoetic stem cell transplant: Possible role of IgA levels
Article
Dec 2008
ANN HEMATOL
Shyam Dang
<here is a image 4e17607a1fabbc9f-6b290c402ff61110> Muslim Atiq
<here is a image 0d6b30ad7397089d-9eb7fb8eb0e73e52> Somashekar G Krishna
Farshad Aduli
Late-Onset Neutropenia After Rituximab Treatment
Article
Sep 2010
MEDICINE
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Ofir Wolaj
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Osnat Bairey
Meir Lahav
Purpose of review: Late-onset neutropenia (LON) after rituximab administration may be encountered in various clinical settings. The identification of neutropenia after rituximab treatment may have immediate implications for the clinical management of the patient and on subsequent treatment strategies. Although the pathogenesis of LON is incompletely understood, various putative mechanisms are suggested. These may be of special importance in the advent of the newer monoclonal anti-CD20 antibodies. Recent findings: The incidence of LON varies with the clinical setting in which rituximab is administered. Administration of rituximab in the setting of stem cell transplantation significantly increases the risk for LON. The timing of rituximab administration after transplantation may affect the risk and severity of neutropenia. Recent data suggest that in rheumatologic diseases, the incidence of LON is comparable to that in the hematologic population. Suggested mechanisms for LON include humoral and cellular immune mechanisms as well processes that stem from B-cell recovery and its impact on neutrophil kinetics. Recently, an association between specific polymorphism in the immunoglobulin G Fc receptor FCγRIIIa 158 V/F and LON was demonstrated. Summary: LON is an increasingly recognized late adverse event of rituximab therapy. Acquaintance with the incidence, risk factors, natural history, and expected complications of LON may improve proper clinical management. Many aspects in the clinical management of LON remain to be answered during further studies aimed at this goal.
Severe Ulcerative Colitis After Rituximab Therapy
Article
Jul 2010
Pediatrics
<here is a image 5602e597229a7d51-c100c6443ddafa01> Daniela Simona Ardelean
<here is a image 852273483e5f8b6b-36fe5f42d3341fff> Tanja Gonska
Shannon Wires
<here is a image ccf523e13304eb57-db1e3b640907c710> Susanne Benseler
B-cell-depletion therapy with rituximab is efficacious against steroid-dependent nephrotic syndrome (NS) in children and adults. Safety data are limited. Results of small studies have suggested that rituximab is usually well tolerated but that adverse events (such as severe mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and bowel perforation) can occur. We report here the first case (to our knowledge) of a pediatric patient with refractory minimal-change NS who developed severe immune-mediated ulcerative gastrointestinal disease 42 days after rituximab therapy. The disease was characterized by deep ulcers throughout the intestines and predominantly affected the colon. The child presented with severe abdominal pain, bloody diarrhea, weight loss, and fever. Her inflammatory markers were significantly elevated. Extensive evaluation revealed no evidence of infections and no characteristics of defined inflammatory bowel disease or Behçet disease. Colonoscopy revealed severe intestinal inflammation with deep ulcers. Histology of the colonic biopsy specimens revealed extensive infiltrates predominantly composed of CD8(+) T lymphocytes and evidence of high forkhead box P3 (FOXP3) expression. During this significant gastrointestinal disease, the NS remained quiescent. Corticosteroid therapy successfully controlled the severe immune-mediated intestinal inflammation after rituximab therapy. NS relapsed subsequently when CD19(+) and CD20(+) B-cell populations recovered.
Rituximab-Associated Neutropenia
Article
Apr 2010
<here is a image e3b4582b84551cd2-f0d185fd2d36b291> Kieron Dunleavy
Kevin Tay
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Wyndham H Wilson
Several recent studies have reported the phenomenon of late-onset neutropenia occurring usually several months following the administration of rituximab or rituximab-based therapies. While it appears that late-onset neutropenia is usually not clinically significant and is self-limited, it is important to recognize its existence given the expanding use of rituximab in both hematologic and nonhematologic disorders. Late-onset neutropenia is intriguing biologically and while its pathogenesis and mechanism are not completely understood, many interesting hypotheses have been proposed to explain its occurrence.
Odynophagia From Aphthous Ulcers of the Pharynx and Esophagus in the Acquired Immunodeficiency Syndrome (AIDS)
Article
Sep 1988
M C Bach
A J Valenti
D A Howell
T J Smith
Esophageal ulceration in human immunodeficiency virus infection. Causes, response to therapy, and long-term outcome
Article
Aug 1995
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Charles Melbern Wilcox
<here is a image 4330ed9d85c09827-9d3f89f2d689ca52> David Schwartz
<here is a image 083b5576271d9cd6-8e1c4f72cb01cd01> W. Scott Clark
TRANSPLANTATION
| https://www.researchgate.net/publication/232249888_Idiopathic_giant_oesophageal_ulcer_and_leucopoenia_after_renal_transplantation |
Aaron Simpson vs. Tom Lawlor
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VIPM Updates
Biweekly vegetable integrated pest management updates
Insect Management
Early Corn Earworm Activity in Spring Lettuce
Insect activity over the past week has started to pick up. We have seen a significant increase in green peach aphid pressure here at the Yuma Ag Center. Similarly, most PCAs I’ve visited with have noted similar increases in aphid activity and are keeping them under control. Although worm pressure has been light in the field for the past month or so, it would be wise to keep a keen eye out for corn earworm (CEW). In the past, high CEW abundance has occurred on late head lettuce (March), particularly in the Dome/Wellton areas. Surprisingly, our most recent trap catches showed significant moth flights in Roll, Dome Valley, and north Gila Valley following several weeks of inactivity ( see graphs below). This is typical for February and could be the calm before the storm. The last time we saw CEW moth activity this early (2015), we had reports of high numbers of CEW larvae in the field at harvest. These most recent trap counts should be used as an early indicator that moths are actively flying at night at higher abundance and PCAs should start to scout more aggressively for eggs and larvae. You should be especially wary of CEW given the higher nighttime temperatures forecasted for the next 2 weeks.CEW can be very damaging in spring crops once head formation begins; larvae will usually bore into the head 1-2 days upon hatching.Corn earworm is much more likely to bore into lettuce heads or romaine hearts than other Lepidoptera larvae, rendering the heads/hearts unmarketable. If fields are not watched closely, infestations may not be noticed until harvest. Once inside the head/heart, control of larvae with currently available insecticides is not possible. Thus, pay careful attention for newly oviposited eggs (laid singly) on lettuce plants, particularly close to the base of the head. If you are beginning to find eggs and suspect that CEW are active in the field when plants are beginning to head, it would be a good idea to treat at regular spray intervals (~ 7 days). The UA nominal threshold for CEW in head lettuce from early heading to harvest is 1-2 larvae / 100 plants. Essentially, you find one larva, you spray. Repeated insecticide treatments may be required to maintain low population levels near harvest. Most contact insecticides recommended for Lepidopterous larvae are active against CEW. Furthermore, the addition of a pyrethroid with thrips, aphid and/or fungicide sprays may be cheap insurance against CEW larvae beginning to emerge as you approach harvest. For more information on CEW management and control recommendations see Corn Earworm Management on Desert Produceand the 2023 Lep Control Char t .
Soil Science
Water and Food Security in the Desert Southwest
The difficulties we are experiencing with water in the west are the consequence of the worst megadrought in 1200 years, which is increasingly clear to be a process of aridification and climate change (Wheeler et al., 2022). These conditions are bearing down on desert agriculture in a very significant way. In the next week, the U.S. Bureau of Reclamation (BoR) is expected to announce the 2023 operational plan for the Colorado River and it will definitely involve reductions in water allocations. On 14 June 2022 BoR Commissioner Camille C. Touton described the need to achieve additional reductions on Colorado River allocations. The BoR has been engaging in discussions with the seven basin states that depend on the Colorado River to develop a plan for the reductions, and that decision will be announced in the next few days. As Commissioner Touton described, the BoR has the authority to “act unilaterally to protect the system, and we will protect the system.” (Bureau of Reclamation, 28 June 2022). Commissioner Touton stated that the seven basin states on the Colorado River must reduce allocations by 2 to 4 million acre-feet (MAF). The basic arithmetic on the Colorado River is as follows: 16.5 MAF is currently the allocated amount of water budgeted with 7.5 MAF allocated to both the upper and lower basins, plus 1.5 MAF allocated to Mexico: (7.5+7.5 MAF = 15 MAF U.S. + 1.5 MAF Mexico = 16.5 MAF total ) In the past two decades, the average annual flow of the Colorado River from 2000 - 2018 has been approximately 12.4 MAF , which is 16 % lower than the 1906-2017 average of 14.8 MAF/year . Thus, we can see where the 4 MAF differential is determined. A reduction of Colorado River water allocations from 16.5 MAF to 12 MAF represents a 27% reduction. That is in line with the climate and hydrological reality we are dealing with and a huge reduction for the Colorado River basin. So, while the good news is that we do have approximately 12 MAF coming down the river, the bad news is that it is almost 1/3 less than what has been allocated on the existing Colorado River water budget. To bring the Colorado River system into better balance will require some major changes. The valleys of the Colorado River watershed are tremendously valuable resources with alluvial soils that are young geologically, extremely fertile, and highly productive if sufficient water is provided. These are some of the richest agricultural areas in the western United States. For example, the lower Colorado River valley, particularly the valleys in the Yuma, Arizona and Imperial Valley, California areas, provide more than 90% of the leafy green vegetables (all types of lettuce, broccoli, cauliflower, etc.) for the U.S. and Canada every year from November through March. These valleys produce an abundance of other crops including high quality durum wheat production that supports the pasta industry, including most Italian pastas, and a seed production industry that provides high quality seed stocks regionally, nationally, and internationally. An extremely well developed and sophisticated infrastructure system is in place to direct and manage water to the fields for highly efficient and productive irrigation systems. The management of these systems requires a high level of specialized and well-developed expertise which is in place and operating in the rich and productive valleys of the lower Colorado River. Thus, the valleys of the Colorado River and the people on the ground in the field are managing some of the most productive farms in the U.S. and anywhere in the world. These are resources that we should value and protect for both water and food security that is both regionally and nationally significant. Analysis of the desert Southwest’s paleoclimate have shown a distinct susceptibility of the region to experience extraordinary megadroughts that can last for decades or even centuries (Baum, 2015; Stahle et al., 2000; and Acuna-Soto et al., 2002). For example, paleoclimate records show that a fifty-year drought struck the Southwest, Northern Mexico, and the Rocky Mountains between about AD 1540 and 1590. Three hundred years earlier, records reveal the Great Drought of AD 1267-1299. It is believed that this 32 year Great Drought period was at least partially responsible for the abandonment of concentrated Native American populations throughout the Southwest (Cook et al., 2007; Benson et al., 2007; and Cook et al., 2010). Paleoclimate records indicate that droughts of more than a century in length have hit this region in the past (Stine, 1994). The result of this overall situation is that we are reaching a crossroads in the development of a strategy to deal with the changing conditions in the west and immediate action is needed. All efforts that have been directed to deal with this issue in the past 20 years, although well-intended, have not been sufficient in addressing the problem, including the 2007 interim guidelines, the Intentionally Created Surplus program, the Drought Contingency Plan, and the 500+ Plan. The climate is changing much faster than our system of governance. Thus, we are facing an existential crisis for the desert Southwest that includes the interface between the agricultural and urban sectors of our society. It seems to be one of the classic cases of “If you are not at the table, you are probably on the menu.” In this case, it might be both. One of the difficulties with this overall situation is the past tendency to develop short-term responses to a situation that has long-term implications and needs. In general, people have a tendency in strategic management at all levels, from international relations, to national, state, and local governance towards “Strategic Narcissism”, which is the tendency to define challenges as we would like them to be while ignoring the agency that other entities have over our results. This term of strategic narcissism was first presented by Hans J. Morgenthau and he expanded on this theme in his 1948 book Politics Among Nations where he introduced the concept of political realism, presenting a realist view of power politics. He pointed out that strategic narcissism and the tendency to think idealistically and narrowly about the scope of the problem or challenge usually leads to narrow solutions and strategies, which commonly fail. In his 2020 book Battlegrounds: The Fight to Defend the Free World , H.R. McMaster reinforces Morgenthau’s point regarding the dangers of indulging in strategic narcissism and the corresponding tendency to artificially separate interconnected problem sets, which encourages short term and simplistic solutions to complex problems. He describes the common tendency to define and address a problem in a manner that allows us to develop a response that we favor. This is often based on wishful thinking and our own capacity for self-delusion with flawed assumptions rather than dealing with a realistic assessment of basic facts. While Morgenthau and McMaster are addressing strategic issues on the international scale, we are confronted with similar challenges of avoiding the indulgence in strategic narcissism in our efforts to develop effective strategies to manage our water resources in the desert Southwest, as exemplified in the Colorado River situation. It is important for us to recognize the legitimacy and importance of all involved components, current and future, including both urban and agricultural interests and understand that the decisions made today will have an impact on residents of the desert Southwest in the decades to come in all sectors. Thus, we need to be considerate of more than ourselves and the immediate needs and include the prospects for our children, grandchildren, and the unborn generations yet to come. Considering the basic facts associated with the current Southwestern megadrought and the realistic indications that we are dealing with increasing aridification of the climate through the process of climate change is a good example. We have consistently held onto the hope that the drought will end, and we will soon return to the climate and hydrological patterns of the mid-20 th century. Instead, it would be better to plan for the probable contingency that aridification is taking place and future generations in the desert Southwest will be forced to continue to deal with it. As the paleoclimate records show us, this is within the range of possibilities. A case of strategic narcissism is the belief and conviction that some people hold that commercial agriculture in the desert Southwest should be eliminated with the food and fiber production being replaced by distant and perhaps international sources or small farm local crop production operations. Placing future generations at the mercy of long-distance sources of food production is dangerous and it would be irresponsible to do at this time. These are rather simplistic and idealistic visions. For example, small scale local farming can serve as a nice food supplement to some communities, particularly in urban areas, but it is not going to replace the needs for large scale food and fiber production supporting 7.4 M Arizonans, 330 M people in the United States and nearly 8 B people on the planet today. These ideas run counter to good and practical strategic planning for water and food security for the desert Southwest. Admittedly, it is exceedingly difficult for humans to have the necessary discipline to avoid strategic narcissism and develop a better sense of empathy for strategic planning. As Jamil Zaki, a psychologist from Stanford University has pointed out, it is difficult for people to develop the necessary empathy because it runs counter to our basic nature and instincts (Zaki, 2019). Both time and distance diminish our capacity for empathy because “humans caring instincts are short sighted. Our ability to feel empathy about future development is limited because we tend not to feel for our future selves. It goes against our instincts to tackle problems that we have not yet been forced to confront.” As we plan and develop a functional strategy for future water and food security in the desert Southwest, it is realistic to consider that large urban areas will exist and continue to grow. Agriculture is essential to any society and that is certainly true for the large cities of the Southwest, present and future. In 2022 we should be very alert to the dangers of depending on long supply chains and the single points of failure in supply chains that can be devastating to the dependent populations. The current situation is an opportunity to strategically plan for the future of the desert Southwest in a manner that provides for both water and food security. Based on the agricultural capacities of the desert Southwest, Arizona could be self-sustaining, or very nearly so. Considering Arizona, New Mexico, and California collectively, the possibility of long-term agricultural sustainability is entirely possible. But sufficient water is required to support the agricultural systems necessary to support that population. I am confident that we can work through these challenges in a balanced and effective manner but “business as usual” will not be sufficient in addressing the demands of today. This is a complex situation environmentally, geographically, politically, economically, and socially. Compounding the current challenges is the fact that actions need to take place rather swiftly and here are many factors to consider simultaneously. It is important that we develop a consideration of the broad and long-term impacts of our decisions for all parties with critical issues such as the management of our water resources for both water and food security in the desert Southwest. This requires a conscious and concerted effort to do so and all parties taking Colorado River water should share in absorbing the changes that are coming, nobody should get a pass. It is possible to develop a balance of coexistence with agriculture and urban development with the water resources available in this region but it will not be easy. As stated in the old Greek proverb: “ Society grows great when old men plant trees whose shade they know they shall never sit in .” We can see the value of that line of thought that was true 3,000 years ago and also with what we are dealing with today. This is one of the great challenges of our time and I believe we can step up and deliver in a balanced and constructive manner. References: Acuna-Soto, R., D.W. Stahle, M.K. Cleaveland, and M.D. Therrell. 2002. Megadrought and Megadeath in16th Century Mexico. Historical Review 8(4): 360-362. Baum, R. 2015. Climate change and drought in the American Southwest. The Climate Institute. https://climate.org/effects-of-21st-century-climate-change-on-drought-disk-in-the-american-southwest/#:~:text=Drought%20is%20a%20common%20occurrence%20in%20the%20American,completely%20unprecedented%20within%20the%20past%2010%2C000%20years.%208 Benson, LV., M.S. Berry, E.A. Jolie, J.D. Spangler, and D.W. Stahle. 2007. Possible impacts of early-11th-, middle-12th-, and late-13th-century droughts on western Native Americans and the Mississippian Cahokians. Quaternary Science Reviews 26(3): 336-350. Bureau of Reclamation, 28 June 2022 https://www.usbr.gov/ColoradoRiverBasin/ Cook, E.R., R. Seager, M.A. Cane MA, D.W. Stahle. 2007. North American drought: Reconstructions, causes, and consequences. Earth Science Reviews 81(1): 93-134. Cook, E.R., R. Seager, R.R. Heim Jr., R.S. Vose, C. Herweijer, and C. Woodhouse C. 2010. Megadroughts in North America: placing IPCC projections of hydroclimatic change in a long-term paleoclimate context. Journal of Quaternary Science 25(1): 48-61. McMaster, H.R., 2020. Battlegrounds: The Fight to Defend the Free World. Harper Collins Publishers, New York, NY. Morgenthau, H.J. and K. Thompson. 1948. Politics Among Nations. New York: McGraw-Hill. (1985, 6th ed.). Stahle, D.W., E.R. Cook, M.K. Cleaveland, M.D. Therrell, D.M. Meko, H.D. Grissino-Mayer, E. Watson, and B.H. Luckman. 2000. Tree-ring Data Document 16th Century Megadrought Over North America. EOS 80(12): 121-125. Stine, S. 1994. Extreme and persistent drought in California and Patagonia during mediaeval time. Nature 369: 546-549. Wheeler, K.G, B. Udall, J. Wang, E. Kuhn, H. Salehabadi, and J.C. Schmidt. 2022. What will it take to stabilize the Colorado River? Science, 377 (6604) p. 373-375. • DOI: 10.1126/science.abo4452 Zaki, J. 2019. The War for Kindness: Building Empathy in a Fractured World. Crown Publishing Group (NY).
Lettuce dieback is a soil-borne disease caused by two closely related viruses from the family Tombusviridae Tomato Bushy Stunt Virus(TBSV) and Lettuce Necrotic Stunt Virus(LNSV) that has been reclassified as Moroccan Pepper Virus(MPV). The disease has been observed throughout the main lettuce producing areas of California and Arizona.This year we have been receiving some samples that looked like lettuce dieback disease. The samples came positive for a new virus named as Lettuce dieback associated virus and negative for tomato bushy stunt virus. In the past we have seen symptoms in resistant cultivars (with Tvr1 gene) which suggests that the new virus is involved in the symptomology.The virus is soilborne, and has been found to have more correlation with the dieback disease more than Tomato bushy stunt virus. Flooding or poor drainage, high salinity, plant stress, and soil saturation have been associated with high incidence of virus .If you have plants showing symptoms of Tomato bushy stunt virus, please bring the samples to Yuma Plant Health Clinic for diagnosis. https://www.extension.iastate.edu
Weed Sciences
Prefar (bensulide)
Prefar (bensulide) is an organophosphate herbicide that has been used for more than 50 years in Arizona for lettuce production. In fact, it is one of the standard herbicides used for this purpose.The University of Arizona Vegetable IPM Team conducted a Yuma County and Imperial Valley Survey evaluating a portion of the acres checked by Pest Control Advisors. The 2017 data indicated that in 58% of the lettuce acreage reported was treated with Prefar. Similarly, in the 2018 survey 52% received a Prefar application.This product performs well when incorporated with sprinkler irrigation at stand establishment. It also works best in course textured soil’s such as the ones found in Coachella Valley, California. One of the weeds controlled by Prefar is pigweed (Amaranthus palmeri), which was found to be resistant to glyphosate herbicide in Arizona by Dr. William B. McCloskey in 2012. Other weeds are purslane (Portulaca oleracea), goosefoot (Chenopodium murale),Lambquarter (Chenopodium album), and some species of grasses.The list of crops in which bensulide is used demonstrates the importance of this weed control tool for the agricultural industry.According to the 1080 Pesticide Use Reporting Database provided by the Arizona Pest Management Center the list of crops includes: Arugula, Bok choy, Broccoli, Brussel Sprouts, Cabbage, Cantaloupe, Cauliflower, Celery, Cilantro, Corn, Cress, Endive, Fennel, Mustard, Kale, Lettuce, Onion, Parsley, Squash, Swiss chard, and others.Please read the following contribution from Dr. Al Fournier on theEPA Notice- Petition to Revoke Organophosphate Tolerances: (includingBensulide).
Petition to Revoke Tolerances and Cancel Certain OP Uses: Comment Deadline Extended
Al Fournier, IPM Program Manager, Arizona Pest Management Center10 August 2022The EPA has extended its deadline for public comment on a Petition to Revoke Tolerances and Cancel Registrations for Certain Organophosphate Uses untilSeptember 25, 2022.The petitioners, including United Farm Workers, Earthjustice, and several other groups, request that the Agency revoke all tolerances and cancel all associated registrations for food uses of 15 listed OPs, and further requests that the Agency complete its registration review process for these chemicals no later than October 1, 2022. The pesticides are currently at various stages of review, and the proposed deadline does not align with EPA’s published schedule to complete scientific reviews.Among 15 Organophosphates named in the petition are 10 with reported uses in Arizona (bolded below). Those with known uses in lettuce and other produce include Bensulide (Prefar) and Acephate (Orthene).Acephate,Bensulide,Chlorethoxyfos, Chlorpyrifos-methyl,Diazinon,Dichlorvos,Dicrotophos, Dimethoate,Ethoprop,Malathion, Naled, Phorate,Phosmet,Terbufos, TribufosRead the full EPA Notice here:https://www.regulations.gov/document/EPA-HQ-OPP-2022-0490-0001To submit comments to the docket, use the following link:https://www.regulations.gov/commenton/EPA-HQ-OPP-2022-0490-0001To contribute to Arizona Pest Management Center comments, contact Al Fournier
Areawide Insect Trapping Network
Area wide Insect Trapping Network (June 29, 2022)
Area wide Insect Trapping Network VegIPM Update, Vol. 13, No. 13, Jun 29, 2022 Results of pheromone and sticky trap catches can be viewed here. Corn earworm : CEW moth counts decreased in the past 2 weeks, but still higher than the previous 2 summers. Beet armyworm : Trap counts remain active in some locations (Yuma Dome Valley and Tacna) but lower than last summer Cabbage looper: Cabbage looper numbers remain low consistent with the lack of activity this fall compared to last season. Diamondback moth: DBM counts very low and average for this time of the year. Whitefly: Adult movement continuing to increase, particularly in Gila and Yuma Valleys consistent with melon harvests. Thrips: Thrips adult decreasing in most locations, and trending comparable to this previous years. Aphids: Aphid movement is absent consistent with what we typically observe in the summer. Leafminers: Adult activity has highest in Yuma Valley, and above average for late-June.
| https://acis.cals.arizona.edu/agricultural-ipm/vegetables/vegetable-ipm-updates/22?Insectpage=10&PlantDiagnosticpage=11&Trappingpage=20&Weedspage=11 |
Intravenous VEGF Trap in Treating Patients With Relapsed or Refractory Advanced Solid Tumors or Non-Hodgkin's Lymphoma - Tabular View - ClinicalTrials.gov
Intravenous VEGF Trap in Treating Patients With Relapsed or Refractory Advanced Solid Tumors or Non-Hodgkin's Lymphoma
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00083213 Recruitment Status :
Completed First Posted : May 19, 2004 Last Update Posted : June 3, 2016
Sponsor:
Regeneron Pharmaceuticals
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Regeneron Pharmaceuticals
Study Details
Tabular View
Tracking Information
First Submitted Date ICMJE May 14, 2004
First Posted Date ICMJE May 19, 2004
Last Update Posted Date June 3, 2016
Study Start Date ICMJE January 2004
Actual Primary Completion Date May 2008 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE Not Provided
Original Primary Outcome Measures ICMJE Not Provided
Change History Complete list of historical versions of study NCT00083213 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE Not Provided
Original Secondary Outcome Measures ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title ICMJE Intravenous VEGF Trap in Treating Patients With Relapsed or Refractory Advanced Solid Tumors or Non-Hodgkin's Lymphoma
Official Title ICMJE An Open Label, Sequential Cohort Dose-Escalation Safety, Tolerability and Pharmacokinetic Study of VEGF Trap Administered Intravenously in Patients With Advanced Solid Tumors or Lymphoma
Brief SummaryRATIONALE: VEGF Trap may stop the growth of solid tumors or non-Hodgkin's lymphoma by stopping blood flow to the tumor.PURPOSE: This phase I trial is studying the side effects and best dose of intravenous VEGF Trap in treating patients with relapsed or refractory advanced solid tumors or non-Hodgkin's lymphoma.
Detailed Description
OBJECTIVES:Primary Determine the safety and tolerability of intravenous VEGF Trap in patients with relapsed or refractory advanced solid tumors or non-Hodgkin's lymphoma.Secondary Determine the maximum tolerated intravenous dose of this drug in these patients. Determine the pharmacokinetics of this drug in these patients. Determine the ability of this drug to bind circulating vascular endothelial growth factor in these patients. Determine, preliminarily, the ability of this drug to alter tumor blood flow and tumor vascular permeability in these patients. Determine whether antibodies to this drug develop in these patients.OUTLINE: This is an open-label, dose-escalation, multicenter study.Patients receive VEGF Trap IV over 1 hour on days 1 and 15 for a total of 2 doses.Cohorts of 3-6 patients receive escalating doses of VEGF Trap until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional 6 patients are treated at that dose level.In the absence of dose-limiting toxicity, patients with stable disease or partial or complete remission may continue to receive VEGF Trap on a separate extension protocol.Patients are followed at weeks 1, 3, and 7 and then at 3 months.PROJECTED ACCRUAL: A maximum of 25 patients will be accrued for this study.
Study Type ICMJE Interventional
Study Phase ICMJE Phase 1
Study Design ICMJE Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment
Condition ICMJE Cancer
Intervention ICMJE Biological: ziv-aflibercept
Study Arms ICMJE Not Provided
Publications *
Lockhart AC, Rothenberg ML, Dupont J, Cooper W, Chevalier P, Sternas L, Buzenet G, Koehler E, Sosman JA, Schwartz LH, Gultekin DH, Koutcher JA, Donnelly EF, Andal R, Dancy I, Spriggs DR, Tew WP. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol. 2010 Jan 10;28(2):207-14. doi: 10.1200/JCO.2009.22.9237. Epub 2009 Nov 30. Wang-Gillam A, Tew WP, Rothenberg ML, Dupont J, Cooper W, Sternas L, Buzenet G, Sosman JA, Spriggs DR, Lockhart AC. A phase I study of subcutaneously administered aflibercept (VEGF trap) in a new formulation in patients with advanced solid tumors. Invest New Drugs. 2012 Oct;30(5):1958-61. doi: 10.1007/s10637-011-9753-y. Epub 2011 Oct 15.
* Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE Completed
Actual Enrollment ICMJE (submitted: November 8, 2006) 25
Original Enrollment ICMJE Not Provided
Study Completion Date ICMJE Not Provided
Actual Primary Completion Date May 2008 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE
DISEASE CHARACTERISTICS:
Histologically confirmed diagnosis of one of the following:
Non-Hodgkin's lymphoma
Primary or metastatic solid tumor located, by radiography, in at least one of the following sites:
Liver
Soft tissue
Pelvis
Other site that is suitable for delayed contrast-enhanced MRI (e.g., peripheral lung field)
Relapsed or refractory (including unresectable) disease
Patients with solid tumors must have failed all curative chemotherapeutic regimens
Patients with non-Hodgkin's lymphoma must be refractory to at least 2 standard chemotherapeutic regimens and rituximab
Not amenable to available conventional therapies AND no standard therapy exists
Measurable disease
No prior or concurrent CNS metastases (brain or leptomeningeal)
No primary intracranial tumor by MRI or CT scan
No histologically confirmed squamous cell carcinoma of the lung
PATIENT CHARACTERISTICS:
Age
18 and over
Performance status
ECOG 0-2
Life expectancy
Not specified
Hematopoietic
WBC ≥ 3,500/mm^3
Absolute neutrophil count ≥ 1,500/mm^3
Hemoglobin ≥ 9.0 g/dL
Platelet count ≥ 100,000/mm^3
No severe or uncontrolled hematologic condition
Hepatic
Bilirubin ≤1.5 times upper limit of normal (ULN)
AST and ALT ≤ 2.5 times ULN
PT and PTT normal
INR normal
Hepatitis B surface antigen negative
Hepatitis C antibody negative
Renal
Creatinine ≤ ULN
Urine protein/creatinine ratio ≤ 1
No severe or uncontrolled renal condition
Cardiovascular
No clinically significant acute electrocardiographic abnormalities
LVEF normal by echocardiogram or MUGA within the past 12 months if there was prior exposure to anthracyclines
No untreated or uncontrolled hypertension
No blood pressure > 150/100 mm Hg (despite treatment)
No isolated systolic hypertension (i.e., systolic blood pressure > 180 mm Hg on at least 2 determinations [on separate days] within the past 3 months)
No New York Heart Association class II - IV heart disease
No active coronary artery disease requiring acute medical management
No angina requiring acute medical management
No congestive heart failure requiring acute medical management
No ventricular arrhythmia requiring acute medical management
No stroke or transient ischemic event within the past 6 months
No prior or concurrent peripheral vascular disease
No angiographically or ultrasonographically documented arterial or venous occlusive event
No symptomatic claudication
No symptomatic orthostatic hypotension
No other severe or uncontrolled cardiovascular condition
Pulmonary
No severe or uncontrolled pulmonary condition
No pulmonary embolism within the past 6 months
Immunologic
HIV negative
No severe or uncontrolled immunologic condition
No active current infection requiring antibiotics
No prior hypersensitivity reaction to any recombinant proteins, including VEGF Trap
Other
No severe or uncontrolled gastrointestinal or musculoskeletal condition
No psychiatric condition or adverse social circumstance that would preclude study participation
No other condition that would preclude study participation
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective double-barrier contraception during and for 3 months after study treatment
PRIOR CONCURRENT THERAPY:
Biologic therapy
See Disease Characteristics
No prior participation in a VEGF Trap, interleukin-1 Trap, or interleukin-4/13 Trap clinical trial
At least 3 weeks since prior immunotherapy and recovered
No concurrent epoetin alfa, filgrastim (G-CSF), or sargramostim (GM-CSF)
Chemotherapy
See Disease Characteristics
At least 3 weeks since prior chemotherapy and recovered
Endocrine therapy
No concurrent adrenal corticosteroids except low-dose replacement therapy
No concurrent systemic hormonal contraceptive agents
Radiotherapy
At least 3 weeks since prior radiotherapy and recovered
Surgery
At least 3 weeks since prior major or laparoscopic surgery and recovered
More than 6 months since prior surgical procedure for correction or prophylaxis of peripheral vascular insufficiency or cerebral ischemic events
Other
More than 30 days since prior investigational drugs
No concurrent anticoagulant or antiplatelet drugs (e.g., warfarin, heparin, or aspirin) other than low-dose (1 mg) warfarin for maintaining patency of venous access devices
No concurrent non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 (COX-2) inhibitors
No other concurrent anticancer investigational agents
No other concurrent anticancer therapy
| https://clinicaltrials.gov/ct2/show/record/NCT00083213 |
Difference between revisions of "Riboswitches" - GcatWiki
Difference between revisions of "Riboswitches"
<table><tbody><tr><td colspan=2> Revision as of 16:22, 13 November 2007 (view source) Erzwack (talk|contribs) (→ Design) ← Older edit</td><td colspan=2> Revision as of 22:18, 5 December 2007 (view source) Erzwack (talk|contribs) (→ From Concept to Wet Lab) Newer edit →</td></tr><tr><td colspan=2> Line 9:</td><td colspan=2> Line 9:</td></tr><tr><td></td><td> Simply using a visual check, a difference in color is visible between cells with the riboswitch but no theophylline or cells with the riboswitch and caffeine but no theophylline and cells with the riboswitch and theophylline. Quantification of the amount of beta-galactosidase showed that when theophylline was added the translation increased significantly above base-line. When no aptamer was cloned to make a riboswitch, beta-galactosidase did not vary significantly among the conditions of no ligand, caffeine, and theophylline.</td><td></td><td> Simply using a visual check, a difference in color is visible between cells with the riboswitch but no theophylline or cells with the riboswitch and caffeine but no theophylline and cells with the riboswitch and theophylline. Quantification of the amount of beta-galactosidase showed that when theophylline was added the translation increased significantly above base-line. When no aptamer was cloned to make a riboswitch, beta-galactosidase did not vary significantly among the conditions of no ligand, caffeine, and theophylline.</td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td> −</td><td> [[Image: Riboswitch.JPG]]</td><td> +</td><td> [[Image: Plate.JPG]][[Image:Beta.JPG]][[Image:Beta_bar.JPG]]</td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr></tbody></table>
Revision as of 22:18, 5 December 2007
Riboswitches are small sequences in mRNA that bind small molecules to regulate translation and occasionally transcription. Riboswitches occur naturally in both eukaryotes and prokaryotes. Desai and Gallivan hoped to find new synthetic riboswitches (riboswitches with new ligand specificities) by creating libraries of mutant riboswitches and using genetic selection to pick the functional ones of interest. Desai and Gallivan also employed riboswitches to screen for the presence of specific small molecules. In theory riboswitches are perfect because the number of aptamers already in existence and our capbaility to engineer new aptamers through rational design.
Design
Reviews of previous research showed that the theophylline aptamer worked in riboswitches in wheat germ, a eukaryote, and Bacillus subtilis, a gram positive bacterium. Desai and Gallivan decided to translate the technology to gram negative bacteria. To do this they cloned the theophylline aptamer five base pairs upstream of the RBS for lacZ. The gene is controlled by a weak promoter and a weak RBS allowing for sensitivity to changes in translation because of the presence of theophylline. The construct was then transformed into E. coli. When theophylline is added, translation should be turned on again.
From Concept to Wet Lab
Simply using a visual check, a difference in color is visible between cells with the riboswitch but no theophylline or cells with the riboswitch and caffeine but no theophylline and cells with the riboswitch and theophylline. Quantification of the amount of beta-galactosidase showed that when theophylline was added the translation increased significantly above base-line. When no aptamer was cloned to make a riboswitch, beta-galactosidase did not vary significantly among the conditions of no ligand, caffeine, and theophylline.
To further support that the theophylline was interacting with the aptamer and not just increasing protein translation through another route. By introducing a single point mutation that in vitrodecreases affinity for theophylline and increases affinity for 3-methylxanthine, the lab demonstrated that the translation in the presence of theophylline now was almost the same as translation without any small molecule while translation in the presence of 3-methylxanthine was significantly higher than base-line. These results suggest that the change in translation is controlled by the riboswitch and not some other mechanism.
Finally, the lab worked on optimization of the riboswitch by changing the position of the aptamer in relation to the RBS. The riboswitch showed a greater increase in beta-galactosidase when the aptamer was 8 base pairs upstream of the RBS than when the aptamer was either 2 or 5 base pairs upstream. This result could be because of the surrounding bases being purines or it could have something to do with the actual distance.
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ASI | Free Full-Text | A Design for Wayfinding: Developing a Mobile Application to Enhance Spatial Orientation at Taipei Metro
Taipei Metro, since its inception in 1996, has become the most important public transport option for commuters and travelers in the metropolitan Taipei area, delivering over two million daily rides. Nevertheless, the interior environment of Taipei Metro has a reputation for being disorienting, especially to the infrequent passengers. By incorporating the methods of behavioral mapping and visibility analysis, this study argues that the occurrence of disorientation is highly dependent on visual properties of Taipei Metro’s interior layout. Specifically, the number of decision-making stops and the visibility conditions of stairs and escalators are found to be particularly influential. To enhance the passengers’ wayfinding experience, a mobile application comprised of two components is proposed. The Route Planner is to advise the passengers to avoid the areas that cause disorientation, while the Navigator, by providing the panoramic views of certain locations, can help the passengers reach their destinations more easily.
A Design for Wayfinding: Developing a Mobile Application to Enhance Spatial Orientation at Taipei Metro
by Kuang-Ting Huang * and Meng-Yan Zhou
Department of Architecture, National Taipei University of Technology, Taipei 10608, Taiwan
*
Author to whom correspondence should be addressed.
Appl. Syst. Innov. 2021 , 4 (4), 91; https://doi.org/10.3390/asi4040091
Received: 6 October 2021 / Revised: 9 November 2021 / Accepted: 12 November 2021 / Published: 16 November 2021
(This article belongs to the Special Issue Selected Papers from Eurasian Conference on IEEE SSIM 2021 )
Abstract
Taipei Metro, since its inception in 1996, has become the most important public transport option for commuters and travelers in the metropolitan Taipei area, delivering over two million daily rides. Nevertheless, the interior environment of Taipei Metro has a reputation for being disorienting, especially to the infrequent passengers. By incorporating the methods of behavioral mapping and visibility analysis, this study argues that the occurrence of disorientation is highly dependent on visual properties of Taipei Metro’s interior layout. Specifically, the number of decision-making stops and the visibility conditions of stairs and escalators are found to be particularly influential. To enhance the passengers’ wayfinding experience, a mobile application comprised of two components is proposed. The Route Planner is to advise the passengers to avoid the areas that cause disorientation, while the Navigator, by providing the panoramic views of certain locations, can help the passengers reach their destinations more easily.
Keywords:
wayfinding
;
behavioral pattern
;
visibility
;
space syntax
1. Introduction
The Taipei Metro is a metro system serving the Taipei metropolitan area, and encompasses an area of approximately 2500 km 2 , which has a population of over seven million. Since its inception in 1996, the network of Taipei Metro has quickly expanded from 12 stations to 131, and from 10.5 km to 152.9 km [ 1 ]. In the same time frame, its daily ridership has also experienced a similar growth from forty thousand to over two million, making Taipei Metro the 22nd busiest metro system in the world [ 2 ].
Nevertheless, Taipei Metro has a reputation for being disorienting and confusing, especially to the infrequent passengers. According to a survey on its service quality conducted in 2020 by Taipei Rapid Transit Corporation, the control of passenger flow and the spatial disorientation are, respectively, rated as both the top and the second most in need of improvement by 38.7% and 33.5% of respondents [
3
]. As further detailed in the survey report, the most commonly identified cause of feeling disoriented is the complexity of the floor plan configuration and the lack of wayfinding guidance. Specifically, most of Taipei Metro stations have multiple underground levels that consist of a basement concourse and several boarding platforms (
Figure 1
). Inevitably, the vertical travel between different levels increases the difficulty for the passengers to find their way to either the exit gates or to specific destinations inside the station.
Figure 1. Typical floor plans of Taipei Metro stations.
To minimize the spatial disorientation in Taipei Metro stations, this paper firstly reviews the concept of spatial orientation and presents a case study of Zhongxiao Xinsheng Station using the methods of behavioral mapping and visibility analysis. Based on the data obtained from the case study, a mobile application that will enhance the wayfinding experience of passengers is proposed.
2. Spatial Orientation and Wayfinding in Metro Station
Spatial orientation has long been an important issue in the field of environmental psychology. Since the 1980s, there is a growing scholarship focusing on the identification of factors associated with wayfinding behaviors [ 4 , 5 , 6 ]. Among all identified factors, the authors of [ 7 ], through a review of existing literature, have distinguished two broad types as follows: user factors and environmental factors ( Table 1 ). The former is concerned with the relationship between the cognitive ability to assimilate spatial information and the navigating behaviors, while the latter is focused on the physical elements that may enhance or reduce the spatial cognition.
Table 1. Types of wayfinding factors.
For the type of user factors, the authors of [ 8 ] pointed out that aging is associated with the decline of spatial cognition and is a particularly important issue for studying spatial orientation. By comparing the wayfinding performance of different age groups, it is found that older adults not only demonstrate less effective spatial memory [ 9 ], and the ability to pick up environmental information [ 10 ] and establish logical association [ 11 ], they also need more directional guidance to find their way around. Regarding the environmental factors, the influence of floor plan configuration on wayfinding performance has received the most attention in published literature. Specifically, many studies suggested that in a spatially complex environment there is an observed increase of time needed to perform wayfinding tasks, the number of wrong turns, and the occurrence of backtracking [ 12 , 13 , 14 ].
Despite the rich literature on spatial orientation, most of it is carried out in hospitals, museums, and shopping malls. In the few studies that investigate metro stations, researchers unanimously affirm that the underground multi-level environment is the key factor affecting the passengers’ wayfinding performance [
15
]. The authors of [
16
], by examining the case of two metro stations in Brussels, specified that the main reasons are the absence of direct sunlight and the lack of recognizable spatial features, while the authors of [
17
] studied the case of Hong Kong, pointing out that most passengers lose their orientation during the vertical travel between different levels. The most common way to minimize the negative influence discussed above is to install directional signs and maps to help the passengers understand their orientation [
18
]. Nevertheless, to search for directional guidance itself may be a difficult wayfinding task, especially for the passengers with deficits in either mobility or spatial memory.
In the recent years, to overcome the issue of spatial disorientation, there is a growing interest among both software developers and academic researchers in applying mobile technology on wayfinding [ 19 ]. For example, 3D Wayfinder, developed by 3D Technologies R&D, uses short-range broadcast devices to provide customized digital signage for their users, while NaviLens by Neosistec is an enhanced kind of QR code that can be scanned to access wayfinding information [ 20 , 21 ]. Another example is the mobile application of Gate-to-Go proposed by [ 22 ]. It uses the reference number of platform screen doors and exit gates as the index to help the passengers locate their destinations and find the shortest routes. In sum, although the recent innovations on wayfinding technology have demonstrated the potential of mobile devices in enhancing the accessibility of directional information, not many of them have been formally tested and made available to the public. Despite the passengers’ dissatisfaction about spatial disorientation, especially in the case of the Taipei Metro, there has been a paucity of empirical studies devoted to the topic, until now. In order to fill in the literature gap and propose a viable solution, the rest of this study is structured as follows: Section 3 explains the methods employed in this case study. Section 4 provides the results of the case study and discusses the relationship between the passengers’ behavioral patterns and the metro station’s visibility conditions. In Section 5 , a mobile application called Rideway is presented as a solution to the issue of spatial disorientation. Section 6 concludes this study with a summary along with directions for future research.
3. Methods
To address the two types of factors reviewed above, two methods were applied in this study: behavioral mapping and visibility analysis.
3.1. Behavioral Mapping
Wayfinding is a decision-making process of determining a route from one location to another [
23
]. To understand the influence of user factors on the passengers’ wayfinding experience in metro stations, the method of behavioral mapping was employed in this study. Behavioral mapping is an observational research method that can simultaneously capture the observed behaviors, as well as the information about the environmental location and context where the behaviors take place. This method can not only record the actual use of a space, but more importantly, it can also denote how the environment is supporting or influencing that use. Meanwhile, behavioral mapping is a valuable method for recording environmental behaviors, because it does not rely on the self-report of users [
24
]. For the same reason, it is particularly valuable for capturing the wayfinding behaviors of metro passengers, with whom methods such as interviews and questionnaires may be less effective.
In practice, the observers were required to randomly pick up a passenger, either at the entrance level or platform level, follow him/her and record his/her movements and other behaviors, such as when they checked maps, chatted with friends, took phone calls, etc. The tracing could stop, either when he/she left the metro station or boarded the train. All records were first marked with a pen on a preprinted floor plan and then were converted into an analyzable format of data. Specifically, this study used the solid line to represent the choice of the shortest route between the concourse level and the platform level, and the dashed line to represent the actual route recorded by the observer. By making comparisons between the two types of routes, the purpose was to analyze the pattern of the passengers’ movement and, in the meanwhile, to identify the locations where the spatial disorientation occurred.
3.2. Visibility Analysis
To understand the influence of environmental factors on the passengers’ wayfinding experience, this study specifically applied the method of visibility analysis developed by space syntax. Space syntax is a body of theories and techniques that investigates the relationship between space and behavior. The core work of this theory was introduced by Bill Hillier and Julienne Hanson in 1984 [
25
]. Since then, it has experienced consistent development and has now become an active field, covering multiple overlapping disciplines such as: architecture, urban design, urban planning, transport, and interior design [
26
].
The method of visibility analysis was a space syntax method that features a quantitative analysis of visual properties in the built environment. Based on a graph representation of the gross geometry of built environment, the method could offer a comprehensive modelling of how the space may be used and perceived by its occupants [
27
]. In practice, the modelling method was processed using the open-source software depthMapX, developed by the Space Syntax Laboratory at the Bartlett, University College, London. As
Figure 2
A,B illustrated, the interior space of metro stations in the software was represented as a regular grid with units in the size of a foot step. By measuring the mutual visual relationship between every two grids, the software generated a table containing several visibility measures (depth, connectivity, integration, etc.) and, in the meanwhile, a graph (
Figure 2
D) with a color gradient showed the spatial distribution of visibility. The warmer colors indicated higher values, whereas the cooler colors indicated the lower values. Specifically, this study used the measure of integration as the primary indicator for assessing the visibility conditions of metro stations. The higher value of integration indicated the better permeability and accessibility.
Figure 2. Spatial representation in visibility analysis: ( A ) floor plan, ( B ) grid, ( C ) visual relations, and ( D ) visibility graph.
4. Analysis
To further explain how the methods presented above can be applied to explore the issue of spatial disorientation in the Taipei Metro, this study selected Zhongxiao Xinsheng station as the site for analyzing the behavior patterns and visibility conditions of passengers. As explained in the previous section, the analysis contained two interrelated parts: behavioral mapping and visibility analysis.
For behavioral mapping, it can be observed in the case of Zhongxiao Xinsheng that although most of the passengers were taking the shortest routes, disorientation still occurred quite often and had a very regular pattern. As illustrated in
Figure 3
, all the mismatches between solid lines (the shortest route) and dashed lines (the actual route of passengers) were located at either stairs or escalators, which indicated that most of the disorientation occurred when moving between different levels. For example, among transfer passengers there was a common hesitation and confusion about which stairs (or escalator) to take. Especially in the case of Zhongxiao Xinsheng, because there was a multi-story atrium in the center that provided a direct visual link between the platform at the second basement, and the concourse at the first basement. As such, after many transfer passengers disembarked from the train, they would follow the crowd and proceed upstairs without noticing where the stairs (or escalator) to the other platform actually were (as seen in the dashed line C in
Figure 3
). As a result, they were either driven to the wrong direction or became lost in the wrong platform.
Figure 3. Behavioral pattern of passengers in Zhongxiao Xinsheng.
The second portion of analysis was to quantify the influence of visibility condition on the passengers’ behaviors. As
Figure 4
demonstrated, the average value of visual integration for the concourse level of Zhongxiao Xinsheng station is 5.78, with the highest at 9.55 and the lowest at 3.29. In
Table 2
, it could be further observed that the areas showing the highest visibility were located where the movement of passengers heading to different destinations intersected (with the average value of integration at 9.12; not only 57.8% higher than the average but also the second highest among all spatial divisions). To further compare the results of visibility analysis with the behavioral patterns discussed earlier, two factors that were influential on the passengers’ wayfinding behaviors could be identified.
Figure 4. Visibility analysis of the concourse level at Zhongxiao Xinsheng station.
Table 2. Quantified comparison of visibility between different spatial divisions of the concourse level at Zhongxiao Xinsheng station.
First, the number of decision-making points during the passengers’ wayfinding process was important in influencing their orientation. As seen in
Figure 3
, every point of decision making was where disorientation could occur. Despite multiple directional signs posted, often the passengers still did not have enough visual aids to receive the information for making the right decision. Secondly, the direction of stairs and escalators in relation to the passengers’ movement was another important factor. The stairs and escalators were usually located between two corridors heading in opposite directions, and therefore had higher visibility (with the visual integration at 8.47, 46.5% higher than the average). However, because most of the stairs and escalators were massive and sight-blocking, many passengers when walking through the corridors could not decide where to go, due to the limited vision.
According to the above analysis, there was an apparent corresponding relationship between the passengers’ behavioral patterns and the metro station’s visibility conditions. To enhance the wayfinding experience in Taipei Metro, the following section proposes a mobile application called Rideway, comprising of two functional components: Route Planner and Navigator.
5. Design Solution
Based on the above analysis, the design of Rideway is aimed to generate an interactive route map that can guide the users to reach wherever they want to go. Specifically, the purpose is not simply to provide the shortest route between their origins and destinations, but more importantly, the route will help the app users to avoid the areas that may cause disorientation. As demonstrated in
Figure 5
, once the user opens Rideway, a map of overlapped layers will be displayed on the screen. On the bottom is the floorplan of metro station, with the user’s standing point represented as a red circle. On the top of the floorplan is a color gradient showing the likelihood of disorientation occurrence.
Figure 5. Interface of Rideway: ( A ) Home page and ( B ) Interactive map guiding the user to avoid disorientation.
For those users who already know where they are going, they can click the button on the upper-right corner and use the Route Planner (
Figure 6
). After specifying the destination, a recommended route between their present locations and their destinations will be automatically generated. While following the guiding route, the users will constantly receive notices reminding them of the potential disorientation (highlighted in the color purple). To obtain further directional information, the app users can use the Navigator by clicking the button next to Route Planner. The Navigator provides the users a panoramic view of the areas that they are about to walk into. In the panoramic view, the users can also find other useful information that can help them reach their destination more easily, such as floorplans, sections, directional signs, etc.
Figure 6. Components of Rideway for enhancing wayfinding.
In sum, the mobile application of Rideway is meant to enhance the wayfinding environment of Taipei Metro stations by providing the passengers an instant, easy access to directional guidance. Specifically, the design of Route Planner can help the passengers avoid disorientation, while the Navigator can provide panoramic views that facilitate the passengers to reach their destinations more easily. From avoiding the wrong turns and backtracking, to finding the right way, the passengers’ wayfinding experience is expected to be greatly enhanced in the following three ways: 1. Reducing the time needed for finding their way to a specific destination; 2. Avoiding the unnecessary detours, especially among the transfer passengers; 3. Relieving the congestion and improving the overall efficiency of circulation during rush hour.
6. Conclusions
This study, by analyzing the behavioral patterns and visibility conditions of Taipei Metro passengers, has found that both user factors and environmental factors are important in causing spatial disorientation. Especially for the aging population discussed earlier, their deficits in either mobility or spatial memory can be greatly amplified in the enclosed, multi-level environment of an underground metro station. To minimize the negative influence of spatial disorientation, we designed the mobile application of Rideway. Through our study of the passengers’ behavioral patterns and visibility conditions, Rideway can be easily accessed and used as a directional guidance for anyone in need. Meanwhile, the analytic methods and mobile application presented in this study can also be applied to other metro systems. Despite the differences in the spatial layout and the passengers’ wayfinding habits, we need to better understand the complexity of metro stations’ interior environments, and to enhance their quality of spatial orientation. In the future, more research should be conducted to refine the design of Rideway:
The spatial typology of metro stations is of great significance in influencing the passengers’ wayfinding behaviors. A comparison between different types of metro stations will reveal more details about how the environmental factors may enhance or reduce the passengers’ spatial cognition.
The current analysis of the metro stations’ visibility condition is still limited. Other associated types of information, such as the location of directional signs and maps, should also be considered in the analysis, to provide a more integrated view of wayfinding environment.
Author Contributions
Funding
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data is composed of two parts. The first part, the passengers’ behavioral mapping, was obtained by observation. The second part, the result of visibility analysis, was compiled by the authors by using the open-source software depthMapX.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Typical floor plans of Taipei Metro stations.
Figure 2. Spatial representation in visibility analysis: ( A ) floor plan, ( B ) grid, ( C ) visual relations, and ( D ) visibility graph.
Figure 3. Behavioral pattern of passengers in Zhongxiao Xinsheng.
Figure 4. Visibility analysis of the concourse level at Zhongxiao Xinsheng station.
Figure 5. Interface of Rideway: ( A ) Home page and ( B ) Interactive map guiding the user to avoid disorientation.
Figure 6. Components of Rideway for enhancing wayfinding.
Table 1. Types of wayfinding factors.
Type Subtype Element User factors Wayfinding cognition Spatial memories, logical association, information pick-up, neuroanatomy, etc. Wayfinding behavior Behavioral performance, navigation pattern Individual and group differences Age, sex, psychological state, culture Environmental factors Environmental elements Floor plan configuration, regions, edges, paths, nodes, landmarks Environmental cues Signs, maps, other environmental factors
Table 2. Quantified comparison of visibility between different spatial divisions of the concourse level at Zhongxiao Xinsheng station.
Division Intersection Atrium Aisle Entrance/Exit Visual Integration 9.12 (+57.8%) 9.34 (+61.6%) 3.87 (−33.0%) 4.67 (−19.2%) Division Service Information Elevator Stair/Escalator Visual Integration 6.04 (+4.5%) 5.89 (+1.9%) 7.34 (+26.9%) 8.47 (+46.5%)
Note: The number in brackets represent it’s percent difference with the average visual integration.
MDPI and ACS Style
Huang, K.-T.; Zhou, M.-Y. A Design for Wayfinding: Developing a Mobile Application to Enhance Spatial Orientation at Taipei Metro. Appl. Syst. Innov. 2021, 4, 91.
https://doi.org/10.3390/asi4040091
AMA Style
Huang K-T, Zhou M-Y. A Design for Wayfinding: Developing a Mobile Application to Enhance Spatial Orientation at Taipei Metro. Applied System Innovation. 2021; 4(4):91.
https://doi.org/10.3390/asi4040091
Chicago/Turabian Style
Huang, Kuang-Ting, and Meng-Yan Zhou. 2021. "A Design for Wayfinding: Developing a Mobile Application to Enhance Spatial Orientation at Taipei Metro" Applied System Innovation4, no. 4: 91.
https://doi.org/10.3390/asi4040091
| https://www.mdpi.com/2571-5577/4/4/91/html |
FCDO – UK Foreign, Commonwealth and Development Office (ehemals FCO) (Autor): „Pakistan - Country of Concern: latest update, 30 September 2014“, Dokument #1210990 - ecoi.net
Vierteljährliche Updates zur Menschenrechtslage
FCDO – UK Foreign, Commonwealth and Development Office (ehemals FCO) (Autor)
Pakistan - Country of Concern: latest update, 30 September 2014
There continued to be wide-ranging human rights concerns throughout this period, and little evidence of any reversal in previous trends.
In our previous update, published in July, we reported the Senate’s discussion of the Protection of Pakistan Citizens Act. In July, the National Assembly voted in a one-day special session to accept the act with Senate amendments. The act aims to tackle militancy, and the amendments made provide some human rights safeguards, including greater judicial oversight and a time-limited period of application. Under the act, suspects may be held for questioning for 60 days instead of the current limit of 15. One political party, Jamaat-i-Islami, sought to challenge the law in the Supreme Court, citing violations of citizens’ fundamental rights. The UK government continues to urge the Pakistani authorities to ensure that implementation of the legislation complies with international human rights standards.
In August, Human Rights Watch called on the government to rescind both the suspension of fundamental rights and the granting of a law enforcement role to the military in Islamabad. There are concerns that the powers given to the military risk misuse in the face of ongoing large-scale political protests; however, we have not seen evidence of misuse of these powers since August.
Reports of disappearances and extrajudicial killings continue. In September, the Asian Legal Resource Centre, an NGO, made awritten submission to the UN Human Rights Councilalleging incidents of extrajudicial killing throughout Pakistan, and media outlets have published articles regarding the discovery of suspected victims of extrajudicial killing in Balochistan.
As we also reported in the previous update, in June, the government of Pakistan launched a major operation to clear North Waziristan of militants. The area was largely evacuated of civilians before the operation, and currently more than one million people are registered as internally displaced as a result. However, only 580,000 of these have been verified and are receiving cash assistance from the government. A further 112,000 people have reportedly crossed the border into Afghanistan. The UK is providing significant assistance in this area: the Department for International Development operates a £7 million programme in Pakistan for those displaced within the country, and is delivering an additional £4.7 million to help the most vulnerable.
As of 29 September, serious flooding in the Kashmir and Punjab regions had affected around two million Pakistanis, with more than 300 reported dead. The government and military have provided relief to many of those affected. The UK stands ready to support the government’s efforts if required.
In the last three months, there were two major incidents of human rights concern linked to Pakistan’s blasphemy laws. In July, a man found guilty of writing blasphemous remarks on the wall of a Lahore park was sentenced to death and, in September, a policeman entered the prison cell of British national Mohammad Asghar and shot and seriously wounded him. Mr Asghar, who has a documented history of mental illness in the UK, was arrested last year in Pakistan on a charge of blasphemy; he has been tried under Pakistani law and sentenced to death.
Death sentences continued to be handed down for other offences, including a murder case in August. A man sentenced to death for murder in 1996 was scheduled to be executed on 18 September, but this has been stayed pending the outcome of an appeal hearing currently scheduled for October.
Journalists came under further attacks in the last three months. In July, Express News TV’s bureau chief in Peshawar was targeted with an improvised explosive device. This was the third attack on his house since March. Members of the local media community protested outside the Governor’s House about the lack of police protection. Also in July, a television journalist in Rawalpindi complained to police that he had received death threats from the Pakistani Taleban (TTP) and, in August, the Press Club in Khuzdar, Balochistan, was forced to close for ten days following threats to journalists. In a more hopeful development, a court dismissed a case lodged against Geo TV for broadcasting a “sacrilegious” programme.
Minorities continue to be targeted. An Ahmadiyya businessman was shot dead in July in Nawabshah and four Ahmadiyya men from Badin were charged with preaching their faith. At the end of July, an Ahmadiyya woman and two children were killed in Gujranwala when a mob set fire to houses following accusations of Ahmadiyyas posting blasphemous content on social media sites. Hindus in Hyderabad protested in July that local politicians and land mafia had been regularly harassing them to acquire temple land. Following the murder of two Hindu businessmen in Umerkot, a National Assembly special committee was empowered to investigate alleged murders, kidnappings and attacks on temples. At the end of July, two Hazara boys were found killed on a road in Quetta.
Sectarian killings were reported with greater regularity in the last three months. Shia and Sunni Muslims, including members of the Ahle Sunnat Wal Jamaat (ASWJ) and Majlis Wahdat-i-Muslimeen (MWM) religious parties, were killed in Karachi and Rawalpindi. In July, six men were found murdered at a shrine in Karachi, reportedly by Taleban-linked militants. On 10 September, Maulana Masood, son-in-law of Mufti Muhammad Naeem, was killed by unknown assailants in Karachi. Mufti Naeem is the head of one of the biggest Deobandi madrassas (Islamic seminaries) in Pakistan. On 21 September, Mufti Amanullah Khan, a Deobandi cleric, was shot dead by unknown assailants. Soon after the incident, protesters demonstrating against the killing of Mufti Amanullah attacked an Imambargah (Shia congregation hall) nearby. Protesters alleged the involvement of Shias in the killing of the Mufti. The Deputy Secretary General of pro-Shia party, Majlis Wahdatul Muslimeen (MWM), is being interrogated by police for this murder case.
This last incident occurred at the same location where Sunni-Shia riots, leading to the deaths of ten people, took place during last year’s Ashura (major festival for Shia Muslims). According to media reports, eye witnesses said that police were unwilling to control the mob torching the Imambargah.
On 18 September, Dr Muhammad Shakeel Auj, Dean of the Islamic Studies Department at Karachi University, was shot dead in his car. Dr Auj was considered a liberal scholar, and news reports suggest he was killed following accusations of blasphemy. Four of his colleagues are being investigated by police for perpetrating accusations of blasphemy. Reportedly, around the same time, a religious seminary in Karachi issued a fatwa against Dr Auj, accusing him of blasphemy and calling for his death.
There were also further violent attacks on women throughout this period. Couples and women were murdered in so-called “honour killings” in Mansehra, Nowshera, Shikarpur, Karachi, Sialkot, Faisalabad and numerous other locations across Pakistan. Three separate acid attacks on women and girls were reported in Balochistan in July. In the same month, Prime Minister David Cameron and the UN Children’s Fund (UNICEF) hosted the Girl Summit, which addressed child, early and forced marriages. In Pakistan nearly half of all marriages involve girls younger than 18, and 70% of girls are married before the age of 16.
Vierteljährliche Updates zur Menschenrechtslage
Land:
Pakistan
Quelle:
FCDO – UK Foreign, Commonwealth and Development Office (ehemals FCO) (Autor)
Originallink:
https://www.gov.uk/government/publications/pakistan-country-of-concern/pakistan-country-of-concern-latest-update-30-september-2014
Dokumentart:
Periodischer Bericht
Sprache:
Englisch
Veröffentlicht:
16. Oktober 2014
Dokument-ID:
1210990 (frühere ID 292369 )
| https://www.ecoi.net/de/dokument/1210990.html |
334655529 (Number)
Properties of 334,655,529: prime decomposition, primality test, divisors, arithmetic properties, and conversion in binary, octal, hexadecimal, etc.
334655529 (number)
334,655,529( three hundred thirty-four million six hundred fifty-five thousand five hundred twenty-nine) is an odd nine-digits composite number following334655528and preceding334655530. In scientific notation, it is written as 3.34655529 × 10 8.
The sum of its digits is 42. It has a total of 4 prime factors and 16 positive divisors.
There are 203,816,448 positive integers (up to 334655529) that are relatively prime to 334655529.
Properties
Name
Notation
Prime Factorization
Divisors
Other Arithmetic Functions
Divisibility test
Base converter
Classification
Basic calculations
Geometrical shape
Hash Functions
Basic properties
Is Prime? No
Number parity Odd
Number length 9
Sum of Digits 42
Digital Root 6
Name
Short name 334 million 655 thousand 529 Full name three hundred thirty-four million six hundred fifty-five thousand five hundred twenty-nine
Notation
Scientific notation 3.34655529 × 10 8 Engineering notation 334.655529 × 10 6
Prime Factorization of 334655529
Prime Factorization3 × 13 × 97 × 88463
Composite number
ω (n) Distinct Factors 4 Total number of distinct prime factors Ω (n) Total Factors 4 Total number of prime factors rad (n) Radical 334655529 Product of the distinct prime numbers λ (n) Liouville Lambda 1 Returns the parity of Ω( n ), such that λ( n ) = (-1) Ω( n ) μ (n) Mobius Mu 1 Returns: 1, if n has an even number of prime factors (and is square free) −1, if n has an odd number of prime factors (and is square free) 0, if n has a squared prime factor Λ (n) Mangoldt function 0 Returns log( p ) if n is a power p k of any prime p (for any k >= 1), else returns 0
The prime factorization of 334,655,529 is 3 × 13 × 97 × 88463. Since it has a total of 4 prime factors, 334,655,529 is a composite number.
Divisors of 334655529
1,3,13,39,97,291,1261,3783,88463,265389,1150019,3450057,8580911,25742733,111551843,334655529
16divisors
Even divisors 0 Odd divisors 16 4k+1 divisors 8 4k+3 divisors 8
τ (n) Total Divisors 16 Total number of the positive divisors of n σ (n) Sum of Divisors 485490432 Sum of all the positive divisors of n s (n) Aliquot Sum 150834903 Sum of the proper positive divisors of n A (n) Arithmetic Mean 30343152 Returns the sum of divisors (σ( n )) divided by the total number of divisors (τ( n )) G (n) Geometric Mean 18293.592566798 Returns the nth root of the product of n divisors H (n) Harmonic Mean 11.029029845021 Returns the total number of divisors (τ( n )) divided by the sum of the reciprocal of each divisors
The number 334,655,529 can be divided by 16 positive divisors (out of which 0 are even, and 16 are odd). The sum of these divisors (counting 334,655,529) is 485,490,432, the average is 30,343,152.
Other Arithmetic Functions (n = 334655529)
1 φ (n) n
φ (n) Euler Totient 203816448 Total number of positive integers not greater than n that are coprime to n λ (n) Carmichael Lambda 4246176 Smallest positive number such that a λ(n) ≡ 1 (mod n ) for all a coprime to n π (n) Prime Pi ≈ 18002908 Total number of primes less than or equal to n r 2 (n) Sum of 2 squares 0 The number of ways n can be represented as the sum of 2 squares
There are 203,816,448 positive integers (less than 334,655,529) that are coprime with 334,655,529. And there are approximately 18,002,908 prime numbers less than or equal to 334,655,529.
Divisibility of 334655529
m 2 3 4 5 6 7 8 9 n mod m 1 0 1 4 3 5 1 6
The number 334,655,529 is divisible by 3.
Classification of 334655529
By Arithmetic functions
Arithmetic
Deficient
Expressible via specific sums
Polite
By Powers
Square Free
Other numbers
LucasCarmichael
Base conversion (334655529)
Base System Value 2 Binary 10011111100100111000000101001 3 Ternary 212022201021002020 4 Quaternary 103330213000221 5 Quinary 1141132434104 6 Senary 53112455053 8 Octal 2374470051 10 Decimal 334655529 12 Duodecimal 940aa489 16 Hexadecimal 13f27029 20 Vigesimal 54bbig9 36 Base36 5j8tux
Basic calculations (n = 334655529)
Multiplication
n×y
n×2 669311058 n×3 1003966587 n×4 1338622116 n×5 1673277645
Division
n÷y
n÷2 167327764.500 n÷3 111551843.000 n÷4 83663882.250 n÷5 66931105.800
Exponentiation
n y
n 2 111994323090269841 n 3 37479519438771168392600889 n 4 12542728404447748468373930194165281 n 5 4197493409293787216542617378937454826488649
Nth Root
y √n
2 √n 18293.592566798 3 √n 694.27682415197 4 √n 135.25380795674 5 √n 50.689685993579
334655529 as geometric shapes
Circle
Radius = n
Diameter 669311058 Circumference 2102702702.7792 Area 3.5184054266415E+17
Sphere
Radius = n
Volume 1.5699384390523E+26 Surface area 1.4073621706566E+18 Circumference 2102702702.7792
Square
Length = n
Perimeter 1338622116 Area 111994323090269841 Diagonal 473274387.83494
Cube
Length = n
Surface area 671965938541619046 Volume 3.7479519438771E+25 Space diagonal 579640379.26184
Equilateral Triangle
Length = n
Perimeter 1003966587 Area 4.8494964437908E+16 Altitude 289820189.63092
Triangular Pyramid
Length = n
Surface area 1.9397985775163E+17 Volume 4.417003725128E+24 Height 273245095.21706
Cryptographic Hash Functions
md5 e49c6ce06695d2b2d622552ce521ec41 sha1 fa2028805ffa33fb3b76d61a6af151125656d588 sha256 8d848414ad4e14676f2f9a1aba7dfeb570b11488a2c51e17a68353f8f7043985 sha512 b9fad00b49ccc1a883c909d3526032a1bdad27579c7331445445e0b019a05506fd27d709170d30d16c7b16c7eface4fff13c654100a2bd8194ef7238c8d252b7 ripemd-160 05b1f750b9e41fd82c4dce55314c4dbd803610fe
| https://metanumbers.com/334655529 |
UNIPROT:Q5PY49 - FACTA Search
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Target Concepts:
Query: UNIPROT:Q5PY49 (
Urokinase plasminogen activator
)
119
Using immunohistochemistry and in situ hybridization, we have characterized the expression and localization of components of the plasminogen activator proteolytic cascade in an organotypic coculture system which consists of a "dermal" portion (human dermal fibroblasts throughout a collagen matrix) and a stratified, well-differentiated epidermal portion. Specifically, the following components were examined: the enzymes urokinase-type plasminogen activator and tissue-type plasminogen activator and their type 1 and type 2 inhibitors. Urokinase plasminogen activator mRNA and antigen were found predominantly in the least differentiated, basal keratinocytes; in some fields there was also faint deposition of antigen beneath the basal cells. The distribution of plasminogen activator inhibitor type 1 was similar to that of urokinase, except that inhibitor type 1 antigen deposition beneath the basal cells appeared more intense and uniform. In contrast to the results with urokinase plasminogen activator and inhibitor type 1, tissue plasminogen activator mRNA and antigen were localized focally in the suprabasal, i.e. more differentiated, keratinocytes. Plasminogen activator inhibitor type 2 mRNA and antigen were detected in most epidermal layers, but were more intense suprabasally and often spared the basal layer. These studies demonstrate that the same type of cell, i.e. the keratinocyte, can express different components of the plasminogen activator cascade depending on its state of differentiation. The change in expression of plasminogen activator cascade components with keratinocyte differentiation suggests distinct epidermal functions for these components, related to cell-matrix interaction and epidermal differentiation.
...
PMID:Differential expression of plasminogen activators and their inhibitors in an organotypic skin coculture system. 827 Jun 42
Urokinase plasminogen activator ( uPA ) and tissue plasminogen activator ( tPA ) were assayed in biopsies from the base, edge and adjacent skin of ischaemic and venous ulcers using a functional bioimmunoassay and a standard immunoassay. Two series of 14 biopsies were examined: from seven venous and seven ischaemic ulcers in the first series, eight venous and six ischaemic in the second. It was found that tPA was detected in only four samples of ulcer edge using the bioimmunoassay and in no sample by the standard immunoassay. By contrast, uPA was detected in all but one ulcer edge biopsy and at a significantly lower median concentration in the adjacent skin (16.9 units/g) than the ulcer edge (26.1 units/g) or base (32.3 units/g) (both P < 0.01). Levels of uPA were greater in the edge and base of venous compared with ischaemic ulcers. The predominant plasminogen activator in chronic leg ulcers is uPA ; this activator may play an important role in wound healing.
...
PMID:Tissue and urokinase plasminogen activators in the environs of venous and ischaemic leg ulcers. 851 96
Urokinase plasminogen activator ( uPA ) has been implicated in the healing responses of injured arteries, but the importance of its various properties that influence smooth muscle cell (SMC) proliferation and migration in vivo is unclear. We used three recombinant (r-) forms of uPA , which differ markedly in their proteolytic activities and abilities to bind to the uPA receptor (uPAR), to determine, which property most influences the healing responses of balloon catheter injured rat carotid arteries. After injury, uPA and uPAR expression increased markedly throughout the period when medial SMCs were rapidly proliferating and migrating to form the neointima. Perivascular application of uPA neutralizing antibodies immediately after injury attenuated the healing response, significantly reducing neointima size and neointimal SMC numbers. Perivascular application of r-uPAwt (wild type uPA ) or r- uPA /GDF (r-uPA with multiple mutations in its growth factor-like domain) doubled the size of the neointima. Four days after injury these two uPAs nearly doubled neointimal and medial SMC numbers in the vessels, and induced greater reductions in lumen size than injury alone. Proteolytically inactive r- uPA /H/Q (containing glutamine rather than histidine-204 in its catalytic site) did not affect neointima or lumen size. Also, in contrast to the actions of proteolytically active uPAs, tissue plasminogen activator ( tPA ) did not affect the rate of neointima development. We conclude that uPA is an important factor regulating the healing responses of balloon catheter injured arteries, and its proteolytic property, which cannot be mimicked by tPA , greatly influences SMC proliferation and early neointima formation.
...
PMID:Urokinase plasminogen activator augments cell proliferation and neointima formation in injured arteries via proteolytic mechanisms. 1173 Aug 9
The fibrinolytic characteristics and clinical pathological significance of pleural and ascitic fluid were studied in patients with malignant tumour, tuberculosis or liver cirrhosis. Urokinase plasminogen activator ( uPA ) and urokinase plaminogen activator receptor (uPAR) levels were measured by enzyme-linked immunoadsorbent assay and tissue plasminogen activator ( tPA ), plasminogen activator inhibitor-1 (PAI-1), plasminogen (Plg), plasmin (Pl) and alpha(2) plasmin inhibitor (alpha(2)PI) by colorimetric assay. uPA and uPAR levels were higher in malignant tumour and tuberculosis compared with liver cirrhosis, whereas tPA levels were significantly higher in liver cirrhosis and malignant tumour than in tuberculosis patients. Tuberculosis patients showed statistically higher PAI-1, Plg and Pl concentrations than malignant tumour patients, which, in turn, were higher than those in liver cirrhosis patients. alpha(2)PI levels were markedly higher in malignant tumour and liver cirrhosis than in tuberculosis. In the malignant tumour group, only uPA level was significantly different between the samples that contained cancer cells and those that did not. We found significant differences between the fibrinolytic characteristics in pleural and ascitic fluid in patients with malignant tumour, tuberculosis and liver cirrhosis. The analysis of several fibrinolytic parameters could help to determine the quality of pleural and ascitic fluid, and also to further understand the pathological processes of these diseases.
...
PMID:Fibrinolytic characteristics and their significance in malignant, tuberculous and cirrhotic pleural and ascitic fluids. 1747 86
Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease characterized in its early stages by synovial hyperplasia and inflammatory cell infiltration and later by irreversible joint tissue destruction. The plasminogen activation system (PAS) is associated with a wide range of physiological and pathophysiological states involving fibrinolysis, inflammation and tissue remodeling. Various components of the PAS are implicated in the pathophysiology of RA. Urokinase plasminogen activator ( uPA ) in particular is a pro-inflammatory mediator that appears to play an important role in the bone and cartilage destruction associated with RA. Clinical studies have shown that uPA and its receptor uPAR are overexpressed in synovia of patients with rheumatoid arthritis. Further, genetic knockdown and antibody-mediated neutralization of uPA have been shown to be protective against induction or progression of arthritis in animal models. The pro-arthritic role of uPA is differentiated from its haemodynamic counterpart, tissue plasminogen activator ( tPA ), which appears to play a protective role in RA animal models. This review summarises available evidence supporting the PAS as a critical determinant of RA pathogenesis and highlights opportunities for the development of novel uPAS-targeting therapeutics.
...
PMID:The Urokinase Plasminogen Activation System in Rheumatoid Arthritis: Pathophysiological Roles and Prospective Therapeutic Targets. 3051 4
Analysis of coagulation disorders and assessment of rebalanced hemostasis with the use of traditional coagulation assays is challenging in cirrhotic patients. Therefore, alternative tests are under investigation for the evaluation of coagulopathy in this specific setting. Aim of this study was to analyze the modifications of clot structure and function in cirrhotic patients with different degrees of severity. Cirrhotic patients referred to our Unit were consecutively enrolled. Global test measurements, including clot and lysis assays, clot lysis time, and determination of other fibrinolytic parameters, were performed. Analyses of clot formation, morphology, and lysis were performed with a turbidimetric clotting and lysis assay (EuroCLOT). Lysis of a tissue factor-induced clot by exogenous tissue plasminogen activator was analyzed by studying the modifications of turbidity during clot formation and the following lysis. We evaluated coagulative and fibrinolytic parameters in both plasma and ascites. Urokinase plasminogen activator ( uPA ) and gelatinase activity in ascites were also measured. We analyzed data from 33 cirrhotic patients (11 in Child-Pugh class A; 22 in class B or C and with ascites) and 21 healthy subjects (HS). In class B/C patients prolonged latency time, a decline in clotting absorbance, and decreased fibrin formation were observed in comparison with class A and HS. Generated curves and Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) progressively declined from HS to class C patients, whereas levels of plasminogen activator inhibitor-1 and tissue plasminogen activator increased. D-dimer levels were markedly increased in ascites, together with significantly smaller levels of TAFI, αlfa2-antiplasmin, and plasminogen. Caseinolytic activity was also present. Class C patients showed smaller amount of uPA and significantly lower levels of matrix metallopeptidases (MMP)2 in ascites in comparison with Class B subjects. Clot formation and lysis are altered in cirrhosis and fibrinolysis is activated in ascites. Ascitic levels of uPA and MMP2 are reduced and inversely related to the severity of liver disease.
...
PMID:Altered clot formation and lysis are associated with increased fibrinolytic activity in ascites in patients with advanced cirrhosis. 3244 64
| http://www.nactem.ac.uk/facta/cgi-bin/facta3.cgi?query=UNIPROT%3AQ5PY49%7C111111%7C0%7C0%7C37109%7C0%7C10 |
Sydney Harbour Dinner Cruises - which one is best? - Fodor's Travel Talk Forums
Australia & the Pacific - Sydney Harbour Dinner Cruises - which one is best? - Hi y'all. Anyone been on a Sydney Harbour Dinner cruise and what was the experience? I am looking to book one but not sure if John Cadman is worth the money or not? and has anyone else been on the really expensive 7 course dinner cruise?...
Sydney Harbour Dinner Cruises - which one is best?
Hi y'all. Anyone been on a Sydney Harbour Dinner cruise and what was the experience? I am looking to book one but not sure if John Cadman is worth the money or not? and has anyone else been on the really expensive 7 course dinner cruise? Going in early November 03. Please help.Thanks.
Hi, Clauds!
I guess there are three elements involved here: the sights you see, the commentary, and the food. While I have never heard anyone rave about the food on a harbour cruise, or even to state that it was good value for money, I haven't heard of any horror stories, either. It's just food.... not, of course, as good as you could get at any of the dozen restaurants within a few paces of where the cruise boat leaves from. So my feeling is that you wouldn't go on any of the cruises for the meal.
As for the harbour scenery: well, it's great, especially on a bright sunny day. I know this because I travel in the commuter ferries as often as possible. They are cheap, they leave every few minutes, you can buy a ticket for $13.40 which lets you travel all day and into the night as many times as you want, and they go into every nook and cranny of this wonderful harbour. There is nothing the dinner cruises can show you that you can't see as well, or better, from these. And by doing it this way, you get to rub shoulders with Aussies, not tourists, and you get to be boss of where you go, where you get off, and how long you stay in any place. So you wouldn't go on a Dinner Cruise for the scenery.
Lastly, there's the commentary. Well, you don't get that on a commuter ferry. When you sail past the Opera House, you will have to know, without being told, that this is the Opera House. When you go under the Harbour Bridge, no one will tell you that you are going under it; you'll have to work it out for yourself. So the dinner cruise wins hands down on this aspect. Then again, you could always go on a commuter ferry and take a guide book with you!
I have lived in Sydney now for more than sixty years. I never ever took one of those dinner cruises, because I have always thought that they were an almighty rip-off. However, I have heard tourists (some on this site) praise them highly. I guess it depends on what you want to do: see Sydney Harbour like the Sydneysiders see it, or do the expected tourist thing and line someone else's pocket.
Hi We've taken the Harbor dinner cruise on the Matilda and we really enjoyed it. Food was quite edible and we had no problems with it. With almost ten days in Sydney we used the ferries better than cabs and loved them!! We got to see so much in that beautiful city but we also thought it would be nice to take the dinner cruise on a fairly large catamaran. I'll pass our secret on to you - we did not buy a ticket until the afternoon we were taking the cruise. After 12 or 1 pm the tickets were reduced in cost and we had a really nice and fairly inexpensive 7 course dinner cruise. When the sun goes down the view becomes spectacular. We also had dinner at the Opera House the night we took in a show there. If you're going to enjoy their city, may as well do as much as possible.
I took my husband down to Sydney a couple of years ago for our Anniversary and a harbour dinner cruise - what a waste of money that was. Food - if you are Japanese and are into being shunted around in groups of 200 with food to match its OK. The show was too loud and you could not hear the commentary either for that matter. Value for money........ non or very little Food...................pathetic Cruise................. just about anything else would have been better Ambience............... none unless you are a sheep! Have a wonderful dinner and one of the harbourside venues, take in a show and a trip on the Manley ferry - you will have a much better evening for much less money!
Hey, Janese! You're starting to sound like a lady I used to know once, named LizF! (She was usually right, too, by the way!)
Hi Alan, thanks for that - it's kind of answered my question. I think we will use the ferry or even water taxi now and go to a restaunat that way. How good is the Peir on Rose Bay? C.
Hi, Clauds! Can't tell you a thing about Rose Bay Pier.... but I hear lots of nice things about Doyle's at Watson's Bay, right where the ferry stops. There's another nice-looking place at Mosman Bay, also very near the ferry. I can't comment on the food for either of these, but it's sure a nice way to travel to your restaurant! (And you could probably do one for lunch and the other for dinner and still be ahead, compared to the dinner cruise cost). There are also several nice restaurants around the pier area at Manly, and that is a VERY nice ferry ride, and quite a bargain if used in conjunction with the $13.40 all-day ticket.... you could, if you chose, travel back into the city by bus on the same ticket, which covers trains, buses and ferries.
If you have a $....get the sea plane flight from rose bay to pittwater and go to Jonahs at whale beach for lunch. Get back to manly by bus/cab and catch the manly ferry home.
Pier is excellent. Get the ferry there, and enjoy yourself. May be a tad expensive, but.... As an aside, don't count on a taxi to Bather's Pavilion taking 10 minutes. It's a fair way, and, if travelling in peak hours, could cost an absolute fortune! (but there is sometimes a ferry to Balmoral, as well!) But - horses for courses....
| https://www.fodors.com/community/australia-and-the-pacific/sydney-harbour-dinner-cruises-which-one-is-best-357208/?styleid=8 |
Tolerance Evaluation of Vegetatively Established Miscanthus × giganteus to Herbicides
Weed Technology publishes on how weeds are managed, including work on herbicides, weed biology, new control technologies, and reports of new weed issues.
Tolerance Evaluation of Vegetatively Established
Miscanthus
×
giganteus
to Herbicides
Xiao Li , Timothy L. Grey , Brian H. Blanchett , R. Dewey Lee , Theodore M. Webster , William K. Vencill
Author Affiliations +
Xiao Li, Timothy L. Grey, Brian H. Blanchett, R. Dewey Lee, Theodore M. Webster, William K. Vencill * * First author: Graduate Student, Department of Crop and Soil Sciences, University of Georgia, Athens GA 30602; Second, third and fourth authors: Professor, Graduate student and Professor, Department of Crop and Soil Sciences, University of Georgia, Tifton GA 31793; fifth author: Research Agronomist, Crop Protection and Management Research Unit, USDA-ARS. Tifton GA 31793; sixth author: Professor, Department of Crop and Soil Science, University of Georgia, Athens GA 30602. Corresponding author's E-mail: [email protected]
Weed Technology, 27(4) :735-740 (2013). https://doi.org/10.1614/WT-D-13-00050.1
Abstract
Giant miscanthus is under consideration as a biofuel crop in the United States; however, there is little information on weed management for the establishment and survival of this crop. Therefore, greenhouse and field studies using ornamental pots were conducted in summer 2011 at Tifton, GA, with the objective of screening potential PPI, PRE, and POST herbicides and herbicide combinations for giant miscanthus when establishing from vegetative rhizomes. For the POST treatments, giant miscanthus was established from rhizomes in 7.6-L containers in the field and treated with 27 POST herbicides to evaluate efficacy. Thifensulfuron, metsulfuron, tribenuron, chlorimuron, halosulfuron, rimsulfuron, cloransulam, pinoxaden, bentazon, and metribuzin did not significantly lower shoot height, reduce shoot dry weight, or increase injury compared with nontreated control (NTC) when evaluated at 4 wk after treatment. Nicosulfuron, trifloxysulfuron, sulfometuron, clodinafop, fluazifop, and pyrithiobac caused the greatest injury, reduced plant height, and reduced dry weights compared with the NTC. Sethoxydim, diclofop, flumioxazin, imazamox, imazapic, and imazethapyr decreased plant heights or resulted in increased injury. PPI and PRE treatments included 21 herbicides and herbicide combinations applied at two rates. Results indicated that most treatments containing atrazine, metribuzin, pendimethalin, acetochlor, metolachlor, and mesotrione did not injure or stunt growth; however, EPTC at 4.5 kg ai ha −1significantly reduced height and dry weight and oxadiazon resulted in greater injury compared with NTC at both rates. These results indicate that PPI, PRE, and POST herbicides can be utilized for establishment of giant miscanthus from vegetative rhizomes. Considering the invasive potential of giant miscanthus, several POST herbicides evaluated in this study such as fluazifop, pyrithiobac, and sulfometuron may be viable options to control this species if it becomes invasive.
Nomenclature:Acetochlor; atrazine; bentazon; chlorimuron; clodinafop; cloransulam; diclofop; EPTC; fluazifop; flumioxazin; halosulfuron; imazamox; imazapic; imazethapyr; mesotrione; metribuzin; metolachlor; metsulfuron; nicosulfuron; oxadiazon; pendimethalin; pinoxaden; pyrithiobac; rimsulfuron; sethoxydim; sulfometuron; thifensulturon; tribenuron; trifloxysulfuron; giant miscanthus, Miscanthus× giganteus.
Se está considerando a Miscanthus× giganteus(miscanthus) como cultivo para biocombustibles en los Estados Unidos. Sin embargo, hay poca información acerca del manejo de malezas para el establecimiento y supervivencia de este cultivo. Por esta razón, en el verano 2011 en Tifton, GA, se realizaron experimentos de invernadero y de campo usando macetas para ornamentales, con el objetivo de evaluar herbicidas potenciales PPI, PRE, y POST y combinaciones de herbicidas para miscanthus en establecimiento a partir de rhizomas vegetativos. Para los tratamientos POST, miscanthus se estableció a partir de rhizomas en macetas de 7.6 L en el campo y fue tratado con 27 herbicidas POST para evaluar su eficacia. Thifensulfuron, metsulfuron, tribenuron, chlorimuron, halosulfuron, rimsulfuron, cloransulam, pinoxaden, bentazon, y metribuzin no redujeron significativamente la altura o el peso seco del tejido aéreo, ni incrementaron el daño al compararse con el testigo no-tratado (NTC) cuando se evaluó a 4 semanas después del tratamiento. Nicosulfuron, trifloxysulfuron, sulfometuron, clodinafop, fluazifop, y pyrithiobac causaron el mayor daño, redujeron la altura de planta y el peso seco al compararse con NTC. Sethoxydim, diclofop, flumioxazin, imazamox, imazapic, e imazethapyr disminuyeron la altura de planta o resultaron en mayor daño. Los tratamientos PPI y PRE incluyeron 21 herbicidas y combinaciones de los herbicidas, aplicados a dos dosis. Los resultados indicaron que la mayoría
Citation
Xiao Li , Timothy L. Grey , Brian H. Blanchett , R. Dewey Lee , Theodore M. Webster , and William K. Vencill "Tolerance Evaluation of Vegetatively Established Miscanthus × giganteus to Herbicides," Weed Technology 27(4), 735-740, (1 October 2013). https://doi.org/10.1614/WT-D-13-00050.1
Received: 28 March 2013; Accepted: 1 June 2013; Published: 1 October 2013
Price: $20.00
| https://bioone.org/journals/weed-technology/volume-27/issue-4/WT-D-13-00050.1/Tolerance-Evaluation-of-Vegetatively-Established-Miscanthus--giganteus-to-Herbicides/10.1614/WT-D-13-00050.1.short |
Simulation and design of an electron beam ion source charge breeder for the californium rare isotope breeder upgrade (Journal Article) | DOE PAGES
The U.S. Department of Energy's Office of Scientific and Technical Information
Title:
Simulation and design of an electron beam ion source charge breeder for the californium rare isotope breeder upgrade
Full Record Other Related Research
Authors:
Dickerson, Clayton ; Mustapha, Brahim ; Pikin, Alexander ; Kondrashev, Sergey ; Ostroumov, Peter ;
Levand, Anthony ; Fischer, Rick
Publication Date:
2013-02-15
Sponsoring Org.:
USDOE
OSTI Identifier:
1074671
Resource Type:
Published Article
Journal Name:
Physical Review Special Topics - Accelerators and Beams
Additional Journal Information:
Journal Volume: 16; Journal Issue: 2; Journal ID: ISSN 1098-4402
Publisher:
American Physical Society
Country of Publication:
United States
Language:
English
Citation Formats MLA APA Chicago BibTeX Dickerson, Clayton, Mustapha, Brahim, Pikin, Alexander, Kondrashev, Sergey, Ostroumov, Peter, Levand, Anthony, and Fischer, Rick. Simulation and design of an electron beam ion source charge breeder for the californium rare isotope breeder upgrade . United States: N. p., 2013.
Web. doi:10.1103/PhysRevSTAB.16.024201. Copy to clipboard Dickerson, Clayton, Mustapha, Brahim, Pikin, Alexander, Kondrashev, Sergey, Ostroumov, Peter, Levand, Anthony, & Fischer, Rick. Simulation and design of an electron beam ion source charge breeder for the californium rare isotope breeder upgrade . United States. https://doi.org/10.1103/PhysRevSTAB.16.024201 Copy to clipboard Dickerson, Clayton, Mustapha, Brahim, Pikin, Alexander, Kondrashev, Sergey, Ostroumov, Peter, Levand, Anthony, and Fischer, Rick. Fri .
"Simulation and design of an electron beam ion source charge breeder for the californium rare isotope breeder upgrade". United States. https://doi.org/10.1103/PhysRevSTAB.16.024201. Copy to clipboard @article{osti_1074671, title = {Simulation and design of an electron beam ion source charge breeder for the californium rare isotope breeder upgrade}, author = {Dickerson, Clayton and Mustapha, Brahim and Pikin, Alexander and Kondrashev, Sergey and Ostroumov, Peter and Levand, Anthony and Fischer, Rick}, abstractNote = {}, doi = {10.1103/PhysRevSTAB.16.024201}, journal = {Physical Review Special Topics - Accelerators and Beams}, number = 2, volume = 16, place = {United States}, year = {2013}, month = {2} } Copy to clipboard
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Similar Records in DOE PAGES and OSTI.GOV collections: Simulation and design of an electron beam ion source charge breeder for the californium rare isotope breeder upgrade Journal Article Dickerson, C. ; Pikin, A. ; Mustapha, B. ; ... - Physical Review Special Topics: Accelerators and Beams https://doi.org/10.1103/PhysRevSTAB.16.024201 Design of the injection beamline for the Californium Rare Isotope Breeder Upgrade electron beam ion source charge breeder Journal Article Dickerson, C A ; Mustapha, B ; Kondrashev, S ; ... - Review of Scientific Instruments
The design of the ion injection line connecting the electron beam ion source (EBIS) charge breeder and the Californium Rare Isotope Breeder Upgrade radio frequency quadrupole cooler-buncher at the Argonne Tandem Linear Accelerator System was investigated with particle tracking simulations. The injection line was configured to accommodate several differential pumping sections, individual optical components were optimized to minimize emittance growth, and the ion beam parameters were matched with the EBIS electron beam acceptance to minimize losses upon injection. https://doi.org/10.1063/1.3662958 Design of the injection beamline for the Californium Rare Isotope Breeder Upgrade electron beam ion source for charge breeder Journal Article A, Dickerson C ; Pikin, A ; Mustapha, B ; ... - Review of Scientific Instruments
The design of the ion injection line connecting the electron beam ion source (EBIS) charge breeder and the Californium Rare Isotope Breeder Upgrade radio frequency quadrupole cooler-buncher at the Argonne Tandem Linear Accelerator System was investigated with particle tracking simulations. The injection line was configured to accommodate several differential pumping sections, individual optical components were optimized to minimize emittance growth, and the ion beam parameters were matched with the EBIS electron beam acceptance to minimize losses upon injection. https://doi.org/10.1063/1.3662958 Development of electron beam ion source charge breeder for rare isotopes at Californium Rare Isotope Breeder Upgrade Journal Article Kondrashev, S ; Dickerson, C ; Levand, A ; ... - Review of Scientific Instruments
Recently, the Californium Rare Isotope Breeder Upgrade (CARIBU) to the Argonne Tandem Linac Accelerator System (ATLAS) was commissioned and became available for production of rare isotopes. Currently, an electron cyclotron resonance ion source is used as a charge breeder for CARIBU beams. To further increase the intensity and improve the purity of neutron-rich ion beams accelerated by ATLAS, we are developing a high-efficiency charge breeder for CARIBU based on an electron beam ion source (EBIS). The CARIBU EBIS charge breeder will utilize the state-of-the-art EBIS technology recently developed at Brookhaven National Laboratory (BNL). The electron beam current density in the more » CARIBU EBIS trap will be significantly higher than that in existing operational charge-state breeders based on the EBIS concept. The design of the CARIBU EBIS charge breeder is nearly complete. Long-lead components of the EBIS such as a 6-T superconducting solenoid and an electron gun have been ordered with the delivery schedule in the fall of 2011. Measurements of expected breeding efficiency using the BNL Test EBIS have been performed using a Cs{sup +} surface ionization ion source for external injection in pulsed mode. In these experiments we have achieved {approx}70% injection/extraction efficiency and breeding efficiency into the most abundant charge state of {approx}17%. « less https://doi.org/10.1063/1.3660823 Development of electron beam ion source charge breeder for rare isotopes at Californium Rare Isotope Breeder Upgrade Journal Article Kondrashev, S ; Alessi, J ; Dickerson, C ; ... - Review of Scientific Instruments
Recently, the Californium Rare Isotope Breeder Upgrade (CARIBU) to the Argonne Tandem Linac Accelerator System (ATLAS) was commissioned and became available for production of rare isotopes. Currently, an electron cyclotron resonance ion source is used as a charge breeder for CARIBU beams. To further increase the intensity and improve the purity of neutron-rich ion beams accelerated by ATLAS, we are developing a high-efficiency charge breeder for CARIBU based on an electron beam ion source (EBIS). The CARIBU EBIS charge breeder will utilize the state-of-the-art EBIS technology recently developed at Brookhaven National Laboratory (BNL). The electron beam current density in the more » CARIBU EBIS trap will be significantly higher than that in existing operational charge-state breeders based on the EBIS concept. The design of the CARIBU EBIS charge breeder is nearly complete. Long-lead components of the EBIS such as a 6-T superconducting solenoid and an electron gun have been ordered with the delivery schedule in the fall of 2011. Measurements of expected breeding efficiency using the BNL Test EBIS have been performed using a Cs{sup +} surface ionization ion source for external injection in pulsed mode. In these experiments we have achieved {approx}70% injection/extraction efficiency and breeding efficiency into the most abundant charge state of {approx}17%. « less https://doi.org/10.1063/1.3660823 Similar Records | https://www.osti.gov/pages/biblio/1074671-simulation-design-electron-beam-ion-source-charge-breeder-californium-rare-isotope-breeder-upgrade |
William McKinley
William McKinley 25th President of the United States
Who was
the First U.S. President?
There were actually four first
Presidents
of the United Colonies and States of America
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William Mc Kinley
35th President of the United States
25th under the US Constitution
Message of President William McKinley nominating John Sherman to be Secretary
of State -- Courtesy of:
National Archives and
Records Administration
WILLIAM McKinley, Jr. was born in
Niles, Ohio on January 29, 1843. He was the seventh of the nine children of
William and Nancy Allison McKinley. Both of his grandfathers had fought in the
Revolutionary War and his father’s father had opened a small iron foundry and
settled in Niles, Ohio. His mother was a strong woman and a leader in their
small village. When William was nine, she moved her family to nearby Poland,
Ohio in order that they could pursue a better education, leaving their father
behind for a few years to manage the family foundry.
McKinley was enrolled at Poland Seminary, which was a private school, and
he studied there for eight years. He showed great skills in oratory and became
president of the Everett Literary and Debating Society. His mother held a great
influence over young McKinley and he was greatly attached to her. She had hopes
that he would enter the Methodist ministry and he accepted without question her
strict moral standards.
When he was seventeen, McKinley went to Allegheny College in Meadville,
Pennsylvania. However, his studies there were cut short by an illness. He
returned home in 1861 and taught school briefly. That same year as the Civil War
broke out, McKinley enlisted in the 23rd Ohio Volunteers. His superior officer
was Major Rutherford B. Hayes, the future president of the United States.
McKinley’s bravery under fire impressed Hayes and he was promoted and
eventually made an aide on Hayes’s staff. McKinley left the army in 1865 with
the rank of major.
After the war, McKinley began the study of law in the office of county
judge Charles E. Glidden of Youngstown. In 1866 he attended law school in
Albany, New York and the following year was admitted to the Ohio bar. He settled
in Canton, Ohio to practice law and participate in politics. He was moderately
successful as a lawyer, but became one of Canton’s most popular citizens. He
worked successfully on the campaign of Hayes, his former commanding officer. In
1869, Republican McKinley was elected the prosecuting attorney for Democratic
Stark County. He also had met his future wife, Ida Saxton, daughter of a wealthy
Canton businessman and banker. Two yea.rs later, on January 25, 1871, they were
married. The couple had two daughters, Katherine McKinley, born in 1871 and Ida
McKinley, who died after five months. After Ida’s death in 1873, Mrs. McKinley
suffered a mental breakdown and when Katherine died from typhoid fever in 1873,
it became more than she could bear. She suffered seizures and bouts of mental
depression for the rest of her life
In 1876, McKinley at the age of 33 was elected to represent the
northeastern Ohio district in Congress. He held that seat for 14 years with the
exception of one term. He was noted for his honesty, and as a powerful speaker
– a hardworking, conservative politician.
In 1889, McKinley was elected chairman of the House Ways and Means
Committee, which developed financial legislation and he became a prominent
national figure. In 1890, he wrote the McKinley Tariff Act that imposed the
highest tariffs that the United States had ever placed on imports. It was
devised to protect all American manufacturers but it was very unpopular because
it made it hard for Americans to purchase cheap foreign goods.
McKinley attracted the attention of Cleveland industrialist, Marcus A.
Hanna who was eager to be the maker of a president and to be the man who
exercised power behind the scenes. McKinley was a champion of protective tariffs
and an extremely popular politician and with Hanna’s help, he was elected
Governor of Ohio in 1891. Governor McKinley supported tax reform including
higher rates for corporations and even though he had called out the National
Guard on a coal miner strike that had turned violent, he retained the support of
the workingman.
In 1893, McKinley’s political career was almost ruined when a friend
went bankrupt and left McKinley responsible for debt of $130,000 through bank
notes he had endorsed. Hanna and his wealthy friends who repaid the debt saved
McKinley.
In 1896, with the aid of Hanna, who had left his private business to
devote full time to his candidacy, McKinley was nominated for the presidency.
His opponent was William Jennings Bryan, the Democratic nominee. The campaign
was unusual. Bryan toured the country delivering his famous “cross of gold”
speech and McKinley waged a “front porch” campaign from his home in Canton.
Hanna urged big businesses to rally in support of McKinley and they contributed
an unprecedented sum of $3.5 million to the Republican campaign. The country was
flooded with McKinley pamphlets and posters and factory managers warned their
workers that a victory for Bryan would mean depression and loss of their jobs.
Sweeping all the large industrial states, McKinley won the election by 271
electoral votes to Bryan’s 176. The Republicans also won control of both
houses of Congress. During the next four years McKinley was able to fulfill
party pledges and for the next 14 years, there was unbroken Republican control
of the Presidency, the Senate and the House.
At 54 years of age, McKinley was a handsome vigorous man at his
inauguration. Despite Ida’s poor health, she accompanied her husband and took
part in many of the social activities of the White House. McKinley never allowed
formal duties to interfere with his care for her. His attentiveness to her and
his concern for domestic harmony was mirrored in his efforts to seek harmony in
society at large.
In the friendly atmosphere of the McKinley Administration, industrial
combinations developed at an unprecedented pace. Prosperity returned and took
the demands for economic reform out of the picture. McKinley openly represented
large business interests; he sponsored no reform legislation and ignored
existing laws that were designed to regulate big business. But foreign policy
dominated the McKinley Administration, as many businesses began to favor
expanded foreign trade to obtain new markets for their products.
On February 15, 1898, the American battleship Maine exploded in the
Havana, Cuba harbor and 266 men died. On April 25th, Congress enacted a
resolution declaring war on Spain and in the 100-day war; the United States
destroyed the Spanish fleet outside Santiago harbor in Cuba, seized Manila in
the Philippines and occupied Puerto Rico. Successful conclusion of the war with
Spain brought peace to Cuba and economic concessions to American business.
McKinley also supported the annexation of Hawaii in 1898. In 1893,
American businessmen had overthrown Hawaiian Queen Liliuokalani with help from
American troops. President Grover Cleveland had found the rebellion dishonorable
and refused to annex the islands. McKinley saw the issue differently stating the
country needed Hawaii just as much and more that we did California.
In 1900, McKinley again campaigned against Bryan. Although McKinley did
not personally campaign, he received the largest popular majority ever given a
presidential candidate up to that time. He led in electoral votes 292 to 155.
On March 4, 1901, McKinley was inaugurated for a second time. His term
began auspiciously, but came to a tragic end in September. He appeared at the
Pan American Exposition in Buffalo, New York to make an important speech on
America’s world role. On September 6th, while greeting visitors in the Temple
of Music at the fair, twice Leon Czolgosz, a deranged anarchist, shot McKinley.
One bullet grazed his ribs and a second bullet penetrated his abdomen. The crowd
pounced upon Czolgosz and only McKinley’s order “Don’t let them hurt
him” saved Czolgosz from a fatal beating. Despite early hopes for his
recovery, McKinley died eight days later on September 14, 1901 in Buffalo.
Czolgosz was executed in October in Auburn, New York.
Presidents
of the Continental Congress
United Colonies of The United States
Peyton
Randolph
September 5, 1774 to October 22, 1774
and May 20 to May 24, 1775
Henry Middleton
October 22, 1774 to October 26, 1774
John
Hancock
October 27, 1775 to July 1, 1776
Presidents
of the Continental Congress
United States of America
John
Hancock
July 2, 1776 to October 29, 1777
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Laurens
November 1, 1777 to December 9, 1778
John
Jay
December 10, 1778 to September 28, 1779
Samuel
Huntington
September 28, 1779 to February 28, 1781
Presidents of the United States
in Congress Assembled
Samuel
Huntington
1st President of the United States
in Congress Assembled
March 1, 1781 to July 6, 1781
Thomas
McKean
2nd President of the United States
in Congress Assembled
July 10, 1781 to November 5, 1781
John
Hanson
3rd President of the United States
in Congress Assembled
November 5, 1781 to November 4, 1782
Elias
Boudinot
4th President of the United States
in Congress Assembled
November 4, 1782 to November 3, 1783
Thomas
Mifflin
5th President of the United States
in Congress Assembled
November 3, 1783 to June 3, 1784
Richard
Henry Lee
6th President of the United States
in Congress Assembled
November 30, 1784 to November 23, 1785
John
Hancock
7th President of the United States
in Congress Assembled
November 23, 1785 to June 6, 1786
Nathaniel
Gorham
8th President of the United States
in Congress Assembled
June 1786 - November 13, 1786
Arthur
St. Clair
9th President of the United States
in Congress Assembled
February 2, 1787 to October 29, 1787
Cyrus
Griffin
10th President of the United States
in Congress Assembled
January 22, 1788 to March 4, 1789
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United States Constitution
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Washington (F)
John
Adams (F)
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James Madison (D-R)
James Monroe (D-R)
John Quincy Adams (D-R)
Andrew
Jackson (D)
Martin
Van Buren (D)
William H. Harrison (W)
John Tyler (W)
James K. Polk (D)
David Atchison (D)*
Zachary Taylor (W)
Millard
Fillmore (W)
Franklin
Pierce (D)
James
Buchanan (D)
Abraham Lincoln (R)
Jefferson Davis (D)**
Andrew Johnson (R)
Ulysses S. Grant (R)
Rutherford
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James
A. Garfield (R)
Chester Arthur (R)
Grover
Cleveland (D)
Benjamin
Harrison (R)
Grover Cleveland (D)
William McKinley (R)
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George H. W. Bush (R)
William Jefferson Clinton (D)
George W. Bush (R)
*President for One Day
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An Epidemiological Overview of the Relationship Between HRT and Breast Cancer
PR positive breast cancer,PR+ breast cancer,breast carcinoma,epidemiology,estrogen,estrogen therapy,hormone replacement therapy,hrt (hormone replacement therapy),malignant breast neoplasm,postmenopausal hormone replacement therapy,progesterone receptor positive breast cancer
An Epidemiological Overview of the Relationship Between Hormone Replacement Therapy and Breast Cancer
HRT-associated Breast Cancer Risk is Modulated by Obesity: RRs are Greater in Thinner Women
A large body of evidence exists to suggest that the RRs for breast cancer associated with use of HRT are attenuated in overweight and obese women. [ 3 , 7 , 38 ]Updated analyses from the Million Women Study have found that, compared with those who had never used HRT, the RR of breast cancer for users of estrogen-only HRT was 1.65 (95% CI: 1.54–1.76) in women with a BMI <25 kg/m 2, but 1.22 (95% CI: 1.15–1.30) in women with a BMI of 25 kg/m 2or more. Similarly, for users of combined HRT, the corresponding RRs were 2.20 (95% CI: 2.11–2.30) and 1.81 (95% CI: 1.73–1.90), respectively. [ 8 ]
These recent findings from the Million Women Study have also clarified that the attenuation of the RR with increasing BMI is likely to be driven by the underlying adiposity-related increasing breast cancer incidence among never-users of HRT (the usual reference group for RR calculations of HRT-associated risk). [8]
Cite this: An Epidemiological Overview of the Relationship Between Hormone Replacement Therapy and Breast Cancer - Medscape- May 01, 2011.
Abstract and Introduction
The Use of HRT Increases the Risk of Breast Cancer
The Increased Breast Cancer Risk is Greater for Combined Estrogen–Progestin Therapies than for Estrogen-only Therapies
Current Evidence Indicates Similar Breast Cancer Risks for different Formulations, Doses & Routes of HRT Administration
Breast Cancer Risk Increases with Increasing Duration of HRT Use
The Increased Breast Cancer Risk Diminishes Rapidly After Ceasing Use of HRT
Current Evidence Suggests Greater Increases in Breast Cancer Risk Among Women Initiating HRT Use Closer to Menopause
HRT-associated Breast Cancer Risk is Modulated by Obesity: RRs are Greater in Thinner Women
HRT Use Lowers the Sensitivity & Specificity of Mammographic Screening for Breast Cancer
The HRT-associated Breast Cancer Risk is Higher for Certain Tumor Types
Use of HRT is Associated with a Greater Risk of Estrogen Receptor-positive Breast Cancer
Ecological Trends in Breast Cancer Incidence Reflect Population-level Utilization of Hormone Therapy
Use of HRT is Associated with a Higher Risk of Dying from Breast Cancer
Mechanistic Studies Support the Plausibility of the Epidemiologic & Trial Findings
Overall, the Risks Associated with the Use of HRT Outweigh its Benefits, in Terms of the Risk of Serious Disease
Regulatory Authorities Recommend That HRT be Used by Symptomatic Women Only, for the Shortest Time Possible
Expert Commentary
Five-year View
References
Sidebar 1
Sidebar 3
Table 1.
Estimated relative risks in current versus never-users of hormone replacement therapy, by histological type of breast cancer. Study (year) Study type Preparation type Histological subtype studied Relative risk estimates (95% CI) Ref. Collins et al. (2005) Meta-analysis CombinedM Estrogen only Lobular Ductal Lobular Ductal 2.82 (1.95–4.07) 1.15 (0.86–1.54) 1.44 (0.97–2.13) 0.90 (0.69–1.18) [48] Million Women Study and meta-analysis – Reeves et al. (2006) Cohort study Meta-analysis of Million Women Study and other available data Combined Estrogen only Combined Estrogen only Lobular Ductal Tubular Lobular Ductal Tubular Lobular Ductal Tubular Lobular Ductal Tubular 2.80 (2.46–3.18) 2.00 (1.89–2.12) 3.51 (2.80–4.41) 1.68 (1.43–1.96) 1.22 (1.13–1.31) 1.81 (1.36–2.42) 2.51 (2.27–2.77) 1.76 (1.68–1.85) 3.57 (2.93–4.36) 1.42 (1.27–1.57) 1.10 (1.05–1.15) 1.77 (1.34–2.33) [7] Calle et al. (2009) Cohort study Combined Estrogen only Lobular Ductal Lobular Ductal 2.12 (1.62–2.77) 1.75 (1.53–2.01) 1.30 (0.94–1.78) 0.99 (0.84–1.17) [50] Phipps et al. (2010) Cohort study – Breast Cancer Surveillance Consortium Mostly combined Estrogen only Lobular Ductal Lobular Ductal 1.46 (1.25–1.70) 1.17 (1.11–1.23) 1.26 (1.03–1.54) 0.98 (0.91–1.05) [49]
Authors and Disclosures
Usha Salagame 1 , Karen Canfell †1 and Emily Banks 2 1Cancer Epidemiology Research Unit, Cancer Council NSW, Sydney, Australia 2National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT, 0200 Australia † Author for correspondenceTel.: +61 293 341 852 Fax: +61 283 023 [email protected]
Medscape: Continuing Medical Education Online
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.
Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s) ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation atwww.medscape.org/journal/expertendo; (4) view/print certificate.
Sidebar 2
Learning objectives
Upon completion of this activity, participants will be able to:
Analyze the risk for breast cancer associated with different types of HRT
Evaluate how the timing of HRT affects the risk for breast cancer
Distinguish other factors which contribute to HRT's associated risk for breast cancer
Apply the results of the current review to prescribe postmenopausal hormone therapy effectively
Sidebar 3
Key Issues
The use of hormone replacement therapy (HRT) increases the risk of breast cancer.
The increased breast cancer risk is greater for combined estrogen–progestin therapies than for estrogen-only therapies.
Current evidence indicates similar breast cancer risks for different formulations, doses and routes of HRT administration.
Breast cancer risk increases with increasing duration of HRT use.
The increased breast cancer risk diminishes rapidly after ceasing use of HRT.
Current evidence suggests greater increases in breast cancer risk among women initiating HRT use closer to menopause.
HRT-associated breast cancer risk is modulated by obesity: thinner women demonstrate higher relative risks.
Use of HRT is associated with a higher risk of dying from breast cancer.
Overall, the risks associated with the use of HRT outweigh its benefits, in terms of the risk of serious disease.
| https://www.medscape.com/viewarticle/742984_8 |
1 Kings 11:1-13 NRS - NIV Parallel Bible
Read 1 Kings 11:1-13 in NRS and NIV using our online parallel Bible.
Parallel Bible results for 1 Kings 11:1-13
New Revised Standard
New International Version
1 Kings 11:1-13
NRS1King Solomon loved many foreign women along with the daughter of Pharaoh: Moabite, Ammonite, Edomite, Sidonian, and Hittite women,
NIV1King Solomon, however, loved many foreign women besides Pharaoh’s daughter—Moabites, Ammonites, Edomites, Sidonians and Hittites.
NRS2from the nations concerning which the Lord had said to the Israelites, "You shall not enter into marriage with them, neither shall they with you; for they will surely incline your heart to follow their gods"; Solomon clung to these in love.
NIV2They were from nations about which the LORD had told the Israelites, “You must not intermarry with them, because they will surely turn your hearts after their gods.” Nevertheless, Solomon held fast to them in love.
NRS3Among his wives were seven hundred princesses and three hundred concubines; and his wives turned away his heart.
NIV3He had seven hundred wives of royal birth and three hundred concubines, and his wives led him astray.
NRS4For when Solomon was old, his wives turned away his heart after other gods; and his heart was not true to the Lord his God, as was the heart of his father David.
NIV4As Solomon grew old, his wives turned his heart after other gods, and his heart was not fully devoted to the LORD his God, as the heart of David his father had been.
NRS5For Solomon followed Astarte the goddess of the Sidonians, and Milcom the abomination of the Ammonites.
NIV5He followed Ashtoreth the goddess of the Sidonians, and Molek the detestable god of the Ammonites.
NRS6So Solomon did what was evil in the sight of the Lord, and did not completely follow the Lord, as his father David had done.
NIV6So Solomon did evil in the eyes of the LORD; he did not follow the LORD completely, as David his father had done.
NRS7Then Solomon built a high place for Chemosh the abomination of Moab, and for Molech the abomination of the Ammonites, on the mountain east of Jerusalem.
NIV7On a hill east of Jerusalem, Solomon built a high place for Chemosh the detestable god of Moab, and for Molek the detestable god of the Ammonites.
NRS8He did the same for all his foreign wives, who offered incense and sacrificed to their gods.
NIV8He did the same for all his foreign wives, who burned incense and offered sacrifices to their gods.
NRS9Then the Lord was angry with Solomon, because his heart had turned away from the Lord, the God of Israel, who had appeared to him twice,
NIV9The LORD became angry with Solomon because his heart had turned away from the LORD, the God of Israel, who had appeared to him twice.
NRS10and had commanded him concerning this matter, that he should not follow other gods; but he did not observe what the Lord commanded.
NIV10Although he had forbidden Solomon to follow other gods, Solomon did not keep the LORD’s command.
NRS11Therefore the Lord said to Solomon, "Since this has been your mind and you have not kept my covenant and my statutes that I have commanded you, I will surely tear the kingdom from you and give it to your servant.
NIV11So the LORD said to Solomon, “Since this is your attitude and you have not kept my covenant and my decrees, which I commanded you, I will most certainly tear the kingdom away from you and give it to one of your subordinates.
NRS12Yet for the sake of your father David I will not do it in your lifetime; I will tear it out of the hand of your son.
NIV12Nevertheless, for the sake of David your father, I will not do it during your lifetime. I will tear it out of the hand of your son.
NRS13I will not, however, tear away the entire kingdom; I will give one tribe to your son, for the sake of my servant David and for the sake of Jerusalem, which I have chosen."
NIV13Yet I will not tear the whole kingdom from him, but will give him one tribe for the sake of David my servant and for the sake of Jerusalem, which I have chosen.”
| https://www.biblestudytools.com/parallel-bible/passage/?q=1-Kings+11%3A1-13&t=nrs&t2=niv |
A new species of Polyonyx Stimpson, 1858 (Crustacea: Decapoda: Anomura: Porcellanidae) from the Philippines and Loyalty Islands | Zenodo
Osawa, Masayuki (2007): A new species of Polyonyx Stimpson, 1858 (Crustacea: Decapoda: Anomura: Porcellanidae) from the Philippines and Loyalty Islands. Zootaxa 1450: 21-29, DOI: 10.5281/zenodo.176229
A new species of Polyonyx Stimpson, 1858 (Crustacea: Decapoda: Anomura: Porcellanidae) from the Philippines and Loyalty Islands
Osawa, Masayuki
DataCite XML Export
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<description descriptionType="Other">{"references": ["Dana, J. D. (1852) Crustacea, Part 1. United States Exploring Expedition during the years 1838, 1839, 1840, 1841, 1842, under the command of Charles Wilkes, U. S. N., 13, i-viii, 1-685, Philadelphia.", "Haig, J. (1956) The Galatheidea (Crustacea Anomura) of the Allan Hancock Atlantic Expedition with a review of the Porcellanidae of the western north Atlantic. Allan Hancock Atlantic Expedition, 8, 1-44, pl. 1.", "Haig, J. (1960) The Porcellanidae (Crustacea Anomura) of the eastern Pacific. Allan Hancock Pacific Expedition, 24, i- vii, 1-440, pls. 1-41.", "Haig, J. (1964) Papers from Dr. Th. Mortensen's Pacific Expedition 1914-1916. 81. Porcellanid crabs from the Indo- West Pacific, Part I. Videnskabelige Meddelelser Dansk Naturhistrisk Forening i Kjobenhavn, 126, 355-386.", "Haig, J. (1965) The Porcellanidae (Crustacea, Anomura) of Western Australia with description of four new Australian species. Journal of the Royal Society of Western Australia, 48, 97-117.", "Haig, J. (1966) The Porcellanidae (Crustacea Anomura) of the Iranian Gulf and Gulf of Oman. Videnskabelige Meddelelser Dansk Naturhistrisk Forening i Kj g benhavn, 129, 49-65.", "Haig, J. (1979) Expedition Rumphius II (1975) Crustaces parasites, commensaux, etc. (Th. Monod et R. Serene, ed.). V. Porcellanidae (Crustacea, Decapoda, Anomura). Bulletin du Museum National d'Histoire Naturelle, Paris, 4e, section A, 1, 119-135.", "Haswell, W. A. (1882) Description of some new species of Australian Decapoda. Proceedings of the Linnean Society of New South Wales, 6, 750-763.", "Hsueh, P.-W. & Huang, J.-F. (1998) Polyonyx bella, new species (Decapoda: Anomura: Porcellanidae), from Taiwan, with notes on its reproduction and swimming behaviour. Jounal of Crustacean Biology, 18, 332-336.", "Johnson, D. S. (1958) The Indo-West Pacific species of the genus Polyonyx (Crustacea, Decapoda, Porcellanidae). The Annals of Zoology, the Academy of Zoology, 2, 95-118.", "Lockington, W. N. (1878). Remarks upon the Porcellanidae of the west coast of North America. Annals and Magazine of Natural History, 5, 394-406.", "McNeil, F. A. M. (1968) Crustacea, Decapoda & Stomatopoda. Great Barrier Reef Expedition 1928-29, Scientific Reports, 7, 1-98, pls. 1-2, British Museum (Natural History), London.", "Miers, E. J. (1884) Crustacea. In: Report on the zoological collections made in the Indo-Pacific Ocean during the voyage of H.M.S. 'Alert' 1881-2. British Museum, London, pp. 178-322, 513-575.", "Miyake, S. (1943) Studies on the crab-shaped Anomura of Nippon and adjacent waters. Journal of the Department of Agriculture, Kyushu Imperial University, 7, 49-158.", "Ng, P. K. L. & Nakasone, Y. (1993) Taxonomy and ecology of the porcellanid crab Polyonyx cometes Walker, 1887 (Crustacea: Decapoda), with a description of a new genus. Journal of Natural History, 27, 1103-1117.", "Ng, P. K. L. & Sasekumar, A. (1993) A new species of Polyonyx Stimpson, 1858, of the P. s in ens is group (Crustacea: Anomura: Porcellanidae) commensal with a chaetopterid worm from Peninsular Malaysia. Zoologische Mededelingen, 67, 466-472.", "Nobili, G. (1905) Diagnoses preliminaires de 34 especes et varietes nouvelles et de 2 genres nouveaux de Decapodes de la Mer Rouge. Bulletin du Museum national d'Histoire naturelle, Paris, 11, 1905(1906), 393-411, figs. 1-2.", "Nobili, G. (1906) Faune carcinologique de la Mer Rouge. Decapodes et Stomatomopes. Annales des Sciences naturelles (Zoologie), 9e serie, 4, 1-347, figs. 1-12, pls. 1-11.", "Osawa, M. (2001) Heteropolyonyx biforma, new genus and new species, from Japan, with a redescription of Polyonyx utinomii (Decapoda: Porcellanidae). Journal of Crustacean Biology, 21, 505-520.", "Sankolli, K. N. (1963) On a new species of porcellanid crab (Decapoda, Anomura) from India. Journal of the Zoological Society of India, 15, 79-84.", "Sankolli, K. N. (1965) On a new species of comensal porcellanid crab, Polyonyx loimicola sp. nov., from India (Crustacea, Anomura, Porcellanidae). Journal of the Bombay Natural History Society, 62, 285-291, pls. I, II.", "Southwell, T. (1909) Report on the Anomura collected by Mr. James Hornell at Okhamandal in Kattiawar in 1905-6. In: J. Hornell (ed.), Report to the Government of Baroda on the marine zoology of Okhamandal in Kattiawar, 1, 105- 123, London.", "Stimpson, W. (1858) Prodromus descriptionis animalium evertebratorum, quae in expeditione ad oceanum pacificum septentrionalem, a republica federata missa, Cadwaladaro Ringgold et Johanne Rodgers ducibus, observavit et descripsit. Pars VII. Crustacea Anomura. Proceedings of the Academy of Natural Sciences of Philadelphia, 10, 225- 252.", "Walker, A. O. (1887) Notes on a collection of Crustacea from Singapore. Journal of the Linnean Society of London, Zoology, 20, 107-117.", "Werding, B. (2001) Description of two new species of Polyonyx Stimpson, 1858 from the Indo-West Pacific, with a key to the species of the Polyonyx sinensis group (Crustacea: Decapoda: Porcellanidae). Proceedings of the Biological Society of Washington, 114, 109-119.", "Yang, S. (1996) New species and new records of porcellanids crabs (Crustacea: Decapoda: Anomura) from Nansha Islands, China. Studies on marine fauna and flora and biogeography of the Nansha Islands and neighboring waters, II, 258-269. [In Chinese with English summary]", "Yang, S. & Xu, Z. (1994) Study on the Porcellanidae (Crustacea, Anomura) from Nansha Islands and it's adjacent waters. Studies on marine fauna and flora and biogeography of the Nansha Islands and neighboring waters, I, 112-124. [In Chinese with English summary]", "Zehntner, L. (1894) Crustaces de l'Archipel malais. Voyage de MM. M. Bedot et C. Pictet dans l'Archipel malais. Revue Suisse de Zoologie et Annales du Musee d'Histoire Naturelle de Geneve, 2, 135-214, pls. 7-9."]}</description>
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Part of<here is a image 1e2c897cfd73c604-1c3f5fc13294a942>
Publication date:
December 31, 2007
DOI:
Keyword(s):
Biodiversity Taxonomy Animalia Arthropoda Malacostraca Decapoda Porcellanidae
Published in:
Zootaxa: 1450 pp. 21-29.
Has part
10.5281/zenodo.6249331(Taxonomic treatment)
Source of
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Communities:
Biodiversity Literature Repository
| https://zenodo.org/record/176229/export/dcite4 |
Is It a New Era, Where Architects Should Be Held to Account for the Environmental Impact of Their Work?
Sustainability matters, but so does hypocrisy.
Is It a New Era, Where Architects Should Be Held to Account for the Environmental Impact of Their Work?
CC BY 4.0. 270 Park Avenue being demolished, July 25, 2019/ AEMoreira042281 on Wikipedia
Sustainability matters, but so does hypocrisy.
270 Park Avenue is being demolished as you read this. It’s the tallest building ever demolished on purpose, the tallest building ever designed by a woman architect, and was completely rebuilt to LEED Platinum standards in 2011, where just about everything but the frame was replaced, so it is essentially 8 years old. Much of it probably isn’t out of warranty. According to a basic carbon calculator, its embodied carbon in the building amounts to 64,070 metric tonnes, equivalent to driving 13,900 cars for a year.
Fortune Magazine/viaThat’s roughly the amount of carbon dioxide that will be emitted in the next few years building the first 2,400,352 square feet of the new building replacing 270 Park Avenue, theupfront carbon emissionsreleased making the steel, glass, concrete and other materials sitting there right now.
The new building replacing Natalie de Blois's tower is designed by Foster+Partners, a signatory toArchitects Declare, which includes two goals related to this project:
Upgrade existing buildings for extended use as a more carbon efficient alternative to demolition and new build whenever there is a viable choice.
Include life cycle costing, whole life carbon modelling and post occupancy evaluation as part of our basic scope of work, to reduce both embodied and operational resource use.
(Embodied resources are what I prefer to callUpfront Carbon Emissions.)
Writing in the Guardian, Rowan Moore asks,Where are the architects who will put the environment first?The subhead is, “Should we stop building airports? Return to mud and thatch? The climate crisis is an opportunity for creative thinking, but the values of architecture need a radical overhaul.” He asks:
The profession tends to attract people who want to change the world for the better. And what could matter more than the prevention of environmental and societal collapse? It makes squabbles about architectural style or form seem trivial by comparison. So what would architecture look like – more importantly, what would it be – if all involved really and truly put climate at the centre of their concerns?
Moore wonders how architects who have signed up forArchitects Declarecan keep building things like airports. I wonder how architects who have signed up for Architects Declare can be part of projects like 270 Park Avenue.
It is not enough to reduce what are called the “in-use” costs – heating, ventilation, lighting, water, waste, maintenance – but also the “embodied energy” that goes into construction and demolition: quarrying cement, smelting steel, firing bricks, shipping materials to site, putting them in place, taking them down again and disposing of them.
Moore quotes Jeremy Till of Central Saint Martins School of Art and Design, who says that architects like Norman Foster who are building airports and spaceports are participating in a farce. “You can’t have a carbon-neutral airport,” he says. Architects have to do more than be well-intentioned instruments of what he calls “an extractive industry.”
Spaceport America/ Foster + Partners/ Land Rover via Wikipedia /CC BY 2.0
I quoted Lord Foster when the spaceport, which will fire wealthy tourists into space on rockets literally burning rubber and nitrous oxide, was announced: “This technically complex building will not only provide a dramatic experience for the astronauts and visitors, but will set an ecologically sound model for future Spaceport facilities.”
But building ecologically sound airports and spaceports doesn’t cut it anymore; the use matters. Building giant green office towers while knocking down slightly less giant green office towers doesn’t cut it.
© Enterprise Centre, made of thatch/ Architype architects/ Photo DennisGilbert/VIEW
Some architects, likeWaugh Thistleton, have decided not to take any more work that they can’t build out of sustainable materials like wood. My favourite architects these days,Architype, use thatch, straw and wood and cork to build schools, not airports.
I have admired Lord Foster since his Sainsbury Centre in 1978. But the world has changed. The definition of sustainability has changed.
Is this the start of a new era where people actually care about sustainability?
New York Historical Society/Public Domain
In 1963, the destruction of Pennsylvania Station in New York City drew massive protests. Ada Louise Huxtable wrote that it was the end of an era:
It went not with a bang, or a whimper, but to the rustle of real estate stock shares. The passing of Penn Station is more than the end of a landmark. It makes the priority of real estate values over preservation conclusively clear.
But it was the start of a new era for historic preservation. Laws were passed, heritage organizations founded, and people finally became concerned enough about the loss of our heritage to do something about it.
270 Park Avenue is no Penn Station, but it is an important building that also marks the end of an era where architects can pretend that what they are doing is “sustainable” and “green” while vomiting out the carbon of fourteen thousand cars. Rowan Moore's article gives me hope, that it is perhaps the start of an era where architects who sign statements like Architects Declare are actually held to them.
JP Morgan Chase's Manhattan HQ Will Be New York's Largest All-Electric Tower
Do We Even Need New Office Buildings Post-Pandemic?
The Reuse Imperative: Why Saving Existing Buildings Matters More Than Ever
Greenwash Watch: Whole Life Carbon Assessments Are Being Questioned
Are Skyscrapers Wasteful, Damaging, and Outmoded?
Why We Fight to Save Every Old Building
Stirling Prize Short List Raises the Question: What Is Climate-Responsible Design?
The Preservation of Existing Buildings Is Climate Action
UK Government to Regulate Embodied Carbon (Maybe)
Another One Bites the Dust: Paul Rudolph's Burroughs Wellcome HQ
Dial P for Passivhaus as Telephone Exchange Becomes Ultra-Green Offices
What Happens When You Plan or Design With Upfront Carbon Emissions in Mind?
| https://www.treehugger.com/it-new-era-where-architects-should-be-held-account-carbon-impact-their-work-4855997?utm_source=emailshare&utm_medium=social&utm_campaign=shareurlbuttons |
ADW: Sarcoramphus papa: INFORMATION
Sarcoramphus papa king vulture
Geographic Range
King vultures are found in the southern part of Mexico and throughout Central and South America to northern Argentina. ( del Hoyo, et al., 1994 )
Biogeographic Regions
neotropical
native
Habitat
King vultures generally live in undisturbed forest in the lowland tropics. They have been found in savannas and grasslands also, but usually only when there are forests nearby. They can be found at elevations up to 1200 m. Little is known about king vultures in the wild, but it is believed that they live in the emergent layer of the forest, which is the top most part of the trees above the canopy. Their hard to reach preferred habitat could be why we do not know much about them. ( De Roy, 1998 ; del Hoyo, et al., 1994 )
Habitat Regions
tropical
terrestrial
Terrestrial Biomes
forest
Range elevation
1200 (high) m
3937.01 (high) ft
Physical Description
The most noticeable difference between king vultures and other vultures is that they are largely covered with white plumage. Their wings are mostly white with black tips. The ruff, flight and tail feathers are gray to black; the black areas have an almost opalescent sheen. Their wingspan is between 180 to 198 cm (71 to 78 inches), and from head to tail they are about 71 to 81 cm (28 to 32 inches). An adult can weigh from 3 kg (6.6lbs) up to more than 4.5 kg (9.9lbs). Their bare head, neck, beak and muttle are red, orange and yellow, with very striking eyes that are straw, white or silver in color. Their beaks have a hooked tip and cutting edges, which are very strong. Their feet are gray. These birds are very striking, especially since most other vultures are all black. There are no differences between the males and females of this species. When they are young, king vultures are covered with white downy feathers. ( Chaffee Zoo, Date Unknown ; De Roy, 1998 ; del Hoyo, et al., 1994 ; Stiles and Skutch, 1989 )
Other Physical Features
endothermic
bilateral symmetry
Sexual Dimorphism
sexes alike
Range mass
3000 to 4500 g
105.73 to 158.59 oz
Range length
71 to 81 cm
27.95 to 31.89 in
Range wingspan
180 to 198 cm
70.87 to 77.95 in
Development
The King Vulture lays one egg, which is creamy white and takes 53-58 days to hatch. At times both parents incubate the egg while at other times it is just the female. Not much is known about why this behavior takes place. They do wander away from the nest as they get older, which might be a defense from being eaten. Apparently they begin to acquire their adult plumage around 18 months which grow slowly and takes about four years to fully grow in. The young remain with their parents for that period of time.
(honoluluzoo.org/king_vulture.htm; Stiles, F. Gary and Alexander, F. Skutch,1989; Del Hoyo, Elliot, Sargutal, et al., 1994)
Reproduction
The courting ritual of Sarcoramphus papahas only been observed in captivity; it is quite an elaborate show. While mating they are known to be very loud, making unique wheezing and snorting sounds. Like most other members of their family, king vultures are most likely monogamous. ( Sibley, 2001 )
King vultures are solitary birds and do not nest in big colonies. They usually breed during the dry season. King vultures do not build nests, rather they lay their eggs in hollows of rotting logs or stumps or crevices in trees. They usually lay only one egg which is incubated by both parents. Juveniles begin to show adult plumage after 18 months. ( Chaffee Zoo, Date Unknown ; Honolulu Zoo, 2004 )
Key Reproductive Features
iteroparous
seasonal breeding
gonochoric/gonochoristic/dioecious (sexes separate)
sexual
oviparous
Breeding season
Mainly in the dry season
Average eggs per season
1
Average time to hatching
57 days
AnAge
Both male and female king vultures participate in incubation. Young are altricial. Both parents care for the young at times, while at other times, it is just the mother.
Most birds of prey carry their food to their young in their claws, but New World Vultures (familyCathartidae) have a large crop that enables them to carry quite a bit of food in the gut. They then regurgitate the food to feed their young. Young chicks are fed directly from the parent’s beak, but as they get older, the parents regurgitate the food onto the ground for the young to eat. ( De Roy, 1998 ; del Hoyo, et al., 1994 ; Honolulu Zoo, 2004 ; Sibley, 2001 ; Stiles and Skutch, 1989 )
Parental Investment
no parental involvement
altricial
pre-hatching/birth
protecting
male
female
pre-weaning/fledging
provisioning
male
female
Lifespan/Longevity
There is not very much information about king vultures in the wild, including their lifespan. However, there is at least one pair of birds in Paris that have been studied in captivity for over 30 years. ( De Roy, 1998 )
Average lifespan Status: captivity
40 years
AnAge
Behavior
King vultures stay in family units and do not congregate in large groups. They remain out of sight for the most part, sitting high in the canopy or flying and soaring high in the air looking for food. They are not migratory and are seen in the same areas all year long.
Unlike some other vultures, king vultures do not have a well-developed sense of smell. They rely on other vultures to find prey and will then descend to take part in feeding. King vultures are very rarely aggressive, and will usually back down before fighting. Because of their large wings and bodies they depend totally on air currents for flight, they do not flap their wings unless absolutely necessary. ( Chaffee Zoo, Date Unknown ; De Roy, 1998 ; del Hoyo, et al., 1994 )
Key Behaviors
flies
glides
motile
sedentary
solitary
Home Range
We do not have information on home range for this species at this time.
Communication and Perception
King vultures, as well as all vultures in the familyCathartidae, lack a voice box (a syrinx and the muscles that make it work). They are not completely silent though, they do make very low croaking sounds. They also make noises during breeding, and give warning sounds if anything approaches their nests. ( del Hoyo, et al., 1994 ; Stiles and Skutch, 1989 )
Communication Channels
acoustic
Perception Channels
visual
tactile
acoustic
chemical
Food Habits
King vultures are scavengers. Their only source of food is dead animals. King vultures are not known to kill any animals, not even ones that are obviously sick or ready to die. Unlike other New World vultures (familyCathartidae), king vultures arguably have no sense of smell. They will fly high in the sky watching and waiting for other smaller vultures to get excited about a find, they then swoop down out of the sky to the carrion. They usually end up stealing the carcass from the vulture that found it in the first place. They have more powerful beaks than other vultures, and are able to break through the tough hides of the carrion. It is often necessary for king vultures to make the initial tear through the hide so that other vultures, with less powerful beaks, can feed. Each New World vulture species has a unique part of a carcass that they specialize in eating. King vultures eat the skin and harder parts of tissue from the dead animals. ( del Hoyo, et al., 1994 ; Stiles and Skutch, 1989 )
Primary Diet
carnivore
scavenger
Animal Foods
carrion
Predation
King vultures and other members of the familyCathartidaedo not seem to have many anti-predation adaptations. Their nests are vulnerable to animals that prey opportunistically on young and eggs (such as snakes (suborder Serpentes)). Adults are vulnerable while eating. If a large cat (familyFelidae) comes to a carcass and the vulture is full of food then it may have a hard time getting off of the ground and away from danger. They are also vulnerable to attack if they are injured or ill.
There is some controversy, but it is believed that the nest sites of these birds are very smelly for the purpose of scaring off potential predators. ( De Roy, 1998 )
Known Predators
snakes ( Serpentes )
large cats ( Felidae )
Ecosystem Roles
King vultures, as well as other members of the familyCathartidae, play an important role in their ecosystem. These birds are usually the first to find dead animals and immediately begin to dispose of the rotting remains. As are all scavengers, these birds are important in keeping their environment free of dead, decomposing animals; this may also help reduce possible sources of disease. ( del Hoyo, et al., 1994 )
Ecosystem Impact
biodegradation
Economic Importance for Humans: Positive
As a result of their unique beauty and size, king vultures are an attraction at zoos. ( De Roy, 1998 )
Economic Importance for Humans: Negative
There are no known adverse affects of king vultures on humans.
Conservation Status
King vultures are rarely seen in large numbers and several have been sited in a areas where they were previously thought not to exist. It is apparent, however, that human encroachment and habitat loss have had an adverse affect on king vultures. They are listed as Appendix III by CITES. ( del Hoyo, et al., 1994 )
IUCN Red List
CITES
Appendix III
Other Comments
Even though king vultures and other New World vultures (familyCathartidae) look like Old World vultures (familyAccipitridae), it is believed that New World vultures are actually descendents of storks. They have skeletal, skull and muscle structure similar to storks, as well as some similar behavioral traits. However, they are almost the same size, have the same beak strength and have the same bare head and neck as Old World vultures. The similarity between Old World and New World vultures is a prime example of convergent evolution. ( del Hoyo, et al., 1994 )
Contributors
Alaine Camfield (editor), Animal Diversity Web.
Dawne Ormiston (author), Fresno City College, Carl Johansson (editor), Fresno City College.
Glossary
Neotropical
living in the southern part of the New World. In other words, Central and South America.
acoustic
uses sound to communicate
altricial
young are born in a relatively underdeveloped state; they are unable to feed or care for themselves or locomote independently for a period of time after birth/hatching. In birds, naked and helpless after hatching.
bilateral symmetry
having body symmetry such that the animal can be divided in one plane into two mirror-image halves. Animals with bilateral symmetry have dorsal and ventral sides, as well as anterior and posterior ends. Synapomorphy of the Bilateria.
biodegradation
helps break down and decompose dead plants and/or animals
carnivore
an animal that mainly eats meat
carrion
flesh of dead animals.
chemical
uses smells or other chemicals to communicate
endothermic
animals that use metabolically generated heat to regulate body temperature independently of ambient temperature. Endothermy is a synapomorphy of the Mammalia, although it may have arisen in a (now extinct) synapsid ancestor; the fossil record does not distinguish these possibilities. Convergent in birds.
forest
forest biomes are dominated by trees, otherwise forest biomes can vary widely in amount of precipitation and seasonality.
iteroparous
offspring are produced in more than one group (litters, clutches, etc.) and across multiple seasons (or other periods hospitable to reproduction). Iteroparous animals must, by definition, survive over multiple seasons (or periodic condition changes).
motile
having the capacity to move from one place to another.
native range
the area in which the animal is naturally found, the region in which it is endemic.
oviparous
reproduction in which eggs are released by the female; development of offspring occurs outside the mother's body.
scavenger
an animal that mainly eats dead animals
seasonal breeding
breeding is confined to a particular season
sedentary
remains in the same area
sexual
reproduction that includes combining the genetic contribution of two individuals, a male and a female
solitary
lives alone
tactile
uses touch to communicate
terrestrial
Living on the ground.
tropical
uses sight to communicate
Chaffee Zoo, Date Unknown. "King Vulture" (On-line).
Accessed
03/01/04
at http://www.chaffeezoo.org/zoo/animals/kingVulture.html.
De Roy, T. 1998. King of the Jungle. International Wildlife, 28: 52-57.
Honolulu Zoo, 2004. "King Vulture" (On-line).
Accessed
03/01/04
at http://www.honoluluzoo.org/king_vulture.htm.
Sibley, D. 2001. The Sibley Guide to Bird Life & Behavior. New York: Alfred A. Knopf, Inc.
Stiles, F., A. Skutch. 1989. A guide to the Birds of Costa Rica. Comstock Publishing Associates.
del Hoyo, J., A. Elliot, J. Sargutal, et. al. 1994. Handbook of the Birds of the World, Volume 2. Barcelona: Lynx Edicions.
| https://animaldiversity.org/accounts/Sarcoramphus_papa/ |
Running benefits that keep you young and beautiful | Popular Science
Running regularly is known to help with weight loss and heart health, but it can also give your skin and hair a glow-up.
5 surprising beauty benefits of running
Experts break down what happens to your skin when you go on a run.
Health
DIY
Going for a jog every now and then can make you feel young and look awesome. Deposit Photos
Running does wonders for your body—it lowers your risk of heart disease, boosts brainpower, helps with weight loss, to name a few. But one lesser known benefit is what running does for your looks. Not only does running have you looking your physical best, but it gives you soft and beautiful skin that may fool people into thinking you’ve shaved off a few years.
You don’t need to zoom like a marathon runner or buy the latest athletic wear to start running.Erin Beck, a personal trainer and the director of training and experience atSTRIDE Fitnessbased in California, says a 30-minute run at least three times a week is enough to notice results on your appearance. If that sounds too much for you, Beck recommends starting with a slower workout like a walk or brisk jog that still gets your heart pumping. “You can absolutely still get the benefits even if you’re at a lower intensity.” The key is to remain consistent and eventually challenge yourself to run longer or at a faster pace to see results sooner. Your hard work could pay off with a major glow-up.
1. Rejuvenate dull skin
As you run, your heart rate increases compared to when you’re sitting. Exercising places stress on your muscles, and that requires having enough oxygen to keep them moving. Your cardiovascular and respiratory system responds to the increased demand in oxygen by pumping more blood through the body and at a quicker pace. Blood vessels in the muscles then enlarge to receive more of the oxygen-rich blood. Beck says that as your body pumps more blood, it’s simultaneously flushing out toxins from your bloodstream when you sweat. “It’s great for your veins, your arteries, and especially your capillaries,” says Beck.
Capillaries are small blood vessels that carry blood all over the body. Some run right underneath the skin and help with regulating body temperature by expanding or contracting when exposed to heat or cold. Dilated vessels cool the body down by increasing blood flow to the skin surface, which allows heat to escape into the environment. Beck says the increased blood circulation during a run gives the skin more opportunity to get nutrients from oxygen-rich blood. Better oxygenation of the skin helps with the regeneration of new skin cells, leaving behind supple and glowing skin.
2. Channel luscious locks
That increased blood circulation in your skin during a run also helps with the appearance and growth of your hair roots.Lindsey Bordone, a dermatologist and assistant professor at Columbia University Irving Medical Center, says running works similar to a regularly prescribed hair growth medicine called minoxidil. They both dilate blood vessels so that when blood is delivered to the tiny vessels in your scalp, there is more oxygen-rich blood making its way to feed hair follicles.
3. Tone down acne and breakouts
Bordone says running can help lower hormones that cause acne. The secretion of “stress hormone” cortisol and testosterone increases oil production in skin glands, making you prone to clogged pores and acne breakouts. Running long distances can help with reducing cortisol levels and as you lose weight, you’ll reduce the risk for conditions that cause imbalances in testosterone levels, such as polycystic ovary syndrome.
Another obvious benefit to running: sweating. Sweating opens up clogged pores and flushes out acne-causing bacteria and dirt. Though Beck warns that if you’re not washing your face before and after workouts, the dirt and sweat lingering on your skin can dry it out and create more opportunities for acne breakouts.
In general, your post-workout routine is also important. An indirect benefit of running is that your brain makes healthier decisions after your workout: Running increases brain flow to brain areas involved in emotions and higher thinking—and that includes choosing what you eat. “Typically, when you’re treating your body in a healthy manner, your body reacts bycraving healthy things,” says Beck. “Those urges to get more sleep, drink more water, and eat less unhealthy meals will help with clearing up acne.”
4. Reduce the appearance of cellulite
Cellulite occurs when fat attaches beneath the skin. The more fat cells you have in your body, the more likelycellulite will appear. This is because as fat cells accumulate, it pushes up on the skin before being pulled back down by tough connecting cords between your outer layer of skin and the fat underneath.
“Think about it like bubble wrap,” says Beck. “Those connectors surround air pockets in between your skin and the fat cells. When those connectors pull too tight they create that bubbly-looking effect on your skin the same way bubble wrap has a bubbly texture on top.”
[Related: Pilates can improve your posture and balance. The killer body is just a bonus.]
Once you create a fat cell, it cannot be destroyed. But with exercise, fat cells shrink and your skin tightens. Cellulite, in turn, becomes less visible.
5. Give your face a lift
The increased blood flow and oxygen to your face help with cell turnover, nourishing healthy skin cells and regenerating new ones. The blood circulation flushes outfree radicalsas well—unstable molecules accidentally made during cell metabolism that damage cells and contribute to skin aging.
A run can also decrease cortisol levels and increase the production of endorphins, which help relax the face. “Having tension in our jawlines, for example, can lead to wrinkles,” explains Beck. “But with running, you’ll have less tension in your face and that can prevent you from deepening out those wrinkles.”
However, outdoor runners should be aware of repeated exposure to UV sun radiation. Without taking precautions like using sunscreen or wearing hats, UV raysdamage the DNAin skin cells and make them unable to carry out their jobs. Damage to the skin can lead to premature aging, such as wrinkling and leathery skin.
But no matter whether you enjoy running in the park or on a treadmill, both experts agree the best thing is to get your heart pumping. Even if it’s a short run around the block, over time your small efforts will make a big difference in your health.
Fitness & Exercise
Life Skills
| https://www.popsci.com/health/running-beauty-benefits-skin-hair/?amp_device_id=Qah9vjRzbd-b9iFdlJLhnb |
(PDF) CoasterX: A Case-Study in Component-Driven Hybrid Systems Proof Automation
PDF | Component-driven proof automation (CDPA) exploits component structure to automate deductive verification of large-scale hybrid systems with... | Find, read and cite all the research you need on ResearchGate
Conference Paper
PDF Available
CoasterX: A Case-Study in Component-Driven Hybrid Systems Proof Automation
July 2018
Conference: Analysis and Design of Hybrid Systems
At: Oxford, UK
Download full-text PDF Download full-text PDF
Abstract and Figures
Component-driven proof automation (CDPA) exploits component structure to
automate deductive verification of large-scale hybrid systems with non-trivial continuous
dynamics. We use CDPA to implement a case study CoasterX, which is a toolchain for designing and verifying safety of 2-dimensional roller coaster track designs. Specifically, we verify velocity and acceleration bounds. CoasterX starts with a graphical front-end for point-and-click design of tracks. The CoasterX back-end then automatically specifies and verifies the track in differential dynamic logic (dL) with a custom procedure built in the KeYmaera X theorem prover. We show that the CDPA approach scales, testing real coasters of up to 56 components.
CoasterX GUI: Placing track (left), Design bug detected (center), Design bug fixed (right) …
Line and arc components with tangential, centripetal, radial, and gravitational acceleration …
Figures - uploaded by
André Platzer
2.3+ billion citations
CoasterX: A Case Study in
Component-Driven Hybrid Systems
Proof Automation
Brandon Bohrer, Adriel Luo, Xue An Chuang, Andr´ e Platzer
Computer Science Dep artment, Carnegie Mellon University (email:
{ bbohr er@cs, aluo@andrew, xchuang@alumni, aplatzer@cs } .cmu.e du)
Abstract: Component-driven proof automation (CDP A) exploits component structure to
automate deductive verification of large-scale h ybrid systems with non-trivial continuous
dynamics. W e use CDPA to implemen t a case study CoasterX , which is a toolchain for designing
and verifying safety of 2-dimensional roller coaster trac k designs. Specifically, we v erify velocity
and acceleration bounds. CoasterX starts with a graphical front-end for point-and-click design of
tracks. The CoasterX back-end then automatically specifies and verifies the trac k in differential
dynamic logic ( d L ) with a custom procedure built in the KeYmaera X theorem prover. W e show
that the CDP A approach scales, testing real coasters of up to 56 components.
Keywords: Roller coasters, h ybrid programs, component-driven verification
1. INTRODUCTION
W e introduce comp onent-driven pro of automation (CDPA),
an approach for generating formal hybrid systems speci-
fications and proofs from high-level component-based de-
signs, in order to assure the safety of critical physical sys-
tems. W e explore CDPA through our case study Co asterX :
we present a graphical design tool and automated spec-
ification and verification back end for 2D roller coaster
track designs. CDP A begins with building a high-level
component-based design: in the case of CoasterX, the
user builds track designs by placing components (trac k
sections) in a click-and-point front-end GUI. The bac kend
then automatically follows the component structure to
build a formal model and verify its safety . A key adv antage
of this design is that the technical challenges of modeling
and verification are handled entirely in the CoasterX bac k-
end: an end-user with no formal methods knowledge can
design a coaster in the high-level tool and benefit from our
formal guarantees.
W e build our formal models in differential dynamic logic
( d L ) Platzer (2008, 2017), a logic for hybrid systems
that supports non-linearities in both dynamics and safety
conditions. The back-end deductively v erifies safety using
a custom procedure built on KeYmaera X Fulton et al.
(2015), a theorem-prover for d L designed to maximize the
trustworthiness of proofs.
Reachability is undecidable for ev en simple classes of
hybrid systems, so difficult safety proofs are not auto-
matic: users typically provide high-lev el verification in-
sights through system inv ariants and perform low-level
simplifications to assist proof automation. These manual
steps demand significant expertise. Even when automatic
proofs are possible, formal mo deling is itself a challenge.
The CoasterX study shows that for system classes de-
scribed by reusable components (e.g. coaster tracks are
built from track sections) CDP A can solve the specification
and verification problems once and for all: W e exploit com-
ponent structure to implement reusable proof automation
which verifies the en tire class of systems. Theorem prov-
ing expertise is needed when implementing the automa-
tion and interactively v erifying the individual components.
Howev er, this expertise is not needed to use the resulting
system to build verified designs graphically .
The KeYmaera X prover ac hieves its high reliability
through a smaller trusted core than competing tools and
the ability to add automation without extending the core.
This reliability is especially valuable when v erifying safety-
critical systems. W e show that exploiting component struc-
ture allows CDP A to scale efficiently to models with dozens
of sections without compromising reliability .
W e identify safety conditions and a formal model for roller
coasters. Our safety conditions come from bio dynamics ,
the study of the human body’s response to forces. Be-
cause deductive verification is c hallenging, it is essential
to identify a model that is as simple as possible while
providing sufficiently meaningful guaran tees. Our chosen
model is mechanically simple, ignoring friction, environ-
mental effects, and lateral motion. Y et, we will argue why
the insights provided b y this simple model are applicable
to real coasters.
W e take as a motivating example Kenn ywood’s “Steel
Phantom” (Fig. 1). The Phantom caused headac hes Pitts-
burgh Post-Gazette (2000) throughout its life, posing a
risk factor for more serious medical problems F ukutake
et al. (2000). It was even tually closed and reopened as
the gentler “Phantom’s Rev enge”, with over a third of
the track replaced. W e show that CoasterX can detect the
excessive acceleration of the Steel Phantom. This design-
time analysis can be used to detect problems before manu-
facture, ameliorating medical risks and avoiding expensive
changes. F or our model of Phantom’s Revenge, CoasterX
Fig. 1. Steel Phantom (top) and Revenge (bottom); dotted
lines separate components
automatically proved a bound of 3.55 vertical G’s, close to
the 3.5 G’s of the real coaster. This is much less than the
6.5 G’s for our Steel Phantom model, showing CoasterX
can distinguish safe vs. unsafe acceleration in practice.
W e evaluate CoasterX on 6 models. W e computed a
conservativ e lower bound on the performance gain due to
CDP A, ranging from 1.6x to 20x.
2. RELA TED WORK
V erification of Hybrid Systems. W e summarize ma jor
approaches to hybrid systems v erification. Reachability
analysis F rehse et al. (2011); Chen et al. (2013) provides
automation, but cannot reuse verification results across
component instances, which is important for performance.
Its correctness typically depends on a large code base.
Instead, we use deductive v erification in differential dy-
namic logic ( d L ) Platzer (2008, 2017). It can handle com-
ponent reuse, non-linear dynamics, non-linear safe regions,
and exact representation of reachable sets. The CoasterX
models use all of these: reuse improves performance, our
dynamics are multi-affine, acceleration bounds are non-
linear, and exact reachable sets improv e bound precision.
Because coasters are bounded-time, d L ’s abilit y to verify
unbounded-time systems is not used.
The KeYmaera X F ulton et al. (2015) theorem prover
for d L provides proof automation, which is fundamentally
incomplete because reachability of hybrid systems is un-
decidable Henzinger (1996). Thus, typical d L proofs re-
quire more user interaction than does reachability analysis,
gaining exact, expressive results in return. CoasterX shows
that such results can be fully automated for coasters by
reducing track verification to component v erification.
Rail systems have been verified in d L , including one with
pressure brakes that take time to apply and whic h depend
on the train’s mass and length Mitsch et al. (2017). Roller
coasters are rail systems with a unique focus on gravity
power, for which w e introduce continuously-changing trac k
grade. Roller coasters exert unique accelerations on riders,
so we prov e the first biodynamic safe acceleration b ounds.
Component-based hybrid systems theorem proving has
been explored for traffic network components M¨ uller et al.
(2015), culminating in the (unverified) design tool SAFE-
T. M¨ uller et al. (2017) provide a general rule for composing
components, but do not integrate it with SAFE-T. CDP A
provides the first integrated approac h. CoasterX shows
that integrating high-level design with proof is itself non-
trivial, but possible.
Distributed hybrid systems verification Platzer (2012a)
also allows proof reuse for repeated components. It excels
for highly symmetric systems, e.g. many cars all using
the same controller. CDP A excels when asymmetries are
safety-critical: e.g. our straight trac k component is reused
many times, but e ach exact track shap e is safety-critical .
Component Mo deling and Verific ation. Assume-guarantee
reasoning F rehse et al. (2004); Henzinger et al. (2001)
with Hybrid I/O Automata Lynch et al. (2003) has been
proposed to help hybrid model checking scale. How ever,
it does not provide reuse across instances, nor is it fully
automatic because component specifications are needed.
Hybrid process algebras such as Hybrid χ Schiffelers et al.
(2004) and Hybrid CSP Liu et al. (2010) provide com-
ponent modeling, but component-based verification with
proof reuse across instances is an open problem.
3. ROLLER COASTER DESIGN AND SAFETY
There are an estimated 4600 roller coasters in the
world Marden (2018). Because of the great forces, veloc-
ities, and heights inv olved, roller coasters pose inherent
safety risks. Despite the risks, modern coasters have a
remarkable safet y record: with over a billion annual rides,
only an estimated 450 injuries IAAP A (2017) were re-
ported in 2015. This safety record is achieved through
pervasive safet y engineering, supported by computer anal-
ysis. Modern safety engineering uses computer-aided de-
sign (CAD) software to find problems at design-time,
while they can be fixed cheaply . Industry standards ASTM
(2017) mandate acceleration limits for all coasters along
each dimension of motion, capturing the human body’s
biodynamic limits. Violating these limits can have adverse
medical effects F ukutake et al. (2000). These limits also
help determine the possibility of derailments: derailment
typically occurs if a mechanical component fails during
operation CBC News (1986), and acceleration bounds help
us understand whether forces between mechanical compo-
nents are dangerously high.
In addition, showing a positive low er bound on velocity
ensures coasters do not get stuck Boy ette (2017) or roll
back during operation, an essential correctness property .
Compared with standard CAD software, soundness of
CoasterX depends on only a small amount of code, due
to the small (1700 lines) trusted core of the underlying
prover F ulton et al. (2015). Additional benefits include the
ability to consider infinitely many scenarios (e.g. infinitely
many starting velocities) at once, and high confidence
provided by the use of exact arithmetic in the v erification.
T o make deductive verification in d L easier, w e simplify the
model in multiple ways, ignoring friction, en vironmental
effects, and lateral motion. W e look to the Steel Phantom
example to justify these simplifications. Our main result
is an upper bound on acceleration, which is only made
more conservativ e (and still sound) by ignoring friction.
This conservativ e bound provides practical information:
CoasterX shows a wide gap between the Steel Phan tom
and Phantom’s Revenge. Because Steel Phan tom’s ex-
cessive acceleration was not along the lateral dimension,
providing horizontal and v ertical bounds is useful. We also
use simple components (straight lines and arcs), but these
can approximate arbitrary curves at the cost of increased
verification time. W e model unit mass because mass can-
cels out of our acceleration equations.
Compared to acceleration upper bounds, velocity lower
bounds help show that coasters do not get stuck or roll
back. F riction and environmental (e.g. wind) effects are
essential in establishing a low er bound, so velocity lower
bounds should be taken with a grain of salt.
Nonetheless, the verification enabled by these simplifica-
tions allows us to draw practical conclusions, e.g. sho wing
that the Phantom’s Revenge resolv ed the excess accelera-
tion of the Steel Phantom.
4. TOOL: COASTERX GUI BUILDER
Fig. 2. CoasterX GUI: Placing track (left), Design bug
detected (center), Design bug fixed (right)
The user-facing part of CoasterX is a high-level track
builder GUI (Fig. 2), implemented in Python ( ≈ 600 lines).
The builder is completely point-and-click: T rack sections
are placed with a mouse click, and the builder automati-
cally ensures all sections are contiguous and tangent. An y
sections where the train can get stuck or go backw ards are
automatically highlighted in red. The design tool can also
perform Runge-Kutta (RK4) simulation of the coaster dy-
namics and animate the results. The user can interactively
adjust the coaster’s launch velocity and immediately see
the impact on the safety of model.
The GUI design tool greatly reduces the learning curve vs.
manually specifying and verifying a system in d L . Because
real-time detection of unsafe track sections and dynamical
simulation provide immediate feedbac k, they enable an
efficient design workflo w. However, because track designs
are safety-critical, it is also critical that we main tain a high
degree of assurance while providing that efficient w orkflow.
These assurances do not come from the GUI builder.
Our assurances come from formal specification and veri-
fication in d L . The CoasterX back-end extends the KeY-
maera X F ulton et al. (2015) prover with custom auto-
matic specification ( ≈ 2000 lines) and proof ( ≈ 1500 lines)
procedures in Scala. Because only the specifier and KeY-
maera X’s core (together, 3700 lines) must be trusted, the
resulting proofs have a high level of assurance.
5. BACKGR OUND: DIFFERENTIAL DYNAMIC
LOGIC d L
The CoasterX back-end uses differential dynamic logic
( d L ) to formally express track designs as hybrid pro grams
(HPs) Platzer (2008, 2017), a program notation for hybrid
systems. Hybrid programs combine basic imperative pro-
gramming constructs with nondeterminism and systems of
differential equations. Their syntax is giv en below:
α, β ::= x := θ | x 0 = f ( x ) & Q | ? Q | α ∪ β | α ; β | α ∗
where θ is a term, x is an assignable program variable, f is
a function, α, β are HPs, and Q is a formula. Assignments
x := θ discretely update x to the value of θ . ODEs
x 0 = f ( x ) & Q evolve nondeterministically for an y duration
so long as Q remains true. T ests ? Q have no effect when Q
is true, but abort execution otherwise. Nondeterministic
choices α ∪ β nondeterministically run either α or β , and
sequential composition α ; β runs β in the state(s) resulting
from α . Nondeterministic loops α ∗ run α repeatedly any
nonnegative num ber of times.
The formulas of d L comprise first-order logic operators in
addition to the dynamic logic operators [ α ] φ and h α i φ
meaning φ holds in all or some state resulting from
running α , respectively . All properties in this paper are
[ α ] φ properties. See Platzer (2008, 2017) for details.
6. MODEL GENERA TION
Once a design is created in the CoasterX GUI, the
CoasterX back-end automatically produces a formal model
of the coaster and a proof in d L . Our models are aimed at
showing bounds on acceleration, divided into horizontal
(tangential) acceleration and vertical (cen tripetal) accel-
eration per international standards ASTM (2017).
CoasterX generates this model by following the component
structure of the design. The d L model for each compo-
nent is created by instan tiating a generic d L component
model with concrete parameters from the design. The
model for a complete coaster is formed by composing the
component models. Components compose cleanly b ecause
each one is restricted to an evolution domain InBounds ,
overlapping only at their hando ver points as in Fig. 1. F or
inversion-free coasters, bounding boxes (( x 1 , y 1 ) , ( x 2 , y 2 ))
suffice as constraints. Inv ersions (e.g. in Steel Phantom)
introduce self-intersection and ov erlapping bounds. For
realistic models, overlaps occur only between upw ard and
downw ard sections, thus we restore a clean interface b y
incorporating direction of motion ( Dir is dy ≥ 0 for up or
dy ≤ 0 for down) in the constraint:
InBounds def
≡ Dir ∧ x 1 ≤ x ≤ x 2 ∧ y 1 ≤ y ≤ y 2
Fig. 3 illustrates component model parameters.
Fig. 3. Line and arc components with tangential, cen-
tripetal, radial, and gravitational acceleration
Parametric Line Se gment Model. The generic model α L
for constrained nonuniform motion on the line segment
from ( x 1 , y 1 ) to ( x 2 , y 2 ) is a linear differential equation:
α L
def
≡ { x 0 = v · dx, y 0 = v · dy, v 0 = − dy · g & InBounds }
The position ( x, y ) evolves along the direction vector
( dx, dy ) according to the speed v . The sp eed v evolves
according to the resultant tangential acceleration T , whic h
for constrained linear motion is the component of gravity
parallel to the track − dy · g (the parallel component cancels
with normal force N ). Because the train is constrained
to the track, the direction of motion ( dx, dy ) is also the
track’s tangent v ector. Within any single linear section,
( dx, dy ) is constant. The domain constraint InBounds im-
plements the segment’s bounding box as described above.
Parametric A rc Mo del. We create a generic model α A
for constrained nonuniform motion on an arc by general-
izing α L with continuous ev olution of the direction vector
( dx, dy ), resulting in a multi-affine differential equation.
W e specify the shape of the arc with its center ( cx, cy ),
radius r and bounding box (( x 1 , y 1 ) , ( x 2 , y 2 )). The variable
ω is 1 for counterclockwise arcs, -1 for clockwise:
α A
def
≡ { x 0 = v · dx, y 0 = v · dy, v 0 = − dy · g,
dx 0 = − dy · v · ω/r, dy 0 = dx · v · ω /r & InBounds }
Arcs above the x-axis are clockwise ( ω = − 1) and arcs
below the x-axis are counterclockwise ( ω = 1) normally ,
or vice versa when inv erted. Long arcs are automatically
split at quadrant (Q1–Q4) boundaries to simplify proofs.
Parameter Instantiation. T o build a d L model of a con-
crete design, we instantiate component parameters (e.g.
cx, cy, r for arcs, dx, dy for lines) with concrete values from
the GUI tool. The challenge here is that the GUI tool
works with approximate arithmetic while theorem-pro ving
works with exact arithmetic.
F or example, we wish for ( dx, dy ) to be tangent to the
track (e.g. dx = − ( cy − y ) /r ∧ dy = ( cx − x ) /r in arcs),
which is rarely exactly true in floating point arithmetic.
F or this reason, the model generator pre-processes designs
to convert from appro ximate floating-point arithmetic to
exact real arithmetic while preserving properties such as
tangency of ( dx, dy ). We round trac k geometry to an
Interfacing Between Comp onents. This rounding raises
challenges at the interface betw een components. Ensur-
ing components meet exactly at their endpoints is not a
problem, but ensuring they do so with the same slope
(i.e. perfectly smooth transition) is harder. While track
geometries could be adapted so their slopes agree exactly,
this would cause an exponential explosion in the com-
plexity of the geometric description, making arithmetic
proofs completely non-scalable. Instead, we allow slight
slope disagreements between components, which can be
reduced arbitrarily by increasing model precision. At the
start of each component, we insert a program δ whic h
discretely adjusts the slope to match the track exactly .
F or a straight section we set slope based on the endpoints:
δ L
def
≡ ( dx, dy ) := ( x 2 − x 1 , y 2 − y 1 )
p ( x 2 − x 1 ) 2 + ( y 2 − y 1 ) 2
While for an arc section we set slope based on its center
( cx i , cy i ), radius r i , and direction ω :
δ A
def
Composition. W e model the complete coaster by com-
posing the component models. For each component i , w e
first test whether we are within its respective domain
( InBounds i ), discretely adjust the direction vector ( δ i ),
then follow its contin uous dynamics α i . We nondetermin-
istically choose ( ∪ ) to evaluate any component that is
InBounds i , and repeat the process arbitrarily often ( ∗ ):
α ≡ (? InBounds 1 ; δ 1 ; α 1 ) ∪ · · · ∪ (? InBounds n ; δ n ; α n ) ∗
At each iteration, the coaster ev olves into any component
whose bounds are satisfied. For a safe launc h speed, the
velocity is positive and the train can only mov e in the
rightmost such section. F or an unsafe launch speed, the
train can roll back to the left. By proving positive v elocity,
we will prov e the train proceeds to the right.
7. VERIFICA TION
CoasterX verifies tw o classes of d L properties: (1) quanti-
tative acceleration and velocity en velopes which ascertain
safety and other correctness properties and (2) qualitative
results, e.g. that components follow their expected geome-
tries, which increase confidence in the correctness of the
model. We begin with the qualitative results, whic h then
aid in proving the quantitativ e results.
fundamental laws of mec hanics. Because we wish to prove
velocity bounds and energy is directly linked to velocity ,
conservation of energy is of special interest. The only
energies in the system are potential energy due to altitude
and kinetic energy , so we prove E ( t ) = E (0) at all times
t , where E ( t ) = KE + PE = v ( t ) 2
2 + g · y ( t ).
Geometric Corr ectness. W e show that both line segment
and arc components satisfy the algebraic definitions of
their geometry . For a line segmen t, we show we nev er leave
the line dx · ( y − y 1 ) = dy · ( x − x 1 ). This proof is automatic
because line segments have a simple (i.e. polynomial)
solution. F or arcs, we show we alw ays remain on the circle
( x − cx ) 2 + ( y − cy ) 2 = r 2 . This model is multi-affine and
its solution lies outside decidable arithmetic, so instead
of solving it we reason by differ ential induction Platzer
(2012b). Induction shows the lemma
dx = ( y − cy ) /r ∧ dy = ( cx − x ) /r
proving that ( dx, dy ) is tangent to the arc, then a second
induction shows the train stays on the circle.
V elocity Envelop e. Using the conservation of energy in-
varian t, velocity is a function of altitude:
0 + 2( y 0 − y )
where v 0 , y 0 are the velocity and altitude at the start
of the track. This identit y is only true when v ≥ 0, an
inv ariant which we pro ve as a lemma using a differential
ghost Platzer (2012b) argument based on our knowledge
that initial velocity is sufficiently high. W e then compute
the velocity env elope by computing the extrema of v ( y )
across all sections i and points ( x, y ), then prove:
min
( x,y ) ∈ track v ( y ) ≤ v ≤ max
( x,y ) ∈ track v ( y )
for all track sections, which follo ws by arithmetic from the
geometry of each track and energy conserv ation.
Ac celer ation Envelope. W e verify upper and lower bounds
for tangential and radial acceleration. F or both straight
and arc sections, the tangential acceleration is change in
speed v 0 = − dy · g . As before, we compute the envelope by
checking eac h segment and prove:
min
( i,x,y ) ∈ track − dy ( i, x, y ) · g ≤− dy · g ≤ max
( i,x,y ) ∈ track − dy ( i, x, y ) · g
Radial acceleration is 0 in a straight section, or ω · v 2
r for an
arc of radius r when rotating in direction ω . Building upon
the velocity computation, we deriv e the specification:
min
( i,x,y ) ∈ track
ω i · v ( y ) 2
r i
≤ ω · v 2
r ≤ max
( i,x,y ) ∈ track
ω i · v ( y ) 2
r i
Once the acceleration envelope is specified, it proves b y
arithmetic using the track geometry and velocity bounds.
Composition. The proofs for α L and α A are generic and
need only be done once. We then v erify a complete coaster
by instantiating them to sections α 1 , . . . , α n , v erifying each
branch, and conjoining them with nondeterministic choice
α 1 ∪ · · · ∪ α n . We use a loop inv ariant to show safety holds
for arbitrarily many iterations. The inv ariant J consists of
a global inv ariant G and local invarian ts J i each of which
holds within the bounds of the respective segment:
J ≡ G ∧ ^
i
( InBounds i → J i )
F or each case i of the composed coaster, the domain
constraint implies InBounds i from which w e can conclude
J i holds initially on component i . In each case, we sho w
the implication InBounds k → J k holds as a postcondition
for every k , leading to a quadratic num ber of cases.
In principle, all but linearly-many are computationally
cheap. In the case k = i , we apply the component
proofs from above, using arithmetic solving to prove their
preconditions. In the cases k = i ± 1, the sections meet
at exactly the handover point, and arithmetic solving
suffices to show the sections agree at that point. In
the cases | k − i | > 1, the sections have no o verlap,
making InBounds i and InBounds k disjoint. In principle,
this leads to a quick arithmetic proof by contradiction.
In the present implementation, this step is not fully
optimized, leading to quadratic behavior in Section 8. W e
expect such optimizations to be straightforward.
8. EV ALUA TION
Our goal is to prove safet y of large coaster models au-
tomatically and scalably . We sho w that CoasterX scales
to realistic problems by modeling and proving 5 com-
mercial coasters and one hobbyist coaster. The models of
commercial coasters are estimated from publicly av ailable
materials since the exact geometries are proprietary trade
secrets. W e supplement them with a model of Gregg’s hob-
byist coaster Gregg (2018), which matc hes his published
geometry exactly . Each coaster proves within ≤ 30 min utes
on a modern workstation, with full results in T ab. 1.
There is no other coaster verification work for us to com-
pare with, so we instead assess the speed gained by verify-
ing the generic components once and reusing their proofs
vs. verifying each instance separately . This is conserv ative,
ignoring, e.g. the gains from component-based arithmetic;
the full benefit is almost certainly greater.
The continuous dynamics are of modest complexity: they
are modeled with multi-affine differential equations of
at most 5 variables. A t the same time, our complex
geometries result in models whose sheer size significantly
exceeds previous efforts in KeYmaera X, showing why our
automation and component reuse were important. Our
largest geometries featured 256 modeling variables and
≈ 50KB model files, nearly an order of magnitude more
variables than previous KeYmaera X efforts Jeannin et al.
(2017). Note most of the modeling variables are used to
keep the length of model files manageable, and should not
be confused with the continuous v ariables.
F or large coasters, a proof with comp onent reuse is any-
where from 1.6x to 3.5x as fast as the same proof after
disabling reuse. This shows that the v alue of reuse depends
greatly on the cost of the components: the benefit is mod-
est for arcs using optimized differential inv ariant proofs,
but major for line pro ofs using general automation with
no attempt at optimization, which dominate the runtime.
F or small coasters, the speedup is up to 20x. The sp eedup
presently decreases on big models because the current,
unoptimized arithmetic proofs are quadratic.
Lastly , we wish to know that the bounds derived by
CoasterX are tight enough to be useful in practice. While
our Phantom’s Revenge model is only an estimate, we
proved a bound of 3.55 vertical G’s, close to the 3.5 G’s of
the real coaster. This is much less than the 6.5 G’s for our
Steel Phantom coaster, showing CoasterX can distinguish
well between safe and unsafe acceleration in real coasters.
9. CONCLUSION AND FUTURE WORK
W e introduced CDPA and implemen ted a case study,
CoasterX, implemented on top of KeYmaera X. By ex-
ploiting component structure and reuse, CoasterX scales
well to 50+ component instances. Because formal specifi-
cations are automatically generated from high-level graph-
ical designs, CoasterX end-users need no formal methods
experience. The conversion from inexact high-level models
to mathematically exact specifications was subtle.
W e modeled coaster dynamics and identified bounded
acceleration as our safety specification. In the process, we
prove v elocity bounds, which assess also the absence of
stuck coasters. W e applied these analyses to several real
coasters. F or our motivating Steel Phantom example, w e
show that even simple dynamics can distinguish an unsafe
coaster design (Steel Phantom) from a safe version of it
(Phantom’s Revenge), in this case b y a wide margin of 3
G’s. In future work we can get tigh ter acceleration bounds,
faster verification times, and lateral acceleration bounds
by modeling additional forces, adding new track types, and
Coaster Model Sections Geo. Time No Reuse Speedup Steps Size Component Dim. (ODE) Time # Steps
Top Thrill Dragster 8 37 23s 466s 20x 5K 4.7KB Line 21 (3) 140s 900K
Paul Gregg BYRC 12 57 47s 502s 11x 8K 9.2KB Q1 Arc 29 (5) 3.1s 9K
Lil’ Phantom 22 107 206s 708s 3.4x 14K 21.4KB Q2 Arc 29 (5) 5.1s 14K
Phantom’s Revenge 42 192 723s 2058s 2.8x 19K 37.9KB Q3 Arc 29 (5) 3.6s 10K
El Toro 53 256 1517s 2467s 1.6x 29K 52.3KB Q4 Arc 29 (5) 6.3s 17K
Steel Phantom 56 232 1120s 3965s 3.5x 26K 40.4KB
T able 1. Coaster and component proof stats. Columns (coasters): Number of component
instances, # geometric variables, time with reuse, time without reuse, speedup factor with reuse,
total atomic proof steps, size of theorem statement. Columns (components): total dimension
(continuous v ars), proof time, total atomic proof steps
modeling in 3D, respectively. These forces w ould improve
the velocity low er bound and thus the analysis of stuck
coasters. 3D vs. 2D models are conceptually similar, but a
3D GUI is a larger implementation effort.
Our results for coasters suggest CDP A is a promising
approach for scalable, trustw orthy , automation in other
domains including rail networks, road net works, and UA V
flight plans, which w e wish to verify in future work.
10. ACKNOWLEDGEMENTS
Special thanks to Jim McCann, Nick W eisenberger, Brian
Ondrey , Jessica Hodgins, and Hunter Lawrence for their
insights about roller coasters. This material is based upon
work supported by the National Science F oundation under
NSF CAREER Award CNS-1054246. The first author
was supported by the Department of Defense through
the National Defense Science & Engineering Graduate
F ellowship Program.
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... Many model-checkers support multi-affine ODEs [2,5,9,11], but struggle with scalability, compared to affine systems [3,14]. Our small-scale results potentially enable future scalability: multi-affine component-based proofs scale to hundreds of variables
[6]
, an order of magnitude beyond nonlinear ODE benchmarks [5,9,11]. ...
... This paper provides a parametric model that supports nonlinear dynamics through approximation, and formally proves the approximation correct against nonlinear dynamics. Because dL is amenable to constrained optimization for control [17] and efficient verification of compound systems by decomposition into reusable components
[6]
, it is expected that the dL-based approach can be extended to overcome the aforementioned industrial challenges in future work. If successful, the benefits to the chemical industry would include increased confidence in software correctness and potential improvements in scalability and efficiency of parameter changes, when designing plants and controllers. ...
... A component-based approach could compose the models and proofs for individual reactions into complete reaction networks or chemical plants. Previous proofs suggest a component-based approach could scale to hundreds of variables
[6]
, indicating potential to improve upon the scalability of competing approaches [43]. Secondly, a black-box approach [8] incorporating constrained optimization [17] could make our work useful for realistic industrial controllers, which may involve components too complex for current white-box verification techniques. ...
Chemical Case Studies in KeYmaera X
Chapter
Full-text available
Sep 2022
Rose Bohrer
Safety-critical chemical processes are well-studied in the formal methods literature, including hybrid systems models which combine discrete and continuous dynamics. This paper is the first to use a theorem-prover to verify hybrid chemical models: the KeYmaera X prover for differential dynamic logic. KeYmaera X provides parametric results that hold for a whole range of parameter values, non-linear physical dynamics, and a small trusted computing base.We tell a general story about KeYmaera X: recent advances in automated reasoning about safety and liveness for differential equations have enabled elegant proofs about reaction dynamics.KeywordsHybrid SystemsTheorem ProvingChemical Reactor
A Formally Verified Hybrid System for Safe Advisories in the Next-Generation Airborne Collision Avoidance System
Nov 2017
Int J Software Tool Tech Tran
Jean-Baptiste Jeannin
Khalil Ghorbal
Yanni Kouskoulas
André Platzer
The Next-Generation Airborne Collision Avoidance System (ACAS X) is intended to be installed on all large aircraft to give advice to pilots and prevent mid-air collisions with other aircraft. It is currently being developed by the Federal Aviation Administration (FAA). In this paper we determine the geometric configurations under which the advice given by ACAS X is safe under a precise set of assumptions and formally verify these configurations using hybrid systems theorem proving techniques. We consider subsequent advisories and show how to adapt our formal verification to take them into account. We examine the current version of the real ACAS X system and discuss some cases where our safety theorem conflicts with the actual advisory given by that version, demonstrating how formal hybrid systems proving approaches are helping to ensure the safety of ACAS X. Our approach is general and could also be used to identify unsafe advice issued by other collision avoidance systems or confirm their safety.
A Complete Uniform Substitution Calculus for Differential Dynamic Logic
Aug 2017
J AUTOM REASONING
André Platzer
This article introduces a relatively complete proof calculus for differential dynamic logic (dL) that is entirely based on uniform substitution, a proof rule that substitutes a formula for a predicate symbol everywhere. Uniform substitutions make it possible to use axioms instead of axiom schemata, thereby substantially simplifying implementations. Instead of subtle schema variables and soundness-critical side conditions on the occurrence patterns of logical variables to restrict infinitely many axiom schema instances to sound ones, the resulting calculus adopts only a finite number of ordinary dL formulas as axioms, which uniform substitutions instantiate soundly. The static semantics of differential dynamic logic and the soundness-critical restrictions it imposes on proof steps is captured exclusively in uniform substitutions and variable renamings as opposed to being spread in delicate ways across the prover implementation. In addition to sound uniform substitutions, this article introduces differential forms for differential dynamic logic that make it possible to internalize differential invariants, differential substitutions, and derivatives as first-class axioms to reason about differential equations axiomatically. The resulting axiomatization of differential dynamic logic is proved to be sound and relatively complete.
View
Show abstract
| https://www.researchgate.net/publication/324900234_CoasterX_A_Case-Study_in_Component-Driven_Hybrid_Systems_Proof_Automation |
Life | Free Full-Text | Correlation between Bone Mineral Density and Progression of Hip Osteoarthritis in Adult Men and Women in Bulgaria& mdash;Results from a 7-Year Study
Changes in clinical presentation, radiographic progression (RP), bone mineral density (BMD), bone turnover (BT), and cartilage turnover (CT) markers were compared in two groups of patients with hip osteoarthritis (HOA) over a period of 7 years. Each group consisted of 150 patients, including a control group on standard-of-care therapy (SC) with simple analgesics and physical exercises, and a study group (SG) on standard-of-care therapy supplemented by vitamin D3 and intravenous administration of zoledronic acid (5 mg) yearly for 3 consecutive years. Patient groups were homogenized regarding the following: (1) radiographic grade (RG), including 75 patients with hip OA RG II according to the Kellgren& ndash;Lawrence grading system (K/L), and 75 with RG III on K/L; (2) radiographic model (RM), as each of the K/L grades was subdivided into three subgroups consisting of 25 patients of different RMs: atrophic (& lsquo;A& rsquo;), intermediate (& lsquo;I& rsquo;), and hypertrophic (& lsquo;H& rsquo;); (3) gender-equal ratio of men and women in each subgroup (Female/Male = 15/10). The following parameters were assessed: (1) clinical parameters (CP), pain at walking (WP-VAS 100 mm), functional ability (WOMAC-C), and time to total hip replacement (tTHR); (2) radiographic indicators(RI)& mdash;joint space width (JSW) and speed of joint space narrowing (JSN), changes in BMD (DXA), including proximal femur (PF-BMD), lumbar spine (LS-BMD), and total body (TB-BMD); (3) laboratory parameters (LP)& mdash;vitamin D3 levels and levels of BT/CT markers. RV were assessed every 12 months, whereas CV/LV were assessed every 6 months. Results: Cross-sectional analysis (CsA) at baseline showed statistically significant differences (SSD) at p & lt; 0.05 in CP (WP, WOMAC-C); BMD of all sites and levels of CT/BT markers between the & lsquo;A& rsquo; and & lsquo;H& rsquo; RM groups in all patients. Longitudinal analysis (LtA) showed SSD (p & lt; 0.05) between CG and SG in all CP (WP, WOMAC-C, tTHR) parameters of RP (mJSW, JSN), BMD of all sites, and levels of CT/BT markers for all & lsquo;A& rsquo; models and in 30% of & lsquo;I& rsquo;-RMs (those with elevated markers for BT/CT at baseline and during the observation period). Conclusion: The presence of SSD at baseline (& lsquo;A& rsquo; vs. & lsquo;H& rsquo;) supported the thesis that at least two different subgroups of HOA exist: one associated with & lsquo;A& rsquo; and the other with & lsquo;H& rsquo; models. D3 supplementation and the intravenous administration of bisphosphonate were the treatment strategies that slowed down RP and postponed tTHR by over 12 months in the & lsquo;A& rsquo; and & lsquo;I& rsquo; RM with elevated BT/CT markers.
Correlation between Bone Mineral Density and Progression of Hip Osteoarthritis in Adult Men and Women in Bulgaria—Results from a 7-Year Study
by
Lyubomir Sapundzhiev 1,2,* ,
Tanya Sapundzhieva 1,2 ,
Martin Mitev 2 ,
Kiril Simitchiev 3 and
Anastas Batalov 1,4
Rheumatology Department, University Hospital ‘Pulmed’ Plovdiv, 4002 Plovdiv, Bulgaria
3
Department of Analytical Chemistry and Computer Chemistry, Faculty of Chemistry, University of Plovdiv, 4001 Plovdiv, Bulgaria
4
Rheumatology Clinic, University Hospital ‘Kaspela’, 4001 Plovdiv, Bulgaria
*
Author to whom correspondence should be addressed.
Life 2023 , 13 (2), 421; https://doi.org/10.3390/life13020421
Received: 22 December 2022 / Revised: 22 January 2023 / Accepted: 30 January 2023 / Published: 2 February 2023
(This article belongs to the Special Issue Current Views on Knee Osteoarthritis: 2nd Edition )
Abstract
Changes in clinical presentation, radiographic progression (RP), bone mineral density (BMD), bone turnover (BT), and cartilage turnover (CT) markers were compared in two groups of patients with hip osteoarthritis (HOA) over a period of 7 years. Each group consisted of 150 patients, including a control group on standard-of-care therapy (SC) with simple analgesics and physical exercises, and a study group (SG) on standard-of-care therapy supplemented by vitamin D3 and intravenous administration of zoledronic acid (5 mg) yearly for 3 consecutive years. Patient groups were homogenized regarding the following: (1) radiographic grade (RG), including 75 patients with hip OA RG II according to the Kellgren–Lawrence grading system (K/L), and 75 with RG III on K/L; (2) radiographic model (RM), as each of the K/L grades was subdivided into three subgroups consisting of 25 patients of different RMs: atrophic (‘A’), intermediate (‘I’), and hypertrophic (‘H’); (3) gender-equal ratio of men and women in each subgroup (Female/Male = 15/10). The following parameters were assessed: (1) clinical parameters (CP), pain at walking (WP-VAS 100 mm), functional ability (WOMAC-C), and time to total hip replacement (tTHR); (2) radiographic indicators(RI)—joint space width (JSW) and speed of joint space narrowing (JSN), changes in BMD (DXA), including proximal femur (PF-BMD), lumbar spine (LS-BMD), and total body (TB-BMD); (3) laboratory parameters (LP)—vitamin D3 levels and levels of BT/CT markers. RV were assessed every 12 months, whereas CV/LV were assessed every 6 months. Results: Cross-sectional analysis (CsA) at baseline showed statistically significant differences (SSD) at
p
< 0.05 in CP (WP, WOMAC-C); BMD of all sites and levels of CT/BT markers between the ‘A’ and ‘H’ RM groups in all patients. Longitudinal analysis (LtA) showed SSD (
p
< 0.05) between CG and SG in all CP (WP, WOMAC-C, tTHR) parameters of RP (mJSW, JSN), BMD of all sites, and levels of CT/BT markers for all ‘A’ models and in 30% of ‘I’-RMs (those with elevated markers for BT/CT at baseline and during the observation period). Conclusion: The presence of SSD at baseline (‘A’ vs. ‘H’) supported the thesis that at least two different subgroups of HOA exist: one associated with ‘A’ and the other with ‘H’ models. D3 supplementation and the intravenous administration of bisphosphonate were the treatment strategies that slowed down RP and postponed tTHR by over 12 months in the ‘A’ and ‘I’ RM with elevated BT/CT markers.
Keywords:
bone mineral density
;
osteoarthritis progression
;
subchondral bone remodeling
1. Introduction
During the course of osteoarthritis (OA) of weight-bearing joints, articulate cartilage (AC) and subchondral bone (SB) act as one functional unit (osteochondral junction (OCJ)) against the altered biomechanical load [ 1 , 2 , 3 , 4 ].
SB is an composite term that includes the subchondral bone plate, the underlying trabecular bone, and the bone marrow space. The vertical portions of the arcades of collagen type II pass through it, anchoring the articular cartilage to the SB. In response to changed biomechanics, SB reacts with an increased turnover, leading to the accumulation of osteoid substance (sclerosis), in parallel with decreased mineralization due to the production of abnormal trimeric collagen, which has a low affinity for calcium. Thus, the process of thickening of the SB, known as eburnation, is the result of increased material density, together with decreased mineral density, increased porosity, and effacement of the cortical plate and the underlying trabecular bone. Besides eburnation, SB remodeling comprises the formation of subchondral bone cysts, new bone osteophytes, and changes in bone marrow (bone marrow lesions (BML)), detected with magnetic resonance imaging (MRI) and contrast-enhanced MRI (CE-MRI) [ 1 , 2 , 3 , 4 ]. The cytokines-mediated ‘cross-talk’ between chondrocytes and bone cells contributes to OA pathogenesis [ 2 , 3 , 4 , 5 ]. An alteration in the composition or structure of any of the individual components of the OCJ can initiate the pathogenetic processes leading to OA. In particular, in MRI studies, cartilage degeneration has been proven to be preceded by subchondral bone lesions (SBL), suggesting a key role for this mechanism in the pathogenesis and progression of OA, as well as in the formation of ectopic bone and osteophytes [ 3 , 4 , 5 , 6 , 7 , 8 ].
The changes in SB can be analyzed using parallel analyses of standard radiographic images (bone geometry, RG, and RM of HOA), MRI/CE-MRI (synovitis, BML, SBL), and BMD changes using DXA and/or quantitative computed tomography (QTC), with the latter assessing femoral strength using software for hip structural analysis. Histological sampling and analysis of BT/CT markers add further value to the imaging data.
Over the past 40 years, researchers have tried to determine the relationship between BMD and the progression of clinical and morphological changes in HOA [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. However, most studies have reported somewhat contradictory data, such as an association between HOA and increased or decreased BMD, both on a local level (PF-BMD) [ 10 , 11 , 15 , 18 , 22 ] and in the whole body (TB-BMD) [ 12 , 13 , 14 , 16 , 17 , 18 ], including patients with advanced HOA waiting for THR [ 19 , 20 , 21 ]. In the cited studies [ 9 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ], the effect of several important factors was not taken into account. Despite the fact that CP, RP, and LP have been linked to the type of radiographic model (RM) (‘A’ vs. ‘I’ vs. ‘H’), this relationship was not factored into the research designs [ 10 , 23 , 24 , 25 , 26 , 27 ]. Furthermore, the inclusion of patients from a wide age range (35–85 years) does not allow control of secondary HOA. Patients aged 35 to 50 typically represent ‘H’ models of HOA, which are characterized by mild forms of hip dysplasia [ 28 ]. Gender-related differences (e.g., presence of SSD) in CP, mJSW, BMD, D3, and BT/CT markers between men and women of the same age, the same BMI, and the same RG/RM) have also been overlooked [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].
The current study aimed to investigate the relationship between BMD, microarchitecture, and SB remodeling, and the progression of HOA. For this purpose, a study group of HOA patients who received the standard-of-care treatment together with vitamin D3 supplementation [
38
] and intravenous administration of zolendronic acid (an anti-resorptive drug) [
39
] was compared to a control group of HOA patients receiving the standard-of-care therapy. To control for confounding factors, the RMs of HOA, gender differences, and the exclusion of all types of secondary HOA were taken into consideration when designing the study.
2. Methods and Materials
This was a single-center, observational, randomized, double-blinded, and controlled study (DBRCT) that was conducted over a 7-year period (2014–2022) at the outpatient clinic of a rheumatology department. Each patient signed an informed consent form, approved by the Ethics Committee of the University Hospital “Pulmed”. The study was approved and registered at the Regional Health Inspectorate under the section “Radiation Control” with No. XI-214/06.07.2011 and by the Bulgarian Drug Agency with No. KИ-109-3-0009/12.01.2014.
2.1. Patients
The study included 300 participants in two groups, each consisting of 150 SG/CG patients, of whom 75 were RG-II K/L and 75 were RG-III K/L. Each RG was subdivided into three subgroups of 25 patients from different RMs (‘A’, ‘I’, ‘H’) with a fixed female to male ratio of 15/10 in each subgroup. In the SG group, in addition to the standard-of-care therapy, which included a simple analgesic (paracetamol—of up to 2.0 g/24 h) and physical exercises, the patients were also given the following: (1) vitamin D3 once daily, in the form of soft capsules ALPHA D3
®
1 μg, each containing 1 mcg. Alfacalcidol, Teva Pharmaceutical Industries Ltd., Tel Aviv, Israel (target level of 60 ng/mL, reference range 20–120 ng/mL); (2) ZA 5 mg/yearly (Aclasta
®
5 mg/100 mL Infusion, Novartis India Ltd, Mumbai, Maharastra, India.) for 3 consecutive years.
Inclusion and Exclusion Criteria
The following inclusion criteria were applied: (1) a diagnosis of primary, one or double-sided HOA according to the ACR criteria [ 40 ]; (2) symptomatic HOA (WP by VAS ≥39/100 mm [ 41 ]), WOMAC-A ≥6/20, WOMAC-C ≥30/68 [ 42 ]); (3) radiographically confirmed HOA (RG II-III according to K/L classification [ 43 ]); (4) signed informed consent.
Patients with the following characteristics were excluded from the study: (1) secondary HOA; (2) severe deviations in the weight-bearing axis; (3) presence of synovitis or effusion; (4) signs of rapidly progressing HOA in ‘A’-RM; (5) any intraarticular treatment or treatment with sulfate sugars, biocollagen, hyaluronic acid, diacerein, or avocado and soybean unsaponifiables within the 6 months prior to the baseline visit; (6) age above 60 and below 70; (7) body mass index (BMI) less than 21 kg/m
2
or more than 28 kg/m
2
; (8) poorly controlled internal diseases, including hypertension, diabetes, cardiovascular, and cerebrovascular disease.
The age restrictions were introduced in order to exclude mild hip dysplasia (clinical presentation before 55 years of age) [ 28 ], the effect of hormonal changes in the early menopause (50–55 years) over SB [ 34 ], and the high rate of HOA in people over 60 years of age [ 18 , 22 ], as well as due to data regarding life duration (decreasing the chance of successfully finishing the 7-year follow-up period). The restriction in BMI and severe deviations in the weight-bearing axis were introduced in order to eliminate the effect of these variables on the RP of HOA [ 26 , 27 ]. The need for a fixed gender distribution in the patient groups was discussed previously [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].
2.2. Study Design
The sample size of each patient group and subgroup was calculated using the methodology described by J. Wittes [ 44 ], considering a 2% possible loss of patients in the treatment groups, as compared to 1% in the control group. Restricted block randomization [ 45 ] was applied during the screening and selection process, resulting in the formation of the following six blocks: K/L-II’A’; K/L-II’I’; K/L-II’H’; K/L-III’A’; K/L-III’I’; and K/L-III’H’. From each block of 50 patients, subgroups with a fixed female to male ratio (15/10) were randomly generated using a computer program ( Table 1 ).
Table 1. Research design: patient groups, methods, follow-up, indicators, and analyses.
Blinding
The rheumatologists performing the clinical follow-up were blinded to the group types and numbers, as well as the laboratory and radiographic (DXA and X-ray) follow-up results. The medication was administered by the hospital pharmacist, who knew the randomization group and number but was blinded to the clinical and radiological data. The radiologists were blinded to the design, randomization group and number, and clinical data of the patients. The study coordinators (external, non-medical personnel provided by the Bulgarian Drug Agency) were responsible for contact with the patients (calling for the visits) and knew which randomization number corresponded to which patient, but were blinded to the clinical and radiological data of the patients. Only the principal monitor (external medical personnel provided by the Bulgarian Drug Agency) had access to the randomization group numbers and all data from CP and RI, but they did not know the patients. A summary of the research design, including the patient groups, methods, follow-up, and analyses, is presented in
Table 1
.
2.3. Physical Examination
Patient physical examinations and recording of the clinical data were performed by a board-certified rheumatologist. At each patient visit, the following factors were evaluated: vital signs, height, weight (BMI), walking pain (VAS-100 mm) [ 41 ], functional ability (WOMAC-C) [ 42 ], the presence of adverse events, and quality of life (SF-36 and PtGA) [ 46 ]. Treatment responses by OMERACT-OARSI set of responder criteria [ 47 ] and minimal clinically important improvement (MCII) [ 48 ] were also assessed.
2.4. Radiological Examinations
The radiographic images
were taken in an upright weight-bearing position, anterior–posterior projection, with a slight (15–20 degrees) inner rotation of the feet, which was ensured by using a ‘V ‘-shaped pad placed 100 cm away from the source, with a perpendicular ray, focused on 4 cm above the symphysis. The following parameters were assessed: RG on K/L grade [
37
]; RM— ‘H’, ‘I’, ‘A’; JSW—the measurement of each joint was performed manually using software for measuring distances in digital radiographic images at three points: superolateral, apical, and superomedial (
Figure 1
). For the statistical analyses, the mean value of the three distances was used (mean joint space width—mJSW) and the annual speed of JSN-mm/year (JSNM12 = mJSW-M0 – mJSWM-12), according to the recommendations of the 2004 Barcelona Consensus Group [
29
].
Figure 1. Measurement of JSW at three points according to the Barcelona consensus ( left image ) [ 29 ], and in a patient from our study ( right image ).
DXA
measurements were conducted using
Lunar Prodigy Primo-en CORE, version 17,
according to the methodology of ISCD, including recommendations for calibration, measurement, and interpretation of results from 2015 [
30
]. The following parameters were assessed: PF-BMD; LS-BMD; TB-BMD (proximal femur, lumbar spine, total body); and parameters for bone geometry for HSA: HAL (hip axis length); NSA (neck shaft angle); CSA (cross-sectional area); CSMI (cross-sectional moment of inertia); MNW (minimal neck width); FN-CT (cortical thickness of the femoral neck); FS-CT (cortical thickness of femoral shaft); SM (section modulus); BR (buckling ratio) (
Figure 2
,
Figure 3
and
Figure 4
).
Figure 2. DXA measurements: dual femur—this scan was used to obtain the BMD parameters: femoral neck (FN-BMD); femoral head (FH-BMD); total hip BMD (TH-BMD); parameters of bone geometry (HAL—hip axis length; NSA—neck shaft angle; MNW—minimal neck width; CSA—cross-sectional area; CSMI—cross-sectional moment of inertia; FN-CT—cortical thickness of femoral neck; FS-CT—cortical thickness of femoral shaft; SM—section modules; BR—buckling ratio) and also for the comparisons between the mentioned parameters—left/right (target/non-target) joint.
Figure 3. DXA measurements: anterior posterior spine—this scan was used to obtain the BMD parameters from the lumbar spine (LS-BMD), both from the individual vertebrae (L1; L2; L3; L4) and the total score (L1–L4).
Figure 4. DXA measurements: total body—this scan was used to obtain the BMD parameters from the different regions (head-BMD; arms-BMD; legs-BMD; trunk-BMD; ribs-BMD; spine-BMD; pelvis-BMD) and a total body score (TB-BMD).
The measurements and interpretation of the results from the radiographic and DXA investigations were conducted by two separate certified by ISCD radiologists, who were blinded to the design and clinical and laboratory data, and with very good inter-reader reliability (intraclass correlation coefficient ICC of 0.918, 95% CI: 0.846–0.960) and PABAK (prevalence-adjusted and bias-adjusted kappa) values for X-ray/DXA reading of 0.860 and 0.880, respectively.
2.5. Biochemical Analyses
The biochemical analyses were performed and interpreted at the certified laboratory of the University Hospital ‘Pulmed’ in Plovdiv, Bulgaria. The serum levels of several markers were assessed, including
○
25-hydroxy vitamin D (25-OH-D)—chemiluminescent immunoenzymatic assay (CLIA (reference range 20–120 ng/mL)) [ 31 ]
○
β-beta-isomerized carboxy-terminal cross-linking telopeptide of type I collagen (CTX-I, in our country - β-Cross Laps), a product of the break-down of collagen type I by the osteoclasts, with the former comprising 90% of the organic bone matrix, a marker of bone degradation [ 31 ], CLIA methodology (reference range: men (>60 years old) <0.7 ng/mL; women >60 years old (postmenopausal) <0.9 ng/mL).
○
Urine C-terminal crosslinking telopeptides of collagen type II (CTX-II)—a marker of CT [ 32 , 33 , 34 , 35 , 36 , 37 ] (competitive ELISA, Cartilaps, IDS, Boldon, UK, (reference range 129 and 345 ng/mmol Cr), with intra- and inter- assay CVs below 8% and 10%, respectively).
The concentration of CTX-II (ng/L) was standardized to the total urine creatinine (mmol/L), and the units for the corrected CTX-II concentration were ng/mmol [ 33 ]. Quantitative detection of creatinine in urine was performed using a Human Creatinine ELISA Kit, Chongqing Biospes Co., Ltd. (Catalog No: BYEK2883). The corrected concentration of uCTX-II for urinary creatinine was calculated using the formula: corrected uCTX-II (ng/mmol) = 1000 × uCTX-II (ug/L)/urinary creatinine (mmol/L).
2.6. Follow-Up
The following parameters were assessed for the patients in both groups (CG and SG): RV (JSW/JSN; BMD-DXA); CV—(WP; F - WOMAC-C; PtGA; tTHR); LV—levels of vitamin D3 and levels of BT/CT markers. RV were assessed every 12 months, whereas CV and LV were assessed every 6 months.
2.7. Statistical Analyses
The data were analyzed using Statistical Package for the Social Sciences (SPSS) version 21. The results were presented as numbers and percentages (%) for the qualitative variables and as medians with interquartile ranges (IQRs) for the continuous variables. For the detection of statistically significant differences (SSDs), Mann–Whitney and Kruskal–Wallis non-parametric tests were used. If SSD was present, post hoc multiple comparisons with Dunn–Bonferroni were performed. Pearson correlation analysis and multiple logistic regression were used to analyze the effect of BMD and bone geometry markers on radiographic progression. All statistical tests were two-tailed and performed at a level of significance (α) of 0.05 and a power of 80%. Exact p -values were used to interpret the results, with a p < 0.05 meaning a statistically significant change.
3. Results
3.1. Results from the Cross-Sectional Study
There were no significant differences in the values of the clinical, laboratory, and radiographic parameters at baseline between the SG and CG groups in all three models ( Table 2 ).
Table 2. Baseline characteristics of the control and study group.
All ‘A’ models from both RGs of the two groups had decreased BMD at all measurement sites (PF-BMD; LS-BMD; TB-BMD) and 70% of them met the ISCD criteria [ 30 ] for osteoporosis. On the other hand, all ‘I’ and ‘H’ models were with normal (‘I’) or slightly increased (‘H’) local BMD ( p < 0.05), as compared to the controls without HOA ( Figure 5 ).
Figure 5. Bone mineral density (BMD) in patients from the three RMs of HOA (hypertrophic; normotrophic and atrophic). The results are shown as Z scores of femoral neck (FN), lumbar spine (LS), scull (Head), and total body (Total) for each RM. Z scores were used to compare to controls without HOA after standardization for gender, age, and BMI. *- a statistically significant difference ( p < 0.05) when comparing to controls without HOA after standardization for gender, age, and BMI.
All ‘A’ models had increased levels of CT or BT markers as compared to the ‘I’ model. The latter showed increased CT/BT markers as compared to the ‘H’ model, p < 0.05 ( Table 2 and Figure 6 ).
Figure 6. Values of markers for bone (serum β-CTX-I) and cartilage (urine CTX-II) turnover in the different RG/RM of HOA. Serum β-CTX-I—beta-isomerized carboxy-terminal cross-linking telopeptide of type I collagen in nanogram per milliliter; urine CTX-II—C-terminal crosslinking telopeptides of collagen type II, presented as corrected concentrations of uCTX-II for urinary creatinine concentration, as ng/mmol Cr.
The comparison between ‘A’ and ‘H’ models showed statistically significant differences in CP ( p < 0.01), the levels of BT/CT markers, and BMD and bone geometry markers (a wider femoral neck and increased FSI, p < 0.05), and no significant differences in mJSW. The comparisons of ‘H’ vs. ‘I’ and of ‘I’ vs. ‘A’ showed some differences, but they were not statistically significant ( p > 0.05), even at the interim analyses ( Table 3 ).
Table 3. Within-group comparisons (‘H’ vs. ‘I’ vs. ‘A’) of the values of CP, RI, and CT/BT markers in both groups.
3.2. Results from the Longitudinal Study
Serious adverse effects were not observed in either group, and there was no loss of patients during the 7-year follow-up period. Transient myalgia (2–6 h with spontaneous resolution) after the intravenous administration of ZA was observed in 46 patients (31%) from the SG group.
The loss of whole subgroups was observed at the following times: M36—CG-III’A’; M42—CG-III’I’/SG-III’A’; M54—CG-III’H’ + II’A’ /SG-II’H’ + III’I’; M66—CG-II’I’/SG-II’A’; and M78—CG-II’H’/SG-II’H’+II’I’ ( Figure 7 ). This was an expected result of HOA’s natural and therapy-modified evolution, rather than the loss of subjects. The final clinical and radiographic investigations were completed, with a clear path toward conversion to total hip replacement (THR) and the possibility of follow-up.
Figure 7. Follow-up data.
In the CG group, the natural evolution of HOA did not demonstrate unexpected results. While the CT and BT markers were constantly increasing, CP (WP and F) worsened over time, along with advances in morphological changes (mJSW) and decreases in BMD at all measurement visits ( Figure 8 and Table 4 ).
Figure 8. Change in BMD for a period of 36 months in the control (SC) and treatment (SG) groups. TH-BMD—total hip bone mineral density. The levels are presented as standard error of the mean (SEM) percentage changes, in order to present the characteristics (changes in BMD) of the sample data and allow comparisons of how much discrepancy was likely to appear in the sample mean as compared to the population mean.
Table 4. Changes in the clinical and radiographic parameters in the CG and SG groups over time.
In the SG group, a delay in the decrease in BMD followed by a transient increase in BMD was observed in all RMs from both RGs, albeit at different rates: at month 12 (M12) in the ‘A’ and ‘I’ models and at M36 in the ‘H’ model. This increase was followed by a rapid decrease in BMD, starting from M48 (12 months after the last administration of ZA), at the same rate of change as in the SC group (
Table 4
). BMD changes were accompanied by similar changes in the levels of BT/CT markers, namely a decrease followed by an increase after M48 at the same rate as in the CG group. The described changes in CT/BT and BMD were accompanied by transient but statistically significant differences in the values of CP and RI (SG vs. CG).
3.3. Within Group Comparisons
At baseline (M0) in both patient groups (SC and SG), a significant difference existed between the endmost RMs (‘H’ vs. ‘A’) in CP (WP/F). No significant differences were found in mJSW, including the end RMs. During the follow-up, at points M12 (CP’s/ JSN) and M36 (mJSW), significant differences were observed between all RMs of the SC group ( Table 5 and Table 6 ).
Table 5. Within-group comparisons in clinical parameters (WP/F) between the RMs of the same RG at different time points.
Table 6. Within-group comparisons of the radiological indicators (JSN/mJSW) between RMs of the same RG and on the same treatment.
The within-group comparisons in CP in the SG sample (‘H’ vs. ‘I’) did not show significant differences throughout the study period (K/L-II M78; K/L-III –M54). On the other hand, the comparisons of ‘I’ vs. ‘A’ revealed significant differences at M60 (K/L-II) and at M36 (K/L-III) (
Table 5
). Regarding the radiological indicators, the comparisons in the SG showed no significant differences (‘H’ vs. ‘I’ vs. ‘A’) in the slow progression stage (K/L-II) until the end of the follow-up. In the rapidly progressing stage (K/L-III), the intragroup comparisons of ‘H’ vs. ‘I’ vs. ‘A’ showed no significant differences in JSN, despite the presence of differences in mJSW (M12/M36), suggesting a slowing down of the speed of JSN (
Table 6
).
Therapeutic responses, according to the OMERACT-OARSI set of responder criteria [ 49 ] and Tubach F. (minimal clinically important improvement –MCII) [ 50 ] were registered in ‘A’ and 30% of ‘I’ RMs from both radiological grades, K/L-II and III (CG vs. SG) in CP (WP; WOMAC-C; PtGA). These responses were first detected at month six after the first application of ZA and persisted until the sixth (OMERACT-OARSI set) or twelfth month (MCII) after the last ZA administration ( Table 4 ).
3.4. Between Group (SC vs. SG) Comparisons
The first occurrence of significant differences in JSN between the two groups (SG and CG) was detected at month 12 after the first application of ZA in the ‘A’ models of both RGs and in 30% of ‘I’ models, namely those with elevated markers for BT and CT at baseline and during the observation period. These differences were accompanied by analogous ones in mJSW with a later onset at M36 and persisted during all follow-up visits, until the end of the study ( Table 7 ).
Table 7. Between-group comparisons of the changes in the radiological indicators JSN at M12 and mJSW at M36.
Statistically significant differences between the study and control groups were observed in the ‘A’ and ‘I’ models from both RGs regarding the length of time before THR had to be performed. Due to the longer natural evolution of HOA in the K/L-II grade (K/L-II’A’ vs. K/L-III’A’) these differences were highly significant ( p < 0.001) ( Table 8 ).
Table 8. Between-group comparisons (SC vs. SG) regarding the length of time before THR had to be performed.
By using multiple logistic regression, the observed changes in BMD (CG vs. SG) were identified as the main reason ( Table 9 ) for the observed changes in CP and RP. The decrease in their values by one standard deviation (SD) was associated with an accelerated progression (OR = 6.561, p < 0.001; OR = 6.495, p < 0.001, respectively).
Table 9. Multiple logistic regression to determine the factors associated with radiographic progression in HOA.
4. Discussion
The methodology of computer-simulated models, which is widely used today [ 49 , 50 ], had been not developed in detail at the time of the current study’s planning (2011–2013), resulting in the planning and execution of an experimental study instead of a simulation study.
The gender-related differences in the levels of CB and CT markers and radiological indicators (mJSW/BMD) in men and women with the same values of CP (WP/F), radiological grade, and model, are well-known and have been discussed in the literature [ 29 , 30 , 31 , 32 , 33 , 34 ]. However, these gender differences, as well as the differences in CP, levels of the CT-BT markers, and BMD between ‘A’ and ‘H’ models of the same RG, suggest that patient groups should be homogenized not only by RG, but also by RM, with a fixed ratio in the number of men and women in each group. Furthermore, the significant differences in CP, CT/BT markers, and BMD in the absence of corresponding changes in mJSW between ‘A’ and ‘H’ RMs of the same RG suggest that the value of the CP (WP/F) is dependent not only on mJSW (loss of AC), but also on the quality (changes) in the SB.
Differences in bone geometry, BMD, levels of BT/CT markers, and bone histomorphometry between the different RMs of HOA were reported in a number of studies [ 10 , 24 , 25 , 26 ]. ‘H’ models had a wider femoral neck, increased BMD at all measurement points, and increased FSI compared to ‘A’ models, which had a narrower femoral neck, decreased BMD at all measurement points, and decreased FSI. The levels of BT/CT markers showed delayed or accelerated bone resorption in the ‘H’ as compared to ‘A’ models [ 24 , 36 ], whereas histomorphometric studies of specimens from THR surgeries showed smaller bone volumes and thinner trabeculae in ‘A’ models [ 25 ].
One of the objectives of our study was to examine the relation between RM and BMD in the Bulgarian population and the treatment options available to delay RP in patients with different types of RM of HOA through vitamin D3 supplementation and intravenous administration of ZA (which causes a change in BMD).
The results from the comparison between bone geometry parameters, BMD, and the levels of serum CTX-I and urine CTH-II at baseline in our study were similar to those reported in other similar studies [ 10 , 24 ]. The abovementioned results (ours and from other studies) suggest the presence of at least two different types of HOA, associated with ‘A’ and ‘H’ models.
At baseline, within-group comparisons in both groups (SC and SG) showed significant differences between the endmost RMs (‘H’ vs. ‘A’) in CP (WP/F) and an absence of significant differences in mJSW, even between the endmost models.
During the follow-up, the natural evolution of the SC group led to the appearance of significant differences at M12 in the clinical parameters and JSN and at M36 in mJSW among all RMs. The absence of such differences (‘H’ vs. ‘I’) and their later onset (‘I’ vs. ‘A’ at M60 for K/L-II and at M36 for K/L-III) in the SG group could be attributed to the therapy-modified (D3 + ZA) evolution of the HOA. These factors suggest that the changes in BMD due to the anti-resorptive therapy equalized the rate of the radiographic progression of the models with reduced BMD (‘A’) to those with a normal (‘I’) or slightly increased (‘H’) BMD.
At baseline, all ‘A’ models in both RGs in the two groups (SC and SG) had decreased BMD at all measurement sites (PF-BMD; LS-BMD; TB-BMD), all ‘I’ models had normal BMD, and all ‘H’ models had normal or slightly increased local BMD.
The analysis of the BMD change over the follow-up period demonstrated that the BMD of the control group decreased, reaching the normal, or lower than the normal, BMD of patients without HOA (at all measurement sites) as early as the second (‘I’) or the third year (‘H’), which was accompanied by a decrease in vitamin D3 levels and an increase in serum CTX-I and urinary CTX-II. A possible explanation for the changes in vitamin D3, s-CTX-I, and u-CTX-II levels could be the decreased physical activity and lifestyle changes related to HOA progression. Nevertheless, the observed significant differences at baseline (CsA) in TB-BMD and head BMD (which are not related to the biomechanics in HOA), cannot be explained in this way, but rather by the presence of different types of HOA, as was discussed earlier.
A possible explanation for the changes in vitamin D3, s-CTX-I, and u-CTX-II levels is the decreased physical activity and lifestyle changes related to HOA progression. Nevertheless, the observed significant differences at baseline (CsA) in TB-BMD and head BMD, which are not related to the biomechanics in HOA, cannot be explained in this way, but rather by the presence of different types of HOA, as was discussed earlier.
The longitudinal significant differences in RP (JSN-M12/mJSW-M36) between the two groups (SC vs. SG), as well as in the tTHR between the ‘A’ and ‘I’ models of both groups, showed a clear relationship with the detected changes in BMD (FN-BMD; TH-BMD. This relation correlates by grade with the well-known impact of these parameters on the fracture risk. In our study, a decrease in FN-BMD and TH-BMD by 1 SD was associated with accelerated radiographic progression and increased fracture risk.
To our knowledge, no other studies have examined the effect of intravenous ZA on the progression of HOA [ 51 ]. The only study evaluating the effect of a bisphosphonate administration on the progression of HOA used oral alendronate [ 52 ]. In the present study, we observed a significant improvement in VAS and WOMAC scores and BMD, with a parallel decrease in the values of sCTX-I and uCTX-II, but no significant delay in the progression of HOA, defined as a decrease in JSW >0.30 mm or conversion to total hip arthroplasty [ 52 ].
At the same time, a number of studies have analyzed the efficacy of ZA administration in reducing postoperative complications after THR [ 53 ]. There have also been a large number of studies similar to ours but on the efficacy of ZA administration in knee OA (KOA) [ 54 ]. Those KOA studies showed contradictory results, which, in addition to the failure of alendronate to slow the radiographic progression of HOA [ 52 ], are most likely due to the inconsistency of the study designs used; the discussed influence of the radiographic model and gender on the clinical and radiographic variables.
Considering the rates of the different RMs of HOA in the general population (60% ‘I’-RM; 30% ‘H’-RM; 10% ‘A’-RM) [
23
,
24
], and this study’s results, which showed that the treatment was effective in all ‘A’ models and in 30% of ‘I’ models (those with persistently elevated BP/CT), it can be extrapolated that 30% of patients with HOA would benefit from a combined treatment of D3 with ZA. At first glance, this percentage does not seem so high, but considering the prevalence of HOA among the population over 60 years of age, 0.1–0.2% of people in the general population would benefit from the treatment strategy used in our study.
With regard to when an anti-resorptive therapy in patients with ‘A’ models of HOA should be started, our recommendation is as early as possible. At baseline, all ‘A’ models of HOA had DXA scores of osteopenia or osteoporosis (70%) at all measurement sites and increased levels of BT and CT markers.
All ‘I’ models with increased BT and CT markers had slightly reduced BMD at all measurement sites, as compared to the controls without HOA, without fulfilling the ISCD criteria for osteopenia [ 30 ]. However, within the two-year follow-up, these values changed and fulfilled the criteria for osteopenia in 100% of patients and for osteoporosis in 56% of them.
Our findings suggest that patients with ‘I’ models of HOA who have elevated BP and CT markers should be followed up on an annual basis. If a significant decrease in BMD is detected on two consecutive measurements, antiresorptive therapy should be started, even if the DXA scores do not meet the ISCD criteria for osteoporosis.
However, it is important to remember that all ‘H’ and ‘I’ models of HOA with normal BT and CT markers, which accounts for 70% of HOA patients, do not benefit significantly from anti-resorptive therapy.
Our study has several limitations that need to be addressed. One of them is the small number of bone (serum CTX-I) and cartilage (urinary -II) turnover markers, which could not adequately demonstrate the composite mechanism of the processes occurring at the osteochondral junction. Another limitation stems from the dual nature of the DXA investigation used for HSA, in the absence of parallel data from a three-dimensional imaging modality (QTC). Another area for improvement is the calculation of mJSW and JSN based on manual measurements of JSW at three points rather than MRI-based assessments.
In conclusion, the significant differences in CP, BMD, bone geometry parameters, and levels of BT and CT markers observed at baseline between the ‘A’ and ‘H’ models support the hypothesis of the existence of two distinct subgroups of HOA. The one associated with ‘A’ models and the other with ‘H’ models exhibit specific characteristics of AC-breakdown, SB-remodeling, and clinical and radiological progression, and a different response to anti-resorptive drugs. In ‘A’ and ‘I’ models with increased BT and CT markers, D3 supplementation and intravenous administration of ZA constitute a treatment strategy that slows RP and delays tTHR for more than a year.
Given the limitations of our study and the significant socioeconomic impact of hip osteoarthritis, larger randomized controlled trials with an appropriate design, sample size, and duration should be conducted.
Informed consent was obtained from all individual participants included in the study.
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Figure 1. Measurement of JSW at three points according to the Barcelona consensus ( left image ) [ 29 ], and in a patient from our study ( right image ).
Figure 2. DXA measurements: dual femur—this scan was used to obtain the BMD parameters: femoral neck (FN-BMD); femoral head (FH-BMD); total hip BMD (TH-BMD); parameters of bone geometry (HAL—hip axis length; NSA—neck shaft angle; MNW—minimal neck width; CSA—cross-sectional area; CSMI—cross-sectional moment of inertia; FN-CT—cortical thickness of femoral neck; FS-CT—cortical thickness of femoral shaft; SM—section modules; BR—buckling ratio) and also for the comparisons between the mentioned parameters—left/right (target/non-target) joint.
Figure 3. DXA measurements: anterior posterior spine—this scan was used to obtain the BMD parameters from the lumbar spine (LS-BMD), both from the individual vertebrae (L1; L2; L3; L4) and the total score (L1–L4).
Figure 4. DXA measurements: total body—this scan was used to obtain the BMD parameters from the different regions (head-BMD; arms-BMD; legs-BMD; trunk-BMD; ribs-BMD; spine-BMD; pelvis-BMD) and a total body score (TB-BMD).
Figure 5. Bone mineral density (BMD) in patients from the three RMs of HOA (hypertrophic; normotrophic and atrophic). The results are shown as Z scores of femoral neck (FN), lumbar spine (LS), scull (Head), and total body (Total) for each RM. Z scores were used to compare to controls without HOA after standardization for gender, age, and BMI. *- a statistically significant difference ( p < 0.05) when comparing to controls without HOA after standardization for gender, age, and BMI.
Figure 6. Values of markers for bone (serum β-CTX-I) and cartilage (urine CTX-II) turnover in the different RG/RM of HOA. Serum β-CTX-I—beta-isomerized carboxy-terminal cross-linking telopeptide of type I collagen in nanogram per milliliter; urine CTX-II—C-terminal crosslinking telopeptides of collagen type II, presented as corrected concentrations of uCTX-II for urinary creatinine concentration, as ng/mmol Cr.
Figure 7. Follow-up data.
Figure 8. Change in BMD for a period of 36 months in the control (SC) and treatment (SG) groups. TH-BMD—total hip bone mineral density. The levels are presented as standard error of the mean (SEM) percentage changes, in order to present the characteristics (changes in BMD) of the sample data and allow comparisons of how much discrepancy was likely to appear in the sample mean as compared to the population mean.
Table 1. Research design: patient groups, methods, follow-up, indicators, and analyses.
K/L—according to Kellgren–Lawrence grading scale; ‘H’/’I’/‘A’—hypertrophic/intermediate/atrophic-radiographic patterns (models) of hip osteoarthritis according to the balance between the narrowing of the joint space and the osteophyte growth; VAS—visual analogue scale; WOMAC-C—WOMAC-function scale; tTHR—time to conversion to total hip replacement; D3—25-hydroxy vitamin D; s-CTX-I—serum-beta-isomerized carboxy-terminal cross-linking telopeptide of type I collagen; u-CTX-II—urine -C-terminal crosslinking telopeptides of collagen type II; mJSW—mean joint space width; JSN—joint space narrowing; BMD—bone mineral density; PF/LS/TB—proximal femur, lumbar spine, total body.
Table 2. Baseline characteristics of the control and study group.
Parameter # ‘H’ Models ‘I’ Models ‘A’ Models p * Median ± IQR Median (IQR) Median (IQR) Median (IQR) CG vs. SG Age K/L-II 0.997 Control group (SC) 65 (64–67) 64 (63–66) 62 (61–63) Treatment group (SG) 65 (64–67) 64 (63–66) 62 (61–63) Age K/L-III Control group 66 (64–68) 65 (63–68) 63 (62–64) Treatment group 66 (63–69) 65 (64–68) 63 (61–65) BMI K/L-II 0.995 Control group 25.5 (24–27) 24.5 (23.5–26.5) 24.0 (23.0–25.0) Treatment group 25.7 (23.7–27.7) 25.0 (23.0–27.0) 23.5 (22.5–25.0) BMI K/L-III Control group 26.5 (25.0–27.0) 26.0 (25.0–27.0) 24.5 (23.5–25.5) Treatment group 26.8 (25.0–27.8) 25.5 (24.5–26.5) 25.0 (24.0–26.0) Gender K/L-II 1.000 Control group ♀-15/♂-10 ♀-15/♂-10 ♀-15/♂-10 Treatment group ♀-15/♂-10 ♀-15/♂-10 ♀-15/♂-10 Gender K/L-III Control group ♀-15/♂-10 ♀-15/♂-10 ♀-15/♂-10 Treatment group ♀-15/♂-10 ♀-15/♂-10 ♀-15/♂-10 WP (VAS mm.) K/L-II 0.993 Control group 41 (40–42) 43 (42–44) 45 (42–48) Treatment group 41 (39–42) 43 (41–45) 45 (43–47) WP (VAS mm.) K/L-III Control group 48 (46–50) 50.5 (48.5–52.5) 53 (51–55) Treatment group 48 (45–51) 51 (49–53) 54(53–55) F (WOMAC-C) K/L-II 0.951 Control group 31.5 (30–33) 34.5 (33–36) 36.5 (35–38) Treatment group 32 (30–34) 35 (34–36) 37 (36–38) F (WOMAC-C) K/L-III Control group 37.5 (36–39) 40.5 (39–42) 42.5 (41–44) Treatment group 38 (36–40) 41 (39–43) 43 (41–45) 25-OH-D (ng/mL) K/L-II 0.921 Control group 39.5 (33.5–45.5) 36.0 (30.5–41.5) 31.5 (27.5–33.5) Treatment group 39.0 (33.0–45.0) 35.6 (30.6–40.6) 31.0 (27.5–33.0) 25-OH-D (ng/mL) K/L-III Control group 35.8 (31.8–39.8) 32.4 (29.4–35.4) 27.5 (25.5–29.5) Treatment group 35.5 (31.5–39.5) 32.0 (29.0–35.0) 27.0 (25.5–29.5) s-CTX-I (ng/mL) K/L-II 0.913 Control group 520 (460–600) 590 (510–670) 650 (600–700) Treatment group 525 (465–600) 594 (514–680) 655 (610–700) s-CTX-I (ng/mL) K/L-III Control group 560 (500–620) 645 (600–700) 715 (650–780) Treatment group 564 (510–620) 654 (604–700) 720 (660–790) u-CTX-II (ng/mmol Cr) K/L-II 0.912 Control group 346 (300–390) 378 (330–415) 456 (416–496) Treatment group 354 (304–394) 382 (334–420) 464 (420–500) u-CTX-II (ng/mmol Cr) K/L-III Control group 378 (318–438) 418 (350–478) 476 (426–526) Treatment group 384 (324–442) 423 (353–483) 484 (430–530) mJSW (mm.) K/L-II 0.956 Control group 4.5 (4.4–4.6) 4.4 (4.0–4.8) 4.3 (4.0–4.6) Treatment group 4.5 (4.3–4.7) 4.4 (4.1–4.7) 4.3 (4.1–4.5) mJSW (mm.) K/L-III Control group 3.7 (3.6–3.8) 3.5 (3.4–3.6) 3.3 (3.1–3.5) Treatment group 3.7 (3.5–3.9) 3.5 (3.3–3.7) 3.3 (3.0–3.6) AP spine L1–L4 BMD (g/cm 2 ) K/L-II 0.948 Control group 1.3 (1.0–1.5) 1.1 (0.9–1.3) 0.8 (0.7–0.9) Treatment group 1.3 (1.1–1.5) 1.1 (0.8–1.3) 0.8 (0.6–0.9) AP spine L1–L4 BMD (g/cm 2 ) K/L-III Control group 1.0 (0.8–1.2) 0.8 (0.5–1.1) 0.6 (0.5–0.7) Treatment group 1.0 (0.9–1.1) 0.8 (0.6–1.0) 0.6 (0.53–0.67) Total hip BMD (g/cm 2 ) K/L-II 0.947 Control group 0.8 (0.6–1.0) 0.6 (0.5–0.7) 0.45 (0.39–0.51) Treatment group 0.8 (0.7–0.9) 0.6 (0.5–0.65) 0.45 (0.38–0.51) Total hip BMD (g/cm 2 ) K/L-III Control group 0.7 (0.63–0.8) 0.5 (0.43–0.60) 0.35 (0.32–0.38) Treatment group 0.7 (0.61–0.8) 0.5 (0.41–0.61) 0.35 (0.33–0.37) Femoral neck BMD (g/cm 2 ) K/L-II 0.946 Control group 0.9 (0.8–1.0) 0.7 (0.6–0.8) 0.5 (0.4–0.6) Treatment group 0.9 (0.7–1.1) 0.7 (0.62–0.78) 0.5 (0.43–0.57) Femoral neck BMD (g/cm 2 ) K/L-III Control group 0.8 (0.67–0.9) 0.64 (0.6–0.68) 0.4 (0.36–0.44) Treatment group 0.8 (0.7–0.91) 0.63 (0.6–0.67) 0.42 (0.38–0.44) Total body BMD (g/cm 2 ) K/L-II 0.945 Control group 1.5 (1.3–1.7) 1.4 (1.3–1.5) 1.3 (1.2–1.4) Treatment group 1.5 (1.4–1.6) 1.4 (1.2–1.6) 1.3 (1.1–1.5) Total body BMD (g/cm 2 ) K/L-III Control group 1.4 (1.3–1.5) 1.3 (1.2–1.4) 1.2 (1.1–1.3) Treatment group 1.4 (1.2–1.6) 1.3 (1.1–1.5) 1.2 (1.0–1.4)
# —Each study subgroup consisted of 25 subjects; *—The Kruskal–Wallis test was applied; WP—pain at walking; F (WOMAC-C)—WOMAC function scale; mJSW—mean joint space width; 25-OH-D—25-Hydroxy vitamin D in nanogram per milliliter; s-CTX-I—serum-beta-isomerized carboxy-terminal cross-linking telopeptide of type I collagen in nanogram per milliliter; u-CTX-II—urine-C-terminal crosslinking telopeptides of collagen type II, given as corrected concentration of uCTX-II for urinary creatinine concentration in ng/mmol Cr.
Table 3. Within-group comparisons (‘H’ vs. ‘I’ vs. ‘A’) of the values of CP, RI, and CT/BT markers in both groups.
X-Ray Grade K/L-II K/L-III X-Ray Model ‘H’ ‘I’ ‘A’ ‘H’ ‘I’ ‘A’ Groups # SC SG SC SG SC SG SC SG SC SG SC SG WOMAC-C M0-Median (IQR) 31 (30–32) 32 (31–33) 33 (33–35) 34 (32–36) 36 (35–37) 36 (35–37) 38 (37–39) 38 (37–40) 41 (40–42) 41 (39–43) 43 (42–44) 43 (41–45) p * ‘H’ vs. ‘A’ p † < 0.001; p ‡ < 0.001 p † < 0.001; p ‡ < 0.001 p * ’H’ vs. ‘I’ p † = 0.061; p ‡ = 0.063 p † = 0.056; p ‡ = 0.059 p * ’I’ vs. ‘A’ p † = 0.051; p ‡ = 0.049 p † = 0.054; p ‡ = 0.055 WP-VAS M0-Median (IQR) 41 (38–44) 41 (39–43) 43 (41–45) 43 (41–45) 45 (42–48) 45 (41–49) 48 (46–50) 48 (47–49) 50 (47–53) 50 (46–54) 52 (50–54) 53 (50–56) p * ‘H’ vs. ‘A’ p † < 0.001; p ‡ < 0.001 p † < 0.001; p ‡ < 0.001 p * ’H’ vs. ‘I’ p † = 0.051; p ‡ = 0.053 p † = 0.046; p ‡ = 0.048 p * ’I’ vs. ‘A’ p † = 0.047; p ‡ = 0.049 p † = 0.052; p ‡ = 0.054 s-CTX-I M0- Median (IQR) 520 (460–600) 525 (465–600) 590 (510–670) 594 (514–680) 650 (600–700) 655 (610–700) 560 (500–620) 564 (510–620) 645 (600–700) 654 (604–700) 715 (650–780) 720 (660–790) p * ‘H’ vs. ‘A’ p † < 0.001; p ‡ < 0.001 p † < 0.001; p ‡ < 0.001 p * ’H’ vs. ‘I’ p † = 0.56; p ‡ = 0.059 p † = 0.051; p ‡ = 0.053 p * ’I’ vs. ‘A’ p † = 0.049; p ‡ = 0.051 p † = 0.047; p ‡ = 0.049 u-CTX-II M0-Median (IQR) 346 (300–390) 354 (304–394) 378 (330–415) 382 (334–420) 456 (416–496) 464 (420–500) 378 (318–438) 384 (324–442) 418 (350–478) 423 (353–483) 476 (426–526) 484 (430–530) p * ‘H’ vs. ‘A’ p † < 0.001; p ‡ < 0.001 p † < 0.001; p ‡ < 0.001 p * ’H’ vs. ‘I’ p † = 0.061; p ‡ = 0.063 p † = 0.056; p ‡ = 0.059 p * ’I’ vs. ‘A’ p † = 0.049; p ‡ = 0.053 p † = 0.047; p ‡ = 0.049 TH-BMD M0-Median (IQR) 0.8 (0.6–1.0) 0.8 (0.7–0.9) 0.6 (0.5–0.7) 0.6 (0.5–0.65) 0.45 (0.39–0.51) 0.45 (0.38–0.51) 0.7 (0.63–0.80) 0.7 (0.61–0.80) 0.5 (0.43–0.60) 0.5 (0.41–0.61) 0.35 (0.32–0.38) 0.35 (0.33–0.37) p * ‘H’ vs. ‘A’ p † < 0.001; p ‡ < 0.001 p † < 0.001; p ‡ < 0.001 p * ’H’ vs. ‘I’ p † = 0.065; p ‡ = 0.069 p † = 0.055; p ‡ = 0.059 p * ’I’ vs. ‘A’ p † = 0.055; p ‡ = 0.058 p † = 0.049; p ‡ = 0.051 mJSW M0-Median (IQR) 4.5 (4.4–4.6) 4.5 (4.3–4.7) 4.4 (4.0–4.8) 4.4 (4.1–4.7) 4.3 (4.0–4.6) 4.3 (4.1–4.5) 3.7 (3.6–3.8) 3.7 (3.5–3.9) 3.5 (3.4–3.6) 3.5 (3.3–3.7) 3.3 (3.1–3.5) 3.3 (3.0–3.6) p * ‘H’ vs. ‘A’ p † = 0.060; p ‡ = 0.061 p † = 0.068; p ‡ = 0.069 p * ’H’ vs. ‘I’ p † = 0.171; p ‡ = 0.173 p † = 0.163; p ‡ = 0.165 p * ’I’ vs. ‘A’ p † = 0.149; p ‡ = 0.152 p † = 0.149; p ‡ = 0.153
SC—standard of care (control) group; SG—study group; WOMAC-C—WOMAC function scale; WP-VAS—pain at walking by visual analogue scale; s-CTX-I—serum- beta-isomerized carboxy-terminal cross-linking telopeptide of type I collagen, the levels are presented as nanogram per milliliter; u-CTX-II—urine-C-terminal-crosslinking telopeptides of collagen type II, levels are presented as corrected concentrations of uCTX-II for urinary creatinine concentration, as ng/mmol Cr.; TH-BMD—total hip BMD; mJSW—median joint space width; *—Kruskal–Wallis test with Dunn–Bonferroni post hoc analysis; # —each study group consisted of 25 subjects; p † — p -values from the comparisons between the different radiographic models in the SC group; p ‡ — p -values from the comparisons between the different radiographic models in the SG group.
Table 4. Changes in the clinical and radiographic parameters in the CG and SG groups over time.
Month Group M0 (Baseline) M12 M24 M36 M48 M60 M72 M78 CG K/L-II”H” WP-VAS 41 (38–44) 43 (41–45) 48 (46–49) 53 (51–54) 59 (57–60) 64 (62–65) 69 (68–70) Conversion to THR-M78 WOMAC-C 32 (31–33) 34 (31–36) 38 (37–39) 43 (42–44) 49 (48–50) 55 (54–56) 60 (59–61) s-CTH-I 520 (460–600) 525 (460–610) 530 (470–610) 540 (480–620) 560 (500–640) 600 (540–680) 680 (620–740) u-CTX-II 346 (300–390) 348 (300–394) 350 (305–395) 355 (310–400) 365 (320–420) 385 (350–440) 425 (395–475) TB-BMD 1.5 (1.3–1.7) 1.4 (1.3–1.5) 1.3 (1.2–1.4) 1.2 (1.1–1.3) 1.1 (1.0–1.2) 1.0 (0.9–1.1) 0.9 (0.8–1.0) mJSW 4.4 (3.9–4.9) 3.9 (3.8–4.2) 3.3 (3.2–3.6) 2.6 (2.5–2.9) 1.8 (1.8–2.1) 1.1 (1.0–1.1) 0.5 (0.4–0.6) K/L-II” I” WP-VAS 43 (42–44) 46 (45–48) 51 (50–53) 57 (56–58) 62 (62–64) 69 (68–71) Conversion to THR-M66 WOMAC-C 33 (33–35) 36 (35–38) 41 (41–43) 47 (46–49) 53 (52–55) 59 (58–61) s-CTH-I 590 (510–670) 600 (520–680) 610 (530–690) 630 (550–710) 670 (590–750) 750 (670–830) u-CTX-II 378 (330–415) 382 (335–420) 390 (340–430) 400 (350–440) 420 (370–460) 440 (410–500) TB-BMD 1.4 (1.3–1.5) 1.3 (1.2–1.4) 1.2 (1.1–1.3) 1.1 (1.0–1.2) 1.0 (0.9–1.1) 0.9 (0.8–1.0) mJSW 4.3 (4.0–4.6) 3.8 (3.7–4.0) 3.1 (3.1–3.4) 2.4 (2.4–2.7) 1.7 (1.6–1.9) 0.8 (0.8–1.0) K/L-II” A” WP-VAS 45 (44–47) 50 (49–52) 55 (55–57) 61 (60–63) 68 (67–70) Conversion to THR-M54 WOMAC-C 36 (35–37) 40 (39–42) 45 (45–47) 51 (51–53) 58 (57–60) s-CTH-I 650 (600–700) 670 (620–720) 710 (660–760) 780 (720–840) 940 (880–990) u-CTX-II 456 (416–496) 460 (420–500) 475 (435–520) 505 (465–550) 570 (530–610) TB-BMD 1.3 (1.2–1.4) 1.2 (1.1–1.3) 1.1 (1.0–1.2) 1.0 (0.9–1.1) 0.9 (0.8–1.0) mJSW 4.2 (3.8–4.6) 3.6 (3.5–3.9) 2.9 (2.9–3.2) 2.2 (2.1–2.4) 1.3 (1.3–1.6) K/L-III”H” WP-VAS 48 (47–49) 48 (47–50) 54 (54–56) 61 (61–63) 69 (68–71) Conversion to THR-M54 WOMAC-C 38 (37–39) 38 (37–40) 45 (44–47) 52 (51–54) 59 (58–61) s-CTH-I 560 (500–620) 570 (510–630) 590 (530–650) 630 (570–690) 750 (690–810) u-CTX-II 378 (318–438) 384 (320–440) 395 (330–450) 420 (350–470) 480 (410–550) TB-BMD 1.4 (1.3–1.5) 1.3 (1.2–1.4) 1.2 (1.1–1.3) 1.1 (1.0–1.2) 1.0 (0.9–1.1) mJSW 3.6 (3.1–4.1) 3.0 (2.9–3.3) 2.3 (2.3–2.6) 1.6 (1.5–1.8) 0.8 (0.8–0.9) K/L-III” I” WP-VAS 50 (49–52) 51 (51–54) 58 (57–61) 66 (65–69) Conversion to THR-M42 WOMAC-C 41 (40–42) 42 (41–44) 49 (48–50) 56 (55–58) s-CTH-I 645 (600–700) 660 (620–715) 690 (650–730) 750 (710–800) u-CTX-II 418 (350–478) 425 (360–485) 440 (380–500) 480 (420–540) TB-BMD 1.3 (1.2–1.4) 1.2 (1.1–1.3) 1.1 (1.0–1.2) 1.0 (0.9–1.1) mJSW 3.5 (3.0–4.0) 2.9 (2.7–3.2) 2.1 (2.0–2.4) 1.2 (1.2–1.5) K/L-III” A” THR-M36 WP-VAS 52 (52–54) 54 (55–56) 60 (60–62) 72 (74–75) WOMAC-C 43 (42–44) 45 (44–46) 52 (51–53) 64 (63–65) s-CTH-I 715 (650–780) 745 (695–800) 820 (770–870) 950 (905–995) u-CTX-II 476 (426–526) 490 (440–540) 520 (470–570) 590 (540–640) TB-BMD 1.2 (1.1–1.3) 1.1 (1.0–1.2) 0.9 (0.8–1.0) 0.5 (05–0.6) mJSW 3.4 (2.9–3.9) 2.6 (2.6–2.9) 1.7 (1.6–1.8) 0.5 (0.5–0.6) SG K/L-II”H” Conversion to THR-M78 WP-VAS 41 (40–42) 37 (34–38) 34 (32–36) 34 (32–36) 38 (37–39) 47 (46–49) 67 (66–69) WOMAC-C 31 (31–33) 27 (26–28) 24 (23–26) 25 (24–27) 28 (27–29) 38 (37–39) 58 (57–59) s-CTH-I 525 (465–600) 500 (440–675) 490 (420–560) 480 (410–550) 520 (450–590) 590 (520–650) 690 (620–750) u-CTX-II 354 (304–394) 350 (300–390) 354 (300–390) 360 (310–400) 370 (320–420) 390 (340–440) 430 (370–470) TB-BMD 1.5 (1.4–1.6) 1.5 (1.4–1.6) 1.6 (1.4–1.6) 1.6 (1.5–1.7) 1.7 (1.6–1.8) 1.6 (1.6–1.8) 1.5 (1.4–1.6) mJSW 4.4 (4.0–4.8) 3.9 (3.8–4.2) 3.4 (3.3–3.7) 2.9 (2.8–3.1) 2.3 (2.3–2.5) 1.6 (1.5–1.7) 0.7 (0.7–0.9) K/L-II” I” Conversion to THR-M78 WP-VAS 43 (42–44) 38 (36–40) # 33 (32–34) * 33 (31–34) * 38 (36–40) # 48 (47–50) 67 (66–69) WOMAC-C 34 (33–35) 29 (28–30) # 24 (23–25) * 24 (22–25) * 29 (28–30) # 39 (38–40) 58 (57–59) s-CTH-I 594 (514–680) 545 (465–725) 450 (390–550) 350 (300–400) 440 (390–490) 550 (500–600) 700 (650–750) u-CTX-II 382 (334–420) 370 (320–400) 340 (290–430) 290 (240–380) 330 (280–420) 380 (340–420) 450 (410–490) TB-BMD 1.4 (1.3–1.5) 1.6 (1.3–1.5) 1.7 (1.4–1.6) 1.7 (1.5–1.7) 1.7 (1.6–1.8) 1.6 (1.6–1.8) 1.5 (1.4–1.6) mJSW 4.3 (3.9–4.7) 3.8 (3.8–4.1) 3.3 (3.3–3.5) 2.9 (2.8–3.0) 2.3 (2.2–2.4) 1.6 (1.5–1.7) 0.8 (0.7–0.9) K/L-II” A” Conversion to THR-M66 WP-VAS 45 (44–48) 39 (38–40) # 35 (34–36) * 35 (34–37) * 40 (40–42) # 62 (60–64) WOMAC-C 36 (35–37) 29 (28–30) # 26 (24–27) * 25 (24–27) * 31 (30–32) # 52 (51–54) s-CTH-I 655 (610–700) 500 (450–550) 410 (360–470) 330 (290–370) 420 (370–470) 650 (590–710) u-CTX-II 464 (420–500) 415 (370–460) 370 (320–420) 280 (240–320) 340 (290–430) 420 (360–480) TB-BMD 1.3 (1.2–1.4) 1.5 (1.2–1.4) 1.7 (1.3–1.5) 1.7 (1.4–1.6) 1.7 (1.5–1.7) 1.5 (1.4–1.6) mJSW 4.2 (3.8–4.6) 3.7 (3.7–4.0) 3.2 (3.2–3.4) 2.6 (2.6–2.9) 2.0 (2.0–2.3) 1.4 (1.4–1.6) K/L-III”H” Conversion to THR-M54 WP-VAS 48 (47–50) 45 (44–47) 49 (48–50) 56 (55–58) 67 (65–68) WOMAC-C 38 (37–40) 35 (34–37) 39 (38–40) 46 (45–48) 58 (57–59) s-CTH-I 564 (510–620) 560 (500–610) 550 (500–600) 530 (470–590) 680 (620–740) u-CTX-II 384 (324–442) 380 (320–440) 370 (310–430) 360 (300–420) 430 (390–470) TB-BMD 1.4 (1.3–1.5) 1.4 (1.3–1.5) 1.4 (1.3–1.5) 1.5 (1.4–1.6) 1.5 (1.4–1.6) mJSW 3.6 (3.2–4.0) 3.1 (3.0–3.4) 2.3 (2.0–2.3) 1.6 (1.4–1.6) 0.8 (0.7–0.9) K/L-III” I” Conversion to THR-M54 WP-VAS 50 (48–52) 46 (45–48) # 50 (490–51) 57 (56–58) 67 (65–68) WOMAC-C 40 (39–42) 36 (35–38) # 41 (40–42) 47 (56–59) 59 (59–62) s-CTH-I 654 (604–700) 600 (540–660) 520 (470–570) 460 (400–520) 650 (590–710) u-CTX-II 423 (353–483) 410 (370–450) 380 (320–420) 350 (290–410) 450 (390–510) TB-BMD 1.3 (1.2–1.4) 1.4 (1.2–1.4) 1.5 (1.3–1.5) 1.6 (1.4–1.6) 1.6 (1.4–1.6) mJSW 3.5 (3.1–3.9) 2.9 (2.8–3.1) 2.2 (2.1–2.3) 1.6 (1.5–1.6) 0.8 (0.7–0.9) K/L-III” A” Conversion to THR-M42 WP-VAS 53 (52–55) 50 (49–51) # 56 (55–58) 68 (67–70) WOMAC-C 43 (42–45) 40 (39–41) # 46 (45–48) 58 (47–60) s-CTH-I 720 (660–790) 590 (540–640) 500 (440–560) 550 (490–610) u-CTX-II 484 (430–530) 455 (400–510) 440 (380–500) 450 (390–510) TB-BMD 1.2 (1.1–1.3) 1.4 (1.1–1.3) 1.5 (1.2–1.4) 1.6 (1.4–1.6) mJSW 3.4 (3.0–3.8) 2.7 (2.6–2.8) 1.9 (1.7–1.9) 0.9 (0.9–1.0)
Each group consisted of 25 subjects; CG—control group; SG—study group; WP—pain at walking; VAS—visual analogue scale -100 mm.; WOMAC-C—WOMAC-function scale; s-CTX-I—serum-beta-isomerized carboxy-terminal cross-linking telopeptide of type I collagen in nanogram per milliliter; u-CTX-II—urine-C-terminal crosslinking telopeptides of collagen type II, presented as corrected concentrations of uCTX-II for urinary creatinine concentration in ng/mmol Cr. mJSW—mean joint space width. Values associated with the OARSI responses are marked with * and these with MCII responses, with # .
Table 5. Within-group comparisons in clinical parameters (WP/F) between the RMs of the same RG at different time points.
Treatment Groups # Time (Months) for the Occurrence of SSD in Clinical Parameters (WP/F) SC K/L-II’H’ vs. K/L-II’A’ M0 ( p < 0.001) * K/L-II’H’ vs. K/L-II’I’ M12( p = 0.044) * K/L-II’I’ vs. K/L-II’A’ M12 ( p = 0.033) * K/L-III’H’ vs. K/L-III’A’ M0 ( p < 0.001) * K/L-III’H’ vs. K/L-III’I’ M12 ( p = 0.044) * K/L-III’I’ vs. K/L-III’A’ M12 ( p = 0.033) * SG K/L-II’H’ vs. K/L-II’A’ M0 ( p < 0.001) * K/L-II’H’ vs. K/L-II’I’ No SSD were detected between M0-M78 ( p > 0.05) * K/L-II’I’ vs. K/L-II’A’ M60 ( p < 0.001) * K/L-III’H’ vs. K/L-III’A’ M0 ( p < 0.001) * K/L-III’H’ vs. K/L-III’I’ No SSD were detected between M0-M54 (THR) ( p > 0.05) * K/L-III’I’ vs. K/L-III’A’ M36 ( p = 0.044) *
K/L—radiographic grade according to Kellgren–Lawrence; ‘A’/’I’/’H’—radiographic models (atrophic/intermediate/hypertrophic); CG—control group; SG—study group; WP—pain at walking; F—function (WOMAC-C); # —Each subgroup consists of 25 subjects; *—Kruskal–Wallis test was applied.
Table 6. Within-group comparisons of the radiological indicators (JSN/mJSW) between RMs of the same RG and on the same treatment.
X-ray Grade Applied Treatment # X-ray Model JSN-M12 Median (IQR) mm./yearly p * Value mJSW-M36 Median (IQR) mm. p * Value K/L-II SC ‘H’ 0.55 (0.50–0.60) ‘H’ vs. ‘A’; p < 0.001 2.6 (2.5–2.9) ‘H’ vs. ‘A’; p < 0.001 ‘I’ 0.57 (0.54–0.60) ‘H’ vs. ‘I’; p = 0.044 2.4 (2.4–2.7) ‘H’ vs. ‘I’; p = 0.044 ‘A’ 0.61 (0.60–0.62) ‘I’ vs. ‘A’; p = 0.022 2.2 (2.1–2.3) ‘I’ vs. ‘A’; p = 0.044 SG ‘H’ 0.55 (0.50–0.60) ‘H’ vs. ‘A’; p = 0.059 2.6 (2.5–3.0) ‘H’ vs. ‘A’; p = 1.0 ‘I’ 0.56 (0.52–0.60) ‘H’ vs. ‘I’; p = 0.796 2.6 (2.4–2.8) ‘H’ vs. ‘I’; p = 1.0 ‘A’ 0.50 (0.45–0.55) ‘I’ vs. ‘A’; p = 0.049 2.6 (2.3–2.9) ‘I’ vs. ‘A’; p = 1.0 K/L-III SC ‘H’ 0.62 (0.59–0.65) ‘H’ vs. ‘A’; p < 0.001 1.6 (1.5–1.8) ‘H’ vs. ‘A’; p < 0.001 ‘I’ 0.67 (0.67–0.70) ‘H’ vs. ‘I’; p = 0.021 1.2 (1.2–1.5) ‘H’ vs. ‘I’; p = 0.023 ‘A’ 0.80 (0.70–0.90) ‘I’ vs. ‘A’; p < 0.001 0.5 (0.4–0.6) ‘I’ vs. ‘A’; p < 0.001 SG ‘H’ 0.61 (0.58–0.64) ‘H’ vs. ‘A’; p = 0.767 1.7 (1.5–1.9) ‘H’ vs. ‘A’; p < 0.001 ‘I’ 0.62 (0.59–0.65) ‘H’ vs. ‘I’; p = 0.796 1.3 (1.2–1.6) ‘H’ vs. ‘I’; p = 0.049 ‘A’ 0.62 (0.59–0.65) ‘I’ vs. ‘A’; p = 1.0 0.8 (0.7–0.9) ‘I’ vs. ‘A’; p = 0.045
K/L—radiographic grade according to Kellgren–Lawrence; ‘A’/’I’/’H’—radiographic models (atrophic/intermediate/hypertrophic); CG—control group; SG—study group; JSN—joint space narrowing; mJSW—mean joint space width; # —Each subgroup consists of 25 subjects; *—Kruskal–Wallis test was applied.
Table 7. Between-group comparisons of the changes in the radiological indicators JSN at M12 and mJSW at M36.
X-ray Grade X-ray Model Applied Treatment # mJSN-M12 Median (IQR) p -Value * mJSW-M36 Median (IQR) p -Value * K/L II H SC 0.55 (0.50–0.60) SG vs. SC; p = 1.0 2.6 (2.5–2.9) SG vs. SC; p = 1.0 SG 0.55 (0.50–0.60) 2.6 (2.5–3.0) I SC 0.57 (0.54–0.60) SG vs. SC; p = 1.0 2.4 (2.4–2.7) SG vs. SC; p = 0.23 SG 0.56 (0.52–0.60) 2.5 (2.4–2.8) A SC 0.61 (0.60–0.62) SG vs. SC; p < 0.001 2.2 (2.1–2.3) SG vs. SC; p < 0.001 SG 0.50 (0.45–0.55) 2.6 (2.4–2.8) K/L III H SC 0.62 (0.59–0.65) SG vs. SC; p = 1.0 1.6 (1.5–1.8) SG vs. SC; p = 1.0 SG 0.61 (0.58–0.64) 1.7 (1.5–1.9) I SC 0.67 (0.67–0.70) SG vs. SC; p =1.0 1.2 (1.2–1.5) SG vs. SC; p = 0.21 SG 0.62 (0.59–0.65) 1.3 (1.2–1.6) A SC 0.80 (0.70–0.90) SG vs. SC; p < 0.001 0.5 (0.4–0.6) SG vs. SC; p = 0.03 SG 0.62 (0.59–0.65) 0.8 (0.7–0.9)
The time points M12 and M36 were selected as the time of first occurrence (M12) and presence at follow-up in all subgroups (M36). CG—control group; SG—study group; ‘A’/’I’/’H’—atrophic/intermediate/hypertrophic radiological models of HOA; JSN—joint space narrowing (millimeter/yearly); mJSW—median joint space width (millimeter); *—Kruskal–Wallis test was applied; # —Each group consisted of 25 subjects.
Table 8. Between-group comparisons (SC vs. SG) regarding the length of time before THR had to be performed.
X-ray Pattern Treatment # Treatment 1 vs. Treatment 2 tTHR -Median (Months) p -Value * K/L III-‘A’ SG vs. CG 42 vs. 36 <0.001 K/L III-‘I’ SG vs. CG 54 vs. 42 <0.001 K/L III-‘H’ SG vs. CG 54 vs. 54 1.000 K/L-II-‘A’ SG vs. CG 66 vs. 54 <0.001 K/L-II’I’ SG vs. CG 78 vs. 66 <0.001 K/L-II’H’ SG vs. CG 78 vs. 78 1.000
CG—control group; SG—study group; THR—total hip replacement; # —Each study group consisted of 25 subjects; *—Kruskal–Wallis test was applied.
Factors OR 95% CI of OR p -Value Lower Upper FM-BMD b 6.561 2.590 16.617 <0.001 TH-BMD b 6.495 2.688 15.696 <0.001 HAL a 2.212 1.182 4.141 0.013 NSA b 2.377 1.171 4.826 0.017 CSA b 4.038 1.863 8.752 <0.001 CSMI b 2.724 1.301 5.706 0.008 MNW b 1.099 0.614 1.967 0.751 FN-CT b 1.578 0.812 3.104 0.177 FS-CT b 1.236 0.603 2.533 0.563 SM b 3.431 1.617 7.280 0.001 BR a 1.833 1.012 3.321 0.045
FM-BMD—femoral neck-BMD; TH-BMD—total hip-BMD; HAL—hip axis length; NSA—neck shaft angle; CSA—cross-sectional area; CSMI—cross-sectional moment of inertia; MNW—minimal neck width; FN-CT—cortical thickness of femoral neck; FS-CT—cortical thickness of femoral shaft; SM –section modulus; BR—buckling ratio; a —increased values of these variables were associated with accelerated progression; b —decreased values of these variables were associated with accelerated progression.
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Approaches to the Patient with Prior Bypass Surgery | Thoracic Key
Approaches to the Patient with Prior Bypass Surgery
Approaches to the Patient with Prior Bypass Surgery
Overview
The important issues in the patient who has undergone coronary artery bypass grafting (CABG) and who has recurrent angina or ischemia are providing relief with the least morbidity and cost and doing it in a manner that provides durable benefit. It takes considerable judgment to make the best decision in these patients because there are frequently many options, most of which have substantial baggage in the form of complications and short-term benefit.
Historical Perspective
Advent and Maturation of Surgical Revascularization
As was later true of percutaneous transluminal coronary angioplasty (PTCA) (
1
,
2
), surgical coronary artery revascularization began more than 30 years ago with attempts to revascularize a single coronary artery. The result of these efforts was a dramatic change in cardiologic practice as surgical techniques adequate to palliate multivessel obstructive disease evolved. Within a decade, the growth of CABG surgery was exponential (
Fig. 81.1
). Hundreds of thousands of patients were operated on annually, creating a large population of several million postbypass patients in the United States alone. Owing to the progressive nature of the atherosclerotic process and the limited durability of venous conduits and in spite of widespread use of arterial grafts and antiplatelet agents, recurrent ischemia after surgical revascularization is a problem all cardiologists face with increasing frequency. Recurrence of angina in the first year alone was reported in 24% of patients in the Coronary Artery Surgery Study, and by the fifth postoperative year, almost one half of the broad spectrum of postoperative patients will have recurrent symptoms (
3
).
Recurrent angina sufficient to require reoperation occurred in 12% to 15% of patients within 1 decade of a first coronary operation at Emory University in Atlanta, Georgia and at the Cleveland Clinic in Cleveland, Ohio, and by the twelfth to fifteenth year, 30% required reoperation (
4
,
5
). Reoperative coronary surgery when compared with initial operation proved to be more costly, two to three times more likely to lead to in-hospital death or myocardial infarction (MI), and less effective in relieving angina. Among 2,030 patients who underwent reoperation at Emory University, in-hospital mortality was 7.0% (4.6% < 60 years, 8.2% aged 60 to 69, 10.0% ≥ 70 years). Five- and 10-year survival was 76% and 55%, respectively (
6
). Reported outcome data confined to patients who underwent reoperation in the 1990s confirmed the relatively high operative mortality noted earlier (7.4%) and reported a higher rate of Q-wave infarction, a longer length of stay, and higher costs than initial operations (
7
). The increase in complications and reduced efficacy of reoperative coronary surgery are probably related to the more extensive disease present, the requirement to use second-line venous conduits in many cases, and the technically more difficult and operator-dependent nature of reoperative heart surgery.
Percutaneous Postbypass Intervention
Percutaneous catheter revascularization in patients who had prior CABG surgery ( Fig. 81.2 ) was first described by Gruentzig, who treated 8 patients, 6 successfully, among the first 50 patients he reported. Seven of the 8 postbypass patients had angioplasty of saphenous vein graft (SVG) lesions, and 3 of 5 treated successfully had recurrences, findings that led Gruentzig to make the following insightful comments based on such limited observations: “The different kind of disease may explain the high incidence of recurrence in graft stenosis. Further experience will show whether we should eliminate this lesion from consideration” ( 8 ).
Among the first 1,116 patients treated with coronary angioplasty in the National Heart, Lung, and Blood Institute PTCA Registry, 62 patients had had previous bypass surgery. The in-hospital mortality rate in these patients, 8.1%, was significantly higher than in patients without prior surgery, 0.7%, thus causing concern about the safety of the procedure in this group of patients ( 9 ). The early experience at Emory University was reassuring, however; 116 treated patients had no procedural deaths, 3 had emergency operations, and one had a Q-wave MI ( Fig. 81.2 ). One late death occurred during an 8.3-month mean follow-up. Gruentzig’s observation of higher restenosis rates for SVGs was reaffirmed for medial and proximal graft sites, but an acceptable restenosis rate for distal anastomosis lesions of 18% (4 of 22) was first reported ( Fig. 81.3 ), as well as the initial report of attempted internal mammary artery (IMA) graft angioplasty ( 10 ). In subsequent experience with more than 34,000 coronary angioplasty procedures at Emory University, a history of prior bypass surgery was not associated with an increased risk of death or Q-wave MI and was negatively correlated with the need for in-hospital CABG surgery ( 11 ).
FIGURE 81.1. Coronary artery revascularization procedures at Emory University Hospitals in Atlanta, Georgia. CABG, coronary artery bypass grafting; PTCA, percutaneous transluminal coronary angioplasty.
FIGURE 81.2.
Targets for percutaneous coronary intervention include saphenous vein grafts and native coronary artery sites in unbypassed and bypassed vessels. In addition, internal mammary artery, radial, subclavian, innominate, and gastroepiploic artery grafts are potential targets. (Adapted from
Douglas JS Jr, Gruentzig AR, King SB III, et al. Percutaneous transluminal coronary angioplasty in patients with prior coronary bypass surgery. J Am Coll Cardiol 1983;2:745–754
, with permission from the American College of Cardiology.)
FIGURE 81.3.
A 57-year-old man underwent saphenous vein bypass grafting to the distal left anterior descending (LAD) artery; coronary arteriography a few months later (
A
) revealed high-grade stenosis at the junction of the saphenous vein graft to the LAD artery (left lateral view). Percutaneous transluminal coronary angioplasty was successful (residual stenosis 13%), and recatheterization 9 months later showed a widely patent anastomosis (
B
). The patient subsequently remained completely asymptomatic, and at last follow-up 19 years later, he had a negative stress thallium scan. (From
Douglas JS Jr, Gruentzig AR, King SB III, et al. Percutaneous transluminal coronary angioplasty in patients with prior coronary bypass surgery. J Am Coll Cardiol 1983; 2:745–754
, with permission from the American College of Cardiology.)
Percutaneous coronary intervention (PCI) became a less invasive revascularization alternative for many symptomatic postbypass patients, including increasing numbers who, because of contraindications (pulmonary and renal failure, old age, malignancy), were not candidates for reoperative coronary artery surgery. Patients with patent arterial grafts that would be jeopardized by reoperation, patients with relatively small amounts of ischemic, symptom-producing myocardium, and patients with no available venous or arterial conduits for grafts underwent percutaneous revascularization at an acceptable risk. At many centers, patients with prior bypass surgery account for up to 25% of the PCI procedures performed.
Anatomic Considerations
Among the anatomic factors influencing revascularization decisions ( Table 81.1 ), the status of the left anterior descending coronary artery (LAD) and its graft are paramount. Placement of an IMA, a conduit immune to atherosclerosis, as a graft to the LAD has been shown to enhance survival and to reduce ischemic events 10 to as long as 20 years later. In a patient with a patent IMA graft to the LAD, reoperative surgery to treat non-LAD ischemia has been reported to offer no survival benefit, may jeopardize the arterial graft, and, in our experience and that of others, more frequently leads to percutaneous intervention. Multivessel involvement, small number of patent grafts, severe vein graft disease (especially if to the LAD), and a moderately impaired left ventricle are factors more likely to lead to reoperative surgery.
Pathophysiology: Basis for Recurrent Ischemia
Incomplete Revascularization
In many patients, complete surgical revascularization was not achieved because of the presence of distal coronary disease,
whereas less common causes include the following: an inadequate amount of venous or arterial conduit, inadequate conduit lumen resulting from small vessel size (IMA especially) or injury, intramyocardial location of target coronary vessel, placement of grafts to wrong coronary artery or to a coronary vein, creation of an arteriovenous fistula, use of an IMA in the presence of significant stenosis of the subclavian or innominate arteries, or coronary steal phenomenon attributed to large arterial graft side branches, a cause that has been questioned. Intentional incomplete surgical revascularization is an increasingly frequent phenomenon in patients selected for “beating heart” operations because of the technical difficulty of bypassing posteriorly located coronary arteries. In some patients, this strategy has resulted in subsequent percutaneous revascularization because of inadequate relief of symptoms. In others, incomplete surgical revascularization has been dealt with up front with adjunctive percutaneous revascularization during the same hospitalization, the so-called hybrid approach. In addition to less complete revascularization with beating heart surgery, there is some evidence that less precise anastomoses may compromise graft patency, especially in the surgical learning curve (see the later discussion of
venous graft attrition
and
arterial graft compromise
).
TABLE 81.1 Anatomic Factors Influencing Revascularization Decisions in Postbypass Patients
Often leads to percutaneous intervention Often leads to coronary artery bypass grafting
Patent arterial graft ( especially left anterior descending coronary artery ) Diseased saphenous vein graft to left anterior descending
≥2 patent grafts Bulky saphenous vein graft atheroma
1–3 culprit lesions >3 culprit lesions
Difficult surgical access Multiple saphenous vein graft lesions
Mediastinal scarring secondary to radiation, infection, or pericarditis Available arterial conduits
Prior muscle transfer closure of unhealed sternotomy Ejection fraction 25%–35%
Posterior lateral target vessel
Inadequate conduits
Near-normal left ventricle
Future cardiac surgery anticipated
In situ prosthetic valve
Mild to moderate aortic or mitral valve disease
Loss of Revascularization Benefit
Venous Graft Attrition
In patients with recurrent ischemia and infarction after bypass surgery, stenosis or occlusion of SVGs is the most common cause. Thrombotic occlusion related to surgical technical problems or slow graft flow secondary to a small or compromised distal coronary arterial bed results in closure of 10% to 15% of SVGs within the first month, and even with aspirin therapy, one report noted that 7% of vein grafts were shown to be occluded by 9 days, and up to 17% of patients had a closed graft at that time ( 12 ). Subsequently, 15% to 20% of vein grafts occluded by 1 year, 1% to 2% per year from years 1 to 6, and 4% per year from 6 to 10 years after surgery. After 10 years, a few vein grafts were free of significant occlusive disease.
Native Coronary Artery Progression
Worsening of native coronary artery disease after bypass surgery has been reported in about 5% of patients annually ( 13 ). Frequency of disease progression at native vessel sites at 5 years was reported as follows: proximal to graft insertion (70%), unbypassed artery (15%), and distal to graft insertion (0%) ( 14 ). Loop noted that progression of disease distal to grafts was uncommon, and at 2 years, progression of disease proximal to grafts was more common for SVG than for IMA grafts (67% versus 39%) ( 15 ). Progression of native coronary disease proximal to grafts has implications for coronary intervention when graft disease or occlusion occurs and is an important cause of ischemia resulting from poor retrograde perfusion of side branches (e.g., diagonal coronary arteries).
Arterial Graft Compromise
Although numerous publications attest to the excellent long-term patency of arterial grafts, several hundred patients have been reported who required IMA, radial artery, or subclavian artery intervention ( 16 , 17 , 18 , 19 , 20 , 21 , 22 ). In most instances, IMA interventions were needed for anastomotic lesions, but proximal and midgraft sites have been treated (see the discussion of arterial graft intervention ). The technical difficulty of performing an anastomosis in beating heart surgery probably accounts for more anastomotic problems following this type of surgery. Whether radial artery grafts are superior to SVGs has been questioned.
Principles of Management
Preventive Measures
Patients who have had CABG surgery are at substantial risk for subsequent cardiac events related in large part to progressive arteriosclerosis. Recurrence of angina, angiographic progression of vein graft atheroma, and pathologic changes at autopsy have been correlated with increased serum lipids and smoking, and lipid lowering has been shown to be beneficial (
23
,
24
). Given the increased effectiveness of current strategies for lipid lowering and smoking cessation, and reduced cardiac events that accrue, an aggressive approach to risk factor modification is mandatory in all postbypass patients. An aggressive lipid-lowering strategy resulted in a 30% reduction in revascularization and a 24% reduction in a composite clinical end point during 7.5 years of follow-up in the post-CABG Trial. The place of more aggressive antiplatelet therapy in the post-CABG patient is not clear, but recently reported mortality benefits with clopidogrel are provocative and suggest that the use of this or other adjunctive agents may become routine in the future. However, data from randomized controlled trials currently support only aspirin and lipid-lowering agents for routine therapy in all post-CABG patients (
25
).
Treatment of Ischemia in the Postoperative Patient
Patients with recurrent symptoms or signs of ischemia after bypass surgery constitute an extremely heterogenous group (
Fig. 81.2
). Treatment strategies must be based on a careful analysis of multiple factors (many angiographically based) including anatomic factors (
Table 81.1
), the likelihood of a successful percutaneous intervention, risk of complications, probability of long-term symptomatic benefit, and resource consumption compared with other viable options. Patient preferences must be considered because reinterventions are common with percutaneous revascularization in postbypass patients and occur in about 50% of patients at 5 years. In the postbypass patient, the ability to effect ischemia relief percutaneously is influenced by the time that has lapsed since surgery, the type of conduit (SVG versus native vessel versus IMA graft), and the location of the stenotic segment.
Results of Native Coronary Intervention
The procedural outcome of angioplasty for native coronary intervention after CABG was reported for the first 372 such patients treated at Emory University in 1987 (
26
). Most were men (81%), and 78% had multivessel disease. Angiographic success was achieved in 91%, and in-hospital complications were infrequent: mortality, 0.3%; Q-wave MI, 2%; non–Q-wave MI, 4%; CABG surgery, 6%. At the Mid-America Heart Institute (Kansas City, MO), 1,543 postbypass patients underwent angioplasty of native coronary arteries. Angiographic success was 94%, in-hospital mortality was 0.8%, Q-wave MI was 1.5%, and emergency bypass surgery was 1.0% (
27
). At Emory University between 1980 and 1995, 2,246 postbypass patients underwent coronary intervention of native arteries with favorable outcome: procedural success, 89%; in-hospital mortality, 1%, Q-wave MI, 1%; non–Q-wave MI 4% (creatine kinase greater than three times normal); and emergency or elective surgery, 2.8%. Although the definitions of outcomes were slightly different in these series, the overall procedural results were favorable, with a trend toward less need for in-hospital bypass surgery for failed percutaneous intervention. These outcomes were largely that of conventional balloon angioplasty. The Mayo Clinic (Rochester, MN) experience with 937 post-CABG patients treated between 1995 and 1998 reflected a dramatic increase in stent use to 76% of patients and a reduction in use of atherectomy and laser strategies. Patients who underwent interventions in native vessels were younger, more likely female, had less severe coronary disease, and had a more favorable long-term outlook than those who underwent venous bypass graft intervention (
28
). Results of the use of drug-eluting stents in native coronary intervention after CABG have not been reported.
Numerous reports have described the results of balloon angioplasty in SVG disease, indicating that, in selected patients, success rates of approximately 90% were achieved, with mortality of about 1%, Q-wave MI of less than 2%, and in-hospital CABG in approximately 2% of patients. Many of these patients had relatively favorable anatomy with focal lesions free of obvious thrombus. Non–Q-wave MI, the most frequent complication, occurred in 78 (13%) of 599 patients at Emory University (
29
,
30
). The length of time since surgery was an important predictor of restenosis (<6 months, 32%; 6 months to 1 year, 43%; 1 to 5 years, 61%; and 64% for >5 years;
p
< .02), as was the location of the lesion (proximal anastomosis, 68%; midgraft, 61%; distal anastomosis, 45%;
p
< .06). The lowest restenosis rate, 22%, was noted for lesions that occurred at the distal anastomosis within 1 year of surgery, and these patients had excellent, event-free survival (
Fig. 81.3
).
Stenting of SVGs has become the dominant percutaneous strategy (
31
,
32
,
33
,
34
,
35
,
37
,
38
,
39
,
40
,
41
,
42
Tags: Textbook of Cardiovascular Medicine
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Atmosphere | Free Full-Text | Air Quality in Two Northern Greek Cities Revealed by Their Tropospheric NO2 Levels
In this article, we aim to show the capabilities, benefits, as well as restrictions, of three different air quality-related information sources, namely the Sentinel-5Precursor TROPOspheric Monitoring Instrument (TROPOMI) space-born observations, the Multi-Axis Differential Optical Absorption Spectroscopy (MAX-DOAS) ground-based measurements and the LOng Term Ozone Simulation-EURopean Operational Smog (LOTOS-EUROS) chemical transport modelling system simulations. The tropospheric NO2 concentrations between 2018 and 2021 are discussed as air quality indicators for the Greek cities of Thessaloniki and Ioannina. Each dataset was analysed in an autonomous manner and, without disregarding their differences, the common air quality picture that they provide is revealed. All three systems report a clear seasonal pattern, with high NO2 levels during wintertime and lower NO2 levels during summertime, reflecting the importance of photochemistry in the abatement of this air pollutant. The spatial patterns of the NO2 load, obtained by both space-born observations and model simulations, show the undeniable variability of the NO2 load within the urban agglomerations. Furthermore, a clear diurnal variability is clearly identified by the ground-based measurements, as well as a Sunday minimum NO2 load effect, alongside the rest of the sources of air quality information. Within their individual strengths and limitations, the space-borne observations, the ground-based measurements, and the chemical transport modelling simulations demonstrate unequivocally their ability to report on the air quality situation in urban locations.
Background:
Air Quality in Two Northern Greek Cities Revealed by Their Tropospheric NO 2 Levels
by
Maria-Elissavet Koukouli 1,* ,
Andreas Pseftogkas 1 ,
Dimitris Karagkiozidis 1 ,
Ioanna Skoulidou 1 ,
Theano Drosoglou 1 ,
Dimitrios Balis 1 ,
Alkiviadis Bais 1 ,
Dimitrios Melas 1 and
Nikos Hatzianastassiou 2
1
Laboratory of Atmospheric Physics, Aristotle University of Thessaloniki, GR-54634 Thessaloniki, Greece
2
Laboratory of Meteorology, Department of Physics, University of Ioannina, GR-45110 Ioannina, Greece
*
Author to whom correspondence should be addressed.
Atmosphere 2022 , 13 (5), 840; https://doi.org/10.3390/atmos13050840
Received: 27 April 2022 / Revised: 17 May 2022 / Accepted: 17 May 2022 / Published: 20 May 2022
(This article belongs to the Special Issue Urban Climate and Air Quality in Mediterranean Cities )
Abstract
In this article, we aim to show the capabilities, benefits, as well as restrictions, of three different air quality-related information sources, namely the Sentinel-5Precursor TROPOspheric Monitoring Instrument (TROPOMI) space-born observations, the Multi-Axis Differential Optical Absorption Spectroscopy (MAX-DOAS) ground-based measurements and the LOng Term Ozone Simulation-EURopean Operational Smog (LOTOS-EUROS) chemical transport modelling system simulations. The tropospheric NO
2
concentrations between 2018 and 2021 are discussed as air quality indicators for the Greek cities of Thessaloniki and Ioannina. Each dataset was analysed in an autonomous manner and, without disregarding their differences, the common air quality picture that they provide is revealed. All three systems report a clear seasonal pattern, with high NO
2
levels during wintertime and lower NO
2
levels during summertime, reflecting the importance of photochemistry in the abatement of this air pollutant. The spatial patterns of the NO
2
load, obtained by both space-born observations and model simulations, show the undeniable variability of the NO
2
load within the urban agglomerations. Furthermore, a clear diurnal variability is clearly identified by the ground-based measurements, as well as a Sunday minimum NO
2
load effect, alongside the rest of the sources of air quality information. Within their individual strengths and limitations, the space-borne observations, the ground-based measurements, and the chemical transport modelling simulations demonstrate unequivocally their ability to report on the air quality situation in urban locations.
Keywords:
remote sensing
;
air quality
;
NOx emissions
;
S5P/TROPOMI
;
MAX-DOAS
;
LOTOS-EUROS
1. Introduction
In recent decades, with the ever-increasing urbanisation and human need for modern living conditions, air quality has become a major concern affecting billions of people globally. According to the World Health Organization, WHO, in 2016, 91% of the world population was exposed to conditions where the WHO air quality guidelines levels were not met [ 1 ] while ambient air pollution, both in urban and rural areas, was estimated to cause 4.2 million premature deaths worldwide. For Greece and the year 2015, the European Environment Agency [ 2 ] estimated that about 12,000 premature deaths were attributable to particulate matter (PM2.5 and PM10) concentrations, over 6100 to ozone (O 3 ), concentrations and 2300 to nitrogen dioxide (NO 2 ) concentrations. Monitoring of air quality is traditionally performed by ground-based in situ stations and the European Environmental Agency, EEA, is basing its annual assessments of the status, impact and recent air quality trends on measurements at fixed sampling stations [ 3 ]. The EU Environmental Implementation Review 2019 for Greece [ 4 ] reports that exceedances related to the annual limit value for NO 2 were registered in one out of four air quality zones (the capital city of Athens), in one out of four zones for PM2.5 and in three out of four zones for PM10. These official statistics are however relying on the network of in situ air quality stations reporting to the EEA Air Quality Data Service [ 5 ] which are rarely indicative of the true situation; in Greece, only four cities are represented in this database, with no indication on the status over the rest of the mainland, the islands and background locations that are likely affected by inter-regional or trans-boundary pollution events. More recently, however, new technologies and modelling capabilities have given rise to complementary sources of information on air quality adding value to its monitoring. These include increased spatial coverage, with satellite remote sensing observations, city-wide analysis of pollutants at different heights in the atmosphere, with ground-based instrumentation, as well as attribution of increased pollutant levels to the original emitting sources, with state-of-the-art regional chemical transport modelling.
In this work, the tropospheric NO
2
concentrations will be studied as an air quality indicator. On a global scale, emissions of nitrogen oxides (NO
x
= NO + NO
2
) from natural sources far outweigh those generated by human activities (e.g., [
6
]). Natural sources include microbial processes in soils, oxidation of biogenic ammonia, wildfires and lightning. However, the NO
2
levels attributable to natural NOx emissions sources, typically referred to as background, are rather small compared to the magnitude of anthropogenic emissions. Currently, fossil fuel combustion is the largest source of NOx and, together with biomass burning emissions, anthropogenic activities dominate the NOx budget. As a trace gas with a relatively short lifetime, NO
2
is usually confined to a local scale with respect to its source and therefore exhibits strong spatial and temporal variations, rendering its monitoring dependent on the spatiotemporal resolution of its observations.
In the following, we aim to demonstrate the abilities, benefits, as well as limitations, of three different air quality-related pools of information, namely the Sentinel-5 Precursor TROPOspheric Monitoring Instrument (TROPOMI) space-born observations, the Multi-Axis Differential Optical Absorption Spectroscopy (MAX-DOAS) ground-based measurements and the LOng Term Ozone Simulation-EURopean Operational Smog (LOTOS-EUROS) chemical transport modelling system. Using as case studies the Greek cities of Thessaloniki, with a population of 1 million, and Ioannina, with a population of 110 thousand, and the tropospheric NO
2
concentrations as air quality indicators, the local air quality levels and patterns between 2018 and 2021 are studied. These two cities are selected as two study cases representative of a large and a medium-sized urban agglomeration, exhibiting different characteristics regarding the strength and the nature/type of emission sources, as well as their individual geomorphology and topography. The aim of this work differs from that typically seen in literature, that of directly inter-comparing, validating, merging and contrasting the observations and simulations, as we aim to treat each dataset as autonomous and, without disregarding their differences, clearly present the common air quality picture that they provide.
In Section 2 , both observational datasets and the model simulations are briefly described alongside the pre-processing of the original datasets specific to the requirements of this study. In Section 3 , the findings per city are separately expanded and analysed. In Section 4 , an executive summary of this work is provided alongside suggestions for future semi-operational use of these monitoring systems, with ideas that stemmed during this research.
2. Materials and Methods
2.1. Two Northern Greece Cities
Thessaloniki, Figure 1 a, a port city located in the North of Greece, is the second-largest city of the country, with over one million inhabitants in its metropolitan area, while the majority of industrial activity is concentrated in the west and north-west part of the city. The meteorological features affecting air quality in the city are defined by the Gulf of Thermaikos and the mountain on Hortiatis, causing both sea and land breeze and valley mountain winds [ 7 ]. Road transport and industrial emissions are the two main sources of NOx emissions in the greater area of Thessaloniki [ 8 ] while according to [ 9 ] these two anthropogenic emission sources of Thessaloniki contribute by 35 ± 8% and 45 ± 3%, respectively, to the annual mean NOx emissions for Greece. The study of [ 10 ] reported that even small reductions in NOx emissions (~5%) are sufficient for the NO 2 annual average to remain below the EU limit of 40 μg/m 3 . The recent lockdown due to the Severe Acute Respiratory Syndrome Coronavirus-2, COVID-19, has offered the unique possibility to quantify NOx emissions changes due to transport. The study [ 11 ], which was based on satellite observations and chemical transport modelling simulations, reported an ~10% reduction in NO 2 levels over the city while [ 12 ], using a machine learning technique and measurements from two traffic air quality monitoring stations, reported a mean reduction of ~22%. These findings appear counter-intuitive since, in terms of the number of vehicles circulating in Thessaloniki, private cars and motorcycles are the vast majority. However, [ 13 ] have recently shown that a significant decrease in the concentrations of atmospheric pollutants related to road traffic, reaching up to −65% for NOx levels, is achieved when public buses circulating in a major road axis of Thessaloniki are replaced with battery electric vehicles. They conclude that a reduction of the circulation of private vehicles by −20% in combination with the use of battery-electric vehicles for public transportation is the best scenario for improved air quality in the city.
Figure 1. The Thessaloniki ( a ) and Ioannina ( b ) urban areas, including the location of the MAX-DOAS instrument and their respective viewing geometries.
Ioannina,
Figure 1
b, a town of ~110,000 habitants, is located on a plateau of about 480 m in height, surrounded by four mountains and a lake. With respect to NO
2
levels, the air quality of the city is characterized by a “good” air quality index, as per the Index of Air Pollution from the European Commission [
14
] while a small weekend effect is also reported, with Sundays appearing as the cleanest days. A rather weak seasonal variability was also found for Ioannina; during summertime, two counteracting factors affect the local NO
2
levels, the absence of rain preventing NO
2
deposition, whereas the available solar radiation favours its destruction to O
3
formation. The city is however known, in recent years, to suffer from residential wood burning emissions, leading to persistent wintertime smog episodes [
15
].
2.2. MAX-DOAS Measurements
Multi-axis differential optical absorption spectroscopy (MAX-DOAS) is a ground-based passive remote sensing technique that is widely used for the detection of aerosols and trace gases in the Planetary Boundary Layer (PBL) and in the lowermost free troposphere (e.g., [ 16 , 17 , 18 ]). MAX-DOAS systems perform spectrally resolved measurements of scattered sunlight in the ultraviolet (UV) and visible (VIS) parts of the electromagnetic spectrum at different elevation angles [ 19 ]. The spectral analysis of the recorded spectra by differential optical absorption spectroscopy (DOAS) [ 20 ] allows the simultaneous detection of several trace gases that have distinct absorption structures, such as NO 2 , formaldehyde (HCHO), O 3 , sulfur dioxide (SO 2 ), water vapour (H 2 O) and glyoxal (CHOCHO). The primary retrieved product from a MAX-DOAS system is the differential Slant Column Density (dSCD), i.e., the difference in trace gas column amount between a measured spectrum and a Fraunhofer reference spectrum (FRS), typically measured at the zenith. By recording spectra at different elevation angles (typically from close to the horizon towards the zenith) that belong to the same azimuth viewing direction, MAX-DOAS systems allow the retrieval of the trace gases vertical distribution in the lower troposphere.
Several MAX-DOAS systems (Phaethon) have been operating since 2014 on the rooftop of the Physics Department building of the Aristotle University of Thessaloniki (40.634° N, 22.956° E). The instruments have been gradually upgraded ever since for the retrieval of tropospheric NO 2 Vertical Column Densities (VCDs) [ 21 , 22 ], total ozone columns [ 23 ] and recently for the retrieval of aerosol and trace gas vertical profiles [ 24 ]. In the current study, scattered radiation spectra are measured at eleven elevation angles (i.e., 1, 2, 3, 4, 5, 6, 8, 10, 12, 15 and 30°) with an integration time of ~1 min per angle and a sequential zenith-sky measurement is used as the FRS for the retrieval of the NO 2 dSCDs. The dSCDs are calculated with the QDOAS (version 3.2, September 2017) spectral fitting software suite ( https://uv-vis.aeronomie.be/software/QDOAS/ , last access: 11 April 2022) and the NO 2 vertical profiles are retrieved by applying the Mexican MAX-DOAS Fit (MMF) [ 25 ] inversion algorithm to the measured NO 2 dSCDs. Details about the instrumentation, the slant column retrieval settings and the input parameters for the inversion algorithm can be found in [ 24 ]. One year of measurements between May 2020 to May 2021 over Thessaloniki is considered in this work, with the system configured to measure at four azimuth viewing directions, i.e., 142, 185, 220 and 255°, illustrated in Figure 1 a as the different coloured lines. Depending on the known local NO 2 sources, these viewing directions roughly translate into a suburban (142°), an urban (185°), a sea (220°) and a rural location (255°). As will be discussed in the results section, the variability of the MAX-DOAS observations in the different azimuth viewing directions was found to be high. As a result, no clear distinction between the expected NO 2 loads could be differentiated, and the MAX-DOAS observations for the different azimuth viewing directions were averaged into one mean NO 2 time series.
During the PANhellenic infrastructure for Atmospheric Composition and climatE chAnge (PANACEA;
https://panacea-ri.gr/
, access on 19 May 2022) measurement winter campaign 2020, a MAX-DOAS system was installed on the rooftop of the Physics Department building at the University of Ioannina from 3 January 2020 to 18 February 2020. No remote sensing instruments operate regularly in Ioannina and the air quality is monitored only by in situ measurement sites that are distributed around the city centre. Tropospheric NO
2
VCDs are retrieved for the first time in Ioannina using MAX-DOAS observations. The system was configured to perform elevation scans at three azimuth viewing directions (15, 35 and 80°, illustrated in
Figure 1
b). The azimuth directions of 15° and 35° point towards the urban direction, while the 80° azimuth direction points to a suburban area. The viewing directions at elevation angles close to the horizon (i.e., less than 4°) are blocked by the surrounding mountains at all azimuths and thus NO
2
vertical profiles cannot be reliably retrieved. Hence, the NO
2
VCDs for Ioannina are derived from the dSCDs measured at 30 and 15° elevation angles by division with appropriate differential Air Mass Factors (dAMFs) that were calculated based on Radiative Transfer Model (RTM) simulations, taking into account the viewing geometry, the aerosol optical properties, and the instrument’s viewing direction relative to the sun [
21
]. The NO
2
dSCDs at these elevation angles are lower than those measured at lower elevation angles and the associate fitting errors are larger. Furthermore, the NO
2
levels measured in Ioannina are considerably lower than in Thessaloniki and the differential optical densities are usually very low, reaching the spectrometer’s detection limit. Hence, in order to obtain data of higher quality, the NO
2
VCDs are calculated from the average VCDs at 30 and 15° when those agreed to at least 50%. Similarly as for Thessaloniki, for Ioannina, one azimuth-averaged MAX-DOAS time series is analysed.
2.3. S5P/TROPOMI Observations
The Sentinel 5 Precursor (S5P) mission is a low Earth orbit polar satellite system to provide information and services on air quality, climate and the ozone layer in the timeframe between 2016 and 2023. The S5P satellite was launched on 13 October 2017, carrying the TROPOspheric Monitoring Instrument, TROPOMI [ 26 ]. TROPOMI is a double channel, nadir-viewing grating spectrometer, measuring solar backscattered earthshine radiances in the ultraviolet, visible, near-infrared, and shortwave infrared with global daily coverage [ 27 , 28 ]. The instrument has a swath width of 2600 km with a near nadir resolution at 3.5 × 5.5 km 2 since 6 August 2019 (3.5 × 7 km 2 initial spatial resolution). The wavelength range for the NO 2 column retrieval is between 405 and 465 nm and detailed information on the algorithm and data can be found in the TROPOMI NO 2 Algorithm Theoretical Basis Document [ 27 , 28 ]. The data are constantly being validated by the Mission Performance Center Validation Data Analysis Facility, VDAF ( https://mpc-vdaf.tropomi.eu/ , last access: 16 September 2021). According to the latest validation report, TROPOMI L2_NO 2 tropospheric column data show a negative median bias of −34% when compared to MAX-DOAS ground-based observations, well within the mission requirement of 50% [ 29 ]. This bias is reduced by approximately 20% when the MAX-DOAS profile data are vertically smoothed using the S5P averaging kernels.
In this work, we use offline v1.2 and v1.3 S5P/TROPOMI NO
2
tropospheric vertical column densities for a long sensing period, from May 2018 to March 2021, over the Greek cities of Thessaloniki and Ioannina. The data are filtered with a quality assurance value (qa_value > 0.75) to ensure cloud-free satellite observations and are gridded onto a 0.01° × 0.01° grid so as to extract the observations of the specified pixels required for this research. The day-of-week, monthly and seasonal variations of NO
2
are studied over urban, suburban, rural and sea areas in Thessaloniki and over urban and rural areas in Ioannina. In order to demonstrate the space-based monitoring capabilities more clearly, for Thessaloniki, the urban and suburban pixels were averaged into one, the sea and rural pixels into another and the central pixel over AUTH, where the bulk of the NOx emissions reside, is studied separately. Similarly, for Ioannina, the urban and suburban pixels are averaged while the central pixel over the UOI is studied separately.
2.4. LOTOS-EUROS Simulations
LOTOS-EUROS is the chemical transport model used to simulate atmospheric pollutants in this study [ 30 ]. The model is designed to simulate trace gases and aerosols in three dimensions in the lower atmosphere. LOTOS-EUROS is one of the state-of-the-art models used in the Copernicus Atmosphere Monitoring Service (CAMS, http://www.copernicus-atmosphere.eu ) providing atmospheric information to a broad range of users, while it has been widely used in different studies concerning different parts of the world (e.g., [ 31 , 32 ]). The model behaviour has been studied and validated in Greece and, for the city of Thessaloniki, it exhibits a mild underestimation of ~−10% when comparing simulated tropospheric NO 2 columns with S5P/TROPOMI and MAX-DOAS observations in summer [ 33 ].
The gas chemical mechanisms in LOTOS-EUROS are based on the updated version of CBM IV [
34
], while the secondary inorganic aerosols are represented by the ISORROPIA II module [
35
]. The simulations were driven by operational meteorological data from the European Centre for Medium-Range Weather Forecasts (ECMWF) with a horizontal resolution of 7 km × 7 km. Atmospheric variables were simulated in 12 vertical layers expanding from the surface to about 200 hPa. The anthropogenic emission inventory used is based on CAMS-REG (CAMS regional European emissions) v4.2 inventory for the year 2017 and the temporal profiles used are the default profiles provided by CAMS for Europe. The CAMS-REG inventory provides European total annual gridded emissions on a 0.10° × 0.05° grid. The model calculates biogenic NO
x
emissions from soils online, depending on soil type and temperature [
36
].
In this study, a nested domain configuration was used. Three different model runs with varying horizontal resolutions were performed so as to obtain a smooth transition in the dynamics from the large European scales to the desired local scale of the cities of Thessaloniki and Ioannina. First, a coarse resolution run that covers the region of Europe expanding from 15° W to 45° E and 30° N to 60° N and a horizontal resolution of 0.25° × 0.25° was performed. The initial and boundary conditions in this run were derived from the CAMS global near-real-time (NRT) product with a spatial resolution of 35 km × 35 km. Secondly, a medium resolution run was performed over Greece (20° E to 27° E and 34° N to 42° N) with a horizontal resolution of 0.10° longitude × 0.05° latitude, while the boundary conditions, in this case, were retrieved from the lower-resolution domain. Finally, we performed two higher-resolution runs with a spatial resolution of 0.01° × 0.01°, covering the regions of Thessaloniki (22.775° E to 23.075° E and 40.5° N to 40.75° N) and Ioannina (20.7° E to 20.9° E and 39.55° to 39.85° N) deriving concentration of pollutants on an hourly basis, between April 2018 and April 2021. Concentrations of gases and aerosols simulated in the medium resolution run were used as boundary conditions for the runs of Thessaloniki and Ioannina.
While the aim of this work is not to validate the model simulations against the ground- and space-born observations, in order to have a homogeneous discussion, the simulations were also aggregated in the same manner as the space-borne observations, i.e., for Thessaloniki, the urban and suburban pixels are shown as one, the sea and rural pixels as a second another and the central pixel over AUTH as a third. Similarly, for Ioannina, the urban and suburban pixels are averaged while the central pixel over the UOI is studied separately.
In Table 1 , the main characteristics of each dataset used in this work as an air quality information pool are given, including their strong points and limitations. In such a format, it becomes clearer that these are all complementary to one another and each is an asset to any study performed on the urban scale.
Table 1. The important characteristics of each dataset discussed in this work.
3. Results
3.1. Thessaloniki Metropolitan Area
3.1.1. Spatial Variability within the City
The average lifetime of NOx in the boundary layer depends on many factors such as meteorological conditions, photolysis strengths, the duration of night-time, temperature, OH and H
2
O concentrations. Typically, 2–6 h are considered a good estimate for summertime with this value reaching one day during wintertime and the absence of sunlight. As a result, a clear seasonality is expected especially between winter and summer loads. In
Figure 2
, the wintertime (left) and summertime (right) TROPOMI tropospheric NO
2
concentrations are shown for Thessaloniki, including: the locations of urbanized areas (city centre, Pylaia, Kalamaria, Stavroupoli), the port, the airport, the heavily used ring road, the industrial area (Sindos) and a possible source of agricultural NOx emissions in the rice fields of Chalastra. The satellite data were hyper-gridded using standard space-borne atmospheric analysis tools onto a 0.01 × 0.01° grid, however, for the discussion below, these were aggregated according to the colour-coded 5 × 5 grid boxes. The centre of the city which includes the location of the MAX-DOAS system is depicted in black; with red, the two urban and suburban MAX-DOAS viewing geometries are shown and with green, the rural and sea MAX-DOAS viewing geometries are represented (see
Figure 1
, left). These same pixels are also be used in the analysis of the LOTOS-EUROS simulations. The time period between May 2018 and March 2020 is presented in this work, while TROPOMI typically overpasses between 11:00 and 12:00 UTC over Greece. Since the aim of this work is to demonstrate the individual dataset capabilities in monitoring air quality, and not to inter-compare them, no homogenization between them was applied. This is typically performed by the application of the averaging kernel information between different datasets that are sensitive at different altitudes within the atmosphere. Hence, the NO
2
reported levels are expected to vary in magnitude.
Figure 2. TROPOMI tropospheric NO 2 seasonal load (10 15 molecules/cm 2 ) over Thessaloniki during wintertime ( a ) and summertime ( b ). Important locations of possible NO 2 emitting sources are also shown. Coloured cells represent the cells used in the analysis.
Over the entire domain shown, the wintertime loads range between 2.40 and 5.20 × 10
15
molecules/cm
2
, with a mean of 3.70 ± 0.65 × 10
15
molecules/cm
2
while the summertime loads range between 1.45 and 2.45 × 10
15
molecules/cm
2
, with a mean of 1.88 ± 0.24 × 10
15
molecules/cm
2
. Furthermore, one already observes a clear distinction in the NO
2
loads in accordance with the expected emission locations annotated on the maps, discussed in the monthly mean time series in the next figure.
3.1.2. Time Series and Diurnal Variability
The time series of the TROPOMI tropospheric NO
2
monthly mean loads (
Figure 3
) show a clear seasonal pattern for all locations studied, more pronounced for the city centre (black line) and the urban–suburban pixels (red line) than the rural–sea locations (green line) with the summertime lows at the ~1.5 × 10
15
molecules/cm
2
level and the wintertime highs at ~5.85, ~5.00 and ~4.15 × 10
15
molecules/cm
2
level, respectively. A curiously high load was observed for the month of February 2020, before COVID-19 related measures were enforced in Greece 11, which has been attributed to unusual meteorological conditions during that month, as also seen in the LOTOS-EUROS simulations, discussed below. Since the TROPOMI observations occur once per day, typically around 11:00–12:00 UTC over Thessaloniki, the shaded areas in the monthly mean time series represent the spatial variability of the chosen pixels. This variability is small, hence further testifying to the ability of the satellite sensor in viewing the different NO
2
loads within the urban agglomeration.
Figure 3. Monthly mean TROPOMI tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Thessaloniki for specific locations according to their known emission capabilities. The shaded areas represent the standard deviation of the spatial mean.
The MAX-DOAS monthly mean tropospheric NO
2
columns (10
15
molecules/cm
2
) over Thessaloniki (
Figure 4
a) are presented as an average of all the viewing geometries shown in
Figure 1
, left, for the same sensing time as that of TROPOMI. The variability of the MAX-DOAS observations between the different viewing geometries was rather large and did not permit an analysis per viewing geometry. A possible reason is the horizontal distance of the MAX-DOAS observations which span more than one 0.05 × 0.05° (~5 × 5 km-pixels), ranging between 10–20 km depending on the season. This fact does not enable us to distinguish statistical significance between the different locations around Thessaloniki from the MAX-DOAS observations. Hence, one averaged MAX-DOAS dataset is shown in this work. Overall, the MAX-DOAS reports lows around 5 × 10
15
molecules/cm
2
for the summertime and highs reaching ~12 × 10
15
molecules/cm
2
in December, with a mean of 7.34 ± 2.15 × 10
15
molecules/cm
2
, replicating the expected seasonal NO
2
pattern albeit with higher absolute values than the satellite sensor.
Figure 4. ( a ) Monthly mean MAX-DOAS tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Thessaloniki. Diurnal variability during wintertime ( b ) and summertime ( c ).
The ability of the MAX-DOAS system to measure through the daylight hours, one of the strengths of this observational system, permits the discussion of the diurnal pattern of atmospheric gas. In
Figure 4
b the diurnal variability during wintertime is presented, as a box-plot, while the summertime is shown in
Figure 4
c. We note that during wintertime the mean levels remain high during the different sensing times, between ~6–7 × 10
15
molecules/cm
2
, with high variability as shown by the standard error bars and the marked difference between mean (in blue) and median (in red) levels. This picture is well expected as the photochemical destruction of NO
2
is weaker and the background levels of the species remain high, due to its increased lifetime. During summertime, the expected diurnal variability is very clear, with higher levels of ~7–8 × 10
15
molecules/cm
2
, during rush hour (~05:00–06:00 UTC) and lows (~3–4 × 10
15
molecules/cm
2
) after 10:00 UTC when sunlight is strong, with the secondary maximum appearing after 16:00 UTC when the photochemical NO
2
destruction has slowed down.
The LOTOS-EUROS CTM simulations over the different locations around Thessaloniki are in complete agreement with that which the two observational sets have already revealed. In
Figure 5
a, the monthly mean time series of the same pixels and same overpass time as shown for TROPOMI (
Figure 3
) also show lows during the summertime and highs during the winter months, a clear distinction for the three different expected NO
2
concentrations, including the peak of February 2020. As the entire timeline of the CTM simulations depends on the same NO
2
emission inventory for the year 2017, this February 2020 increase may only be attributed to the special meteorological conditions of that month and corroborate the findings of the TROPOMI observations.
Figure 5. ( a ) Monthly mean LOTOS-EUROS tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Thessaloniki for specific locations as per Figure 3 . Diurnal variability during wintertime ( b ) and summertime ( c ).
In more detail, the city centre location hosting the MAX-DOAS instrument reports a seasonality between 4.0 and 10.5 × 10
15
molecules/cm
2
, with a mean load of 6.45 ± 1.68 × 10
15
molecules/cm
2
, while the seasonality is similar for the urban-suburban and rural pixels, between 3.0 and 8.75 × 10
15
molecules/cm
2
, albeit with somewhat different mean loads: for the urban–suburban, this was estimated to be 5.60 ± 1.50 × 10
15
molecules/cm
2
while for the rural location at 4.85 ± 1.50 × 10
15
molecules/cm
2
. Recall that the standard deviations reported here, and shown as coloured shaded areas in the figures, represent the spatial variability of the hyper-grid and not a temporal variability.
Contrary to the satellite observations, which provide a picture of the situation for a specific time of day, and the MAX-DOAS observations, which provide the picture during daylight hours, the LOTOS-EUROS can provide estimates of the NO 2 concentrations throughout the entire day. Of course, the CTM simulations depend on accurate input parameters and the correct representation of different physicochemical processes within the model. The CTM diurnal variability for winter ( Figure 5 b) and summer ( Figure 5 c) revealed issues in the modelling system, already identified by [ 33 ].
The first point of interest, for the winter diurnal patterns, is the unexpected higher night-time NO
2
concentrations (after 16:00 UTC) which reach around 10–12 × 10
15
molecules/cm
2
well over the daytime maximum of ~9 × 10
15
molecules/cm
2
. Study [
33
] validated LOTOS-EUROS surface NO
2
simulations against air quality monitoring stations around Athens and Thessaloniki. The night-time comparisons were the most difficult to interpret; during the night period, the model overestimates the low NO
2
measurements and underestimates the higher concentrations over the air quality stations. They concluded that the diurnal evolution of the boundary layer height appears to strongly affect both the mixing processes within the CTM and the photochemical NO
2
destruction strength. These two processes may well be responsible for the unexpectedly high night-time NO
2
concentrations for all locations examined during winter (
Figure 5
b). During summer (
Figure 5
c) a similar issue appears to occur, with the night-time max, however, only rising to the morning peak levels (~7–8 × 10
15
molecules/cm
2
), possibly due to the rapid NO
2
photochemical destruction.
The second point of interest is the model behaviour over the rural–sea pixel (green lines) both during wintertime ( Figure 5 b) and summertime ( Figure 5 c). With the absence of known strong emission sources, the very high levels reported in winter starting during the night-time hours after 18:00 UTC and flowing into daytime hours up to 10:00 UTC, were entirely unexpected. In Figure A1 , maps of the LOTOS-EUROS tropospheric NO 2 levels with colour-coded annotations of the locations of the pixels shown in Figure 5 , are presented for winter and summertime averaged for 00:00–06:00, 06:00–12:00, 12:00–18:00 and 18:00–24:00 UTC. It is clear that the rural and sea pixels both depict extremely high NO 2 levels during the entire day, apart from during the peak of the strong photochemical processing during the daylight hours. This surprising finding is corroborated by the Copernicus Atmospheric Monitoring Service, CAMS, regional ensemble re-analysis publicly available via the European air quality|Copernicus Atmosphere Monitoring Service. While this feature will be further investigated in the future, we can already note that the large scale dominant wind patterns for the region, shown in Figure A2 , do not appear to explain this behaviour in themselves. During wintertime, northern winds are prominent throughout the day while during summertime more variable wind patterns can be observed depending on the time of day. These wind fields depict the ECMWF meteorological fields provided in a 7 × 7 km 2 resolution to the LOTOS-EUROS model. The topography of the bay of Thessaloniki is however known to host extremely complex wind patterns which greatly affect the photochemical processes, discussed extensively in [ 7 ]. They reported moderate ozone levels for Thessaloniki throughout the day which are decisively affected by the break-up of the night-time temperature inversion and the onset of the sea breeze. Lessons learned from their work, which focuses on tropospheric O 3 , will be used to investigate this phenomenon further.
3.1.3. Day-of-Week Variability
The day-of-week, or weekly, variability of tropospheric NO
2
has been examined in the past for major megacities on a global scale using different observational platforms. The authors of [
37
] studied the space-borne Global Ozone Monitoring Experiment (GOME)/ERS-2 tropospheric NO
2
columns for industrialized regions and cities in the US, Europe and Japan and reported a clear Sunday minimum, of about 25–50% lower than working day levels. [
38
], using the Ozone Monitoring Instrument (OMI)/Aura and S5P/TROPOMI observations also reported a minimum ranging between 25% and 38% for large cities globally, for the traditional resting day of Sunday. Focusing on the continental US, [
39
], using only the high spatially resolution S5P/TROPOMI observations found that Saturday and Sunday NO
2
concentrations are 16% and 24% lower, respectively, than during weekdays. These space-based dataset reports are well in line with the work of [
40
], who used in situ air quality monitoring stations for the agglomeration of Los Angeles, USA, where a 30%–35% Sunday decline in NO
2
atmospheric content was reported.
Most of these studies focus on areas with a high anthropogenic NO
2
atmospheric load which is not the case for the two Greek cities discussed here. The authors of [
41
] estimated that the S5P/TROPOMI tropospheric columns are about 20–30% lower during weekends over Helsinki, Finland, while a ground-based spectrophotometer, Pandora, also showed lower values but only by about 10–20%. In
Figure 6
, the wintertime (left column) and summertime (right column) day-of-week tropospheric NO
2
concentrations are shown for the TROPOMI observations (top row), the LOTOS-EUROS simulations (middle row) and the MAX-DOAS measurements (bottom row). Even though the relative magnitudes for the NO
2
concentrations differ greatly between the two seasons and type of dataset, the weekend effect is present in all three: TROPOMI reports a −20.2 ± 1.1% (−22.1 ± 2.5%) decline for Sunday, LOTOS-EUROS reports a −15.2 ± 2.1% (−7.8 ± 0.9%) and MAX-DOAS reports a −25.3% (−33.1%) during wintertime (summertime).
Figure 6. Day-of-week variability of tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Thessaloniki revealed by TROPOMI observations during wintertime ( a ) and summertime ( b ), LOTOS-EUROS simulations during wintertime ( c ) and summertime ( d ) and MAX-DOAS observations during wintertime ( e ) and summertime ( f ).
One further notes, from Table 2 , that larger NO 2 loads were sensed for Fridays with the LOTOS-EUROS CTM reporting the highest deviations of the weekly mean, at 10.5 ± 2.8% for winter and 6.0 ± 4.0% for the summer. The CTM results are attributed to the temporal profile used in the LOTOS-EUROS [ 42 ] which has recently been thoroughly updated in [ 43 ] and discussed by [ 44 ]. The resulting emissions are shown in Figure A3 , where one notes the gradual increase of the input emissions between Monday and Friday, with a sharp drop on Saturday and even sharper on Sundays. An extensive analysis based on traffic count measurements at numerous locations around the Globe, including Athens, was developed for the road transport sector so as to calculate the monthly, weekly and hourly profiles required by the CTM. This increase is also reproduced by the TROPOMI observations which also show increased Friday loads by 15.7 ± 3.8% for winter and 10.0 ± 4.7% for summer.
Table 2. The percentage deviation of day-of-week NO 2 columns from the weekly average for Thessaloniki. The std values represent the variability of the different locations sensed, where applicable.
3.2. Ioannina City and Environs
3.2.1. Spatial Variability within the City
Ioannina, a medium-sized city with no industrial zone, is exhibiting as expected far lower tropospheric NO
2
loads than Thessaloniki. In
Figure 7
, the TROPOMI-reported NO
2
levels are presented for the wintertime (left) and the summertime (right) including the location of the University of Ioannina, UOI, where the MAX-DOAS instrument was placed during the PANACEA winter campaign, the city centre, the small provincial airport as well a suburban location (Anatoli) and a rural location (Kastritsa.) Over the entire domain shown, the wintertime loads range between 1.02 and 2.02 × 10
15
molecules/cm
2
, with a mean of 1.33 ± 0.23 × 10
15
molecules/cm
2
while the summertime loads range between 0.90 and 1.20 × 10
15
molecules/cm
2
, with a mean of 1.04 ± 0.06 × 10
15
molecules/cm
2
. The locations of the pixels chosen for further discussion are shown in red, for the urban–suburban locations and two of the MAX-DOAS viewing angles and in green, for the rural location and the third MAX-DOAS viewing angle.
Figure 7. TROPOMI tropospheric NO 2 seasonal load over Ioannina in wintertime ( a ) and summertime ( b ). Important locations of possible NO 2 emitting sources are also shown. Coloured cells represent the cells used in the analysis.
3.2.2. Time Series and Diurnal Variability
When focusing on the two urban and rural pixels, a distinction between the tropospheric NO
2
columns becomes clearer, especially during the wintertime months. For the urban pixels, which encompass the city of Ioannina and the main suburban location, the monthly mean time series of the TROPOMI observations (
Figure 8
, red line) show summertime lows at ~1.0 × 10
15
molecules/cm
2
and wintertime highs at ~3.0 × 10
15
molecules/cm
2
with mean annual loads of 1.44 ± 0.43 × 10
15
molecules/cm
2
. For the rural pixel, in green, the summertime lows are ~ 0.67 × 10
15
molecules/cm
2
, the wintertime highs at ~2.02 × 10
15
molecules/cm
Figure 8. Monthly mean TROPOMI tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Ioannina for specific locations according to their known emission capabilities. The shaded areas represent the standard deviation of the spatial mean.
Due to the short time that the PANACEA campaign took place in Ioannina, the MAX-DOAS observations are limited to January and February 2020. From Figure 9 a, where the daily mean observed tropospheric NO 2 columns are shown, one notes that at the beginning of the PANACEA campaign the overall load over Ioannina was on average ~6.6 × 10 15 molecules/cm 2 while in the second part, after 25 January, the average load was ~3.65 × 10 15 molecules/cm 2 . The shaded areas represent the variability of the hourly observations. In Figure 9 b, the wintertime diurnal NO 2 levels sensed by the MAX-DOAS are presented between 06:00 and 14:00 UTC, the full daytime hours. The increase in NO 2 levels, between ~4 to ~6 × 10 15 molecules/cm 2 ), in the morning hours does not seem to abate, but rather levels remain high throughout the afternoon hours as well. The afternoon levels have a high variability associated with them, showing a very similar picture as what is measured by an in situ air quality monitoring station operating on location (not shown here).
Figure 9. ( a ) Daily mean time series of MAX-DOAS tropospheric NO 2 columns (10 15 molecules/cm 2 ) during wintertime over Ioannina. ( b ) The respective diurnal variability.
A similar seasonal variability with higher overall NO 2 levels as observed by TROPOMI is simulated by the CTM ( Figure 10 a) with summertime lows around 2 × 10 15 molecules/cm 2 , and wintertime highs between 3–4 × 10 15 molecules/cm 2 , depending on the year. The difference between the urban and rural locations is not so high, and in most cases within the spatial variability of the simulations. The LOTOS-EUROS diurnal variability in the case of Ioannina, shown for winter in Figure 10 b and for summer in Figure 10 c, presents an expected evolution with a double peak in the urban locations in the morning and evening. The wintertime evening levels are, as for the case of Thessaloniki, higher than the morning traffic-related levels and merit further investigation as to the exact physico-chemical processes that are driving these night-time increases.
Figure 10. ( a ) Monthly mean LOTOS-EUROS tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Ioannina for specific locations as per Figure 3 . Diurnal variability during wintertime ( b ) and summertime ( c ).
3.2.3. Day-of-Week Variability
The day-of-week variability over Ioannina ( Figure 11 ) follows the same patterns as for Thessaloniki, with the lowest tropospheric NO 2 columnar value deviations reported for Sunday by all three data sources, with a different magnitude. The wintertime (left column) and summertime (right column) day-of-week tropospheric NO 2 concentrations are shown for the TROPOMI observations (top row), the LOTOS-EUROS simulations (middle row) and the MAX-DOAS measurements (bottom row). The weekend effect is present in all three: TROPOMI reports a −16.3 ± 0.5% in winter (−21.5 ± 5.2% in summer) decline for Sunday, LOTOS-EUROS reports corresponding declines of −17.3 ± 2.8% in winter (−6.8 ± 1.2% in summer) and MAX-DOAS reports a very strong Sunday decrease, of −49%, which is based on five Sundays during winter 2020. All statistics are reported in Table 3 .
Figure 11. Day-of-week variability of tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Ioannina revealed by TROPOMI observations during wintertime ( a ) and summertime ( b ), LOTOS-EUROS simulations during wintertime ( c ) and summertime ( d ) and MAX-DOAS observations during wintertime ( e ).
Table 3. The percentage deviation of day-of-week NO 2 columns from the weekly average for Ioannina. The std values represent the variability of the different locations sensed, where applicable.
4. Conclusions
In this work, the air quality due to nitrogen dioxide levels over two Northern Greek cities has been studied using Sentinel-5Precursor TROPOspheric Monitoring Instrument (TROPOMI) space-born observations, Multi-Axis Differential Optical Absorption Spectroscopy (MAX-DOAS) ground-based measurements and the LOng Term Ozone Simulation-EURopean Operational Smog (LOTOS-EUROS) chemical transport modelling system simulations. Each of these systems offers a different perspective on the current air quality situation over Thessaloniki and Ioannina depending on their spatiotemporal monitoring capabilities of the tropospheric NO 2 levels. While these levels differ in magnitude between the two cities, following the different magnitudes of their NOx emitting sources, a common picture emerges as follows:
▪
A clear seasonal pattern, with high NO 2 levels during wintertime and lower NO 2 levels in summer was found, clearly reflecting the effect of the high photochemistry strengths during the main sunlight summer months over Greece, by all three systems.
▪
A marked distinction between locations with high emitting sources and clean locations around the urban sprawl were reported by both the space-borne observations and the model simulations.
▪
The expected NO 2 diurnal variability, less pronounced during wintertime but quite strong during summertime, was seen in both the ground-based measurements as well as the model simulations.
▪
All three systems identified a discernible day-of-week variability with the lowest levels reported for Sundays in both seasons, reflecting the effect of reduced traffic emissions in both Greek cities.
Furthermore, the following open questions were identified and are thought to merit further investigation in the future:
▪
The effect of the small scale wind patterns around the city of Thessaloniki and its bay was divulged in both the space-borne observations and the model simulations. The continuous transport of the pollutant in nearby locations may be responsible for a constant background NO 2 level, which cannot be assessed by the air quality monitoring stations that are located within the city boundaries.
▪
Extremely high NO 2 levels during the night-time hours are simulated by the CTM which were unexpected considering the relatively low NO 2 loads over the two cities were reported for the first time. The main physicochemical mechanism behind these enhancements should be investigated so as to assess its representativeness to the true situation.
The launch of the EUMETSAT Sentinel-4 UVN (Ultraviolet–Visible Near-infrared) imaging spectrometer on the geostationary MTG-S platform in early 2024 will offer a complete hourly space-borne observational dataset that will undoubtedly provide further insights on the air quality status over Greece.
Author Contributions
Conceptualization, D.B. and A.B.; methodology, M.-E.K. and D.B.; software, A.P. and M.-E.K.; validation, D.K. and I.S.; investigation, A.P. and I.S.; data curation, M.-E.K., A.P., D.K. and T.D.; writing—original draft preparation, M.-E.K.; writing—review and editing, A.P. and I.S.; supervision, D.B., D.M. and N.H. All authors have read and agreed to the published version of the manuscript.
Funding
This research has been financed by the European Union (European Regional Development Fund) and Greek national funds through the Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) by the “Panhellenic Infrastructure for Atmospheric Composition and Climate Change” project (MIS 5021516) implemented under the Action “Reinforcement of the Research and Innovation” infrastructure.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
The S5P/TROPOMI observations are publicly available from the Copernicus Open Access Hub ( https://scihub.copernicus.eu/ ) [ 45 ]. The LOTOS-EUROS CTM simulations shown in this work are performed with the open-source version v02.02.001 and are available upon request from A.P. The MAX-DOAS observations are available upon request from D.K.
Acknowledgments
We would like to wholeheartedly thank Astrid Manders and Arjo Segers, TNO, Climate, Air and Sustainability, Utrecht, the Netherlands, for their valuable advice on the LOTOS-EUROS CTM. Results presented in this work have been produced using the Aristotle University of Thessaloniki (AUTH) High Performance Computing Infrastructure and Resources. The authors would like to acknowledge the support provided by the AUTH IT Centre throughout the progress of this research work. We further acknowledge the Atmospheric Toolbox ® .
Conflicts of Interest
The authors declare no conflict of interest.
Appendix A
Figure A1. LOTOS-EUROS tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Thessaloniki for ( a ) winter and ( b ) summertime, averaged within four 6 h increments.
Figure A1. LOTOS-EUROS tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Thessaloniki for ( a ) winter and ( b ) summertime, averaged within four 6 h increments.
Figure A2. Wind speed (ms −1 ) and direction rose diagrams for the AUTH pixel for ( a ) winter and ( b ) summertime.
Figure A2. Wind speed (ms −1 ) and direction rose diagrams for the AUTH pixel for ( a ) winter and ( b ) summertime.
Figure A3. Weekly and seasonal variability of the NO 2 emissions (μgm −2 s −1 ) over the specific locations around the urban area.
Figure A3. Weekly and seasonal variability of the NO 2 emissions (μgm −2 s −1 ) over the specific locations around the urban area.
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Figure 1. The Thessaloniki ( a ) and Ioannina ( b ) urban areas, including the location of the MAX-DOAS instrument and their respective viewing geometries.
Figure 2. TROPOMI tropospheric NO 2 seasonal load (10 15 molecules/cm 2 ) over Thessaloniki during wintertime ( a ) and summertime ( b ). Important locations of possible NO 2 emitting sources are also shown. Coloured cells represent the cells used in the analysis.
Figure 3. Monthly mean TROPOMI tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Thessaloniki for specific locations according to their known emission capabilities. The shaded areas represent the standard deviation of the spatial mean.
Figure 4. ( a ) Monthly mean MAX-DOAS tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Thessaloniki. Diurnal variability during wintertime ( b ) and summertime ( c ).
Figure 5. ( a ) Monthly mean LOTOS-EUROS tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Thessaloniki for specific locations as per Figure 3 . Diurnal variability during wintertime ( b ) and summertime ( c ).
Figure 6. Day-of-week variability of tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Thessaloniki revealed by TROPOMI observations during wintertime ( a ) and summertime ( b ), LOTOS-EUROS simulations during wintertime ( c ) and summertime ( d ) and MAX-DOAS observations during wintertime ( e ) and summertime ( f ).
Figure 7. TROPOMI tropospheric NO 2 seasonal load over Ioannina in wintertime ( a ) and summertime ( b ). Important locations of possible NO 2 emitting sources are also shown. Coloured cells represent the cells used in the analysis.
Figure 8. Monthly mean TROPOMI tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Ioannina for specific locations according to their known emission capabilities. The shaded areas represent the standard deviation of the spatial mean.
Figure 9. ( a ) Daily mean time series of MAX-DOAS tropospheric NO 2 columns (10 15 molecules/cm 2 ) during wintertime over Ioannina. ( b ) The respective diurnal variability.
Figure 10. ( a ) Monthly mean LOTOS-EUROS tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Ioannina for specific locations as per Figure 3 . Diurnal variability during wintertime ( b ) and summertime ( c ).
Figure 11. Day-of-week variability of tropospheric NO 2 columns (10 15 molecules/cm 2 ) over Ioannina revealed by TROPOMI observations during wintertime ( a ) and summertime ( b ), LOTOS-EUROS simulations during wintertime ( c ) and summertime ( d ) and MAX-DOAS observations during wintertime ( e ).
Table 1. The important characteristics of each dataset discussed in this work.
Table 2. The percentage deviation of day-of-week NO 2 columns from the weekly average for Thessaloniki. The std values represent the variability of the different locations sensed, where applicable.
Monday Tuesday Wednesday Thursday Friday Saturday Sunday Winter TROPOMI 11.5 ± 5.5% −2.1 ± 4.0% −5.7 ± 1.0% 8.6 ± 1.8% 15.7 ± 3.8% −7.8 ± 4.1% −20.2 ± 1.1% LOTOS-EUROS −2.5 ± 3.9% −7.2 ± 2.4% −3.8 ± 4.1% 8.3 ± 1.7% 10.5 ± 2.8% 9.8 ± 4.0% −15.2 ± 2.1% MAX-DOAS 3.5% −1.6% 5.8% 11.1% 0.2% 6.4% −25.3% Summer TROPOMI 5.8 ± 1.7% 9.1 ± 1.9% 0.4 ± 3.6% 4.6 ± 2.0% 10.0 ± 4.7% −7.7 ± 1.2% −22.1 ± 2.5% LOTOS-EUROS 4.3 ± 2.0% 1.1 ± 0.9% 4.8 ± 1.7% 5.0 ± 1.6% 6.0 ± 4.0% −13.4 ± 3.7% −7.8 ± 0.9% MAX-DOAS 6.2% 16.4% 3.6% 7.2% 13% −13.4% −33.1%
Table 3. The percentage deviation of day-of-week NO 2 columns from the weekly average for Ioannina. The std values represent the variability of the different locations sensed, where applicable.
Monday Tuesday Wednesday Thursday Friday Saturday Sunday Winter TROPOMI 1.1 ± 1.1% −2.9 ± 1.0% 9.4 ± 1.2% −3.3 ± 5.5% 8.6 ± 0.7% 3.4 ± 5.6% −16.3 ± 0.5% LOTOS-EUROS −0.1 ± 4.2% 3.9 ± 0.8% 9.5 ± 6.3% 2.8 ± 0.2% 7.3 ± 2.8% −6.2 ± 1.1% −17.3 ± 2.8% MAX-DOAS 24.4% 23.4% 9.8% −10.7% 0.1% 2% −49% Summer TROPOMI 15.2 ± 2.8% −10.0 ± 1.3% −0.1 ± 4.8% 9.8 ± 4.7% 11.1 ± 1.2% −4.6 ± 4.6% −21.5 ± 5.2% LOTOS-EUROS 2.0 ± 0.9% −0.6 ± 1.9% 3.6 ± 1.6% 4.4 ± 0.8% 2.4 ± 0.5% −5.0 ± 0.3% −6.8 ± 1.2% MAX-DOAS n/a
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MDPI and ACS Style
Koukouli, M.-E.; Pseftogkas, A.; Karagkiozidis, D.; Skoulidou, I.; Drosoglou, T.; Balis, D.; Bais, A.; Melas, D.; Hatzianastassiou, N. Air Quality in Two Northern Greek Cities Revealed by Their Tropospheric NO 2Levels. Atmosphere 2022, 13, 840.
https://doi.org/10.3390/atmos13050840
AMA Style
Koukouli M-E, Pseftogkas A, Karagkiozidis D, Skoulidou I, Drosoglou T, Balis D, Bais A, Melas D, Hatzianastassiou N. Air Quality in Two Northern Greek Cities Revealed by Their Tropospheric NO 2Levels. Atmosphere. 2022; 13(5):840.
https://doi.org/10.3390/atmos13050840
Chicago/Turabian Style
Koukouli, Maria-Elissavet, Andreas Pseftogkas, Dimitris Karagkiozidis, Ioanna Skoulidou, Theano Drosoglou, Dimitrios Balis, Alkiviadis Bais, Dimitrios Melas, and Nikos Hatzianastassiou. 2022. "Air Quality in Two Northern Greek Cities Revealed by Their Tropospheric NO 2Levels" Atmosphere13, no. 5: 840.
https://doi.org/10.3390/atmos13050840
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Tables of Working Life for Women, 1950 : Bulletin of the United States Bureau of Labor Statistics, No. 1204
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Tables of Working Life: The Increment-Decrement Model : Bulletin of the United States Bureau of Labor Statistics, No. 2135
Take On Payments
Taking Stock: Independent Views on TARP's Effectiveness : Hearing, Congressional Oversight Panel, One Hundred Eleventh Congress, First Session, November 19, 2009
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TARP and Executive Compensation Restrictions : Hearing Before the Congressional Oversight Panel, One Hundred Eleventh Congress, Second Session, October 21, 2010
TARP and Other Government Assistance for AIG : Hearing Before the Congressional Oversight Panel, One Hundred Eleventh Congress, Second Session, May 26, 2010
TARP Foreclosure Mitigation Programs : Hearing Before the Congressional Oversight Panel, One Hundred Eleventh Congress, Second Session, October 27, 2010
TARP Oversight: Evaluating Returns on Taxpayer Investments : Hearing Before the Committee on Banking, Housing, and Urban Affairs, United States Senate, One Hundred Twelfth Congress, First Session, March 17, 2011
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Techniques of the Federal Reserve Trading Desk in the 1960's Contrasted with the "Bills Preferably" Period : Staff Study
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Technological Change and Productivity in the Bituminous Coal Industry, 1920-60 : Bulletin of the United States Bureau of Labor Statistics, No. 1305
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Technological Changes and Employment in the United States Postal Service : Bulletin of the United States Bureau of Labor Statistics, No. 574
Technological Changes in Relation to Women's Employment : Women's Bureau Bulletin, No. 107
Technological Trends in Major American Industries : Bulletin of the United States Bureau of Labor Statistics, No. 1474
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Technology and Labor in Five Industries: Bakery Products, Concrete, Air Transportation, Telephone Communication, Insurance : Bulletin of the United States Bureau of Labor Statistics, No. 2033
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Tomorrow's Manpower Needs: National Manpower Projections and a Guide to Their Use as a Tool in Developing State and Area Manpower Projections : Bulletin of the United States Bureau of Labor Statistics, No. 1606
Tomorrow's Manpower Needs: Research Report on Manpower Projection Methods : Bulletin of the United States Bureau of Labor Statistics, No. 1769
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To Provide for Loans to Certain Officers of Federal Credit Unions and Federal Reserve Member Banks : Hearing Before the Committee on Banking and Currency, House of Representatives, Ninetieth Congress, First Session, on H.R. 7347, May 2, 1967
Total Weeks of Unemployment: A New Measure of Labor Market Distress : A Staff Study Prepared for the Use of the Subcommittee on Economic Goals and Intergovernmental Policy of the Joint Economic Committee, Congress of the United States
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Toward Better Working Conditions for Women: Methods and Policies of the National Women's Trade Union League of America : Women's Bureau Bulletin, No. 252
Trade Act of 1974
Trade Agreement in the Silk-Ribbon Industry of New York City : Bulletin of the United States Bureau of Labor Statistics, No. 341
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Trade-Union Policy and Technological Change, Report No. L-8
Training Mature Women for Employment: The Story of 23 Local Programs : Women's Bureau Bulletin, No. 256
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Training Opportunities for Women and Girls: Preemployment Courses, Initial Training Programs : Women's Bureau Bulletin, No. 274
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Trends in the Employment of Women, 1928-36 : Women's Bureau Bulletin, No. 159
Trends in the Use of Payment Instruments in the United States
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Troubled Asset Relief Program : Additional Actions Needed to Better Ensure Integrity, Accountability, and Transparency
Troubled Asset Relief Program : Automaker Pension Funding and Multiple Federal Roles Pose Challenges for the Future
Troubled Asset Relief Program : Bank Stress Test Offers Lessons as Regulators Take Further Actions to Strengthen Supervisory Oversight
Troubled Asset Relief Program : Continued Stewardship Needed as Treasury Develops Strategies for Monitoring and Divesting Financial Interests in Chrysler and GM
Troubled Asset Relief Program : Further Actions Needed to Fully and Equitably Implement Foreclosure Mitigation Programs
Troubled Asset Relief Program : Government's Exposure to AIG Lessens as Equity Investments Are Sold
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Troubled Asset Relief Program : March 2009 Status of Efforts to Address Transparency and Accountability Issues
Troubled Asset Relief Program : One Year Later, Actions Are Needed to Address Remaining Transparency and Accountability Challenges
Troubled Asset Relief Program : Opportunities Exist to Apply Lessons Learned from the Capital Purchase Program to Similarly Designed Programs and to Improve the Repayment Process
Troubled Asset Relief Program : Status of Efforts to Address Transparency and Accountability Issues
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Trust Indenture Act of 1939
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Twentieth Anniversary of the Employment Act of 1946: An Economic Symposium : Hearing Before the Joint Economic Committee, Congress of the United States, Eighty-Ninth Congress, Second Session, February 23, 1966
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Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Report
Themes
Assistive & Accessible Technology
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Vicki Austin,Dilisha Patel,Jamie Danemayer,Kate Mattick,Anna Landre,Marketa Smitova,Maryam Bandukda, Aoife Healy, Nachiappan Chockalingam,Diane Bell,Cathy Holloway
This report was prepared by Global Disability Innovation (GDI) Hub for the Disability Unit in the Cabinet Office His Majesty’s Government (HMG). The report presents findings from a Country Capacity Assessment (CCA) of AT access in England. Findings illustrate a complex state of AT in England. While delivery systems tend to provide quality products that have a strong, positive impact on people’s lives, processes are often slow and stressful for users and providers alike. Startlingly, there is also an AT access gap of 31% of disabled people not having the assistive products they need to flourish, thrive, or even participate in daily life.
The Cabinet Office; 2023
Abstract
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
The aim of this research was to undertake a Country Capacity Assessment (CCA) to inform a more integrated approach to Assistive Technology (AT) provision in England. The results aim to support policymakers in identifying actions to strengthen service delivery to better meet disabled people’s needs, improving outcomes for AT users and reducing inefficiencies in the current approach.
The research was undertaken from November 2022 to March 2023 and led by the Global Disability Innovation (GDI) Hub, which is the World Health Organization (WHO) Global Collaborating Centre on AT access, using WHO tools in the Assistive Technology Assessment (ATA) suite.
Cite
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Suggested Citation: Austin, V, Patel, D, Danemayer, J, Mattick, K, Landre, A, Smitova, M, Bandukda, M, Healy, A, Chockalingam, N, Bell D, and Holloway, C; Assistive Technology Changes Lives: an assessment of AT need and capacity in England; Cabinet Office, HMG; 2023
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Type
Journal Paper
Themes
Assistive & Accessible Technology
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Jamie Danemayer,Cathy Holloway,Youngjun Cho, Nadia Berthouze, Aneesha Singh, William Bhot, Ollie Dixon, Marko Grobelnik, John Shawe-Taylor
Paper highlights: Assistive technology (AT) information networks are insular among stakeholder groups, causing unequal access to information. Participants often cited fragmented international marketplaces as a barrier and valued info-sharing across industries. Current searches produce biased results in marketplaces influenced by commercial interests and high-income contexts. Smart features could facilitate searching, update centralised data sources, and disseminate information more inclusively.
International Journal of Human-Computer Studies; 2023
Abstract
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Ninety percent of the 1.2 billion people who need assistive technology (AT) do not have access. Information seeking practices directly impact the ability of AT producers, procurers, and providers (AT professionals) to match a user's needs with appropriate AT, yet the AT marketplace is interdisciplinary and fragmented, complicating information seeking. We explored common limitations experienced by AT professionals when searching information to develop solutions for a diversity of users with multi-faceted needs. Through Template Analysis of 22 expert interviews, we find current search engines do not yield the necessary information, or appropriately tailor search results, impacting individuals’ awareness of products and subsequently their availability and the overall effectiveness of AT provision. We present value-based design implications to improve functionality of future AT-information seeking platforms, through incorporating smarter systems to support decision-making and need-matching whilst ensuring ethical standards for disability fairness remain.
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Type
Journal Paper
Themes
Assistive & Accessible Technology
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Giulia Barbareschi, Wesley Teerlink, Josepg Gakunga Njuguna, Purity Musungu, Mary Dama Kirino, andCatherine Holloway
According to estimates from the World Health Organization, in 2010, there were more than 30 million people in need of prosthetic and orthotic devices across Africa, Asia, and Latin America. 1This number is likely to have grown significantly in the past decade, in line with trends recorded for the general need of assistive technology. 2For many people who undergo a lower limb amputation, access to an appropriate prosthesis is essential to restore functional mobility and ensure good quality of life. 3Ultimately, an appropriate lower-limb prosthesis (LLP) can enable people with amputation to fulfill their desired role in their family, work, and community life. 4
Prosthetic and Orthotics International; 2022
Abstract
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Background:
Many people with amputations who live in low-resourced settings struggle to access the workshops where qualified prosthetists provide appropriate care. Novel technologies such as the thermoplastic Confidence Socket are emerging, which could help facilitate easier access to prosthetic services.
Objectives:
The objective of this study was to evaluate the satisfaction and the performance of transtibial prosthesis featuring the Confidence Socket.
Study design:
This is a longitudinal repeated-measures design study.
Methods:
A convenience sample of 26 participants who underwent transtibial amputation were fitted with the Confidence Socket. The performance of the socket was evaluated after a follow-up period between 1 month and 6 months using the L test of functional mobility and the amputee mobility predictor. Satisfaction with the prosthesis was measured using the Trinity Amputation and Prosthetic Experience Scales and purposefully designed 7-point Likert scales.
Results:
Ten of the 26 participants returned for follow-up. Perceived activity restriction and L test times improved significantly at follow-up, but the self-reported satisfaction with the Confidence Socket was lower at follow-up compared with that after fitting.
Conclusions:
The Amparo Confidence Socket represents a potentially viable alternative to improve access to appropriate prosthesis in Kenya, but some aspects of users’ self-reported satisfaction should be further investigated.
Cite
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Barbareschi G, Teerlink W, Njuguna JG, Musungu P, Kirino MD, Holloway C. Evaluating the use of a thermoplastic socket in Kenya: A pilot study. Prosthet Orthot Int. 2022 Oct 1;46(5):532-537. doi: 10.1097/PXR.0000000000000130. Epub 2022 Mar 25. PMID: 35333813; PMCID: PMC9554758.
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Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Type
Journal Paper
Themes
Assistive & Accessible Technology
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Jamie Danemayer, Andrew Young, Siobhan Green, Lydia Ezenwa, Michael Klein
This study synthesizes learnings from three distinct datasets: innovator applications to the COVIDaction data challenges, surveys from organizers from similarly-aimed data challenges, and a focus group discussion with professionals who work with COVID-19 data. Thematic and topic analyses were used to analyze these datasets with the aim to identify gaps and barriers to effective data use in responding to the pandemic.
Data & Policy; 2023
Abstract
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Innovative, responsible data use is a critical need in the global response to the coronavirus disease-2019 (COVID-19) pandemic. Yet potentially impactful data are often unavailable to those who could utilize it, particularly in data-poor settings, posing a serious barrier to effective pandemic mitigation. Data challenges, a public call-to-action for innovative data use projects, can identify and address these specific barriers. To understand gaps and progress relevant to effective data use in this context, this study thematically analyses three sets of qualitative data focused on/based in low/middle-income countries: (a) a survey of innovators responding to a data challenge, (b) a survey of organizers of data challenges, and (c) a focus group discussion with professionals using COVID-19 data for evidence-based decision-making. Data quality and accessibility and human resources/institutional capacity were frequently reported limitations to effective data use among innovators. New fit-for-purpose tools and the expansion of partnerships were the most frequently noted areas of progress. Discussion participants identified building capacity for external/national actors to understand the needs of local communities can address a lack of partnerships while de-siloing information. A synthesis of themes demonstrated that gaps, progress, and needs commonly identified by these groups are relevant beyond COVID-19, highlighting the importance of a healthy data ecosystem to address emerging threats. This is supported by data holders prioritizing the availability and accessibility of their data without causing harm; funders and policymakers committed to integrating innovations with existing physical, data, and policy infrastructure; and innovators designing sustainable, multi-use solutions based on principles of good data governance.
Cite
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Danemayer, J., Young, A., Green, S., Ezenwa, L., & Klein, M. (2023). Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges. Data & Policy, 5, E11. doi:10.1017/dap.2023.6
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Type
Journal Paper
Themes
Assistive & Accessible Technology
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Emma M Smith, Maria Luisa Toro Hernandez, Ikenna D Ebuenyi, Elena V Syurina,Giulia Barbareschi, Krista L Best,Jamie Danemayer,Ben Oldfrey, Nuha Ibrahim,Catherine Holloway, Malcolm MacLachlan
The coronavirus disease 2019 (COVID-19) pandemic has impacted all segments of society, but it has posed particular challenges for the inclusion of persons with disabilities, those with chronic illness and older people regarding their participation in daily life. These groups often benefit from assistive technology (AT) and so it is important to understand how use of AT may be affected by or may help to mitigate the impacts of COVID-19.Objective:The objectives of this study were to explore the how AT use and provision have been affected during the initial stages of the COVID-19 pandemic, and how AT policies and systems may be made more resilient based on lessons learned during this global crisis.
International Journal of Health Policy and Management; 2020
Abstract
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Abstract
Background:The coronavirus disease 2019 (COVID-19) pandemic has impacted all segments of society, but it has posed particular challenges for the inclusion of persons with disabilities, those with chronic illness and older people regarding their participation in daily life. These groups often benefit from assistive technology (AT) and so it is important to understand how use of AT may be affected by or may help to mitigate the impacts of COVID-19.Objective:The objectives of this study were to explore the how AT use and provision have been affected during the initial stages of the COVID-19 pandemic, and how AT policies and systems may be made more resilient based on lessons learned during this global crisis.
Methods:This study was a rapid, international online qualitative survey in the 6 United Nations (UN) languages (English, French, Spanish, Russian, Arabic, Mandarin Chinese) facilitated by extant World Health Organization (WHO) and International Disability Alliance networks. Themes and subthemes of the qualitative responses were identified using Braun and Clarke's 6-phase analysis.
Results:Four primary themes were identified in in the data: Disruption of Services, Insufficient Emergency Preparedness, Limitations in Existing Technology, and Inadequate Policies and Systems. Subthemes were identified within each theme, including subthemes related to developing resilience in AT systems, based on learning from the pandemic.
Conclusion:COVID-19 has disrupted the delivery of AT services, primarily due to infection control measures resulting in lack of provider availability and diminished one-to-one services. This study identified a need for stronger user-centred development of funding policies and infrastructures that are more sustainable and resilient, best practices for remote service delivery, robust and accessible tools and systems, and increased capacity of clients, caregivers, and clinicians to respond to pandemic and other crisis situations.
Cite
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Smith EM, Toro Hernandez ML, Ebuenyi ID, Syurina EV, Barbareschi G, Best KL, Danemayer J, Oldfrey B, Ibrahim N, Holloway C, MacLachlan M. Assistive Technology Use and Provision During COVID-19: Results From a Rapid Global Survey. Int J Health Policy Manag. 2022 Jun 1;11(6):747-756. doi: 10.34172/ijhpm.2020.210. PMID: 33201656;
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Type
Journal Paper
Themes
Assistive & Accessible Technology
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Margaret Savage, Sarah Albala, Frederic Seghers, Rainer Katte, Cynthia Liao, Mathilde Chaudron, Novia Afdhila
Development outcomes are inextricably linked to the health of the marketplace that delivers products and services to people in low- and middle- income countries (LMIC). Shortcomings in the market for assistive technology (AT) contribute to low access in LMIC. Market shaping is aimed at improving a market’s specific outcomes, such as access to high quality, affordable AT, by targeting the root causes of these shortcomings. The paper summarizes the findings of a market and sector analysis that was conducted under the UK aid funded AT2030 programme and aims to discuss how market shaping can help more people gain access to the AT that they need and what are the best mechanisms to unlock markets and commercial opportunity in LMICs.
Assistive Technology The Official Journal of RESNA; 2021
Abstract
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Development outcomes are inextricably linked to the health of the marketplace that delivers products and services to people in low- and middle-income countries (LMIC). Shortcomings in the market for assistive technology (AT) contribute to low access in LMIC. Market shaping is aimed at improving a market’s specific outcomes, such as access to high quality, affordable AT, by targeting the root causes of these shortcomings. The paper summarizes the findings of market analyses conducted under the UK aid funded AT2030 programme in support of ATscale and aims to discuss how market shaping can help more people gain access to the AT that they need and what are the best mechanisms to unlock markets and commercial opportunity in LMICs. The paper also explores how market shaping for AT markets could be part of a mission-oriented approach AT policy. A mission-oriented approach can help accelerate progress toward a common objective among stakeholders, at country or global level. While market-shaping activities direct the outcomes of the market toward a specific end goal, such as access to quality, affordable products and services, missions are more comprehensive and include other policy interventions and stakeholder collaborations in order to create a robust and sustainable structure.
Cite
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Margaret Savage, Sarah Albala, Frederic Seghers, Rainer Kattel, Cynthia Liao, Mathilde Chaudron & Novia Afdhila (2021) Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries, Assistive Technology, 33:sup1, 124-135, DOI: 10.1080/10400435.2021.1991050
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Type
Journal Paper
Themes
Assistive & Accessible Technology
Assistive technology access in longitudinal datasets: a global review
Jamie Danemayer, Sophie Mitra,Cathy Holloway, Shereen Hussein
A person’s access to assistive products such as hearing aids, wheelchairs, and glasses, is an essential part of their ability to age in a healthy way. But, according to the World Health Organization, a staggering 90% of people who need assistive products worldwide, do not have access to them. In many instances access is limited or simply non-existent. This is often due to assistive products being too expensive, demand outweighing supply, not always being suitable to use in different environments, or even the lack of availability of trained providers. In such circumstances, people are more likely to age ‘unhealthily’ if they do not have access to assistive products that are designed to support their day to day functioning and independence.
International Journal of Population Data Science; 2023
Abstract
Assistive technology access in longitudinal datasets: a global review
Functional limitations become more prevalent as populations age, emphasising an increasingly urgent need for assistive technology (AT). Critical to meeting this need trajectory is understanding AT access in older ages. Yet few publications examine this from a longitudinal perspective.
This review aims to identify and collate what data exist globally, seeking all population-based cohorts and repeated cross-sectional surveys through the Maelstrom Research Catalogue (searched May 10, 2022) and the Disability Data Report (published 2022), respectively. Datasets incorporating functional limitations modules and question(s) dedicated to AT, with a wave of data collection since 2009, were included.
Of 81 cohorts and 202 surveys identified, 47 and 62 meet inclusion criteria, respectively. Over 40% of cohorts were drawn from high-income countries which have already experienced significant population ageing. Cohorts often exclude participants based on pre-existing support needs. For surveys, Africa is the most represented region (40%). Globally, 73% of waves were conducted since 2016. 'Use' is the most collected AT access indicator (69% of cohorts and 85% of surveys). Glasses (78%) and hearing aids (77%) are the most represented AT. While gaps in data coverage and representation are significant, collating existing datasets highlights current opportunities for analyses and methods for improving data collection across the sector.
Assistive technology access in longitudinal datasets: a global review
Danemayer, J., Mitra, S., Holloway, C. and Hussein, S. (2023) “Assistive technology access in longitudinal datasets: a global review”, International Journal of Population Data Science, 8(1). doi: 10.23889/ijpds.v8i1.1901.
Assistive technology access in longitudinal datasets: a global review
Type
Journal Paper
Themes
Assistive & Accessible Technology
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Jamie Danemayer, Dorothy Boggs, Vinicius Delgado Ramos, Emma M. Smith, Ariana Kular, William Bhot, Felipe Ramos Barajas, Sarah Polack,Catherine Holloway
Assistive technology (AT) includes assistive products (APs) and related services that can improve health and well-being, enable increased independence and foster participation for people with functional difficulties, including older adults and people with impairments or chronic health conditions. 1This paper uses the umbrella term ‘functional difficulty’ (FD) to refer to all of these groups. This systematic review was undertaken to identify studies presenting population-based estimates of need and coverage for five APs (hearing aids, limb prostheses, wheelchairs, glasses and personal digital assistants) grouped by four functional domains (hearing, mobility, vision and cognition).
BMJ Global Health; 2021
Abstract
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Introduction:To improve access to assistive products (APs) globally, data must be available to inform evidence based decision-making, policy development and evaluation, and market-shaping interventions.
Methods:This systematic review was undertaken to identify studies presenting population-based estimates of need and coverage for five APs (hearing aids, limb prostheses, wheelchairs, glasses and personal digital assistants) grouped by four functional domains (hearing, mobility, vision and cognition).
Results:Data including 656 AP access indicators were extracted from 207 studies, most of which (n=199, 96%) were cross-sectional, either collecting primary (n=167) or using secondary (n=32) data. There was considerable heterogeneity in assessment approaches used and how AP indicators were reported; over half (n=110) used a combination of clinical and self-reported assessment data. Of 35 studies reporting AP use out of all people with functional difficulty in the corresponding functional domains, the proportions ranged from 4.5% to 47.0% for hearing aids, from 0.9% to 17.6% for mobility devices, and from 0.1% to 86.6% for near and distance glasses. Studies reporting AP need indicators demonstrated >60% unmet need for each of the five APs in most settings.
Conclusion:Variation in definitions of indicators of AP access have likely led to overestimates/underestimates of need and coverage, particularly, where the relationship between functioning difficulty and the need for an AP is complex. This review demonstrates high unmet need for APs globally, due in part to disparate data across this sector, and emphasises the need to standardise AP data collection and reporting strategies to provide a comparable evidence base to improve access to APs.
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Danemayer J, Boggs D, Delgado Ramos V, et al. Estimating need and coverage for five priority assistive products: a systematic review of global population-based research. BMJ Global Health 2022;7:e007662. doi:10.1136/bmjgh-2021-007662
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Type
Workshop
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Sahan Bulathwela, María Pérez-Ortiz,Catherine Holloway, John Shawe-Taylor
This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies.
Workshop on Machine Learning for the Developing World (ML4D) at the Conference on Neural Information Processing Systems 2021; 2021
Abstract
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Artificial Intelligence (AI) in Education has been said to have the potential for building more personalised curricula, as well as democratising education worldwide and creating a Renaissance of new ways of teaching and learning. Millions of students are already starting to benefit from the use of these technologies, but millions more around the world are not. If this trend continues, the first delivery of AI in Education could be greater educational inequality, along with a global misallocation of educational resources motivated by the current technological determinism narrative. In this paper, we focus on speculating and posing questions around the future of AI in Education, with the aim of starting the pressing conversation that would set the right foundations for the new generation of education that is permeated by technology. This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies. Finally, we ask what would it take for this educational revolution to provide egalitarian and empowering access to education, beyond any political, cultural, language, geographical and learning ability barriers.
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Type
Workshop
Themes
Assistive & Accessible Technology
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Tabish Ahmed, Sahan Bulathwela
The informational needs of people are highly contextual and can depend on many different factors such as their current knowledge state, interests and goals [1, 2, 3]. However, an effective information retrieval companion should minimise the human effort required in i) expressing a human information need and ii) navigating a lengthy result set. Using topical representations of the user history (e.g. [4]) can immensely help formulating zero shot queries and refining short user queries that enable proactive information retrieval (IR). While the world has digital textual information in abundance, it can often be noisy (e.g. extracted through Automatic Speech Recognition (ASR), PDF text extraction etc.), leading to state-of-the-art neural models being highly sensitive to the noise producing sub-optimal results [5]. This demands denoising steps to refine both query and document representation. In this paper, we argue that Wikipedia, an openly available encyclopedia, can be a humanly intuitive knowledge base [6] that has the potential to provide the world view many noisy information Retrieval systems need.
Published at the First Workshop on Proactive and Agent-Supported Information Retrieval at CIKM 2022; 2022
Abstract
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Extracting useful information from the user history to clearly understand informational needs is a crucial feature of a proactive information retrieval system. Regarding understanding information and relevance, Wikipedia can provide the background knowledge that an intelligent system needs. This work explores how exploiting the context of a query using Wikipedia concepts can improve proactive information retrieval on noisy text. We formulate two models that use entity linking to associate Wikipedia topics with the relevance model. Our experiments around a podcast segment retrieval task demonstrate that there is a clear signal of relevance in Wikipedia concepts while a ranking model can improve precision by incorporating them. We also find Wikifying the background context of a query can help disambiguate the meaning of the query, further helping proactive information retrieval.
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Type
Journal Paper
Themes
Assistive & Accessible Technology
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
Kate Mattick,Ben Oldfrey, Maggie Donovan-Hall, Grace Magomere, Joseph Gakunga,Catherine Holloway
An estimated 1.5 million people undergo limb amputation each year [1]. Low- and middle-income countries (LMICs) are projected to have a rapid increase in people living with an amputation in the coming years due to prevalence of non-communicable dis-ease, trauma and conflict [1–3]. This paper explores the personal and system factors that motivate and enhance outcomes for patients accessing a prosthetic service and using a lower-limb prosthesis within a low resource setting.
Disability and Rehabilitation; 2022
Abstract
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
PurposeTo explore the personal and system factors that motivate and enhance outcomes for patients accessing a prosthetic service and using a lower-limb prosthesis within a low resource setting.
Materials and methodsThis study employed a qualitative approach to explore the motivations and satisfaction of individuals with lower limb loss engaging with a prosthetic service in Mombasa, Kenya. In-depth interviews were conducted over Microsoft Teams with 10 lower limb prosthesis users and thematic analysis was applied.
ResultsFive key themes emerged: acceptance, self-determination, hope, clinician relationship and perception. These findings demonstrate the importance of hopeful thinking and a supportive community in overcoming physical and stigmatising challenges. The findings further highlight the value of the service provider relationship beyond just prescribing an assistive device.
ConclusionThese results have relevance in developing patient-centred services, assistive devices and personnel training that are responsive, motivating, and cognisant of the service user. This is of particular interest as assistive technology services are newly developed in low resource settings.
Cite
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
Kate Mattick, Ben Oldfrey, Maggie Donovan-Hall, Grace Magomere, Joseph Gakunga & Catherine Holloway (2022) Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes, Disability and Rehabilitation, DOI:10.1080/09638288.2022.2152875
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
Type
Journal Paper
Themes
Culture and Participation
Research Group
Social Justice
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
Victoria Austin,Catherine Holloway, Ignacia Ossul Vermehren, Abs Dumbuya,Giulia Barbareschiand Julian Walker
The World Health Organisation (WHO) estimates that there are currently one billion people in the world who need access to assistive technology (AT). Yet over 90% currently do not have access to assistive products (AP)—such as wheelchairs, hearing aids, walking sticks and eyeglasses—they need, nor and the systems and services necessary to support their appropriate provision [1]. This shocking deficit is set to double by 2050, with about two billion of us likely to require AT but no anticipated reduction in lack of access. The World Health Organisation defines AT as the “the umbrella term covering the systems and services related to the delivery of assistive products and services”, which are products that “maintain or improve an individual’s functioning and independence, thereby promoting their well-being” [2], and the importance of AT provision is strongly highlighted in the Convention on the Rights of Persons with Disabilities (CRPD) [3]. AT has also been shown to be essential to achieving many of the United Nation’s Sustainable Development Goals (SDG) [4]. Without access to AT, many persons with disabilities are unable to go to school, be active in their communities, earn an income, or play a full role in their families [5]. As a recent study found, “AT can make the impossible possible for people living with a wide range of impairments, but a lack of access to basic AT …excludes individuals and reduces their ability to live full, enjoyable, and independent lives” [6].
International Journal of Environmental Research and Public Health; 2021
Abstract
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
The importance of assistive technology (AT) is gaining recognition, with the World Health Organisation (WHO) set to publish a Global Report in 2022. Yet little is understood about access for the poorest, or the potential of AT to enable this group to participate in the activities of citizenship; both formal and informal. The aim of this qualitative study was to explore AT as mediator of participation in citizenship for persons with disabilities who live in two informal settlements in Freetown, Sierra Leone (SL). The paper presents evidence from 16 participant and 5 stakeholder interviews; 5 focus groups and 4 events; combining this with the findings of a house-to-house AT survey; and two national studies—a country capacity assessment and an informal markets deep-dive. Despite citizenship activities being valued, a lack of AT was consistently reported and hindered participation. Stigma was also found to be a major barrier. AT access for the poorest must be addressed if citizenship participation for persons with disabilities is a genuine global intention and disability justice is to become a reality.
Cite
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
Austin, V.; Holloway, C.; Ossul Vermehren, I.; Dumbuya, A.; Barbareschi, G.; Walker, J. “Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone. Int. J. Environ. Res. Public Health2021, 18, 5547.https://doi.org/10.3390/ijerph...
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
Additive manufacturing techniques for smart prosthetic liners
B Oldfrey, A Tchorzewska, R Jackson, M Croysdale, R Loureiro,C Holloway, M Miodownik
Elastomeric liners are commonly worn between socket and limb by prosthetic wearers. This is due to their superior skin adhesion, load distribution and their ability to form a seal. Laboratory tests suggest that elastomeric liners allow reduced shear stress on the skin and give a higher cushioning effect on bony prominences, since they are soft in compression, and similar to biological tissues [1]. However, they also increase perspiration reducing hygiene and increasing skin irritations. Prosthetic users in general face a myriad of dermatological problems associated with lower limb prosthesis such as ulcers, cysts, and contact dermatitis, which are exacerbated by the closed environment of a fitted socket where perspiration is trapped and bacteria can proliferate [2].
Medical Engineering & Physics; 2021
Abstract
Additive manufacturing techniques for smart prosthetic liners
Elastomeric liners are commonly worn between the prosthetic socket and the limb. A number of improvements to the state of the art of liner technology are required to address outstanding problems. A liner that conforms to the residuum more accurately, may improve the skin health at the stump-socket interface. Previous work has shown that for effective thermal management of the socket environment, an active heat removal system is required, yet this is not available. Volume tracking of the stump could be used as a diagnostic tool for looking at the changes that occur across the day for all users, which depend on activity level, position, and the interaction forces of the prosthetic socket with the limb. We believe that it would be advantageous to embed these devices into a smart liner, which could be replaced and repaired more easily than the highly costly and labour-intensive custom-made socket. This paper presents the work to develop these capabilities in soft material technology, with: the development of a printable nanocomposite stretch sensor system; a low-cost digital method for casting bespoke prosthetic liners; a liner with an embedded stretch sensor for growth / volume tracking; a model liner with an embedded active cooling system.
Cite
Additive manufacturing techniques for smart prosthetic liners
, Additive manufacturing techniques for smart prosthetic liners, Medical Engineering & Physics, Volume 87, 2021, Pages 45-55, ISSN 1350-4533,https://doi.org/10.1016/j.mede....
Additive manufacturing techniques for smart prosthetic liners
Type
Journal Paper
Themes
Assistive & Accessible Technology
Culture and Participation
Research Group
Disability Interactions
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Giulia Barbareschi, Mark T. Carew, Elizabeth Aderonke Johnson, Norah Kopi,Catherine Holloway
Stigmatizing attitudes and beliefs towards disability represent one of the most pervasive and complex barriers that limits access to health care, education, employment, civic rights and opportunities for socialization for people with disabilities [1,2,3]. The damaging impact of disability stigma is widely acknowledged and, according to article 8 of the UN Convention on the Rights of Persons with disabilities, developing strategies, campaigns, policies and other initiatives to combat disability stigma and ensure that all people with disabilities are treated with dignity and respect is also a duty of the 182 countries who ratified the treaty [4]. Although the majority of literature focused on understanding disability stigma has been carried out in high-income settings [5,6,7], in the last decade, an increasing number of scholars have conducted studies looking at the negative stereotypes, prejudices and inaccurate beliefs that shape disability stigma in the Global South [3,8,9,10]. Most of these studies have described how these stigmatizing beliefs are often driven by a combination of personal and societal factors, ranging from misconceptions concerning the causes of different impairments (e.g., disability to be seen as a form of curse or punishment); assumptions about the lack of capabilities of people with disabilities; or discriminatory practices that actively endorse separation between people with and without disabilities [3,9,11,12]. Yet, there is a dearth of comparative studies that examine the perspectives of both people with and without disabilities of disability stigma and discrimination, including how the use of assistive technology may shape stigmatizing interactions.
International Journal of Environmental Research and Public Health; 2021
Abstract
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Disability stigma in many low- and middle-income countries represents one of the most pervasive barriers preventing people with disabilities from accessing equal rights and opportunities, including the uptake of available assistive technology (AT). Previous studies have rarely examined how disability stigma may be shaped through factors endemic to social interactions, including how the use of assistive technology itself may precipitate or alleviate disability stigma. Through two strands of work, we address this gap. Via a series of focus groups with Kenyans without disabilities (Study 1) and secondary data analysis of consultations with Kenyans with disabilities and their allies (Study 2), we identify shared and divergent understandings of what shapes disability stigma and discrimination. Specifically, Kenyans with and without disabilities were cognizant of how religious/spiritual interpretations of disability, conceptions of impairments as “different” from the norm, and social stereotypes about (dis)ability shaped the experience of stigma and discrimination. Moreover, both groups highlighted assistive technology as an influential factor that served to identify or “mark” someone as having a disability. However, whereas participants without disabilities saw assistive technology purely as an enabler to overcome stigma, participants with disabilities also noted that, in some cases, use of assistive technologies would attract stigma from others.
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“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Barbareschi G, Carew MT, Johnson EA, Kopi N, Holloway C. “When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya. International Journal of Environmental Research and Public Health. 2021; 18(8):4272.https://doi.org/10.3390/ijerph...
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Type
Journal Paper
Themes
Inclusive Design
Culture and Participation
Research Group
Disability Interactions
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Giulia Barbareschi,Ben Oldfrey, Long Xin, Grace N. Magomere, Wyclife A. Wetende, Carol Wanjira, Joyce Olenja,Victoria Austin, andCatherine Holloway
The World Health Organisation estimate that there are approximately a billion people with disabilities who require access to appropriate assistive technology and this number is set to double by 2050 [82]. Assistive technologies (ATs) play a crucial role in the lives of people with disabilities and are necessary to be able to access essential services and participate in family and community life according to one’s aspirations [40, 62, 68, 81]. Although this is not often specifcally mentioned, the large majority of people with disabilities will routinely use more than one assistive device in their everyday lives [25, 26]. For example a person with a visual impairment is likely to use a white cane to navigate from their house to the office where they work and have a screen-reader, or an equivalent accessibility software, on their computer to be able to do their work once in the office [17].
ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020
Abstract
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Living in informality is challenging. It is even harder when you have a mobility impairment. Traditional assistive products such as wheelchairs are essential to enable people to travel. Wheelchairs are considered a Human Right. However, they are difficult to access. On the other hand, mobile phones are becoming ubiquitous and are increasingly seen as an assistive technology. Should therefore a mobile phone be considered a Human Right? To help understand the role of the mobile phone in contrast of a more traditional assistive technology – the wheelchair, we conducted contextual interviews with eight mobility impaired people who live in Kibera, a large informal settlement in Nairobi. Our findings show mobile phones act as an accessibility bridge when physical accessibility becomes too challenging. We explore our findings from two perspective – human infrastructure and interdependence, contributing an understanding of the role supported interactions play in enabling both the wheelchair and the mobile phone to be used. This further demonstrates the critical nature of designing for context and understanding the social fabric that characterizes informal settlements. It is this social fabric which enables the technology to be useable.
Cite
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Giulia Barbareschi, Ben Oldfrey, Long Xin, Grace Nyachomba Magomere, Wycliffe Ambeyi Wetende, Carol Wanjira, Joyce Olenja, Victoria Austin, and Catherine Holloway. 2020. Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal settlement. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 50, 1–13.https://doi.org/10.1145/337362...
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Type
Book
Research Group
Disability Interactions
Disability Interactions Creating Inclusive Innovations
Catherine Holloway,Giulia Barbareschi
; 2021
Abstract
Disability Interactions Creating Inclusive Innovations
Disability interactions (DIX) is a new approach to combining cross-disciplinary methods and theories from Human Computer Interaction (HCI), disability studies, assistive technology, and social development to co-create new technologies, experiences, and ways of working with disabled people. DIX focuses on the interactions people have with their technologies and the interactions which result because of technology use. A central theme of the approach is to tackle complex issues where disability problems are part of a system that does not have a simple solution. Therefore, DIX pushes researchers and practitioners to take a challenge-based approach, which enables both applied and basic research to happen alongside one another. DIX complements other frameworks and approaches that have been developed within HCI research and beyond. Traditional accessibility approaches are likely to focus on specific aspects of technology design and use without considering how features of large-scale assistive technology systems might influence the experiences of people with disabilities. DIX aims to embrace complexity from the start, to better translate the work of accessibility and assistive technology research into the real world. DIX also has a stronger focus on user-centered and participatory approaches across the whole value chain of technology, ensuring we design with the full system of technology in mind (from conceptualization and development to large-scale distribution and access). DIX also helps to acknowledge that solutions and approaches are often non-binary and that technologies and interactions that deliver value to disabled people in one situation can become a hindrance in a different context. Therefore, it offers a more nuanced guide to designing within the disability space, which expands the more traditional problem-solving approaches to designing for accessibility. This book explores why such a novel approach is needed and gives case studies of applications highlighting how different areas of focus—from education to health to work to global development—can benefit from applying a DIX perspective. We conclude with some lessons learned and a look ahead to the next 60 years of DIX.
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Disability Interactions Creating Inclusive Innovations
Type
Journal Paper
Themes
Assistive & Accessible Technology
Climate & Crisis Resilience
Research Group
Disability Interactions
Measuring assistive technology supply and demand: A scoping review
Jamie Danemayer,Dorothy Boggs, Emma M. Smith, Vinicius Delgado Ramos, Linamara Rizzo Battistella,Cathy Holloway,and Sarah Polack
An assistive product (AP) is defined as a product used exter-nally to the human body, whose primary purpose is to main-tain or improve an individual’s functioning and independence and thereby promote his or her well-being (WHO, 2016). Global population aging forecasts a rise in the need for solu-tions that support participation and independence, including APs. In this paper, we review current population-level AP supply and demand estimation methods for five priority APs and provide recommendations for improving national and global AP market evaluation.
Assistive Technology The Official Journal of RESNA; 2021
Abstract
Measuring assistive technology supply and demand: A scoping review
The supply of and market demand for assistive products (APs) are complex and influenced by diverse stakeholders. The methods used to collect AP population-level market data are similarly varied. In this paper, we review current population-level AP supply and demand estimation methods for five priority APs and provide recommendations for improving national and global AP market evaluation. Abstracts resulting from a systematic search were double-screened. Extracted data include WHO world region, publication year, age-groups, AP domain(s), study method, and individual assessment approach.497 records were identified. Vision-related APs comprised 65% (n = 321 studies) of the body of literature; hearing (n = 59), mobility (n = 24), cognitive (n = 2), and studies measuring multiple domains (n = 92) were proportionately underrepresented. To assess individual AP need, 4 unique approaches were identified among 392 abstracts; 45% (n = 177) used self-report and 84% (n = 334) used clinical evaluation. Study methods were categorized among 431 abstracts; Cross-sectional studies (n = 312, 72%) and secondary analyses of cross-sectional data (n = 61, 14%) were most common. Case studies illustrating all methods are provided. Employing approaches and methods in the contexts where they are most well-suited to generate standardized AP indicators will be critical to further develop comparable population-level research informing supply and demand, ultimately expanding sustainable access to APs.
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Measuring assistive technology supply and demand: A scoping review
Jamie Danemayer, Dorothy Boggs, Emma M. Smith, Vinicius Delgado Ramos, Linamara Rizzo Battistella, Cathy Holloway & Sarah Polack (2021) Measuring assistive technology supply and demand: A scoping review, Assistive Technology, 33:sup1, S35-S49, DOI: 10.1080/10400435.2021.1957039
Measuring assistive technology supply and demand: A scoping review
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Humanitarian & Disasters
Meeting AT needs in humanitarian crises: The current state of provision
Golnaz Whittaker, Gavin Adam Wood, Giulia Oggero,Maria Kett, Kirstin Lange
This paper discusses the evidence available in the literature for the scale and quality of AT provision interventions in crises, and what is known about the challenges and facilitators of provision. We conducted a search of the academic literature and retained literature that reported on any form of AT provision following crisis, where international humanitarian response was in place, published in English between January 2010 and June 2020.
Assistive Technology The Official Journal of RESNA; 2021
Abstract
Meeting AT needs in humanitarian crises: The current state of provision
Humanitarian coordination systems increasingly recognize and aim to respond to the needs of people with disabilities within populations affected by crises, spurred on by the UN Convention on the Rights of Persons with Disabilities (CRPD) which was adopted in 2006. Many agencies state their aim to meet the requirements of the CRPD using a “twin track” approach: ensuring the inclusion of people with disabilities in mainstream provision, alongside targeted support for their needs, which may include the need for Assistive Technology (AT). However, there is very little evidence of AT provision in humanitarian settings, which is a specific and urgent need for many people including the elderly and people with disabilities, and an implicit requirement of Article 11 of the CRPD and World Health Assembly resolution on improving access to assistive technology. There is also little evidence of effective mechanisms for AT provision in humanitarian settings. This is despite high and growing levels of unmet AT need in crises, and despite the legally binding requirement in the CRPD to provide AT for those who need it. AT provision faces unique challenges in humanitarian settings. This paper discusses the evidence available in the literature for the scale and quality of AT provision interventions in crises, and what is known about the challenges and facilitators of provision. We conducted a search of the academic literature and retained literature that reported on any form of AT provision following crisis, where international humanitarian response was in place, published in English between January 2010 and June 2020. We found very few examples in that academic literature of systematic and coordinated AT provision at the acute stage of crisis, and even less in the preparedness and post-acute stages. However, it is difficult to assess whether this is the result of insufficient academic attention or reflects a lack of provision. The small body of academic literature that describes AT provision in humanitarian settings paints a picture of small-scale provision, specialized to single types of impairments, and delivered by predominantly by NGOs. We also conducted a search of the gray literature, using the same inclusion criteria, in two countries: Afghanistan and South Sudan (case studies forthcoming). This gray literature provided supplementary evidence of the types of AT providers and AT provision available in those protracted crises. There are very few examples of how AT services can be scaled up (from a very low baseline) and maintained sustainably within a strengthened health system. The literature also describes more examples of provision of assistive products for mobility over assistive products for other impairments. If the paucity of literature on AT provision in humanitarian settings is a reflection of the scale of provision, this implies a deficiency in humanitarian response when it comes to providing people with AT needs with the essential products and services to which they have a right, and which will enable their access to basic, life-saving assistance. We conclude by providing recommendations for urgent actions that the AT and humanitarian community must take to fill this critical gap in the provision of essential products and services for a potentially marginalized and excluded group.
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Meeting AT needs in humanitarian crises: The current state of provision
Golnaz Whittaker, Gavin Adam Wood, Giulia Oggero, Maria Kett & Kirstin Lange (2021) Meeting AT needs in humanitarian crises: The current state of provision, Assistive Technology, 33:sup1, S3-S16, DOI: 10.1080/10400435.2021.1934612
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Meeting AT needs in humanitarian crises: The current state of provision
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
Ben Oldfrey,Giulia Barbareschi, Priya Morjaria, Tamara Giltsoff, Jessica Massie, Mark Miodownik andCatherine Holloway
From multiple studies conducted through the FCDO AT2030 Programme, as well as key literature, we examine whether Assistive Technology (AT) provision models could look towards more sustainable approaches, and by doing this benefit not only the environment, but also address the problems that the current provision systems have.
Sustainability
Abstract
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
From multiple studies conducted through the FCDO AT2030 Programme, as well as key literature, we examine whether Assistive Technology (AT) provision models could look towards more sustainable approaches, and by doing this benefit not only the environment, but also address the problems that the current provision systems have. We show the intrinsic links between disability inclusion and the climate crisis, and the particular vulnerability people with disabilities face in its wake. In particular, we discuss how localised circular models of production could be beneficial, facilitating context driven solutions and much needed service elements such as repair and maintenance. Key discussion areas include systems approaches, digital fabrication, repair and reuse, and material recovery. Finally, we look at what needs be done in order to enable these approaches to be implemented. In conclusion, we find that there are distinct parallels between what AT provision models require to improve equitable reliable access, and strategies that could reduce environmental impact and bring economic benefit to local communities. This could allow future AT ecosystems to be key demonstrators of circular models, however further exploration of these ideas is required to make sense of the correct next steps. What is key in all respects, moving forward, is aligning AT provision with sustainability interventions.
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Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
Oldfrey, B.; Barbareschi, G.; Morjaria, P.; Giltsoff, T.; Massie, J.; Miodownik, M.; Holloway, C. Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World? Sustainability2021, 13, 10867.https://doi.org/10.3390/su1319...
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
Catherine Holloway, Dafne Zuleima Morgado Ramirez,Tigmanshu Bhatnagar,Ben Oldfrey, Priya Morjaria, Soikat Ghosh Moulic, Ikenna D. Ebuenyi,Giulia Barbareschi,Fiona Meeks, Jessica Massie, Felipe Ramos-Barajas, Joanne McVeigh, Kyle Keane, George Torrens, P. V.M. Rao, Malcolm MacLachlan,Victoria Austin, Rainer Kattel, Cheryl D Metcalf & Srinivasan Sujatha
It is essential to understand the strategies and processes which are deployed currently across the Assistive Technology (AT) space toward measuring innovation. The main aim of this paper is to identify functional innovation strategies and processes which are being or can be deployed in the AT space to increase access to AT globally.
Assistive Technology The Official Journal of RESNA
Abstract
A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
It is essential to understand the strategies and processes which are deployed currently across the Assistive Technology (AT) space toward measuring innovation. The main aim of this paper is to identify functional innovation strategies and processes which are being or can be deployed in the AT space to increase access to AT globally. We conducted a scoping review of innovation strategies and processes in peer-reviewed literature databases and complemented this by identifying case studies demonstrating innovation strategies. The review includes WHO world region, publication year, AT type and a sector analysis against the Systems-Market for Assistive and Related Technologies Framework. We analyzed the case studies and interviews using thematic analysis. We included 91 papers out of 3,127 after review along with 72 case studies. Our results showed that product innovations were more prevalent than provision or supply innovations across papers and case studies. Case studies yielded two themes: open innovation (OI); radical and disruptive innovation. Financial instruments which encourage OI are needed and we recommend pursuing OI for AT innovation. Embedding AT within larger societal missions will be key to success governments and investors need to understand what AT is and their translational socioeconomic value.
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A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
Catherine Holloway, Dafne Zuleima Morgado Ramirez, Tigmanshu Bhatnagar, Ben Oldfrey, Priya Morjaria, Soikat Ghosh Moulic, Ikenna D. Ebuenyi, Giulia Barbareschi, Fiona Meeks, Jessica Massie, Felipe Ramos-Barajas, Joanne McVeigh, Kyle Keane, George Torrens, P. V.M. Rao, Malcolm MacLachlan, Victoria Austin, Rainer Kattel, Cheryl D Metcalf & Srinivasan Sujatha (2021) A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems, Assistive Technology, 33:sup1, 68-86, DOI:10.1080/10400435.2021.1970653
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A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
Type
Journal Paper
Themes
Inclusive Design
Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
Mikaela Patrick,Iain McKinnon
Public spaces, including recreational and social spaces, are often not prioritised. Inclusive public spaces are fundamental to participation and inclusive in society. Including persons with disabilities in the design and planning of the built environment supports equal rights and helps identify people’s aspirations for inclusive environments. Four city case studies will be discussed in this paper: Ulaanbaatar, Mongolia; Varanasi, India; Surakarta, Indonesia; and Nairobi, Kenya.
The Journal of Public Space
Abstract
Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
This paper presents some of the findings from a global research study on inclusive infrastructure and city design and will focus on inclusive public spaces. Persons with disabilities can experience multi-dimensional exclusion from urban life, including but not limited to physical, attitudinal and social barriers. Public spaces, including recreational and social spaces, are often not prioritised. Inclusive public spaces are fundamental to participation and inclusive in society. Including persons with disabilities in the design and planning of the built environment supports equal rights and helps identify people’s aspirations for inclusive environments.Four city case studies will be discussed in this paper: Ulaanbaatar, Mongolia; Varanasi, India; Surakarta, Indonesia; and Nairobi, Kenya. Research participants and objectives are organised by three stakeholder groups:
People- first-hand experiences of persons with disabilities living in the city and their aspirations for a more inclusive city
Policy- the awareness and understanding of inclusive design among policy-makers
Practice- the awareness and understanding of inclusive design among practitioners including barriers to implementation, opportunities and the relationship with assistive technology
Methods include document reviews, interviews, photo diaries and co-design workshops with participatory and inclusive engagement of persons with disabilities throughout. Findings on public spaces are discussed in three ways:
The types of public spaces valued by participants in each of the four cities.
The barriers and challenges experienced by persons with disabilities in the public realm.
Aspirations for more inclusive public spaces and opportunities for inclusive design
The paper concludes by discussing how the targeted stakeholder groups of people, policy and practice also help represent three essential dimensions of inclusive city design and forming a framework for successful implementation and delivery and supporting targets set out through the UNCRPD and Sustainable Development Goals (SDGs).
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Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
Patrick, M. and McKinnon, I. (2022) “Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities”, The Journal of Public Space, 7(2), pp. 93–116. doi: 10.32891/jps.v7i2.1500.
Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
Type
Journal Paper
Themes
Culture and Participation
Research Group
Social Justice
Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
Jessica Noske-Turner, Emma Pullen, Mufunanji Magalasi, Damian Haslett, Jo Tacchi
Communication & Sport
Abstract
Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
The purpose of this commentary is to discuss how Paralympic coverage in sub-Saharan Africa can be effectively mobilised to stimulate discursive and structural change around disability. Paralympic coverage has demonstrated its pedagogical power to engage public(s) and challenge stigma toward disability. Yet, the Global picture of Paralympic broadcasting is deeply uneven, with audiences in parts of the Global South afforded limited opportunities to watch the Games. Considering this, the International Paralympic Committee has begun to broadcast Paralympic coverage across sub-Saharan Africa with an explicit aim to challenge stigma toward disability. In this article, we draw on examples from research to argue that ideas from the field of Communication for Social Change (CfSC) can add value towards this aim. We begin by providing a brief overview of CfSC before critically examining one of the field’s key concepts – Communicative (E)ecologies. Following this, we critically reflect on the potential of Paralympic broadcasting as a vehicle for social change and disability rights agendas in sub-Saharan Africa. We argue that thinking with CfSC concepts show the importance of a ‘decentred’ media approach that engages with disability community advocacy groups, localised communication activities and practices, and culturally specific disability narratives.
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Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
Noske-Turner, J., Pullen, E., Magalasi, M., Haslett, D., & Tacchi, J. (2022). Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change. Communication & Sport, 10(5), 1001–1015.https://doi.org/10.1177/216747...
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Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Troy Bodkin
Doctoral Thesis. This work is one of four multidisciplinary research studies conducted by members of this research cluster, focusing on the area of Computer Aided Design (CAD) for improving the interface with Additive Manufacture (AM) to solve some of the challenges presented with improving prosthetic socket design, with an aim to improve and streamline the process to enable the involvement of clinicians and patients in the design process.
Loughborough University
Abstract
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
For many years, the biggest issue that causes discomfort and hygiene issues for patients with lower limb amputations have been the interface between body and prosthetic, the socket. Often made of an inflexible, solid polymer that does not allow the residual limb to breathe or perspire and with no consideration for the changes in size and shape of the human body caused by changes in temperature or environment, inflammation, irritation and discomfort often cause reduced usage or outright rejection of the prosthetic by the patient in their day to day lives. To address these issues and move towards a future of improved quality of life for patients who suffer amputations, Loughborough University formed the Next Generation Prosthetics research cluster. This work is one of four multidisciplinary research studies conducted by members of this research cluster, focusing on the area of Computer Aided Design (CAD) for improving the interface with Additive Manufacture (AM) to solve some of the challenges presented with improving prosthetic socket design, with an aim to improve and streamline the process to enable the involvement of clinicians and patients in the design process. The research presented in this thesis is based on three primary studies. The first study involved the conception of a CAD criteria, deciding what features are needed to represent the various properties the future socket outlined by the research cluster needs. These criteria were then used for testing three CAD systems, one each from the Parametric, Non Uniform Rational Basis Spline (NURBS) and Polygon archetypes respectively. The result of these tests led to the creation of a hybrid control workflow, used as the basis for finding improvements. The second study explored emerging CAD solutions, various new systems or plug-ins that had opportunities to improve the control model. These solutions were tested individually in areas where they could improve the workflow, and the successful solutions were added to the hybrid workflow to improve and reduce the workflow further. The final study involved taking the knowledge gained from the literature and the first two studies in order to theorise how an ideal CAD system for producing future prosthetic sockets would work, with considerations for user interface issues as well as background CAD applications. The third study was then used to inform the final deliverable of this research, a software design specification that defines how the system would work. This specification was written as a challenge to the CAD community, hoping to inform and aid future advancements in CAD software. As a final stage of research validation, a number of members of the CAD community were contacted and interviewed about their feelings of the work produced and their feedback was taken in order to inform future research in this area.
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Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Bodkin, Troy L. (2017): Specifying a hybrid, multiple material CAD system for next-generation prosthetic design. Loughborough University. Thesis.https://hdl.handle.net/2134/25...;
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Giulia Barbareschi
Doctoral Thesis. This thesis makes two contributions to facilitate wheelchair users’ engagement in the participatory design process for ATs, while being mindful of the burden of participation. The first contribution is a framework that provides a modular structure guiding the participatory design process from initial problem identification and analysis to facilitating collaborations between wheelchair users and designers. The framework identifies four factors determining the need and adoption process for ATs: (i) People focuses on the target population, (ii) Person includes personal characteristics, (iii) Activity refers to the challenges associated with the task, and (iv) Context encompasses the effect of the environment in which the activity takes place. The second contribution constitutes a rich picture of personal and external elements influencing real world wheelchair transfers that emerged from four studies carried out to investigate the effect of the framework factors on the design process for ATs.
UCL (University College London)
Abstract
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Transferring independently to and from their wheelchair is an essential routine task for many wheelchair users but it can be physically demanding and can lead to falls and upper limb injuries that reduce the person’s independence. New assistive technologies (ATs) that facilitate the performance of wheelchair transfers have the potential to allow wheelchair users to gain further independence. To ensure that users’ needs are addressed by ATs, the active involvement of wheelchair users in the process of design and development is critical. However, participation can be burdensome for many wheelchair users as design processes where users are directly involved often require prolonged engagement. This thesis makes two contributions to facilitate wheelchair users’ engagement in the participatory design process for ATs, while being mindful of the burden of participation. The first contribution is a framework that provides a modular structure guiding the participatory design process from initial problem identification and analysis to facilitating collaborations between wheelchair users and designers. The framework identifies four factors determining the need and adoption process for ATs: (i) People focuses on the target population, (ii) Person includes personal characteristics, (iii) Activity refers to the challenges associated with the task, and (iv) Context encompasses the effect of the environment in which the activity takes place. The second contribution constitutes a rich picture of personal and external elements influencing real world wheelchair transfers that emerged from four studies carried out to investigate the effect of the framework factors on the design process for ATs. A related outcome based on these contributions is a framing document to share knowledge between wheelchair users and designers to provide focus and promote an equal collaboration among participants.
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YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Barbareschi, Giulia. “YouTransfer, YouDesign : a Participatory Approach to Design Assistive Technology for Wheelchair Transfers / Giulia Barbareschi.” Thesis (Ph.D.)--University College London, 2018., 2018. Print.
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YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Understanding wrist splint user needs and personalisation through codesign
Charlotte Pyatt
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy at Loughborough University.
Loughborough University
Abstract
Understanding wrist splint user needs and personalisation through codesign
Wrist splints are a common treatment for rheumatoid arthritis, however their effectiveness is compromised by patients not wearing splints as often as prescribed. Previous research has identified a number of reasons for non-compliance, but typically lacks insights that could lead to improved splint design.
This thesis investigates the motivators for patients to wear and not wear their wrist splints and, the impact of personalisation of splint appearance on patient wear. The work is based on the premise that digital design and manufacturing processes, such as Computer-Aided Design (CAD) and 3D Printing, can produce bespoke splints on demand.
The research begins with a literature review across the core areas of: splinting, additive manufacture, product appearance and personalisation. This literature review identifies gaps in knowledge from which research questions are established for the work.
The research employs a qualitative, generative design research approach and, follows a codesign framework employing telling, making and enacting tools. The thesis is made up of three studies. The first study is a sensitisation study and uses design probes to prepare the participants for the research and begin exploring the problem space. The second is a comprehensive study into participants splint wear behaviour and uses context mapping and scenario picture card tools to investigate the motivators for participants to wear and not wear wrist splints, along with positive and negative outcomes or wearing/not wearing splints. The final study uses a personalisation toolkit to elicit patient needs for a future wrist splint design and investigate self-reported expectations regarding compliance of patients who used the toolkit.
The research finds that patient compliance is affected by practical and aesthetic limitations of current splints. It identifies 4 motivating factors to wear a splint and 10 motivating factors to not wear a splint. Additionally, it identifies 6 positive outcomes of wearing splints, 6 negative outcomes of wearing splints, 3 positive outcomes of not wearing splints and 3 negative outcomes of not wearing splints. Requirements for an improved splint design are established and form the basis of the design for a prototype personalisation toolkit. Testing of this toolkit reveals that patients are keen to own more than one splint and personalise splints to match the scenario in which it is to be worn. Patients reported that they expected to be more compliant with a personalised splint when compared to their current splint.
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Understanding wrist splint user needs and personalisation through codesign
Pyatt, Charlotte (2018): Understanding wrist splint user needs and personalisation through codesign. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
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Understanding wrist splint user needs and personalisation through codesign
Type
PhD
Themes
Assistive & Accessible Technology
Shared Control for Wheelchair Interfaces
Dr Chinemelu Ejiamatu Muoma Ezeh
Doctoral Thesis. Independent mobility is fundamental to the quality of life of people with impairment. Most people with severe mobility impairments, whether congenital, e.g., from cerebral palsy, or acquired, e.g., from spinal cord injury, are prescribed a wheelchair. A small yet significant number of people are unable to use a typical powered wheelchair controlled with a joystick. Instead, some of these people require alternative interfaces such as a head- array or Sip/Puff switch to drive their powered wheelchairs. However, these alternative interfaces do not work for everyone and often cause frustration, fatigue and collisions. This thesis develops a novel technique to help improve the usability of some of these alternative interfaces, in particular, the head-array and Sip/Puff switch.
UCL (University College London)
Abstract
Shared Control for Wheelchair Interfaces
Independent mobility is fundamental to the quality of life of people with impairment. Most people with severe mobility impairments, whether congenital, e.g., from cerebral palsy, or acquired, e.g., from spinal cord injury, are prescribed a wheelchair. A small yet significant number of people are unable to use a typical powered wheelchair controlled with a joystick. Instead, some of these people require alternative interfaces such as a head- array or Sip/Puff switch to drive their powered wheelchairs. However, these alternative interfaces do not work for everyone and often cause frustration, fatigue and collisions. This thesis develops a novel technique to help improve the usability of some of these alternative interfaces, in particular, the head-array and Sip/Puff switch. Control is shared between a powered wheelchair user, using an alternative interface and a pow- ered wheelchair fitted with sensors. This shared control then produces a resulting motion that is close to what the user desires to do but a motion that is also safe. A path planning algorithm on the wheelchair is implemented using techniques in mo- bile robotics. Afterwards, the output of the path planning algorithm and the user’s com- mand are both modelled as random variables. These random variables are then blended in a joint probability distribution where the final velocity to the wheelchair is the one that maximises the joint probability distribution. The performance of the probabilistic approach to blending the user’s inputs with the output of a path planner, is benchmarked against the most common form of shared control called linear blending. The benchmarking consists of several experiments with end users both in a simulated world and in the real-world. The thesis concludes that probabilistic shared control provides safer motion compared with the traditional shared control for difficult tasks and hard-to-use interfaces.
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Shared Control for Wheelchair Interfaces
Ezeh, Chinemelu Ejiamatu Muoma. Shared Control for Wheelchair Interfaces. UCL (University College London), 2018. Print.
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Shared Control for Wheelchair Interfaces
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Materials For Facial Prostheses In Resource Limited Countries
Sophia Esther Liiba Tetteh
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University
Loughborough University
Abstract
Materials For Facial Prostheses In Resource Limited Countries
Facial prostheses are artificial devices that replace a missing body part in the facial and neck regions of the body. Defects or deformities in these regions can lead to functional deficiencies; social and psychological effects in addition to cosmetic defects. Restoration or rehabilitation in resource limited countries is usually provided by charities and organisations volunteering assistance overseas, with some training of local staff in the fabrication of these prostheses. Furthermore, these countries typically lack technical knowhow and trained personnel. In industrialised nations maxillofacial prosthetics has developed into a sophisticated medical speciality requiring highly skilled staff and expensive facilities. In resource limited countries surgical procedures may be an option for rehabilitation of these deformities/defects however, they tend to be unavailable or unaffordable and donated prostheses are not suitable. Hence, this research explores, from first principles, the appropriate and affordable local provision of maxillofacial prostheses in resource constrained regions. The investigation provides knowledge on identifying requirements for resource limited areas, resulting in the creation of a guideline constituting priorities, requirements and specifications. It further explores the viability of potentially cheaper, locally available candidate materials via weathering and antimicrobial methods in ascertaining material longevity.
Cite
Materials For Facial Prostheses In Resource Limited Countries
Tetteh, Sophia (2019): Materials for facial prostheses in resource-limited countries. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
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Materials For Facial Prostheses In Resource Limited Countries
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Rhys James Williams
Thesis: Firstly, the research provides a methodological contribution showing how to conduct mixed-methods research to obtain rich insights into complex prosthesis phenomena. Secondly, the research highlights the need to appreciate psychological and contextual factors when researching prosthesis wearer thermal comfort. The research contributions are also converted into an implication for prosthesis design. The concept of 'regaining control' to psychologically mitigate thermal discomfort could be incorporated into technologies by using 'on-demand' thermal discomfort relief, rather than 'always-on' solutions, as have been created in the past.
UCL, ProQuest Dissertations Publishing
Abstract
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Amongst lower-limb prosthesis wearers, thermal discomfort is a common problem with an estimated prevalence of more than 50%. Overheating does not just create discomfort to the user, but it has been linked to excessive sweating, skin damage caused by a moist environment and friction. Due to impermeable prosthetic components and a warm moist environment, minor skin damage can result in skin infections that can lead to prosthesis cessation, increased social anxiety, isolation and depression. Despite the seriousness of thermal discomfort, few studies explore the issue, with research predominantly constrained to controlled laboratory scenarios, with only one out of laboratory study. In this thesis, studies investigate how thermal discomfort arises and what are the consequences of thermal discomfort for lower-limb prosthesis wearers. Research studies are designed around the principles of presenting lived experiences of the phenomenon and conducting research in the context of participants' real-life activities. A design exploration chapter investigates modifying liner materials and design to create a passive solution to thermal discomfort. However, this approach was found to be ineffective and unfeasible. Study 1 presents a qualitative study which investigates the user experience of a prosthesis, thermal discomfort and related consequences. Study 2 explores limb temperature of male amputees inside and outside the laboratory, with the latter also collecting perceived thermal comfort (PTC) data. Finally, Study 3 investigates thermal discomfort in the real-world and tracks limb temperature, ambient conditions, activities, and experience sampling of PTC. While there were no apparent relationships presented in sensor data, qualitative data revealed that in situations where prosthesis wearers perceived a lack of control, thermal discomfort seemed to be worse. When combined, the studies create two knowledge contributions. Firstly, the research provides a methodological contribution showing how to conduct mixed-methods research to obtain rich insights into complex prosthesis phenomena. Secondly, the research highlights the need to appreciate psychological and contextual factors when researching prosthesis wearer thermal comfort. The research contributions are also converted into an implication for prosthesis design. The concept of 'regaining control' to psychologically mitigate thermal discomfort could be incorporated into technologies by using 'on-demand' thermal discomfort relief, rather than 'always-on' solutions, as have been created in the past.
Cite
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Williams, Rhys James. “Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers.” ProQuest Dissertations Publishing, 2020. Print.
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Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Design rules for additively-manufactured wrist splints
Sarah Kelly
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University.
Loughborough University
Abstract
Design rules for additively-manufactured wrist splints
Additive Manufacturing (AM) often known by the term three-dimensional printing (3DP) has been acknowledged as a potential manufacturing revolution. AM has many advantages over conventional manufacturing techniques; AM techniques manufacture through the addition of material - rather than traditional machining or moulding methods. AM negates the need for tooling, enabling cost-effective low-volume production in high-wage economies and the design & production of geometries that cannot be made by other means. In addition, the removal of tooling and the potential to grow components and products layer-by-layer means that we can produce more from less in terms of more efficient use of raw materials and energy or by making multifunctional components and products. The proposed Centre for Doctoral Training (CDT) in Additive Manufacturing and 3D Printing has the vision of training the next generation of leaders, scientists and engineers in this diverse and multi-disciplinary field. As AM is so new current training programmes are not aligned with the potential for manufacturing and generally concentrate on the teaching of Rapid Prototyping principles, and whilst this can be useful background knowledge, the skills and requirements of using this concept for manufacturing are very different. This CDT will be training cohorts of students in all of the basic aspects of AM, from design and materials through to processes and the implementation of these systems for manufacturing high value goods and services. The CDT will also offer specialist training on aspects at the forefront of AM research, for example metallic, medical and multi-functional AM considerations. This means that the cohorts graduating from the CDT will have the background knowledge to proliferate throughout industry and the specialist knowledge to become leaders in their fields, broadening out the reach and appeal of AM as a manufacturing technology and embedding this disruptive technology in company thinking. In order to give the cohorts the best view of AM, these students will be taken on study tours in Europe and the USA, the two main research powerhouses of AM, to learn from their international colleagues and see businesses that use AM on a daily basis. One of the aims of the CDT in AM is to educate and attract students from complementary basic science, whether this be chemistry, physics or biology. This is because AM is a fast moving area. The benefits of having a CDT in AM and coupling with students who have a more fundamental science base are essential to ensure innovation & timeliness to maintain the UK's leading position. AM is a disruptive technology to a number of industrial sectors, yet the CDTs industrial supporters, who represent a breadth of industrial end-users, welcome this disruption as the potential business benefits are significant. Growing on this industry foresight, the CDT will work in key markets with our supporters to ensure that AM is positioned to provide a real and lasting contribution & impact to UK manufacturing and provide economic stability and growth. This contribution will provide societal benefits to UK citizens through the generation of wealth and employment from high value manufacturing activities in the UK.
Cite
Design rules for additively-manufactured wrist splints
Kelly, Sarah (2020): Design rules for additively-manufactured wrist splints. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Design rules for additively-manufactured wrist splints
Type
PhD
Themes
Assistive & Accessible Technology
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Anna Vlachaki
The literature shows that research into the aesthetic aspects of prostheses is limited. Although there are suggestions that prostheses with high levels of emotionally-driven design may improve users’ well-being, they are based only on theoretical findings. Therefore, in this thesis the effects of emotionally-driven prostheses on users’ lives and society’s attitudes were explored, with respect to culture and more specifically, the theories of individualism/ collectivism. In order to investigate the effects of culture, the research was conducted in two countries with different cultures; the UK (individualistic) and Greece (collectivistic). The thesis began with a literature review across three core areas: user, product and environment, and revealed the importance of investigating an additional area; that of prosthetists. The research employed a qualitative approach and consisted of four studies.
Loughborough University
Abstract
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
The literature shows that research into the aesthetic aspects of prostheses is limited. Although there are suggestions that prostheses with high levels of emotionally-driven design may improve users’ well-being, they are based only on theoretical findings. Therefore, in this thesis, the effects of emotionally-driven prostheses on users’ lives and society’s attitudes were explored, with respect to culture and more specifically, the theories of individualism/ collectivism. In order to investigate the effects of culture, the research was conducted in two countries with different cultures; the UK (individualistic) and Greece (collectivistic). The thesis began with a literature review across three core areas: user, product and environment, and revealed the importance of investigating an additional area; that of prosthetists. The research employed a qualitative approach and consisted of four studies. Study I was an online questionnaire to explore users’ preferences towards prostheses, with respect to their culture. Study II consisted of semi-structured interviews and informational probes to comprehend the role of prostheses on users’ lives, with respect to prosthetic appearance. In Study III, the aim was to investigate prosthetists’ attitudes towards the needs of prosthetic users by conducting semi-structured interviews. Finally, Study IV was an online questionnaire to explore non-users’ attitudes towards the design of prostheses. The research showed that the use of prostheses for the completion of users’ body was not an adequate factor to improve their well-being, and a shift on users’ desires towards emotionally-driven prostheses has occurred. From the variables that were tested, sex, age, cause and area of limb-loss may affect people’s attitudes towards the design of prostheses. Furthermore, the results showed that prostheses with high emotionally-driven design evoked emotions, in both users and non-users, with higher levels of pleasantness and arousal than the emotions that were elicited by the prostheses of lower emotionally-driven designs and thus, they may trigger a greater behavioural reaction. This suggested that emotionally-driven prostheses may eliminate users’ stigmatisation by increasing their self-confidence and altering society’s attitudes. However, attention needs to be paid in collectivistic countries, as emotionally-driven prostheses may enhance users’ stigmatisation.
Cite
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Vlachaki, Anna (2020): Emotionally-driven prostheses: exploring the effects on users’ lives and societies’ attitudes in the UK and Greece. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
| https://www.disabilityinnovation.com/publications?page=5&type=journal-paper+workshop+report+book+phd |
Downregulation of vasopressin V2 receptor promoter activity via V1a receptor pathway | American Journal of Physiology-Renal Physiology
Vasopressin V1a and V2 receptors (V1aR and V2R, respectively) distribute in the collecting duct of the kidney. Although the function of V2R mediating the antidiuretic effect of AVP has been investi...
ARTICLES
Downregulation of vasopressin V 2receptor promoter activity via V 1areceptor pathway
Yuichiro Izumi
,
Yushi Nakayama
,
Tomohiko Mori
,
Hiroki Miyazaki
,
Hideki Inoue
,
Yukimasa Kohda
,
Takeaki Inoue
,
Hiroshi Nonoguchi
, and
Kimio Tomita
Published Online: 01 May 2007 https://doi.org/10.1152/ajprenal.00358.2006
Abstract
Vasopressin V 1aand V 2receptors (V 1aR and V 2R, respectively) distribute in the collecting duct of the kidney. Although the function of V 2R mediating the antidiuretic effect of AVP has been investigated in detail, the role of V 1aR in the collecting ducts has not been elucidated. In the present study, we have investigated the role of the V 1aR pathway in V 2R promoter activity. We cloned the 5′-flanking region of rat V 2R (rV 2R) and investigated rV 2R promoter activity in the LLC-PK 1cell line transfected to express rat V 1aR (rV 1aR) dominantly (LLC-PK 1/rV 1aR). AVP induced a transient increase, followed by a sustained decrease, of rV 2R promoter activity in these cells. This AVP-induced decrease of rV 2R promoter activity was inhibited by V 1aR, but not V 2R, antagonist. PMA mimicked this decrease of rV 2R promoter activity. On the contrary, 8-(4-chlorophenylthio)-cAMP increased rV 2R promoter activity. These PMA- and 8-(4-chlorophenylthio)-cAMP-induced effects were not observed on the deletion segment of the 5′-flanking region lacking CAAT and SP1 sites. In conclusion, 1) expression of the V 2R is downregulated via the V 1aR pathway in LLC-PK 1/rV 1aR cells, and 2) expression of the V 2R is downregulated by the PMA-induced PKC pathway and upregulated by the cAMP-PKA pathway. These opposite effects of PKC and PKA appear to be regulated by the same promoter region of CAAT and SP1.
the main role of the kidneyis to maintain body fluid homeostasis by producing concentrated or diluted urine. Among many hormones, AVP plays a major role in the urine-concentrating mechanism. There are two types of AVP receptors in the kidney: vasopressin V 1aand V 2receptors (V 1aR and V 2R, respectively).
The V 2R is distributed at the basolateral membrane of the collecting ducts and mediates the antidiuretic effect of AVP (22,25). The V 2R is coupled to G sproteins and increases cAMP in cytoplasm as a second messenger. Subsequently, PKA is activated. As a consequence of V 2R stimulation from the basolateral membrane, excretion and reabsorption of water, electrolytes, and urea are induced through transporters such as aquaporin-2 (AQP2), Na-K-Cl cotransporter type 1, and renal urea transporter type A 1in the collecting ducts (16,34,37).
The V 1aR is localized mainly in the vascular system and glomeruli and exerts a vasopressor effect (24). The V 1aR is coupled to G q/11proteins and stimulates phospholipase C. Activation of phospholipase C releases Ca 2+from the endoplasmic reticulum, and subsequently PKC is activated. In the kidney, V 1aR mRNA is expressed not only in the glomeruli but also in the collecting ducts (28,30). Although the function of the V 2R has been investigated in detail, the physiological role of the V 1aR in the collecting ducts remains unclear.
Previous studies have suggested that the V 1aR is present at the luminal membrane of the collecting ducts. Ando et al. (1) demonstrated that luminal AVP induces sustained hyperpolarization of transepithelial voltage. Naruse et al. (21) demonstrated that luminal AVP induces changes in luminal conductance. Our previous immunohistochemical study (22,28) revealed that the V 1aR was mainly localized at the luminal membrane and in the cytoplasm, whereas the V 2R is localized at the basolateral membrane in the rat collecting duct.
Bankir (2) proposed a role for urinary AVP via the V 1aR and the interaction between V 1aR- and V 2R-mediated effects. We previously demonstrated that fractional extraction of AVP is closely related to fractional excretion of Na +in patients with chronic renal failure (23). Our previous study also showed that luminal AVP decreases osmotic water permeability in the presence of basolateral AVP in the inner medullary collecting ducts (22). In addition, the increase of V 1aR mRNA and decrease of V 2R mRNA were simultaneously observed during metabolic acidosis (28). These studies strongly indicate that body fluid homeostasis is maintained not only by basolateral AVP, but also by luminal AVP, presumably via the V 1aR pathway.
On the basis of previous reports, we hypothesized that V 1aR stimulation by luminal AVP might modulate the basolateral AVP-induced activity by regulating V 2R expression at the transcriptional level. To address this hypothesis, we characterized the rat V 2R (rV 2R) promoter region and investigated the regulation of rV 2R promoter activity in LLC-PK 1cells that were transfected to express rat V 1aR (rV 1aR) dominantly. Furthermore, we analyzed the effects of the PKC and PKA pathways on V 2R promoter activity and investigated the cross talk between V 1aR and V 2R signaling pathways in LLC-PK 1cells.
MATERIALS AND METHODS
Reagents.
[Arg 8]-vasopressin (AVP) was obtained from Sigma-Aldrich (St. Louis, MO). RO 31-8220 and 8-(4-chlorophenylthio)-cAMP (cpt-cAMP) were obtained from Sigma-Aldrich (Steinheim, Germany). PMA and 4α-PMA were purchased from Promega (Madison, WI). OPC-21268 and OPC-31260 were kind gifts from Otsuka Pharmaceutical (Tokushima, Japan).
Cloning of the 5′-flanking region of the rV 2R gene.
The 1,092-bp 5′-flanking region of the rV 2R gene was cloned by PCR amplification, with rat genomic DNA used as a template. An Expand High Fidelity PLUSPCR System (Roche Applied Science, Penzberg, Germany) was used for PCR amplification. Gene-specific sense and antisense primers were designed on the basis of the published cDNA sequence of the rV 2R gene (17).
Reporter plasmid construction.
For analysis of rV 2R promoter activity, a series of deletion mutants were synthesized by PCR using sense primers designed to downstream (−664, −345, −245, −225, −165, −155, −124, −92, and −46 bp) and antisense primers on exon 1 (+57 bp). A deletion mutant, lacking −164 to 47 bp from the 5′-flanking region, was synthesized by the in vitro overlap-extension PCR method, as described previously (20). PCR-amplified products were subcloned into a pGL3-basic luciferase reporter vector (Promega).
Cell culture, transfection, and determination of promoter activity.
LLC-PK 1cells (catalog no. JCRB0060, Health Science Research Resources Bank, Tokyo, Japan) were maintained in DMEM supplemented with 100 IU/ml penicillin-streptomycin and 10% fetal bovine serum (Invitrogen, Tokyo, Japan).
For transfection studies, cells were seeded in 12-well clusters (Corning) and grown to reach 50% confluence. FuGENE6 transfection reagent (Roche Applied Science, Indianapolis, IN) was used to cotransfect 0.314 pmol of pGL3-rV 2R promoter constructs and 3.75 fmol of pRL-TK constructs into the cells. Promoter activity was examined after treatment with AVP, cpt-cAMP, PMA, and vehicle (DMSO).
For determination of reporter activity, firefly luciferase activity from the pGL3 reporter vector and Renillaluciferese activity from the pRL-TK vector were measured by the Dual-Luciferase Assay System (Promega) on a luminometer (model TD-20/20, Turner Design).
Establishment of a stable LLC-PK 1cell line expressing rV 1aR.
The rV 1aR gene (GenBank accession no.BC088095) was synthesized by PCR amplification from a pExpress1 vector containing rV 1aR cDNA (Open Biosystems) and subcloned into a pcDNA5/FRT vector. Gene-specific sense and antisense primers were designed on the basis of the published cDNA sequence of the rV 1R gene (19).
LLC-PK 1stably expressing the rV 1aR was constructed using the Flp-In System (Invitrogen Life Technologies, Carlsbad, CA), which is able to create isogenic cell lines with one or more Flp recombination targets (FRT). To prepare a new LLC-PK 1/FRT cell line, LLC-PK 1cells were transfected with pFRT/lacZeo and selected in Zeocin (250 μg/ml) for 2 wk. Cells were confirmed to have the FRT site by β-galactosidase staining assay (Invitrogen Life Technologies). Positive cells were named LLC-PK 1/FRT.
The LLC-PK 1/FRT cell line was cotransfected with pOG44, a vector for transient expression of Flp recombinase, and pcDNA5/FRT/rV 1aR, an expression vector containing the coding region for the rV 1aR protein, and possesses the FRT site for homologous recombination. Since the pcDNA5/FRT vector also contained the hygromycin B-resistant gene, LLC-PK 1/FRT cells stably transfected with rV 1aR (LLC-PK 1/rV 1aR) were selected in 800 μg/ml hygromycin B. Single-cell colonies were used to analyze the interaction between rV 1aR stimulation and rV 2R promoter activity.
mRNA isolation and cDNA synthesis.
MgNA Pure LC mRNA Isolation Kit II (Roche Diagnostics, Tokyo, Japan) was used for mRNA extraction. The cell pellets were diluted with 300 μl of lysis buffer and dissolved in a buffer containing a chaotropic salt and an RNase inactivator. The 3′-poly(A +) from the released mRNA hybridizes to the added biotin-labeled oligo(dT). This complex is immobilized onto the surface of streptavidin-coated magnetic beads. After a DNase digestion step, unbound substances were removed by three washing steps, and purified mRNA was eluted with a low-salt buffer. cDNA was synthesized using the High-Capacity cDNA Archive Kit (Applied Biosystems).
Intracellular Ca 2+measurement.
LLC-PK 1cells expressing the rV 1aR were cultured in 96-well black plates to reach 100% confluence. According to the protocol for the Calcium Kit Fluo 3 (Dojindo Laboratories, Kumamoto, Japan), cells were preincubated in 100 μl of loading buffer containing 5 mg/l fluo 3-AM, 1.25 mM probenecid, and 0.04% Pluronic F-127 at 37°C for 1 h. After preincubation, loading buffer was replaced with 100 μl of recording medium containing 1.25 mM probenecid. Fluorescence intensity was measured as the Ca 2+concentration for 5 min after AVP treatment with use of a plate reader (Mulch Micro MTP-800Lab, Corona, Niigata, Japan).
Data analysis.
Values are means ± SE. Statistical analysis was performed by ANOVA and multiple comparison (Bonferroni's or Sheffé's test) or by Student's t-test. P< 0.05 was considered significant.
RESULTS
Analysis and characterization of the 1,092-bp segment from the 5′-flanking region of the rV 2R gene.
The sequence up to 1,092 bp upstream from the transcriptional initiation site of the rV 2R was identified by Mandon et al. (17) (Fig. 1). We confirmed the whole sequence using our PCR product. This region contains multiple motif sequences that may play an important role in transcriptional regulation. This gene has no TATA box, but it does have a CAAT box at −82 bp from the transcription initiation site. There are seven binding sites for PEA3 and one each for AP1, AP3, and SP1. As is the case for other genes, these consensus sequences are located close to the transcription initiation site.
<here is a image 64171623fc6fd7c0-17ba2fbd5235be93>
CaptionFig. 1.Nucleotide sequence of the 5′-flanking region of the rat vasopressin V 2receptor (rV 2R) gene. Inverse PCR was used to clone the 5′-flanking region. Possible promoter regulatory elements are shown in boxes.
Basal promoter activity of the rV 2R is shown inFig. 2. Deletion of the 1,092-bp 5′-flanking region to 345 bp significantly increased promoter activity: 25- to 30-fold greater in the 345-bp promoter segment than in control pGL3-basic. However, deletion of the segment further downstream decreased promoter activity. By deletion to 46 bp, the promoter activity was completely abolished.
<here is a image 86f36612e8efe430-1728c9ec9239cb7f>
CaptionFig. 2.Promoter activity of the rV 2R in LLC-PK 1cells with deletion analysis. LLC-PK 1cells were cotransfected with pGL3-rV 2R promoter constructs and pRL-TK constructs. Luciferase activity was measured 42 h after transfection. The 345-bp 5′-flanking region of rV 2R showed the highest promoter activity among deletion segments. Values are means ± SE ( n= 6). * P< 0.05 vs. pGL3 basic.
Effect of AVP on intracellular Ca 2+concentration in LLC-PK1 cells transfected with rV 1aR.
RT-PCR was used to confirm mRNA expression of the rV 1aR in LLC-PK 1cells transfected with rV 1aR by the Flp-In System. cDNA (2 μg) obtained by reverse transcription from cell lysate was amplified for 35 cycles by PCR. Agarose gel electrophoresis showed the PCR products at the appropriate molecular weight, as well as the rV 1aR-positive control (Fig. 3). These findings indicate that the rV 1aR is expressed in LLC-PK 1/rV 1aR cells at the mRNA level. To demonstrate the function of the rV 1aR in this cell line, we investigated the accumulation of intracellular Ca 2+by measuring the change of fluo 3 fluorescence intensity (Fig. 4). In LLC-PK 1/rV 1aR cells, treatment with 10 −9M AVP increased fluorescence intensity, indicating an increase of the intracellular Ca 2+concentration. Maximal intensity was achieved <30 s after addition of AVP (Fig. 4 A). AVP dose dependently increased intracellular Ca 2+(Fig. 4 B). These results indicate that rV 1aR protein is present on the cell membrane and is functionally active in LLC-PK 1/rV 1aR cells. In contrast, in non-rV 1aR-transfected LLC-PK 1(LLC-PK 1/FRT) cells, only a high dose (10 −7M) AVP increased Ca 2+concentration.
<here is a image c56c01726be67226-9fb9aebd9de53de4>
CaptionFig. 3.Agarose gel electrophoresis for detection of rat vasopressin V 1areceptor (rV 1R) mRNA in LLC-PK 1/rV 1aR cells. The 1.5-kbp bands indicate rV 1aR. cDNA (2 μg) obtained by RT with cell as template was amplified for 35 cycles by PCR. Lane 2, amplification by cDNA in LLC-PK 1/rV 1aR cells (transfected with rV 1aR using Flp-In System); lane 3, negative control amplified by purified mRNA in LLC-PK 1/rV 1aR cells; lane 4, positive control amplified by pcDNA5 plasmid with rV 1aR as template; lane 5, negative control amplified by cDNA in LLC-PK 1/FRT cells; lane 6, negative control amplified by purified mRNA in LLC-PK 1/FRT cells; lanes 1and 7, molecular markers.
<here is a image 57442538be54e03f-c28fed7ef2288b59>
CaptionFig. 4.Alteration of relative fluorescence intensity for accumulation of intracellular Ca 2+. Fluorescence intensity for fluo 3, indicating accumulation of intracellular Ca 2+, was measured in LLC-PK 1/FRT and LLC-PK 1/rV 1aR cells at 1-s intervals for 5 min after treatment with AVP or DMSO (vehicle). A: alteration of fluorescence intensity relative to mean basic intensity (before AVP stimulation). AVP at 10 −9M increased intracellular Ca 2+in LLC-PK 1/rV 1aR, but not LLC-PK 1/FRT, cells. B: dose-response effect of AVP on intracellular Ca 2+in LLC-PK 1/rV 1aR and LLC-PK 1/FRT cells shown as mean fluorescence intensity 30 s after treatment with AVP or vehicle. AVP dose dependently increased intracellular Ca 2+in LLC-PK 1/rV 1aR cells. Values are means ± SE ( n= 6). * P< 0.05 vs. vehicle. † P< 0.05 vs. LLC-PK 1/FRT.
Downregulation of rV 2R promoter activity via rV 1aR stimulation.
Deletion study of the promoter element demonstrated the greatest activity at a 345-bp segment of the rV 2R promoter (Fig. 2). Therefore, we transfected the 345-bp 5′-flanking region of the rV 2R in LLC-PK 1/rV 1aR cells to investigate the interaction between V 2R promoter activity and V 1aR stimulation. First, we examined the time course of the effect of 10 −8M AVP on rV 2R promoter activity (Fig. 5 A ). AVP transiently increased rV 2R promoter activity 2 h after AVP treatment. Sustained suppression of rV 2R promoter activity was observed 12–24 h after AVP treatment. Although rV 2R promoter activity was transiently increased 2–4 h after AVP treatment in LLC-PK1/FRT cells, a significant decrease of rV 2R promoter activity was not observed at 12–24 h (Fig. 5 B). In addition, rV 2R promoter activity was decreased over a wide range of AVP concentrations in LLC-PK 1/rV1aR cells (Fig. 6). The decrease of rV 2R promoter activity by 10 −10M AVP was inhibited by a V 1aR-specific antagonist (OPC-21268) in LLC-PK 1/rV 1aR cells (Fig. 7 A). This restoration of rV 2R promoter activity by a V 1aR-specific antagonist was more distinct when the cells were treated with high-dose (10 −8M) AVP (Fig. 7 C). In contrast, a V 2R-specific antagonist (OPC-31260) did not restore V 2R promoter activity. A PKC inhibitor (RO 31-8220), as well as the V 1aR-specific antagonist, inhibited the decrease of rV 2R promoter activity. Although AVP slightly decreased rV 2R promoter activity in LLC-PK 1/FRT cells (Fig. 7 B), the change was not statistically significant, and neither V 1aR nor V 2R antagonists restored V 2R promoter activity.
<here is a image 0a729dd355129c31-0d1c1e74f4a60609>
CaptionFig. 5.Time course of effect of AVP on rV 2R promoter activity in LLC-PK 1/rV 1aR and LLC-PK 1/FRT cells. Each cell was cotransfected with the 5′-flanking region (−345 to +57 bp) of rV 2R. At 18 h after transfection, cells were incubated with 10 −8M AVP. Luciferase assay was performed 0, 2, 4, 12, and 24 h after AVP stimulation. A: luciferase activity in LLC-PK 1/rV 1aR cells. AVP transiently increased rV 2R promoter activity 2 h after AVP treatment. Sustained decrease of activity was observed at 12–24 h. B: luciferase activity in LLC-PK 1/FRT cells. AVP transiently increased rV 2R promoter activity. Values are means ± SE ( n= 6). * P< 0.05 vs. vehicle.
<here is a image e313d7d41f26a96d-84ca411fe3bdea9d>
CaptionFig. 6.Dose-dependent effect of AVP on rV 2R promoter activity in LLC-PK1/rV 1aR cells. LLC-PK 1/rV 1aR cells were cotransfected with the 5′-flanking region (−345 to +57 bp) of rV 2R and incubated with 10 −11–10 −7M AVP for 24 h. rV 2R promoter activity was decreased over a wide range of AVP concentrations. Values are means ± SE ( n= 6). * P< 0.05 vs. vehicle.
<here is a image 9b6683b7f3d4af2c-5c31c02ed270b1fc>
CaptionFig. 7.Effect of AVP on rV 2R promoter activity in LLC-PK 1/rV 1aR and LLC-PK 1/FRT cells. Each cell was cotransfected with the 5′-flanking region (−345 to +57 bp) of rV 2R and incubated with AVP, antagonists, and PKC inhibitor for 12 or 24 h. Final concentration of each solution is as follows: 10 −10or 10 −8M AVP, 10 −6M OPC-21268 (a V 1aR-specific antagonist), 10 −7M OPC-31260 (a V 2R-specific antagonist), and 10 −7M RO 31-8220 (a PKC inhibitor). A: luciferase activity in LLC-PK 1/rV 1aR cells treated with 10 −10M AVP for 12 h. B: luciferase activity in LLC-PK 1/FRT cells treated with 10 −10M AVP for 12 h. AVP significantly decreased rV 2R promoter activity in LLC-PK 1/rV 1aR, but not LLC-PK 1/FRT, cells. AVP effect was abolished by OPC-21268 and RO 31-8220, but not by OPC-31260. C: luciferase activity in LLC-PK 1/rV 1aR cells treated with 10 −8M AVP for 24 h. Note distinct restoration of rV 2R promoter activity by OPC-21268. Values are means ± SE ( n= 6). * P< 0.05 vs. AVP.
Identification of PKC and PKA response element in the rV 2R promoter region.
To analyze signal transduction, we treated LLC-PK 1cells with PMA, a PKC activator. First, we used the 1,092-bp 5′-flanking region of the rV 2R to examine the time course of the effect of PMA on rV 2R promoter activity (Fig. 8 A ). rV 2R promoter activity was decreased 6–12 h after treatment with PMA. rV 2R promoter activity was suppressed by PMA in a dose-dependent manner (Fig. 8 B). On the basis of this finding, we performed additional experiments on the cells 12 h after they were treated with 10 −6M PMA. In contrast to PMA, 4α-PMA, a PMA analog, did not change rV 2R promoter activity (Fig. 9). rV 2R promoter activity was downregulated by PMA, even in short segments (Fig. 10). However, this downregulation was abolished by deletion of the promoter region to 46 bp.
<here is a image a108614fe8b9b893-caf8c9b5957d52b2>
CaptionFig. 8.Dose- and time-dependent effect of PMA on rV 2R promoter activity. A: time-dependent effect of PMA and 8-(4-chlorophenylthio)-cAMP (cpt-cAMP) on rV 2R promoter activity in LLC-PK 1cells. LLC-PK 1cells were cotransfected with the 5′-flanking region (−1,092 to +57 bp) of rV 2R. At 18 h after transfection with promoter construct, cells were exposed to 10 −6M PMA or 4 × 10 −4M cpt-cAMP. Luciferase activity was assayed 0, 2, 4, 6, and 12 h after PMA or cpt-cAMP stimulation. rV 2R promoter activity was increased 2–12 h after cpt-cAMP and decreased 6–12 h after PMA. B: dose-dependent effect of PMA on rV 2R promoter activity in LLC-PK 1cells. LLC-PK 1cells were cotransfected with the 5′-flanking region (−1,092 to +57 bp) of rV 2R and exposed to 10 −8–10 −6M PMA for 12 h. PMA dose dependently decreased rV 2R promoter activity. Values are means ± SE ( n= 6). * P< 0.05 vs. vehicle.
<here is a image 2da52157b0ab1a40-8bd212778f4ce53f>
CaptionFig. 9.Effect of PMA, cpt-cAMP, and 4α-PMA on rV 2R promoter activity in LLC-PK 1cells. LLC-PK 1cells were cotransfected with the 5′-flanking region (−1,092 to +57 bp) of rV 2R and exposed to DMSO, 10 −6M PMA, 4 × 10 −4M cpt-cAMP, or 10 −6M 4α-PMA for 12 h. rV 2R promoter activity was significantly decreased by PMA and decreased by cpt-cAMP. 4α-PMA did not change rV 2R promoter activity. Values are means ± SE ( n= 6). * P< 0.05 vs. vehicle.
<here is a image cccf58999a9193df-0290332211bab713>
CaptionFig. 10.Deletion series of rV 2R promoter element and promoter activity. LLC-PK 1cells were cotransfected with a deletion series of the 5′-flanking region from −1,092 to −46 bp of rV 2R and exposed to 10 −6M PMA for 12 h. PMA suppressed rV 2R promoter activity, even in short segments. Effect of PMA was abolished in the deletion mutant lacking CAAT and SP1 elements (−345, −165/−46, and +57). Values are means ± SE ( n= 6). * P< 0.05.
To examine the role of the PKA pathway in V 2R signal transduction, we added cpt-cAMP to LLC-PK 1cells. rV 2R promoter activity was significantly increased 2–12 h after treatment with cpt-cAMP (Fig. 8 A). These opposite effects caused by PMA and cpt-cAMP were abolished by deletion at −164 to −47 bp on the 345-bp 5′-flanking region of rV 2R (Fig. 11 B). This mutant lacks consensus sequences of CAAT and Sp1 from the original 5′-flanking region.
<here is a image 694393e1cfa48a0a-2bd65b6ad57bfb67>
CaptionFig. 11.Effect of PMA and cpt-cAMP on rV 2R promoter activity of the deletion mutant in LLC-PK 1cells. LLC-PK 1cells were cotransfected with the deletion mutant lacking CAAT and SP1 elements (from −164 to −47 bp) and exposed to 10 −6M PMA or 4 × 10 −4M cpt-cAMP or DMSO for 12 h. A: effect of PMA and cpt-cAMP on the 5′-flanking region (−345 to +57 bp). B: effect of PMA and cpt-cAMP on the deletion mutant (−345, −165/−46, and +57). Opposite effects of PMA and cpt-cAMP on rV 2R promoter activity were abolished on the deletion mutant. Values are means ± SE ( n= 6). * P< 0.05 vs. vehicle.
DISCUSSION
In the present study, we used an LLC-PK 1cell line to investigate the interaction between V 2R promoter activity and the V 1aR pathway. The LLC-PK 1cell line, which is derived from the proximal tubule of porcine kidney, has been widely used to investigate the kinetics of the V 2R and AQP2 because of its response to vasopressin stimulation (12,13). Moreover, the promoter analysis, trafficking, and recycling of AQP2 have been investigated in LLC-PK 1cells (5,9,13). Preliminarily, we also measured rV 2R promoter activity in Madin-Darby canine kidney, COS-7, and HEK-293 cells, but the greatest increase of V 2R promoter activity was observed in LLC-PK 1cells. On the basis of these reports and our preliminarily data, we considered the LLC-PK 1cell line to be suitable for our purpose.
In previous studies, stimulation of LLC-PK 1cells with 10 −10–10 −7M AVP increased cAMP, indicating expression of the V 2R in LLC-PK 1cells (11). In contrast, the increase of intracellular Ca 2+in response to V 1aR stimulation required the high dose (10 −7–5 × 10 −6M) of AVP in LLC-PK 1cells (3,7,27). Our present results also showed an increase of intracellular Ca 2+in LLC-PK 1/FRT cells in response to only high-dose AVP (Fig. 4 B). It is considered that LLC-PK 1cells might express endogenous V 1aR; however, this functional role could be small at physiological AVP concentration.
In the present study, using the Flp-In System, we have established an LLC-PK 1cell line stably expressing the rV 1aR. This cell line expresses rV 1aR mRNA and shows an increase of intracellular Ca 2+in response to 10 −10–10 −7M AVP, suggesting functional expression of the rV 1aR (Figs. 3and4). Since the host cell line (LLC-PK 1/FRT) can be transfected with any other genes of interest in FRT sites, this cell line could be useful for further study. It should be possible to compare the kinetics of plural genes or proteins in isogenic cell conditions. For example, it might be interesting to analyze a functional interaction of the V 1aR with the oxytocin receptor, which has been demonstrated to cross-react with vasopressin (6,10,32,33).
AVP caused a sustained decrease of rV 2R promoter activity in LLC-PK 1/rV 1aR cells (Fig. 5). In addition, suppression of the AVP-induced V 2R was inhibited by a V 1aR-specific antagonist and a PKC inhibitor (Fig. 7, Aand C). These findings strongly indicate that V 2R promoter activity could be downregulated via the V 1aR-PKC pathway. It is known that the physiological concentration of urinary AVP usually ranges from 10 −11to 10 −9M (18). Our results were obtained within this range of AVP concentrations, indicating that V 1aR stimulation affects V 2R promoter activity under physiological conditions.
However, some issues remain unresolved. In contrast to the dose-dependent increase of intracellular Ca 2+by AVP, rV 2R promoter activity showed the two-phased decrease over a wide range of AVP concentrations (Fig. 6). In addition, the V 1aR antagonist and the PKC inhibitor did not completely restore V 2R promoter activity. Perhaps a pathway other than the rV 1aR-PKC pathway decreases V 2R promoter activity in LLC-PK1 cells.
rV 2R promoter activity was increased in the early phase by addition of AVP to LLC-PK 1/rV 1aR and LLC-PK 1/FRT cells (Fig. 5). It is suggested that AVP increased rV 2R promoter activity via the V 2R pathway. In the late phase, rV 2R promoter activity was slightly decreased, even in LLC-PK 1/FRT cells (Fig. 7 B). However, this slight decrease in LLC-PK 1/FRT cells was also observed after treatment with V 1aR antagonist, V 2R antagonist, and PKC inhibitor (not shown) and was not statistically significant.
Wong and Tsui (35) showed that V 2R mRNA is upregulated by PKA stimulation and downregulated by PKC stimulation in the rat inner medullary collecting duct. As shown inFig. 9, rV 2R promoter activity was decreased by PMA and increased by cpt-cAMP. These results indicate that rV 2R promoter activity is modulated by PKC and PKA pathways.
The time-dependent effects of AVP, PMA, and cpt-cAMP on rV 2R promoter activity demonstrate that differences in time course between V 1aR and V 2R stimulation affect rV 2R promoter activity. rV 2R promoter activity was increased in the early phase and decreased in the late phase by AVP (Fig. 5 A). The increase of rV 2R promoter activity by cpt-cAMP was observed 2 h after AVP treatment, whereas the decrease of rV2R promoter activity appeared 6 h after addition of AVP (Fig. 8 A ). Although intracellular Ca 2+was rapidly increased to maximal concentration via V 1aR stimulation (Fig. 4), the effect of cAMP on V 2R promoter activity via V 2R stimulation could be more potent and could occur before the effect of V 1aR stimulation. It is suggested that the early AVP-induced increase of rV 2R promoter activity is caused by V 2R stimulation and the delayed AVP-induced decrease is mediated by V 1aR stimulation. As discussed in previous studies, a 10- to 100-fold higher dose of AVP seems to be required for V 1aR than for V 2R activation (2,26). The response of the V 1aR to AVP might be slower than the response of the V 2R.
By the deletion mutant study of the rV 2R promoter, consensus sequences of CAAT and SP1 were speculated to be the PKC-responsive element. Interestingly, our results showed that the same element was also crucial for cAMP-induced V 2R promoter activity. It is suggested that the opposite effects of PKC and PKA on regulation could affect the same consensus sequences, such as CAAT and/or SP1, in this gene. Several reports have demonstrated that CAAT and/or SP1 are related to cAMP-inducible promoter activity (8,9,14). However, a direct correlation between these consensus sequences and PKC has not been reported. An indirect mechanism for suppression of V 2R expression via the PKC pathway at the transcriptional level could be supposed.
Klingler et al. (15) demonstrated that long-term (5 h) exposure to PMA decreased cAMP accumulation in Chinese hamster ovary cells stably transfected with the V 1aR and V 2R, suggesting an interaction between PMA stimulation and cAMP accumulation. Previous reports have indicated a connection between PKC and cAMP in cultured collecting tubular cells (4,29). These studies have suggested that PKC caused phosphorylation of adenylyl cyclase or, alternatively, phosphorylation of G iprotein. We confirmed the PMA-induced decrease of cAMP accumulation in LLC-PK 1cells (not shown). The interaction between PMA-induced PKC and AVP-induced cAMP could support our hypothesis of cross talk between the V 1aR and V 2R signaling pathways.
It is well known that expression of V 2R mRNA and protein is decreased when plasma AVP increases in vivo (31,36). We have demonstrated that inhibition of V 1aR increased V 2R mRNA in the rat outer medullary collecting duct (28). However, downregulation of V 2R expression has not been investigated in detail. Our present study could support this downregulation of the V 2R at the transcriptional level.
Our results can be summarized as follows. 1) Expression of the V 2R is downregulated via the V 1aR pathway and upregulated via the V 2R pathway. 2) Expression of the V 2R is downregulated by the PMA-induced PKC signaling pathway and upregulated by the cAMP-PKA signaling pathway. These opposite effects of PKC and PKA stimulation could be exerted on the same consensus sequences in the V 2R promoter region, such as CAAT and SP1. 3) Intracellular cross talk between the V 1aR and V 2R pathways in the collecting duct cells appears to strictly and sensitively maintain body fluid homeostasis.
GRANTS
This study was supported by Ministry of Education, Culture, Sports, Science, and Technology of Japan Grants-in-Aid for Scientific Research 18590895, 17590833, 167904660, 16590791, 16590792, 16390246, 15590852, and 14370321.
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Dr. Tetsushi Kagawa for valuable suggestions regarding the luciferase assay and Takanobu Matsuzaki and Noriko Teramoto for technical assistance. We are grateful for support by the staff at the Gene Technology Center at Kumamoto University. We also thank Dr. Mark A. Knepper for critical reading of the manuscript.
AUTHOR NOTES
Address for reprint requests and other correspondence: Y. Izumi, 1-1-1 Honjo, Kumamoto, Kumamoto 860-8556, Japan (e-mail:[email protected])
| https://journals.physiology.org/doi/full/10.1152/ajprenal.00358.2006 |
Wilson v. Goldman, No. 83CA1325 - Colorado - Case Law - VLEX 890467399
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Wilson v. Goldman, No. 83CA1325
Docket Nº No. 83CA1325 Citation 699 P.2d 420 Case Date March 21, 1985 Court Court of Appeals of Colorado
Page 420
699 P.2d 420
Don E. WILSON; William G. Barber; Patricia W. Barber; Herb Baker; Jesse M. Black; James R. Raine; Gary L. Fabiano; T.J. Trogdon, III; Ray P. Dinsmore; Donald C. Carroll; Duane Gray; Castle Mountain Subdivision Architectural Control Committee by its members, Jesse M. Black, Harold B. Ross, and Gale Nash; and Castle Mountain Irrigation Road and Recreation Association, a non-profit Colorado corporation, Plaintiffs-Appellees-Cross-Appellants, v. William A. GOLDMAN, Defendant-Appellant-Cross-Appellee.
No. 83CA1325.
Colorado Court of Appeals, Div. II.
Charles Alexander, Gunnison, William G. Barber, Pro Se/Pro Haec Vice, Austin, Tex., for plaintiffs-appellees-cross-appellants Wilson, William G. Barber, Patricia W. Barber, and Raine.
Ranous, Stern & Patrick, P.C., J. Steven Patrick, Gunnison, for plaintiffs-appellees-cross-appellants Baker, Black, Fabiano, Trogdon, Dinsmore, Carroll, Gray, Castle Mountain Subdivision Architectural Control Committee, Ross, Nash, and Castle Mountain Irr. Road and Recreation Assn.
Andrew J. Kasic, Gunnison, for defendant-appellant-cross-appellee.
VAN CISE, Judge.
Defendant, William Goldman, appeals from a judgment enforcing protective covenants, requiring him to remove a new fence and restore an old one, and denying his affirmative defenses and counterclaims relating to the fence construction. Plaintiffs cross-appeal from that portion of the judgment relating to their claim for attorney fees. We affirm in part, reverse in part, and remand the matter with directions.
The relevant facts are not in dispute. Castle Mountain Company Wilderness Streams Filing No. 2 (the subdivision) is a rural residential subdivision located in Gunnison County. It consists of approximately 400 acres in a mountainous region adjoining a national wilderness area and is divided into approximately 80 lots ranging in size from one to more than 12 acres. The "platted roads, ways and streets" and the "open space and public lands" in the subdivision are owned by Castle Mountain Irrigation, Road and Recreation Association (the Association) for the use and benefit of the owners of the lots in this and the other Castle Mountain Company (the Company) subdivisions.
Protective covenants applicable to the subdivision were recorded in 1972. These provide in pertinent part that the Association shall maintain the roads and water systems for the subdivision and that the costs for such services shall be assessed by it against the individual lot owners on a pro rata basis. No buildings or structures are to be maintained or constructed on any lot without the written approval of an Architectural Control Committee (the Committee). The Committee is given the authority to lease the common pastures in the subdivision "not within an approved fence or enclosure" to third parties for the purpose of grazing horses and cattle, with all income from such leasing activity to "be utilized for the improvement and maintenance of the pasture and open spaces."Lot owners
Page 423
and their families are granted fishing rights on any streams within this and all other Company subdivisions. Further, under the covenants, the Company retained a 30-foot easement along each side of any fishing streams.
In 1979, defendant acquired seven contiguous lots inside the subdivision encompassing approximately 40 acres. In May 1981, without the written approval of the Committee, he constructed a fence around the perimeter of his property and removed part of an existing fence. Paragraph 21 of the covenants provides in pertinent part that:
"No fences may be erected, constructed or maintained upon any lot unless ... [it] is a fence currently existing on the property, provided that holding corrals for horses and fences around dwellings and yards may be allowed upon the approval of the Committee."
Plaintiffs (the Association, the Committee, and various individual lot owners) commenced the present action against the defendant, seeking a mandatory injunction requiring him to remove the fence surrounding his 40 acres that he constructed and to replace the previously existing fence. Plaintiffs also sought damages for loss of leasing income and attorney fees.
In his answer, defendant alleged, inter alia, that the Committee, through one of its members, had orally approved the construction of the fence. He also relied on a provision in the covenants requiring the Committee to approve or disapprove the construction of a proposed structure within 30 days and providing that in the event the Committee fails to act within the prescribed 30-day period, the structure "shall be deemed to have been approved." In addition, he filed six counterclaims against the plaintiffs, seeking to have various covenants declared void and unenforceable. He also sought an accounting of all income derived from the leasing of the common pastures, damages for an alleged failure on the part of the Association to irrigate his property properly, and an injunction prohibiting the exercise of fishing rights by persons who did not own lots in the subdivision.
The matter was heard by the court. It determined that, by constructing a fence around the perimeter of his property, defendant had violated paragraph 21 of the covenants and that this was so regardless of whether the Committee approved the construction of the fence. Defendant was therefore ordered to remove the fence and to replace the previously existing fence.
With respect to defendant's counterclaims, the court determined that he was entitled to an accounting of the leasing income but that his remaining counterclaims against the Association and the Committee were without merit. A counterclaim against one of the individual plaintiffs was deferred for trial at a later date. The judgment appealed from was certified as final pursuant to C.R.C.P. 54(b).
I. Fencing
Defendant first contends that paragraph 21 of the covenants was ambiguous and unenforceable because the...
14 practice notes
Beaver Creek Prop. Owners Ass'n, Inc. v. Bachelor Gulch Metro. Dist., No. 10CA1024. United States Colorado Court of Appeals of Colorado December 8, 2011 ...the effect of the statute of limitations, such as an after-the-fact effort to create a basis for a fee award. Wilson v. Goldman, 699 P.2d 420 , 426 (Colo.App.1985), which Beaver Creek inappropriately brought to our attention by way of a C.A.R. 28(j) submission of supplemental authority, see ......
Woodward v. Board of Directors of Taco, No. 05CA0457. United States Colorado Court of Appeals of Colorado February 8, 2007 ...association must use its authority to enforce protective covenants in good faith and in a reasonable manner. Wilson v. Goldman, 699 P.2d 420 , 424 (Colo.App.1985). A homeowners' association has a fiduciary duty to homeowners to enforce restrictive covenants. "This duty has been imposed in re......
Lookout Mountain Paradise Hills Homeowners' Ass'n v. Viewpoint Associates, No. 92CA0989 United States Colorado Court of Appeals of Colorado June 17, 1993 ...as a whole and interpreted in view of their underlying purposes, giving effect to all provisions contained therein. Wilson v. Goldman, 699 P.2d 420 (Colo.App.1985). Here, application of these principles to the declaration of covenants does not support Viewpoint's First, by separating from t......
Tucker v. Wolfe, No. 97CA1446 United States Colorado Court of Appeals of Colorado October 29, 1998 ...are to be construed as a whole and interpreted according to their plain language, in view of their underlying purpose. Wilson v. Goldman, 699 P.2d 420 (Colo.App.1985). Any doubts as to the meaning of a restrictive covenant are to be resolved in favor of permitting free enjoyment and maximum......
14 cases
Beaver Creek Prop. Owners Ass'n, Inc. v. Bachelor Gulch Metro. Dist., No. 10CA1024. United States Colorado Court of Appeals of Colorado December 8, 2011 ...the effect of the statute of limitations, such as an after-the-fact effort to create a basis for a fee award. Wilson v. Goldman, 699 P.2d 420 , 426 (Colo.App.1985), which Beaver Creek inappropriately brought to our attention by way of a C.A.R. 28(j) submission of supplemental authority, see ......
Woodward v. Board of Directors of Taco, No. 05CA0457. United States Colorado Court of Appeals of Colorado February 8, 2007 ...association must use its authority to enforce protective covenants in good faith and in a reasonable manner. Wilson v. Goldman, 699 P.2d 420 , 424 (Colo.App.1985). A homeowners' association has a fiduciary duty to homeowners to enforce restrictive covenants. "This duty has been imposed in re......
Lookout Mountain Paradise Hills Homeowners' Ass'n v. Viewpoint Associates, No. 92CA0989 United States Colorado Court of Appeals of Colorado June 17, 1993 ...as a whole and interpreted in view of their underlying purposes, giving effect to all provisions contained therein. Wilson v. Goldman, 699 P.2d 420 (Colo.App.1985). Here, application of these principles to the declaration of covenants does not support Viewpoint's First, by separating from t......
Tucker v. Wolfe, No. 97CA1446 United States Colorado Court of Appeals of Colorado October 29, 1998 ...are to be construed as a whole and interpreted according to their plain language, in view of their underlying purpose. Wilson v. Goldman, 699 P.2d 420 (Colo.App.1985). Any doubts as to the meaning of a restrictive covenant are to be resolved in favor of permitting free enjoyment and maximum......
| https://case-law.vlex.com/vid/wilson-v-goldman-no-890467399 |
Neural representation of abstract task structure during generalization | eLife
The human brain maintains a representation of latent task states within frontoparietal networks during the generalization of behaviors to novel settings.
Neural representation of abstract task structure during generalization
https://doi.org/10.7554/eLife.63226
Avinash R Vaidya
Henry M Jones
Johanny Castillo
Neural representation of abstract task structure during generalization
eLife 10 :e63226.
https://doi.org/10.7554/eLife.63226
Version of Record published
March 31, 2021 (This version)
Accepted Manuscript published
March 17, 2021 (Go to version)
Accepted
March 16, 2021
Received
September 18, 2020
Avinash R Vaidya
Henry M Jones
Johanny Castillo
David Badre
(2021)
Neural representation of abstract task structure during generalization
eLife 10 :e63226.
https://doi.org/10.7554/eLife.63226
Abstract
Cognitive models in psychology and neuroscience widely assume that the human brain maintains an abstract representation of tasks. This assumption is fundamental to theories explaining how we learn quickly, think creatively, and act flexibly. However, neural evidence for a verifiably generative abstract task representation has been lacking. Here, we report an experimental paradigm that requires forming such a representation to act adaptively in novel conditions without feedback. Using functional magnetic resonance imaging, we observed that abstract task structure was represented within left mid-lateral prefrontal cortex, bilateral precuneus, and inferior parietal cortex. These results provide support for the neural instantiation of the long-supposed abstract task representation in a setting where we can verify its influence. Such a representation can afford massive expansions of behavioral flexibility without additional experience, a vital characteristic of human cognition.
Introduction
Many complex tasks we perform daily, though different in their details, share an abstract structure. For example, riding a bike and driving a car differ in many details, including the actions they require, but they share an abstract similarity as modes of transportation. It has long been proposed that humans can learn this abstract structure and leverage it to think creatively, make novel inferences and rapidly generalize knowledge to unique problems we have never encountered before (Gick and Holyoak, 1980;Harlow, 1949;Tenenbaum et al., 2011;Tolman, 1948) – e.g. applying rules learned about when to break on a bicycle to an automobile. Reproducing this generativity continues to vex even the most impressive artificial intelligences (Lake et al., 2017;Russin et al., 2020), and is arguably one of the most defining features of human cognition (Penn et al., 2008).
In reinforcement learning, the structure of a task is described by its decomposition into ‘states’ – variables that specify the condition of the environment (Sutton and Barto, 2018). The definition of states is critical to determining how learning takes place, such as whether new information is restricted to a specific set of circumstances or is shared between conditions with overlapping features. States that cannot be resolved from sensory information alone are said to be ‘hidden’ or ‘latent’ – in such cases, the organization of these states be must inferred from the distribution of rewards, or other outcomes, throughout the task. In practice, latent states (LSs) have been defined as distributions over the spatio-temporal occurrence of rewards or punishments (Gershman et al., 2013;Nassar et al., 2019), task stimuli or stimulus features (Collins and Frank, 2013;Gershman and Niv, 2013;Tomov et al., 2018), or conditionalization of action values based on recent task history (Schuck et al., 2016;Zhou et al., 2019). From this distribution over task features, an agent can infer which conditions might belong to the same LSs and which do not. This information can then be used to segregate or lump together observations, making learning more efficient, and enabling generalization of learning between settings that share the same LSs (Gershman and Niv, 2010;Niv, 2019).
Recent work has provided evidence that the orbitofrontal cortex (OFC) and hippocampus (HPC) maintain structured, abstract representations of tasks during planning and navigation in conceptual spaces, including latent task states (Liu et al., 2019;McKenzie et al., 2014;Schuck et al., 2016;Tavares et al., 2015;Wilson et al., 2014;Zhou et al., 2019). Likewise, other studies have investigated the neural processes supporting fast acquisition of stimulus-response rules based on latent task knowledge (Badre et al., 2010;Collins et al., 2014;Eichenbaum et al., 2020;Frank and Badre, 2012). However, an essential feature of an abstract representation is that it can be used to generalize behaviors to new settings, in absence of feedback, through a process of inference. To date, no study has investigated the neural systems that maintain an abstract task representation that is observed to satisfy this criterion. As a consequence, it remains unknown how the brain carries out this essential function. To address this gap, we used fMRI to test the hypothesis that latent, generalizable task representations used to control our behavior during a task are instantiated in neural activity, particularly in OFC and HPC.
Participants completed a task where they gathered rewards in an environment where a latent, generalizable structure was available. Throughout the experiment, images of trial-unique items from three categories appeared beneath a context, denoted by a scene (Figure 1). Participants decided whether to ‘sell’ each item or pass. If they sold, they would receive or lose reward probabilistically, as determined by the combination of item category and context. Participants saw each of these combinations in short batches of trials termed mini-blocks. Importantly, the contexts could be clustered based on the expected values associated with each item category. This structure provided an opportunity to link these contexts together using an abstract, LS representation based on the distribution of category-value associations over contexts. We hypothesized that participants would form, and later use, this representation to generalize adaptive behaviors to new conditions without any need for reinforcing feedback.
Figure 1 with 1 supplement see all
Schematic of the experimental task, and its design and logic.
( a) In each trial of the training and generalization phases, participants were asked to make a decision to sell or pass on an image, the value of which depended on contexts shown above the image. … see more
Results
Participants were tested in three sessions. In session 1, participants completed a behavioral version of the task where performance in the generalization phase determined their inclusion in the fMRI experiment in sessions 2 and 3. 48% of participants passed a criterion of ≥70% accuracy in all 18 generalization conditions and so were recruited for two fMRI sessions. Participants who failed to meet this criterion performed the same task in two additional behavioral sessions rather than in the scanner. Of these participants, 50% ultimately passed the accuracy criterion by the third session. Thus, the majority of participants (75%) could carry out this generalization task given sufficient experience (Figure 2—figure supplement 1).
In session 2, all participants carried out the same task, but with new context stimuli – requiring them to learn which contexts linked to which LSs anew. This session also included additional blocks of the generalization phase with conditions pseudo-randomized (rather than organized in mini-blocks). fMRI participants completed these additional blocks in the scanner and the rest of the experiment behaviorally. In session 3, all participants completed a shortened version of the training as a reminder of the task and were presented with new pseudo-randomized generalization blocks (in the scanner for fMRI participants).
Abstract task structure affords inference of novel behaviors without feedback
Analysis of learning curves within mini-blocks of trials demonstrates that participants immediately made use of the abstract task structure in the first segment of the generalization phase. Through the first few trials of each mini-block of the initial and new category training, fMRI participants’ accuracy steadily improved. In contrast, in the generalization phase, accuracy was near ceiling from the first trial (mean p(correct)=0.96, SD = 0.06;Figure 2a). The rate of this learning curve in the generalization phase was significantly lower than either of the other phases (Figure 2b), consistent with participants inferring an adaptive behavior without need for additional experience or feedback (Wilcoxon signed rank tests: Z’s ≥ 3.21, p’s ≤ 0.004, Bonferroni-corrected for multiple comparisons). Similar results were observed in participants who completed the behavioral version of the task in session 2 and passed the generalization accuracy criterion (Figure 2—figure supplement 2a), with a significantly lower rate of change in the accuracy learning curve in the generalization phase compared to the initial training or new category training phases (Wilcoxon signed rank tests: W’s = 45, p’s = 0.01, Bonferroni-corrected for multiple-comparisons).
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Learning curves and repetition effects from training and generalization phases for fMRI participants in session 2.
( a) Mean accuracy across participants for first six trials of the first nine mini-blocks of initial and new category training, as well as blocked generalization phase. Dashed line indicates … see more
Notably, high accuracy during generalization was accompanied by elevated reaction times (RT; mean = 4.04 s, SD = 1.7 s) on the first trial, with a sharp drop-off subsequently (mean = 1.15 s, SD = 0.08 s;Figure 2c). The rate of speeding was significantly steeper in the generalization phase compared to the initial or new category training phases averaged across the first three contexts in each phase (Wilcoxon signed rank tests: Z≥ 3.46, p≤0.002, Bonferroni corrected for multiple comparisons;Figure 2d). The same pattern in the rate of speeding was observed in participants from the behavioral group who passed the generalization criterion in session 2 (generalization versus initial training RT rates: W = 36, p=0.047, Bonferroni-corrected for multiple-comparisons;Figure 2—figure supplement 2d). Thus, rather than immediately applying a structure learned incidentally during training, participants took additional time to infer values during the first generalization trials – indicative of a concerted, deliberative process.
As each LS was repeated twice via two contexts during generalization, we could test how previously encountering a LS impacted RTs during a repetition. Participants were faster for the second presentation of contexts from the same LS during generalization compared to contexts from different LSs (repeated measures t-tests: (15)≥2.13, p’s < 0.05, d’s ≥ 0.53), indicating that additional inferences were made more quickly when a LS had been accessed previously (Figure 3a). Comparison of the rate of exponential curves fit to these RT data in each participant demonstrated that these curves were steeper in the first context compared to the second context averaged across LSs (Wilcoxon signed rank test: Z= 3.36, p=0.0007), but there were no differences in the rate of these curves according to the sequential order of LSs (Wilcoxon signed rank test: Z≤ 1.13, p≥0.2, uncorrected;Figure 3b). A numerically similar pattern of results was observed for the rate of change for learning curves in the behavioral group who passed the generalization criterion, but did not reach statistical significance (Figure 3—figure supplement 1). These data argue that participants were faster in completing the transfer of new category values to contexts if a context belonging to the same LS representation had already been activated, but did not necessarily use information about other LSs they had encountered in narrowing this inference problem.
Reaction times (RT) for fMRI participants in mini-blocks during generalization in session 2, organized by the presentation of latent states (LS 1, 2, 3) and contexts (first and second).
Participants were significantly slower on the first trial of mini-blocks when encountering the first context in a LS compared to the second context in the same LS, but not in subsequent trials. ( a) … see more
Latent task states continue to influence behavior after initial inference
After an initial inference, participants may have formed rules for responding to the new context-category combinations and no longer used the LS representation throughout the scanned generalization task. We reasoned that if participants are continuing to utilize the latent abstract task structure, this would be evident in switch costs when the active LS changed between-trials (Collins and Frank, 2013). To avoid conflating LS and context switches, we isolated this analysis to only trials where the context changed between trials. We found a significant switch cost in RT for trials when the LS changed versus stayed the same between trials (repeated-measures t-test: t(15) = 2.33, p=0.03, d= 0.58;Figure 2e), which did not differ between scanner sessions (p=0.8). The same effect was independently observed in participants in the behavioral group who passed the generalization criterion (Figure 2—figure supplement 2; t(8) = 3.45, p=0.009, d= 1.15). These data indicate that participants used these LS representations throughout the scanned task. Participants were also faster when both the context and LS remained the same ( t(15) = 5.29, p<0.0001, d= 1.32).
Generalization behavior is best explained by a hierarchical LS representation
Notably, generalization in this task might not only be achieved through the use of a LS representation to bridge contexts. For example, an associative retrieval process could also explain these results if newly trained category values could be transferred through mediated retrieval of contexts held-out of the generalization phase via shared category-value associations learned in the initial training (Kumaran and McClelland, 2012;Schapiro et al., 2017).
To test this possibility, we compared four alternative computational models that generated predictions for participants’ RTs based on different memory network configurations where contexts, category-values, and LSs were represented as nodes with different levels of activation.
Figure 4 with 1 supplement see all
Computational modeling of reaction times (RT) during generalization phase for fMRI participants in session 2.
Each panel shows simplified schematics for spreading activation in four alternative model networks for a trial involving a decision about an image of an object in context A1 (i.e. A1-O-). ( a) … see more
The independent associative retrieval (IAR) model similarly did without a LS representation, but rather than only representing contexts and categories as conjunctions, maintained independent representations of each and linked contexts to each other based on shared category-value associations (Figure 4b).
In contrast to these associative retrieval models, we included two LS models. A simple LS model connected category-values to three LSs, but forewent any representation of context (Figure 4c). A hierarchical latent state (HLS) model connected category-values to contexts, and further clustered these contexts around LSs, so that activation of each context and category was inherited from the LS representation (Figure 4d).
Each of these models relied on the basic assumption that RTs depend on the degree of activation in the network nodes currently activated. On each trial, activation within the network would increase at different rates depending on the relation of nodes to those that were activated during retrieval. Three rate parameters determined this increase for nodes that were directly activated on a trial (α 1), nodes directly connected to those activated (α 2), and the rest of the network which might be searched but was not directly relevant to the current trial (α 3). To establish that these models differed substantially in their predictions, we tested each model on data simulated using the best fit model parameters from itself and the three alternatives. This cross-model comparison clearly demonstrated that the predictions of these four models were dissimilar and each model provided a much better fit to itself than its alternative counterparts (Figure 4—figure supplement 1a).
The HLS model provided the best fit to participants’ RT data in the fMRI group in sessions 1 and 2, and the nine participants in the behavioral group who passed the generalization accuracy criterion in session 2 (Table 1;Figure 4—figure supplement 1a). Comparison of the three rate parameters of this model showed an ordering consistent with the expectation that the degree of activation of items should fall off at a distance from the items presented on the current trial (Figure 4—figure supplement 1b), where values for α 1were significantly greater than α 2and α 3(Wilcoxon signed rank test: Z’s = 3.51, p’s = 0.001, Bonferroni corrected), and values for α 2were significantly greater than α 3( Z= 2.68, p=0.02, Bonferroni corrected).
Table 1
Sum of negative log-likelihood for four alternative models across participants and fraction of participants where each model was lowest in this measure in parentheses, for each group and session.
Conjunctive associative retrieval Independent associative retrieval Latent state Hierarchical latent state fMRI group – session 1 3537.78 (1/16) 3227.38 (2/16) 3428.23 (0/16) 3061.04 (13/16) fMRI group – session 2 3849.60 (0/16) 3413.20 (4/16) 3569.10 (0/16) 3264.13 (12/16) Behavioral group – session 2 2063.65 (0/9) 1851.76 (0/9) 1921.61 (0/9) 1713.73 (9/9)
Table 1—source data 1
Sum of negative log-likelihoods for individual participants in fMRI and behavioral groups for each model in each session.
https://cdn.elifesciences.org/articles/63226/elife-63226-table1-data1-v2.zip
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To understand why the HLS model better accounted for participants’ data, we compared RTs simulated from the best fit model parameters for each participant with each of the four models, focusing on data from session 2 for the fMRI group, as it was more pertinent to the neuroimaging results (Figure 4a–d). We organized these data by the order of presentation of each context associated with each LS (as inFigure 3), switches of category mini-block, and all other trials within a mini-block and then compared the root-mean squared deviation (RMSD) of each model for each trial type. We found that both the LS models provided a better fit on category switch trials compared to the CAR model (repeated-measures t-test, t(15) ≥ 4.76, p’s ≤ 0.002, d≥ 1.19, Bonferroni-corrected for multiple comparisons). Numerically, the HLS model also provided a better fit to these trials than the IAR model, though this difference was not statistically significant ( t(15) = 2.02, p=0.06, d= 0.50, uncorrected). The two associative retrieval models tended to systematically overestimate RTs on these category switch trials, likely because category-values associated with the trained context in the new category training phase were only activated by mediated retrieval, whereas in the LS models these category-values benefited from inherited direct retrieval of the higher-order LS representation. The HLS model also had lower RMSD for the first presentation of the second context compared to the LS model ( t(15) = 4.76, p=0.001, d= 1.19, Bonferroni-corrected for multiple comparisons). As the LS model had no separate representation of context, any activation related to a prior LS would be fully transferred to its second presentation through another context, resulting in an underestimation of RTs. Instead, the results were more consistent with separate context representations that inherit activation from a higher-order LSs, that is, the use of a HLS structure.
Representation of an abstract task representation in multi-voxel activity patterns
Having verified that participants form and use an abstract task representation to control behavior, we sought to test the neural systems that support this representation. We carried out a representational similarity searchlight analysis (RSA) using multiple linear regression to compare empirical representational dissimilarity matrices (RDMs) from pattern activity to hypothesis RDMs quantifying the predicted distances between conditions based on LSs, contexts, item categories, expected value, interactions between these factors, and control regressors (Figure 5—figure supplement 1).
We found evidence for a LS representation in bilateral dorsal- and ventrolateral prefrontal cortex (PFC) with a rostral distribution, as well as the bilateral precuneus, left middle temporal gyrus, and bilateral inferior parietal lobules (Figure 5a;Supplementary file 1). Comparing this statistical map with resting-state functional networks fromYeo et al., 2011revealed that this LS representation overlapped most with a frontoparietal network centered on the inferior frontal and intraparietal sulci (Figure 5—figure supplement 2).
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Whole-brain representational similarity searchlight analysis for main effects of interest.
Each upper panel shows hypothesis representational dissimilarity matrix (RDM) for task factors. Lower panels show t-statistic map from a searchlight analysis testing these predictions in pattern … see more
In contrast, context was associated with activity in the bilateral fusiform gyri (Figure 5b). Expected value was associated with activity in OFC, as well as left superior frontal and angular gyri (Figure 5c). Item category was robustly represented throughout visual areas and PFC (caudally on the left and broadly on the right;Figure 5—figure supplement 3).
To test whether these results were consistent across fMRI sessions, we carried out separate whole-brain searchlight RSAs within each session. The resultant statistical maps for the main effects of interest were similar in both sessions (Figure 5—figure supplement 4). Contrasts between statistical maps for all terms in the multiple regression model only revealed a stronger effect for value in the left middle temporal gyrus in session 2 compared to session 3 (MNI coordinates: −48,–22, 0), and no other significant differences in either direction.
As a secondary question, we were also interested in whether higher-order representations of latent task states and expected value influenced each other, or perceptual-semantic representations of item category. To test this, we included regressors for hypothesis RDMs that captured interactions between LSs, value, and item category, as well as control regressors for interactions of these factors with context. Interactions between item category with value and LS were not significant; though items with same value in the same LS were represented more similarly in ventral temporal cortex (VTC) (Figure 5—figure supplement 1), observations recapitulated in ROI-based analyses of activity within the VTC (Figure 6b).
Figure 6 with 1 supplement see all
Representational similarity analysis results from all voxels included in regions of interest (ROIs).
Plots show distribution of beta coefficients across participants from multiple linear regression analyses comparing hypothesis representational dissimilarity matrices (RDMs) with empirical RDMs … see more
We also conducted ROI-based RSAs focused on HPC and OFC, given a priori expectation that these regions are involved in representing latent task structure during task performance. RSAs within these ROIs were null for LS representations (Figure 6a,c). To test these effects at a finer grain, we conducted second-level tests of the whole-brain searchlight analysis masked by these ROIs. Here, we found signals consistent with LS and expected value representations in central OFC, but not HPC (Figure 6—figure supplement 1;Supplementary file 2). There were significant effects for category representations in both of these ROIs, in line with broad discrimination between semantically and perceptually distinct categories of stimuli in these regions (Chikazoe et al., 2014;Kuhl et al., 2012;McNamee et al., 2013;Pegors et al., 2015).
Univariate contrast of accuracy
Lastly, we tested a univariate contrast of correct and error responses. Although less functionally specific than the above analyses, we expected this contrast to reveal regions broadly involved in engaging with this generalization task. This contrast revealed greater activation in the HPC and OFC on correct responses (Figure 7;Supplementary file 3).
Figure 7
Univariate whole-brain contrast of correct and erroneous responses projected onto inflated cortical surfaces and on a single axial slice showing orbitofrontal cortex and hippocampus.
This statistical map was defined with a cluster forming threshold of p<0.001 and corrected for multiple comparisons with permutation tests for defining a cluster extent threshold at p<0.05. Cluster … see more
Discussion
Here, we observed that a LS representation capable of supporting generalization of knowledge to new settings is instantiated most strongly within activity in mid-lateral PFC and parietal cortex. This pattern overlaps with a network previously implicated in contextual modulation of behavior in hierarchical reinforcement learning and cognitive control tasks (Badre et al., 2010;Choi et al., 2018;Collins et al., 2014). Like hierarchical task structure in those experiments, latent task states enable faster learning, reduced memory load, and greater behavioral flexibility (Frank and Badre, 2012;Koechlin and Summerfield, 2007). Recent work has similarly implicated mid-lateral and inferior parietal cortex in inferring latent causes within tasks (Tomov et al., 2018) and discovering hierarchical rules (Collins et al., 2014;Eichenbaum et al., 2020). Our findings extend these observations to indicate that this network is not just involved in discovering and maintaining task structure, but more generally represents tasks in an abstract format that facilitates novel behaviors, even in the absence of reinforcement. Once formed, such a fully abstract task representation could potentially be used not only for online, stable task control in the face of changing circumstances, but also as the generative mechanism for rapidly generalizing diverse knowledge between settings, affording great behavioral flexibility with minimal training.
Our behavioral results offer insights into the timing and nature of processes that form this abstract task representation. While some accounts of generalization argue that integration of related items occurs during encoding (Shohamy and Wagner, 2008;Zeithamova et al., 2012a), others have suggested that this can happen online during retrieval through statistical inference (Kumaran and McClelland, 2012). In this task, participants could build their task representation at any point prior to the generalization phase, including during the initial training phase. The lengthy RTs during the first trials of generalization suggest that this inference required additional online processing, and this abstract task structure may not have been fully constructed until it was probed. These data are consistent with accounts arguing that generalization during acquired equivalence can also occur at retrieval (De Araujo Sanchez and Zeithamova, 2020) and depends on the demand to make new inferences. It is likely that linking of contexts to a LS occurs at both encoding and retrieval, with the timecourse of this process varying across individuals.
Modeling of RTs during the first mini-blocked section of the generalization phase has also provided some insights into the process of how generalization of task information takes place. An associative retrieval model without any LS representation underestimated RTs on category switch trials, as this model did not separate category-values by context or LS. However, a fully integrative representation of LSs was also insufficient, as this alternative collapsed related contexts into the same LS, and underestimated the time needed to make additional inferences about contexts that had not been presented earlier. Instead, our data were most consistent with an intermediate solution where related contexts were bridged by a LS, and category-values were separated by contexts. Thus, our data were consistent with participants accomplishing generalization via an integrated task representation on the basis of shared features (Schlichting and Preston, 2015;Shohamy and Wagner, 2008;Zeithamova et al., 2012b), while still retaining independent representations of each context.
Our task design may have shaped this representation: the instructions strongly encouraged participants to link contexts to an unseen latent variable (see Materials and methods), and the mini-block trial structure likely encouraged learning the values of each category within each context. Thus, ours is an evidence that we can form such LS representations, use them for generalization, and represent them in frontoparietal network while performing a task based on them. We do not rule out that people cannot also use associative retrieval or that they may do so instead of using a LS in other task contexts. Nonetheless, evidence that we can, and do, form LSs under certain circumstances is an important observation that confirms a long held hypothesis in the field.
Behavioral evidence also indicated that this LS representation was maintained throughout the scanned generalization task. Analysis of RTs showed switch costs for latent task states that exceeded those for changes of context alone. In principle, this representation was not necessary for this portion of the task, as participants could have instead consulted the inferred values of the 18 context-category combinations, or simply memorized which six conditions were associated with negative expected values. Instead, participants appeared to continue referencing this more abstract, and compact, representation of the three latent task states to aid decision-making. Maintaining such a representation would be particularly helpful as a means of compressing task information in memory, and it could be useful in case of further need to update information about these latent task states and propagate this information to linked task conditions (e.g. in a reversal of the expected values for a particular context-category combination). Characterizing if, and how, the neural representation of latent task states described here comes to influence decision-making and learning in such settings remains an important outstanding question.
In this experiment, we were able to cross two factors previously associated with OFC function within the same experiment: latent task states and expected value (Stalnaker et al., 2015). We found limited evidence for OFC representing latent task states, though expected value was robustly represented in this ROI. These data are consistent with rodent electrophysiological data indicating that expected value signals contribute more to the variance of activity within this region than representations of task space (Farovik et al., 2015;Zhou et al., 2019). However, both OFC and HPC were activated for correct responses compared to errors, possibly consistent with their role in retrieving relevant task knowledge, if not in actively representing latent task structure in this experiment.
Prior observations may be reconciled with our results if distinct neural circuits are involved in representing latent task states under different cognitive demands. Much recent work has focused on the involvement of the medial PFC, OFC, and HPC in learning and representing structured knowledge, from the relations of paired associates to complex schemas (Baldassano et al., 2018;Chen et al., 2017;Garvert et al., 2017;Ghosh et al., 2014;van Kesteren et al., 2013). However, the network identified here as representing latent task states shares greater similarity with regions in lateral PFC and inferior parietal cortex identified by past studies focused on abstract representations of a task in cognitive control settings (Loose et al., 2017;Woolgar et al., 2011). While these regions belong to mostly distinct functional networks (Choi et al., 2018;Yeo et al., 2011), information may be shared via strong connections between mid-lateral PFC with medial PFC, OFC, and HPC (Averbeck and Seo, 2008;Petrides, 2005), and regions that straddle these networks, such as the angular and superior frontal gyri (Margulies et al., 2009). Information passed through these select pathways might allow structured knowledge about abstract task elements to inform a control representation in mid-lateral PFC (Badre and Nee, 2018).
Frontoparietal systems may be more involved in representing this kind of abstract task structure when it is necessary for actively controlling behavior contingent on changing contexts, as in this experiment. Other work that has examined analogous abstract task representations in the context of conditional action selection and selecting between causal models have found evidence for the involvement of frontoparietal cortex (Collins et al., 2014;Eichenbaum et al., 2020;Tomov et al., 2018), similar to our results. In contrast, OFC and HPC could be engaged more by resolving uncertainty about the prevailing latent task state (Chan et al., 2016;Saez et al., 2015), or planning within a cognitive map of latent task states (Schuck et al., 2016;Zhou et al., 2019). Other related work indicates that these regions are involved in, and necessary for, constructing abstract representations (Kumaran et al., 2009;Schuck and Niv, 2019;Spalding et al., 2018;Zeithamova et al., 2012a), and so may be particularly engaged by the process of bridging contexts and forming a representation of latent task states. Thus, while OFC and HPC may work together to form an understanding of the latent task structure, mid-lateral PFC and parietal cortex are perhaps more involved in implementing this representation for the purposes of controlling behavior. Indeed, such a division of labor would be consistent with the long-standing observation of a knowledge-action dissociation from the study of patients with frontal lobe disorders (Milner, 1964). As we did not scan participants during training, or the first mini-blocked section of the generalization phase, we cannot yet speak to the neural circuits engaged in initially forming this abstract task representation.
In sum, we have discovered evidence of a neural instantiation of a long-supposed construct of cognitive models: an abstract task representation that enables generalization to new tasks in absence of reinforcement. Future studies could evaluate how and when this representation is formed, when and if this neural representation is necessary for generalization behavior, and why some participants take longer to leverage this abstract task structure. This study thus opens new ground in understanding the neural systems supporting some of the key cognitive processes and behavioral features that distinguish species like humans in their behavioral flexibility and capacity for rapid leaning (Lake et al., 2017;Penn et al., 2008).
Materials and methods
Experimental procedure
The study design and analyses were pre-registered on the Open Sciences Framework prior to collecting the data (https://osf.io/x6fmb). Participants completed an acquired equivalence task where they learned that nine contexts belonged to three different LSs (three per state) on the basis of their shared value associations for three object categories. They then used this knowledge to complete a generalization task where they inferred values for a new set of categories in contexts with which they had not been previously paired. A schematic overview of the structure of this experiment is provided inFigure 1andFigure 1—figure supplement 1.
To aid in building a structured representation of the task, participants were told they were playing the role of a photographer selling photos of different item categories in three goblin kingdoms with distinct preferences for these categories. In each trial, participants had to make a bet on whether to sell an image or to pass. This decision was a risky choice where selling could be paid off with a reward in fictitious gold or punished with a loss of gold. After a decision to sell, feedback was provided in terms of the gold won or lost. Passing would lead to no change in gold, but feedback was provided in terms of the outcome had the participant chosen to sell. Thus, in all phases of the experiment except for generalization (see below), fully informative feedback was provided independent of participants’ choices. Participants were incentivized with a monetary bonus proportional to the amount of gold they earned in the task. All photos were trial-unique so that participants never learned the values of specific images, but of general image categories.
This experiment took place over three sessions. Each experimental session was comprised of three main phases. First, in the beginning of the initial training phase, participants were tasked with selling photos of hands, foods, and leaves in three contexts, represented by a natural scene image above the photo they were selling (A1, B1, C1). Participants were told that the contexts each came from a different ‘kingdom’, equivalent to the generative LSs (LS A, LS B, LS C), and that each of these kingdoms preferred one category of items strongly over the other two categories. Within each context one item category was associated with a 90% probability of reward and 10% probability of punishment for a decision to sell, while the other two categories were associated with a 10% chance of reward and 90% chance of punishment. In each trial in this initial training phase, participants could gain 50 gold or lose 25 gold for choosing to sell a photo. Thus, the expected value of selling, without knowledge of the probability of reward for each category, was zero.
After two blocks of this training, participants then encountered ‘roadwork’ after which they would learn about a new context in each kingdom represented by novel natural scenes (A2, B2, C2). This roadwork repeated a second time after another two blocks so that participants learned about three contexts in each of the three kingdoms. Importantly, all contexts associated with a given LS had the same reward probability structure across item categories. Participants were not directly informed of which contexts corresponded to which kingdoms, but had to make these inferences based on their shared category values. The scene images for each context were randomly selected from a set of nine for each participant, so there was no systematic visual relationship between the contexts of each kingdom. Further, as contexts belonging to each ‘kingdom’ were encountered after each episode of roadwork, this event bound was not a cue to task structure and no aspect of temporal adjacency could link contexts to a LS.
These initial training blocks consisted of 54 trials with six trials per condition. This initial training phase was organized in batches consisting of a series of trials for each context-category combination (i.e. a ‘mini-block’). These mini-blocks were nested by context, so that participants saw each category in the same context one after another (e.g. A1-hands, A1-leaves, A1-foods), before switching to a new context and looping once again through each combination of context-category pairs (e.g. B1-leaves, etc.). The order of presentation for these categories within each context was randomized, as was the order of these contexts. Following these six initial training blocks, participants completed a final reminder training block with the three categories presented in all nine contexts in mini-blocks of eight trials (216 trials total).
In the second phase, participants completed training on new image categories (faces, animals, and man-made objects) within a subset of the previous contexts (e.g. A3, B3, C3). Which set of contexts was presented in this phase (i.e. A1, B1, C1 versus A2, B2, C2 or A3, B3, C3) was randomized across participants. Participants completed 90 trials in the course of a single block, consisting of 10 trial mini-blocks for each combination of the three contexts and three categories.
In the new category training phase, two categories of items were now associated with a 90% chance of reward and 10% chance of punishment in each context, while these values were reversed in one context. The categories that were rewarded and punished in each context were randomized with respect to the categories in the initial training across participants. For example, there was no rule in the experiment that faces have high value in contexts where hands have low value. The punishment associated with selling a photo was increased to 100 gold in this block so that the expected value of selling a photo without knowing the probability of reward in a specific category-context combination was still zero.
Finally, in the third phase, participants carried out a generalization test where they were presented with photos from these new categories in conjunction with the six contexts held out of the prior new category training (e.g. A1, B1, C1 and A2, B2, C2, if A3, B3, C3 were trained with the new categories). Critically, participants did not receive feedback throughout this phase and could thus not learn the values of these new categories from experience. Instead, they would have to rely on their knowledge about which contexts belonged to which kingdoms (i.e. LSs) based on the shared category value associations learned in the initial training phase. This generalization test included 10 trial mini-blocks for each of the 18 conditions (each context-category combination, with three categories and six contexts), resulting in 180 trials total. Participants were informed that the value in gold earned and lost on each trial had been doubled from the new category training phase to further incentivize performance.
It is important to emphasize that generalization during this phase was only possible based on a representation of the shared LSs among contexts. The particular pairings of items and contexts during generalization had never been encountered previously. And, as no feedback was provided during this phase, mappings could not be learned through reinforcement. Further, as the item categories themselves were different from the initial training phase, nothing about the objects or values could link the contexts encountered during generalization to what was learned during phases 1 or 2 except for an abstract LS. That LS already clustered the contexts encountered during generalization with that encountered during new category learning because they had shared a value structure during initial learning, albeit a different value structure on different object categories. Thus, performing accurately during the generalization phase of this task provides unambiguous evidence for reliance on an abstract LS representation.
For all blocks of the training and mini-blocked generalization phases, there was no response deadline. The inter-trial interval (ITI) was generated from a lognormal distribution with a mean of 1 s, maximum time of 4 s, and minimum of 0.5 s. Participants’ choice was underlined and the stimuli remained on screen for a 0.5 s inter-stimulus interval. In all blocks, except the generalization test, feedback was displayed for 1.5 s, after which the trial would end. Participants also briefly saw the total gold they had earned within the block after it had ended. However, as there was no way for participants to link these earnings back to the specific trials within the generalization phase, they could not learn the structure of the task from this kind of feedback once they had reached this section of the experiment.
As already noted, this experiment took place over three sessions. The first session was entirely behavioral and served to test how well participants could complete the generalization phase. Prior behavioral pilot experiments had found that approximately 50% of participants did not successfully infer all new context-category values during generalization based on only one experience with training, and so failed to completely learn the latent task structure. As our pre-registered analysis plan depended on participants understanding this structure, we planned, a priori, to exclude from fMRI any participants who did not meet a performance criterion of ≥70% accuracy in all 18 conditions of the generalization test in this first session. Instead these participants were asked to return and complete the rest of the experiment in two additional behavioral sessions. This allowed us to test whether these participants could generalize in this task, given sufficient experience (see main text). That observation helps limit any concerns about generalizability raised by our selection procedures.
In the second and third sessions, after completing the blocked generalization test, participants completed three functional runs of the generalization task but without the nested trial structure (i.e. mini-blocks nested by contexts). These blocks also had a three second response deadline for each trial. In each run, 10 trials from each of the 18 conditions were presented in a pseudo-random sequence optimized for efficiency using Optseq2 with ITIs ranging from 1 to 9 s (180 trials in total) (Greve, 2002). This also ensured that the rate of transitions between trials that shared features was effectively at chance (i.e. 33% for LSs, 16.7% for contexts). After each response, the chosen option (‘sell’ or ‘pass’) was underlined and the stimulus would remain on-screen until the end of the response deadline. A random subset of six of these 12 optimized sequences was selected for the six functional runs for each participant. Thus, each participant completed 1080 trials of this generalization task over the course of two sessions in the scanner (60 trials per 18 conditions), or behaviorally for those participants who did not pass the generalization criterion in the first session. This dense sampling per participant provided more statistical power for our study by reducing within-subject measurement error. Before completing this task, participants also completed a short practice task with the same mixed trial structure with just one trial from each condition.
Participants were given ample information about the structure of the task in instructions that preceded each new phase of the experiment, but not specific information that about which categories were rewarding in which contexts, and which contexts were part of the same kingdoms (i.e. LSs). Specifically, participants were informed that the outcomes were stable but probabilistic (without being explicitly informed of this probability), and were told how many categories of photos each kingdom preferred in each phase of the task. Participants were also instructed that they would later complete a test phase without feedback, so they should strive to commit the values of photo categories in each context to memory. They were also informed of the latent task structure in a general sense, namely that contexts represented locations within distinct kingdoms, and that the relation of contexts to different kingdoms could be uncovered by their shared values for the item categories, but were never explicitly told which contexts were associated with which kingdoms. Participants were also informed that the contexts within each kingdom could appear to be visually very different from each other to discourage them from using such a strategy to link contexts together. To facilitate forming such an abstract task representation, the instructions specifically suggested that participants use a semantic elaboration strategy that tied together the distinct contexts within each kingdom, and the values of the categories within these contexts. These instructions and the cover story about the goblin kingdoms were included to help encourage participants to learn the abstract structure of the task rather than try and individually commit the values of all 54 context-category conjunctions to memory.
At the end of the third session, outside of the scanner, participants completed a similarity judgment task for the context natural scene images that were shown in their specific generalization test. Participants were shown these images on a black background in random starting positions and asked to use the mouse to drag and drop these images on-screen so that their distances reflected the similarity. Participants were specifically instructed not to use any information about to which kingdoms the contexts belonged, but only the visual content of the image. The Euclidean distances between these images were then used to estimate a subjective, participant-specific estimate of the visual similarity of these images used as a nuisance regressor for RSA analyses.
Participants
Fifty participants were recruited for this study. Four participants were found to not meet eligibility requirements for the study after session 1 (e.g. they had piercings or implants that were not compatible with MRI), and their data was not analyzed. Twenty-four did not reach criterion performance in the generalization phase (see above) in session 1 and were invited to complete the second and third sessions in behavioral testing settings rather than in the scanner. Six of these participants dropped out of the study before completing both remaining sessions and two did not have complete data due to computer errors. Twenty-two participants passed the generalization criterion and were asked to complete the remaining two sessions in the scanner. Of these participants, two had low accuracy in the generalization phase in the fMRI sessions, indicating a failure to learn the task structure, and their data was not analyzed. Two further participants were excluded because of excessive movement (more than one voxel) in more than one run. One participant had excessive movement only in the last run of the last session and this single run was discarded from analysis. One participant could not complete the experiment due to problems with the scanner on the day of testing, and one participant dropped out of the study before finishing both scanned sessions. In total, 16 participants (10 female, mean age 21.3 years, SD = 3.3 years) passed the generalization criterion on the first day, completed both days of the fMRI experiment and were included in analyses, while 16 participants (11 female, mean age 22.3 years, SD = 2.5 years) did not pass this criterion on the first day and completed the remaining 2 days of testing in behavioral sessions. All participants gave their written informed consent to participate in this study, as approved by the Human Research Protections Office at Brown University, and were compensated for their participation.
The sample size for this study was determined by the target sample size for the fMRI experiment. Data collection was ceased once 16 participants had completed both fMRI scanning sessions while meeting eligibility for inclusion in our analysis (i.e. very little movement and high accuracy during the generalization phase of the experiment). The target sample size was based on a related experiment that successfully used RSA within an OFC ROI (Chan et al., 2016). This target sample was halved, as the current experiment involved two sessions of fMRI scanning and we expected within-subject measurement error to be reduced by this dense sampling approach.
Materials
Eighteen images of natural scenes fromKonkle et al., 2010were used to represent contexts within kingdoms (nine for session 1 and nine for sessions 2 and 3). These scenes were chosen to be distinct from each other in content and did not include any visible animals, people, or man-made objects (i.e. the image categories included in the fMRI task). Over the course of the experiment, participants saw 360 images in the initial category training for each image category (randomly sampled from a larger set of 468 images). Hand images were taken from the 11 k Hands Database (Afifi, 2019), leaf images from the Leafsnap database (Kumar et al., 2012), and food images from the Bank of Standardized Stimuli (BOSS) (Brodeur et al., 2014), as well as the Foodpics database (Blechert et al., 2014). In the new category training and generalization phases, 546 images were used from each stimulus category. These included faces from the Chicago Face Database (Ma et al., 2015), animals from the BOSS and CARE databases (Russo et al., 2018), and man-made objects, also from the BOSS database. All category images were cropped or padded with white pixels to fit within a square image with a white background.
Exponential curve fitting
To test the rate of change in RTs and accuracy, we fit an exponential function to these data in the form of
y = a b x y = a b x
where y yindicates the predicted trial RT or mean accuracy, b bindicates the trial number, and a aand x xare free parameters that determine the scale and rate of the function respectively. The MATLAB function fminunc(Mathworks, Natick, MA) was used to find values for a aand x xthat produced a function that best fit individual participants’ data using a least squares cost function. This model-fitting process was run 10 times for each parameter fit for each subject, each time with a different random starting point drawn from a standard normal distribution. We chose the parameters that resulted in the lowest sum of squares from these 10 iterations to avoid fits that had converged to local minima.
Computational modeling of reaction times
We developed a set of simple learning models to compare and contrast different explanations for how participants carried out the transfer of option values during the initial generalization phase. The models express retrieval and generalization in terms of spreading activation among a set of nodes that represent the various task elements. In each model, we structured the memory network differently according to the hypothesis tested. However, these models relied on the same basic assumptions and parameters: 1. RTs are a function of the activation strength of the nodes containing retrieved items (Anderson, 1983). 2. The activation strength for each item is initialized at zero and increases according to a Rescorla-Wagner learning rule (Rescorla and Wagner, 1972), controlled by a single rate parameter bounded by 0 to 1 (α 1), each time an option is retrieved, until it reaches an asymptotic value of 1. 3. Activation spreads to contexts and categories linked with retrieved items, controlled by a ‘mediated retrieval’ parameter (α 2). 4. Memory search increases activation in all other task-related items in each trial according to an ‘incidental retrieval’ parameter (α 3). 5. Increases in activation that are inherited from connected nodes falls off according to a power law where the rates of successive steps are multiplied together.
We tested four model variants that each differed in how they represented this memory network, and how activation of task elements propagates during generalization. Importantly, these models are not meant to simulate any particular neural system, but only describe how the format of these representations in memory might differentially affect the retrieval process and, by extension, RTs:
CAR – This model implements generalization through associative retrieval by assuming that the memory system stores conjunctions of task-relevant features which can be retrieved if any one of these features is later encountered. This memory network was represented as a matrix of contexts-by-category conjunctions. On each generalization trial, the presented context (e.g. A1) would activate related context-category-value conjunctions from the initial training based on the rate parameter α 1(e.g. A1-leaves- [negative value], A1-food-, A1-hands+ [positive value]). This would lead to the mediated activation of context-category conjunctions with the same value associations from initial training with the rate parameter α 2(e.g. A3-hands+, A2-hands+, etc.), which would in turn lead to activation of conjunctions of new categories associated with the context that appeared in the second training phase (e.g. A3-objects-, A3-Faces+, etc.), as determined by the rate of α 2 2. At the same time, the category presented on the current trial (e.g. objects) would activate conjunctions with that category from the new category training phase (e.g. A3-objects-, B3-objects+) at a rate determined by α 1The conjunction shown on the current trial (e.g. A1-objects-) would inherit activation from the related conjunction from the new category training phase (e.g. A3-objects-) and increase in activation at a rate determined by α 1 2*α 2 2. Similarly, the same category conjunction with the held out related context (e.g. A2-objects-) would receive a mediated increase in activation at a rate of α 1 2*α 2 3. All other nodes not activated by the current trial would also increase their activation as a rate of α 3.
IAR – This model also implements generalization through associative retrieval, but rather than relying on episodic conjunctions of context and category, it stores each individual task element independently and links them together based on experience. The memory network was represented as two vectors of contexts and category-value conjunctions (i.e. separate nodes for faces+ faces-, etc.). Each context was linked to their associated category-values from the initial training phase, and only the held-out contexts were directly linked to category-values from the new category training. In each trial (e.g. A1-objects-), activation in the current context (e.g. A1) would increase with the rate parameter α 1. This activation would result in direct retrieval of category-values from initial training at a rate of α 1 2, and direct retrieval of the context from the new category training phase with the same category-value associations (e.g. A3) at the rate α 1 3. Retrieval of this context then led to activation of the relevant category-value node for the current trial (e.g. objects-) from the new training phase at a rate of α 1 4, allowing generalization, as well as mediated retrieval of other category-values (e.g. faces+, animals+) at a rate of α 1 3*α 2. Activation of category values from the initial training would also lead to mediated retrieval of the other related context (e.g. A2) at a rate of α 1 2*α 2. All other nodes would increase their activation with a rate set by α 3.
LS – This model implements generalization through the formation of a LS that replaces separate representations of individual contexts. Here the memory network was represented as a vector of LSs and a matrix of LSs-by-categories, so category-values were separately nested in each LS. In this case, there was no separate representation of a context, so any increase in activation from a trial involving context A1 immediately carried over to context A2. On each trial, activation in the current LS (e.g. LS A) would increase according to the rate parameter α 1, and in the current category-value node according to α 1 2. All other category nodes linked to the active LS increase in activation according to α 2, and all other LSs increase activation according to α 3, and their nested categories according to α 3 2.
HLSs – This model also implements generalization through a LS, but builds on the basic LS model to hierarchically cluster contexts within LSs. Thus, this model builds on the LS model but includes a distinct vector for contexts, as well as a matrix of contexts-by-categories. These contexts and context-category nodes are hierarchically nested within each LS (e.g. contexts A1 and A2 are nested within LS A). Thus, activation for each of these contexts and category nodes is inherited from activation of the LSs and LS-category nodes. On each trial, activation in the current context increases at a rate of α 1 2, and in the current context-category at α 1 3. Contexts linked to the current LS also increase in activation according to α 1*α 2, as these contexts inherit mediated activation from the LS. Categories nested in these contexts increase activation according to the rate α 1*α 2 2. Activation in all other LSs increases at a rate of α 3, contexts not linked to the current LS increase at a rate of α 3 2, and their nested categories according to α 3 3.
For each model, predicted RTs were calculated simply as the sum of the activation level in the current context (or LS in case of the third model) and category, subtracted from the maximum asymptotic activation level for both combined. These values were then z-scored and compared to participants’ z-scored RTs so that both model predictions and behavioral data were on the same scale. The fit of each of these models was calculated as the negative log-likelihood for a simple linear function. Only correct responses were included in this analysis, as the model assumes correct recovery of option values from memory on each trial. Across all 16 participants in the fMRI group, only 17 trials were errors in session 2, and thus accounted for a very small fraction of the data (0.6%). Parameters were optimized using the MATLAB function fmincon, with each model fit for each participant 30 times with random starting points in order to avoid convergence on local minima.
To test whether these models made substantially different RT predictions, we carried out a cross-model comparison using simulated data. We simulated data using the optimized parameters from each participant for each model. We then fit each model on these simulated data, in the same way as with participants’ behavioral data and calculated the negative log-likelihood of this fit to test if the generative model provided a better explanation of the simulated data than the three alternatives.
fMRI acquisition procedures
Whole-brain imaging was acquired using a Siemens 3T Magnetom Prisma system with a 64-channel head coil. In each fMRI session, a high resolution T1 weighted MPRAGE image was acquired for visualization (repetition time (TR), 1900 ms; echo time (TE), 3.02 ms; flip angle, 9°; 160 sagittal slices; 1 × 1 × 1 mm voxels). Functional volumes were acquired using a gradient-echo echo planar sequence (TR, 2000 ms; TE, 25 ms; flip angle 90°; 40 interleaved axial slices tilted approximately 30° from the AC-PC plane; 3 × 3 × 3 mm voxels). Functional data were acquired over three runs. Each run lasted 15.1 min on average (452 acquisitions). After the functional runs, a brief in-plane anatomical T1 image was collected, which was used to define a brain mask that respected the contours of the brain and the space of the functional runs (TR, 350 ms; TE 2.5 ms; flip angle 70°; 40 axial slices; 1.5 × 1.5 × 3 mm voxels). The sequence of scans was identical on both sessions. Soft padding was used to restrict head motion throughout the experiment. Stimuli were presented on a 32-inch monitor at the back of the bore of the magnet, and participants viewed the screen through a mirror attached to the head coil. Participants used a five-button fiber optic response pad to interact with the experiment (Current Designs, Philadelphia, PA).
fMRI preprocessing and analysis
Functional data were preprocessed using SPM12. Quality assurance for the functional data of each participant was first assessed through visual inspection and TSdiffAna (https://sourceforge.net/projects/spmtools/) and ArtRepair (http://cibsr.stanford.edu/tools/human-brain-project/artrepair-software.html). Outlier volumes (defined by standard deviations from the global average signal) were interpolated when possible. If interpolation was not possible, a nuisance regressor was added to the run with a stick function at the time points for these volumes. Slice timing correction was carried out by resampling slices to match the first slice. Next, motion during functional runs and days was corrected by registering volumes to the first volume in the first session using rigid-body transformation.
A deformation matrix for spatial normalization to Montreal Neurological Institute (MNI) stereotaxic space using fourth order B-spline interpolation was calculated for the motion corrected functional volumes. The in-plane T1 anatomical image was used to create a brain mask for functional analysis using the Brain Extraction Tool in FSL (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/). This mask was then normalized to MNI space using the inverse deformation matrix from the normalization of the functional data.
Functional data were analyzed under the assumptions of the GLM using SPM12. Separate regressors were included for correct, erroneous, and missed responses for each condition with the duration of each response set to participants trial-wise RT (or the duration of the stimulus display for missed responses). Nuisance regressors for participant motion (six translational and rotational components) were also included, as was an additional regressor for scan session. Regressors and parametric modulators were convolved with the SPM canonical hemodynamic response function (HRF). Functional data were pre-whitened and high-pass filtered at 0.008 Hz.
Representational similarity analysis
Whole-brain searchlight and ROI-based RSA were carried out in a two-step process.
First, in participant-level analyses, an empirical RDM was estimated from the cross-validated Mahalanobis distances of the regressors for the 18 conditions (six contexts × three categories) averaged over six runs within the generalization phase from a designated subset of voxels in each participant (either defined by an ROI or a spherical searchlight) using the RSAtoolbox v.2.0 (Nili et al., 2014;Walther et al., 2016). The lower triangle of this empirical RDM was extracted giving the distances for the 153 condition pairs in this multivoxel space.
Hypothesis RDMs were constructed based on the similarities/dissimilarities that would be expected for a pure representation of a given type. These included five main effects (LS, context, value, image category, and subjective visual similarity of contexts), as well as five interactions (LS × category, LS × value, value × category, context × category, context × value).
In the case of LS, value, and context RDMs, the hypothesized distances were simply set so that conditions that were the same on these factors would have smaller expected distances and larger distances where these conditions were not the same. For the category RDM, hypothesized distances were based on asymmetric distances related to the perceptual-semantic distances of animate and inanimate stimuli observed in many other studies (Chikazoe et al., 2014;Thorat et al., 2019). Namely, that animate categories (faces and animals) were expected to be more similar to each other than inanimate objects, but inanimate objects were expected to be more similar to animals than to faces. Distances for these hypothesis RDMs were set as ordinal integer numbers to reflect predicted distances (e.g. for the category RDM, the expected distance between two conditions with faces would be 1, the distance between faces and animals would be 2, and between faces and objects would be 4). The RDM for the subjective visual similarity of contexts was specific to each participant and derived from the Euclidean distances of these natural scene images in the similarity judgment task completed at the end of the third session of the experiment. Interaction RDMs were created by extracting main effect RDMs below the diagonal (i.e. the lower triangle of the RDM matrix) as a vector, z-scoring these values and multiplying them together. These interaction regressors allowed us to test where pattern-similarity reflected the modulation of one task component another (e.g. where items belonging to different categories were represented more similarly because of shared value associations).
Second, these hypothesis RDMs were related to the empirical RDM through multiple linear regression analysis, where a coefficient was estimated relating each hypothesis RDM to empirical RDMs allowing us to parcel out variance in representational distances due to multiple factors in the same model (e.g.Nassar et al., 2019). Main effects and interaction terms within this model were allowed to compete for variance simultaneously. The lower-triangle of all hypothesis RDMs were extracted as vectors, z-scored, and included as predictors, along with an intercept term, in a multiple linear regression analysis to calculate beta coefficients relating each hypothesis RDM to the empirical RDM.
Searchlight analyses
Whole-brain analyses were carried out by passing a spherical searchlight with a radius of 9 mm over each voxel within participants’ brain mask in native space. For each participant, beta coefficients for hypothesis RDMs were calculated at each step and averaged over searchlight passes for all voxels included in the searchlight to compute fixed-effects in a first-level analysis. This approach is similar to a common approach of assigning coefficients to a the central voxel of each searchlight and then smoothing these maps before second-level tests (e.g.Devereux et al., 2013), but requires one less experimenter degree of freedom in defining the full-width half-maximum (FWHM) of the smoothing kernel. Group level analyses were conducted by normalizing participants’ beta coefficient maps to MNI space using the deformation field from the normalization of participants’ functional data and computing a one-sample t-test against zero. These volumes were kept in a 1.5 × 1.5 × 1.5 mm space and not resampled. Whole brain t-statistic maps were thresholded at a cluster defining threshold of p<0.001 uncorrected. Non-parametric permutation tests (10,000 permutations) were used to derive a cluster extent threshold (k) for each test by randomly flipping the sign for half of participants’ contrasts and generating a null distribution based on the suprathreshold maximum cluster statistics. The cluster extent threshold in each contrast was defined as the 95th percentile of this null distribution in order to test for statistical significance at p<0.05, corrected for multiple comparisons. (Nichols and Holmes, 2002).
Region of interest analyses
We defined three a priori anatomical ROIs in this study based on prior work using the Automated Anatomical Labelling (AAL2) atlas (Rolls et al., 2015). First, the OFC ROI was given the same definition used by a study examining LS representations in this region (Schuck et al., 2016), which followed that ofKahnt et al., 2012(Kahnt et al., 2012). This definition included the bilateral combination of the following regions: the superior orbital gyri, middle orbital gyri, inferior orbital gyri medial orbital gyri, and rectal gyri. The VTC ROI was given the same definition used by a study that showed that pattern activity in this region differentiated between visual images based on animacy (Chikazoe et al., 2014), excepting the bilateral parahippocampal gyri. This definition included the bilateral lingual gyri, fusiform gyri, and inferior temporal cortices. The HPC ROI was defined as the bilateral hippocampi. These masks were warped into participants’ native brain space using the inverse deformation matrix for all ROI-based analyses. We first conducted an RSA analysis using all voxels within these ROIs by calculating empirical RDMs for the cross-validated Mahalanobis distances from voxels within these ROIs in the same way as in the searchlight analyses, and then using the same multiple linear regression model to relate hypothesis RDMs to these empirical RDMs. These beta-coefficients were then subjected to a second-level, one-sample t-test against zero to estimate statistical significance.
These ROIs were also used as an explicit mask in searchlight analyses to test for effects that were below threshold at a whole-brain cluster-corrected level within HPC and OFC. For these analyses, statistical significance was evaluated as in the whole-brain searchlight analysis with cluster-based permutation tests to compute a cluster extent threshold within these smaller volumes for each contrast, controlling for multiple comparisons at p<0.05.
Univariate analyses
Functional volumes were normalized to a 1.5 × 1.5 × 1.5 mm MNI space and smoothed with an 8 mm FWHM Gaussian isotropic kernel. Beta coefficients for single subject effects were estimated using a fixed-effects model in a first-level analysis. For whole-brain contrasts, these estimates were then included in a second-level analysis using a one-sample t-test against zero at each voxel. As with whole-brain RSA analyses, t-statistical maps were thresholded at a cluster forming threshold of p<0.001 and cluster-based permutation tests were used to compute a cluster extent threshold controlling for multiple comparisons at p<0.05.
Comparison with functional networks
Request a detailed protocol
The results of the whole-brain LS RSA searchlight was compared with a cortical parcellation based on resting state functional connectivity data from 1000 individuals byYeo et al., 2011. To find the degree of overlap within each of these functional networks, we calculated the proportion of voxels in the cluster-corrected LS statistical map that fell within these 17 networks projected to MNI152 space and defined with liberal boundaries around the cortex.
Comparison across sessions
To assess the stability of task-relevant representations across scanning sessions, we carried out two separate searchlight RSA analyses using data from within each session, as above. The resultant coefficient maps from the multiple linear regression analysis were then contrasted between sessions in both directions using paired t-tests. These contrasts were then assessed with the same cluster-forming threshold and cluster-based permutation tests to control for multiple comparisons, as in univariate and multivariate analyses.
Data availability
Complete behavioral data from all participants who completed all three sessions of this experiment, un-thresholded statistical maps for whole-brain analyses and beta coefficients for ROI-level analyses have been deposited on the project site for this experiment on the Open Science Framework.
The following data sets were generated
Vaidya AR
Jones HJ
Castillo J
Badre D
(2020)
Open Science Framework
ID g8yj6. Category Betting Task.
https://osf.io/g8yj6
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Decision letter
Senior Editor; University of California, Berkeley, United States
Reviewer
Reviewer; Princeton University, United States
In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses.
Acceptance summary:
Combining a clever experimental design with rigorous computational cognitive modeling and neuroimaging, the researchers provide evidence suggesting that latent state structures are encoded by a network of fronto-parietal regions. The bridge between abstract reasoning and adaptive decision-making is an important contribution.
Decision letter after peer review:
Thank you for submitting your article "Neural representation of abstract task structure during generalization" for consideration by eLife. Your article has been reviewed by Richard Ivry as the Senior Editor, Mimi Liljeholm as Reviewing Editor, and two reviewers. The following individuals involved in review of your submission have agreed to reveal their identity: Charan Ranganath (Reviewer #1); Sebastian Michelmann (Reviewer #2).
The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.
We would like to draw your attention to changes in our revision policy that we have made in response to COVID-19 (https://elifesciences.org/articles/57162). Specifically, when editors judge that a submitted work as a whole belongs in eLifebut that some conclusions require a modest amount of additional new data, as they do with your paper, we are asking that the manuscript be revised to either limit claims to those supported by data in hand, or to explicitly state that the relevant conclusions require additional supporting data.
Our expectation is that the authors will eventually carry out additional experiments and report on how they affect the relevant conclusions either in a preprint on bioRxiv or medRxiv, or if appropriate, as a Research Advance in eLife, either of which would be linked to the original paper.
Summary:
Vaidya and colleagues present a carefully designed study in order to investigate how the brain represents abstract task structure in a generalization task. Subjects in this study learned "latent states" (i.e., sets of statistically associated scenes) that determined the reward probabilities of objects from different categories. Later, new object categories were introduced and associated with the previously learned task states. Behaviorally, subjects were able to use their knowledge of the abstract task structure to speed new learning and inference on the new object categories. Pattern similarity analyses revealed that abstract task structure, independent from visual information, was represented in left-mid lateral prefrontal cortex, bilateral precuneus, and inferior parietal cortex.
Essential revisions:
All the reviewers thought that this study addresses an important question: Identifying how the brain represents abstract task structure in a generalization task. They agreed that this study uses a very clever behavioral design and a nice combination of behavioral and neuroscientific methods. However, several claims need to be tampered or better justified, and a much more thorough consideration of a broad, heterogeneous and highly relevant literature is warranted.
1) A major concern is that the main claim of the paper – that behavioral and neural data reflect a "latent state" – cannot be evaluated theoretically unless the nature of the latent state representation is carefully and concretely defined. This will require that the authors address the link to prior research on abstract representations of tasks and contexts more broadly, clarifying how they are similar or different in the context of your experiment in both the Introduction and Discussion.
2) As a case in point, the design appears to be one of acquired equivalence (AE) – an extensively studied paradigm in which distinct cues are paired with a common outcome, and subsequent training with one of the cues with a novel outcome generalizes to the second cue during test: that is, given A◊O1, B◊O1 followed by A◊O2, tests reveal expectations of O2 given B. The consensus explanation for such effects is the associative retrieval of O1 by A, and of B by O1, allowing for mediated conditioning of B to O2 during A◊O2 trials. While the current study employs more complex contingencies than those commonly used in studies on AE, it is not clear that some form of associative mediation and retrieval can be ruled out for these effects. The question becomes, then, whether the process or content of complex associative retrieval is what the authors mean by a "latent state representation", or whether they are instead referring to the explicit abstraction of some invariant feature, more in line with previous work on relational reasoning. Either way, the definitions of terms such as "latent state" and "abstract structure" must be clearly laid out and framed in the context of previous relevant work.
3) The authors do not show a clear link between their neural and behavioral results. Some link between these two effects may help strengthen the conclusions that the authors draw. A couple of additional analyses should assess (i) if individual differences in phase 3 accuracy or RT exponential fit relate to subjects latent state representation, (ii) if there is a relationship between switch costs (between latent states) and the fidelity of neural task representation, (iii) To further support that regions in the brain are representing latent states and tracking which state the participant is in, a univariate analysis that identifies regions that are active during latent state switches should be performed. For example, the authors could contrast activity immediately following a latent state switch vs. within a latent state (e.g. trial 1 vs. trial 4 w/in mini block). Is this response bigger when both the context and latent state switches?
4) The latent task RSA analysis revealed a network of regions that is very similar to a network of regions representing "event schemas" across individuals (e.g. Baldassano et al., 2018; Chen et al., 2017). These results should be discussed in a broader context of how the brain represents structure more generally. The supplemental analysis is nice and shows the link to prior work but is not sufficient. The authors do find evidence for "category" representations in a priori ROIs but do not really discuss what the interpretation of these results is. Why is the hippocampus and OFC representing category information during generalization? What does this mean for the field as a whole? For example, it is well established that hippocampus is essential for creating orthogonal representations that are used to disambiguate similar events. How do these results agree or disagree with this interpretation?
https://doi.org/10.7554/eLife.63226.sa1
Author response
Essential revisions:
All the reviewers thought that this study addresses an important question: Identifying how the brain represents abstract task structure in a generalization task. They agreed that this study uses a very clever behavioral design and a nice combination of behavioral and neuroscientific methods. However, several claims need to be tampered or better justified, and a much more thorough consideration of a broad, heterogeneous and highly relevant literature is warranted.
1) A major concern is that the main claim of the paper – that behavioral and neural data reflect a "latent state" – cannot be evaluated theoretically unless the nature of the latent state representation is carefully and concretely defined. This will require that the authors address the link to prior research on abstract representations of tasks and contexts more broadly, clarifying how they are similar or different in the context of your experiment in both the Introduction and Discussion.
We agree that this is an important point to address, as a lack of precision can add confusion to the literature regarding this observation. Our revision attempts to clarify how we are using the term “latent state” in the introduction. We define “states” consistent with their use in the reinforcement learning literature: variables that describe the condition of the environment. In the case of a gambling task, for example, the shape or color of a “bandit” could define the state, in other tasks the location on a screen or in a maze might serve the same purpose. States are thus a key substrate for learning, and their formulation dictates how information about the task is shared or separated between different settings. For example, if only the color of the bandit determines the likelihood of reward, it may be useful to represent all bandits of the same color as belonging to a single state, rather than forming separate representations for each bandit by shape and color. This example is a form of generalization, or state abstraction, where information about the value of bandits of the same color is shared across locations, which would speed learning along the color dimension.
Building on this definition, we define “latent states” as states that are not defined by sensory evidence alone, but must be inferred from a distribution of outcomes or other task-relevant information over a set of task features. Thus, the concept “latent state” has been operationalized differently across studies depending on the task at hand. For example, other experiments have defined latent states based on the temporal frequency of tone-shock pairing (Gershman et al., 2013), the spatiotemporal distribution of rewards (Nassar et al., 2019), or action-values conditioned on recent task history (Zhou et al., 2019). In the case of our experiment, a latent state is defined by distribution of rewards and punishments for categories in contexts during the initial training phase. As such, latent states in the present experiment share a similarity to past work examining generalization behavior over latent task sets (Collins and Frank, 2013) or latent causes (Tomov et al., 2018).
The definition of latent state in our task aside, we believe the way latent states are used in our task might provide another account for the difference between our observations and prior reports that have highlighted a role for the hippocampus and OFC in representing latent states. In particular, our task focused on generalization in a phase where there was no external feedback or new information that would allow participants to update their representation of how contexts were related to a latent state. In contrast, other work that focused on active inference of the current latent state from available evidence has found a representation of this information in OFC (Chan et al., 2016). Similarly, other work has focused on latent state representations in OFC and hippocampus that are putatively involved in planning future actions based on recent task history (Schuck et al., 2016; Schuck and Niv, 2019). We discuss this point in the revised manuscript.
2) As a case in point, the design appears to be one of acquired equivalence (AE) – an extensively studied paradigm in which distinct cues are paired with a common outcome, and subsequent training with one of the cues with a novel outcome generalizes to the second cue during test: that is, given A◊O1, B◊O1 followed by A◊O2, tests reveal expectations of O2 given B. The consensus explanation for such effects is the associative retrieval of O1 by A, and of B by O1, allowing for mediated conditioning of B to O2 during A◊O2 trials. While the current study employs more complex contingencies than those commonly used in studies on AE, it is not clear that some form of associative mediation and retrieval can be ruled out for these effects. The question becomes, then, whether the process or content of complex associative retrieval is what the authors mean by a "latent state representation", or whether they are instead referring to the explicit abstraction of some invariant feature, more in line with previous work on relational reasoning. Either way, the definitions of terms such as "latent state" and "abstract structure" must be clearly laid out and framed in the context of previous relevant work.
This is an insightful point that raises the question: Do participants integrate contexts into a representation of a latent task state to help complete the generalization task, or do they generalize through a process of associative retrieval? We believe this is important to resolve because a mediated associative retrieval account would suggest that an integrated task representation is not used to carry out generalization, and it would have different implications for the interpretation of our functional imaging results. To distinguish between these alternatives, we conducted a computational modeling analysis to formalize these hypotheses and compare how well they account for participants’ reaction time data in the first mini-blocked section of the generalization phase.
We developed a set of simple learning models to compare and contrast different explanations for how participants carried out the transfer of option values during the initial generalization phase. The models express retrieval and generalization in terms of spreading activation among a set of nodes that represent the various task elements. In each model, we structured the memory network differently according to the hypothesis tested. However, these models relied on the same basic assumptions and parameters: (1) Reaction times are a function of the activation strength of the nodes containing retrieved items (Anderson, 1983). (2) The activation strength for each item is initialized at zero and increases according to a Rescorla-Wagner learning rule (Rescorla and Wagner, 1972), controlled by a single rate parameter bounded by 0 to 1 (α 1), each time an option is retrieved, until it reaches an asymptotic value of one. (3) Activation spreads to contexts and categories linked with retrieved items, controlled by a ‘mediated retrieval’ parameter (α 2). (4) Memory search increases activation in all other task-related items in each trial according to an ‘incidental retrieval’ parameter (α 3). (5) Increases in activation that are inherited from connected nodes falls off according to a power law where the rates of successive steps are multiplied together.
We tested four model variants that each differed in how they represented this memory network, and how activation of task elements propagates during generalization (see Figure 4). Importantly, these models are not meant simulate any particular neural system, but only describe how the format of these representations in memory might differentially affect the retrieval process and, by extension, reaction times:
1) Conjunctive associative retrieval – This model implements generalization through associative retrieval by assuming that the memory system stores conjunctions of task-relevant features which can be retrieved if any one of these features is later encountered. This memory network was represented as a matrix of contexts-by-category conjunctions. On each generalization trial, the presented context (e.g. A1) would activate related context-category-value conjunctions from the initial training based on the rate parameter α 1(e.g. A1-leaves- (negative value), A1-food-, A1-hands+ (positive value)). This would lead to the mediated activation of context-category conjunctions with the same value associations from initial training with the rate parameter α 2(e.g. A3-hands+, A2-hands+, etc.), which would in turn lead to activation of conjunctions of new categories associated with the context that appeared in the second training phase (e.g. A3-objects-, A3-Faces+ etc.), as determined by the rate of α 2 2. At the same time, the category presented on the current trial (e.g. objects) would activate conjunctions with that category from the new category training phase (e.g. A3-objects-, B3-objects+) at a rate determined by α 1. The conjunction shown on the current trial (e.g. A1-objects-) would inherit activation from the related conjunction from the new category training phase (e.g. A3-objects-) and increase in activation at a rate determined by α 1 2*α 2 2. Similarly, the same category conjunction with the held out related context (e.g. A2-objects-) would receive a mediated increase in activation at a rate of α 1 2*α 2 3. All other nodes not activated by the current trial would also increase their activation as a rate of α 3.
2) Independent associative retrieval – This model also implements generalization through associative retrieval, but rather than relying on episodic conjunctions of context and category, it stores each individual task element independently and links them together based on experience. The memory network was represented as two vectors of contexts and category-value conjunctions (i.e. separate nodes for faces+ faces-, etc.). Each context was linked to their associated category-values from the initial training phase, and only the held-out contexts were directly linked to category-values from the new category training. In each trial (e.g. A1-objects-), activation in the current context (e.g. A1) would increase with the rate parameter α 1. This activation would result in direct retrieval of category-values from initial training at a rate of α 1 2, and direct retrieval of the context from the new category training phase with the same category-value associations (e.g. A3) at the rate α 1 3. Retrieval of this context then led to activation of the relevant category-value node for the current trial (e.g. objects-) from the new training phase at a rate of α 1 4, allowing generalization, as well as mediated retrieval of other category-values (e.g. faces+, animals+) at a rate of α 1 3*α 2. Activation of category values from the initial training would also lead to mediated retrieval of the other related context (e.g. A2) at a rate of α 1 2*α 2. All other nodes would increase their activation with a rate set by α 3.
3) Latent state – This model implements generalization through the formation of a latent state that replaces separate representations of individual contexts. Here the memory network was represented as a vector of latent states and a matrix of latent states-by-categories, so category-values were separately nested in each latent state. In this case, there was no separate representation of a context, so any increase in activation from a trial involving context A1 immediately carried over to context A2. On each trial, activation in the current latent state (e.g. latent state A) would increase according to the rate parameter α 1, and in the current category-value node according to α 1 2. All other categories nodes linked to the active latent state increase in activation according to α 2, and all other latent states increase activation according to α 3, and their nested categories according to α 3 2.
4) Hierarchical latent states – This model also implements generalization through a latent state, but builds on the basic latent state model to hierarchically cluster contexts within latent states. This model was equivalent to the structure assumed a prioriin our original submission (see schematic in Figure 1). Thus, this model builds on the latent state model but includes a distinct vector for contexts, as well as a matrix of contexts-by-categories. These contexts and context-category nodes are hierarchically nested within each latent state (e.g. contexts A1 and A2 are nested within latent state A). Thus, activation for each of these contexts and category nodes is inherited from activation of the latent states and latent state-category nodes. On each trial, activation in the current context increases at a rate of α 1 2, and in the current context-category at α 1 3. Contexts linked to the current latent state also increase in activation according to α 1*α 2, as these contexts inherit mediated activation from the latent state. Categories nested in these contexts increase activation according to the rate α 1*α 2 2. Activation in all other latent states increases at a rate of α 3, contexts not linked to the current latent state increase at a rate of α 3 2, and their nested categories according to α 3 3.
For each model, predicted reaction times were calculated simply as the sum of the activation level in the current context (or latent state in case of the third model) and category, subtracted from the maximum asymptotic activation level for both combined. These values were then z-scored and compared to participants’ z-scored reaction times so that both model predictions and behavioral data were on the same scale. The fit of each of these models was calculated as the negative log-likelihood for a simple linear function. Only correct responses were included in this analysis, as the model assumes correct recovery of option values from memory on each trial. Across all 16 participants in the fMRI group, only 17 trials were errors in session 2, and thus accounted for a very small fraction of the data (0.6%). Parameters were optimized using the MATLAB function fmincon, with each model fit for each participant 30 times with random starting points in order to avoid convergence on local minima.
To test whether these models made substantially different reaction time predictions, we carried out a cross-model comparison using simulated data. We simulated data using the optimized parameters from each participant for each model. We then fit each model on these simulated data, in the same way as with participants’ behavioral data, to test if the generative model better fit the simulated data than the two alternatives (Figure 4 —figure supplement 1D). This analysis confirmed that these models made distinct predictions with little confusion between models.
To briefly summarize the results, the hierarchical latent state model provided the best fit to the reaction time data for a large majority of fMRI participants in sessions 1 (13/16) and 2 (12/16), as well as all of the behavioral participants who passed the generalization criterion in session 2 (N = 9; Table 1). We did not examine session 1 of the behavioral group, as they failed the generalization criterion in this session — and our models assumed retrieval of the correct response. We also did not examine data from session 3, as participants had already completed the same generalization task in session 2 and this session served only as a reminder.
Examining the data of fMRI participants in session 2 more closely, we found that, compared to the hierarchical latent state model, the associative retrieval models overestimated RT on category switch trials, likely because category-values associated with the current context only increased activation through mediated retrieval in these two models. In contrast, in the latent state models, these nodes inherited activation from direct retrieval of the latent state. However, the (non-hierarchical) latent state model primarily underestimated reaction times on the presentation of a second context, as this model did not have an independent representation of context from latent state and carried over this activation from the previously presented context. Thus, the hierarchical latent state model that maintained separate representations of contexts clustered around each latent state provided the best fit to these data as it was able to capture both category shifts and responses to the second context in line with participant behavior (see Figure 4—figure supplement 1).
In the revised manuscript, we describe the results of this modeling analysis in the Results section and a description of the analysis and model fitting in the Materials and methods section. We believe that this analysis makes an important new contribution by clarifying the nature of latent state generalization and explicitly formalizing and testing how different formats for this representation would influence behavior.
We believe that these results support our claim that participants used a latent state representation to complete this generalization task. However, we cannot speak to whether participants form such a representation obligatorily to complete acquired equivalence tasks in general, or if this finding reflects specific characteristics of our task. In particular, task instructions emphasizing the existence of “goblin kingdoms” (i.e. latent states) to which contexts were linked, and the mini-blocked structure of the generalization task and training (where categories were presented sequentially in each context), may have encouraged the use of such a hierarchically organized latent state representation. The kind of representation used to complete acquired equivalence tasks remains a point of some debate, and may depend on task demands (De Araujo Sanchez and Zeithamova, 2020; Shohamy and Wagner, 2008). We now raise these points in the Discussion.
It is also worth noting that this modeling analysis focuses on the mini-blocked generalization phase, not the scanned mixed generalization phase that was the focus of our fMRI analyses. In principle, it would be possible for participants to use a different representation to complete this task after having completed the initial generalized (e.g. memorizing the values of the 18 new context-category combinations, or just the six items with negative expected values). However, we found participants had RT switch costs for latent states that exceeded those switch costs for context alone in this phase of the experiment. These data thus argue that participants continued to refer to this latent state representation throughout the scanned generalization phase. We discuss this point in the Discussion section.
3) The authors do not show a clear link between their neural and behavioral results. Some link between these two effects may help strengthen the conclusions that the authors draw. A couple of additional analyses should assess (i) if individual differences in phase 3 accuracy or RT exponential fit relate to subjects latent state representation, (ii) if there is a relationship between switch costs (between latent states) and the fidelity of neural task representation, (iii) To further support that regions in the brain are representing latent states and tracking which state the participant is in, a univariate analysis that identifies regions that are active during latent state switches should be performed. For example, the authors could contrast activity immediately following a latent state switch vs. within a latent state (e.g. trial 1 vs. trial 4 w/in mini block). Is this response bigger when both the context and latent state switches?
We agree that a clear link between the neural evidence for a latent task state representation and behavior would be helpful in clarifying the role of this representation in this task. However, our experiment was not designed for the purpose of detecting such a relationship, and is ill-suited for testing these possibilities, as we explain below. We have pursued each line of analysis suggested by the reviewers, but did not find any result that we felt confident including in the revised manuscript. Nonetheless, we believe that the main results of our manuscript demonstrating evidence of a latent state representation that is generative and demonstrably abstract during generalization are important and worth reporting. We believe that the question of how this representation impacts behavior will ultimately require more work and future experiments designed to answer this question.
Here we address each of these suggested analyses in turn below:
i) If individual differences in phase 3 accuracy or RT exponential fit relate to subjects latent state representation
We took a dense-sampling approach in this experiment, collecting two sessions of fMRI data for a relatively small number of participants (N=16). We expect that we would thus be underpowered to detect any effect driven by between-subjects variance, and would be skeptical of any correlation across these 16 participants in neural and behavioral data.
However, for exploratory purposes, we extracted β coefficients for the latent task state representation from an ROI defined by voxels that exceeded the permutation-based cluster-correction threshold for statistical significance at P < 0.05 (Figure 5). There was a moderate, but not statistically significant, negative correlation between this neural measure and the rate of the exponential function fit to participants’ accuracy (ρ = -0.347, P= 0.18, Spearman correlation), and no relationship between the mean exponential rate for reaction times for the first context in each latent state (r = -0.08, P =0.77, Pearson correlation). Please seeAuthor response image 1(left, reaction time (RT) rate; right, accuracy (ACC) rate):
Author response image 1
Visual inspection of the data is suggestive of a trend towards a negative correlation for both the RT and accuracy rates, perhaps offset by one or two participants. However, given the small sample size, we are not confident enough in these results to present them in the manuscript.
ii) If there is a relationship between switch costs (between latent states) and the fidelity of neural task representation
We agree that this is an interesting and important question. However, we used a rapid event-related design that was optimized for the estimation of efficiency of the 18 context-category combinations that were the focus of our main RSA analysis. We did not optimize this design for the estimation of single-trials. Moreover, estimates of neural activity for single-trials in a rapid event-related design are heavily contaminated by adjacent trials (Mumford et al., 2012), which is especially problematic for this question where we would be interested in how the strength of a representation on a previous trial influenced reaction times on the next. In particular, we would expect that switching would be harder, and hence RTs longer, when the representation of the latent state was stronger on the previous trial (similar to an analysis of EEG data by Kikumoto and Mayr, 2020).
These points notwithstanding, we set out to examine if this test was feasible by carrying out a single-trial RSA analysis. We estimated a GLM for each trial in each participant, using the approach of Mumford et al., (2012), where a single regressor is created for the trial of interest in each GLM, and all other trials are modeled with regressors grouped by condition. We then extracted data from voxels in an ROI defined by the whole-brain RSA analysis (as above), and calculated cross-validated Mahalanobis distances between patterns on each trial and the average patterns for each of the 18 conditions.
Given that we did not optimize the design to obtain these effects, we were particularly concerned about backwards contamination of pattern activity on switch trials, such that the hemodynamic response on the trial where the latent state switched (trial n+0) might affect estimates of activity in the preceding trial (trial n-1). This would make it challenging to obtain an estimate of the strength of the latent state from pattern activity on trial n-1 that is not biased by trial n+0. To test this, we compared the cross-validated Mahalanobis distances of trial n-1 to the latent task state in trial n+0 for short and long inter-trial intervals (ITIs) – with the expectation that backward contamination would be worse for shorter ITIs. The analysis bore out this prediction, as this distance was significantly smaller on trials where the ITI was less than the median ITI ( t= 2.30, P= 0.036, within-subject t-test). SeeAuthor response image 2showing these distances for all 16 participants, each plotted as a single line. Having confirmed backward contamination from the hemodynamic response in the subsequent trial we would be very hesitant to draw conclusions from any analysis testing how the strength of pattern activity on trial n-1 influenced behavior on trial n. Similarly, forward contamination from the previous trial would certainly impact our ability to draw conclusions about how pattern activity on trial n+0 affects behavior on these switch trials.
Author response image 2
iii) To further support that regions in the brain are representing latent states and tracking which state the participant is in, a univariate analysis that identifies regions that are active during latent state switches should be performed. For example, the authors could contrast activity immediately following a latent state switch vs. within a latent state (e.g. trial 1 vs. trial 4 w/in mini block). Is this response bigger when both the context and latent state switches?
We believe that this suggestion may have partially arisen from a misunderstanding of our experimental design. Conditions in the scanned portion of the generalization phase were presented in a pseudo-randomized order to optimize efficiency for a rapid event-related design, rather than presented in mini-blocks with several trials of the same consecutive type repeated in a row. Participants completed a mini-blocked segment of the generalization phase (similar to the training phases) prior to entering the scanner (this data is presented in Figure 2A-D and Figure 3). Please also see Figure 1—figure supplement 1 for further detail about our study design.
However, this did not prevent us from carrying out the suggested univariate contrast for switch costs related to the latent state. We ran a new GLM with condition regressors for repetitions and switches of category, context and latent state. Contrasting context switch trials where the latent state remained the same or switched, there were no voxels that survived correction for multiple comparisons or passed the peak threshold of P< 0.001, uncorrected.
While it may be somewhat puzzling that we do not observe a neural effect despite finding an effect of latent state switches in our behavioral analysis, it is possible that we are somewhat underpowered for this analysis. Again, we did not design trial ordering in the magnet to optimize efficiency to estimating switch vs. repeat differences. Thus, the latent state only remained the same in approximately 1/3 of trials, making switches far more common and expected —likely mitigating any neural switch cost effect.
In sum, the results of these posthoc analyses did not yield definitive results. However, in the pre-registration of our experimental design and analysis plan we focused on testing for a latent state representation based on an RSA of task conditions and did not power our experiment for individual differences analyses, or univariate contrasts between latent state repeat and switch conditions. We believe our main results still stand without a direct link between behavior and neural data in the scanner, and are an important contribution to understanding the network representing task structure for the purpose of generalization. Moreover, the computational modeling analyses described above that were prompted by the reviewer comments have deepened our understanding of how this latent state representation may be organized and relate to behavior. In the discussion of the revised manuscript, we note the need to draw a more direct connection between this neural representation and behavior, and the importance of addressing this question in future work in the Discussion section.
4) The latent task RSA analysis revealed a network of regions that is very similar to a network of regions representing "event schemas" across individuals (e.g. Baldassano et al., 2018; Chen et al., 2017). These results should be discussed in a broader context of how the brain represents structure more generally. The supplemental analysis is nice and shows the link to prior work but is not sufficient.
We appreciate and agree with the need for a broader comparison of our results to other data in the literature examining representations of task and event structure. To address the specific point regarding the correspondence of these networks, we sought to more formally characterize the overlap of our latent state RSA network with these prior results. A copy of the Pearson correlation coefficient map for between-participant pattern similarity during spoken recall from Chen et al., (2017) was graciously provided to us by the first author (Figure 3B in that paper). Comparison of the overlap of this statistical map with the statistical map from our RSA analysis revealed some overlap in the posterior medial cortex and inferior parietal lobule, but very limited overlap in lateral PFC or medial PFC.
Author response image 3shows the latent state t-statistic map thresholded at P< 0.001, uncorrected in blue-green in order to be inclusive, and the Pearson correlation map thresholded at r ≥ 0.03 in red-yellow. Numbers above slices correspond to z-coordinate of slices in MNI space.
Author response image 3
While interesting, we think the overlap of these networks is only moderate at most. The region of the posterior medial cortex with the maximum t-statistic in our sample was also fairly posterior and dorsal to that found by Chen et al. These regions of posterior medial cortex differ in their anatomical and functional connectivity with other parts of the brain: the more dorsal peak found in our analysis corresponding closer to a division of the precuneus with projections to rostrolateral PFC, and the peak from Chen et al. and corresponding closer to posterior cingulate cortex — with more connections in medial PFC (Margulies et al., 2009), which may relate to differences in the pattern of overlap in PFC subregions. The event schema results of Baldassano et al., 2018 appear to be similar to those of Chen et al., with results in posterior medial cortex being even more constrained to the posterior cingulate cortex (Figure 2 of that paper).In the revision, we discuss correspondence of our results to these data and others in the Discussion section. In particular, we believe that the regions implicated in this study correspond more closely to frontoparietal networks implicated in cognitive control and abstract stimulus invariant representations of tasks (also supported by our comparison to resting state networks from Thomas Yeo et al., 2011 in Figure 5—figure supplement 1). Networks identified as representing abstract structure related to schematic world knowledge, like those in the papers referenced by the reviewers, may be more involved in processing the congruity between events or items and a schema — while those implicated in the current experiment may be more involved in using this schema-level knowledge to control action selection and decision-making. We do not think these functions are necessarily completely segregated though. Overlap within these networks and anatomical connections bridging the two may prove to be important lines of communication between networks allowing schematic knowledge to be flexibly updated with new experience, and maintained for the purpose of control, during the performance of a task.
The authors do find evidence for "category" representations in a priori ROIs but do not really discuss what the interpretation of these results is. Why is the hippocampus and OFC representing category information during generalization? What does this mean for the field as a whole? For example, it is well established that hippocampus is essential for creating orthogonal representations that are used to disambiguate similar events. How do these results agree or disagree with this interpretation?
We are hesitant to draw strong conclusions from the finding of category information in hippocampal or OFC pattern activity. We do not believe that these results are surprising or particularly revealing about the function of these regions. OFC receives inputs from higher-order visual areas in inferior temporal cortex (Price, 2007), and has neurons tuned to stimuli like faces (Rolls et al., 2006). Past work examining pattern activity in OFC has found evidence for an animacy signal (Chikazoe et al., 2014), like our category regressor, and other work has found that stimulus categories like faces versus scenes, or food versus objects, can be decoded from OFC activity (McNamee et al., 2013; Pegors et al., 2015). We might speculate that the function of this category representation in OFC during our task relates to calculating the value of a decision based on the current context and/or latent state.
The finding of category information in hippocampus may be a bit more surprising for the reasons mentioned by the reviewers, but on consideration we do not think this contradicts conventional ideas about the function of the structure. Human hippocampal neurons have been observed to have selective responses to categories like faces and objects (Kreiman et al., 2000), and pattern activity in hippocampus carries information about visual categories that distinguishes stimuli like faces and scenes (Kuhl et al., 2012). Our results are consistent with these observations. We also do not think that our results are necessarily instructive as evidence for or against the claims about a hippocampal role in orthogonalizing events, per se, as the task did not place particular demands on separating events from each other. In general, the task demanded that participants pool information over multiple events and trial-unique stimuli to infer the values of each stimulus category in each latent state. Thus, while it would be helpful to have orthogonal representations of stimulus category, it would not be helpful to have distinct representations of each event in this task. It is possible, rather, that the hippocampus is using this category information in service of retrieving option values, but this is a speculative conclusion.
We have revised the portion of the Results where we report these effects in order to place these results in this context.
https://doi.org/10.7554/eLife.63226.sa2
Article and author information
Author details
Avinash R Vaidya
Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, United States
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Conceptualization, Data curation, Software, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing
For correspondence
[email protected]
Competing interests
No competing interests declared
"This ORCID iD identifies the author of this article:" 0000-0001-5423-5655
Henry M Jones
Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, United States
Department of Psychology, Stanford University, Stanford, Stanford, United States
Contribution
Software, Investigation, Methodology, Writing - review and editing
Competing interests
No competing interests declared
Johanny Castillo
Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, United States
Department of Psychology and Brain Sciences, University of Massachusetts Amherst, Amherst, United States
Contribution
Investigation, Methodology, Writing - review and editing
Competing interests
No competing interests declared
Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, United States
Carney Institute for Brain Science, Brown University, Providence, United States
Contribution
Conceptualization, Supervision, Funding acquisition, Methodology, Project administration, Writing - review and editing
Competing interests
Reviewing editor, eLife
Funding
Office of Naval Research (N00014-16-1-2832)
David Badre
National Institute of General Medical Sciences (R25GM125500)
Johanny Castillo
David Badre
National Institute of Mental Health (F32MH116592)
Avinash R Vaidya
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Acknowledgements
This work was supported by a Multidisciplinary University Research Initiative award from the Office of Naval Research (N00014-16-1-2832), a Postbaccalaureate Research Education Program grant from the National Institute of General Medical Sciences (R25GM125500), and a Ruth L Kirschstein National Research Service Award to AV from the National Institute of Mental Health (F32MH116592). We thank Apoorva Bhandari and other members of the Badre Lab for constructive discussion and consultation on task design and fMRI analysis, as well as Linda Q Yu for comments on this manuscript. We also thank Emily Chicklis for assistance with data collection.
Ethics
Human subjects: All participants gave their written informed consent to participate in this study, as approved by the Human Research Protections Office at Brown University, and were compensated for their participation.
Senior Editor
Richard B Ivry, University of California, Berkeley, United States
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Charan Ranganath
Sebastian Michelmann, Princeton University, United States
Publication history
Received: September 18, 2020
Accepted: March 16, 2021
Accepted Manuscript published: March 17, 2021 (version 1)
Version of Record published: March 31, 2021 (version 2)
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© 2021, Vaidya et al.
This article is distributed under the terms of theCreative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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Cosmetics | Free Full-Text | The Beast of Beauty: Environmental and Health Concerns of Toxic Components in Cosmetics
Cosmetic products are used in large quantities across the world. An increasing number of chemical compounds are being added to the formulation of cosmetic products as additives, fragrances, preservatives, stabilizers, surfactants, dye and shine to potentiate their quality, property and shelf life. Owing to their widespread use, active residues of cosmetic products are continuously introduced into the environment in several ways. Many of these chemicals are bioactive and are characterized by potential bioaccumulation ability and environmental persistence, thus exerting a major risk to humans and the health of ecosystems. Hence, the indiscriminate consumption of cosmetics may present a looming issue with significant adverse impacts on public health. This review intends to spotlight a current overview of toxic ingredients used in formulating cosmetics such as parabens, triclosan, benzalkonium chloride, 1,4-dioxane, plastic microbeads, formaldehyde, diazolidinyl urea, imidazolidinyl urea, sunscreen elements (organic and inorganic UV filters) and trace metals. Specific focus is given to illustrate the biological risks of these substances on human health and aquatic system in terms of genotoxicity, cytotoxicity, neurotoxicity mutagenicity, and estrogenicity. In addition to conclusive remarks, future directions are also suggested.
The Beast of Beauty: Environmental and Health Concerns of Toxic Components in Cosmetics
by Muhammad Bilal 1,* , Shahid Mehmood 2 and Hafiz M. N. Iqbal 3,*
School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian 223003, China
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
Tecnologico de Monterrey, School of Engineering and Sciences, Campus Monterrey, Ave. Eugenio Garza Sada 2501, Monterrey, NL CP 64849, Mexico
Authors to whom correspondence should be addressed.
Cosmetics 2020 , 7 (1), 13; https://doi.org/10.3390/cosmetics7010013
Received: 30 January 2020 / Revised: 21 February 2020 / Accepted: 25 February 2020 / Published: 28 February 2020
Abstract
Cosmetic products are used in large quantities across the world. An increasing number of chemical compounds are being added to the formulation of cosmetic products as additives, fragrances, preservatives, stabilizers, surfactants, dye and shine to potentiate their quality, property and shelf life. Owing to their widespread use, active residues of cosmetic products are continuously introduced into the environment in several ways. Many of these chemicals are bioactive and are characterized by potential bioaccumulation ability and environmental persistence, thus exerting a major risk to humans and the health of ecosystems. Hence, the indiscriminate consumption of cosmetics may present a looming issue with significant adverse impacts on public health. This review intends to spotlight a current overview of toxic ingredients used in formulating cosmetics such as parabens, triclosan, benzalkonium chloride, 1,4-dioxane, plastic microbeads, formaldehyde, diazolidinyl urea, imidazolidinyl urea, sunscreen elements (organic and inorganic UV filters) and trace metals. Specific focus is given to illustrate the biological risks of these substances on human health and aquatic system in terms of genotoxicity, cytotoxicity, neurotoxicity mutagenicity, and estrogenicity. In addition to conclusive remarks, future directions are also suggested.
Keywords:
cosmetics
;
toxic ingredients
;
environmental pollutants
;
human health
;
biological risks
;
parabens
;
microplastics
;
Triclosan
1. Introduction
The global cosmetics market is projected to register a CAGR (Compound annual growth rate) of 4.3% during the forecast period (2016–2022) and is anticipated to reach $ 429.8 billion by 2022 [ 1 ]. Reports have documented that the average man and woman practice six and twelve cosmetic products per day, respectively, in the USA [ 2 ]. However, among a list of more than 12,000 industrial and synthetic chemical ingredients included in the formulation of cosmetics, less than 20% of these have been considered safe to use [ 3 ]. Therefore, over the past few years, substantial concerns have been raised for increasing use of pharmaceuticals, cosmetics, and many personal care products (dietary supplements, insect repellents, disinfectants). The cosmetic products are continually introduced into the aquatic systems and their ecological impacts are related to bioactivity, toxicity, and bioaccumulation potential [ 4 ]. Sewage treatment plants do not always effectively remove many of the cosmetic ingredients or chemicals such as micro-plastics [ 5 ], UV organic filters, perfluoroalkyl compounds, and synthetic musks [ 6 , 7 ]. Besides, these compounds are accumulated in sewage sludge during wastewater processing and find a way into the environment because of using this sludge as crop fertilizer [ 8 ]. In contrast to pharmaceuticals, cosmetic products pose the most tenacious ecological risks due to their continuous utilization throughout life. Since they are designed for use in external surfaces and are not intended for metabolic transformation, they enter the environment unaltered in large quantities during washing and showering [ 9 ]. The present review is aimed at providing a recent overview of toxic ingredients that are commonly used in the manufacture of cosmetics such as parabens, triclosan, benzalkonium chloride, 1,4-dioxane, plastic microbeads, formaldehyde, diazolidinyl urea, imidazolidinyl urea, sunscreen elements (organic and inorganic UV filters) and trace metals. Particularly, the focus is devoted to pinpointing the biological risks of these substances of concern on human health and the aquatic system in terms of genotoxicity, cytotoxicity, neurotoxicity mutagenicity and estrogenicity. In addition to conclusive remarks, future directions are also suggested.
2. Parabens and Their Associated Biological Risks
Parabens are a class of chemicals that have been extensively employed as preservatives in pharmaceuticals, and cosmetic products due to their potential antimicrobial activities. Chemically, parabens are esters of the 4-hydroxybenzoic acid with aryl (phenyl, benzyl) or alkyl (butyl, ethyl, isobutyl, heptyl, methyl, propyl, isopropyl, pentyl) substituents [
10
]. Although plants or bacteria can naturally produce these compounds, all commercially used parabens are produced by synthetic methods. It is meaningful to mention that the European Union has circumscribed the inclusion of parabens in formulating cosmetics. Particularly, the consumption of benzyl paraben, isobutyl paraben, isopropyl paraben, methylparaben, and phenyl paraben has been prohibited in cosmetic products (Regulation (EU) No 358/2014). Furthermore, the possible highest level of butylparaben and propylparaben was reduced and their incorporation in products was forbidden especially those used by children (Regulation (EU) No 1004/2014). Notwithstanding all these constraints, there is still extensive paraben use in personal care and cosmetic products due to their low price, marginal toxicity, and pronounced inhibitory activity against bacteria, molds, and yeasts [
10
].
Parabens have been identified in the environmental milieus such as water, dust, and air due to their discharge from manufacturing units and continuous release at elevated concentrations into urban and hospital wastewater effluents given the widespread utilization of paraben-containing household chemicals, and pharmaceutical products. Notably, the level of parabens can reach up to 20,000 and 30,000 ng/L for propylparaben and methylparaben, respectively, in raw wastewaters [
11
]. Many of the parabens in the aqueous media can be effectively removed by wastewater treatment plants by bio-degradation or adhering to the sewage sludge [
12
]. They can undergo the rapid bio-degradation process with the production of 4-hydroxybenzoic acid as the main by-product or might efficiently react with free chlorine resulting in the formation of various chlorinated products [
13
]. In spite of their effective elimination by wastewater treatment plants, these chemicals are still identified in surface waters, particularly rivers [
14
].
Among the list of parabens, propylparaben and methylparaben are the most frequently identified paraben compounds in surface waters due to their frequent utilization in cosmetics [ 10 ]. The occurrence of paraben has been reported in marine mammals and the tissues of fish and marine organisms [ 15 ]. The extensive presence of parabens and their degradation compound, p-hydroxybenzoic acid, in animals reveal their ubiquitous occurrence in the environmental media. Parabens were generally not detected or found at very low levels in tap water. Nevertheless, a survey documented the paraben’s occurrence with a concentration range of ng/L in bottled water [ 16 ]. In addition, parabens have been observed in human serum, urine, milk, amniotic fluid and adipose, placental and human breast cancer tissues [ 17 , 18 , 19 ]. In humans, dermal exposure to products containing paraben is the source of its absorption since some parabens can penetrate human skin. Moreover, some reports have also confirmed the systemic absorption of parabens following environmental exposure, though it is less likely to appear a significant source of paraben [ 20 ]. Likewise, oral ingestion of parabens is also not a meaningful way because orally ingested parabens are readily transformed to p-hydroxybenzoic acid by esterases [ 21 ]. For a long time, it has been taught that parabens exhibit negligible toxicity with an excellent safety profile. However, gravest apprehensions have recently been aroused because of the in vitro as well as in vivo endocrine-disruption activity of parabens. Experimental studies have shown the association of parabens with altering the reproductive system of male animals [ 22 ]. Parabens displayed a feeble estrogenic activity in in vitro studies with a substantially lower estrogen receptor binding affinity compared with the diethylstilboestrol [ 23 ]. Investigations carried out to evaluate the endocrine-disrupting effect of parabens on aquatic biota revealed that these chemicals are capable of interfering with the vitellogenin plasma level in some aquatic wildlife, such as Japanese medaka fish and rainbow trout [ 10 ]. Similarly, many reports have claimed the relationship between the endocrine disruption effect of parabens and breast carcinoma in human species [ 21 ]. However, many scientists and international health authorities subsequently negated these investigations, demonstrating no scientific evidence that connects human breast cancer with the toxicity of parabens [ 24 , 25 ]. On the contrary, Pan et al. [ 26 ] reported a prominent synergism between epidermal growth factor and parabens, indicating the activity of parabens at very low concentrations than considered toxic in earlier studies. Considering the aforementioned discussion, notable adverse impacts of parabens include DNA damage [ 27 ], antiandrogenic activity [ 28 ], estrogenicity [ 29 ], endocrine disruptors [ 30 ], cytotoxic and genotoxic effects on human lymphocytes [ 31 ], risk of cancer in humans [ 32 ], allergic reactions, and reproductive disorders [ 33 , 34 ].
3. Triclosan Persistence and Ecological Impacts
Triclosan (TCS) is a lipid-soluble, antimicrobial agent that is widely employed as a preservative in a variety of personal care products such as shampoos, toothpaste, detergents, hand soaps, deodorants and sunscreens. It is also extensively used as an additive or stabilizer in textiles, packaging, functional clothing and as an antiseptic in numerous household items and medical devices due to its broad-spectrum antibacterial and antifungal functionalities [ 35 ]. However, its extensive consumption in rinsing products results in the release of domestic sewage that is considered as the most crucial source of pollution [ 36 ]. The discharge of large amounts of TCS accompanied by ineffective elimination in sewage treatment plants is the primary cause for its substantial occurrence in the environment, with levels often ranging from nanograms to micrograms per liter in waters and sediments [ 37 , 38 ]. This widespread distribution and persistence of TCS in the aquatic environment is schematically represented in Figure 1 . Reports have shown the ubiquitous presence of TCS in aquatic systems, as well as in sediments with a prevalent accumulation in sediments because of its lipophilic nature [ 39 ]. In terms of concentration and frequency, TCS is amid the top 10 most frequently noticed organic wastewater pollutants [ 40 ]. It has been detected in surface water in the United Kingdom, USA, China, South Korea and Europe [ 41 , 42 , 43 , 44 , 45 ].
Figure 1. Schematic illustration of the fate and general distribution of Triclosan (TCS) in water matrices.
An experimental study conducted on thirteen places (Kyoto: four places, Saitama: five places, Tokushima: four places) in Japanese rivers contaminated by domestic wastewater, effluent, or industrial wastewater reported the ubiquitous detection of TCS with up to 177 ng/L concentrations [ 46 ]. Due to the utilization of sewage sludge on farmland as fertilizer, TCS has also been found in terrestrial surroundings [ 47 ]. Although TCS persists in the environment, it can be transformed into other chlorinated compounds during wastewater treatment that are highly poisonous and even more persistent than original compounds. Owing to lipophilicity and high stability, TCS has revealed a potential propensity for bioaccumulation in plants, algae, animals (such as fish, snails, marine mussels, earthworms, amphibian larvae and marine mammals) [ 48 , 49 , 50 , 51 ]. Likewise, a metabolite of TCS, methyl triclosan, has also been identified in fish from various ponds and lakes in Switzerland [ 52 ]. It is essential to mention that TCS present in the marine ecosystem exerts unfavorable environmental consequences such as toxic effects to algae species, alteration in the composition of bacterial communities, disruption of the endocrine system in fish and teratogenicity and mortality in the larvae and embryos of zebrafish [ 53 , 54 , 55 , 56 ].
Epidemiological studies have documented that TCS is present in a more extensive concentration range in human body fluids such as breast milk, blood, and urine [ 38 ]. Some researchers have revealed that the TCS in human body fluids is primarily related to the application of personal care products containing TCS. According to some other researchers, oral absorption is a significant source taking into consideration that TCS is identified in drinking water [ 57 , 58 ]. Exposure to this antimicrobial agent can induce an array of adverse impacts on the environment and human health, including contact dermatitis [ 59 ], interference with the endocrine system, depression of the central nervous system [ 60 ], decreased sperm production [ 61 ], liver carcinogenesis [ 62 ], oxidative stress, tumor development and impairment of thyroid functions [ 38 , 63 , 64 , 65 ]. Given all data available in the literature concerning TCS and its transformed by-products in the environment and its health effects, this chemical should be deliberated as a serious concern top-priority contaminant [ 65 ].
4. Benzalkonium Chloride and its Cytotoxic Effects
Benzalkonium chloride (BAC) is one of the most extensively used preservatives in cosmetic products. BAC belongs to a cationic family detergent and surfactant preservative. It is also known as a quaternary ammonium compound (QAC) and commonly used as a potential constituent of various cosmetics, household items, pharmaceutical products, personal care products and also used as a surface disinfectant. In a report published in 1986, BAC was considered as one of the important components of 83 well-known cosmetic products at concentrations varying from ≤0.1% to 5%. In 2013, the use of BAC increased up to 567 cosmetic items, which carry the 0.46% weightage as compared to other compounds used in cosmeceutical items. [ 66 ]. In addition, BAC is the most active ingredient and widely used as a preservative in ophthalmic solutions [ 67 ]. Nevertheless, the usage of BAC has been linked to inducing considerable adverse consequences in humans. Reports have documented the cytotoxic effects of BAC in vivo and in vitro models that induce toxicity in corneal and conjunctional epithelial cells. Similarly, continuous and excessive exposure to BAC may cause Dry Eye Disease (DED) [ 2 , 68 , 69 ]. BAC is also used in the pharmaceutical industry. Medications containing BAC result in increased chances of peripheral ocular disorders including itching, irritation, stinging, burning, foreign body sensation (FBS), redness, blurred vision, sensitive to light and sometimes may cause more severe conditions such as failure of glaucoma surgery, conjunctival hyperemia and blepharitis [ 70 , 71 ]. Moreover, a large number of studies have been conducted on ophthalmic toxicities such as corneal injury and irritation and intranasal damage of mucosal membranes [ 72 ]. Experimental results of a study conducted to analyze the effects of BAC in a dose-dependent manner showed neurites concentration decrease in corneal nerves and also induction of oxidative stress that leads to cholinergic neurotoxicity [ 73 ]. Recently, a study showed that the overproduction of ROS results in the destruction of caspase-8 expression, a result, the cell viability waned, when rat neural progenitor cells (NPCs) were exposed to a higher concentration of BAC [ 74 ]. Previous data have shown that cosmetic products with a high concentration of BAC have high potency to induce the severe ROS-mediated neurotoxicity in rats that leads to apoptosis in later stages. Toxicological metadata analysis results revealed that nasal and oral medication containing BAC causes pulmonary toxicity [ 75 ]. Similarly, human nasal epithelial cell viability was used to analyze the toxicological assessment of the gradient concentration of BAC; results showed that 14%–19% of cells were viable after treatment [ 76 ]. Electron microscopic analysis envisaged that the variable concentration of BAC also induces the demolition of the lipid bilayer structure; changes the configuration of cytoskeleton and microvilli destruction [ 75 ]. It has also been documented that a BAC concentration of 10 μg/mL and 1.0 mg/L, and 3.0 mg/L significantly increase the micro-nucleated cell colonization when exposed to human lymphocytes and Vicia faba [ 77 ]. In addition, BAC concentration also increases the lap of cell division. BAC-mediated induction of DNA damage has also been reported in marine organisms Ceriodaphniadubia and Daphnia magna , which are widely used organisms to study the genotoxicity [ 56 ].
5. 1,4-Dioxane, Uses and Adverse Impacts
1,4-Dioxane (C
4
H
8
O
2
, dioxane) is a synthetic chemical that has been previously used as a fixative agent in a chlorinated solvent, but nowadays, is traced in many commercially available products especially food items. 1,4-Dioxane is an organic solvent (ether), which is commonly used as an emulsifying agent and as a detergent. For this reason, it is commonly used in personal cleaning and household products including baby lotion, shower gel, body lotion, toothpaste, mouthwash, and shampoo [
78
]. It is taken by aerosol, by means of inhalation, by physical contact with skin or cutaneous exposure and ingestion of dioxane-contaminated food. The chemical structure and physical properties allow 1,4-Dioxane to reach underground water reservoirs and as a result, drinking water is contaminated once released in the environments [
79
]. It is used to enhance the foaming texture in personal care products such as shampoo, shower gel, soaps and also minimize the adverse effects of chemicals especially sodium lauryl sulfate. 1,4-Dioxane is produced during ethoxylation steps in the manufacturing process of other cosmeceutical constituents such as polyethylene glycol, polyoxyethylene, and polyethylene, hence that is why it is not listed as a cosmeceutical component [
80
].
Previous studies revealed that overconsumption or exceeding the threshold level of 1,4-Dioxane causes severe effects on animal life, for example, skin cell carcinoma, breast, and hepatocellular carcinoma. A study revealed that chronic intake of 1,4-dioxane via drinking water in mice and rats induced hepatocellular toxicity, and long term exposure (more than 3 months) prompted Piecemeal necrosis, progression of pre-neoplastic lesions and Rhinitis or nasal cavity irritation [
81
]. In vitro studies on both prokaryotes and eukaryotes concluded that 1,4-dioxane has not been involved in genotoxicity. In vivo analysis of genotoxicity has shown negative results but only a few studies reported that a high dose of 1-4-Dioxane induced genotoxicity but this dose was much higher than the environmental exposure. However, there is still a need to uncover the genotoxicity of human systems especially the reproductive system. 1-4-Dioxane also interferes with transportation, biosynthesis, metabolism and disruption of endocrine components [
82
,
83
].
6. Microplastic Particles
The plastic pollution of aquatic systems represents an emerging environmental apprehension. According to Moore [ 63 ], microplastic is considered any plastic material that is less than 5 mm in length. Most small plastic materials or particles stem from the disintegration of larger substances; nevertheless, microplastics can also directly incorporate into the marine environment by various sources, such as clothing, cosmetic products, and industrial processing [ 84 ]. Plastic microbeads are widely used as abrasive cleaners or scrubbers in a plethora of cosmetic and personal care products, including toothpaste, hand-cleansers, soaps, shampoos, bubble baths, and scrubs [ 85 ]. In all these products, plastic microbeads are used as a replacement for natural exfoliating compounds (apricot husks, oatmeal and pumice). Apart from the deep cleansing and dead skin removal functions, these microbeads also have a decorative and ornamental role in numerous personal-care products [ 86 ]. Due to the extremely small size, micro-plastic beads incorporated in cosmetic products are trapped in sewage treatment plants and enter into water streams through domestic drainage systems and are finally channeled into oceans and seas [ 87 ]. After entering the environment, high-density micro-plastics such as polyester and polyvinyl chloride settle out of the water system and tend to accumulate in the sediment, whereas the microbeads composed of low-density micro-plastics (polystyrene, polyethylene) float on the surface of the sea [ 88 ]. Aquatic organisms can ingest micro-particle pollutants from the marine environment due to the lack of effective methods for the removal of micro-plastic and high degradation resistance. Extensive reports have described the ingestion and accumulation of micro-plastic materials in various marine entities, including fish, seabirds, bivalves, and copepods [ 89 , 90 , 91 , 92 , 93 ]. Polystyrene microparticles are known to affect adversely the marine biota following their exposure. A worrying concern is the microplastics capacity in aiding the delivery of persistent organic pollutants such as alkylphenols, organochlorine pesticides, polychlorinated biphenyls, polycyclic aromatic hydrocarbons, incorporated during the manufacture of plastics, which subsequently is transferred along the food chain and can potentially damage organisms [ 94 , 95 ]. Figure 2 shows possible bioaccumulation and biomagnification of microplastics in the environment.
Figure 2. Schematic illustration of possible bioaccumulation and biomagnification of microplastics in water matrices. Reprinted from [ 86 ] with permission from Taylor & Francis. Copyright (2019) Informa UK Limited, trading as Taylor & Francis Group.
7. Formaldehyde, Transmission Routes and Health-Related Effects
Formaldehyde (FA) is another organic compound that is widely employed as a stabilizing or protective agent in various household, cosmeceutical products and personal care products. Formaldehyde or formalin (37% v/v solution of formaldehyde) or oxymethylene are an important class of additives used in a broad range of cosmetic industries in the formulation of shampoo, liquid soap, body shower gel, skincare lotion and many other products [
96
]. In USA, the most commonly used preservatives are quaternium-15, imidazolidinyl urea, diazolidinyl urea, 2-bromo-2-nitropropane-1, 3-diol and 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (DMDM)-hydantoin, that released FA [
2
,
97
,
98
].
Formaldehyde follows the various routes of transmission to human bodies such as cutaneous, nasal route and ingestion. However, research has revealed that the nasal route or inhalation is the most common and prominent route of FA exposure, because most indoor contaminants have been found in gaseous form in the air [ 99 ]. The continuous and delayed exposure with FA is associated with a broad range of serious health concerns such as various types of cancers including cutaneous carcinoma and sinus carcinoma, causes allergy, and also produces a mutagenic effect [ 100 ]. Moreover, long-term exposure with a high intensity of FA led to increasing the risk of myeloid leukemia progression [ 101 ]. Various studies have shown that FA exposure is involved in inducing the cytotoxic effects on human lymphocytes, natural killer cells, bronchial epithelial and endothelial cells [ 2 , 102 , 103 ]. A study conducted on rabbits to show the impact of FA on corneal epithelial cells showed that an FA level of 0.5 and 1.0 ppm could elicit the ophthalmic irritation that includes increased blinking frequency and conjunctival redness. On the other hand, nasal and throat irritation happen above the level of 1.0 ppm concentration [ 104 ].
8. Imidazolidinyl Urea and Diazolidinyl Urea—Adverse Effects
Imidazolidinyl urea and diazolidinyl urea are widespread antimicrobial fixative agents used in cosmetics and household products [ 105 ]. A 0.01%–1% concentration of imidazolidinyl urea, when applied to human peripheral cultured blood cells for 24 h, results in ascetically induced cytotoxicity. A similar result has been shown after 3 h of exposure with a 0.1%–0.5% concentration of diazolidinyl urea [ 106 ]. However, the clinical trial study revealed imidazolidinyl urea as a causative agent as a skin allergen that causes dermatitis and skin hypersensitivity [ 107 , 108 ]. Human fibroblast cells, when exposed to a variable concentration of imidazolidinyl urea led to the inflammatory response and steered toward the substantial loss of cell viability [ 109 ].
Since 1982, diazolidinyl urea is being used as an antimicrobial fixative agent in cosmeceutical industries and personal-care products, especially skincare products, childcare products, hair treatment products, skin and face makeup, and nails. In Europe, 0.5% diazolidinyl urea can be used in cosmetic products, because many studies have confirmed that dermal exposure to the high concentration of diazolidinyl urea causes an allergic reaction. Besides, it is also reported as a carcinogenic and genotoxic agent because of releasing formaldehyde [
110
]. Upon the hydrolysis of diazolidinyl urea, formaldehyde is released that may cause itching, skin redness, and irritation. Ryu et al. [
74
] reported different types of cosmetic preservatives such as diazolidinyl urea, benzalkonium chloride, and imidazolidinyl on rat NPCs cell culture. In this study, they assessed the ROS released by treated cells at different concentrations of 1–50 μM diazolidinyl urea or imidazolidinyl urea and 1–1000 nM benzalkonium chloride at different time laps. The results showed that cellular viability and count severely decreased after 24 h of treatment with imidazolidinyl or diazolidinyl urea and ROS production and apoptosis significantly increased. These results also showed that imidazolidinyl urea and diazolidinyl urea induce oxidative stress in mitochondria [
74
]. However, there is still ambiguity because these compounds can also be involved in cell death followed by autophagy. Due to the triggering properties of ROS and formaldehyde-releasing agents, use of these chemicals or diazolidinyl urea and imidazolidinyl urea-based cosmetics are strictly prohibited during pregnancy [
105
].
9. Organic and Inorganic UV-Filters/Absorbers
UV-filters, chemicals that absorb or scatter UV radiation in sunlight, are increasingly employed in a plethora of personal care and cosmetic products for skin protection from UV-triggered impairment and as a stabilizer of fragrance and color of cosmetic preparations. These filters are referred to as broad-spectrum since they are believed to provide protection against different UV rays such as UV-A (400–320 nm), UV-B (320–280 nm), or both UV-A and UV-B rays. At present, active sunscreen elements are categorized into organic (chemical) or inorganic (physical) filters or absorbers. Organic filters first absorb radiations, followed by efficient dissipation of the absorbed energy by several photochemical and photophysical pathways. On the other hand, inorganic filters partially absorb and reflect UV rays [ 111 ]. It is documented that UV filters account for approximately 20% of sunscreen products [ 112 ], but are considered as emergent contaminants because of their ubiquitous occurrence in the environment. These chemicals can enter the aquatic system either directly or through wash-off from the skin surface during recreational activities [ 113 ]. Studies have reported the detection of UV filters in wide environmental compartments such as surface waters, oceans, seas, coastal waters, groundwater, lakes, rivers, and sediments [ 114 , 115 ]. The most commonly detected organic filters in sediment are octocrylene (OC), Ethylhexyl methoxycinnamate (EHMC), octyl dimethyl-p-aminobenzoic acid (OD-PABA), butyl methoxydibenzoylmethane (BMDM), and benzophenone derivatives [ 116 , 117 ]. Likewise, sun blockers including homosalate, Ethylhexyl salicylate, isoamyl p-methoxycinnamate, and 4-methylbenzyliden camphor have been identified in surface waters but are not detected or recovered in sediment presumably due to their limited consumption in sunscreen products or decomposition by microbial strains [ 118 ]. Recent investigations have reported the presence of organic UV filters in water samples in many countries, including USA, China, Thailand, Switzerland, Japan, Hong Kong, Taiwan, Korea, and Norway [ 119 , 120 , 121 ].
A large number of studies have documented the toxic effect of organic UV filters in various aquatic organisms; in particular, some widely consumed UV filters have been found to be very toxic to protozoa, crustaceans, and microalgae [ 122 ]. Similar to other xenobiotics, the endocrine-disrupting tendencies of some organic UV filters have been noticed in both in vivo and in vitro models. For illustration, BP-3 exhibited a potent anti-androgenic along with weak estrogenic activities in murine models. Besides, this compound has also shown destructive effects on the reproductive outcome of aquatic organisms [ 43 ]. With a receptor-based test, Faass et al. [ 123 ] assessed the estrogenicity of a series of organic UV filters on fish both in vivo and in vitro. Two UV filters explicitly, 3-BC and 4-MBC, are known to have an estrogenic-like effect and were capable of impairing female sexual outcome in a rodent model [ 123 ]. Schlumpf et al. [ 124 ] analyzed human milk samples and found that they consisted of UV filters in higher than 75% of the tested cases that indicated a probable exposure to the suckling infants or neonate to these toxic substances [ 124 ].
ZnO and TiO 2 are among the important inorganic UV filter compounds that were authorized as a sunscreen by European Regulation. Both oxides (ZnO and TiO 2 ) are increasingly utilized as nanoparticles in sun blockers because of the improved consumer’s acceptance, skin retention, and UV reduction attributes in comparison to their bulk equivalents [ 125 ]. In recent years, the toxicological influences of nano-TiO 2 on fish, algae, and marine invertebrates have been described in many reports [ 126 ]. Although some researchers have demonstrated the negligible impacts of nano-TiO 2 on various aquatic organisms, its toxic effects were dramatically increased in the presence of UV radiation or strong sunlight due to ROS generation [ 127 , 128 ]. Likewise, nano-ZnO is also categorized as “extremely toxic”, and the toxicity of ZnO is well recognized towards aquatic entities such as including sea urchins, marine algae, zebrafish, and many other organisms [ 127 , 129 , 130 ]. The elevated toxicity of ZnO might be ascribed to the release of Zn 2+ ions and oxidative damage because of the elevated ROS production [ 131 ].
10. Trace Metals and Their Adverse Effects
Many chemicals including natural mineral mica, shine, dyes, coloring agents, and different trace metals, are used as additives in cosmetics formulation to augment their brightness and realize superior quality with boosted effects [ 4 ]. Incorporation of high contents of trace metals including arsenic, antimony, chromium, cadmium, copper, cobalt, manganese, lead and nickel into lip cosmetics is a major issue in cosmetics application because of their potential adverse consequences [ 132 , 133 ]. These trace metals used in cosmetic formulations can accumulate in the skin, and some metals including aluminum, lead, cadmium, and mercury, are capable of diffusing across the skin barrier and thus entering blood vessels [ 134 ]. Reports have revealed the elevated level of heavy metals in the individual’s blood with wide exposure to these heavy metals due to extensive consumption of cosmetics [ 135 , 136 , 137 ]. High concentrations of toxic metals in the bloodstream results in the accumulation of these elements in various parts of the body, and consequently, leads to dysfunctioning and damaging of vital multi organs i.e., the kidneys [ 138 ]. The ophthalmic related adverse consequences of heavy metals have been widely documented in different reports since heavy metals can bind with retinal epithelium pigments and accumulated at higher concentrations [ 139 , 140 , 141 ]. It is reported that prolonged exposure to copper, lead, cadmium, arsenic, chromium and nickel are associated with an improved menace of numerous cardiovascular and neurologic disorders [ 142 , 143 ]. Particular exposure to arsenic, lead, cadmium, and mercury with vital organs can result in nephrotoxicity, neurotoxicity and hepatotoxicity. Additionally, a combination of lead, mercury, arsenic, and cadmium can generate synergistic effects leading to cognitive damage and dysfunction [ 144 ]. Introduction of antimony, commonly used in skin creams, face powder, lipsticks, eyeshadows, and eye pencils, can cause severe respiratory complications such as altered pulmonary functions, emphysema, bronchitis, and pneumoconiosis as well as hostile gastrointestinal related disorders including abdominal pain, ulcers, vomiting, and diarrhea [ 145 ]. Prolonged contact with cadmium provokes kidney damage, skin tumors, and bone brittleness and breakages. Increasing the use of mercury exerts potential risk to human health by causing gastrointestinal, nephro- and neurological ailments [ 146 ]. Allergic contact dermatitis may occur by the inhalation of nickel and cobalt metals, which are widely used in eyeshadow, lipstick, hair cream and face paint cosmetics. Consumption of lead in large amounts interrupt the synthesis of calcium and heme channels, which are very critical for transmitting nerve signals [ 142 , 147 ]. Furthermore, lead also interferes with the functionality of central nervous system in children [ 148 ].
11. Synthetic Musk Compounds
Synthetic musk compounds (SMCs) are semi-volatile cyclic organic compounds that are added to various consumer products including shampoo, soaps, body lotion, deodorants, cleansing agents, fish bait. These compounds are also used as food additives and fragrance materials such as air fresheners and perfumes [ 149 ]. Based on their physiochemical properties, SMCs are categorized into four group’s namely polycyclic musks, nitro-musks (first-ever commercially available SMCs), alicyclic musks and macrocyclic musks [ 150 ]. SMCs have been used as a food additive in various personal care products such as shampoo, soaps, body gels and lotion, deodorants and perfumes, household products like cleaning agents and air fresheners [ 151 ]. First-ever synthetic musk was commercialized in the early 20 th century and was the derivative of nitro-musk called dinitro and trinitrobenzene [ 152 ]. The production of polycyclic musk fragrances has exponentially increased over the last fifty years, for example, galaxolide is one important polycyclic musk [ 153 ] and musk ketone and musk xylene are also widely used SMCs [ 151 ]. Synthetic musks can bioaccumulate in the aquatic environment due to its lipophilic nature and thus can be easily detected in dust, indoor air, human adipose tissue, blood and breast milk [ 154 ].
12. Siloxanes and Silicones
Siloxanes (silicones) constitute a group of low molecular weight compounds, which are used in various cosmetics to soften, smooth and moisten. They make hair products dry faster and improve the spreadability of deodorant creams. They are most often used in moisturizers and facial treatments [ 155 ]. It should be noted that the worldwide siloxanes production in 2002 amounted to 2,000,000 tons, and currently, it is more than 8,000,000 tons [ 156 ]. The highest consumption of silicones was noted in China, North America and Western Europe [ 157 ]. Currently, nearly 50% of new skincare products contain at least one type of silicone [ 158 ]. The commonly used siloxane i.e., cyclopentasiloxane and cyclopentasiloxane are toxic and have the potential of bioaccumulating in aquatic organisms. Cyclotetrasiloxane is a type of endocrine disruptor that interferes with human hormone function. As a possible reproductive toxicant, it may also impair human fertility [ 159 ].
13. Conclusions and Outlook
In recent times, a large number of chemical compounds are being incorporated into the manufacture of cosmetic, beauty and personal care products as additives, fragrances, preservatives, stabilizers, surfactants, stains and shine to potentiate their quality, performance, and shelf life. However, based on the cosmetics-related literature assessment and this study, it is not unsurprising to comprehend that many of these substances are bioactive, environmentally persistent, and exhibit a potential bioaccumulation ability, thus can exert a serious threat to the environment and human health because of indiscriminate, widespread and prolonged exposure. Prohibiting the use of cosmetic products associated with environmental problems is not a practicable choice. Different novel strategies and approaches are required to address this issue realistically. Although the worldwide cosmetic regulation authorities and management are keenly concerned about this context, they should be more stringent and meticulous in incorporating new ingredients/substances with health hazard effects in the manufacture of cosmetics to circumvent undesirable environmental and health damages. Further comprehensive studies should be done on the acute or chronic intoxication of these pollutants of high concern allowing a more accurate monitoring and explicit inspection of their tangible health and ecological risks. Finally, information concerning the environmental and health influences of cosmetic products on their packaging would reassure consumers and encourage informed and more responsible employment of these products.
The literature contents covered in this review were solely conceptualized and expressly written by the listed author(s). The listed author(s) are highly obliged to their representative institutes and universities for providing the literature services.
Conflicts of Interest
The listed authors declare that no competing, conflicting, and financial interests exist in this work.
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Figure 1. Schematic illustration of the fate and general distribution of Triclosan (TCS) in water matrices.
Figure 2. Schematic illustration of possible bioaccumulation and biomagnification of microplastics in water matrices. Reprinted from [ 86 ] with permission from Taylor & Francis. Copyright (2019) Informa UK Limited, trading as Taylor & Francis Group.
| https://www.mdpi.com/2079-9284/7/1/13/xml |
Synthesizing Sodium Tungstate and Sodium Molybdate Microcapsules via Bacterial Mineral Excretion | Protocol (Translated to Dutch)
Scientific Article | Dit werk presenteert een protocol voor vervaardiging natrium wolframaat en natrium molybdaat microcapsules via bacteriën en hun...
Chemistry
Synthese van natrium wolframaat en natriummolybdaat Microcapsules via bacteriële minerale uitscheiding
doi: 10.3791/57022
Pao-Hung Lin 1 , Ying-Tang Huang 2 , Fu-Wen Lin 3
1 Department of Electronic and Computer Engineering, National Taiwan University of Science and Technology , 2 Department of Marine Biotechnology, National Kaohsiung Marine University , 3 Institute of Applied English, National Taiwan Ocean University
Summary
Dit werk presenteert een protocol voor vervaardiging natrium wolframaat en natrium molybdaat microcapsules via bacteriën en hun overeenkomstige nanodeeltjes.
Abstract
Presenteren we een methode, de bacteriële minerale uitscheiding (BMT), voor de synthese van twee soorten microcapsules, natrium wolframaat en natriummolybdaat en de twee metaaloxiden bijbehorende nanodeeltjes — de eerste zo klein als 22 nm en de laatste 15 nm. We gevoed twee stammen van bacteriën, Shewanella algenen Pandoraea sp., met verschillende concentraties van wolframaat of molybdaat ionen. De concentraties van wolframaat en molybdaat werden aangepast om microcapsules van verschillende lengte-naar-diameter verhouding. We vonden dat hoe hoger de concentratie hoe kleiner de nanodeeltjes waren. De nanodeeltjes kwam met drie lengte-naar-diameter verhouding: 10:1, 3:1 en 1:1, die werden bereikt door het voeren van de bacteriën respectievelijk met een lage concentratie, een middelgrote concentratie en een hoge concentratie. De beelden van de holle microcapsules werden genomen via de scanning electron microsfeer (SEM). Hun kristalstructuren werden gecontroleerd door röntgendiffractie (XRD) — de kristalstructuur van molybdaat microcapsules is Na 2MoO 4en die van wolframaat microcapsules nb 2WO 4met Na 2W 2O 7. Deze syntheses alle werden uitgevoerd onder een in de omgeving van ambient voorwaarde.
Introduction
Metaaloxide nanodeeltjes worden uitgebuit voor drug delivery 1, bouw kunstmatige botten 2, heterogene katalyse 3, veld emissie 4 , 5, zonnecellen 6, gas sensoren 7, en Lithium batterijen 8. Voor praktische toepassingen zijn de mechanische sterkte van nanokristallen én hun microstructuur van cruciaal belang. Onder de microstructuren, kunnen lege huls structuren worden gebruikt voor het maken van lichtgewicht, mechanisch robuuste materialen 9. Onder lege huls structuren, is een bolvorm bekend om zijn meer rigide dan een ellipsoïdale vorm; de laatste heeft een grotere lengte-naar-diameter verhouding dan de voormalige 10 , 11. Dit werk beschrijft een protocol voor het synthetiseren van sferische microcapsules via bacteriën met een niet-toxisch methode onder een ambient aandoening, die met de alternatieve methoden contrasteert, met inbegrip van de sjabloon synthese methode 12, Ultrasone-spray-bijgewoonde synthese methode 13en hydrothermale methode 14. Sommige van de alternatieve methoden vereisen sjablonen 12, wat een temperatuur zo hoog als 500 ° C 13en sommige een hoge druk 14. Wat betreft de resulterende structuur, de sjabloon synthese methode met behulp van de sjabloon gist bewerkstelligt een kern-shell structuur 15, in plaats van met een enkele muur, en degene die met behulp van de sjabloon E. coli produceert een structuur met lengte-naar-diameter verhouding van 1.7:0.8, en is niet bolvormig. 16.
In dit werk hebben wij een metaaloxide microcapsules met een enkele muur en van sferische vorm onder een ambient voorwaarde door te profiteren van bacteriële metabolisme. In de bacteriële glycolyse, een chemisch proces dat koolstof bronnen, zoals glucose en lactose metaboliseert, koolstof bronnen worden beschouwd als de oorsprong van het reducerend vermogen gegenereerd daarin. We bacteriële metabolisme gemanipuleerd door de concentratie van koolstof bronnen om gewenste uiteinden passen. Deze methode is milieuvriendelijk, met behulp van niet-toxische agentia en verbruikt veel minder stroom van elektriciteit. Ten slotte, met deze methode kunt de massaproductie van microcapsules gewoon door het verhogen van het volume van Bouillon.
Voorafgaand aan de methode, zijn er een andere twee methoden gebruik te maken van bacteriële metabolisme zodat mineralen: biologisch geïnduceerde mineralisatie (BIM) 17en biologisch gecontroleerde mineralisatie (BCM) 18. BIM en niet BCM kan worden gebruikt voor het maken van natrium wolframaat en molybdaat wolframaat microcapsules zoals onze proces, dat is uitgeroepen tot de bacteriële minerale uitscheiding (BMT) 19. In dit experiment, de vorm van microcapsules kan worden gecontroleerd om een lengte-naar-diameter verhouding van 10:1 tot 1:1, en de grootte van nanoparticle korrels dat formulier de schelpen kunnen worden aangepast aan de variërend van 15 nm tot 110 nm.
Protocol
Let op: Gebruik latex handschoenen, beschermende brillen en de vacht van een laboratorium voor het uitvoeren van het experiment. Wanneer u gebruikmaakt van het kabinet van de bioveiligheid, zet de kast ventilator en houden de kastdeur half gesloten.
1. bereiding van glaskralen
100 glaskralen 3 mm diameter plaats in een fles van 100 mL laboratorium en vervolgens het kapje strak.
Autoclaaf de inhoud bij 120 ° C gedurende 10 minuten.
Laat de fles om afkoelen tot kamertemperatuur, dan plaatst u deze in het biosafety kabinet.
2. bereiding van lysogenie Bouillon (LB)
Los 8 g poeder van LB-Lennox Bouillon in een fles van 500 mL laboratorium met 400 mL water.
Roer de inhoud met een magnetische roeren bar PTFE voor 20 min, en vervolgens het kapje strak.
Autoclaaf de inhoud bij 120 ° C gedurende 10 minuten.
Laat de oplossing afkoelen tot kamertemperatuur en breng dit in de bioveiligheid kabinet.
Met behulp van een precisiepipet, aliquoot de Bouillon in acht 15 mL centrifuge buizen in het biosafety kabinet (12,5 mL elk).
Aliquot de resterende Bouillon tot drie flessen van 100 mL laboratorium in het biosafety kabinet (van elke 100 mL). De drie flessen strak Cap. Houd ze in de bioveiligheid kabinet.
3. cultuur van Shewanella algen
Gebruik de diepgevroren cryopreserved stam.
1 mL van de ingevroren materiaal uit de bevroren buis uitzoeken met een spatel roestvrij staal in het biosafety kabinet, en plaats deze in een centrifugebuis bereid in stap 3.5.
De culturen gedurende 24 uur in een incubator 37 ° C te incuberen.
4. voorbereiding van de petrischaaltjes LB-Lennox (Bouillon met Agar)
Los twee tabletten van LB-Lennox (Bouillon met agar) in een fles van 100 mL laboratorium met 100 mL water.
Roer de inhoud met een PTFE magnetische roeren bar gedurende 20 minuten en vervolgens het kapje strak.
Autoclaaf de inhoud bij 120 ° C gedurende 10 minuten.
In het biosafety kabinet ontvangen door hand 100 mL oplossing in 4 petrischalen, ervoor te zorgen elk aliquot ~ 25 mL. Laat de oplossing afkoelen tot kamertemperatuur.
5. bereiding van Monoclonal bacteriën
Label in het biosafety kabinet, de drie flessen bereid in stap 2.6, #1 en #2 #3, respectievelijk.
Pipetteer 0,1 mL van de resulterende bacteriële suspensie in stap 3.3 in fles #1. Dop van de fles en swing het met de hand voor 1 min om een homogene oplossing.
Pipetteer 0,1 mL van de resulterende bacteriële vloeistof in stap 5.2 in fles #2. Dop van de fles en swing het met de hand voor 1 min om een homogene oplossing.
Pipetteer 0,1 mL van de resulterende bacteriële vloeistof in stap 5.3 in fles #3. Dop van de fles en schud het met de hand voor 1 min om een homogene oplossing.
Pipetteer de vloeistof in de fles #3 in de 4 petrischalen bereid in stap 4.4, met behulp van een volume van elk 0,02 mL.
Zet de glazen kralen in stap 1.3 naar de 4 petrischalen gebruikt, 4 kralen in elk gerecht bereid.
Sluit de deksels van de petrischaaltjes en schud ze met de hand voor 1 min.
De petrischaaltjes ondersteboven en broeden in een incubator 37 ° C gedurende 24 uur.
6. de vermenigvuldiging van Monoclonal bacteriën
7 buizen bereid in stap 2.5 halen.
De resulterende monoclonal bacteriën uit de 4 Petri gerechten bereid in stap 5.8 met een RVS-spatel uitzoeken, en leg ze in 7 buizen afzonderlijk.
Laat de 7 buizen in een incubator 37 ° C gedurende 24 uur.
Degene met de grootste lichtverstrooiing visuele colorimetrische methode uitzoeken.
7. bereiding van LB-Lennox bouillon met Glucose en zout
LB-Lennox Bouillon 10 g, 10 g NaCl en 10 g glucose in een fles van 500 mL laboratorium gebracht. Voeg water toe totdat het volume 450 mL bereikt.
Roer de inhoud met een PTFE magnetische roeren bar gedurende 20 minuten.
Autoclaaf de inhoud bij 120 ° C gedurende 10 minuten.
8. bereiding van natrium wolframaat
Zet 16.5 g natrium wolframaat nb 2 WO 4 .2H, 2 O in een fles van 100 mL laboratorium met een spatel roestvrij staal. Voeg water toe totdat het volume 50 mL bereikt.
Roer de inhoud met een PTFE magnetische roeren bar gedurende 20 minuten.
Autoclaaf de inhoud bij 120 ° C gedurende 10 minuten.
In het biosafety kabinet, krijgen filtraat via een vacuüm polyester filter met poriën van 1 µm.
9. voorbereiding van LB met Glucose, zout en natrium wolframaat
Giet in het biosafety kabinet, het filtraat opgedaan in stap 8.4 met de hand in de oplossing met glucose en zout bereid in stap 7.3.
In de bioveiligheid kast, aliquoot met een pipet de resulterende oplossing van 500 mL in stap 9.1 in 10 x 50 mL centrifuge buizen.
10. cultuur van bacteriën
In het biosafety kabinet, halen de bereid in stap 6.4 en aliquoot het met een pipet in de 10 reageerbuisjes bereid in stap 9.2, met elke buis ontvangen van 0,05 mL vloeistof.
Incubeer de 10 buizen in een 37 ° C incubator voor 120 h.
11. de oogst van BMT mineralen
Ultrasonicate elk van de 10 buizen in stap 9.2 op 20 KHz met 150 W voor 1 h.
Centrifugeer de buizen bij 2.025 x g gedurende 1 h.
Verwijderen van de heldere vloeistof in de buizen met een pipet, voeg water toe en herhaalt u vervolgens stap 11.1 en 11.2 één meer tijd.
Verwijderen van de heldere vloeistof in de buizen met een pipet, alcohol toevoegen en klik vervolgens ultrasonicate hen op 20 KHz met 150 W voor 1 h.
Centrifugeer de buizen bij 2.025 x g gedurende 1 h.
Herhaal stap 11.4 en 11,5 nog een keer
Oogst BME mineralen door het verwijderen van de heldere vloeistof in de buizen met een pipet; Daarna, cap onmiddellijk de buizen zonder het uitvoeren van een droogprocédé.
12. oscillerende temperatuur met Pandoraea sp.en molybdaat
Cultuur, Pandoraea sp. , op dezelfde manier als in stap 2, 3, 4, 5 en 6 voor Shewanella algen . Het resultaat van deze stap komt overeen met die van stap 6.4.
Maak van de pond-Bouillon met zowel glucose en zout in de dezelfde manier als in stap 7, 8 en 9, behalve dat de 16.5 g natrium wolframaat in stap 7.1 wordt vervangen door 12 g van natriummolybdaat, Na 2 MoO 4 · 2H 2 O. Het resultaat van deze stap komt overeen met die van stap 9.2.
In het biosafety kabinet, fetch de vloeistof bereid in stap 12.1 en aliquoot met een pipet in de 10 buizen bereid in stap 12.2, met elk ontvangende 0,05 mL tube.
Incubeer de 10 buizen in stap 12.3 bij schommelende temperaturen voor 120 h in een wederzijdse bad, de temperatuur 5 keer tussen 25 ° C en 37 ° C, bij elke temperatuur gedurende 12 h oscillerende schudden.
Representative Results
Figuur 1toont echte sferische microcapsules. Beide de twee stammen van de bacterie, Shewanella algenen Pandoraea sp., oorspronkelijk hebben een lengte-naar-diameter verhouding van 3:1. Voor het bereiken van de lengte-naar-diameter verhouding van 1:1, een hoge concentratie (> 100 mM) van metalen oxyanions vereist is. Een lage concentratie (< 5 mM) oxyanions kan leiden tot een lengte / diameterverhouding van 10:1, als dat inFiguur 2, die leiden de instroom van de oxyanions tot kan, het blokkeren van de binaire deling van bacteriën. Tot slot, voor het bereiken van een lengte-naar-diameter verhouding van 3:1, zoals die inFiguur 3, is een middelgrote concentratie (~ 20 mM) van oxyanions nodig. De vorming van sferische shells, met een lengte-naar-diameter verhouding van 1:1, kan worden veroorzaakt door bacteriële stations die zich krimpen hun oppervlakte als tegenwicht voor de inname van oxyanions terwijl het verspreiden van oxyanions door de celmembraan. De drie cijfers geven samen dat het lengte-naar-diameter verhouding kan worden afgestemd op 10:1 tot 1:1 gewoon door de concentratie van oxyanions aan te passen.
Figuur 4enFiguur 5tonen de nanoparticle korrels van natriummolybdaat in verschillende maten: de kleinere één wordt 15 nm, en de grotere één 110 nm. Merk op dat inFiguur 5, op de niet-verbrijzeld shells, deeltjes van 110 nm kan nog steeds worden omhoog geketend aan elkaar, vorming van poreuze schelpen. Grotere degene werd opgedaan door het schommelen van de temperatuur van het kweken Bouillon 5 keer tussen 25 ° C en 37 ° C, met elke temperatuur gedurende 12 h. Tijdens de trilling van de temperatuur, korrels van verschillende grootte kan niet alleen worden geproduceerd, maar ook de handhaving van de micro-bolvormige structuur, waardoor we kunnen microcapsules met verschillende korrelgroottes, van 15 nm tot 110 nm, gewoon door het beheersen van de temperatuur van de Bouillon .
Figuur 6toont de gebroken muur met grotere korrels verblijft naast de opening van de muur. De wanddikte is ongeveer 22 nm en de grotere korrel gaat 40-60 nm. Het verschil in grootte kan voortvloeien uit verschillende metabole processen, die zijn nog niet geïdentificeerd.
Figuur 1: het SEM-beeld van holle sferische schelpen met een lengte-naar-diameter verhouding van 1:1.Deze structuur is gemaakt van natrium wolframaat uitgescheiden door Shewanella algenmet glucose als de koolstofbron. Overgenomen met toestemming van ECS J. van Solid State Sci. en Tech., 6, lid 3, N3113 (2017). Copyright 2017, de elektrochemische Society.Klik hier voor een grotere versie van dit cijfer.
Figuur 2: het SEM-beeld van holle lange gloeidraad schelpen met een lengte-naar-diameter verhouding van 10:1.Deze structuur is gemaakt van natriummolybdaat uitgescheiden door Pandoraea sp.met glucose als de koolstofbron. Overgenomen met toestemming van ECS J. van Solid State Sci. en Tech., 6, lid 3, N3113 (2017). Copyright 2017, de elektrochemische Society.Klik hier voor een grotere versie van dit cijfer.
Figuur 3: het SEM-beeld van gebroken holle staafvormig schelpen met een lengte-naar-diameter verhouding van 3:1.Deze structuur is gemaakt van natrium wolframaat uitgescheiden door Shewanella algenmet glucose als de koolstofbron. Overgenomen met toestemming van ECS J. van Solid State Sci. en Tech., 6, lid 3, N3113 (2017). Copyright 2017, de elektrochemische Society.Klik hier voor een grotere versie van dit cijfer.
Figuur 4: het SEM-beeld verbrijzelde natriummolybdaat houders met een deeltjesgrootte van graan van 15 nm.Klik hier voor een grotere versie van dit cijfer.
Figuur 5: het SEM-beeld van verbrijzeld en niet-verbrijzelde natriummolybdaat schelpen met een deeltjesgrootte van graan van 110 nm.Klik hier voor een grotere versie van dit cijfer.
Figuur 6: het SEM-beeld van gebroken holle schelpen met een lengte-naar-diameter verhouding van 1:1.Deze structuur is gemaakt van natrium wolframaat uitgescheiden door Shewanella algenmet glucose als de koolstofbron. Korrels met een grootte over 40-60 nm hangen buiten de shell rechts naast een groot gat, terwijl de shell zelf bestaat uit korreltjes met een grootte van ongeveer 22 nm. Overgenomen met toestemming van ECS J. van Solid State Sci. en Tech., 6, lid 3, N3113 (2017). Copyright 2017, de elektrochemische Society.Klik hier voor een grotere versie van dit cijfer.
Discussion
Wat betreft de zelf-consistentie van de experimentele resultaten zijn de voorbereiding en de vermenigvuldiging van monoclonal bacteriën kritisch. Dit experiment, anders dan de sjabloon synthese experimenten 15 , 16, werkzaam bioactieve gram-negatieve bacteriën. Als u op een enkele muur, kozen we voor prokaryote bacteriën in plaats van eukaryotische bacteriën zoals gist 15. Om te bereiken een bolvorm met een lengte-naar-diameter verhouding van 1:1, in plaats van een grotere lengte-naar-diameter verhouding 16, we gevoed bacteriën met een veel hogere concentratie van oxyanions om te manipuleren om te krimpen in een bolvorm, microcapsules waardoor met een honkslag, ronde, en dunne muur (< 30 nm).
Aangezien de BMT hoofdzakelijk een beroep op het aanpassen van de concentratie van oxyanions om te controleren van het metabolisme van de bacteriën, beschikt het over twee beperkingen. Ten eerste, de concentratie van oxyanions wordt beperkt door de oplosbaarheid, hoewel de concentratie zo hoog mogelijk moet. Tweede, meest bacteriële stofwisseling stopt bij een temperatuur van meer dan 45 ° C of onder 5 ° C, respectievelijk de boven- en ondergrenzen van ons experiment.
Ondanks deze twee beperkingen heeft de BMT een groot potentieel voor het maken van metaaloxide materialen van praktisch belang. Om deze bewering te staven, gaan wij proberen deze methode om zirkonium microcapsules en ijzer microcapsules — de eerste een goede kandidaat materiaal voor kunstmatige botten, en de laatste voor drug delivery.
Disclosures
De auteurs hebben niets te onthullen.
Acknowledgments
Dit werk wordt ondersteund door het ministerie van wetenschap en technologie, Taiwan, Republiek van China, onder nummer meest 105-2221-E-011-008 verlenen, en ook door Geavanceerd-Connectek Inc, Taipei, Taiwan, ROC onder contract nummer RD Ref. No. 6749 en Dept. Ref. nr. 011 via de Afgestudeerd Instituut voor elektro-optische Engineering, National Taiwan University of Science en technologie.
Materials
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| https://www.jove.com/t/57022/synthesizing-sodium-tungstate-sodium-molybdate-microcapsules-via?language=Dutch |
(PDF) Clinical examination for the detection of protective sensation in the feet of diabetic patients. International Cooperative Group for Clinical Examination Research
PDF | We compared the reproducibility and accuracy of conventional clinical examination of the diabetic foot to monofilament examination. We also sought... | Find, read and cite all the research you need on ResearchGate
Clinical examination for the detection of protective sensation in the feet of diabetic patients. International Cooperative Group for Clinical Examination Research
August 1999
Journal of General Internal Medicine 14(7):418-24
Authors:
M Smieja
D L Hunt
D Edelman
Abstract and Figures
We compared the reproducibility and accuracy of conventional clinical examination of the diabetic foot to monofilament examination. We also sought to simplify the monofilament examination by reducing it to fewer touch points.
In a cross-sectional study at 10 centers in the United States, Canada, and Switzerland, general internists and residents performed a structured history and physical examination for neuropathy on the feet of diabetic patients. Independent examination by two observers included monofilament sensation, pinprick, vibration, position sense, and ankle reflexes.
A total of 304 patients were examined by at least one practitioner, and 200 received duplicate examinations. Monofilament examination and ankle reflexes had the best reproducibility, with moderate agreement (kappa = 0.59); pinprick, position, and vibration sense had fair agreement (kappa = 0.28-0.36). No component of the history or physical examination, singly or in aggregate, was both sensitive and specific for identifying a patient with an abnormal monofilament examination. A simplified monofilament examination using only 4 sites per foot (total 8 sites) detected 90% of patients with an abnormal 16-site monofilament evaluation.
Conventional clinical examination had low reproducibility and correlated poorly with monofilament examination for the identification of the at-risk patient. The Semmes-Weinstein monofilament examination, a reproducible, valid, and generalizable test of foot sensation, is recommended as the screening procedure of choice for examining diabetic feet.
. Demographic and Clinical Characteristics of the Patients Enrolled in the Study …
Ten touch points (9 plantar and 1 dorsal), and the model 1 "a priori" abridged 4-point monofilament examination. …
. Diagnostic Test Properties of Clinical Findings for the Presence of Abnormal Monofilament Examination Status * …
Figures - uploaded by
David L Simel
... It determines the patient's threshold for light touch and pressure of the foot by applying gentle pressure by blocking nylon filament buckled for 2 seconds; this can be used generally on four sites at great toes and the base e of, first, third, and fifth metatarsals
[18]
. It has 66% to 91% sensitivity for diabetic patients at high risk for foot ulceration. ...
Diabetic Foot Disease Comprehensive Management for Primary Care
Chapter
Full-text available
Jan 2023
Rajesh Jain
Anju Gahlot
Chitra Rani Chauhan
Globally, Diabetes foot affects nearly 6% of diabetes patients due to ulceration, infection, and tissue destruction [1], and 0.03% to 1.5% of them require amputation [2]; screening for the diabetic foot to assess the risk for complications. Diabetic foot complication includes infection, ulceration, or demolition of foot tissues. It may harm patients' value of life and affect social sharing and maintenance. Around 2-3% of patients with diabetic foot may need an amputation, but Most ulcers can be prevented with good foot care and screening for risk factors for a foot at risk of complications. We here summarise and provide an update on the prevention and management of diabetic foot in the primary care setup. Peripheral arterial disease (PAD) is common among persons with diabetes, and prevalence range from 10% to 20%. Most often is asymptomatic. Persons with diabetes are at accelerated threat for PAD and frequently have more significant distal vascular disorders than humans without diabetes. PAD is related to immense morbidity, which includes aches and purposeful impairment, amputation, and the hazard of death. Diabetic foot ulcer (DFU) generally happens in humans with diabetes, with a lifetime risk between 12% and 25%. Healing of DFU might also take months to years, and those lesions frequently result in increased lower extremity amputation (LEA).
... While our study seems to be the first to report the negative association between physician continuity and amputation, this result is consistent with findings from previous studies on diabetes care: Subjects that had a regular health care provider were more likely than those without to receive higher frequency of glycosylated hemoglobin (HbA1c) testing and more foot examinations (42% vs 17%) [32]. The P4P program in Taiwan mandates that a foot examination [33], which includes artery palpation, Semmes-Weinstein monofilament examination, and vibration perception
[34]
, to be conducted at the enrollment visit, annual visit and, if indicated, interposed quarterly visits. Therefore, when DM patients are enrolled into the P4P program, they are more likely to follow a structured education program, and thereby, have higher adherence to medications [15,16], and by screening for neuropathy which can be serious and prevent ulcerations from being noticed, the P4P program would mitigate the risk of ulcerations, severe infections, and eventually, amputations. ...
Pay-for-performance and continuity of care synergistically reduced amputation of lower extremity in patients with diabetes: a population-based cohort study
Article
Full-text available
Jun 2022
BMC HEALTH SERV RES
Yu-Ching Chen
Yi-Han Liao
Li-Jung E Ku
Jung-Der Wang
s
Background
Diabetic foot is a common and costly complication of diabetes. No existing study has looked at the effect of continuity of care on amputations of diabetes (DM) patients while considering pay-for-performance (P4P) participation. We investigated the impact of the P4P program and the continuity of care index (COCI) on the incidence of lower extremity amputations (LEA) among diabetics in Taiwan.
Methods
This was a population-based cohort study using insurance claims data from 1997 to 2013. We selected 15,650 DM patients in the P4P program along with age- and sex-matched non-P4P participants at a 1:4 ratio. Time-weighted average (TWA) of the COCI was calculated and included in the time-dependent Cox proportional hazard models to examine the impact of P4P and COCI on the risk of LEA, while controlling for individual and area level characteristics.
Results
During four-year follow-up, 1816 subjects experienced LEA. The cumulative LEA hazard rate of the P4P group ( n = 153) was significantly lower than that of the non-P4P group ( n = 1663) (hazard ratio = 0.37, 95% CI = 0.31–0.43, p < 0.0001, by log-rank test). In the time-dependent Cox proportional hazard model, the adjusted hazard ratios (aHR) for the P4P group was 0.35, ( p < 0.0001). With the low COCI (< 0.360) group as the reference, the aHR of LEA was 0.49 ( p < 0.0001) for the middle COCI group, ( p < 0.0001), and the aHR of LEA for the high COCI (≥0.643) group was 0.23 ( p < 0.0001).
Conclusions
Participating in the P4P program and increasing COCI might reduce the risk of amputation for DM patients, independently and synergistically.
... Although it is a highly subjective measure the absence of vibration sensation at the great toe is significantly associated with the development of foot ulcers. [16]
[17]
[18] Because ankle reflex is a poor predictor of ulceration we combined it with foot inspection and vibration and monofilament testing in a composite assessment called physical examination which was predicting DN in 54% of patients. ...
Variations in the Bedside Methods of Evaluating Diabetic Peripheral Neuropathy among Patients with Type 2 Diabetes. A Challenge for Primary Health Care Physicians in Trinidad a High Prevalence Setting for Type 2 Diabetes
Kameel Mungrue
Rene Marchan
... 90% of patients with insensate diabetic foot can be detected on testing four planter sites of the foot viz. the great toe and the bases of first, third and fifth metatarsals.
16
Impaired perception of vibration sensation is one of the earliest signs of diabetic peripheral neuropathy which can be assessed by 128 Hz tuning fork at the medial malleolus or the tibial tuberosity. Tuning fork assessment carries about 53% sensitivity as compared to monofilament test which has shown a sensitivity in the range of 66%-91% proving that tuning fork is less predictive in comparison to Semmes-Weinstein monofilament for development of foot ulceration. ...
Diyabetik Ayakta Anatomik Değişiklikler Anatomical Changes in Diabetic foot
Full-text available
Gurmeet Singh Sarla
Objective: Diabetic patients are 15 times more likely to develop gangrene, requiring amputation. Most of the non-traumatic limb amputations are due to complications of diabetes. The aim of this study was to analyse the various anatomical changes occurring in patients with diabetic foot ulcers.Materials and Methods: A prospective study was carried out in 70 patients presenting to the Diabetic Clinic at a tertiary care hospi-tal in Delhi, India under the Professor and Head of Department Surgery BHDC India, regarding the site, size, nature of foot le-sion, etiology of foot lesions and culture and sensitivity patterns of the wound swabs.Results: Most common lesions were noticed to have skin and nail changes (47 patients,67.1%) in the form of corns, callosities, dry skin, fissures, hypertrophied and brittle nails.20 patients (28.5%) presented with ulcers and 3 patients (4.2%) had gangrene. 56 patients (80%) were managed by multiple wound debridements and serial dressings.11 patients (15.7%) required skin grafting for wound healing.3 patients (4.2%) required some form of amputa-tion.Conclusion: It was found that with strict diabetic control, daily dressings, surgical intervention in the form of adequate, aggressive and timely debridement and culture specific antibiotics, the diabetic foot wounds healed well. Amputation at appropriate levels should be performed as life-saving measures in severe infections to pre-vent septicaemia and lifesaving takes precedence over limb / toe saving.
... 7 When the patients exhibited loss of protective sensation, neuropathy was considered through clinical examination using 10 g monofilament assessment, vibration, and temperature sensation.
23
Peripheral arterial disease was defined based on patient history of intermittent claudication and absent or diminished feet pulses (posterior tibial artery and dorsalis pedis artery) with assessment of ankle-brachial index measurements using a Doppler device. Values of 0.70-0.90 ...
Vitamin B12 Deficiency and Foot Ulcers in Type 2 Diabetes Mellitus: A Case–Control Study
Article
Dec 2019
Mohammed Badedi
Hussain Darraj
Abdulrahman Hummadi
Ahmed Budaydi
Objective:
To assess the association between vitamin B12 deficiency and the development of diabetic foot ulcers (DFU) in type 2 diabetes mellitus (T2DM).
Methods:
This is a case-control study that enrolled 323 Saudi adults with T2DM randomly selected from the Jazan Diabetes & Endocrine Center, Saudi Arabia from January 1, 2019, to July 31, 2019. The sample included 108 newly diagnosed cases with DFU and 215 control participants with T2DM unaffected by and free of foot ulcers (1:2 ratio). Logistic regression analysis was performed to determine the DFU predictors and to examine the association of DFU and vitamin B12 deficiency.
Results:
The highest DFU rates were found among the male participants and the participants older than 45 years. Neuropathy, vasculopathy, vitamin B12 deficiency, poor glycemic control, poor feet self-care, Charcot foot, physical inactivity, and spending long time standing at work were significantly associated with DFU, and all except physical inactivity and spending long time standing at work were independent predictors of DFU. After adjustment for the covariates, vitamin B12 deficiency was significantly associated with DFU (odds ratio 3.1), indicating that the patients with T2DM and vitamin B12 deficiency had a three times higher risk of developing DFU than those with normal vitamin B12 levels.
Conclusion:
Vitamin B12 deficiency had a significant association with DFU among the Saudi participants with T2DM. Establishing the causality and clarifying the biological role of vitamin B12 deficiency in DFU is important aims for future studies.
... Many different sizes of filaments are available with the 10-g pressure monofilament (5.07 monofilament) to be the most commonly used for pressure sensation evaluation. Around 90% of the patients with insensate diabetic foot could be identified on testing four planter sites (great toe and the base of first, third and fifth metatarsals)
[41]
. Monofilament test has shown a sensitivity of (66%-91%) in detection of diabetic patients at high risk for foot ulceration in several studies [18,42,43] . ...
Diabetic foot disease: From the evaluation of the "foot at risk" to the novel diabetic ulcer treatment modalities
Full-text available
John Doupis
Noha Gaber Amin
The burden of diabetic foot disease (DFD) is expected to increase in the future. The incidence of DFD is still rising due to the high prevalence of DFD predisposing factors. DFD is multifactorial in nature; however most of the diabetic foot amputations are preceded by foot ulceration. Diabetic peripheral neuropathy (DPN) is a major risk factor for foot ulceration. DPN leads to loss of protective sensation resulting in continuous unconscious traumas. Patient education and detection of high risk foot are essential for the prevention of foot ulceration and amputation. Proper assessment of the diabetic foot ulceration and appropriate management ensure better prognosis. Management is based on revascularization procedures, wound debridement, treatment of infection and ulcer offloading. Management and type of dressing applied are tailored according to the type of wound and the foot condition. The scope of this review paper is to describe the diabetic foot syndrome starting from the evaluation of the foot at risk for ulceration, up to the new treatment modalities.
... Sensorimotor measures included sensation on the plantar surface of feel and extension control in standing. Deep pressure sensation in the feet were measured using Semmes-Weinstein aesthesiometer
(35,
36). The aesthesiometer filaments were placed perpendicular to the plantar surface of the first ray. ...
Perturbation-Induced Stepping Post-stroke: A Pilot Study Demonstrating Altered Strategies of Both Legs
Full-text available
Jul 2019
Katherine M Martinez
Mark W Rogers
Mary T. Blackinton
Marie-Laure Mille
Introduction: Asymmetrical sensorimotor function after stroke creates unique challenges for bipedal tasks such as walking or perturbation-induced reactive stepping. Preference for initiating steps with the less-involved (preferred) leg after a perturbation has been reported with limited information on the stepping response of the more-involved (non-preferred) leg. Understanding the capacity of both legs to respond to a perturbation would enhance the design of future treatment approaches. This pilot study investigated the difference in perturbation-induced stepping between legs in stroke participant and non-impaired controls. We hypothesized that stepping performance will be different between groups as well as between legs for post-stroke participants. Methods: Thirty-six participants (20 persons post-stroke, 16 age matched controls) were given an anterior perturbation from three stance positions: symmetrical (SS), preferred asymmetrical (PAS−70% body weight on the preferred leg), and non-preferred asymmetrical (N-PAS−70% body weight on the non-preferred leg). Kinematic and kinetic data were collected to measure anticipatory postural adjustment (APA), characteristics of the first step (onset, length, height, duration), number of steps, and velocity of the body at heel strike. Group differences were tested using the Mann-Whitney U-test and differences between legs tested using the Wilcoxon signed-rank test with an alpha level of 0.05. Results: Stepping with the more-involved leg increased from 11.5% of trials in SS and N-PAS up to 46% in PAS stance position for participants post-stroke. Post-stroke participants had an earlier APA and always took more steps than controls to regain balance. However, differences between post-stroke and control participants were mainly found when stance position was modified. Compare to controls, steps with the preferred leg (N-PAS) were earlier and shorter (in time and length), whereas steps with the non-preferred leg (PAS) were also shorter but took longer. For post-stroke participants, step duration was longer and utilized more steps when stepping with the more-involved leg compared to the less-involved leg. Conclusions: Stepping with the more-involved leg can be facilitated by unweighting the leg. The differences between groups, and legs in post-stroke participants illustrate the simultaneous bipedal role (support and stepping) both legs have in reactive stepping and should be considered for reactive balance training.
Guía de Práctica Clínica Nacional sobre detección y manejo ambulatorio de complicaciones microvasculares de la Diabetes Mellitus
Full-text available
Jul 2022
Méndez Julieta
Maria lopez Mujica
Bruno Boietti
Brunilda Casetta
GPC interdisciplinaria con metodología GRADE. Aborda pie diabético, nefropatía, neuropatía dolorosa, y retinopatía.
View
GPC DIABETES complicaciones microvasculares final
Book
Full-text available
Feb 2021
Méndez Julieta
Brunilda Casetta
Alcuaz María Alejandra
Lucia Poggio
Responde preguntas clínicas sobre pie diabético, nefropatía diabética, neuropatía dolorosa y retinopatía diabética
Classification of Prediabetes and Healthy Subjects in Plantar Infrared Thermal Imaging Using Various Machine Learning Algorithms
Chapter
Apr 2020
Usharani Thirunavukkarasu
Snekhalatha umapathy
In the course of recent years, the size of individuals with diabetes mellitus has been dramatically increased than before. There is a need for screening and interventions which could prevent the individuals from the serious diabetic complications. Prediabetes may be a forerunner of type two diabetes mellitus, as well as a risk factor for heart illness. The body temperature is an essential parameter used for indicating the abnormal activity of human tissues. The thermal imaging primarily uses the infrared radiation emitted from the body naturally. The aim of this study was to evaluate the potential of thermography in screening the prediabetes. Sixty subjects were recruited for this study. Group I: HbA1c is <5.7%, Group II: HbA1c is 5.7–6.4%, Group III: HbA1c is >6.5%. The plantar thermograms were captured, and the temperature was measured at toe, metatarsal 1, metatarsal 3, metatarsal 5, instep and heel, respectively. The HbA1c was measured using the standard biochemical method. Three groups were categorized based on the accuracy rate obtained by five different machine learning algorithms (support vector machine, random forest, Naïve Bayes, multilayer perceptron and k-nearest neighbour). In prediabetes group, HbA1c exhibited positive correlation with measured temperature at toe region (r = 0.917, p < 0.01) and the negative relationship with measured temperature at metatarsal 1 (r = −0.474, p < 0.05), metatarsal 3 and heel regions (r = −0.895, −0.901, p < 0.01). The support vector machine has outperformed the other classifiers with good accuracy rate as 81.6%. The findings from this preliminary study indicate that measured temperature from plantar thermograms may be useful in screening the population for prediabetes.
Lower-Extremity Amputation in People With Diabetes: Epidemiology and Prevention
Article
| https://www.researchgate.net/publication/12881145_Clinical_examination_for_the_detection_of_protective_sensation_in_the_feet_of_diabetic_patients_International_Cooperative_Group_for_Clinical_Examination_Research |
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Mar 23, 2022
Insecticide Modes of Action and IRM
With the desert produce season almost completed and the spring melon season beginning, now is a good time to review the insecticide chemistries commonly used in your insect management programs. This is an important consideration as you make the transition from winter produce to alfalfa, spring melons and summer cotton where many of the same insecticide products are available in all these commodities. Sustaining long-term insecticide efficacy that provides cost-effective crop protection requires a conscious effort on the part of PCAs and growers to use insecticides responsibly. Over the past 30 years, Agrochemical Manufacturers have developed and brought to market over 20 new classes of chemistry that are highly effective, selective, and significantly safer than their chemical predecessors. These include the neonicotinoids, spinosyns, tetramic acid derivatives and anthranilic diamides to name a few. Most recently, we have seen new feeding disruptor products, PQZ ( pyrifluquinazon)
and Versys/Sefina ( afidopyropen)
being applied to fall melons for virus management and in winter vegetables for aphid management. Although, the development of new insecticide chemistries has been a bit slow over the past few years, we’re now seeing industry beginning to develop several new experimental insecticides for desert crops. You’ll be pleased to know that several compounds are being targeted for western flower thrips. Of course, at best many of these products are a few years away from registration. But this is great news as many of the older products are slowly being phased out of the marketplace. It was just a couple of years ago that flubendiamide (Belt, Vetica) was removed from the market, chlorpyrifos (Lorsban) is now gone, and EPA is currently proposing label changes to the neonicotinoids which could impact their use on many important crops. Thus, it is imperative to sustain the efficacy of the newer insecticide tools currently available and Insecticide Resistance Management (IRM) is now more important than ever. The most fundamental approach to IRM is to minimize the selection of resistance by a pest to any one type of insecticide chemistry. The key to sustaining insecticide susceptibility is to avoid exposure of successive generations of an insect pest population to the same MOA. Historically, alternating, or rotating compounds with different modes of action (MOA) each time you spray has provided sustainable and effective IRM in our desert cropping systems. When it is comes to IRM; “rotation, rotation, rotation”. In other words, never expose a generation of insects to the same MOA more than twice. The Insecticide Resistance Action Committee (IRAC), a coordinated crop protection industry group, was formed to develop guidelines to delay or prevent resistance. Using their most recent information we have produced a brief publication which provides the latest local information on the modes of actions, routes of activity and pest spectrum for important insecticide chemistries used in desert produce and melon crops - see the attached
Insecticide Modes of Action on Desert Produce Crops
. This classification list will provide you with an additional set of guidelines for the selection of insecticides that can be used in desert IPM programs.
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Soil Science
Jun 14, 2023
Crop Growth, Development, Nutrient, and Water Demand for Irrigated Chile (Capsicum annuum) (2023)
Southwestern Chile Production
Chile (Capsicum annuum) production is an important aspect of vegetable crop production systems in the desert Southwest. In many respects, chiles are a trademark feature of crop production in the desert Southwest. The Southwestern (SW) Chile Belt extends from southeast Arizona, across southern New Mexico, into far-west Texas, and northern Chihuahua, Mexico. The SW Chile Belt is dominated by production of New Mexico-type chile, also commonly referred to as “Hatch chile” and sometimes referred to as “Anaheim” type chile.
Recent acreages across the SW Chile Belt have consisted of approximately 7-8,000 acres in NM, 3-4,000 in TX, approximately 90,000 acres in Chihuahua, and about 300-500 acres in Arizona. Chiles are often associated with New Mexico, but Arizona also has a strong connection to this chile industry. For example, the Curry Chile Seed Company, based in Pearce, AZ, provides the seed for >90% of the total green chile acreage across the SW Chile Belt.
Chile peppers (Capsicum species) are among the first crops domesticated in the Western Hemisphere about 10,000 BCE (Perry et al., 2007). The Capsicum genus became important to people and as result, five different Capsicum species that were independently domesticated in various regions of the Americas (Bosland &Votava, 2012). Early domestication of chile peppers by indigenous peoples was commonly driven for use as medicinal plants. Due to their flavor and heat characteristics, chile peppers are a populate food ingredient in many parts of the world, including Latin America, Africa, and Asia cuisines. Chiles have been increasingly important to the U.S. and European food industries, particularly as these populations become more familiar with chile (Guzman and Bosland, 2017).
There are five domesticated species of chile peppers. 1) Capsicum annuum
is probably the most common to us and it includes many common varieties such as bell peppers, wax, cayenne, jalapeños, Thai peppers, chiltepin, and all forms of New Mexico chile. 2)
Capsicum frutescens
includes malagueta, tabasco, piri piri, and Malawian Kambuzi. 3) Capsicum chinense
includes what many consider the hottest peppers such as the naga, habanero, Datil, and Scotch bonnet. 4) Capsicum pubescens
includes the South American rocoto peppers. 5) Capsicum baccatum
includes the South American aji peppers.
The Capsicum annuum
species is the most common group of chiles that we encounter and there are at least 14 very different pod types in this single species that includes: New Mexico (aka Anaheim), bell peppers, cayennes, jalapeños, paprika, serrano, pequin, pimiento, yellow wax, tomato, cherry, cascabel, ancho (mulato, pasilla), and guajillo (Guzman and Bosland, 2017).
Crop Phenology
Plants vary tremendously in their physiological behavior over the course of their life cycles. As plants change physiologically and morphologically through their various stages of growth, water and nutritional requirements will change considerably as well. Efficient management of a crop requires an understanding of the relationship between morphological and physiological changes that are taking place and the input requirements.
Heat units (HUs) can be used as a management tool for more efficient timing of irrigation and nutrient inputs to crop and pest management strategies. Plants will develop over a range of temperatures which is defined by the lower and upper temperature thresholds for growth (Figure 1). Heat unit systems consider the elapsed time that local temperatures fall within the set upper and lower temperature thresholds and thereby provide an estimate of the expected rate of development for the crop. Heat unit systems have largely replaced days after planting in crop phenology models because they take into account day-to-day fluctuations in temperature. Phenology models describe how crop growth and development are impacted by weather and climate and provide an effective way to standardize crop growth and development among different years and across many locations (Baskerville and Emin, 1969; Brown, 1989).
The use of HU-based phenology models are particularly important and applicable in irrigated crop production systems where water is a non-limiting factor. Water stress will alter phenological plant development and it is a major source of variation in crop development models. Accordingly, irrigated systems are more consistent in crop development patterns and HU models can be much more consistent and reliable.
Chiles are a warm season, perennial plant with an indeterminant growth habit that we grow and manage as an annual crop. The fruiting cycle begins at the crown stage of growth and continues until the plant reaches a point of “cut-out” with hiatus in blooming as the plant works to mature the chile fruit crop that has been developed.
The first step in developing a phenological guideline for chiles would be to look for critical stages of growth in relation to HU accumulation. Figure 2 describes the basic phenological baseline for New Mexico – type chile and was developed from field studies conducted in New Mexico and Arizona (Silvertooth et al., 2010 and 2011; Soto et al., 2006; and Soto and Silvertooth, 2007).
Water and nutrient demands coincide with the fruiting cycle and efficient management of irrigation water and plant nutrients is enhanced by tracking crop development in the field. The use of HUs (86/55 o
F thresholds) can be applied since the thermal environment impacts the development of all crop systems, including chiles, (Figures 2 and 3).
Use of HUs to predict chile development is generally superior to using days after planting due to the simple fact that the crop responds to environmental conditions and not calendar days. This approach, using phenological timelines or baselines, works best for irrigated conditions where crop vigor and environmental growth conditions are more consistent than in non-irrigated or dryland situations where irregularity in year-to-year rainfall patterns can alter growth and development patterns significantly. Accordingly, water stress in an irrigation system will alter phenological plant development and usually accelerate crop maturity and create an earlier crop and increase fruit abortion or cause smaller fruit development.
Crop Phenology Relationship to Nutrient and Water Demand
Phenological guidelines can be used to identify or predict important stages of crop development that impact physiological requirements. For example, a phenological guideline can help identify stages of growth in relation to crop water use (consumptive use) and nutrient uptake patterns. This information allows growers to improve the timing of water and nutrient inputs to improve production efficiency. For some crops or production situations HU based phenological guidelines can be used to project critical dates such as harvest or crop termination. Many other applications related to crop management (e.g., pest management) can be derived from a better understanding of crop growth and development patterns.
Figure 1. Typical relationship between the rate of plant growth and development and temperature. Growth and development ceases when temperatures decline below the lower temperature threshold (A) or increase above the upper temperature threshold (C). Growth and development increases rapidly when temperatures fall between the lower and upper temperature thresholds (B).
Figure 2. Basic phenological guideline for irrigated New Mexico-type chiles.
References
Baskerville, G.L. and P. Emin. 1969. Rapid estimation of heat accumulation from maximum and minimum temperatures. Ecology 50:514-517.
Bosland, P.W., E.J. Votava, and E.M. Votava. 2012. Peppers: Vegetable and spice capsicums. Wallingford, U.K.: CAB Intl.
Brown, P. W. 1989. Heat units. Bull. 8915, Univ. of Arizona Cooperative Extension, College of Ag., Tucson, AZ.
Guzmán, I. and P.W. Bosland. 2017. Sensory properties of chile pepper heat - and its importance to food quality and cultural preference. Appetite, 2017 Oct 1;117:186-190. doi: 10.1016/j.appet.2017.06.026.
Perry, L., Dickau, R., Zarrillo, S., Holst, I., Pearsall, D. M., Piperno, D. R., et al. 2007. Starch fossils and the domestication and dispersal of chili peppers (Capsicum spp. L.) in the Americas. Science, 315, 986-988.
Silvertooth, J.C., P.W. Brown, and S. Walker. 2010. Crop Growth and Development for Irrigated Chile (Capsicum annuum). University of Arizona Cooperative Extension Bulletin No. AZ 1529
Silvertooth, J.C., P.W. Brown and S.Walker. 2011. Crop Growth and Development for Irrigated Chile (Capsicum annuum). New Mexico Chile Association, Report 32. New Mexico State University, College of Agriculture, Consumer and Environmental Science.
Soto-Ortiz, Roberto, J.C. Silvertooth, and A. Galadima. 2006. Crop Phenology for Irrigated Chiles (Capsicum annuum L.) in Arizona and New Mexico. Vegetable Report, College of Agriculture and Life Sciences Report Series P-144, November, University of Arizona.
Soto-Ortiz, R. and J.C. Silvertooth. 2007. A Crop Phenology Model for Irrigated New Mexico Chile (Capsicum annuum L.) The 2007 Vegetable Report. Jan 08:104-122.
To contact Jeff Silvertooth go to:
[email protected]
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Plant Pathology
Jun 1, 2022
Cucurbit Yellow Stunting Disorder Virus (CYSDV) (2022)
With melon season on full bloom, you will also start seeing diseases on melons. Cucurbit yellow stunting disorder is more of a problem on fall melons but they can also occur in summer melons. And it is always a good idea to be prepared for the next crop. Cucurbit yellow stunting disorder is a cucurbit disease caused by a plant virus named
Cucurbit yellow stunting disorder virus
(CYSDV; genus Crinivirus,
family Closteroviridae)
. This virus was first detected in southern California and Arizona in 2006 and infects cantaloupe and honeydew melon, watermelon, and various types of squash. CYSDV is transmitted exclusively by the whitefly,
Bemisia tabaci.
Symptoms always start from the oldest leave which is a diagnostic feature of the virus.
All biotypes of B. tabaci
known to exist in North America can transmit the virus efficiently, including biotypes A, B and Q. Whitefly transmission is responsible for virus spread over short distances (e.g., within and between fields). However, with high winds whiteflies can move long distances and transport the virus. The virus can stay infectious within whiteflies for up to 9 days. As virus infection is systemic (meaning they have to be circulated inside the plant system to show symptoms) it can take 3 to 4 weeks for disease symptoms to develop following infection. This gives a window for infected symptomless plants can be unknowingly transported and can lead to epidemics. The virus is not transmitted mechanically (by touch, mechanical damage, cuts etc) or via seed. However, the virus can be efficiently transmitted even if there is low whitefly pressure in the field.
The best management approach is to monitor the whitefly population and be proactive with insecticides application. Rotate insecticides with different modes of action Group numbers to minimize development of insecticide resistance. Practice good weed management in and around fields to the extent feasible.
Remove and destroy old crops/volunteers, enforce regional cucurbit -free period to eliminate the virus from the cropping system.
Sweet Shield and Novira varieties seem to do well in Yuma area.
To contact Bindu Poudel go to:
[email protected]
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Mechanization
Jun 14, 2023
High-Speed Centimeter Scale Resolution Sprayer for Precision In-Row Weeding
Please watch a demonstration of a spray assembly delivering herbicidal spray (blue dye) to spot spray targeted weeds. The device will be integrated with an imaging system for precision, automated / robotic weed control. Weed targets and crop plants are indicated on paper by green and yellow squares respectively. The same targeting pattern is used for simulated weeds (small plastic plants) and crop plants (white roses). Off target spray on paper is due to liquid splashing on a hard surface and is not observed on plastic weed targets. The travel speed is 2 mph and nozzle height - 5".
Click on the following demonstration link
or the picture area:
To contact Mark C. Siemens go to:
[email protected]
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Weed Sciences
Jun 14, 2023
Teff Grass: Forage Grown Between Vegetables Seasons
Teff grass (Eragrostis tef)
is originally from Ethiopia and has gained a lot of interest in Arizona. This crop is planted between vegetables and grows under different conditions and soil types. It is a fast-growing crop and can be harvested multiple times. According to the Teff Grass Crop Overview and Forage Production Guide from 2007-09 in California it was cut an average of 4 times yielding 6.89 tons/acre. The palatability to livestock is good and some report that its preferred over other traditional grass hays 1
.
There is also a need for good weed control in Teff grass to satisfy buyers.
One herbicide that was tested for postemergence broadleaf weed control and crop safety is Simplicity (pyroxulam). A 24(c) Special Local Need Registration was extended for this product. Also, another product that is successfully used in our area for broadleaf weed control is Clarity (dicamba).
Teff is grown during the summer between other crops that could be susceptible to residue of herbicides, and it is important that any herbicide that is used doesn’t have long-term soil activity.
We conducted a trial last summer in the Yuma Valley to evaluate the crop safety of pyroxulam, dicamba and other herbicides. Our results for pyroxulam were consistent with the injury observed in the visual ratings obtained by B.J. Hinds-Cook, D.W. Curtis, A.G. Hulting and C.A. Mallory-Smith with a 10% recorded 2
.
Also, efficacy for the control Purslane (Portulaca oleracea)
was evaluated. The following chart shows data obtained.
To contact Marco Pena go to:
[email protected]
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Areawide Insect Trapping Network
Aug 24, 2022
Area wide Insect Trapping Network (August 24, 2022)
Area wide Insect Trapping Network
VegIPM Update, Vol. 13, No. 17, Aug 24, 2022
Results of pheromone and sticky trap catches can be viewed here.
Corn earworm :
CEW moth counts increased slightly in the past 2 weeks, about average for late summer
Beet armyworm :
Trap counts stay active in some locations (Yuma Dome Valley and Wellton) particularly near alfalfa.
Cabbage looper:
Cabbage looper numbers remained low consistent previous years.
Diamondback moth:
DBM moths not active in any trap since June; average for this time of the year.
Whitefly:
Adult movement decreased in past 2 weeks consistent with previous years
Thrips:
Thrips adults decreasing in most locations, and trending comparable to previous years.
Aphids:
Aphid movement is absent and consistent with what we typically see during the summer.
Leafminers:
Adult activity tending downward, average for early late August
To contact John Palumbo go to:
[email protected]
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Links
Vegetable IPM Updates Archive
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College of Agriculture and Life Sciences
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37860 W. Smith-Enke Road
Maricopa, AZ 85239
FULL CONTACT
LIST | https://acis.cals.arizona.edu/agricultural-ipm/vegetables/vegetable-ipm-updates/3145ac0e-1857-484e-84a3-96d1f95e456f?Insectpage=32&PlantDiagnosticpage=27&Trappingpage=16 |
Climate Fiction in English | Oxford Research Encyclopedia of Literature
In the 21st century, a new genre of Anglophone fiction has emerged—the climate change novel, often abbreviated as “cli-fi.” Many successful authors of literary fiction, such as Margaret Atwood, Paolo Bacigalupi, T. C. Boyle, Michael Crichton, Ian McEwan, Amitav Ghosh, Barbara Kingsolver, Ursula Le Guin, Lydia Millet, David Mitchell, Ruth Ozeki, Nathaniel Rich, Kim Stanley Robinson, Leslie Marmon Silko, and Marcel Theroux, have contributed to this new genre’s efforts to imagine the causes, effects, and feeling of global warming. Together, their work pulls the issue-oriented and didactic approach of activist fiction into contact with the intensive description and site specificity of Romantic nature writing. Cli-fi knits these tendencies together into a description of the effects of a dramatic change in the Earth’s climate on a particular location and a vision of the options available to a population seeking to adapt to or mitigate those effects.Although cli-fi is resolutely contemporary and dedicated to creating new narratives adequate to current conditions, criticism devoted to the genre has carefully documented the persistence of national, masculinist, and anthropocentric tendencies in some of its major works. The dependence of cli-fi (and the environmental activism that inspires it) on capitalist visions of social progress has also received scrutiny. Some of these habits of representation have been inherited from literary predecessors such as Henry David Thoreau, Rachel Carson, Ernest Callenbach, and J. G. Ballard. Ballard’s Drowned World has proved an especially complicated source of inspiration for this new genre of the novel. In their efforts to update the motifs of these predecessors to the needs of the present, 21st-century cli-fi writers have experimented with the temporality, central figures, and mood of their fiction. These efforts have brought distinctive types of speculative and science fiction, as well as satires of climate change activism and new hybrid realisms, under the cli-fi umbrella. Although the genre still wrestles with inherited limitations, in every permutation, cli-fi novelists have prized innovation, experimentation, and creativity. Finally, all of their varied efforts involving cli-fi unite around an expectation that humanity and the planet can survive the changes associated with the Anthropocene.
Climate Fiction in English<here is a image b47154b71c8938f7-d58d83c2b8d08190>
Climate Fiction in English<here is a image b47154b71c8938f7-d58d83c2b8d08190>
Caren Irr<here is a image 95f2707bf46eb0ac-c87d796492628e13> Caren Irr Brandeis University
https://doi.org/10.1093/acrefore/9780190201098.013.4
Published online:27 February 2017
Summary
In the 21st century, a new genre of Anglophone fiction has emerged—the climate change novel, often abbreviated as “cli-fi.” Many successful authors of literary fiction, such as Margaret Atwood, Paolo Bacigalupi, T. C. Boyle, Michael Crichton, Ian McEwan, Amitav Ghosh, Barbara Kingsolver, Ursula Le Guin, Lydia Millet, David Mitchell, Ruth Ozeki, Nathaniel Rich, Kim Stanley Robinson, Leslie Marmon Silko, and Marcel Theroux, have contributed to this new genre’s efforts to imagine the causes, effects, and feeling of global warming. Together, their work pulls the issue-oriented and didactic approach of activist fiction into contact with the intensive description and site specificity of Romantic nature writing. Cli-fi knits these tendencies together into a description of the effects of a dramatic change in the Earth’s climate on a particular location and a vision of the options available to a population seeking to adapt to or mitigate those effects.
Although cli-fi is resolutely contemporary and dedicated to creating new narratives adequate to current conditions, criticism devoted to the genre has carefully documented the persistence of national, masculinist, and anthropocentric tendencies in some of its major works. The dependence of cli-fi (and the environmental activism that inspires it) on capitalist visions of social progress has also received scrutiny. Some of these habits of representation have been inherited from literary predecessors such as Henry David Thoreau, Rachel Carson, Ernest Callenbach, and J. G. Ballard. Ballard’s Drowned Worldhas proved an especially complicated source of inspiration for this new genre of the novel. In their efforts to update the motifs of these predecessors to the needs of the present, 21st-century cli-fi writers have experimented with the temporality, central figures, and mood of their fiction. These efforts have brought distinctive types of speculative and science fiction, as well as satires of climate change activism and new hybrid realisms, under the cli-fi umbrella. Although the genre still wrestles with inherited limitations, in every permutation, cli-fi novelists have prized innovation, experimentation, and creativity. Finally, all of their varied efforts involving cli-fi unite around an expectation that humanity and the planet can survive the changes associated with the Anthropocene.
Keywords
climate change
genre
environmental writing
contemporary Anglophone fiction
Subjects
North American Literatures
British and Irish Literatures
Oceanic Literatures
Fiction
20th and 21st Century (1900-present)
The Emergence of Climate Fiction
One of the most successful new genres of Anglophone fiction is the climate change novel, often abbreviated as “cli-fi.” The exact origins of the term “cli-fi” are obscure, but the journalist Dan Bloom has certainly played a crucial role in its history, as is documented by his invaluable website, The Cli-Fi Report. Reviewers began referring to cli-fi regularly in the 2000s, and in his definitive study, Anthropocene Fictions: The Novel in a Time of Climate Change,1Adam Trexler documents the prominence that “cli-fi” had achieved in newspaper accounts by 2013.
Characterized most frequently by efforts to imagine the impact of drastic climatological change on human life and perceptions, cli-fi narratives can be set in the past, present, or near future of the planet. The styles and voices used in cli-fi range widely, but these works often pay marked attention to the perspectives of scientists, especially where these deviate from popular ideas about the environment. Setting is of crucial importance for cli-fi; endangered cities, islands, and remote Arctic regions are common locations. Events of the genre often turn on a dramatic transformation in the setting, such as floods or the collapse of the food system. The pacing of these narratives tends to be accelerated and punctuated by crisis. This temporality creates an anxious, fearful mood and a preoccupation with the instability of objects and the permeable boundaries between human and nonhuman lives. Together, these motifs cohere in an apocalyptic sensibility, and differences of opinion about the necessity of apocalyptic patterns of guilt, crisis, and salvation have been an important source of controversy surrounding the genre.
Ecocriticism and Cli-fi
Critical discussions about cli-fi express many of the concerns that have animated the broader field of literary and social criticism known as “ecocriticism.” This field examines the significance of nature in literary culture from ancient to contemporary times and in many linguistic traditions and genres. Historicist ecocritics, such as John Gatta and Lawrence Buell, have deepened readings of the figures of nature in Romantic poetry and the 19th-century novel, for instance, teaching readers to recognize the ongoing role of the sacred in purportedly secular depictions of nature and urging reconsiderations of pastoralism. Groundbreaking works, such as Carolyn Merchant’s Ecological Revolutions: Nature, Gender, and Science in New England,2brought the gendered aspects of this process clearly into view. In the 21st century, a second wave of ecocritics has begun to focus more on contemporary crisis and to call for for a sweeping transformation of the project of literary and cultural criticism on environmental themes. Some of this work examines built environments, such as the city, seen in ecological terms, in addition to emphasizing the intersection of race, ethnicity, and the postcolonial condition with ecocritical concerns. Outstanding examples of work of all of these types can be found in Greg Garrard’s Oxford Handbook of Ecocriticism.3The revisionist turns made by the second wave of ecocritics has gone straight to the roots of the movement’s enterprise. Dipesh Chakrabarty, for example, asserts that from the vantage point of ecocriticism we must rethink the foundations of political and social history.4Progress, Enlightenment rationality, the struggle for human freedom—all of these important themes pale in significance in the context of a looming environmental crisis of planetary proportions, he argues. Chakrabarty is particularly interested in the examining the challenge ecocriticism poses to postcolonial studies and the project of liberation that has been crucial to that field.
A third wave of ecocritics may also be emerging, influenced by object-oriented ontology. Critics such as Timothy Morton turn away from the more sociological ambitions of the second wave and attempt to imagine the earth without reference to its human subjects. This has consequences for both the scale and the temporality of environmental narratives. In a related vein, Donna Haraway describes the condition preceding and—one hopes—following the period of climate crisis as the “Chthulucene.”5Developing this term not from H. P. Lovecraft but rather from the concept of the chthonic or indigenous, Haraway understands the Chthulucene as entangling “myriad temporalities and spatialities and myriad intra-active entities-in assemblages—including the more-than-human, other-than-human, inhuman, and human-as-humus.” She argues that humans and nonhumans alike rely on the earth as a place of refuge. Recent debates within ecocriticism about the relation of an arguably global nature to national or regional culture also influence accounts of cli-fi as a genre. E. Ann Kaplan argues that the cli-fi narrative, whether literary or filmic, is embedded in a trauma-laden sensibility that is recognizably American, and Heather Houser explores the ways that the affectively moving figure of the ill protagonist embeds eco-consciousness in culturally specific accounts of bodily vulnerability.6These figures, Houser argues, condense several interlocking features of contemporary American life (from biomedical technologies to digital networks), joining these to a holistic perception of the environment. Raymond Malewitz makes a similar argument about the emergence of cli-fi out of American literary regional aesthetics, and Heidi Hansson demonstrates the impact of a Canadian Arctic sensibility on the genre.7While Kaplan, Houser, Malewitz, and Hansson argue for a productive emergence of cli-fi motifs out of North American national conventions, Adam Trexler and Kate Marshall both shift the terms, insisting that climate fiction is not a development within a particular tradition but rather a direct, multigenre response to the narrative challenges involved in representing the global changes to the environment wrought by human activity—a response, in other words, to the geological age increasingly known as the Anthropocene. Climate fiction, by their account, largely renders national and generic traditions irrelevant, opening up to a planetary scale.
Discussions surrounding cli-fi have also provoked an inquiry into the genre’s depiction of the future. Critics have asked whether the genre inevitably envision apocalyptic destruction of the human species, carbon-based life, or the planet as a whole. Or does it mainly anticipate—whether eagerly or anxiously—the demise of economic, political, and social arrangements that have triggered climate change? What kind of posthuman or postcapitalist world can the genre imaginatively call into being? Is the crisis envisioned by cli-fi one of the Anthropocene or, in Jason Moore’s important turn of the concept, the Capitalocene—the geological age that records the impact of global capitalism?8Building on a longstanding conversation in science fiction studies, the Capitalocene question for cli-fi is why and whether it is easier to imagine the end of the world through climate-induced flooding than it is to ponder life after capitalism, to paraphrase Fredric Jameson.9This frequently reiterated question invites critics to scour the genre for moments when it potentially looks beyond crisis. The movement of ecocriticsm, in other words, urges readers to recognize the subliminal commitment of cli-fi to utopian invention as well as its most readily perceptible commitment to apocalyptic terror. These two gestures take on different weights in various incarnations of climate change fiction, but both are recurring and essential features in the genre.
Predecessors to Cli-Fi
The roots of 21st-century cli-fi are varied, but no account would be complete without mentioning the genre’s entanglement with major prose works in the pastoral tradition, especially Henry David Thoreau’s Waldenand Rachel Carson’s Silent Spring. Famously intermingling social satire, spiritual allegory, and close observation of his site, Thoreau’s Waldeninhabits a genre of its own. Nonetheless, despite Thoreau’s explicit warning to his readers not to imitate his project of living largely alone in the woods, his book has inspired many later writers. In Edward Abbey’s Desert Solitaire, Annie Dillard’s Pilgrim at Tinker Creek, Terry Tempest Williams’s Refuge, and other works, a genre of non-fictional nature writing has arisen that is dedicated to the solitary Thoreauvian observer’s meditations on natural phenomena at a remote site.10Cli-fi shares with this nonfictional writing a fascination with subjective human responses; its perplexed, injured, or psychically damaged heroes often participate in this eremitic tradition. The hero of Nathaniel Rich’s Odds against Tomorrow, for example, takes up a satirically exaggerated but clearly Thoreauvian project of house building in the final third of the novel, when he fortifies a compound in one of Manhattan’s outer boroughs after a devastating flood.11Striking out to discover a new way “to live deliberately,” in Thoreau’s often-quoted phrase, is also an important motif in Marcel Theroux’s Far North, a novel of heroic scavenging set in the post-apocalyptic Arctic.12In a somewhat less satiric vein, T. C. Boyle’s historical novel San Miguelexplores the inward-looking communion with the Santa Barbara Channel Islands undertaken by some of their early inhabitants.13This focus on the site and moods of the scientist’s hermitage owes a great deal to Thoreau.
At the same time, other features of the post-apocalyptic scene so prevalent in cli-fi can be traced back to Silent Spring. A poetically rendered analysis of the impact of commercially manufactured pesticides on migratory birds, Carson’s book imagines the devastated and lifeless (hence silent) spring resulting if steps are not taken to prevent species die-off. This extrapolation to a possible future whose origins we may have already seen anchors the complex temporality of the apocalyptic novel, as does Silent Spring’s cautionary and didactic attitude. Carson’s vision culminates in a stark assertion: “No witchcraft, no enemy action had silenced the rebirth of new life in this stricken world. The people had done it themselves.” Dialing back to an anthropogenic cause before swooping forward and outward to a vision of a devastated land are the twin movements of the apocalyptic sensibility. Many writers—from Margaret Atwood in her Oryx and Craketrilogy to Paolo Bacigalupi in The Wind-Up Girl—are interested in this sense of human culpability and the posthuman remainder that might survive in a “stricken,” finite, and possibly irrevocably damaged world. Atwood describes a horrific plague released upon a corporate-dominated system of food and reproduction by a zealous avenger, while Bacigalupi sets his novel in a near-future Thailand that houses one of the only remaining seed banks capable of introducing non-mutated foods back into the commodity chain.
While the influence of Thoreau and Carson grounds cli-fi firmly in a narrative of post-apocalyptic survival, the genre also shows the influence of writing in the utopian tradition. Here, Ernest Callenbach’s Ecotopiais a touchstone.14Callenbach’s programmatic novel imagines a sustainable group of interlinked urban centers in the Pacific Northwest, describing in detail the systems of job sharing, communal housing, holistic healthcare, and organic composting that characterize this postcapitalist society. A similar set of concerns and locations clearly informs much of Kim Stanley Robinson’s environmentally themed science fiction, most notably his “Three Californias” trilogy. But the same sensibility is also displaced to the elaborately conceived and purpose-built ecosystems in Robinson’s award-winning hard-science utopias, Red Mars, Green Mars, and Blue Mars.15Programmatic utopianism focused on the envisioning of specific technologies and processes that make possible a new form of sustainable living is perhaps not the most dominant strain in cli-fi, given the genre’s preoccupation with simple survival, but a utopian impulse toward rebuilding and post-crisis endurance is a vital component of the genre.
The apocalyptic scene and the utopian drive of cli-fi progenitors memorably cohere in the novel that has been claimed retrospectively as the source for this genre’s post-diluvian imaginary: J. G. Ballard’s The Drowned World. Although a minor classic since its publication in 1962, The Drowned Worldhas been reclaimed and reissued in the 21st-century context. Resolutely fictional rather than autobiographical or documentary like Thoreau and Carson’s writing, Ballard’s short novel describes the hallucinogenic journey of Robert Kerans, a UN scientist charged with mapping the drowned cities of western Europe in a period of non-anthropogenic tropical climate change. While holed up in a deluxe apartment building floating like an island above a flooded London, Kerans encounters a sexy Vogue-reading straggler, a crew of barbaric Afro-Caribbean scavengers headed by a crazed white leader, and the remnants of other phases of his own techno-military expedition. After a series of undersea explorations that double as journeys through the unconscious and into the instinctual limbic system, Kerans ventures off alone, braving a perilous jungle stocked with giant iguanas, bats, and crocodiles—his destination the deadly Equator. The novel is easily read in light of Ballard’s own upbringing in colonial Shanghai, a reading justified by the hero’s name (which alludes to a British anticommunist naval hero active in the region, John Kerans). Focusing on the British Empire means interpreting the flooding allegorically and the national/racial conflicts literally. However, in the context of cli-fi, Ballard’s flood is treated literally, and it is the movement of the apparently remote Conradian periphery into Europe’s urban centers that calls out for a more allegorical interpretation.
In addition to this reversal of figures, Ballard’s novel has proved an important rediscovered progenitor for cli-fi because of his novel’s complicated resistance to politics. Kerans’s narrative ultimately retreats inwards, focusing on consciousness and figures for social and personal regression. The Drowned Worldpresses hard on the scientist’s commitment to rationality and adventurous machismo, situating these within a narrative that insists on the failures of liberal progress narratives and the limitations of rationalist efforts to know and organize the world for humanity’s benefit. The oddly persistent figure of cannibalism also marks for Ballard the limit point of the human, because cannibalism encodes not only the horrific sacrifices associated with survival plots but also the endangerment of the very possibility of coexistence in a human community. At The Drowned World’s climax, Kerans discovers his wan, costumed love interest has been held captive at the center of a tableau of bones and “savage” dancing orchestrated by his Kurtz-like nemesis. This scene suggests that the social and psychological regressions toward the primitive that have been triggered by the high temperatures in the flooded world have eroded the foundations of reason and any morality premised on human species-feeling. This figure of the cannibal as the outer limit of the endurable arguably perpetuates the anxieties evident in narratives of European contact with the indigenous peoples of the New World, a tainted history that makes its persistence in Ballard’s writing and elsewhere notable. This legacy suggests that, where it culminates in cannibalism, the apocalyptic sensibility of climate-change fiction may be recognizing its own anxious ongoing attachment to a much-sullied model of Western civilizational so-called superiority.
At least, this is a conclusion suggested by Ballard’s cannibals. Given the widespread acceptance among cli-fi authors of anthropogenic accounts of climate change and Ballard’s explicit use of the solar-flare theory of global warming, it is surely not the scientific theory of this novel that makes it so important for cli-fi authors. Instead, Ballard’s influence likely derives from his envisioning of the scene of the drowned city and his investment in affectively intense portraits of crises of confidence among the would-be scientific analysts of a world spinning out of control. These have become essential touchstones of climate change fiction as a genre in all of its various manifestations.
Cli-fi and Sci-fi
If science fiction proper has often been concerned with either extrapolating technological development from existing social conditions or providing alternate histories that reimagine the supposed inevitability of the present, then cli-fi has deviated from those norms. The near-future, post-apocalyptic scenarios so prevalent in the genre often assume that the turning point for change occurred before our own historical moment, and consequently they frequently rely on archaic images, such as the drowned city. Readers encounter literally flooded cities in Le Guin’s Oregon, Ballard’s London, Bacigalupi’s dammed-up Bangkok, and Rich’s hurricane-damaged Manhattan. A preoccupation with islands extends the metaphor, as evidenced in Boyle’s Santa Barbara Channel Islands, Amitav Ghosh’s Sundarbans, David Mitchell’s Hawaii, Ian MacEwan’s Spitsbergen, and even Michael Crichton’s Vanuatu. In The Year of the Flood, the second volume of her Oryx and Craketrilogy, Margaret Atwood extends the urban flooding motif even farther, explicitly recalling its biblical origins and the Noah’s Ark narrative and using these as metaphors for planetary crisis.
The use of these flood motifs in cli-fi also affects the temporality of the genre, shifting it away from the future orientation or alternate presents of science fiction. Cli-fi is consistently concerned with a temporality that is retrospective, looking back to a change that has already begun to occur and to which humans and other species must adapt. Cli-fi rarely, if ever, allows its protagonists a chance to mitigate those effects, let alone alter the conditions for their occurrence (as in time travel narratives). John Connor cannot go back in time to battle the climatological Terminator. The terminus may not be prevented through manipulations of temporality in this genre.
Instead, as Srinivas Aravamudan explains, the temporality of cli-fi is catachronistic.16That is, by inverting anachronism or the projection of the present into the past, cli-fi synthesizes past and present and projects the result into a largely unavoidable but still emergent or creeping future. To this way of thinking, the turning point, such as it is, in climate fiction is an event that went unnoticed in the recent past but whose effects permeate the present and future. This sensibility raises the specter of a world in which only weak forms of human progress and control are possible, and consequently a renewed emphasis on the plasticity of the human body and its vulnerability to environmental change arises.
This catachronistic temporality is expressed in the recurring figure of the Last Book. This is a common cli-fi motif, appearing in stories such as Helen Simpson’s “Diary of an Interesting Year,” published in the New Yorkerin 2009and anthologized in I’m with the Bears.17Set in a post-apocalyptic 2040, this story concludes with the unnamed author of the titular diary describing how she will wrap her writing “in six plastic bags, sealing each one with duct tape against the rain” before burying it—a gesture made with little hope that anyone will be “mad enough” to read it. Margaret Atwood’s MaddAddamconcludes similarly with the “Book of Toby,” a quasi-biblical record of the expiring Toby’s exploits and maxims being offered by her young protegé—the first or, more likely, last literate humanoid in Atwood’s post-flood North America. This motif can be traced back to Ballard; John Kerans scrawls an “All is well” message to comfort any unlikely followers at the tomb of the dying soldier he carefully nursed in his final hours.
These and other abandoned documents associate the author’s own literary work with the embedded figure of a written record of a lost civilization, looping the reader’s own experience of the text into the story. When it is most effective, this gimmick intensifies a sense of gothic foreboding about the present, because it catachronistically unites contemporary practice with a future on the brink of extinction. If the text one is reading is the last book produced by the future civilization our own passivity has consigned to doom, then one’s own solitary reading becomes a portal through which travels our empathetic horror with those who do not yet exist. This identification with a future loss differs significantly from the ponderous revelations of, say, the discovery of the half-buried Statue of Liberty in Planet of the Apes. The substance of the revelation in cli-fi is not that our own (liberal, progressive) civilization is doomed by a transition we have yet to experience but ought to anticipate; it is, rather, that we may already inhabit a post-apocalyptic future without even realizing it. We are no longer who we thought we were, if we thought we were modern, human, and progressive.
Consequently, as Aravamudan suggests, cli-fi reveals a complex preoccupation with posthuman modifications to the body. Here again, the genre draws on sci-fi fascination with cyborgs, robotics, and technological extensions of the biological body. There is also some, though not much, interest in cli-fi in digital systems of ultra-rapid “cyberpunk” communication. These mainly manifest in the figure of the human with alterations to the genetic code, a figure imagined—at least by Atwood and Bacigalupi—as a potential survivor of the social collapse triggered by climate change.
In The Wind-up Girl, Bacigalupi investigates the technologically enhanced body most explicitly. The titular girl appears mechanically “wound up” and moves with a mechanical, stuttering gait except in situations when her survival is in question. Then, a hidden capacity for instinctive super-speed is revealed. Both of these adaptations were designed by a genetic engineer. At the novel’s climax, the wind-up girl confronts her Pygmalion, and he not only appreciates his handiwork but also offers to upgrade her design so that she might, against precedent, become capable of biological reproduction as well. The manipulated genetic code thus signals in Bacigalupi’s novel a determinant relation to the needs of the dominant powers, making the self an effect and the future a phase in which, at best, those designed mutations might proliferate unexpectedly. The malleable, plastic aspects of DNA make it susceptible to both conscious design and open futurity. It is not the incorporation of the human into a machine-controlled collectivity (like Star Trek’s Borg) that the posthuman wind-up girl’s enhancements signify. It is instead the malleability of the human biological organism itself, its susceptibility to failed or incomplete human projects to adapt to environmental change.
This cli-fi version of a posthuman plasticity generates some tension with the residue of heroic hypermasculinity that, Jeanne Hamming has persuasively argued, characterizes the imaginary of American science-fictional techno-thrillers in particular.18Hamming describes both Michael Crichton’s State of Fearand Kim Stanley Robinson’s Science in the Capitaltrilogy as reactions to a perceived loss of social authority experienced by heroic masculine science. Despite their diametrically opposed assessments of climate change (Crichton considers it a hoax perpetrated by academic elites, and Robinson sees it as an effect of capitalist exploitation), the two authors share, in Hamming’s analysis, a common figure in the compensatory masculinity of the heroic scientist. This reactive shoring up of masculinity is especially apparent in Crichton’s MIT researcher-turned-superspy John Kenner. With a name remarkably close to Terminator’s John Connor, Crichton’s hero heads off a series of explosions designed by malevolent environmentalists to whip up fear and generate support for their cause so they can present solutions to the problems they have created. Kenner almost singlehandedly discovers, explains, prevents, and invalidates the green conspiracy in four remote locations around the world, and along the way he converts a weak man to his cause, allowing his rebirth and recovery, as well as fortifying admiring women who are sexually endangered by the environmentalists’ cannibalistic allies in the South Pacific. Throughout these escapades, Kenner’s body is presented as being as heroically invulnerable as his logic is irrefutable. He is John Connor and the Terminator rolled into one.
Traces of this ultramasculine and robotically unflappable scientist-hero appear in many places in cli-fi. The male romantic lead in Barbara Kingsolver’s Flight Behavior, Ovid Byron, certainly falls into this tradition, since he is both physically metamorphic and exceptionally knowledgeable, changing the direction of the heroine’s life in a few short months.19The figure is common enough that it is reproduced through satire—especially in McEwan’s Solar, where the central scientist-hero is well past his prime intellectually and trapped in a spiral of domestic and professional decline. Even more vigorously, Nathaniel Rich’s Odds against Tomorrowsatirizes the masculine scientist-hero by taking a nerdy, obsessive statistician as its central figure. Driven by anxiety, not mastery, Rich’s hero Mitchell Zukor is intellectually ahead of the curve but survives physically only by chance. His final conversion into a parody of a survivalist hard-body, building a fortified bunker in a former bank and living off the profits of his earlier predictions, makes sense mainly as a satiric play on the heroic adventurer so amply envisioned by Crichton.
Even when they are falling apart (like McEwan’s hero) or engaged in over-the-top survivalist paranoia (like Rich’s Mitchell), these masculine heroes have little capacity to police a post-apocalyptic environment characterized by a revival of extreme sexual violence. Along with cannibalism, widespread heterosexual rape is repeatedly imagined in cli-fi as a consequence of climate-induced social breakdown. This is especially true in a burgeoning counter-tradition of feminist and queer-positive contributions to the genre. Inspired, perhaps, by the important example of Octavia Butler’s Parable of the Sower(a 1993novel focused on strongly empathic responses to racialized and sexual violence in a post-apocalyptic walled city),20Bacigalupi’s Emiko begins the novel as an abused and publicly humiliated sex toy in fortified Bangkok and is repeatedly assaulted, while Atwood’s peaceful, vegetarian, collectivist Crakers present a sexual menace to the former prostitutes who have survived the flood, precisely because they were genetically engineered not to experience sexual shame. How an imagined post-apocalyptic society manages sexual violence reveals a good deal about how that author envisions (if she does) the potential for social rebuilding, one capable of resolving conflict, resisting exploitation, and redirecting brutality. Post-apocalyptic sexual violence presents a new cycle of environmental damage in microcosm, particularly in feminist cli-fi.
In Atwood’s MaddAddam, the peaceful Crakers are successfully educated away from violence, while more vicious pre-collapse rapists are systematically hunted, captured, and (most surprisingly) subjected to trial. Their cruelty is a continuation of the socially approved institutions of sexual exploitation that characterized pre-flood North America in Atwood’s trilogy. To distinguish the post-apocalyptic concept of right behavior from the old, a new justice is necessary in order to recognize, punish, and prevent abuses. Once the violent Painballers are finally executed, their remains are symbolically disposed, and the recording of the disposal forms the first episode of the last book. In Atwood’s ecofeminist vision, in other words, sexual violence and the abuse of the environment that is entangled with it must be excised, bred out, and actively unlearned so that new values and new writing can emerge. New sexes and new social relations can be redesigned from the remnants of the old.
Bacigalupi’s imagination moves in a different direction. Rather than stressing regulatory mechanisms, he depicts a more open-ended and pansexual multiplicity as part of the posthuman condition. Pansexuality is, by implication, an expression of a less exploitative and production-oriented relation to nature. Sexual violence in The Wind-Up Girlis mainly associated with forms of heterosexual prostitution and enslavement that aim to reinforce human dominion over the nonhuman and masculine dominion over the feminine. The concentration on flesh (as in many scenes in which Emiko is groped or manhandled) encapsulates that desire to grip, control, and drive another organism. Homosexual relations, by contrast, are described in terms of intangible emotional bonds and aesthetic appreciation, even in the case of the disturbing genetic engineer who drools over “lady boys” and wind-up girls alike. The novel closes with Emiko’s escape from her pimp and flight toward a utopian and possibly nonexistent community of genetically modified New People in the North, a community that readers infer will be free from violence or at least capable of multiplying its directions and outcomes by multiplying the body parts involved.
These two celebrated works of cli-fi represent two major efforts to move beyond the residue of science fictional hypermasculinity and toward a more speculative multigender universe. It is genetic code and gender that are signs of the human’s embeddedness in this transforming world. At different registers, the invisible yet expressed code and the social meaning of the gendered body become sites for novelty; they emblematize efforts to transform the human—albeit with unpredictable effects. This theme is one cli-fi shares with sci-fi, but in this genre it fuses the potential for transformative modification to the human with the catachronistic effects of an environmental transformation already underway.
Satires of Cli-Fit
The conventions of cli-fi are already so well established that they have invited satire. In particular, the dystopian conventions of climate-themed films have attracted attention. The media studies scholar E. Ann Kaplan argues in Climate Traumathat the white male scientist-hero provides the default perspective for these narratives.21Even when this vantage does not coalesce in a named character, the attitude Kaplan designates as nostalgic masculine melancholy for an imagined future loss sets the terms for a more systemic anticipatory dread. The cynical anomie of the dystopian future, according to Kaplan’s account, itself provides a satirical means for imagining the effects of our pre-traumatic present, even while it triggers a satire of its own conventions. This analysis provides a useful premise for considering films such as Bong Joon Ho’s Snowpierceror Christopher Nolan’s Interstellar; these narratives disrupt the presumed heroism of the white male scientist by inserting nonwhite and female counterparts, respectively. 22
While Kaplan turns to feminist variants on dystopia featuring female protagonists, such as Margaret Atwood’s The Handmaid’s Tale, to explore the limitations of masculinist nostalgia as a point of view, some authors of cli-fi have turned inward to dissect the protocol of the nerdy hero.23For example, in Nathaniel Rich’s Odds against Tomorrow, the hero Mitchell Zukor begins the novel as a cliché, the ultra-anxious statistics genius. His fear drives him to calculate the odds of disasters obsessively and develop a complex crush on a female classmate who suffers bravely from a condition that could kill her at any moment. In the middle portions of the novel, as Mitchell’s worst fears are realized in a terrible storm, he rushes to her farm, hoping to rescue her from an abusive, crazed boyfriend. This would-be quest quickly inflates to self-satirizing proportions, as Mitchell and a friend advance toward and then retreat from the farm in mock-heroic fashion—first in a gaudily painted canoe and then less glamorously by bus. The satirical inversion is completed when our hero learns, by postcard, that his idol has become an environmental lawyer, taking up the battle that he has renounced in his isolated bunker. Rich’s satire, in other words, at once involves exaggeration and undercutting of the characterization, plot structure, and outcome of the quest romance that organizes the dystopian mood so common in cli-fi.
Ian McEwan’s Solardevotes even more attention to satirizing the scientist-hero’s sullied motives and scandalous behavior, making a petty and accidental murderer of his plagiarizing man of reason.24In Game Control, Lionel Shriver also uses thwarted sexual desire to satirize the overweening ambition and pettiness of would-be population control experts.25Similarly, Margaret Atwood takes apart the authority of the scientist in the character of Crake, a leader in the titular MaddAddam conspiracy. “Mad” in the comic-book sense of mad scientists, Crake has also been wounded and scarred by his father’s untimely death, a history of parental problems shared by his friend Jimmy the Snowman and his antagonists Adam One, as well as the omega to his alpha, the bear-like Zeb. But, as observed by Atwood’s Toby, a middle-aged wisewoman, his madness also contains an extra “dad.” Crake’s madness is compounded by dadness, alphabetically and psychologically. He becomes a mystical father figure for the Crakers he genetically engineers, thus risking a repetition of the patriarchal religiosity that generated his own intense reactions. Atwood’s satire thus underscores the potential for the masculine hero at the center of so much cli-fi to re-create the very crises whose destructive effects he so fearfully anticipates.
The same preoccupation with cult-like authority and the perverse effects of an overemphasis on dread also features prominently in Michael Crichton’s climate-denying bestseller, State of Fear.26Although quite firmly entrenched in the cli-fi tradition of the ultra-masculine scientific hero, this novel also undercuts the genre’s quest plot. Through satiric exaggerations of the powers of organization and financial resources of the activist wings of the environmental movement, Crichton imagines a scenario in which shadowy extremists use explosives to damage Antarctic ice sheets, trigger deadly flooding, and launch a massive tidal wave. The narrative heart of the novel does not consist of its confusing and misleading speeches that attempt to rebut the scientific consensus on the existence and anthropogenic nature of climate change. Crichton’s novel is, instead, best understood as a satire of the dread motif—one opposed in attitude but conceptually similar in part to the satires created by Rich, McEwan, and Atwood.
The implicit argument of these satires (and the explicit thesis for scholars such as Ursula Heise)27is that cli-fi has too readily restricted itself to a limited set of persons, sites, moods, and effects. Reaching not only beyond the scientist-hero but also beyond the drowned city, dread, and vague open-ended calls to heightened awareness seems vital for the genre’s wellbeing and, more importantly, the planet’s. Satires of cli-fi point toward the genre’s arrival as a bona fide phenomenon and its need for continuing improvement and variation.
Realist Hybrids in Cli-Fi
In criticism devoted to environmental literature and the novel more generally, realism has for several decades been under fire for its purportedly antipolitical comfort with dominant social conditions. In The Truth of Ecology, for instance, critic Dana Phillips argues that a predilection for description among realist authors offers at best a clumsy tool for recording perceptions of the natural world, and at worst a misguided confusion of literary technique with scientific method.28Although literary critics who follow György Lukács in distinguishing realist narration from naturalist description might quibble with Phillips’s conflation of the realist project with description, it is certainly true that ekphrastic meditation on scene has been a recurring feature of realist works on environmental themes. A good deal of attention has been given, since Thoreau’s famous description of the train whistle disturbing the serenity of Walden, to developing prose tools that might capture a scene on the verge of disappearing. Like some of the cli-fi satirists, Phillips doubts the effectiveness of this preoccupation and calls for a wilder and more aesthetically innovative approach to writing about ecological systems.
Despite these important critiques, authors of cli-fi have indisputably remained interested in literary realism, testing its history, merits, and flexibility for purposes of the present. Sometimes the results are perhaps too familiarly Dickensian. But some versions of their work also explore alternative geographies and temporalities and push forward to imagine human experiences of the earth in a distinctly contemporary variant of the realist framework.
Barbara Kingsolver’s Flight Behavior, for instance, combines this author’s recurring interest in biological systems with her even more prominent interest in the psychology of women.29Set in the Appalachian Mountains, the novel links mountains of Mexico and a Caribbean childhood to this location through a swarm of overwintering monarch butterflies. The swarm is described repeatedly, and the plot turns on its reinterpretation, thus fusing description and narration. Local residents interpret the swarm in light of biblical scripture before trying to capitalize on it financially; television journalists cover it as a sensational human interest story; a visiting lepidopterist and his research team see it as evidence of climate change; and a migrant family from Mexico view the butterflies as a sad reminder of their destroyed home. The protagonist conventionally shifts perspective on her home and the visiting swarm, moving from the eschatological and short-term financial interpretation toward the scientific. The red-haired Dellarobia’s symbolic identification with the fiery monarchs also launches her into flight as she finally realizes her own need to leave the cocoon of the Appalachian community and pursue higher education. In a classic realist gesture, then, the protagonist abandons illusions—including a romantic attraction to the Caribbean-born scientist—in favor of a more grounded project of self-improvement, a project coupled with a broadening of perspective that allows her to place her own history and ideals on a more global but still unseen map.
Amitav Ghosh’s The Hungry Tidealso situates the perspectives of local informants on a scientifically verified map.30Set in the Sundarban Islands off the coasts of India and Bangladesh, the novel traces the encounter of an ethnically Indian-American scientist with the dolphins that inhabit that area, as well as with the local people who know the history of the area and the endogamous species. The scientist’s GPS mapping device places the tidal islands on a verifiable map, and the use of this device and the grid it encodes play an important part in the resolution of the novel’s plot. The tangible solidity of an apparently volatile, fluid, mythic environment is crucial to Ghosh’s realism, as is (once again) the conversion of circumscribed locals to the project of gathering knowledge about their locale.
T. C. Boyle’s many environmentally themed novels are not all rigidly committed to literary realism. A Friend of the Earthin particular alternates between a dystopian near future and a somewhat romantically described eco-activism in the 1980s.31But even this future is presented in a manner characteristic of the downbeat observational irony of the realist, beginning as it does with the muddy shoes, persistent phlegm, and deflated ambitions of its aged hero. Boyle has been consistently interested in imaginative investigations of current social issues from gun violence ( The Harder They Come)32to identity theft ( Talk Talk)33, as well as in carefully researched historical fiction devoted to techno-scientific innovators such as Frank Lloyd Wright (in The Women)34, Alfred Kinsey (in The Inner Circle)35, and John Harvey Kellog (in The Road to Wellville).36Boyle’s two novels set in the Santa Barbara Channel Islands, When the Killing’s Doneand San Miguel( 2012)37, unite these interests. Pulling the realist’s eye for description, research, and mapping of a social situation into contact with the didactic writer’s project of explaining and interpreting a social problem, these two novels examine the control of non-native species and anthropocentric land use regulations, respectively. Aesthetically, they respect the realist convention of distinguishing between imagined action and observational description; striking passages devoted to observable settings such as island cliffs alternate with scenes of impassioned family conflicts. While classically realist in this respect, Boyle nonetheless employs cli-fi’s confounding catachronisms—finding a kind of geological or at least climatological drama in the slow transformations of the scene of the islands. He closes San Miguelwith a burning of keepsakes, letters, magazine articles, even a copy of Mozart’s Requiem. The note of anticipatory trauma that Kaplan and Aravamudan identify as central to cli-fi is here struck retrospectively. The future damage and regulation of the islands is something that the heroine does not foretell, though the narrator does. “She didn't know that the Navy would use the island as a bombing range or that the house she was standing in would burn mysteriously twenty-seven years later so that only the chimney remained amidst the blowing ash. And she didn't know that the Park Service would finally take charge of all of San Miguel and its waters and that anyone who wanted to come here or dream here or walk the hills and breathe the air would need to have a permit in hand,” the narrator reflects in the novel’s final pages. This heroine’s regretful retrospective mourning unknowingly colors the future that she cannot see and that extends, by implication, beyond the reader’s own present. Naturalist or realist description here does the work of building up a temporality of dread that is endemic to the cli-fi genre.
Kingsolver’s, Ghosh’s, and Boyle’s novels are all interested in plagues, from locusts to flood and fire. They fuse realist prose style with an apocalyptic sensibility. While perhaps they do not go far enough in the direction of experimentation to satisfy all of their critics, they do add variety to the three plots that, according to Lawrence Buell, have organized environmental writing since Thoreau: the chronicle, the excursion, and the inventory. In cli-fi, as in environmental literature generally, the apocalyptic mood is absolutely central. Realist, satirical, and dystopian writers are all anchored to some degree in apocalyptic conventions, and ultimately it may be the force (or weakness) of these conventions rather than the secondary style on which the fortunes of the genre lie.
The Future of Cli-Fi
Given its popularity and potential for deepening understanding of environmental issues (at least among the novel-reading portion of the Anglophone public), climate fiction seems likely to expand its foothold in contemporary fiction. If its authors are responsive to provocations from critics, they will continue to develop new temporalities, moods, and locations, and new stylistic variations as well as new subject matter that will energize the genre. Further experimentation with genre writing, along the lines of David Mitchell’s The Bone Clocks, seem like a promising direction, as do narratives focused on the environmental and social impact of particular extractive industries (such as the oil industry examined in Helon Habila’s Oil on Water) or the industrial food system (as in Ruth Ozeki’s My Year of Meats).38Habila introduces some visions of spiritual cleansing and healing for human bodies, if not for the land, in his novel, and this motif appears as well in works such as Susan Elderkin’s The Voicesthat locate some resistance to industrial and capitalist methods of extraction in so-called traditional cultures (in Elderkin’s case, the culture of aboriginal Australians).39Leslie Marmon Silko’s Gardens in the Dunesalso sounds this note, focusing on the circulation of seeds and cross-pollinations between the traditional cultures of Europe and the Americas. 40
Whether inflected by magical realism or not, the turn that Habila, Elderkin, and Silko (and, to a lesser extent, Ghosh) make toward alternative modernities also seems a promising direction for cli-fi. Radically diversifying not just the stated identity and perspective of the scientist-hero but also the locations, conflicts, moods, and motives of the genre is crucial for the long-term viability of the genre. Its longer-term success may hinge on the degree to which it takes seriously an engagement with forms of climate rescue that survive crisis.
That said, recognizing and learning from the climate change activism undertaken proactively in the developing world in particular requires interested novelists to resist the metropolitan center’s too frequent romanticization of an underdeveloped periphery it imagines as saturated with a spiritual depth that compensates for material deprivation and powerlessness. Rob Nixon and other postcolonial critics have drawn attention to fiction that resists this temptation, such as the sharply biting response to despoliation that appears in Indra Sinha’s Animal’s People(a picaresque fictionalization of responses to the disastrous chemical spill in Bhopal in the 1980s).41Similar attention might also be devoted to works such as Thomas King’s The Back of the Turtle(a humorous fable that also addresses spills and science gone wrong while depicting Native American communities that actively rebound from crisis).42Still others have sought not just an expansion of human voices but also an extension into the deeply posthuman universe of hyperobjects, and a new literature narrating at the scale of and temporality of the animal, the plant, or even the atom or the Earth could potentially result from those provocations. Amid all these current and possible initiatives, though, what remains certain is that the genre of cli-fi will continue to flourish in a broader range of moods, sites, and literary forms so long as the climate crisis continues to worsen. The growing critical recognition afforded to this emergent genre is one hopeful sign that a global public may be readying itself to rise to the challenges faced by the planet as a whole.
Those interested in exploring this field further might wish to anchor their research in Wai Chee Dimock’s influential work on deep time and postnational planetary spaces.43Franco Moretti’s insights into the lifespan of genres may also provide a fruitful resource for mapping cli-fi.44Finally, in Molecular Red, McKenzie Wark challenges theorists to invent new tools for criticism, tools adequate to the concrete problems of the Anthropocene.45He suggests developing a new concept of the Earth, beginning with Jean-Paul Sartre’s concept of the practico-inert, or that intractable material that is the object of human activity as well as an effect of labor. Overcoming a romantic conception of pristine, alien wilderness by envisioning the natural world as integrated with sometimes damaging human activity is a pressing task for eco-criticism and cli-fi authors alike.
Primary Sources
Atwood, Margaret. MaddAddam. New York: Anchor, 2013.
Bacigalupi, Paolo. The Wind-up Girl. San Francisco: Night Shade, 2013.
Ballard, J. G. The Drowned World. London: Victor Gollancz, 1962.
Boyle, T. C. San Miguel. New York: Random House, 2012.
Callenbach, Ernest. Ecotopia. New York: Bantam, 1977.
Carson, Rachel. Silent Spring. New York: Houghton Mifflin, 1962.
Crichton, Michael. State of Fear. New York: Harper Collins, 2004.
Elderkin, Susan. The Voices. London: Fourth Estate, 2003.
Ghosh, Amitav. The Hungry Tide. New York: Mariner, 2004.
Habila, Helon. Oil on Water. New York: Norton, 2010.
King, Thomas. The Back of the Turtle. Toronto: Doubleday Canada, 2014.
Kingsolver, Barbara. Flight Behavior. New York: Harper, 2012.
Le Guin, Ursula. “The New Atlantis.” In The Blind Geometer. Edited by Kim Stanley Robinson. New York: Tor, 1989.
McEwan, Ian. Solar. New York: Random House, 2010.
Martin, Mark, ed. I’m with the Bears: Short Stories from a Damaged Planet. London: Verso, 2011.
Mitchell, David. The Bone Clocks. London: Sceptre, 2014.
Ozeki, Ruth. My Year of Meats. New York: Penguin, 1999.
Rich, Nathaniel. Odds against Tomorrow. New York: Picador, 2013.
Robinson, Kim Stanley. Wild Shore Triptych. New York: MacMillan/Orb, 1995.
Silko, Leslie Marmon. Gardens in the Dunes. New York: Simon & Schuster, 1999.
Sinha, Indra. Animal’s People. New York: Simon & Schuster, 2007.
Thoreau, Henry David. Walden. New York: Library of America, 2010 [1854].
Links to Digital Materials
Henry David Thoreau,Walden. Full text of Thoreau’s classic book.
The Cli-Fi Report. Growing compilation of news and reviews related to cli-fi.
Teaching Cli-Fi. Resources for teachers.
Further Reading
Aravamudan, Srinivas. “The Catachronism of Climate Change.” Diacritics41.3 (2013): 6–30.
Buell, Lawrence. The Environmental Imagination: Thoreau, Nature Writing and the Formation of American Culture. Cambridge, MA: Harvard University Press, 1996.
Chakrabarty, Dipesh. “The Climate of History: Four Theses.” Critical Inquiry35 (2009): 197–222.
DeLoughrey, Elizabeth, and George, B. Handley, eds. Postcolonial Ecologies: Literatures of the Environment. Oxford: Oxford University Press, 2011.
Dimock, Wai Chee. Through Other Continents: American Literature across Deep Time. Princeton, NJ: Princeton University Press, 2006.
Garrard, Greg, ed. The Oxford Handbook of Ecocriticism. Oxford: Oxford University Press, 2014.
Gatta, John. Making Nature Sacred: Literature Religion, and the Environment in America. Oxford: Oxford University Press, 2004.
Hamming, Jeanne. “Nationalism, Masculinity and the Politics of Climate Change in the Novels of Kim Stanley Robinson and Michael Crichton.” Extrapolation54.1 (2013): 21–45.
Hansson, Heidi. “Arctopias: The Arctic As No Place and New Place in Fiction.” In The New Arctic. Edited by Birgitta Evengårdet al., 69–77. New York: Springer, 2015.
Haraway, Donna. “Anthropocene, Capitalocene, Plantationocene, Chthulucene: Making Kin.” Environmental Humanities6 (2015): 159–165.
Heise, Ursula. A Sense of Place, a Sense of Planet: The Environmental Imagination of the Global. Oxford: Oxford University Press, 2008.
Houser, Heather. Ecosickness in Contemporary U.S. Fiction: Environment and Affect. New York: Columbia University Press, 2016.
Jameson, Fredric. Archaeologies of the Future: The Desire Called Utopia and Other Science Fictions. New York: Verso, 2005.
Kaplan, E. Ann. Climate Trauma: Foreseeing the Future in Dystopian Film and Fiction. New Brunswick, NJ: Rutgers University Press, 2015.
Malewitz, Raymond. “Climate-Change Infrastructure and the Volatilizing of American Regionalism.” Modern Fiction Studies61.4 (2015): 715–730.
Marshall, Kate. “What Are the Novels of the Anthropocene?: American Fiction in Geological Time.” American Literary History27.3 (2015): 523–538.
Merchant, Carolyn. Ecological Revolutions: Nature, Gender and Science in New England. Chapel Hill: University of North Carolina Press, 1989.
Moore, Jason W. Capitalism in the Web of Life: Ecology and the Accumulation of Capital. London: Verso, 2015.
Moretti, Franco. Graphs, Maps, Trees: Abstract Models for Literary History. London: Verso, 2005.
Morton, Timothy. Hyperobjects: Philosophy and Ecology after the End of the World. Minneapolis: University of Minnesota Press, 2013.
Nixon, Rob. Slow Violence and the Environmentalism of the Poor. Cambridge, MA: Harvard University Press, 2013.
Phillips, Dana. The Truth of Ecology: Nature, Culture and Literature in America. Oxford: Oxford University Press, 2003.
Trexler, Adam. Anthropocene Fictions: The Novel in a Time of Climate Change. Charlottesville: University of Virginia Press, 2015.
Wark, McKenzie. Molecular Red: Theory for the Anthropocene. London: Verso, 2015.
Notes
1. Adam Trexler, Anthropocene Fictions: The Novel in a Time of Climate Change(Charlottesville: University of Virginia Press, 2015).
2. Carolyn Merchant, Ecological Revolutions: Nature, Gender and Science in New England(Chapel Hill: University of North Carolina Press, 1989).
3. Greg Garrard, ed., The Oxford Handbook of Ecocriticism(Oxford: Oxford University Press, 2014).
4. Dipesh Chakrabarty, “The Climate of History: Four Theses,” Critical Inquiry35 (2009): 197–222.
5. Donna Haraway, “Anthropocene, Capitalocene, Plantationocene, Chthulucene: Making Kin,” Environmental Humanities6 (2015): 159–165.
6. E. Ann Kaplan, Climate Trauma: Foreseeing the Future in Dystopian Film and Fiction(New Brunswick, NJ: Rutgers University Press, 2015);and Heather Houser, Ecosickness in Contemporary U.S. Fiction: Environment and Affect(New York: Columbia University Press, 2016).
7. Raymond Malewitz, “Climate-Change Infrastructure and the Volatilizing of American Regionalism,” Modern Fiction Studies61, no. 4 (2015): 715–730;and Heidi Hansson, “Arctopias: The Arctic As No Place and New Place in Fiction,” in The New Arctic, ed. Birgitta Evengårdet al. (New York: Springer, 2015), 69–77.
8. Jason W. Moore, Capitalism in the Web of Life: Ecology and the Accumulation of Capital(London: Verso, 2015).
9. Fredric Jameson, Archaeologies of the Future: The Desire Called Utopia and Other Science Fictions(New York: Verso, 2005).
10. Edward Abbey, Desert Solitaire(New York: McGraw-Hill, 1968); Annie Dillard, Pilgrim at Tinker Creek(New York: Harper’s Magazine Press, 1974); and Terry Tempest Williams, Refuge: An Unnatural History of Family and Place(New York: Vintage, 1992).
11. Nathaniel Rich, Odds against Tomorrow(New York: Picador, 2013).
12. Marcel Theroux, Far North(New York: Farrar Straus Giroux, 2009).
13. T. C. Boyle, San Miguel(New York: Random House, 2012).
14. Ernest Callenbach, Ecotopia(New York: Bantam, 1977).
15. Kim Stanley Robinson, Red Mars(New York: Bantam, 1993), Green Mars(New York: Bantam, 1994), and Blue Mars(New York: Bantam, 1996).
16. Srinivas Aravamudan, “The Catachronism of Climate Change,” Diacritics41, no. 3 (2013): 6–30.
17. Helen Simpson, “Diary of an Interesting Year,” in I’m with the Bears, ed. Mark Martin(London: Verso, 2011).
18. Jeanne Hamming, “Nationalism, Masculinity and the Politics of Climate Change in the Novels of Kim Stanley Robinson and Michael Crichton,” Extrapolation54, no. 1 (2013): 21–45.
19. Barbara Kingsolver, Flight Behavior(New York: Harper, 2012).
20. Octavia Butler, Parable of the Sower(New York: Seven Stories, 1998).
21.Kaplan, Climate Trauma.
22. Snowpiercer. Dir. Bong Joon Ho. CJ Entertainment, 2013. Film; and Interstellar. Dir. Christopher Nolan. Paramount Pictures, 2014. Film.
23. Margaret Atwood, The Handmaid’s Tale(New York: Houghton Mifflin, 1986).
24. Ian McEwan, Solar(New York: Random House, 2010).
25. Lionel Shriver, Game Control(New York: HarperPerennial, 2007).
26. Michael Crichton, State of Fear(New York: Harper Collins, 2004).
27. Ursula Heise, A Sense of Place, a Sense of Planet: The Environmental Imagination of the Global(Oxford: Oxford University Press, 2008).
28. Dana Phillips, The Truth of Ecology: Nature, Culture and Literature in America(Oxford: Oxford University Press, 2003).
29.Kingsolver, Flight Behavior.
30. Amitav Ghosh, The Hungry Tide(New York: Mariner, 2004).
31. T. C. Boyle, A Friend of the Earth(New York: Viking, 2000).
32. T. C. Boyle, The Harder They Come(New York: Ecco, 2015).
33. T. C. Boyle, Talk Talk(New York: Viking, 2006).
34. T. C. Boyle, The Women: A Novel(New York: Viking, 2009).
35. T. C. Boyle, The Inner Circle(New York: Viking, 2004).
36. T. C. Boyle, The Road to Wellville(New York: Viking, 1993).
37. T. C. Boyle, When the Killing’s Done(New York: Viking, 2011).
38. David Mitchell, The Bone Clocks(London: Sceptre, 2014); Helon Habila, Oil on Water(New York: Norton, 2010);and Ruth Ozeki, My Year of Meats(New York: Penguin, 1999).
39. Susan Elderkin, The Voices(London: Fourth Estate, 2003).
40. Leslie Marmon Silko, Gardens in the Dunes(New York: Simon & Schuster, 1999).
41. Rob Nixon, Slow Violence and the Environmentalism of the Poor(Cambridge, MA: Harvard University Press, 2013);and Indra Sinha, Animal’s People(New York: Simon & Schuster, 2007).
42. Thomas King, The Back of the Turtle(Toronto: Doubleday Canada, 2014).
43. Wai Chee Dimock, Through Other Continents: American Literature across Deep Time(Princeton, NJ: Princeton University Press, 2006).
44. Franco Moretti, Graphs, Maps, Trees: Abstract Models for Literary History(London: Verso, 2005).
45. McKenzie Wark, Molecular Red: Theory for the Anthropocene(London: Verso, 2015).
| https://oxfordre.com/literature/display/10.1093/acrefore/9780190201098.001.0001/acrefore-9780190201098-e-4?result=7&rskey=gxOT4u |
Amiloride Hydrochlorothiazide as Treatment of Acute Inflammation of the Optic Nerve - Full Text View - ClinicalTrials.gov
Amiloride Hydrochlorothiazide as Treatment of Acute Inflammation of the Optic Nerve
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01879527 Recruitment Status : Unknown Verified May 2015 by Prof. Fritz Leutmezer, Medical University of Vienna. Recruitment status was: Recruiting First Posted : June 18, 2013 Last Update Posted : May 12, 2015
Sponsor:
Medical University of Vienna
Information provided by (Responsible Party):
Prof. Fritz Leutmezer, Medical University of Vienna
Study Details
Study Description
Brief Summary:
Following acute inflammation of the optic nerve region, as commonly seen in multiple sclerosis patients, the optic nerve often undergoes atrophy, thus representing permanent damage. Data from animal studies suggest that amiloride may prevent this process. The aim of this study is to assess a potential neuroprotective effect of amiloride in acute autoimmune inflammation of the optic nerve region.
Condition or disease Intervention/treatment Phase Optic; Neuritis, With Demyelination Drug: Amiloride hydrochlorothiazide Drug: Sugar pill Phase 2
Detailed Description:
Recent studies have shown that the acid-sensing ion channel 1 (ASIC1) contributes to the axonal degeneration in CNS lesions Physiologically, ASIC1 has been described as a postsynaptic proton receptor on hippocampal neurons influencing the intracellular Ca2+ concentration. In MS, ASIC1 seems to activate under acidic conditions predominating in the inflammatory CNS lesions leading to a Na+ and Ca2+ overload and consecutive damage and apoptosis of axons. Consecutively, in a MS mousemodel axonal damage was significantly less pronounced after administering amiloride, a clinically safe blocker of ASICs. So ASIC1 seems to play a major role in axonal degeneration in MS. To our knowledge no clinical studies have tested those promising in vitro results in humans so far.
Only one retrospective registry-based cohort study was performed. This study showed no difference in the risk of incident MS or hospitalization and death among MS patients using amilorid compared to those using thiazide diuretics. However, this study has numerous limitations with respect to it's retrospective designone and the fact that amilorid users were at the vast majority older individuals. Such a late stage of the MS course does not seem to be the best window of opportunity for interventions with neuroprotective agents. Moreover, death may be a too multifactorial parameter to correspond with axonal damage alone. Consequently, a more sensitive parameter for axonal damage in MS is needed to test the impact of amiloride on neuroprotection and repair.Based on the findings described above we intend to assess the potential neuroprotective effect of amiloride hydrochlorothiazide (Amilostad HCT®) in patients with optic neuritis (ON), which has already been demonstrated in a mouse model. ON is one of the most common manifestations of MS and has already been proven appropiate to test neuroprotective agents.
Study Design
Layout table for study information Study Type : Interventional
(Clinical Trial) Estimated Enrollment : 78 participants Allocation: Randomized Intervention Model: Parallel Assignment Masking: Triple (Participant, Investigator, Outcomes Assessor) Primary Purpose: Treatment Official Title: A Randomized, Placebo-Controlled, Double-Blind, Phase IIa Study of Amiloride in the Treatment of Acute Autoimmune Optic Neuritis Study Start Date : March 2014 Estimated Primary Completion Date : April 2016 Estimated Study Completion Date : April 2016
Resource links provided by the National Library of Medicine
Drug Information available for: Hydrochlorothiazide Amiloride Amiloride hydrochloride
Genetic and Rare Diseases Information Center resources: Acute Graft Versus Host Disease Optic Neuritis
U.S. FDA Resources
Arms and Interventions
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Arm Intervention/treatment Active Comparator: Amiloride hydrochlorothiazide 5,68 mg Amiloridhydrochloride 2H20 (analogue 4,32 mg Amilorid) und 50 mg Hydrochlorothiazid. Trade name of the agent: Amilostad HCT 5/50mg tablets Manufacturer: Stada initial dose: 1 x 5/50mg once daily target dose: 2 x 5/50mg once daily Patients will be provided with capsules (size 00) containing one tablet of study medication and instructed to take these capsules once daily in the morning together with breakfast. Visit 2 will be scheduled one week after baseline and at visit 2 patients will be provided with capsules containing two tablets of study medication Drug: Amiloride hydrochlorothiazide Blinding will be done by over-encapsulating amiloride HCT tablets and providing corresponding placebo capsules.Patients will be provided with capsules (size 00) containing one tablet of study medication (Amilostad HCT 5/50mg tablet or placebo) and instructed to take these capsules once daily in the morning together with breakfast. Visit 2 will be scheduled one week after baseline and at visit 2 patients will be provided with capsules containing two tablets of study medication. This maintenance dose will not be changed throughout the remaining study period. Placebo will be administered in the exact same manner. Other Names: Marketing Authorisation number: 1-22734 Trade name: Amilostad HCT Placebo Comparator: Sugar pill Patients will be provided with capsules (size 00) containing sugar and instructed to take these capsules once daily in the morning together with breakfast. Drug: Sugar pill containing placebo Other Name: placebo
Outcome Measures
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Primary Outcome Measures
:
Change in thickness of retinal nerve fiber layer (RNFL) [ Time Frame: Baseline versus follow-up at 24 weeks ]
Eligibility Criteria
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 18 Years to 50 Years (Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Patients between 18 and 50 years of age with a first episode of optic neuritis (ON) and a visual acuity decreased to <0,6 will be eligible for inclusion in the study. Diagnosis of ON has to be confirmed by an ophthalmologist. Onset of symptoms has to be within 10 days prior to inclusion into the study
Exclusion Criteria:
Known allergy or hypersensitivity to amilostad HCT or any of its ingredients
Known allergy or hypersensitivity to other sulphonamide-derived drugs
Impaired renal function or any known renal disease
Intake of other potassium-conserving diuretics
Intake of potassium supplements or a special potassium rich diet
Intake of spironolactone or triamterene
Moderate to severe hepatic failure
Morbus Addison
Known hypercalcaemia
Intake of lithium therapy
Blood urea > 10mmol/l
Diabetes mellitus
History of ON or any other ocular disease (affected as well as unaffected eye)
Pregnancy or lactation period
Treatment with corticosteroids or amiloride within 30 days prior to the inclusion into the study
Use of any immunomodulatory or immunosuppressive agents anytime in the past
Dearrangement of serum sodium or potassium levels on the lab
Contacts
Layout table for location contacts Contact: Fritz Leutmezer, MD +43140400 ext 3120 [email protected]
Locations
Layout table for location information Austria Medical University of Vienna, Department of Neurology Recruiting Vienna, Austria, 1090 Contact: Fritz Leutmezer, MD +43140400 ext 3120 [email protected] Principal Investigator: Fritz Leutmezer
Sponsors and Collaborators
Medical University of Vienna
Investigators
Layout table for investigator information Principal Investigator: Fritz Leutmezer, MD Medical University of Vienna
Layout table for additonal information Responsible Party: Prof. Fritz Leutmezer, MD, Medical University of Vienna ClinicalTrials.gov Identifier: NCT01879527 History of Changes Other Study ID Numbers: SSP-2 2012-005113-39 ( EudraCT Number ) First Posted: June 18, 2013 Key Record Dates Last Update Posted: May 12, 2015 Last Verified: May 2015
Additional relevant MeSH terms:
Layout table for MeSH terms Neuritis Demyelinating Diseases Optic Neuritis Peripheral Nervous System Diseases Neuromuscular Diseases Nervous System Diseases Optic Nerve Diseases Cranial Nerve Diseases Eye Diseases Hydrochlorothiazide Amiloride Amiloride, hydrochlorothiazide drug combination Antihypertensive Agents Diuretics Natriuretic Agents Physiological Effects of Drugs Sodium Chloride Symporter Inhibitors Membrane Transport Modulators Molecular Mechanisms of Pharmacological Action Acid Sensing Ion Channel Blockers Sodium Channel Blockers Epithelial Sodium Channel Blockers Diuretics, Potassium Sparing
| https://clinicaltrials.gov/show/NCT01879527 |
(PDF) Quantification of Diffuse Hydrothermal Flows Using Multibeam Sonar
PDF | The Cabled Observatory Vent Imaging Sonar (COVIS) deployed at the Main Endeavour node of the NEPTUNE Canada observatory has provided acoustic time... | Find, read and cite all the research you need on ResearchGate
Conference Paper
Quantification of Diffuse Hydrothermal Flows Using Multibeam Sonar
December 2014
Conference: AGU Fall Meeting
At: San Francisco, California
Volume: V21A. Dynamics of Continental and Submarine Hydrothermal Systems IV. Poster V21A-4727
Abstract
The Cabled Observatory Vent Imaging Sonar (COVIS) deployed at the Main Endeavour node of the NEPTUNE Canada observatory has provided acoustic time series extending over 2 years. This includes 3D images of plume scattering strength and Doppler velocity measurements as well as 2D images showing regions of diffuse flow. The diffuse-flow images display the level of decorrelation between sonar echos with transmissions separated by 0.2 s. The present work aims to provide further information on the strength of diffuse flows. Two approaches are used: Measurement of the dependence of decorrelation on lag and measurement of phase shift of sonar echos, with lags in 3-hour increments up to several days. The phase shifts and decorrelation are linked to variations of temperature above the seabed, which allows quantification of those variations, their magnitudes, spatial and temporal scales, and energy spectra. These techniques are illustrated using COVIS data obtained near the Grotto vent complex.
Session Title: V21A. Dynamics of Continental and Submarine Hydrothermal Systems IV Posters
Poster Number: V21A-4727
Back ground:
A Cabled Observatory V ent Imaging Son ar (COVIS)
based upon the Reson 7125 multibeam sonar is connected to
the NEPTUNE Canada cabled seafl oor observatory . Data
obtained at 200 kH z are used to image r egions of diffuse
flow , which cause acoustic scintillation.
Wide - Beam Source
Fan - Beam Source
Receiv er
Reson 7125 T ransducers
Mounted on C OVIS
Conclusions and Future W ork:
New method provides r emote measur ement of
diffuse- flow temperatu re variation s over ar eas of size
~50 m and over a wide range of tim e scales.
Ground - truth needed: r apid - resp onse thermistor
measur ements concurr ent with sonar measu rement.
Signal desi gn will alleviate pr esent pr oblem with zer o
crossi ng of sinc functi on.
Error sour ces must be identified and quantifie d.
Method can pr oduce imagery drap ed over bathym etry .
A vailable data allow time series > 2 years to be
developed and examin ed for events.
New Method :
The cr oss - corr elation between successive pings can b e
shown to be det ermined by changes in s ound speed at the
seafloor . This, in turn, allows estimation of tem perature
change between pi ngs. Decorrelati on occurs because arrival
times ar e altered by sound speed changes.
Echoes due t o individual scatterers are displaced
as temper ature (hence sound speed) increases
(blue - > red curves)
Ping- ping correlatio n is a function of sound -
speed change
Measured
correla tion
Results:
T emperatur e change is quantifi ed by the structure
function, the mean - square tem perature di fference as a
function of lag t ime. The asympt ote is twice the temperatur e
variance.
Locations of 8 sites
chosen for analysis
Thermistor dat a from nearby diffuse - flow site have slow
response time but similar varianc e
Estimat ed
tempera ture change
Diffuse - flow site near
CO VIS with RA S
temperature sensor
CO VIS deployed at Main
Endeavour Field
Example of diffuse - flow
imaging
Paper No. V21A -4727
... Our recent work
[17]
has shown how to provide more quantitative information on diffuse flows, and has provided proof-of-concept results. In particular, it has been shown that the cross-correlation between successive pings is determined by changes in sound speed at the seafloor. ...
A correlation approach for characterizing diffuse hydrothermal flows using multi-beam sonar
Conference Paper
Full-text available
Jun 2015
Anatoliy N. Ivakin
D.R. Jackson
Karen G Bemis
Guangyu Xu
Multi-beam sonars are normally used for bottom bathymetry and backscatter intensity measurements, which provide a base for remotely characterizing and classification of the seabed. If not only sonar echo intensity (squared magnitude of acoustic pressure) but also the cross-correlation between successive echoes is measured, then temporal changes in sound speed in the near-bottom environment can be determined. This, in turn, allows estimation of the change of environmental parameters, e.g. temperature variations, as there is a simple linear relationship between sound speed and temperature changes. Stochastic modeling shows that the dependence of the echo decorrelation on the lag time has a relationship with the statistics of temperature variations above the seabed that determine their spatial and temporal scales, power spectra, and structure functions. This approach has been applied to quantify the bottom diffuse hydrothermal flow activity at the Main Endeavour Field on the Juan de Fuca Ridge using the Cabled Observatory Vent Imaging Sonar (COVIS) connected to the Ocean Network Canada’s NEPTUNE observatory. The new technique and results are discussed.
... The question is whether even the lower rate of 1 MW/m 2 can be applied uniformly across the detected or inferred areas. The strength of the decorrelation (Appendix B- Fig. B4) varies significantly across the detected area, which may indicate that the flux of diffuse discharge also varies (Jackson and Dworski, 1992;
Ivakin et al., 2014)
. Determining that variation and how to either estimate it directly or extrapolate more accurately is a needed area of research. ...
Partitioning Between Plume and Diffuse Flow at the Grotto Vent Cluster, Main Endeavour Vent Field, Juan de Fuca Ridge: Past and Present
Article
Dec 2010
Peter A. Rona
Karen G Bemis
C. Jones
D. R. Palmer
Seafloor hydrothermal systems discharge as plumes from discrete vents and as diffuse flow from surrounding areas that transfer heat and chemicals from the lithosphere into the ocean in quantitatively significant amounts. Our VIP (Vent Imaging Pacific) July 2000 experiment was designed to acoustically image and quantify these flows at vent clusters in the Main Endeavour field using a sonar system (Simrad SM 2000) mounted on ROV Jason from fixed positions on the seafloor using three methods that we developed. Buoyant plumes are reconstructed applying visualization techniques to volume backscatter from suspended particulates and density discontinuities in plumes. A Doppler algorithm is used to measure mean vertical velocity through plume cross sections and to calculate volume flux at different altitudes in a plume. Acoustic Scintillation Thermography (AST) is used to image irregular areas of diffuse flow. Results from a sulfide edifice (north tower of Grotto Vent cluster; height 12 m; diameter 10 m; sonar range 12 m) supplemented by additional AST measurements and in situ measurements of flow rate and temperature are tabulatd below: The higher diffuse than plume heat flux is consistent with prior studies at other sites. However, the ratio of diffuse to plume heat flux (range 23-353) is exceptionally large suggesting an overestimation of diffuse flow area at the high end and/or underestimation of plume flux. We are scheduled this fall to connect our next generation sonar system (COVIS=Cable Operated Vent Imaging Sonar) to the NEPTUNE Canada cabled observatory at the Grotto vent cluster. COVIS is designed to image plume and diffuse flow in space and in time, which will contribute to interpreting our past observations and to provide new insights on how partitioning may vary with time.
Estimations of heat transfer from Grotto's North Tower: A NEPTUNE Observatory case study
Article
Jun 2015
DEEP-SEA RES PT II
Peter A. Rona
Karen G Bemis
Guangyu Xu
Kyohiko Mitsuzawa
The overall heat transfer through an active hydrothermal sulfide edifice, in particular the north tower of Grotto, has been estimated at 80 MW or greater based on the following in situ measurements and assumptions: 1) The heat transfer by diffuse flow is estimated at 33–380 MW based on extrapolating the acoustically mapped area to all sides of the North Tower (“visible” area=30 m2; extrapolated area=100 m2) and using the range of available spot measurements of temperature (6–23 °C) and vertical velocity (0.07–0.28 m/s). The lower number (33 MW) is more likely, but there is insufficient knowledge of the temporal and spatial variability of diffuse flow to be certain. 2) The heat transfer by focused flow is estimated at 30–70 MW based on summing the estimated individual rates of heat transfer for 4 out of 7 documented black smokers and flanges. 3) Conductive heat transfer out of the mound is unknown, but is likely to be much less than the advective heat transfer. Additionally, the plume transport of heat is estimated at 20–40 MW based on the direct measurement of temperature within the plume (at 5–25 m above the top of the edifice). Despite uncertainties, the lower estimate of plume versus smoker heat transfer suggests that heat transfer is dominantly by diffuse flow. Furthermore, not all plumes from individual smokers may merge even for so small an area as the north tower of Grotto.
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Guangyu Xu
D.R. Jackson
Karen G Bemis
Anatoliy N. Ivakin
Mark V. Trevorrow
David M. Farmer
On the effect of dynamic bed topography on turbulent flow structure in a gravel-bed river
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Arvind Singh
Fernando Porté-Agel
Efi Foufoula-Georgiou
December 2016
Shawn Harrison
Peter A. Traykovski
John C. Warner
Jeffrey H. List
| https://www.researchgate.net/publication/310506195_Quantification_of_Diffuse_Hydrothermal_Flows_Using_Multibeam_Sonar |
Lewis v. State, 1 Div. 553 - Alabama - Case Law - VLEX 886503645
0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object]. 4: [object Object]. 5: [object Object]
Alabama
Lewis v. State, 1 Div. 553
Court Alabama Court of Criminal Appeals Writing for the Court BOWEN W. SIMMONS Citation 57 Ala.App. 545,329 So.2d 596 Parties Winston LEWIS v. STATE. Docket Number 1 Div. 553 Decision Date 01 October 1975
Page 596
329 So.2d 596
57 Ala.App. 545
Winston LEWIS v. STATE.
1 Div. 553.
Court of Criminal Appeals of Alabama.
Page 597
John F. Butler, Mobile, for appellant.
William J. Baxley, Atty. Gen., and Gary R. Maxwell, Asst. Atty. Gen., for the State.
BOWEN W. SIMMONS, Supernumerary Circuit Judge.
A jury convicted appellant-defendant, pursuant to an incident, of possessing heroin contrary to law.Act No. 1407, Vol. 3, Acts 1971, p. 2378, § 204 (Schedule 1) (c)(10), p. 2384.
The trial court fixed punishment at three years imprisonment in the penitentiary. Defendant, an indigent here, appealed from the judgment.
The police officers in Mobile procured a valid search warrant for an apartment at a designated address in Mobile, and on Monday, March 18, 1974, proceeded to the address, in the daytime, to search the premises for narcotics.
Officer Seals knocked on the front door of the (two-story) apartment in response to which occupant, Raphael Morse, came to the door, and asked who it was. Officer Seals gave his name and official title. Morse, according to Officer Seals, pulled back the curtain over the glass window in the door and then proceeded to leave without making any effort to open the door.
Within five to ten seconds after the hurried departure, Officer Seals kicked the door open and entered just in time to see defendant make a hurried exit through a rear window to the ground. Officer Seals restrained Morse pending the chase of defendant.
The officer gave chase of defendant for a short distance, when the latter stumbled and fell. About this time the officer fired [57 Ala.App. 546] his pistol one time into the air to try to stop the fleeing Lewis.
This officer observed when he got to Morse that he had in his hand some paraphernalia (we omit identification of items) for injection of heroin. Possession of such paraphernalia is a misdemeanor, § 507, p. 2401, Act No. 1407, supra. The officer arrested defendant thereupon for such unlawful possession and took him back into the apartment.
After this episode, the officers, Seal, Calhoun and Orso made a careful search of the premises and found five capsules of white powder (identified in the trial as heroin) under a rug in the bathroom. The officers seized the powder.
At the voir dire hearing in camera it appears that while in the apartment one of the officers read defendant his Miranda rights. Soon thereafter defendant and Morse were taken to the police station where defendant was detained in the interrogation room and again reminded of his rights previously read to him. The defendant admitted that
Page 598
he possessed the heroin which he bought from a 'dude' in Prichard.
After an extended examination, direct and cross,...
10 practice notes
Billups v. State, No. CR-05-1767 (Ala. Crim. App. 11/13/2009), CR-05-1767. United States Alabama Court of Criminal Appeals November 13, 2009 ...v. State, 333 So. 2d 865 (Ala. Cr. App. 1976); McDonald v. State, 57 Ala. App. 529, 329 So. 2d 583 (1975), writ quashed, 295 Ala. 410, 329 So. 2d 596 (1976), cert, denied, 429 U.S. 834, 97 S. Ct. 99, 50 L. Ed. 2d 99 "As previously stated, probative evidence of collateral bad acts may be exc......
Billups v. State, CR–05–1767. United States Alabama Court of Criminal Appeals January 22, 2010 ...McGhee v. State, 333 So.2d 865 (Ala.Cr.App.1976); McDonald v. State, 57 Ala.App. 529, 329 So.2d 583 (1975), writ quashed, 295 Ala. 410, 329 So.2d 596 (1976), cert. denied, 429 U.S. 834, 97 S.Ct. 99, 50 L.Ed.2d 99 (1976).’ “As previously stated, probative evidence of collateral bad acts may ......
Irvin v. State, CR-01-2229. United States Alabama Court of Criminal Appeals June 24, 2005 ...v. State, 333 So.2d 865 (Ala.Cr.App.1976); Page 352 McDonald v. State, 57 Ala.App. 529, 329 So.2d 583 (1975), writ quashed, 295 Ala. 410, 329 So.2d 596 (1976), cert. denied, 429 U.S. 834, 97 S.Ct. 99, 50 L.Ed.2d 99 As previously stated, probative evidence of collateral bad acts may be exclu......
Kelley v. State, 3 Div. 915 United States Alabama Court of Criminal Appeals January 30, 1979 ...v. State, 45 Ala.App. 178, 227 So.2d 809 (1969), and (2) that the confession was voluntary and not improperly adduced. Lewis v. State, 57 Ala.App. 545 , 329 So.2d 596, affirmed, 295 Ala. 350, 329 So.2d 599...
8 cases
Irvin v. State, CR-01-2229. United States Alabama Court of Criminal Appeals June 24, 2005 ...v. State, 333 So.2d 865 (Ala.Cr.App.1976); Page 352 McDonald v. State, 57 Ala.App. 529, 329 So.2d 583 (1975), writ quashed, 295 Ala. 410, 329 So.2d 596 (1976), cert. denied, 429 U.S. 834, 97 S.Ct. 99, 50 L.Ed.2d 99 As previously stated, probative evidence of collateral bad acts may be exclu......
Billups v. State, No. CR-05-1767 (Ala. Crim. App. 11/13/2009), No. CR-05-1767. United States Alabama Court of Criminal Appeals November 13, 2009 ...v. State, 333 So. 2d 865 (Ala. Cr. App. 1976); McDonald v. State, 57 Ala. App. 529, 329 So. 2d 583 (1975), writ quashed, 295 Ala. 410, 329 So. 2d 596 (1976), cert, denied, 429 U.S. 834, 97 S. Ct. 99, 50 L. Ed. 2d 99 "As previously stated, probative evidence of collateral bad acts may b......
Kelley v. State, 3 Div. 915 United States Alabama Court of Criminal Appeals January 30, 1979 ...v. State, 45 Ala.App. 178, 227 So.2d 809 (1969), and (2) that the confession was voluntary and not improperly adduced. Lewis v. State, 57 Ala.App. 545 , 329 So.2d 596, affirmed, 295 Ala. 350, 329 So.2d 599...
Deloach v. State, 6 Div. 216 United States Alabama Court of Criminal Appeals December 20, 1977 ...of Miranda and as to voluntariness. He properly allowed the evidence to then be presented in the presence of the jury. Lewis v. State, 57 Ala.App. 545 , 329 So.2d 596 (1975), affirmed, 295 Ala. 350, 329 So.2d 599 (3) The evidence was amply sufficient to support the trial court's finding that......
| https://case-law.vlex.com/vid/lewis-v-state-1-886503645 |
Treatment of Onychomycosis With Loceryl (Amorolfine) Nail Lacquer 5% Versus Ciclopirox Nail Lacquer - Full Text View - ClinicalTrials.gov
Treatment of Onychomycosis With Loceryl (Amorolfine) Nail Lacquer 5% Versus Ciclopirox Nail Lacquer (LOOP)
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02679911 Recruitment Status :
Completed First Posted : February 11, 2016 Results First Posted : October 3, 2018 Last Update Posted : March 22, 2021
Sponsor:
Galderma R&D
Information provided by (Responsible Party):
Galderma R&D
Study Details
Study Description
Brief Summary:
The main objective of this study is to compare subject's compliance and satisfaction for two modes of treatment of toenails infection (Onychomycosis) with Loceryl Nail Lacquer (Loceryl NL) and Ciclopirox Nail Lacquer (Ciclopirox NL).
Condition or disease Intervention/treatment Phase Foot Dermatoses Drug: Loceryl NL Drug: Ciclopirox NL Phase 4
Detailed Description:
A total of 20 subjects are to be included in 1 site in Germany.
Methodology:
Subjects will receive the following treatments on the right or left toenails:
Loceryl Nail Lacquer to be applied once weekly for 12 weeks on all affected toenails of one foot.
Ciclopirox Nail Lacquer to be applied once daily for 12 weeks on all affected toenails of the opposite foot.
Study Design
Layout table for study information Study Type : Interventional
(Clinical Trial) Actual Enrollment : 20 participants Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Intra-individual study Masking: Single (Investigator) Primary Purpose: Treatment Official Title: Subject Adherence and Satisfaction for Treatment of Onychomycosis With Loceryl Nail Lacquer 5% Versus Ciclopirox Nail Lacquer Study Start Date : September 2015 Actual Primary Completion Date : June 2016 Actual Study Completion Date : June 2016
Resource links provided by the National Library of Medicine
MedlinePlus related topics: Foot Health
Drug Information available for: Ciclopirox Ciclopirox olamine
U.S. FDA Resources
Arms and Interventions
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Arm Intervention/treatment Experimental: Loceryl NL Amorolfine hydrochloride NL 5% to be applied once weekly for 12 weeks on all affected toenails of one foot Drug: Loceryl NL Topical over the entire toenail plate of all affected toenails, once weekly in the evening (at bed time) after filing down the affected toenails. Other Name: Loceryl Nail Lacquer Active Comparator: Ciclopirox NL Ciclopirox NL 8% to be applied once daily for 12 weeks on all affected toenails of the opposite foot Drug: Ciclopirox NL Topical over the entire toenail plate of all affected toenails and surrounding skin, once daily in the evening (at bed time) after removing the free toenail edge and diseased toenails if needed Other Name: Ciclopirox Nail Lacquer
Outcome Measures
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Primary Outcome Measures
:
Percent of "in Label" Adherent Subjects [ Time Frame: Week 12 ]
Percent of subjects having applied both treatments as instructed per labeling (once a week for Loceryl NL and once a day for Ciclopirox after 2 weeks)
Secondary Outcome Measures
:
Percent of Subjects Satisfied to Very Satisfied With Each Study Treatment at Week 12 [ Time Frame: Week 12 ]
Percent of subjects satisfied to very satisfied with both treatments (Loceryl nail lacquer and/or Ciclopirox nail lacquer) at week 12
Eligibility Criteria
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Subject with clinically Distal and Lateral Subungual Onychomycosis (DLSO) due to dermatophytes and/or yeast (including Candida) on at least one toenail of each foot at screening visit,
Subject with less than 80% of the nail surface area with disease involvement and without matrix involvement, no dermatophytoma, streaks (spikes) or subungual hyperkeratosis > 2mm,
Subjects with positive mycological results (direct microscopy and culture) for dermatophytes and/or yeasts (including Candida) at baseline,
Subjects with same number of affected toenails on both feet or no more than one additional affected toenail on one of the feet,
Exclusion Criteria:
Subject with a surgical, medical condition or clinically important abnormal physical findings, which, in the judgement of the investigator, might interfere with interpretation of the objectives of the study (i.e. lack of autonomy),
Subjects with post-traumatic nail, lichen planus, eczema, psoriasis, or other abnormalities of the nail unit, which could affect/influence the subject's compliance of the investigational products, or mask the effects of treatment (cure),
Subjects with known immunodeficiency, radiation therapy, immune suppressive drugs.
Contacts and Locations
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02679911
Locations
Layout table for location information Germany Tübingen, Germany
Sponsors and Collaborators
Galderma R&D
Investigators
Layout table for investigator information Principal Investigator: Prof. Schaller Universitäts-Hautklinik
More Information
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Layout table for additonal information Responsible Party: Galderma R&D ClinicalTrials.gov Identifier: NCT02679911 History of Changes Other Study ID Numbers: RD.03.SPR105082 2015-001237-24 ( EudraCT Number ) First Posted: February 11, 2016 Key Record Dates Results First Posted: October 3, 2018 Last Update Posted: March 22, 2021 Last Verified: February 2018 Individual Participant Data (IPD) Sharing Statement: Plan to Share IPD: No
Keywords provided by Galderma R&D:
Onychomycosis
Additional relevant MeSH terms:
Layout table for MeSH terms Onychomycosis Skin Diseases Foot Dermatoses Tinea Dermatomycoses Mycoses Bacterial Infections and Mycoses Infections Skin Diseases, Infectious Nail Diseases Foot Diseases Ciclopirox Amorolfine Antifungal Agents Anti-Infective Agents
For Study Record Managers
Home
U.S. Department of Health and Human Services
| https://clinicaltrials.gov/ct2/show/study/NCT02679911 |
Mathematics | Free Full-Text | Intelligent Image Super-Resolution for Vehicle License Plate in Surveillance Applications
Vehicle license plate images are often low resolution and blurry because of the large distance and relative motion between the vision sensor and vehicle, making license plate identification arduous. The extensive use of expensive, high-quality vision sensors is uneconomical in most cases; thus, images are initially captured and then translated from low resolution to high resolution. For this purpose, several traditional techniques such as bilinear, bicubic, super-resolution convolutional neural network, and super-resolution generative adversarial network (SRGAN) have been developed over time to upgrade low-quality images. However, most studies in this area pertain to the conversion of low-resolution images to super-resolution images, and little attention has been paid to motion de-blurring. This work extends SRGAN by adding an intelligent motion-deblurring method (termed SRGAN-LP), which helps to enhance the image resolution and remove motion blur from the given images. A comprehensive and new domain-specific dataset was developed to achieve improved results. Moreover, maintaining higher quantitative and qualitative results in comparison to the ground truth images, this study upscales the provided low-resolution image four times and removes the motion blur to a reasonable extent, making it suitable for surveillance applications.
Intelligent Image Super-Resolution for Vehicle License Plate in Surveillance Applications
by
Mohammad Hijji 1,*,† ,
Abbas Khan 2,† ,
Mohammed M. Alwakeel 1 ,
Fahad Aradah 1 ,
Faouzi Alaya Cheikh 3 ,
Muhammad Sajjad 2,3,* and
Khan Muhammad 4,*
1
Faculty of Computers and Information Technology, University of Tabuk, Tabuk 47711, Saudi Arabia
2
Digital Image Processing Laboratory, Department of Computer Science, Islamia College Peshawar, Peshawar 25000, Pakistan
3
The Software, Data and Digital Ecosystems (SDDE) Research Group, Department of Computer Science, Norwegian University of Science and Technology (NTNU), 2815 Gjøvik, Norway
4
Visual Analytics for Knowledge Laboratory (VIS2KNOW Lab), Department of Applied Artificial Intelligence, School of Convergence, College of Computing and Informatics, Sungkyunkwan University, Seoul 03063, Republic of Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work and are co-first authors.
Mathematics 2023 , 11 (4), 892; https://doi.org/10.3390/math11040892
Received: 15 December 2022 / Revised: 29 January 2023 / Accepted: 4 February 2023 / Published: 9 February 2023
(This article belongs to the Section Mathematics and Computer Science )
Browse Figures
Versions Notes
Abstract
Vehicle license plate images are often low resolution and blurry because of the large distance and relative motion between the vision sensor and vehicle, making license plate identification arduous. The extensive use of expensive, high-quality vision sensors is uneconomical in most cases; thus, images are initially captured and then translated from low resolution to high resolution. For this purpose, several traditional techniques such as bilinear, bicubic, super-resolution convolutional neural network, and super-resolution generative adversarial network (SRGAN) have been developed over time to upgrade low-quality images. However, most studies in this area pertain to the conversion of low-resolution images to super-resolution images, and little attention has been paid to motion de-blurring. This work extends SRGAN by adding an intelligent motion-deblurring method (termed SRGAN-LP), which helps to enhance the image resolution and remove motion blur from the given images. A comprehensive and new domain-specific dataset was developed to achieve improved results. Moreover, maintaining higher quantitative and qualitative results in comparison to the ground truth images, this study upscales the provided low-resolution image four times and removes the motion blur to a reasonable extent, making it suitable for surveillance applications.
Keywords:
AI
;
SRGAN
;
image super-resolution
;
generator
;
discriminator
;
generative adversarial networks
;
motion blur
;
surveillance
;
SRGAN-LP
;
machine learning
MSC:
68T45
1. Introduction
Navigant research [
1
] suggests that the number of vehicles in the world will grow to two billion by 2035. This huge increase in the number of vehicles poses a significant challenge to humans in managing them manually. In this regard, smart cities require a significant focus to manage the flow of vehicles intelligently [
2
]. Different vision sensors, position identification sensors, and many more applications are used to ensure the concept of vehicles communicating autonomously, that is, the flow of traffic or smart parking management. Several identification tags are used to achieve this; however, vehicle license plates are the most traditional and unique elements used for the correct identification of the vehicle type and model year.
Vehicles are uniquely identified based on an important component known as the license plate. Finding a stolen car, tracking a trouble-making vehicle, smart parking management, and automatic toll collection all use vehicle license plates to perform these tasks. For the smooth execution of such tasks, the correct identification of the vehicle license plate is indispensable. However, in some cases, the captured license plate images develop some sort of perturbation, owing to low lightning conditions, low resolution, and motion blur, making this process difficult. Therefore, several image super resolution (SR) techniques have been developed over time to overcome these challenges.
Image SR is a technique used to reconstruct high resolution (HR) images based on provided low resolution (LR) counterparts. The application domain of super resolution (SR) is vast, and it can be used in remote sensing [ 3 ], hyperspectral SR [ 4 , 5 ], and medical imaging [ 6 , 7 , 8 ]. However, in some cases the images acquired by different imaging devices such as surveillance cameras, cell phones, X-rays, MRI, and CT-scans are of low-resolution. These images are mostly blurred and contain noise due to relative motion, lamination variation, distance variation, and low-quality imaging devices. Applications such as restoration [ 9 ], surveillance, and medical imaging systems [ 10 , 11 ] require HR images for recognition and diagnosis, respectively. Although some applications such as Blu-ray movies, video conferencing, and web videos are often in HR, to preserve server storage and bandwidth, they are often stored in LR.
To transform an LR image into an HR image, several techniques are available, that can be classified into two broad categories: traditional image processing techniques and convolutional neural networks (CNNs)-based SR algorithms [
12
]. Traditional methods, such as bi-linear and bi-cubic methods, are computationally inexpensive and easy to deploy; however, these methods have a few limitations that make them inefficient to deploy in certain circumstances. One of the basic limitations of these methods is that they generate overly smooth textures in reconstructed images. In addition, these methods typically fail to reconstruct the original content of an image. However, the modern techniques available are usually based on deep learning techniques, specifically CNNs. These techniques iteratively enhance image quality by minimizing the loss between the original image and the reconstructed image. Numerous optimization techniques are available to help CNN models reduce the loss between the original image and the reconstructed image.
The proposed super-resolution generative adversarial network for license plates (SRGAN-LP) was based on one of the most promising techniques for image SR resolution, known as a super-resolution generative adversarial network (SRGAN) [
13
]. The original architecture of SRGAN utilizes three models, that is, a deep generator, a discriminator consisting of several residual blocks, and a novel function called perceptual loss, for realistic image reconstruction. However, our solution is largely based on the identification of digits on the license plate of a vehicle, rather than realistic image generation. Therefore, we reduced the size of the actual SRGAN generator to a minimum, to reduce computational cost. In addition, we incorporated the motion deblurring method into the original SRGAN so that the digits and letters were correctly identified. Our extensive experimental results justify the changes to the original architecture.
Our proposed SRGAN-LP method is compared with traditional techniques such as the bilinear, bicubic, and single image-based super resolution method SRCNN [
8
]. The experimental results show the promising performance of our method. Similarly, the results were compared with the SRGAN trained on the ImageNet dataset. To justify the effectiveness of the SRGAN-LP, we conducted comprehensive experiments on two different testing sets. First, we used the same testing set of images as the training images, and in the second phase, we performed experiments on independent images, that is, images independently collected from vehicles. Considering all these experiments and comparisons, we concluded our contributions to vehicle license plate image SR as follows:
In light of the usefulness of SRGAN in the current literature, we incorporated motion deblurring in its architecture, thus achieving good-quality HR and deblurred images.
We reduced the size of the original SRGAN by reducing the number of residual blocks in the generator network from 16 to 8, consequently achieving less inference time while preserving the same performance.
We developed a comprehensive and new domain-specific dataset that originally contains 3112 images of different regions and color patterns. Furthermore, we diversified the angles of the images and increased the size of the dataset to 12,388 using different augmentation techniques.
The remainder of this paper is organized as follows. Section 2 and Section 3 present related work and the proposed methodology, respectively. The experimental results and evaluations are presented in Section 4 . Section 5 concludes the paper with a discussion of future work.
2. Related Work
As image SR and deblurring are applied to tackle various challenges in real-world scenarios, the related work is divided into two parts, where 2.1 focuses on the topic of super resolution and deblurring, and 2.2 specifies existing literature related to intelligent vehicle license plate recognition.
2.1. Image Super Resolution and Deblurring
Image SR and deblurring [
14
] has remained a hot research area among the computer vision research community. Earlier approaches relied on pure image processing techniques by applying sharpening filters followed by interpolation-based methods, such as bicubic and bilinear interpolations [
15
]. These methods have remained benchmarks for a reasonable period of time, however, they exhibit a persistent problem of generating overly smooth textures in the reconstructed images. With the emergence of CNNs, and their promising results in other fields, researchers have applied them in the SR domain as well. In this regard, a breakthrough approach, SRCNN [
8
], applied convolutional layers to enhance an LR image, and the results were very impressive when it was first published. Succeeding SRCNN, a very deep convolutional network named VDSR was proposed in [
16
], where 16 convolutional layers were added with the implementation of residual learning. The output of the VDSR produced a better result than the one in the SRCNN. Both SRCNN and VDSR aimed to increase the peak signal to noise ratio (PSNR) between the recovered image SR image and the HR image, by reducing the mean square error (MSE) between the SR and HR images. Although CNN-based methods performed much higher than the traditional methods, however, with the invention of generative adversarial networks (GAN), and its incredible results, the domain of SR largely shifted to GAN-based methods.
The idea of GAN was first coined by Goodfellow et al. [ 17 ], who trained a generative model and discriminative model simultaneously through an adversarial process. Based on GAN, Ledig et al. proposed a method called SRGAN [ 13 ]. The SRGAN framework is capable of inferring photorealistic natural images for 4x up-scaling factors. A new methodology using GAN was proposed by Mao et al. [ 18 ], generating least squares GANs (LSGANs) in which the least squares loss function is calculated for the discriminator, and it was found that LSGANs can generate higher quality images than regular GANs. In addition, LSGANs remain more stable during the learning process than regular GANs. Lim et al. [ 19 ] developed an enhanced deep SR network called EDSR. This improvement was achieved by removing unnecessary modules from the conventional residual networks. They found that the proposed EDSR was more optimized in terms of generating SR images than the original GAN. A novel approach for synthesizing HR photorealistic images from semantic label maps, using conditional generative adversarial networks (conditional GANs), was proposed by Wang et al. [ 20 ], which generated 2048 × 1024 visually appealing results with a novel adversarial loss along with new multi-scale generator and discriminator architectures.
However, less attention has been paid to deblurring in the SR arena. The former works relied primarily on using Laplacian filters for sharpening; however, sharpening the image alone does not usually guarantee the reconstruction of the original content of the image. A comparatively recent work by Kupyn et al. [
21
] proposed the idea of DeblurGAN, which is an end-to-end learned method for motion deblurring. The DeblurGAN training process involves conditional GAN and content loss. They showed that the proposed DeblurGAN was five times faster than the DeepDeblur [
22
] model in terms of the structural similarity measure and visual appearance. Similarly, Nah et al. [
23
] presented an averaging-based technique; however, it lacks generalization capability owing to the lack of diversity in datasets generated using averaging.
2.2. License Plate Super Resolution and Deblurring
There are two different methods for license plate recognition (LPR): segmentation-based [ 24 ] and non-segmentation-based [ 25 ]. Segmentation-based techniques mainly trace back to the traditional machine learning techniques, whereas non-segmentation-based techniques largely subsume recent deep learning-based approaches, including CNNs, for the identification or reconstruction of license plate images. Segmentation-based methods first divide the license plate into segments of characters, which are then recognized using a projection-based classifier [ 26 ] and connected-component-based classifiers [ 27 ]. In contrast, a non-segmentation-based method was first proposed by Shi et al. [ 28 ], where a deep CNN was applied for feature extraction directly without a sliding window, and a bidirectional long short-term memory network was used for sequence labeling. The literature reveals that non-segmentation-based methods are promising for license plate image-quality enhancement.
3. Proposed Methodology
The goal of image SR is to obtain an HR image from the provided LR image, as shown in
Figure 1
, depicting the proposed SRGAN-LP. Our aim is to train a generator that predicts a high-resolution
I H
image from the provided low-resolution
I L
image with minimum loss. To perform this process, we construct a generator network
G
, which is a deep CNN model with parameter
θ G
. For all training images N, we optimize
θ G
as given in Equation (1). A visual overview of the generator network G is depicted in
Figure 2
and details of the input and output parameters of the proposed method are given in
Table 1
.
θ
^
G
=
arg
min
θ
G
∑
n
=
1
N
l
S
(
G
θ
G
(
I
n
L
)
,
I
n
H
)
(1)
I
H
=
W
H
∗
H
H
∗
C
(2)
Figure 1. Overview of the proposed methodology. I H and I L are acquired from the ( a ) Surveillance environment. In the ( b ) Training process, the generator receives I L and removes blur and upscales the I L to I S . The discriminator and VGG-19 calculate adversarial loss and content loss between the original I H and generated I S . Finally, both losses are added proportionately to form perceptual loss l S . Subsequently, l S updates the generator weights. For ( c ) Testing process, I L is directly inputted to the generator trained in the training process and I S is acquired as the resultant HR image.
Figure 2. Architecture of the generator network. “k” represents filter size, “n” is the number of filters, and “s” is the stride value used in a particular layer. Two types of convolutional blocks are used in the generator. A residual block is used for feature extraction, whereas the “UpSampling” block is used for converting an image from I S to I H .
Table 1. Description of input and output parameters used in the proposed model.
Equation (1) is used to convert
I L
to its
I H
counterpart. Similarly, in Equation (2),
I H
represents the HR image.
W H
and
H H
represent the width and height of the HR images, respectively. Similarly,
C
(
BGR, C
= 3) represents the number of channels in the image. HR images were available only during training.
I H
images are converted to LR
I L
images by applying motion blur (
β
= 16) and a down sampling operation with a specified scale of
δ
. For an image with
C
color channels, we describe
I L
by a real-valued tensor of size
W
×
H
×
C
and
I H
and
I S
by
rW × rH × C
.
I
L
=
β
δ
W
H
∗
β
δ
H
H
∗
C
(3)
The
I L
images are obtained by down sampling using a bicubic kernel with a factor size of
δ
= 4, and applying motion blur
β
to the
I H
images with the number of channels
C
as shown in Equation (3). After the images are converted into
I L
, they are input to
G
.
3.1. Adversarial Loss Function
In adversarial loss, the variable
I H
is an input to the discriminator (
D)
, which is used to compare the
I S
and
I H
images to discriminate between them. For this reason,
I H
images are also given to
D
from the dataset.
D
θ
d
=
1
q
∑
i
=
1
q
[
log
D
(
I
H
)
+
(
1
−
log
D
(
I
S
)
)
]
(4)
The aim of D is to calculate the adversarial loss. Equation (4) represents D and shows how it is parameterized by θ D : In Equation (4), the adversarial loss is calculated, which later contributes to the perceptual loss calculation. The architecture of the discriminator D network is illustrated in Figure 3 .
Figure 3. Architecture of the discriminator network. “k” represents filter size, “n” is the number of filters, and “s” is the stride value used in a particular layer. Two types of convolutional blocks are used in the discriminator. One type of convolutional block comprises a convolution, batch normalization, and leaky ReLU layers. The other type of convolutional block lacks the batch normalization layer.
Equation (5) is used to calculate the adversarial loss in terms of the probabilities returned by
D
. This adversarial loss is then combined with another loss to obtain the final objective function of SRGAN.
I
a
d
v
S
=
1
q
∑
i
=
1
q
(
−
log
D
θ
d
(
I
S
)
)
(5)
3.2. Content Loss Function
VGG19 was used to calculate the pixel-wise MSE as a content loss in this architecture. The content loss used in the MSE is the pixel-wise difference between the generated image
I S
and the original high-resolution image
I H
of the dataset, which can be calculated using Equation (6).
I
M
S
E
S
=
1
δ
2
W
H
∑
x
=
1
δ
W
∑
x
=
1
δ
H
(
I
x
,
y
H
−
G
θ
G
(
I
L
)
x
,
y
)
2
3.3. Perceptual Loss Function
Perceptual loss is a weighted combination of content loss and adversarial loss, which tends to reconstruct the original content of an image. Previously, SR problems were commonly based on the MSE loss function; however, in the proposed SRGAN-LP, MSE combined with adversarial loss was used to push the
G
to reconstruct the original content of the image.
ℓ
S
=
l
X
S
︸
c
o
n
t
e
n
t
−
l
o
s
s
+
10
−
3
l
G
e
n
S
︸
a
e
r
s
a
r
i
a
l
−
l
o
s
s
︸
p
e
r
c
e
p
t
l
−
l
o
s
s
(7)
The weighted sum of content loss (
l
X
S
) and an adversarial loss component are used according to Equation (7). After the perceptual loss calculation, backpropagation occurs and optimizes the
G
network to learn the distribution more efficiently. The process shown in
Figure 1
continues until the
G
network starts generating images that are more realistic and have recognizable digits.
4. Results and Discussion
We conducted extensive experimentation and testing to evaluate the performance of the proposed SRGAN-LP using various evaluation techniques. For this purpose, we collected a large-scale dataset as discussed in Section 4.1 . Similarly, Section 4.2 briefly describes the experimental setup, followed by a comprehensive evaluation of the results in Section 4.3 .
4.1. Dataset Acquisition
Data works as the fuel for deep learning models; however, collecting large amounts of vehicle license plate data with a uniform spatial resolution and almost the same lightning conditions is a challenging task. For this purpose, we accessed a license plate repository [
11
], and downloaded 3700 images with various backgrounds and digit colors as a raw dataset. To increase the number of images and diversify the angle of images, we used the data augmentation library “Augmentor” [
12
]. Using “Augmentor” we incorporated diversity into the images by changing their angles with the standard techniques such as tilt, skew, and rotate. Subsequently, we synthesized a dataset of 12,388 HR images from this raw dataset. The model was trained on the HR images using a standard spatial resolution of 256 × 256 pixels. We maintained a scale factor (δ) of four for the training. For testing purposes, we segregated 100 images from the synthesized dataset (synthetic test set) and downloaded another set of 100 images from Google, which is referred to as the real test set in this section.
4.2. Experimental Setup
We trained our proposed SRGAN-LP network on an NVIDIA GTX 1070 GPU with 12 GB memory and 24 GB RAM. For training G , we obtained low-resolution I L images by applying a motion blur β of size 16 and a down sampling factor δ of four, thus reducing the sizes of the images from 256 × 256 to 64 × 64. For D , we used the original high-resolution images. Our generator network consists of eight identical residual blocks Λ and two transposed convolution layers. We used the Adam optimization algorithm [ 29 ] for our network. For G and D, we maintained learning rates of 10 −5 and 10 −6 , respectively. To train a composite model, that is, SRGAN-LP, we used a learning rate of 10 −3 . We used the deep learning library Keras [ 13 ], with TensorFlow [ 14 ] as the backend for the implementation of this network.
4.3. Performance Evaluation
Qualitative evaluation often involves human ratings, whereas quantitative evaluation comprises standard evaluation metrics in image processing, such as the PSNR and the structural similarity index metric (SSIM) [ 30 ]. In addition to qualitative and quantitative evaluations, the proposed SRGAN-LP was analyzed using optical character recognition (OCR) results.
4.3.1. Quantitative Evaluation
We conducted a quantitative evaluation for both of our test sets, that is, synthetic and real test sets, using the PSNR and SSIM [
23
,
31
].
PSNR ( f , g ) = 10log 10 (255 2 / MSE ( f , g ))
(8)
Equation (8) shows the formula for calculating the PSNR between the original and the reconstructed images. f is the original image and g is the reconstructed image obtained using a certain technique. A higher PSNR value indicates better results for SR.
S
S
I
M
(
g
)
=
l
(
f
,
g
)
∗
c
(
f
,
g
)
∗
s
(
f
,
g
)
(9)
Similarly, Equation (9) represents the SSIM between the original and reconstructed images. The SSIM is the product of the differences in luminance
l
, contrast
c,
and structural similarity
s
between the original and generated images. The range of the SSIM is from 0 to 1, and a score closer to 1 is considered the best in the case of SR.
Table 2 shows the average PSNR and SSIM values for the results of the evaluation conducted on the synthetic test set. The higher values of PSNR and SSIM show the effectiveness of the proposed SRGAN-LP on the synthetic test set.
Table 2. Average PSNR (dB) and SSIM of 100 reconstructed test images for the synthetic test set. Bold scores show the best results, and underlined values represent the second best results.
Table 3 shows the average PSNR and SSIM scores for the results of the evaluation conducted on the real test set. The above tables reveal the effectiveness of the proposed method in comparison to baseline techniques such as bilinear, bicubic, and SRCNN [ 32 ]. Moreover, the results are also compared with SRGAN trained on the ImageNet dataset. For further assessment, qualitative results are discussed in the next subsection.
Table 3. Average PSNR (dB) and SSIM of 100 reconstructed test images for the real test set. Bold scores show the best results and underlined values represent the second best results.
4.3.2. Evaluation Using Inference Time
Deep learning inference time is the time consumed by a deep learning model for a single prediction. In the context of image reconstruction, that is the time required for a model to reconstruct a new image. The inference time depends on the number of model parameters. In
Figure 4
a,b, the size of the bubbles represents the number of parameters of the models. In the experiments, it was evident that the models with a larger parameter space had a higher inference time, whereas the models with a smaller number of parameters had a lower inference time. However, traditional models, without parameters, have remarkably low inference times. Low-parameter models with higher reconstruction scores can be deployed easily on resource-constrained devices.
Figure 4. ( a ) Represents inference time of each reconstruction method on x -axis and mean opinion score (MOS) on y -axis for real-test set. Similarly, ( b ) illustrates the same for the synthetic test set. The results shown in both ( a ) and ( b ) suggest that the proposed SRGAN-LP is the most convincing to the human raters, achieving 4.5 MOS on the real test set and 5.0 on the synthetic test set.
4.3.3. Qualitative Evaluation
In contrast to quantitative image assessment, which tends to assess image quality more technically, qualitative analysis involves human expertise. In qualitative analysis, the reconstructed images are subjected to human raters, who provide their opinions and assess the quality of the reconstructed images. The MOS score is one of the most widely used techniques for qualitative image assessments.
Figure 5 shows the visual quality of the reconstructed images of the synthetic test set. These images were presented to human raters to identify the quality of the images and, more importantly, to identify the digits that were highlighted using the yellow bounding box.
Figure 5. Visual quality along with corresponding PSNR/SSIM of the reconstructed images using different techniques used in the experiments.
Similarly, Figure 6 and Figure 7 show the visual quality of the reconstructed images of the real test set. The same images of the real test set were presented to the human raters, and their opinions on the quality of the reconstructed images are presented in Figure 4 .
Figure 6. ( a ) Ground truth image (original image), ( b ) Motion blur applied on whole image (distorted image), ( c ) Visual quality of the reconstructed images along with the corresponding PSNR/SSIM scores.
Figure 7. ( a ) Ground truth image (original image), ( b ) Motion blur applied on whole image (distorted image), ( c ) Visual quality of the reconstructed images along with the corresponding PSNR/SSIM scores.
4.3.4. Evaluation Using OCR
To further consolidate our experimental results, we subjected both testing sets (synthetic and real) to OCR. For this purpose, we used an OCR “platerecognizer”, publicly available in [
33
]. The accuracy of OCR is based on the number of characters present in an image versus the number of correctly recognized images. For instance, we have an image in the test set originally consisting of the characters GX6933; however, the OCR predicts different values, such as GX693, as shown in
Figure 8
. This misrecognition negatively contributes to the average accuracy of the OCR in recognizing license plate digits. The formula devised for calculating accuracy is as follows:
G
e
r
r
=
100
n
e
n
c
(10)
Figure 8. ( a ) Illustrates the visual results of OCR for the real test set, whereas ( b ) visualizes the results for the synthetic test set. Similarly, the green and red dots indicate the correct and incorrect predictions respectively.
Equation (10) represents the global error calculation rate of OCR for a given image. In the Equation,
n e
is the number of errors committed and
n c
is the number of all characters present in an image. Using this Equation, we present the following table to illustrate the performance of the OCR on different reconstruction techniques used in the experiments.
Table 4 shows the average accuracy of all the images present in both the test sets. The OCR’s accuracy depends significantly on the image’s position. Both test sets contained images that posed difficulties to the OCR in achieving accurate character recognition. However, the higher accuracy of the proposed method compared with the other methods verifies the effectiveness of our work, demonstrating its superiority.
Table 4. Average accuracy calculated for synthetic test set and real test set.
5. Conclusions
This study aimed to enhance the quality of images of vehicle license plates by increasing the resolution and removing motion blurriness. Manual management of vehicles in a smart surveillance environment is an arduous task. Therefore, more attention has been paid to the intelligent management of vehicles in smart surveillance environments. In this regard, license plates are considered unique identification tags for vehicles. However, owing to the high-speed motion of vehicles, motion blur is the most common phenomenon occurring in surveillance environments. To tackle this challenge, we proposed SRGAN-LP, which intelligently performs deblurring as compared to other methods. Extensive experimental results indicate that the proposed method outperforms the existing methods in terms of achieving a high-resolution deblurred image.
The results obtained by the proposed method were better both in terms of qualitative and quantitative evaluations compared to the existing methods. However, the inference time was relatively high. Achieving real-time performance, by reducing the inference time of the proposed SRGAN-LP, is suggested as future work. In addition, the evaluation can be extended using other metrics, and more modules can be added to the system, such as vehicle recognition [ 34 ], vehicle logo recognition [ 35 ], and make/model recognition [ 36 ], for better vehicular analysis.
Author Contributions
All authors contributed to conceptualization, methodology, software, validation, formal analysis, investigation, data curation, writing—original draft preparation, writing—review and editing, visualization, supervision, project administration, and funding acquisition. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by the Deanship of Scientific Research at the University of Tabuk through Research No. 0254-1443-S.
Data Availability Statement
Not applicable.
Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at the University of Tabuk for funding this work through Research No. 0254-1443-S.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Overview of the proposed methodology. I H and I L are acquired from the ( a ) Surveillance environment. In the ( b ) Training process, the generator receives I L and removes blur and upscales the I L to I S . The discriminator and VGG-19 calculate adversarial loss and content loss between the original I H and generated I S . Finally, both losses are added proportionately to form perceptual loss l S . Subsequently, l S updates the generator weights. For ( c ) Testing process, I L is directly inputted to the generator trained in the training process and I S is acquired as the resultant HR image.
Figure 2. Architecture of the generator network. “k” represents filter size, “n” is the number of filters, and “s” is the stride value used in a particular layer. Two types of convolutional blocks are used in the generator. A residual block is used for feature extraction, whereas the “UpSampling” block is used for converting an image from I S to I H .
Figure 3. Architecture of the discriminator network. “k” represents filter size, “n” is the number of filters, and “s” is the stride value used in a particular layer. Two types of convolutional blocks are used in the discriminator. One type of convolutional block comprises a convolution, batch normalization, and leaky ReLU layers. The other type of convolutional block lacks the batch normalization layer.
Figure 4. ( a ) Represents inference time of each reconstruction method on x -axis and mean opinion score (MOS) on y -axis for real-test set. Similarly, ( b ) illustrates the same for the synthetic test set. The results shown in both ( a ) and ( b ) suggest that the proposed SRGAN-LP is the most convincing to the human raters, achieving 4.5 MOS on the real test set and 5.0 on the synthetic test set.
Figure 5. Visual quality along with corresponding PSNR/SSIM of the reconstructed images using different techniques used in the experiments.
Figure 6. ( a ) Ground truth image (original image), ( b ) Motion blur applied on whole image (distorted image), ( c ) Visual quality of the reconstructed images along with the corresponding PSNR/SSIM scores.
Figure 7. ( a ) Ground truth image (original image), ( b ) Motion blur applied on whole image (distorted image), ( c ) Visual quality of the reconstructed images along with the corresponding PSNR/SSIM scores.
Figure 8. ( a ) Illustrates the visual results of OCR for the real test set, whereas ( b ) visualizes the results for the synthetic test set. Similarly, the green and red dots indicate the correct and incorrect predictions respectively.
Table 1. Description of input and output parameters used in the proposed model.
Symbol Description Symbol Description D Discriminator model G Generator model D θ D Discriminator parameterized by θ D G θ G Generator parameterized by θ G A A variable parameter in leaky ReLU used in D θ Model parameters I H High-resolution image I S Super-resolution image C Color channels I L Low-resolution image w Weights of layers b Biases of layers δ Scaling factor β Motion blur Λ Number of residual blocks Q Batch size k Number of filters in a layer s Stride of a convolution filter l S Perceptual loss N Total number of images in dataset
Table 2. Average PSNR (dB) and SSIM of 100 reconstructed test images for the synthetic test set. Bold scores show the best results, and underlined values represent the second best results.
Bilinear [ 15 ] Bicubic [ 15 ] SRCNN [ 8 ] SRGAN-ImageNet [ 13 ] SRGAN-LP PSNR 29.16 28.03 29.38 30.11 41.24 SSIM 0.39 0.42 0.52 0.40 0.81
Table 3. Average PSNR (dB) and SSIM of 100 reconstructed test images for the real test set. Bold scores show the best results and underlined values represent the second best results.
Bilinear [ 15 ] Bicubic [ 15 ] SRCNN [ 8 ] SRGAN-ImageNet [ 13 ] SRGAN-LP PSNR 34.74 35.65 33.58 31.11 38.76 SSIM 0.43 0.43 0.89 0.42 0.72
Table 4. Average accuracy calculated for synthetic test set and real test set.
Recognition Accuracy Distorted Image Bicubic [ 15 ] Bilinear [ 15 ] SRGAN-ImageNet [ 13 ] SRCNN [ 8 ] SRGAN-LP Original Synthetic Test Set (%) 82 83 80 84 85 92 97 Real Test Set (%) 79 78 79 80 81 93 95
MDPI and ACS Style
Hijji, M.; Khan, A.; Alwakeel, M.M.; Harrabi, R.; Aradah, F.; Cheikh, F.A.; Sajjad, M.; Muhammad, K. Intelligent Image Super-Resolution for Vehicle License Plate in Surveillance Applications. Mathematics 2023, 11, 892.
https://doi.org/10.3390/math11040892
Hijji M, Khan A, Alwakeel MM, Harrabi R, Aradah F, Cheikh FA, Sajjad M, Muhammad K. Intelligent Image Super-Resolution for Vehicle License Plate in Surveillance Applications. Mathematics. 2023; 11(4):892.
https://doi.org/10.3390/math11040892
Hijji, Mohammad, Abbas Khan, Mohammed M. Alwakeel, Rafika Harrabi, Fahad Aradah, Faouzi Alaya Cheikh, Muhammad Sajjad, and Khan Muhammad. 2023. "Intelligent Image Super-Resolution for Vehicle License Plate in Surveillance Applications" Mathematics11, no. 4: 892.
https://doi.org/10.3390/math11040892
| https://www.mdpi.com/2227-7390/11/4/892/xml |
Molecular Phylogeny of the Ocelloid-Bearing Dinoflagellates Erythropsidinium and Warnowia (Warnowiaceae, Dinophyceae) - DocsLib
GÓMEZ ET AL.---MOLECULAR PHYLOGENY OF OCELLOID-BEARING DINOFLAGELLATES Molecular Phylogeny of the Ocelloid-bearing Dinoflagellates Erythropsidinium and
Molecular Phylogeny of the Ocelloid-bearing DinoflagellatesErythropsidiniumand Warnowia (Warnowiaceae,Dinophyceae)
FERNANDO GÓMEZ,a PURIFICACIÓN LÓPEZ-GARCÍAb and DAVID MOREIRAb aObservatoire Océanologique de Banyuls sur Mer, Université Pierre et Marie Curie, CNRS- INSU UMR 7621, Avenue du Fontaulé, BP 44, 66651 Banyuls sur Mer, France, and bUnité d’Ecologie, Systématique et Evolution, UMR CNRS 8079, Université Paris-Sud, Bâtiment 360, 91405 Orsay Cedex, France
ABSTRACT. Members of the family Warnowiaceae are unarmoured phagotrophic dinoflagellates that possess an ocelloid. ThegenusErythropsidinium (= Erythropsis) has also developed a unique dynamic appendage, the piston, which is able to independently retract and extend for at least two minutes after the cell lyses. We provide the first small subunit ribosomal RNA gene (SSU rDNA) sequences of warnowiid dinoflagellates, those of the type Erythropsidinium agile and one species of Warnowia. Phylogenetic analyses show that warnowiid dinoflagellates branch within theGymnodiniumsensu stricto group, forming a cluster separated from thePolykrikosclade and with autotrophic Pheopolykrikos beauchampii as closest relative. This reinforces their classification as unarmoured dinoflagellates based on the shape of the apical groove, despite the strong ecological and ultrastructural diversity of the Gymnodinium s.s. group. Other structures, such as the ocelloid and piston, have no systematic value above the genus level.
Key Words. Dinoflagellata,Gymnodiniales, photoreceptororganelle, protist evolution, SSU rRNA phylogeny.
This is an Accepted Article that has been peer-reviewed and approved for publication in the Journal of Eukaryotic Microbiology, but has yet to undergo copy-editing and proof correction. Please cite this article as an “Accepted Article”; doi: 10.1111/j.1550-7408.2009.00420.x
THE warnowiids are the only known unicellular organisms bearing a photoreceptor system withcornea-,lens-, and pigment cup-like structures, a complex organization that, elsewhere, can only be found in metazoaneyes. Hertwig (1884) described the first warnowiiddinoflagellatefrom the western Mediterranean Sea. His delicate Erythropsidinium P.C. Silva (= Erythropsis Hertwig) possessed an ‘eye’ and also a piston, which was easily lost. This description provoked the incredulity of earlier protozoologists who did not believe that unicellular organisms could have such complexorganelles. Erythropsidinium was not admitted in taxonomic schemes and it disappeared from the scientific literature until 1896 (see a review in Kofoid and Swezy 1921; Gómez 2008). Later, Kofoid and Swezy (1921) described many new species of Erythropsidinium, likely overestimating their number, through the observation of single or few specimens, using the color and position of the ocelloid as diagnostic characters. By studying the ultrastructure of the complex organelles of warnowiid and polykrikoid dinoflagellates in the 1970’s, Greuet (1987 and references therein) demonstrated that these features were variable throughout the life cycle of a single individual. He showed that the ocelloid exhibited a striking similarity to the metazoan eye, as it possessed, at the sub-cellular level, analogous structural components. Taylor (1980) speculated that it might serve to detect shadow effects provoked by the passage of a potential prey, but also that it could focus and serve as “range finder”. According to this hypothesis, the dinoflagellate would measure the distance to the prey and fire the nematocysts only when a clear image was received on the retinoid. Some protists are able, by virtue of special organelles, to contract parts of their cell bodies: for example, the stalk ofVorticella, the “tail” of Tontonia, and the tentacle of noctilucid dinoflagellates. In addition to the ocelloid, the warnowiid dinoflagellates Erythropsidinium and Greuetodinium A.R. Loeblich III (=Leucopsis Greuet) display the piston, an extensible appendage that is unique among the protists (Greuet 1987). Do dinoflagellates, such as warnowiids and some polykrikoids, containing complex extrusomes and the ocelloid-bearing warnowiids have a common ancestor? Or are they, on the contrary, polyphyletic? The general oceanic distribution of the warnowiids and their delicacy had prevented the determination of gene sequences of these unique protists, especially of the type species, and their phylogenetic position remains untested with molecular phylogenetic data. We have been able to collect these protists and here provide the first small subunit ribosomal RNA gene (SSU rDNA) sequences of warnowiid dinoflagellates, the type Erythropsidinium agile, collected from the western Mediterranean Sea, its type locality, and an unidentified species of Warnowia. We used phylogenetic analyses to test hypotheses about the origin of complex characters, such asocelloidsand pistons, and discuss the evolutionary origin of such structures and their value as diagnostic characters forsystematics. MATERIALS AND METHODS Specimen collection and isolation. Individual warnowiid cells were collected by slowly filtering surface sea water taken from the pier of the Station Marine d’Endoume at Marseille (43° 16´ 48´´ N, 5° 20´ 57´´ E, bottom depth 3 m) from October 2007 to September 2008. A strainer of 20-, 40- or 60-µm netting aperture was used to collect planktonic organisms from water volumes ranging between 10--100 liters, depending on particle concentration. In addition, we also studied samples collected during several monitoring research cruises to the SOMLIT (Service d’Observation en Milieu LITtoral) station in the Bay of Marseille (43° 14´ 30´´ N, 05° 17´ 30´´ E, bottom depth 60 m). Seawater samples were collected with a 12-l Niskin bottle at 40 and 55 m depth and filtered as described above. Theplanktonconcentrate was scanned in settling chambers at 100X magnification with a Nikon Eclipse TE200 inverted microscope (Nikon, Tokyo, Japan). Cells were photographed alive at 200X or 400X magnification with a Nikon Coolpix E995 digital camera. The selected specimens were individually micropipetted with a fine capillary into another chamber and washed several times in serial drops of 0.2-µm filtered and sterilized seawater. Finally, each specimen was picked up and deposited into a 1.5-ml Eppendorf tube filled with several drops of 100% ethanol. The sample was kept at laboratory temperature and in darkness until the molecular analyses could be performed. PCR amplification of small subunit rRNA genes (SSU rDNAs) and sequencing. The single cells of Erythropsidinium agile and Warnowia sp. fixed in ethanol were centrifuged gently for 5 min at 504 g. Ethanol was then evaporated in a vacuum desiccator and single cells were resuspended directly in 25 µl of Ex TaKaRa (TaKaRa, distributed by Lonza Cia., Levallois-Perret, France) PCR reaction mix containing 10 pmol of the eukaryotic- specific SSU rDNA primers EK-42F (5´-CTCAARGAYTAAGCCATGCA-3´) and EK- 1520R (5´-CYGCAGGTTCACCTAC-3´). The PCR reactions were performed under the following conditions: 2 min denaturation at 94 ºC; 10 cycles of ‘touch-down’ PCR (denaturation at 94 ºC for 15 s; a 30 s annealing step at decreasing temperature from 65 down to 55 °C employing a 1 °C decrease with each cycle-, extension at 72 ºC for 2 min); 20 additional cycles at 55 °C annealing temperature; and a final elongation step of 7 min at 72 ºC. A nested PCR reaction was then carried out using 2--5 µl of the first PCR reaction in a GoTaq (Promega, Lyon, France) polymerase reaction mix containing the eukaryotic-specific primers EK-82F (5´-GAAACTGCGAATGGCTC-3´) and EK-1498R (5´- CACCTACGGAAACCTTGTTA-3´) and similar PCR conditions as above. A third, semi- nested, PCR was carried out using the dinoflagellate specific primer DIN464F (5’- TAACAATACAGGGCATCCAT-3´). Amplicons of the expected size (~ 1,200 bp) were then sequenced bidirectionally using primers DIN464F and EK-1498R (Cogenics, Meylan, France). The sequences obtained were 1,211 bp long and deposited in GenBank with Accession numbers FJ467491--FJ467492. Phylogenetic analyses. The new warnowiid sequences were aligned to a large multiple sequence alignment containing 890 publicly available complete or nearly complete (> 1,300 bp) dinoflagellate SSU rDNA sequences using the profile alignment option of MUSCLE 3.7 (Edgar 2004). The resulting alignment was manually inspected using the program ED of the MUST package (Philippe 1993). Ambiguously aligned regions and gaps were excluded in phylogenetic analyses. Preliminary phylogenetic trees with all sequences were constructed using the Neighbour Joining (NJ) method (Saitou and Nei 1987) implemented in the MUST package (Philippe 1993). These trees allowed identifying the closest relatives of our sequences, which were selected, together with a sample of other dinoflagellate species, to carry out more computationally-intensive Maximum Likelihood (ML) and Bayesian Inference (BI) analyses. ML analyses were done with the program TREEFINDER (Jobb et al. 2004) applying a GTR + Γ + I model of nucleotide substitution, taking into account a proportion of invariable sites, and a Γ-shaped distribution of substitution rates with four rate categories. This model was chosen using the model selection tool implemented in TREEFINDER (Jobb et al. 2004) with the Akaike Information Criterion (AICc) as fitting criterion. Bootstrap values were calculated using 1,000 pseudoreplicates with the same substitution model. The BI analyses were carried out with the program PHYLOBAYES applying a GTR + CAT Bayesian mixture model (Lartillot and Philippe 2004), with two independent runs and 1,000,000 generations per run. This model was chosen after several preliminary runs as the model providing the best likelihood estimates. After checking convergence (maximum difference between all bipartitions < 0.01) and eliminating the first 1,500 trees (burn-in), a consensus tree was constructed sampling every 100 trees. To test if different tree topologies were significantly different, we carried out the Approximately Unbiased (AU) test (Shimodaira 2002) implemented in TREEFINDER (Jobb et al. 2004). RESULTS Observations of live specimens. Despite one year of intensive sampling, the records of Erythropsidinium were very scarce. We observed only two specimens in late autumn 2007 (Fig. 1) and twenty specimens in June 2008 (Fig. 2--9). The highest abundance was observed at an offshore station in the Bay of Marseille in 10 June 2008 at 55 m depth. Although the general immobility of Erythropsidinium facilitated its capture with a micropipette, the specimens were highly delicate and disintegrated easily during manipulation. Occasionally, the piston vigorously extended and retracted and then the cell quickly displaced in a straight line. Seven specimens resisted the procedure of isolation, washing and deposition into ethanol for fixation prior to single-cell PCR analyses. One specimen (Fig. 2, 3) provided the first SSU rDNA sequence of Erythropsidinium agile, type of the family Warnowiaceae. When a specimen lysed during manipulation, the melanosome, the pigmented cup of the ocelloid, persisted as a red globular mass with its own membrane (Fig. 4, 5). On some occasions, careful examination revealed that the piston also remained after cell lysis, moving independently (Fig. 6, 7). The intensity of the contraction and extension progressively decreased and the piston disintegrated in about two minutes (~ 20 retractions) after cell lysis (Fig. 8). The piston was not visible in one specimen observed under division (Fig. 9). In contrast, the dedifferentiated ocelloid divided in the middle of the dividing cell (Fig. 9). Records of Warnowia individuals were numerous in comparison with those of Erythropsidinium. In contrast to the latter, the specimens of Warnowia were continuously swimming and changing direction. They rapidly disintegrated when they stopped moving. We were unable to identify the collected cells to the species level due to the deficient delimitation of the numerous described species, but we were able to obtain the first SSU rDNA sequence for the genus Warnowia from one of the specimens (Fig. 10, 11). Molecular phylogeny. After preliminary analyses (see Materials and Methods), a selection of 52 sequences, representing different Gymnodiniales and includingPolarella,Symbiodinium, and Woloszynskia as outgroup taxa, was used to construct a ML phylogenetic tree (Fig. 12). The ocelloid-bearing dinoflagellates E. agile and Warnowia sp., formed a strongly supported monophyletic lineage within the Gymnodiniales and, more particularly, within a group of species that branched with the genus Gymnodinium, which has G. fuscum as type species (Fig. 12). For the 1,078-bp sequence positions used to reconstruct the tree, E. agilis and Warnowia sp. differed in 24 substitutions (2.2%). The sequences of the closest relatives to warnowiids in our tree, the two polykrikoid Pheopolykrikos beauchampii sequences differed on average by 58 and 48 substitutions (5.4% and 4.4%) from E. agilis and Warnowia sp. sequences, respectively. After P. beauchampii, the closest relatives in our phylogenetic analysis were diverse species included in a monophyletic group containing several Gymnodinium species (Gymnodinium. catenatum, Gymnodinium microreticulatum, Gymnodinium dorsalisulcum, Gymnodinium impudicum, and Gymnodinium fuscum), Pheopolykrikos hartmanii, and a clade of Polykrikos species, although the statistical support for this relationship is relatively weak (bootstrap value of 69%). The addition of the warnowiids to the Gymnodiniales resulted in the split of the group Gymnodinium s. s. into several lineages: 1) warnowiids and Pheopolykrikos, 2) G. fuscum 3) Polykrikos / Ph. hartmanii, 4)Lepidodiniumand Gymnodinium aureolum, 5) G. catenatum, G. microreticulatum, G. dorsalisulcum and G. impudicum, and 6) three sequences belonging to the genus Gyrodinium, Gyrodinium dorsum, Gyrodinium instriatum, and Gyrodinium uncatenatum (Fig. 12). To further test the robustness of these relationships we carried out Approximately Unbiased (AU) tests (Shimodaira 2002). All tree topologies where E. agilis and Warnowia sp. did not form a monophyletic clade were rejected, as well as those where the E. agilis / Warnowia group was placed outside the Gymnodinium s.s. group (P- value<0.05). In contrast, the relationship of the E. agilis / Warnowia group with Ph. beauchampii, as well as the relationships involving most of the internal nodes among the six lineages cited before, were not significantly supported. In particular, a topology with all Gymnodinium species monophyletic could not be rejected (P-value = 0.14). In contrast, the monophyly of Polykrikos spp. and Ph. hartmannii was significantly supported (P-value = 0.99). DISCUSSION Warnowiids within the Gymnodiniales sensu stricto. The members of Gymnodinium s.s. showed a high ultrastructural diversity and also a high degree of ecological specialization when compared to other groups of dinoflagellates. They are present in freshwater, brackish and marine habitats, exhibiting both planktonic and benthic forms within the same genus (e.g. Polykrikos). The morphology may vary from unicellular to pseudocolonial (multinucleate) and colonial forms. The trophic behavior varies from strictly autotrophic, parasitic, mixotrophic to phagotrophic species with complex organelles (Daugbjerg et al. 2000; Hoppenrath and Leander 2007a; Kim et al. 2008). Based on morphological arguments, three sequences retrieved from GenBank as belonging to the genus Gyrodinium, G. dorsum, G. instriatum and G. uncatenatum should be also considered as members of the Gymnodinium s.s. despite the low statistical support for their position in our tree. In fact, it has been shown that the two latter species have the typical loop- shaped apical groove characterizing the group (Coats and Park 2002; Hallegraeff 2002). The type of the genus Gymnodinium, G. fuscum, also possesses a loop-shaped apical groove running counterclockwise (Daugbjerg et al. 2000). Based on scanning electronmicroscopy, Takayama (1985) showed the presence of this type of apical groove in Polykrikos, Warnowia, and Erythropsidinium. The apical groove of Gymnodinium and Polykrikos turns around once, while it makes more than one turn in several species of Warnowia, Nematodinium, and Erythropsidinium (Takayama 1985). In contrast to the conservation of the apical groove morphology, the occurrence of complex organelles, such as nematocysts, ocelloids or pistons, the presence ofchloroplasts, the habitat, the colonial behavior or the number of zooids in the multinucleate species are not taxonomically significant for the definition of taxa above the genus level (i.e. family or higher). Origin of the complex organelles. In addition totrichocystsand mucocysts, some warnowiid and phagotrophic Polykrikos species possess extrusive organelles (i.e. nematocysts). Since these ejectile bodies for prey capture are remarkably similar to those in cnidarians (cnidoblasts), the hypothesis of a symbiogenetic origin for these stinging structures in metazoans has been advanced (Shostak and Kolluri 1995). A symbiogenetic origin could be speculated based on the precedent that someciliateshave defensive “extrusomes” derived from bacterial ectosymbionts (Petroni et al. 2000). More difficult is to establish a tentative symbiotic origin of the ocelloid and piston. A complex photoreceptor with cornea-, lens- and pigment cup is an organization that can only be found in the metazoan eyes. As some unarmoured dinoflagellates (i.e. Symbiodinium) are symbionts in cnidarians, Gehring (2004, 2005) speculated, without corroborative evidence, that ocelloid-bearing dinoflagellates, the warnowiid Erythropsidinium and Warnowia, might have transferred their photoreceptor genes to cnidarians and be at the origin of photoreceptor cells in metazoans. Although horizontal gene transfer is acknowledged for some ‘evolutionary jumps’ ineukaryotes(Nosenko and Bhattacharya 2007; Raymond and Blankenship 2003), a high number of genes are required for the development of a metazoan eye, which makes its acquisition from unicellular eukaryotes (or the other way round) very improbable. The ontogenesis of the organelle might help unraveling its evolutionary origin. Greuet (1977) found that the retinoid/pigment cup complex (all within the same membranous compartment) dedifferentiated to the point that they appeared to derive from achloroplastduring binary fission in warnowiids. These observations suggested that the warnowiids were able to transform a chloroplast into a complex organelle that is morphologically convergent with the metazoan eye. The origin of the chloroplast in the heterotrophic warnowiids is itself uncertain. However, dinoflagellates have a remarkable facility to acquire and replace chloroplasts from diverse microalgal groups (Saldarriaga et al. 2001), and even non-photosynthetic dinoflagellates haveplastidgenes (Sánchez-Puerta et al. 2007). Kleptoplastidy in dinoflagellates may be the origin of this high diversity ofplastidsthrough secondary or tertiary endosymbiosis (Koike et al. 2005). The warnowiids branched within the Gymnodinium s.s. group, which has a high diversity of chloroplasts (Daugbjerg et al. 2000; Hansen et al. 2008; Hoppenrath and Leander 2007b). Although the support was relatively moderate in our phylogenetic analysis, the closest relative to the ocelloid-bearing dinoflagellates appears to be Pheopolykrikos beauchampii, whose chloroplasts have not been studied in detail. In contrast to Polykrikos, Ph. beauchampii has one nucleus in each zooid and it may dissociate into single uninucleate cells (Chatton 1933, 1952). The warnowiids are considered strictly heterotrophic. Dodge (1982) reported that Nematodinium armatum contains scattered yellow chloroplasts. Sournia (1986) commented that Dodge’s observations of N. armatum are inconsistent with the generic description and require further clarification. Considering that the closest relative to the warnowiids appears to be the photosynthetic Ph. beauchampii, the potential for an ocelloid-bearing dinoflagellate with chloroplasts should not be discarded. The evolutionary origin of the piston is also enigmatic. No other known organism possesses this kind of organelle. Based on transmission electron microscopy, Greuet (1987) illustrated a myofibril system and mitochondrial papillae in the piston. The numerous mitochondria associated with the piston likely provide the energy to maintain its movement even after cell lysis. While the division of the ocelloid is synchronized with the cell division, the piston is retained by one of the daughter cells (Elbrächter 1979; Greuet 1977). Greuet (1969) observed the regeneration of the piston from the bulb. Considering that the warnowiids have been able to develop complex organelles, such as the eye-like structure, the development of a relatively simpler structure, such as the piston, is not unexpected. Consequently, the evolution from simpler structures would explain the origin of complex organelles (ocelloid and piston). ACKNOWLEDGMENTS This is a contribution to the project DIVERPLAN-MED supported by a post-doctoral grant to F.G. of the Ministerio Español de Educación y Ciencia #2007-0213. P.L.G. and D.M. acknowledge financial support from the French CNRS and the ANR Biodiversity program ‘Aquaparadox’. LITERATURE CITED Chatton, E. 1933. Pheopolykrikos beauchampi nov. gen., nov. sp., dinoflagellé polydinide autotrophe, dans l’Etang de Thau. Bull. Soc. Zool. Fr., 58:251--254. Chatton, E. 1952. Classe des Dinoflagellés ou Péridiniens. In: Grassé P. P. (ed.), Traité de Zoologie. Masson, Paris, p. 309--406. Coats, D. W. & Park, M. G. 2002. Parasitism of photosynthetic dinoflagellates by three strains of Amoebophrya (Dinophyta): parasite survival, infectivity, generation time, and host specificity. J. Phycol., 38:520--528. Daugbjerg, N., Hansen, G., Larsen, J. & Moestrup, Ø. 2000. Phylogeny of some of the major genera of dinoflagellates based on ultrastructure and partial LSU rDNA sequence data, including the erection of three new genera of unarmored dinoflagellates. Phycologia, 39:302-- 317. Dodge, J. D. 1982. Marine Dinoflagellates of the British Isles. Her Majesty’s Stationery Office, London. Edgar, R. C. 2004. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res., 32:1792--1797. Elbrächter, M. 1979. On thetaxonomyof unarmored dinophytes (Dinophyta) from the Northwest African upwelling region.‘Meteor’ Forschungs. Reihe D, 3:1--22. Gehring, W. J. 2004. Historical perspective on the development and evolution of eyes and photoreceptors. Int. J. Develop. Biol., 48:707--717. Gehring, W. J. 2005. New perspectives on eye development and the evolution of eyes and photoreceptors. J. Heredity, 96:171--184. Gómez, F. 2008. Erythropsidinium (Gymnodiniales, Dinophyceae) in the PacificOcean, a unique dinoflagellate with an ocelloid and a piston. Eur. J. Protistol., 44:291--298. Greuet, C. 1969. Anatomie ultrastructurale des Péridiniens Warnowiidae en rapport avec la différenciation des organites cellulaires. Ph.D Université de Nice (CNRS AO 2908). Greuet, C. 1977. Évolution structurale et ultrastructurale de l’ocelloide d’Erythropsidinium pavillardi Kofoid et Swezy (Péridinien, Warnowiidae Lindemann) au cours des divisions binaire et palintomiques. Protistologica, 13:127--143. Greuet, C. 1987. Complex organelles. In: Taylor F. J. R. (ed.), The Biology of Dinoflagellates. Botanical Monographs. Vol. 21. Blackwell, Oxford, UK, p. 119--142. Hallegraeff, G. M. 2002. Aquaculturists’ Guide to Harmful Australian Microalgae. Univ. Tasmania, Hobart. Hansen, G., Botes, L. & De Salas, M. 2007. Ultrastructure and large subunit rDNA sequences of Lepidodinium viride reveal a close relationship to Lepidodinium chlorophorum comb. nov. (Gymnodinium chlorophorum). Phycol. Res., 55:25--41. Hertwig, R. 1884. Erythropsis agilis, eine neue Protozoe. Gegenb. Morphol. Jahrb. Z. Anat. Entw., 10:204--212. Hoppenrath, M. & Leander, B. S. 2007a. Character evolution in polykrikoid dinoflagellates. J. Phycol., 43:366--377. Hoppenrath, M. & Leander, B. S. 2007b. Morphology and phylogeny of the pseudocolonial dinoflagellates Polykrikos lebourae and Polykrikos herdmanae n. sp. Protist, 158:209--227. Jobb, G., von Haeseler, A. & Strimmer, K. 2004. TREEFINDER: a powerful graphical analysis environment for molecular phylogenetics. BMC Evol. Biol., 4:18. Kim, K .-Y., Iwataki, M. & Kim, C.-H. 2008. Molecular phylogenetic affiliations of Dissodinium pseudolunula, Pheopolykrikos hartmannii, Polykrikos cf. schwartzii andPolykrikos kofoidiito Gymnodinium sensu stricto species (Dinophyceae). Phycol. Res., 56:89- -92. Kofoid, C. A. & Swezy, O. 1921. The Free-Living Unarmored Dinoflagellata. Memoirs of the University of California. Vol. 5. University of California Press, Berkeley. Koike, K., Sekiguchi, H., Kobiyama, A., Takishita, K., Kawachi, M., Koike, K. & Ogata, T. 2005. A novel type of kleptoplastidy inDinophysis(Dinophyceae): presence of haptophyte- type plastid in Dinophysis mitra. Protist, 156:225--237. Lartillot, N. & Philippe, H. 2004. A Bayesian mixture model for across-site heterogeneities in the amino-acid replacement process. Mol. Biol. Evol., 21:1095--1109. Nosenko, T. & Bhattacharya, D. 2007. Horizontal gene transfer in chromalveolates. BMC Evol. Biol., 7:173. Petroni, G., Spring, S., Schleifer , K. -H., Verni, F. & Rosati, G. 2000. Defensive extrusive ectosymbionts of Euplotidium (Ciliophora) that contain microtubule-like structures arebacteriarelated to Verrucomicrobia. Proc. Nat. Acad. Sci. USA, 97:1813--1817. Philippe, H. 1993. MUST, a computer package of management utilities for sequences and trees. Nucleic Acids Res., 21:5264--5272. Raymond, J. & Blankenship, R. E. 2003. Horizontal gene transfer in eukaryotic algal evolution. Proc. Nat. Acad. Sci. USA, 100:7419--7420. Saitou, N. & Nei, M. 1987. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol. Biol. Evol., 4:406--425. Saldarriaga, J. F., Taylor, F. J. R., Keeling, P. J. & Cavalier-Smith, T. 2001. Dinoflagellate nuclear SSU rRNA phylogeny suggests multiple plastid losses and replacements. J. Mol. Evol., 53:204--213. Sánchez-Puerta, M. V., Lippmeier, J. C., Apt, K. E. & Delwiche, C. F. 2007. Plastid genes in a non-photosynthetic dinoflagellate. Protist, 158:105--117. Shimodaira, H. 2002. An approximately unbiased test of phylogenetic tree selection. Syst. Biol. 51:492--508. Shostak, S. & Kolluri, V. 1995. Symbiogenetic origins of cnidarian cnidocysts. Symbiosis, 19:1--29. Sournia, A. 1986. Atlas du Phytoplancton Marin, vol. 1: Introduction, Cyanophycées, Dictyochophycées, Dinophycées et Raphidophycées. Editions du CNRS, Paris. Takayama, H. 1985. Apical grooves of unarmored dinoflagellates. Bull. Plankton Soc. Jpn, 32:129--140. Taylor, F. J. R. 1980. On dinoflagellate evolution. Biosystems, 13:65--108. Received : 11/24/08, 02/25/09, 03/26/09; accepted : 03/26/09 Corresponding Author: F. Gómez, Observatoire Océanologique de Banyuls sur Mer, Avenue du Fontaulé, BP 44, 66651 Banyuls sur Mer, France---Telephone number: +33 468887325; FAX number : +33 468887398 ; e-mail:[email protected]. 1--11. Photomicrographs of Erythropsidinium and Warnowia collected off Marseille, France. Date of the collection between parentheses. 1. Erythropsidinium agile with extended piston (pier of the Station Marine d’Endoume, 12 Dec 2007). 2, 3. E. agile (SOMLIT station, Bay of Marseille, 10 Jun 2008). 4, 8. Erythropsidinium sp. (SOMLIT station, Bay of Marseille, 24 Jun 2008). 5. Melanosome after lysis of the cell and the ocelloid hyalosome. 6, 7. Note that the piston can vary its extension after cell lysis. 8. The piston beginning to lyse. 9. E. agile in division (pier of the Station Marine d’Endoume, 13 Jun 2008). Note the dedifferentiated ocelloid in the middle of the dividing cell. 10, 11. Warnowia sp. (pier of the Station Marine d’Endoume, 22 Dec 2007). Micrographs in Fig. 2, 3, 10, and 11 illustrate cells used for single-cell PCR. Scale bar = 20 µm. Fig. 12. Maximum likelihood phylogenetic tree of dinoflagellate small subunit rDNA sequences, based on 1,078 aligned positions. Names in bold represent sequences obtained in this study. Numbers at the nodes are bootstrap support (values under 50% were omitted). Nodes supported by posterior probabilities > 0.9 in Bayesian Inference analyses are indicated by black circles. The branch leading to three fast-evolvingAmphidiniumspecies has been shortened to one-third (indicated by 1/3). Accession numbers are provided between brackets. The scale bar represents the number of substitutions for a unit branch length. The symbols represent the ocelloid, piston, and nematocysts.
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How to trim chick's beaks? | BackYard Chickens - Learn How to Raise Chickens
Hi there folks, I'm encountering some problems with my month-old chicks. I have 7 chicks in a fairly large enclosure, they have a box and tunnel in there...
How to trim chick's beaks?
Hi there folks,
I'm encountering some problems with my month-old chicks. I have 7 chicks in a fairly large enclosure, they have a box and tunnel in there and plenty of room and things to hop on etc. I'm in the middle-east and can't find chicken feed but I feed them daily grains and regularly give them cabbage, fish or boiled egg, and our table-craps. But yesterday I found one of the smaller chicks had one of his toes bleeding, I removed him but only had a small box to put him in, he was crying in there, so by the evening I saw that there was no trace of blood so put him back with the others. Now today I saw one of the biggest chicks bleeding on one of his wings and 2 of his toes and most of the chicks covered in blood from where they'd been pecking at him, it was quite a shocking scene! I was surprised he would be picked on as he's one of the biggest. So I separated him, but again he hates being in a small box and is crying a lot. I don't know what to do, I'm scared I'm going to find every day a new chick bleeding. I've been looking online, and I don't understand why my chicks would be pecking each other as they don't seem to have any symptoms that encourage picking (they have plenty of space, not hot, eating protein-rich food, and an interesting large home so shouldn't be bored). So I'm considering trimming the beaks of the bigger ones, as I guess they're the most likely to be starting the picking, I did observe them for a while but can't work out which one is doing it.
So as a last resort I'm thinking to trimming the bigger chicks' beaks, but I don't know how to do it. I read you cut a little off the top portion of the beak. Can I just do it with regular nail clippers? Till what point to I trim, I obviously want to avoid hurting them too much or letting them bleed.
Appreciate any help,
Scarlett
See if you can find some Blu cote or another purple coloured wound care spray. It will mask the red (blood). Or pine tar (traditional antiseptic and hoof care product for horses and cattle) and apply that to the chicks' wounds to stop the others pecking it. Putting them under a red coloured light will also help. Leave the beak trimming as an absolute last resort. It's tricky and it can cause permanent nerve damage to the chick's beaks if done incorrectly.
Also see if you can distract and amuse the chicks somehow. Put some edible toys in there, like apples, corn on the cob or a cabbage. Or just a pile of leaves/straw with some treats or scratch mixed in.
Edited to add: I've had some ex battery hens who had their beaks trimmed. Some of them had great difficulty eating anything if it wasn't in a deep bowl. It was sad to see them out and about, battling to eat things and losing out on treats.
Do you still have a heat lamp on them? If so is it white or red. Red light will discourage pecking. Have you checked for mites or lice, and do they have an area to dust in. They are most likley getting their new feathers in so it make them ichy and irritable, the red light will help, and make sure at that age that they have plenty of room. Please keep in mind that if you trim their top beak, it will make it almost impossible for them to get anything to eat if you free range.
Thanx for your advice.
Well I never did use a heat lamp, in the hot climate here we don't need one! I just had one chick die out of 8. Although these days the weather is cooling down a bit. Unfortunately I found the first little chick who was pecked at has died, I don't know if it was due to the pecking (because he seemed to have healed and it was just his toe bleeding) or maybe due to something else, he was the smallest chick and always seemed a bit meek... The other one seems to be healing and doing better so I put him back with the others, he has places to hide and he seems to be doing OK. I gave them some apple quarters to peck at. No we don't have any of those wound sprays or anything here, I'm in the Middle-East and I don't know of any vets or anything around here. Yes they have a big "sand pit" to bathe in that I mix with lime so that should help against any bugs... So right now they all seem OK and no pecking apparent, so I'm hoping that it'll stay that way and I won't need to consider trimming any beaks.
| https://www.backyardchickens.com/threads/how-to-trim-chicks-beaks.732695/?order=th_mrp_reaction_score |
In vivo detection of external apical root resorption induced by apical periodontitis using periapical radiography and cone-beam computed tomography | ScienceGate
Abstract Objectives: To investigate sensitivity, specificity, predictive values and ac ...
In vivo detection of external apical root resorption induced by apical periodontitis using periapical radiography and cone-beam computed tomography
Mapping Intimacies ◽
10.21203/rs.3.rs-173059/v1 ◽
2021 ◽
Author(s):
Stephanie Diaz Huamán ◽
Maya Fernanda Manfrin Arnez ◽
Fernanda Maria Machado Pereira Cabral de Oliveira ◽
Andiara De Rossi ◽
...
Keyword(s):
Computed Tomography ◽
Cone Beam Computed Tomography ◽
Predictive Value ◽
Root Resorption ◽
Calculated Data ◽
Cone Beam ◽
Predictive Values ◽
Apical Root Resorption ◽
External Apical Root Resorption ◽
Sensitivity Specificity
Abstract
Objectives: To investigate sensitivity, specificity, predictive values and accuracy of periapical radiography (PR) and Cone beam computed tomography (CBCT) for detection of external apical root resorption (EARR).Materials and Methods: Dog’s teeth with experimentally induced root resorption underwent or not root canal treatment (n = 62 roots). True positives (TP), false positives (FP), true negatives (TN) and false negatives (FN) in PR and CBCT diagnoses were determined using histopathologic findings as gold standard. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy (TP + TN) in the diagnosis of EARR were calculated. Data was compared using chi-squared test (⍺= 0.05).Results: We found that PR detected EARR in 35% of roots and CBCT, in 47%. EARR was microscopically diagnosed in 50% (p = 0.03 comparison between PR and microscopy; p = 0.67 comparison between CBCT and microscopy). Overall, CBCT produced more accurate diagnoses than PR (0.93 for CBCT versus 0.70 for PR; p = 0.008). Interestingly, when data was stratified into small and large resorptions, PR and CBCT allowed identification of large resorption in 100% of the cases and showed the same accuracy. However, for small resorptions, PR showed an accuracy of 0.83, whereas CBCT showed an accuracy of 0.96 (p = 0.003).Conclusions: We demonstrated that CBCT showed higher accuracy to detect EARR. These findings shed light on the use of CBCT for detection of initial root resorption.Clinical relevance: Early identification of resorption allows a prompt treatment and reduces the risk of dental structure loss.
10.17576/jsm-2020-4902-12 ◽
2020 ◽
Vol 49 (2) ◽
pp. 343-348
Author(s):
Fazal Shahid ◽
Shifat A Nowrin ◽
Norma Ab Rahman ◽
Saidi Jaafar
Keyword(s):
Computed Tomography ◽
Cone Beam Computed Tomography ◽
Root Resorption ◽
Cone Beam ◽
Validity And Reliability ◽
Apical Root Resorption ◽
External Apical Root Resorption
Journal of Applied Oral Science ◽
10.1590/1678-775720150224 ◽
2015 ◽
Vol 23 (5) ◽
pp. 479-485 ◽
Cited By ~ 7
Author(s):
João Paulo SCHWARTZ ◽
Taísa Boamorte RAVELI ◽
Kélei Cristina de Mathias ALMEIDA ◽
Humberto Osvaldo SCHWARTZ-FILHO ◽
Dirceu Barnabé RAVELI
Keyword(s):
Computed Tomography ◽
Cone Beam Computed Tomography ◽
Root Resorption ◽
Cone Beam ◽
Herbst Appliance ◽
Apical Root Resorption
Volumetric cone-beam computed tomography evaluation and risk factor analysis of external apical root resorption with clear aligner therapy
Author(s):
Wei Liu ◽
Juhua Shao ◽
Shufang Li ◽
Maher Al-balaa ◽
Lulu Xia ◽
...
Keyword(s):
Risk Factors ◽
Computed Tomography ◽
Cone Beam Computed Tomography ◽
Root Resorption ◽
Cone Beam ◽
Volume Loss ◽
Root Volume ◽
Tooth Type ◽
External Apical Root Resorption ◽
Clear Aligner
ABSTRACT
Objectives
To investigate the prevalence and severity of external apical root resorption (EARR) volumetrically with clear aligner therapy using cone-beam computed tomography (CBCT) as well as determine the possible risk factors and develop a prediction model for EARR.
Materials and Methods
In this retrospective study, 320 incisors from 40 Class II patients treated with aligners (Invisalign) were included in this study. CBCT images were obtained at pretreatment (T0) and posttreatment (T1). Root volume was calculated by three-dimensional reconstruction of CBCT images, and apical tooth movement was measured from superimposed CBCT images. Changes in root volume were compared using paired t-tests, and the relationship between root volume loss and potential risk factors was analyzed by multiple linear regression.
Results
All of the measured incisors showed root volume loss, with an average of 11.48 ± 6.70 mm3, and the prevalence of severe resorption was 0.625%. The prediction model for EARR included variables of posttreatment sagittal root position (SRP), extraction, tooth type, and apical intrusion and extrusion displacements, with an R2 of 0.51. Age, sex, duration, pretreatment SRP, attachment, advancement, and retraction movements were excluded from the model.
Conclusions
Most incisors showed mild to moderate resorption during aligner treatment; only a minimal percentage showed severe resorption. Posttreatment SRP (which showed the highest association with EARR), extraction, tooth type, and apical intrusion and extrusion displacements were risk factors for EARR.
Cone-Beam Computed Tomography to Assess Mandibular Invasion in Oral Squamous Cell Carcinoma
Update Dental College Journal ◽
10.3329/updcj.v8i2.40381 ◽
2018 ◽
Vol 8 (2) ◽
pp. 18-22
Author(s):
Md Ariful Islam ◽
Md Nasir Uddin ◽
Md Shahjahan Ali ◽
Md Mahfuz Hossain
Keyword(s):
Computed Tomography ◽
Squamous Cell Carcinoma ◽
Oral Squamous Cell Carcinoma ◽
Positive Predictive Value ◽
Cell Carcinoma ◽
Squamous Cell ◽
Cone Beam Computed Tomography ◽
Predictive Value ◽
Cone Beam ◽
Sensitivity Specificity
Background: Oral squamous cell carcinoma which occurs closely to the mandible has a tendency to invade mandible. An accurate preoperative evaluation of mandibular invasion is important for optimum treatment planning. Aim of this study is to determine the accuracy of CBCT in detection of mandibular invasion in oral squamous cell carcinoma.
Study design: In this prospective observational study 35 patients of histologically proven squamous cell carcinoma which was close proximity to the mandible were selected. The results of preoperative CBCT scan of mandible were compared with that of post operative histopathology of bone and thus sensitivity, specificity, negative predictive value, positive predictive value were calculated.
Results: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of CBCT were 96%, 90.90%, 96%, 90.90%, 97.14% respectively (Chi squared with Yates correction equals 21.844 with 1 degrees of freedom, p value < o.oooo1).
Conclusion: Cone beam computed tomography is a sensitive test and has an acceptable range of specificity.
Update Dent. Coll. j: 2018; 8 (2): 18-22
Detection of apical root resorption after orthodontic treatment by using panoramic radiography and cone-beam computed tomography of super-high resolution
American Journal of Orthodontics and Dentofacial Orthopedics ◽
10.1016/j.ajodo.2008.10.014 ◽
2009 ◽
Vol 135 (4) ◽
pp. 434-437 ◽
Cited By ~ 90
Author(s):
Alexander Dudic ◽
Catherine Giannopoulou ◽
Michael Leuzinger ◽
Stavros Kiliaridis
Keyword(s):
Computed Tomography ◽
High Resolution ◽
Cone Beam Computed Tomography ◽
Orthodontic Treatment ◽
Root Resorption ◽
Panoramic Radiography ◽
Cone Beam ◽
Apical Root Resorption
A cone-beam computed tomography study of orthodontic apical root resorption
BDJ ◽
10.1038/sj.bdj.2013.762 ◽
2013 ◽
Vol 215 (3) ◽
pp. 121-121
Keyword(s):
Computed Tomography ◽
Cone Beam Computed Tomography ◽
Root Resorption ◽
Cone Beam ◽
Apical Root Resorption
Cone-beam computed tomography evaluation of the association of cortical plate proximity and apical root resorption after orthodontic treatment
Journal of Oral Science ◽
10.2334/josnusd.15-0566 ◽
2016 ◽
Vol 58 (2) ◽
pp. 231-236 ◽
Cited By ~ 5
Author(s):
Tomoo Nakada ◽
Mitsuru Motoyoshi ◽
Eri Horinuki ◽
Noriyoshi Shimizu
Keyword(s):
Computed Tomography ◽
Cone Beam Computed Tomography ◽
Orthodontic Treatment ◽
Root Resorption ◽
Cone Beam ◽
Cortical Plate ◽
Apical Root Resorption
Apical root resorption due to orthodontic treatment detected by cone beam computed tomography
The Angle Orthodontist ◽
2012 ◽
Vol 83 (2) ◽
pp. 196-203 ◽
Cited By ~ 38
Author(s):
Iury O. Castro ◽
Ana H. G. Alencar ◽
José Valladares-Neto ◽
Carlos Estrela
Keyword(s):
Computed Tomography ◽
Cone Beam Computed Tomography ◽
Orthodontic Treatment ◽
Root Resorption ◽
Three Dimensional ◽
Cone Beam ◽
Apical Root Resorption ◽
Gender And Age ◽
Before And After
ABSTRACT
Objective:
To determine the frequency of apical root resorption (ARR) due to orthodontic treatment using cone beam computed tomography (CBCT) in a sample of 1256 roots from 30 patients.
Materials and Methods:
All patients had Class I malocclusion with crowding. Of the 30 patients evaluated, 11 were boys and 19 were girls; their mean age was 13 years (11 to 16 years). Orthodontic treatment followed the nonextraction treatment. CBCT images were obtained before and after orthodontic treatment, and ARR was determined using Axial Guided Navigation of CBCT images.
Results:
All patients had ARR. No statistically significant association was found between resorption frequency, gender, and age. ARR was detected using CBCT in 46% of all roots that underwent orthodontic treatment.
Conclusions:
CBCT was effective for detecting in vivo even minimal degrees of ARR due to orthodontic treatment and allowed three-dimensional evaluation of dental roots and visualization of palatine roots of maxillary molars. The highest frequencies and the most significant ARR occurred in incisors and distal roots of first maxillary and mandibular molars.
Long-term evaluation of apical root resorption after orthodontic treatment using periapical radiography and cone beam computed tomography
Dental Press Journal of Orthodontics ◽
10.1590/s2176-94512013000400015 ◽
2013 ◽
Vol 18 (4) ◽
pp. 104-112 ◽
Cited By ~ 11
Author(s):
Jairo Curado de Freitas ◽
Olavo César Porto Lyra ◽
Ana Helena Gonçalves de Alencar ◽
Carlos Estrela
Keyword(s):
Computed Tomography ◽
Cone Beam Computed Tomography ◽
Orthodontic Treatment ◽
Root Resorption ◽
Cone Beam ◽
Posterior Teeth ◽
Apical Root Resorption ◽
Mandibular Molar ◽
Periapical Radiography
OBJECTIVE: To evaluate the frequency of Apical Root Resorption (ARR) after orthodontic treatment at 52-288 months using periapical radiography (PR) and cone beam computed tomography (CBCT). METHODS: Radiographic images obtained from 58 patients, before (T1) and after orthodontic treatment (T2), and following 52-288 months of treatment were analyzed by three members of the Brazilian Board of Orthodontics. Apical structures were evaluated by PR images (T2 and T3), using Levander and Malmgren scores. The presence of ARR on CBCT images were detected only at T3. The Kolmogorov-Smirnov test was used for statistical analyses, and the level of significance was set at 5%. Kappa statistics determined interobserver agreement. RESULTS: The more frequent ARR were with scores 1 in T2 (51.6%) and T3 (53.1%), when evaluated by PR (p > 0.05). When compared the frequencies of ARR in T3 among PR and CBCT images, the differences were significant for maxillary and mandibular pre-molar groups, and for mandibular molar group (p > 0.05). The teeth with highest frequency of ARR presence using CBCT images were maxillary lateral incisors (94.5%) and mandibular central incisors (87.7%), while the premolars showed the lowest frequency. The CBCT images showed that the teeth involved in orthodontic treatment with extraction present higher ARR frequency (p < 0.05). CONCLUSION: PR showed more frequency of ARR in posterior teeth groups when compared with CBCT images. ARR did not change in long-term post treatment.
Comparison of Cone Beam Computed Tomography and Digital Radiography in Detecting Separated Endodontic Files and Strip Perforation
Applied Sciences ◽
10.3390/app10238726 ◽
| https://www.sciencegate.app/document/10.21203/rs.3.rs-173059/v1 |
Sudan-Amherst CCD Texas Education data and school information
Sudan-Amherst CCD Texas Education data with local analysis and research
Sudan-Amherst CCD Texas Education Attainment Charts
This section of charts contains education data for Sudan-Amherst CCD Texas based mainly on the latest year 2022 Census data using the American Community Survey but also the survey from Common Core Data available for Public Elementary through Secondary Schools. In
Figure 1
, the percent of all people aged 25 years or older, who have either graduated from high school or completed the Graduate Equivalency Degree (GED) or some equivalent certification/credential.
Sudan-Amherst CCD
depicts it has a High School Grad or higher of 79% which is the second most percent high school graduates or better of all the places in the greater Sudan-Amherst CCD region. The place with the highest percent high school graduates or better in the area is
Sudan
which depicts a high school graduates of 84% (only about 5.2% larger).
In
Figure 2
, the percentage of people aged 25 years or older who have graduated from college/university with at least a bachelor's degree is provided. Note that the bachelor's degree is also called a four-year degree because it normally takes four years of full-time study to finish the course curriculum required to obtain the degree. This chart portrays the proportion of the population in this region who are college graduates with at least a bachelor degree or higher. In many ways, this analysis alongside the prior chart are very quick measures of the level of education in any particular area. Sudan-Amherst CCD depicts it has a Bachelors Degree or higher of 12% which is the third most percent with a bachelors degree or higher of all other places in the greater Sudan-Amherst CCD region. The place with the highest percent with a bachelors degree or higher in the area is
Sudan
which shows a percent with a bachelors degree of 16% (27.9% larger).
Figure 4
shows the percentage of people 25 years of age or older who either have no schooling at all or dropped out of school before being able to complete high school. Additionally, these are people who also do not have a Graduate Equivalency Degree (GED) or some other high school level type credential/student achievement. This analysis, along with the last two charts, provides another high level review and comparative data on the Sudan-Amherst CCD Texas educational level.
Sudan-Amherst CCD
shows it has a School Dropout Rate of 21% which is the second smallest in terms of percent who dropped out of school of all the other places in the metropolitan area. The place with the highest percent who dropped out of school in the area is
Springlake
which depicts a percent who dropped out of school of 59% (approximately 2.9 times bigger).
Figure 5
provides a more detailed look at the educational attainment for Sudan-Amherst CCD Texas. This chart provides the proportion of people aged 25 years of age or older and what was their level of educational attainment. The chart provides 5 broad categories including: No Education/No School, Some High School, High School or equivalent, Some college or Associates Degree, and Bachelors Degree or higher. Sudan-Amherst CCD has the percentage of percent of people with no schooling the second smallest as measured by percent of people with no schooling of all the other places in the local area at 19% of the total. Second, it has one of the largest proportions of percent of people with less than a high school education at 41% of the total and is ranked #3. Only #2
Sudan
(43%), and #1
Amherst
(48%) are larger.
The next chart shows a break down of people who have received a bachelor's degree or higher advanced degree generally in a campus learning environment. In particular,
Figure 6
, provides the proportional breakdown of all the people who have received a postsecondary education along with what the level of advanced degree that was obtained. Note that these categories do not include any type professional development type activities such as those related to maintaining professional credentials in workshop lessons. Note Professional Degree includes medical, dental, lawyers, etc. Sudan-Amherst CCD has the percentage of percent of people with an associate degree less than most other places in the surrounding region at 43% of the total. Second, it has one of the largest proportions of percent of people with a bachelors degree at 13% of the total and is ranked #3. Only #2
Amherst
(15%), and #1
Springlake
(50%) are larger.
The chart in
Figure 7
shows the broad area of academic concentration or the discipline for people who have received a bachelors degree. This high level classification is essentially the field of study for which a degree was obtained. Sudan-Amherst CCD has one of the largest proportions of percent of people with a degree in a science or engineering related at 21.6% of the total and is ranked #3. Only #2
Amherst
(23.5%), and #1
Littlefield
(41.0%) are larger. Second, it has in the mid range of other places in the area in terms of percent of people with an arts, humanities, or other degree at 9.6% of the total.
The next chart (
Figure 8
) provides a more detailed deep dive on the category of major degree obtained for people aged 25 years or older who earned a bachelor's degree or higher. Specifically, this frequency distribution details out what the major field of study was the degree obtained. Sudan-Amherst CCD has the largest proportion of percent of people with a degree in computers, mathematics and statistics at 21.6% of the total and is ranked #1. Second, it has less than most other places in the greater region in order of percent of people with a degree in biological, agricultural, and environmental sciences at 8.7% of the total. Third, it has in the mid range of other places in the surrounding region as measured by percent of people with a degree in science and engineering related fields at 9.6% of the total.
Figure 9
provides comparative data between the places in the greater Sudan-Amherst CCD Texas region for broad educational attainment. This analysis uses provides five broad education attainment categories including: No Education/No School, Some High School, High School or equivalent, Some college or Associates Degree, and Bachelors Degree or higher. Sudan-Amherst CCD has one of the largest proportions of percent of people with less than a high school degree at 41.4% of the total and is ranked #3. Only #2
Sudan
(43.4%), and #1
Amherst
(47.8%) are larger. Second, it has one of the largest proportions of percent of people with high school (or ged) at 25.9% of the total and is ranked #2. The only larger place being
Littlefield
with 28.9%.
A more detailed frequency distribution of educational attainment is provided in
Figure 10
. In particular this illustration breaks out the highest levels of university educational opportunities beyond the four year college degree. Included in the breakout are the relative proportion of masters degrees, PhD/Doctorate/Doctorial holders, and professional degrees such as medicine, dentistry, lawyers, etc. Sudan-Amherst CCD has the percentage of percent of people with no schooling the second smallest as measured by percent of people with no schooling of all the other places in the area at 19.3% of the total. Second, it has one of the largest proportions of percent of people with less than high school at 41.4% of the total and is ranked #3. Only #2
Sudan
(43.4%), and #1
Amherst
(47.8%) are larger. The next exhibit (
Figure 11
) provides detailed cross tabulation analysis that provides education success data broken out or cross tabulated by age group. Please note that the columns add to 100% and you must use the pagination buttons at the bottom of the table to see all the rows.
Figure 12
is a cross tabulation analysis that shows large educational success categories and is broken out or cross tabulated by racial group. Please note that the columns add to 100% and you must use the pagination buttons at the bottom of the table to see all the rows.The final cross tabulation analysis is provided in
Figure 13
and shows education success broken out by gender. Please note that the columns add to 100% and you must use the pagination buttons at the bottom of the table to see all the rows.
Sudan-Amherst CCD Texas School Enrollment Charts
The next section of chart resources look at school enrollment by a variety of educational institutions and are categorized into a number of other groupings.
Figure 14
provides the overall school enrollment by broad range of school age/level groupings. Sudan-Amherst CCD has the percentage of percent of children in kindergarten in the center range of other places in the local area at 24.0% of the total. Second, it has one of the largest proportions of percent of children in grades 5 to 8 at 37.3% of the total and is ranked #2. The only larger place being
Amherst
with 39.7%.
Figure 15
provides a simple high level comparison of the proportion of students that are enrolled in public schools versus students enrolled in private schools in the Sudan-Amherst CCD Texas region. Sudan-Amherst CCD shows percent enrolled in public schools very much bigger as the percent enrolled in private schools.
The next comparison provided in
Figure 16
shows the proportion of students enrolled in private schools versus students enrolled public schools for students enrolled in Kindergarten through 8th grade (grade 8) or (K through 8). Sudan-Amherst CCD depicts percent of children enrolled in public k-8 grades appreciably bigger as the percent of children enrolled in private k-8 grades.
Figure 17
provides a comparative analysis all students enrolled in a public high school versus those students who are enrolled in private high school schools. Sudan-Amherst CCD depicts percent enrolled in a public high school substantially bigger as the percent enrolled in a private high school.
The next chart (
Figure 18
) provides a similar analysis to the last chart but provides the data for public post secondary education versus private higher education colleges. Sudan-Amherst CCD depicts percent enrolled in a public college quite a bit bigger as the percent enrolled in a private college.
The next chart in this series of resources shown in
Figure 20
looks at the total number of students enrolled in any educational institution for each place in the greater Sudan-Amherst CCD region. (Total enrollment in this case includes all students from preschool all the way through students enrolled in graduate school.) Sudan-Amherst CCD depicts it has a Total Enrolled of 608 which is the third most of all other places in the local area. The place with the highest total population enrolled in school in the area is
Littlefield
which depicts a total population enrolled in school of 1,532 (approximately 2.5 times bigger). Comparing total population enrolled in school to the
United States
average of 81,076,829, Sudan-Amherst CCD is only about 0.0% the size. Also, in comparison with the state of
Texas
, total population enrolled in school of 7,752,643, Sudan-Amherst CCD is only about 0.0% the size.
Sudan-Amherst CCD Texas Area Schools Charts
Figure 23
lists all the schools in the area along with the school district, county location and other program information/credential such as if they are a public charter school or private charter school or magnet school. Some of the Area Schools are: Sudan H S, Sudan El, Amherst School, Littlefield El, and Littlefield Pri. The next illustration in
Figure 24
shows the total child school enrollment for all grades (through 12th grade) at the school shown using NCES data (Common Core of Data, Public Elementary-Secondary School Universe Survey.) Looking at Enrollment for Area Schools we find that Dillman El ranks the largest with a value of 479 enrolled students. The next largest values are for: Littlefield Pri (447), Littlefield H S (374), Muleshoe H S (358), and Webb El (343). The difference between the highest value (Dillman El) and the next highest (Littlefield Pri) is that the enrolled students is about 7.2% larger.
Figure 25
show the ratio of the number of students to the number of teachers in the classroom. A good student to teacher ratio should be low because it indicates that there are less students for any one teacher to educate in a class and generally a better learning environment, better success and optimal teaching excellence. Teachers includes all educational staff such as special education teachers and any other educator. Note that distance learning (online learning/remote learning) is not included in these values. Looking at Student to Teacher Ratio for Area Schools we find that Springlake-Earth H S ranks the largest with a value of 7.3 student to teacher ratio. The next largest values are for: Amherst School (8.2), Sudan H S (8.6), Muleshoe H S (10.5), and Whitharral School (10.9). The difference between the lowest value (Springlake-Earth H S) and the next lowest (Amherst School) is that the student to teacher ratio is 11.8% larger.
The next chart,
Figure 26
, shows the racial mix of students at each location in this district of the state of Texas department of education.
Sudan-Amherst CCD, Texas Education Data
Education
Area Schools
Figure 1: Sudan-Amherst CCD, TX At least High School Education Figure 2: Sudan-Amherst CCD, TX Bachelors Degree or Better Education 0% 50% 100% Springlake Earth Muleshoe Amherst Littlefield Sudan-Amherst CCD Sudan Texas Lubbock-Levelland United States Place High School Grad or higher Springlake 41% Earth 66% Muleshoe 68% Amherst 74% Littlefield 76% Sudan-Amherst CCD 79% Sudan 84% Texas 85% Lubbock-Levelland 86% United States 89% ... 0% 50% 100% Amherst Springlake Earth Littlefield Sudan-Amherst CCD Muleshoe Sudan Lubbock-Levelland Texas United States Place Bachelors Degree or higher Amherst 6% Springlake 8% Earth 9% Littlefield 12% Sudan-Amherst CCD 12% Muleshoe 13% Sudan 16% Lubbock-Levelland 29% Texas 32% United States 34% ...
Figure 3: Advertisement Figure 4: Sudan-Amherst CCD, TX School Dropout Rate 0% 50% 100% United States Lubbock-Levelland Texas Sudan Sudan-Amherst CCD Littlefield Amherst Muleshoe Earth Springlake Place School Dropout Rate United States 11% Lubbock-Levelland 14% Texas 15% Sudan 16% Sudan-Amherst CCD 21% Littlefield 24% Amherst 26% Muleshoe 32% Earth 34% Springlake 59% ...
Figure 5: Sudan-Amherst CCD, TX Education Attainment Breakdown Figure 6: Higher Education Attainment (100%=All People with Bachelor or better) High School or GED Some college or Associates Degree Less than High School Bachelors Degree or higher No schooling 41.4% 12.1% 19.3% 25.9% Place Sudan-Amherst CCD High School or GED 0.414 Some college or Associates Degree 0.259 Less than High School 0.193 Bachelors Degree or higher 0.121 No schooling 0.013 No schooling Bachelors degree % Associate degree % Masters degree % Professional school degree % 43.3% 13.1% 41.9% Place Sudan-Amherst CCD Bachelors degree % 0.433 Associate degree % 0.419 Masters degree % 0.131 Professional school degree % 0.017 Doctorate degree % 0 %
Figure 7: Sudan-Amherst CCD, TX Bachelors Degrees Field of Study Science & Engineering Science and Engineeri… Arts, Humanities, Other Business Education Sudan-Amherst CCD Sudan Amherst Littlefield Earth Springlake Muleshoe United States Texas Lubbock-Levelland 0% 50% 100% Place Science & Engineering Science and Engineering Related Arts, Humanities, Other Business Education Sudan-Amherst CCD 38% 5.8% 21.6% 9.6% 25% Sudan 34.3% 3.8% 21% 9.5% 31.4% Amherst 39.2% 3.9% 23.5% 13.7% 19.6% Littlefield 20.5% 13.4% 41% 6.2% 18.9% Earth 38.6% 12.3% 7% 22.8% 19.3% Springlake 50% 0% 0% 0% 50% Muleshoe 31.3% 1.3% 11.9% 40.7% 14.8% United States 35.8% 9.7% 23.7% 19.6% 11.2% Texas 35.6% 9.4% 21.1% 22.7% 11.1% Lubbock-Levelland 30.6% 10.5% 23.9% 19.6% 15.4% Science and Engineerin…
Figure 8: Sudan-Amherst CCD, TX Bachelors Degree Obtained Computers, Mathemat… Biological, Agricultura… Physical and Related S… Psychology Social Sciences Engineering Multidisciplinary Studies Science and Engineering Related Business Education Literature and Languages Liberal Arts and History 1/2 Sudan-Amherst CCD 0% 5% 10% 15% 20% 25% Place Computers, Mathematics and Statistics Biological, Agricultural, and Environmental Sciences Physical and Related Sciences Psychology Social Sciences Engineering Multidisciplinary Studies Science and Engineering Related Business Education Literature and Languages Liberal Arts and History Visual and Performing Arts Communications Other Sudan-Amherst CCD 0% 21.6% 8.7% 5.8% 0% 1.9% 0% 5.8% 9.6% 25% 0% 12.5% 0.5% 0% 8.7% 0/0
Figure 9: Sudan-Amherst CCD, TX Education Attainment by Level Comparison (Age 25+) No schooling Less than High School High School or GED Some college or Associates Degree Bachelors Degree or higher Sudan-Amherst CCD Sudan Amherst Littlefield Earth Springlake Muleshoe United States Texas Lubbock-Levelland 0% 50% 100% Place No schooling Less than High School High School or GED Some college or Associates Degree Bachelors Degree or higher Sudan-Amherst CCD 1.3% 19.3% 41.4% 25.9% 12.1% Sudan 1.5% 14.9% 43.4% 24.7% 15.5% Amherst 0.8% 24.8% 47.8% 20.4% 6.2% Littlefield 2.4% 21.3% 35.4% 28.9% 11.9% Earth 4.4% 29.4% 34.1% 22.9% 9.2% Springlake 13.8% 45% 17.5% 16.2% 7.5% Muleshoe 3.4% 28.6% 34.9% 19.7% 13.4% United States 1.6% 9.5% 26.5% 28.7% 33.7% Texas 2.3% 12.9% 24.5% 28.8% 31.5% Lubbock-Levelland 1.9% 12.3% 26.7% 29.6% 29.4% Bachelors Degree or higher
Figure 10: Sudan-Amherst CCD, TX Education Attainment Detailed Comparison (Age 25+) No schooling Less than High School High School or GED Some college Not Graduate Associate degree Bachelors degree Masters degree Professional school degree Doctorate degree Sudan-Amherst CCD 0% 20% 40% 60% Place No schooling Less than High School High School or GED Some college Not Graduate Associate degree Bachelors degree Masters degree Professional school degree Doctorate degree Sudan-Amherst CCD 1.3% 19.3% 41.4% 17.2% 8.7% 9% 2.7% 0.4% 0% Doctorate degree
Figure 11: Sudan-Amherst CCD, TX Detailed Education Attainment Breakout by Age Group (Age 18+) Education 18 to 24 years 25 to 34 years 35 to 44 years 45 to 64 years 65 years and over 9th to 12th grade, no diploma 16% 10% 3% 16% 5.9% Associates degree 5% 22% 5% 5% 5.2% Bachelors degree 0% 3% 0% 16% 10.2% Graduate or professional degree 0% 2% 5% 4% 2.0% 1 2
Figure 12: Sudan-Amherst CCD, TX Detailed Education Attainment Breakout by Race (Age 25+) Education White Black American Indian Asian Native Hawaiian Hispanic Bachelors degree or higher 14% 0% 0% 36% 0% 1.5% High school graduate or GED 44% 23% 0% 46% 0% 50.2% Less than high school diploma 18% 23% 0% 0% 0% 34.7% Some college or associates degree 24% 54% 0% 18% 100% 13.6%
Figure 13: Sudan-Amherst CCD, TX Detailed Male and Female breakdown of Educational Attainment Education Total Male Female Associates Degree 9% 13% 4.6% Bachelors Degree 9% 7% 11.1% High school/GED 41% 42% 41.0% Less than High School 19% 17% 21.9% Masters degree 3% 1% 4.6% No schooling completed 1% 2% 1.0% Professional school degree 0% 1% 0.2% Some college-No Degree 17% 19% 15.6% Total 100% 50% 50.2%
Figure 14: Sudan-Amherst CCD, TX School Enrollment by Aggregate Categories Kindergarten Grade 1 to 4 Grade 5 to 8 Grade 9 to 12 College, undergraduate Graduate or prof school Sudan-Amherst CCD Sudan Amherst Littlefield Earth Springlake Muleshoe United States Texas Lubbock-Levelland 0% 50% 100% Place Kindergarten Grade 1 to 4 Grade 5 to 8 Grade 9 to 12 College, undergraduate Graduate or prof school Sudan-Amherst CCD 6.2% 24% 23.7% 37.3% 8.7% 0% Sudan 6.4% 29.1% 21.8% 34.6% 8.1% 0% Amherst 5.1% 23.4% 24.7% 39.7% 7.1% 0% Littlefield 5.5% 30.4% 28.2% 23.5% 11.5% 0.8% Earth 1.1% 18% 44% 27.4% 9.4% 0% Springlake 0% 80% 5% 15% 0% 0% Muleshoe 6.2% 18.8% 34.3% 34.3% 6.4% 0% United States 5.3% 21.1% 22.3% 22.6% 23% 5.8% Texas 5.7% 22.4% 23.4% 23.1% 20.6% 4.9% Lubbock-Levelland 4.6% 17.6% 19.2% 18.4% 33.4% 6.8% Graduate or prof school
Figure 15: Sudan-Amherst CCD, TX Overall Public vs. Private School Enrollment Figure 16: Sudan-Amherst CCD, TX Public vs. Private K-8 School Enrollment Public Sc… Private S… 0% 50% 100% Sudan-Amherst CCD Sudan Amherst Littlefield Earth Springlake Muleshoe United States Texas Lubbock-Levelland Place Public School Enrollment Private School Enrollment Sudan-Amherst CCD 96% 4% Sudan 100% 0% Amherst 94% 6% Littlefield 93% 7% Earth 97% 3% Springlake 100% 0% Muleshoe 100% 0% United States 83% 17% Texas 88% 12% Lubbock-Levelland 89% 11% Private Sc… Public K-… Private K… 0% 50% 100% Sudan-Amherst CCD Sudan Amherst Littlefield Earth Springlake Muleshoe United States Texas Lubbock-Levelland Place Public K-8 Enrollment Private K-8 Enrollment Sudan-Amherst CCD 98% 2% Sudan 100% 0% Amherst 97% 3% Littlefield 93% 7% Earth 95% 5% Springlake 100% 0% Muleshoe 100% 0% United States 88% 12% Texas 92% 8% Lubbock-Levelland 91% 9% Private K-…
Figure 17: Sudan-Amherst CCD, TX Public vs. Private High School Enrollment Figure 18: Sudan-Amherst CCD, TX Public vs. Private College Enrollment Public Hi… Private… 0% 50% 100% Sudan-Amherst CCD Sudan Amherst Littlefield Earth Springlake Muleshoe United States Texas Lubbock-Levelland Place Public High School Enrollment Private High School Enrollment Sudan-Amherst CCD 95% 5% Sudan 100% 0% Amherst 90% 10% Littlefield 90% 10% Earth 100% 0% Springlake 100% 0% Muleshoe 100% 0% United States 89% 11% Texas 93% 7% Lubbock-Levelland 90% 10% Private H… Public C… Private C… 0% 50% 100% Sudan-Amherst CCD Sudan Amherst Littlefield Earth Muleshoe United States Texas Lubbock-Levelland Place Public College Enrollment Private College Enrollment Sudan-Amherst CCD 90% 10% Sudan 100% 0% Amherst 100% 0% Littlefield 100% 0% Earth 100% 0% Muleshoe 100% 0% United States 78% 22% Texas 84% 16% Lubbock-Levelland 89% 11% Private Co…
Figure 19: Sudan-Amherst CCD, TX Public vs. Private Graduate or Professional School Enrollment Figure 20: Sudan-Amherst CCD, TX Total Enrolled in Schools Public Gr… Private… 0% 50% 100% Littlefield United States Texas Lubbock-Levelland Place Public Gradudate or Pro school enrollment Private Gradudate or Pro school enrollment Littlefield 67% 33% United States 60% 40% Texas 71% 29% Lubbock-Levelland 86% 14% Private G… 0 1,000 2,000 Springlake Sudan Earth Amherst Sudan-Amherst CCD Muleshoe Littlefield Place Total Enrolled Springlake 40 Sudan 244 Earth 272 Amherst 298 Sudan-Amherst CCD 608 Muleshoe 1,272 Littlefield 1,532 ...
Figure 21: Advertisement Figure 22: Sudan-Amherst CCD, TX Public vs. Private Preschool Public pr… Private p… 0% 50% 100% Sudan-Amherst CCD Sudan Amherst Littlefield Earth United States Texas Lubbock-Levelland Place Public preschool enrollment Private preschool enrollment Sudan-Amherst CCD 100% 0% Sudan 100% 0% Amherst 100% 0% Littlefield 100% 0% Earth 100% 0% United States 59% 41% Texas 64% 36% Lubbock-Levelland 64% 36% Private pr…
Figure 23: List of Schools in the Sudan-Amherst CCD, TX Area (2013) School Name School District School Level Grade Range Magnet School Charter School Whitharral School Whitharral Isd Other K to 12 No No Webb El Olton Isd Primary School PK to 5 No No Watson J H Muleshoe Isd Middle School 6 to 8 No No Sudan H S Sudan Isd High School 8 to 12 No No Sudan El Sudan Isd Primary School PK to 7 No No Springlake-Earth H S Springlake-Earth Isd High School 9 to 12 No No Springlake-Earth Elem/Middle School Springlake-Earth Isd Primary School PK to 8 No No Muleshoe H S Muleshoe Isd High School 9 to 12 No No Mary Deshazo El Muleshoe Isd Primary School 3 to 5 No No Littlefield Pri Littlefield Isd Primary School PK to 2 No No 1 2
Figure 24: Sudan-Amherst CCD, TX School Enrollment (2013) Enrollment Springlake-Earth H S Amherst School Sudan H S Whitharral School Sudan El Littlefield El Littlefield J H Springlake-Earth Elem/Middle School Mary Deshazo El Watson J H Webb El Muleshoe H S Littlefield H S Littlefield Pri Dillman El 0 500 1000 School Name Enrollment Springlake-Earth H S 100 Amherst School 161 Sudan H S 168 Whitharral School 193 Sudan El 282 Littlefield El 299 Littlefield J H 309 Springlake-Earth Elem/Middle School 315 Mary Deshazo El 326 Watson J H 327 Webb El 343 Muleshoe H S 358 Littlefield H S 374 Littlefield Pri 447 Dillman El 479 Enrollment
Figure 25: Student to Teacher Ratios (2013) - Low Scores Are Better Student to Teacher Ratio Springlake-Earth H S Amherst School Sudan H S Muleshoe H S Whitharral School Littlefield H S Watson J H Webb El Mary Deshazo El Springlake-Earth Elem/Middle School Dillman El Sudan El Littlefield J H Littlefield Pri Littlefield El 0 10 20 School Name Student to Teacher Ratio Springlake-Earth H S 7.3 Amherst School 8.2 Sudan H S 8.6 Muleshoe H S 10.5 Whitharral School 10.9 Littlefield H S 12.3 Watson J H 12.6 Webb El 14.2 Mary Deshazo El 14.2 Springlake-Earth Elem/Middle School 14.7 Dillman El 15 Sudan El 15.1 Littlefield J H 15.7 Littlefield Pri 16.4 Littlefield El 16.9 Student to Teacher Ratio
Figure 26: Sudan-Amherst CCD, TX School Racial Mix (2013) White Black Hispanic Asian Pacific Islander American Indian Two or More Races Amherst School Mary Deshazo El Dillman El Webb El Watson J H Littlefield El Muleshoe H S Littlefield Pri Littlefield J H Springlake-Earth Elem/Middle Sc… Littlefield H S Springlake-Earth H S Sudan El Sudan H S Whitharral School 0% 50% 100% School Name White Black Hispanic Asian Pacific Islander American Indian Two or More Races Amherst School 14.9% 6.2% 78.9% 0% 0% 0% 0% Mary Deshazo El 15.3% 0.3% 84% 0.3% 0% 0% 0% Dillman El 16.5% 0.2% 82.5% 0.6% 0% 0% 0.2% Webb El 16.9% 0.6% 81.9% 0% 0% 0.3% 0.3% Watson J H 17.1% 0% 82.6% 0.3% 0% 0% 0% Littlefield El 18.4% 8% 71.2% 0% 0% 0.3% 2% Muleshoe H S 20.7% 0% 78.8% 0.6% 0% 0% 0% Littlefield Pri 21% 6% 71.4% 0% 0% 0.2% 1.3% Littlefield J H 26.2% 8.1% 64.7% 0% 0% 0.3% 0.6% Springlake-Earth Elem/Middle School 29.2% 2.9% 67.6% 0% 0% 0.3% 0% Littlefield H S 32.9% 8% 57.5% 0% 0% 0.8% 0.8% Springlake-Earth H S 38% 2% 59% 0% 0% 0% 1% Sudan El 39.7% 3.5% 55.3% 0% 0% 0.4% 1.1% Sudan H S 45.8% 2.4% 51.2% 0% 0% 0% 0.6% Whitharral School 70.5% 0% 28% 0% 0% 0% 1.6% Two or More Races
Cities marked with an asterisk ("*") should resemble a city or town but do not have their own government (i.e. Mayor, City Council, etc.) These places should be recognizable by the local community but their boundaries have no legal status. Technically these include both Census Designated Places (CDP) and Census County Divisions (CCD) which are defined by the Census Bureau along with local authorities. (For more information, see: Census Designated Place or "CDP") and Census County Division "CCD".) For comparison purposes, the US national average and the state average value are provided. Additionally, the "Combined Statistical Area" or CSA is shown that is closest to the city, county, or zip code shown. A CSA is a large grouping of adjacent metropolitan areas that identified by the Census Bureau based on social and economic ties. (See: Combined Statistical Area ) Data sources - Mouse over icon in upper right corner of each chart for information.
| https://www.towncharts.com/Texas/Education/Sudan-Amherst-CCD-TX-Education-data.html |
Different Strokes: One Multi-Site WLAN Does Not Fit All
For the upcoming March 2010 Aberdeen benchmark report, Multi-Site and Campus-Area Wireless LANs: Advantages of the Centralized Approach, 163 organizations were surveyed regarding their use of multi-site and campus-area wireless LANs. Certain vertical sectors had an especially strong representation among respondents -- higher education, healthcare, hospitality and retail represented approximately 40 percent of the total respondent base. The pressures of these specific industry sectors differ, and this affects the strategies they choose in response.
Different Strokes: One Multi-Site WLAN Does Not Fit All
For the upcoming March 2010Aberdeenbenchmark report, Multi-Site and Campus-Area Wireless LANs: Advantages of the Centralized Approach, 163 organizations were surveyed regarding their use of multi-site and campus-area (“non-site-contiguous”) wireless LANs (WLANs).
Certain vertical sectors had an especially strong representation among respondents — higher education, healthcare, hospitality and retail represented approximately 40 percent of the total respondent base. The pressures of these specific industry sectors differ, and this affects the strategies they choose in response.
Mobility Drives Increasing WLAN Demand
One of the top pressures driving the integration of multi-site and campus-area wireless LANs was the increasing demand for WLAN coverage at all of the organization’s locations. This is driven in large part by the increasing demand for mobility overall; the 2009 Aberdeen benchmark report More Mobility — Less Budget: Enterprise Strategies in the Current Economic Downturnfound that 84 percent of organizations already had a mobile initiative in place, a rate that has grown consistently since 2006.
From November 2006 through December 2009, the percentage of respondents who had a mobility initiative in place increased 42 percent, while the percentage of those who had no plans for mobility decreased by 93 percent. This demand for mobility, with its accompanying need for wireless connectivity, is the primary force driving the increased demand for WLAN coverage among all respondents.
Top Sector Pressures
Survey respondents were asked to rank-order the top pressures driving the integration of their multi-site or campus-area WLANs.
The pressure to increase staff productivity correlates with prior Aberdeen research that increased mobility results in increased productivity, while the demand for improved WLAN performance illustrates an increasing reliance on the WLAN as core network infrastructure versus simply a “network of convenience.”
There is an inherent logic to the higher level of interest in multi-location WLANs by sector end-users:
Higher education.The (ever-changing) demographics of the student population are creating a demand for full-speed wireless access throughout every corner of the institution, both indoors and out. Every mobile device, smartphone, game machine and media player is a potential consumer of mobile broadband access.
Healthcare (health/medical).Hospitals and medical campuses have quickly adopted wireless technology to keep critical personnel in constant touch, and to track the location of valuable equipment. The move to digital medical records places new security demands and compliance requirements on mobile access to healthcare data.
Hospitality/retail.Although these two sectors do have differentiated needs, they share certain attributes: Both are typically commercial chain or franchise business models that were relatively early adopters of WLAN — hospitality for guest services purposes, retail for mobile point-of-sale and store inventory devices — and both are ripe for system upgrades because of their system longevity. Both are also typically light in local IT support resources at remote locations.
Again, an increase in demand for WLAN coverage at all sites, along with improving WLAN performance, is seen as a top pressure among all respondents. Higher education shows a larger percentage of respondents who chose the coverage issue as a top pressure, corresponding to student demands for constant connectivity in every corner of campus. Healthcare is slightly higher than all respondents, whereas there is considerably less demand in hospitality and retail. Coverage issues are less of a pressure in this sector because they typically have older-generation WLAN infrastructure and their coverage issues have typically already been addressed.
In fact, hospitality and retail experience divergent pressures from all respondents, as well as the other sectors. More of them experience increased demand for improved WLAN performance because their older-generation infrastructure (typically WiFi 802.11b or 802.11a ) is not delivering the performance expected by their guests, customers and staff, many of whom experience a higher level of wireless performance at home or at work.
Higher education respondents selected the same pressure for a similar reason: Students who are Web surfing, downloading video, playing online games — and even studying — are used to uncompromised bandwidth at home, and they carry that expectation forward as a demand at school.
Healthcare feels a markedly higher pressure to secure WLANs from unauthorized access, based on the need to comply with industry and governmental regulations relating to Personally Identifiable Information (PII) such as contact information and social security numbers, medical records protected by the Health Insurance Portability and Accountability Act (HIPAA), and other sensitive medical data. Higher education also feels this pressure, but to a lesser degree, primarily driven by PII compliance, as well the need to protect student academic records.
Hospitality and retail have another strong outlier in their prioritization of the pressure of telecommunications services cost reduction. This is driven in part by their common business structure — typically a franchise or chain operation with central executive, administration and IT services provided by a remote headquarters location. This typically implies executives and other employees who travel extensively from site to site, who therefore incur significant roaming charges for carrier wireless services. This cost is particularly onerous for those who roam across international borders.
Dual-mode smartphones (preconfigured for both WLAN and carrier service connectivity), when enabled for wireless Voice-over-IP (VoIP) calls can dramatically reduce carrier charges by routing all incoming and outgoing calls via the WLAN instead of via the carrier. It’s a logical conclusion that headquarters’ operations would look to leverage the in-place WLAN for voice calls as a way to lower telecommunications expense.
Summary Findings
As in the idiom “different strokes for different folks,” one size does not fit all when it comes to understanding the main pressures and strategies driving multi-site and campus-area WLAN integration. The key to understanding market sector differentials lies in identifying the fundamental behavioral distinctions among each of the market sector constituencies.
In the case of higher education, the high-bandwidth wireless connectivity expectations of the student population are driving the need for speed and coverage. In the healthcare sector, the life and death nature of transactions is driving the delivery of potentially life-saving data and voice-rich communications to every corner of the institution. This, combined with the overriding need to secure patient medical and personal data is driving network upgrades for maximum throughput and security.
Hospitality and retail are responding to different pressures. Their aging ‘first-generation’ wireless infrastructures are underperforming, and straining their limited on-site IT resources. They need to address mounting complaints among hotel guests for faster and better wireless access, while they address corporate demands to leverage the wireless infrastructure to lower their overall telecom costs.
Each of the sectors rated the action of upgrading WLAN hardware among its top three priorities. This coincides with the ratification of the 802.11n standard by theIEEEin September 2009, and may signal the unleashing of a new inflection point of increased adoption of 802.11n by the broader market.
Andrew Borg
is a senior research analyst with the wireless and mobility practice at the Aberdeen Group.
Gaurav Patil
is a research associate with Aberdeen’s communications group.
| https://www.crmbuyer.com/story/different-strokes-one-multi-site-wlan-does-not-fit-all-69683.html?cat_id=156 |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Conference Paper
Themes
Assistive & Accessible Technology
Culture and Participation
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi,Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, Joyce Olenja
We present the findings of a case study of mobile technology use by People with Visual Impairment (VIPs) in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
CHI '20: Proceedings of the 2020 CHI Conference; 2020
Abstract
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Living in an informal settlement with a visual impairment can be very challenging resulting in social exclusion. Mobile phones have been shown to be hugely beneficial to people with sight loss in formal and high-income settings. However, little is known about whether these results hold true for people with visual impairment (VIPs) in informal settlements. We present the findings of a case study of mobile technology use by VIPs in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi, Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, and Joyce Olenja. 2020. The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya. In Proceedings of the 2020 CHI Conference on Human Factors in Computing Systems (CHI '20). Association for Computing Machinery, New York, NY, USA, 1–15.https://doi.org/10.1145/331383...
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Editorial
Themes
Culture and Participation
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ikenna D Ebueny, Emma M Smith,Catherine Holloway, Rune Jensen, Lucía D'Arino, Malcolm MacLachlan
Social empathy is ‘the ability to more deeply understand people by perceiving or experiencing their life situations and as a result gain insight into structural inequalities and disparities’. Social empathy comprises three elements: individual empathy, contextual understanding and social responsibility. COVID-19 has created a population-wide experience of exclusion that is only usually experienced by subgroups of the general population. Notably, persons with disability, in their everyday lives, commonly experience many of the phenomena that have only recently been experienced by members of the general population. COVID-19 has conferred new experiential knowledgeon all of us. We have a rare opportunity to understand and better the lives of persons with disabilities for whom some aspects of the COVID- 19 experience are enduring. This allows us greater understanding of the importance of implementing in full a social and human rights model of disability, as outlined in the UNCRPD.
BMJ Global Health; 2020
Abstract
COVID-19 as social disability: the opportunity of social empathy for empowerment
COVID-19 has conferred new experiential knowledge on society and a rare opportunity to better understand the social model of disability and to improve the lives of persons with disabilities.
The COVID-19 experience may offer contextual knowledge of the prepandemic lives of persons with disabilities and foster greater social awareness, responsibility and opportunities for change towards a more inclusive society.
Information, family and social relationships, health protection and healthcare, education, transport and employment should be accessible for all groups of the population. The means must be developed and deployed to ensure equity – the deployment of resources so that people with different types of needs have the same opportunities for living good lives in inclusive communities.
We have learnt from COVID-19 that inclusive healthcare and universal access should be the new normal, that its provision as a social good is both unifying and empowering for society as a whole.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ebuenyi ID, Smith EM, Holloway C , et alCOVID-19 as social disability: the opportunity of social empathy for empowerment BMJ Global Health2020;5:e003039.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Social Justice
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi,Catherine Holloway&Victoria Austin
While the inadequacies of our existing assistive technology systems, policies, and services have been highlighted by the acute and rapidly changing nature of the COVID-19 pandemic, these failures are also present and important during non-crisis times. Each of these actions, taken together, will not only address needs for more robust and resilient systems for future crises, but also the day-to-day needs of all assistive technology users. We have a responsibility as a global community, and within our respective countries, to address these inadequacies now to ensure an inclusive future.
Disability & Society; 2020
Abstract
Developing inclusive and resilient systems: COVID-19 and assistive technology
Assistive technology is a critical component of maintaining health, wellbeing, and the realization of rights for persons with disabilities. Assistive technologies, and their associated services, are also paramount to ensuring individuals with functional limitations have access to important health and social service information, particularly during a pandemic where they may be at higher risk than the general population. Social isolation and physical distancing have further marginalized many within this population. We have an opportunity to learn from the COVID-19response to develop more inclusive and resilient systems that will serve people with disabilities more effectively in the future. In this Current Issues piece, we present a starting point for discussion, based on our experiences working to promote access to assistive technologies through inclusive and sustainable systems and policies.
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi, Catherine Holloway & Victoria Austin (2021) Developing inclusive and resilient systems: COVID-19 and assistive technology, Disability & Society, 36:1, 151-154, DOI:10.1080/09687599.2020.1829558
Developing inclusive and resilient systems: COVID-19 and assistive technology
Type
Conference Paper
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez,Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney,Catherine Holloway
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes.
ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020
Abstract
Disability design and innovation in computing research in low resource settings
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes. In short, researchers rarely examine what was challenging in the process of collaboration. We present reflections from the field across four studies. Our contributions are: (1) an overview of past work in computing with a focus on disability in low resource settings and (2) learnings and recommendations from four collaborative projects in Uganda, Jordan and Kenya over the last two years, that are relevant for future HCI studies in low resource settings with communities with disabilities. We do this through a lens of Disability Interaction and ICT4D.
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez, Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney, and Catherine Holloway. 2020. Disability design and innovation in computing research in low resource settings. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 11, 1–7.https://doi.org/10.1145/337362...
Type
Editorial
Research Group
Social Justice
Assistive Technology (AT), for What?
Vicki Austin, Catherine Holloway
This year (2022) has seen the publication of the World’s first Global Report on Assistive Technology (GReAT) [1]. This completes almost a decade of work to ensure assistive technology (AT) access is a core development issue. The lack of access to assistive products (APs), such as wheelchairs, hearing aids, and eyeglasses, as well as less well-referenced products such as incontinence pads, mobile phone applications, or walking sticks, affects as many as 2.5 billion people globally. Furthermore, the provision of APs would reap a 1:9 return on investment [2]. This could result in a family in need netting (or living without) over GBP 100,000 in their lifetime [2] or more, if we count dynamic overspills in the economy such as employment of assistive technology services and manufacturing of devices [3].
Societies; 2021
Abstract
Assistive Technology (AT), for What?
Amartya Sen’s seminal Tanner lecture: Equality of What?began a contestation on social justice and human wellbeing that saw a new human development paradigm emerge—the capability approach (CA)—which has been influential ever since. Following interviews with leading global assistive technology (AT) stakeholders, and users, this paper takes inspiration from Sen’s core question and posits, AT for what?arguing that AT should be understood as a mechanism to achieve the things that AT users’ value. Significantly, our research found no commonly agreed operational global framework for (disability) justice within which leading AT stakeholders were operating. Instead, actors were loosely aligned through funding priorities and the CRPD. We suggest that this raises the possibility for (welcome and needed) incoming actors to diverge from efficiently designed collective action, due to perverse incentives enabled by unanchored interventions. The Global Report on Assistive Technology (GReAT) helps, greatly! However, we find there are still vital gaps in coordination; as technology advances, and AT proliferates, no longer can the device-plus-service approach suffice. Rather, those of us interested in human flourishing might explore locating AT access within an operational global framework for disability justice, which recognizes AT as a mechanism to achieve broader aims, linked to people’s capabilities to choose what they can do and be.
Cite
Assistive Technology (AT), for What?
Austin, V.; Holloway, C. Assistive Technology (AT), for What? Societies2022, 12, 169.https://doi.org/10.3390/soc120...
Assistive Technology (AT), for What?
Type
Article
Themes
Assistive & Accessible Technology
These tools help visually impaired scientists read data and journals
Alla Katsnelson
This article was featured in Nature and discusses tools that help visually impaired scientists read data and Journals. Innovation Manager, Daniel Hajas, was interviewed as part of this piece and highlights the need for an ecosystem approach, and access to data / visualisations for blind members of the research and science community.
Nature; 2023
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
The Digital and Assistive Technologies for Ageing initiative: learning from the GATE initiative
Chapal Khasnabis,Catherine Holloway, Malcolm MacLachlan
We are now in an era of assistive care and assistive living—whereby many people, of all ages, in good health, and those who are more frail, or with cognitive or functional impairments, are using a broad range of technologies to assist and enhance their daily living. Assistive living 1is becoming an important part of population health and rehabilitation, which can help to maximise an individual's abilities, regardless of age or functional capacity. This encouraging shift in ethos has been strengthened by the response to the COVID-19 pandemic, in which a plethora of digital and remote technologies have been used.
The Lancet; 2020
Type
Editorial
Themes
Assistive & Accessible Technology
Culture and Participation
Research Group
Social Justice
Critical Junctures in Assistive Technology and Disability Inclusion
Dr Maria Kett,Catherine Holloway,Vicki Austin,Dr Maria Kett
It is clear from the events of the last 18 months that while technology has a huge potential for transforming the way we live and work, the entire ecosystem—from manufacturing to the supply chain—is vulnerable to the vagaries of that ecosystem, as well as having the potential to exacerbate new and existing inequalities [1]. Nowhere has this been more apparent than in the lives of people with disabilities, who make up around 15% of the world’s population and already face barriers to accessing education, employment, healthcare and other services [2]. Some of these barriers are a result of unequal access and opportunities. However, there is a growing movement to better understand how assistive technology systems and services can be designed to enable more robust and equitable access for all. As part of this growing movement, the Paralympic Games in Tokyo this autumn saw the launch of a new global campaign to transform the lives of the world’s 1.2 bn persons with disabilities: the ‘WeThe15’ campaign reached more than 4.5 billion people through its marketing and stands ready to be the biggest of its kind in history. Next year, the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF), AT scale and GDI Hub will publish the first World Report on Access to Assistive Technology, which will include research from the £20 million, UK Aid funded, GDI Hub-led, programme, AT2030. Ahead of that, in this Special Issue, we focus on how some events and situations—as diverse as the coronavirus pandemic and the Paralympics—can act as ‘critical junctures’ that can enable a rethink of the status quo to facilitate and promote change.
Sustainability; 2021
Critical Junctures in Assistive Technology and Disability Inclusion
Kett, M.; Holloway, C.; Austin, V. Critical Junctures in Assistive Technology and Disability Inclusion. Sustainability2021, 13, 12744.https://doi.org/10.3390/su1322...
Critical Junctures in Assistive Technology and Disability Inclusion
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Introduction to the companion papers to the global report on assistive technology
Johan Borg, Wei Zhang, Emma M. Smith,Cathy Holloway
GReAT, but do we care?
If accessible, assistive technology would be life changing for a billion people across the world today – and two billion people in 2050 (WHO,2018). It would make the difference between independence and dependence, inclusion and exclusion, life and death. It holds the potential to improve and transform health, education, livelihood and social participation; fundamental human rights everyone is entitled to. And if we are lucky to grow old, the chances are that we all would use assistive technology by then. But do we care?
Assistive Technology, The Official Journal of RESNA; 2021
Introduction to the companion papers to the global report on assistive technology
Johan Borg, Wei Zhang, Emma M. Smith & Cathy Holloway (2021) Introduction to the companion papers to the global report on assistive technology, Assistive Technology, 33:sup1, 1-2, DOI:10.1080/10400435.2021.2003658
Type
Conference Paper
Themes
Assistive & Accessible Technology
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Barbareschi, G; Daymond, S; Honeywill, J; Singh, A; Noble, D; Mbugua, N; Harris, I;Austin, V;Holloway, C
The World Health Organization (WHO) defines Assistive Technology (AT) as “an umbrella term covering the systems and services related to the delivery of assistive products and services” [6]. This definition highlights how AT encompasses not only the physical and digital products used by millions of persons with disabilities (PWDs) worldwide, but also the systems and services that accompany the provision of these devices [78].
ASSETS '20: The 22nd International ACM SIGACCESS Conference on Computers and Accessibility.; 2020
Abstract
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Innovations in the field of assistive technology are usually evaluated based on practical considerations related to their ability to perform certain functions. However, social and emotional aspects play a huge role in how people with disabilities interact with assistive products and services. Over a five months period, we tested an innovative wheelchair service provision model that leverages 3D printing and Computer Aided Design to provide bespoke wheelchairs in Kenya. The study involved eight expert wheelchair users and five healthcare professionals who routinely provide wheelchair services in their community. Results from the study show that both users and providers attributed great value to both the novel service delivery model and the wheelchairs produced as part of the study. The reasons for their appreciation went far beyond the practical considerations and were rooted in the fact that the service delivery model and the wheelchairs promoted core values of agency, empowerment and self-expression.
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Type
Conference Paper
Themes
Assistive & Accessible Technology
Culture and Participation
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
Nusrat Jahan,Giulia Barbareschi, Clara Aranda Jan, Charles Musungu Mutuku, Naemur Rahman,Victoria Austin,Catherine Holloway
Worldwide it is estimated that there are over a billion people who live with some form of disability[1]. Approximately 80% of people with disabilities live in low-and-middle income countries (LMICs). The combination of an inaccessible environment compounded by socio-economic factors such as poverty and stigma, makes it more likely for people with disabilities to be marginalised and excluded from society[1]. Assistive Technologies (ATs) are known to bridge the accessibility gaps and allow for greater social inclusion. However, there is a lack of adequate access to ATs in LMICs, combined with often poorly designed services, which only magnifies these challenges, thus limiting the opportunities for persons with disabilities to live an independent life[2]. Despite the importance of AT, access to AT globally is inadequate with only 10 percent of those in need having access to the ATs that they need[2].
2020 IEEE Global Humanitarian Technology Conference
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Abstract
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
Globally, mobile technology plays a significant role connecting and supporting people with disabilities. However, there has been limited research focused on understanding the impact of mobile technology in the lives of persons with disabilities in low or middle- income countries. This paper presents the findings of a participatory photovoice study looking at the role that mobile phones play in the daily lives of 16 persons with disabilities in Kenya and Bangladesh. Participants used a combination of pictures and voice recordings to capture their own stories and illustrate the impact that mobile phone use has on their lives. Through thematic analysis, we categorized the benefits of mobile phones captured by participants as 1) Improved social connection; 2) Increased independence and 3) Access to opportunities. While mobile phones are ubiquitously used for communication, for persons with disabilities they become essential assistive technologies that bridge barriers to opportunities which are not accessible otherwise. Our paper adds evidence to the need for mobile phones for persons with disabilities to enable communication and connectivity in support of development.
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
N. Jahan et al., "Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh," 2020 IEEE Global Humanitarian Technology Conference (GHTC), Seattle, WA, USA, 2020, pp. 1-8, doi: 10.1109/GHTC46280.2020.9342934.
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
Type
Conference Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
A Preliminary Study to Understand How Mainstream Accessibility and Digital Assistive Technologies Reaches People in Lower- and Middle-Income Countries
Tigmanshu Bhatnagar, George Torrens, Ben Oldfrey, Priya MorjariaFelipe Ramos Barajas, Katherine PerryandCatherine Holloway
Access to information on digital platforms not only facilitates education, employment, entertainment, social interaction but also facilitates critical governmental services, ecommerce, healthcare services and entrepreneurship [1]. Article 9 of United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) enforces its signatories to commit to provide full accessibility to every citizen of the nation [2]. This has helped to spearhead accessibility directives such as the European Accessibility Act [3] that aims to improve the functioning of markets for accessible products and services. Such directives contribute to ensure that mainstream digital technologies (smartphones, computers etc.) are accessible for everyone and without being socially remarkable, they are able to assist in daily living. Additionally, there is evidence that improving access in mainstream technologies improves product experience and usability for everyone [4]. However, mainstream access has not been fully realized, leading to inferior opportunities for people with disabilities, a disparity which is more prominent in lower and middle-income countries [5].
RESNA Annual Conference; 2021
A Preliminary Study to Understand How Mainstream Accessibility and Digital Assistive Technologies Reaches People in Lower- and Middle-Income Countries
Type
Toolkit
Innovate Now Toolkit
As an entrepreneur, learning how to solve problems by creating and experimenting with different strategies is a core pillar of the entrepreneurial mindset you need to succeed. However, there’s rarely a single correct way to solve problems as an entrepreneur, so you need to learn how to create and compare different solutions.
The open entrepreneurship toolkit is a set of learning materials that can help you and your team do just that. Covering the domains of user, product, market and business development, the set of cards have been designed to be used by two or more group members to actively experiment with different solutions.
Innovate Now
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Troy Bodkin
Doctoral Thesis. This work is one of four multidisciplinary research studies conducted by members of this research cluster, focusing on the area of Computer Aided Design (CAD) for improving the interface with Additive Manufacture (AM) to solve some of the challenges presented with improving prosthetic socket design, with an aim to improve and streamline the process to enable the involvement of clinicians and patients in the design process.
Loughborough University
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Abstract
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
For many years, the biggest issue that causes discomfort and hygiene issues for patients with lower limb amputations have been the interface between body and prosthetic, the socket. Often made of an inflexible, solid polymer that does not allow the residual limb to breathe or perspire and with no consideration for the changes in size and shape of the human body caused by changes in temperature or environment, inflammation, irritation and discomfort often cause reduced usage or outright rejection of the prosthetic by the patient in their day to day lives. To address these issues and move towards a future of improved quality of life for patients who suffer amputations, Loughborough University formed the Next Generation Prosthetics research cluster. This work is one of four multidisciplinary research studies conducted by members of this research cluster, focusing on the area of Computer Aided Design (CAD) for improving the interface with Additive Manufacture (AM) to solve some of the challenges presented with improving prosthetic socket design, with an aim to improve and streamline the process to enable the involvement of clinicians and patients in the design process. The research presented in this thesis is based on three primary studies. The first study involved the conception of a CAD criteria, deciding what features are needed to represent the various properties the future socket outlined by the research cluster needs. These criteria were then used for testing three CAD systems, one each from the Parametric, Non Uniform Rational Basis Spline (NURBS) and Polygon archetypes respectively. The result of these tests led to the creation of a hybrid control workflow, used as the basis for finding improvements. The second study explored emerging CAD solutions, various new systems or plug-ins that had opportunities to improve the control model. These solutions were tested individually in areas where they could improve the workflow, and the successful solutions were added to the hybrid workflow to improve and reduce the workflow further. The final study involved taking the knowledge gained from the literature and the first two studies in order to theorise how an ideal CAD system for producing future prosthetic sockets would work, with considerations for user interface issues as well as background CAD applications. The third study was then used to inform the final deliverable of this research, a software design specification that defines how the system would work. This specification was written as a challenge to the CAD community, hoping to inform and aid future advancements in CAD software. As a final stage of research validation, a number of members of the CAD community were contacted and interviewed about their feelings of the work produced and their feedback was taken in order to inform future research in this area.
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Bodkin, Troy L. (2017): Specifying a hybrid, multiple material CAD system for next-generation prosthetic design. Loughborough University. Thesis.https://hdl.handle.net/2134/25...;
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Giulia Barbareschi
Doctoral Thesis. This thesis makes two contributions to facilitate wheelchair users’ engagement in the participatory design process for ATs, while being mindful of the burden of participation. The first contribution is a framework that provides a modular structure guiding the participatory design process from initial problem identification and analysis to facilitating collaborations between wheelchair users and designers. The framework identifies four factors determining the need and adoption process for ATs: (i) People focuses on the target population, (ii) Person includes personal characteristics, (iii) Activity refers to the challenges associated with the task, and (iv) Context encompasses the effect of the environment in which the activity takes place. The second contribution constitutes a rich picture of personal and external elements influencing real world wheelchair transfers that emerged from four studies carried out to investigate the effect of the framework factors on the design process for ATs.
UCL (University College London)
Abstract
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Transferring independently to and from their wheelchair is an essential routine task for many wheelchair users but it can be physically demanding and can lead to falls and upper limb injuries that reduce the person’s independence. New assistive technologies (ATs) that facilitate the performance of wheelchair transfers have the potential to allow wheelchair users to gain further independence. To ensure that users’ needs are addressed by ATs, the active involvement of wheelchair users in the process of design and development is critical. However, participation can be burdensome for many wheelchair users as design processes where users are directly involved often require prolonged engagement. This thesis makes two contributions to facilitate wheelchair users’ engagement in the participatory design process for ATs, while being mindful of the burden of participation. The first contribution is a framework that provides a modular structure guiding the participatory design process from initial problem identification and analysis to facilitating collaborations between wheelchair users and designers. The framework identifies four factors determining the need and adoption process for ATs: (i) People focuses on the target population, (ii) Person includes personal characteristics, (iii) Activity refers to the challenges associated with the task, and (iv) Context encompasses the effect of the environment in which the activity takes place. The second contribution constitutes a rich picture of personal and external elements influencing real world wheelchair transfers that emerged from four studies carried out to investigate the effect of the framework factors on the design process for ATs. A related outcome based on these contributions is a framing document to share knowledge between wheelchair users and designers to provide focus and promote an equal collaboration among participants.
Cite
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Barbareschi, Giulia. “YouTransfer, YouDesign : a Participatory Approach to Design Assistive Technology for Wheelchair Transfers / Giulia Barbareschi.” Thesis (Ph.D.)--University College London, 2018., 2018. Print.
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Understanding wrist splint user needs and personalisation through codesign
Charlotte Pyatt
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy at Loughborough University.
Loughborough University
Abstract
Understanding wrist splint user needs and personalisation through codesign
Wrist splints are a common treatment for rheumatoid arthritis, however their effectiveness is compromised by patients not wearing splints as often as prescribed. Previous research has identified a number of reasons for non-compliance, but typically lacks insights that could lead to improved splint design.
This thesis investigates the motivators for patients to wear and not wear their wrist splints and, the impact of personalisation of splint appearance on patient wear. The work is based on the premise that digital design and manufacturing processes, such as Computer-Aided Design (CAD) and 3D Printing, can produce bespoke splints on demand.
The research begins with a literature review across the core areas of: splinting, additive manufacture, product appearance and personalisation. This literature review identifies gaps in knowledge from which research questions are established for the work.
The research employs a qualitative, generative design research approach and, follows a codesign framework employing telling, making and enacting tools. The thesis is made up of three studies. The first study is a sensitisation study and uses design probes to prepare the participants for the research and begin exploring the problem space. The second is a comprehensive study into participants splint wear behaviour and uses context mapping and scenario picture card tools to investigate the motivators for participants to wear and not wear wrist splints, along with positive and negative outcomes or wearing/not wearing splints. The final study uses a personalisation toolkit to elicit patient needs for a future wrist splint design and investigate self-reported expectations regarding compliance of patients who used the toolkit.
The research finds that patient compliance is affected by practical and aesthetic limitations of current splints. It identifies 4 motivating factors to wear a splint and 10 motivating factors to not wear a splint. Additionally, it identifies 6 positive outcomes of wearing splints, 6 negative outcomes of wearing splints, 3 positive outcomes of not wearing splints and 3 negative outcomes of not wearing splints. Requirements for an improved splint design are established and form the basis of the design for a prototype personalisation toolkit. Testing of this toolkit reveals that patients are keen to own more than one splint and personalise splints to match the scenario in which it is to be worn. Patients reported that they expected to be more compliant with a personalised splint when compared to their current splint.
Understanding wrist splint user needs and personalisation through codesign
Pyatt, Charlotte (2018): Understanding wrist splint user needs and personalisation through codesign. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Understanding wrist splint user needs and personalisation through codesign
Type
PhD
Themes
Assistive & Accessible Technology
Shared Control for Wheelchair Interfaces
Dr Chinemelu Ejiamatu Muoma Ezeh
Doctoral Thesis. Independent mobility is fundamental to the quality of life of people with impairment. Most people with severe mobility impairments, whether congenital, e.g., from cerebral palsy, or acquired, e.g., from spinal cord injury, are prescribed a wheelchair. A small yet significant number of people are unable to use a typical powered wheelchair controlled with a joystick. Instead, some of these people require alternative interfaces such as a head- array or Sip/Puff switch to drive their powered wheelchairs. However, these alternative interfaces do not work for everyone and often cause frustration, fatigue and collisions. This thesis develops a novel technique to help improve the usability of some of these alternative interfaces, in particular, the head-array and Sip/Puff switch.
UCL (University College London)
Abstract
Shared Control for Wheelchair Interfaces
Independent mobility is fundamental to the quality of life of people with impairment. Most people with severe mobility impairments, whether congenital, e.g., from cerebral palsy, or acquired, e.g., from spinal cord injury, are prescribed a wheelchair. A small yet significant number of people are unable to use a typical powered wheelchair controlled with a joystick. Instead, some of these people require alternative interfaces such as a head- array or Sip/Puff switch to drive their powered wheelchairs. However, these alternative interfaces do not work for everyone and often cause frustration, fatigue and collisions. This thesis develops a novel technique to help improve the usability of some of these alternative interfaces, in particular, the head-array and Sip/Puff switch. Control is shared between a powered wheelchair user, using an alternative interface and a pow- ered wheelchair fitted with sensors. This shared control then produces a resulting motion that is close to what the user desires to do but a motion that is also safe. A path planning algorithm on the wheelchair is implemented using techniques in mo- bile robotics. Afterwards, the output of the path planning algorithm and the user’s com- mand are both modelled as random variables. These random variables are then blended in a joint probability distribution where the final velocity to the wheelchair is the one that maximises the joint probability distribution. The performance of the probabilistic approach to blending the user’s inputs with the output of a path planner, is benchmarked against the most common form of shared control called linear blending. The benchmarking consists of several experiments with end users both in a simulated world and in the real-world. The thesis concludes that probabilistic shared control provides safer motion compared with the traditional shared control for difficult tasks and hard-to-use interfaces.
Shared Control for Wheelchair Interfaces
Ezeh, Chinemelu Ejiamatu Muoma. Shared Control for Wheelchair Interfaces. UCL (University College London), 2018. Print.
Shared Control for Wheelchair Interfaces
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Materials For Facial Prostheses In Resource Limited Countries
Sophia Esther Liiba Tetteh
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University
Loughborough University
Abstract
Materials For Facial Prostheses In Resource Limited Countries
Facial prostheses are artificial devices that replace a missing body part in the facial and neck regions of the body. Defects or deformities in these regions can lead to functional deficiencies; social and psychological effects in addition to cosmetic defects. Restoration or rehabilitation in resource limited countries is usually provided by charities and organisations volunteering assistance overseas, with some training of local staff in the fabrication of these prostheses. Furthermore, these countries typically lack technical knowhow and trained personnel. In industrialised nations maxillofacial prosthetics has developed into a sophisticated medical speciality requiring highly skilled staff and expensive facilities. In resource limited countries surgical procedures may be an option for rehabilitation of these deformities/defects however, they tend to be unavailable or unaffordable and donated prostheses are not suitable. Hence, this research explores, from first principles, the appropriate and affordable local provision of maxillofacial prostheses in resource constrained regions. The investigation provides knowledge on identifying requirements for resource limited areas, resulting in the creation of a guideline constituting priorities, requirements and specifications. It further explores the viability of potentially cheaper, locally available candidate materials via weathering and antimicrobial methods in ascertaining material longevity.
Materials For Facial Prostheses In Resource Limited Countries
Tetteh, Sophia (2019): Materials for facial prostheses in resource-limited countries. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Materials For Facial Prostheses In Resource Limited Countries
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Rhys James Williams
Thesis: Firstly, the research provides a methodological contribution showing how to conduct mixed-methods research to obtain rich insights into complex prosthesis phenomena. Secondly, the research highlights the need to appreciate psychological and contextual factors when researching prosthesis wearer thermal comfort. The research contributions are also converted into an implication for prosthesis design. The concept of 'regaining control' to psychologically mitigate thermal discomfort could be incorporated into technologies by using 'on-demand' thermal discomfort relief, rather than 'always-on' solutions, as have been created in the past.
UCL, ProQuest Dissertations Publishing
Abstract
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Amongst lower-limb prosthesis wearers, thermal discomfort is a common problem with an estimated prevalence of more than 50%. Overheating does not just create discomfort to the user, but it has been linked to excessive sweating, skin damage caused by a moist environment and friction. Due to impermeable prosthetic components and a warm moist environment, minor skin damage can result in skin infections that can lead to prosthesis cessation, increased social anxiety, isolation and depression. Despite the seriousness of thermal discomfort, few studies explore the issue, with research predominantly constrained to controlled laboratory scenarios, with only one out of laboratory study. In this thesis, studies investigate how thermal discomfort arises and what are the consequences of thermal discomfort for lower-limb prosthesis wearers. Research studies are designed around the principles of presenting lived experiences of the phenomenon and conducting research in the context of participants' real-life activities. A design exploration chapter investigates modifying liner materials and design to create a passive solution to thermal discomfort. However, this approach was found to be ineffective and unfeasible. Study 1 presents a qualitative study which investigates the user experience of a prosthesis, thermal discomfort and related consequences. Study 2 explores limb temperature of male amputees inside and outside the laboratory, with the latter also collecting perceived thermal comfort (PTC) data. Finally, Study 3 investigates thermal discomfort in the real-world and tracks limb temperature, ambient conditions, activities, and experience sampling of PTC. While there were no apparent relationships presented in sensor data, qualitative data revealed that in situations where prosthesis wearers perceived a lack of control, thermal discomfort seemed to be worse. When combined, the studies create two knowledge contributions. Firstly, the research provides a methodological contribution showing how to conduct mixed-methods research to obtain rich insights into complex prosthesis phenomena. Secondly, the research highlights the need to appreciate psychological and contextual factors when researching prosthesis wearer thermal comfort. The research contributions are also converted into an implication for prosthesis design. The concept of 'regaining control' to psychologically mitigate thermal discomfort could be incorporated into technologies by using 'on-demand' thermal discomfort relief, rather than 'always-on' solutions, as have been created in the past.
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Williams, Rhys James. “Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers.” ProQuest Dissertations Publishing, 2020. Print.
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Design rules for additively-manufactured wrist splints
Sarah Kelly
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University.
Loughborough University
Abstract
Design rules for additively-manufactured wrist splints
Additive Manufacturing (AM) often known by the term three-dimensional printing (3DP) has been acknowledged as a potential manufacturing revolution. AM has many advantages over conventional manufacturing techniques; AM techniques manufacture through the addition of material - rather than traditional machining or moulding methods. AM negates the need for tooling, enabling cost-effective low-volume production in high-wage economies and the design & production of geometries that cannot be made by other means. In addition, the removal of tooling and the potential to grow components and products layer-by-layer means that we can produce more from less in terms of more efficient use of raw materials and energy or by making multifunctional components and products. The proposed Centre for Doctoral Training (CDT) in Additive Manufacturing and 3D Printing has the vision of training the next generation of leaders, scientists and engineers in this diverse and multi-disciplinary field. As AM is so new current training programmes are not aligned with the potential for manufacturing and generally concentrate on the teaching of Rapid Prototyping principles, and whilst this can be useful background knowledge, the skills and requirements of using this concept for manufacturing are very different. This CDT will be training cohorts of students in all of the basic aspects of AM, from design and materials through to processes and the implementation of these systems for manufacturing high value goods and services. The CDT will also offer specialist training on aspects at the forefront of AM research, for example metallic, medical and multi-functional AM considerations. This means that the cohorts graduating from the CDT will have the background knowledge to proliferate throughout industry and the specialist knowledge to become leaders in their fields, broadening out the reach and appeal of AM as a manufacturing technology and embedding this disruptive technology in company thinking. In order to give the cohorts the best view of AM, these students will be taken on study tours in Europe and the USA, the two main research powerhouses of AM, to learn from their international colleagues and see businesses that use AM on a daily basis. One of the aims of the CDT in AM is to educate and attract students from complementary basic science, whether this be chemistry, physics or biology. This is because AM is a fast moving area. The benefits of having a CDT in AM and coupling with students who have a more fundamental science base are essential to ensure innovation & timeliness to maintain the UK's leading position. AM is a disruptive technology to a number of industrial sectors, yet the CDTs industrial supporters, who represent a breadth of industrial end-users, welcome this disruption as the potential business benefits are significant. Growing on this industry foresight, the CDT will work in key markets with our supporters to ensure that AM is positioned to provide a real and lasting contribution & impact to UK manufacturing and provide economic stability and growth. This contribution will provide societal benefits to UK citizens through the generation of wealth and employment from high value manufacturing activities in the UK.
Design rules for additively-manufactured wrist splints
Kelly, Sarah (2020): Design rules for additively-manufactured wrist splints. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Type
PhD
Themes
Assistive & Accessible Technology
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Anna Vlachaki
The literature shows that research into the aesthetic aspects of prostheses is limited. Although there are suggestions that prostheses with high levels of emotionally-driven design may improve users’ well-being, they are based only on theoretical findings. Therefore, in this thesis the effects of emotionally-driven prostheses on users’ lives and society’s attitudes were explored, with respect to culture and more specifically, the theories of individualism/ collectivism. In order to investigate the effects of culture, the research was conducted in two countries with different cultures; the UK (individualistic) and Greece (collectivistic). The thesis began with a literature review across three core areas: user, product and environment, and revealed the importance of investigating an additional area; that of prosthetists. The research employed a qualitative approach and consisted of four studies.
Loughborough University
Abstract
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
The literature shows that research into the aesthetic aspects of prostheses is limited. Although there are suggestions that prostheses with high levels of emotionally-driven design may improve users’ well-being, they are based only on theoretical findings. Therefore, in this thesis, the effects of emotionally-driven prostheses on users’ lives and society’s attitudes were explored, with respect to culture and more specifically, the theories of individualism/ collectivism. In order to investigate the effects of culture, the research was conducted in two countries with different cultures; the UK (individualistic) and Greece (collectivistic). The thesis began with a literature review across three core areas: user, product and environment, and revealed the importance of investigating an additional area; that of prosthetists. The research employed a qualitative approach and consisted of four studies. Study I was an online questionnaire to explore users’ preferences towards prostheses, with respect to their culture. Study II consisted of semi-structured interviews and informational probes to comprehend the role of prostheses on users’ lives, with respect to prosthetic appearance. In Study III, the aim was to investigate prosthetists’ attitudes towards the needs of prosthetic users by conducting semi-structured interviews. Finally, Study IV was an online questionnaire to explore non-users’ attitudes towards the design of prostheses. The research showed that the use of prostheses for the completion of users’ body was not an adequate factor to improve their well-being, and a shift on users’ desires towards emotionally-driven prostheses has occurred. From the variables that were tested, sex, age, cause and area of limb-loss may affect people’s attitudes towards the design of prostheses. Furthermore, the results showed that prostheses with high emotionally-driven design evoked emotions, in both users and non-users, with higher levels of pleasantness and arousal than the emotions that were elicited by the prostheses of lower emotionally-driven designs and thus, they may trigger a greater behavioural reaction. This suggested that emotionally-driven prostheses may eliminate users’ stigmatisation by increasing their self-confidence and altering society’s attitudes. However, attention needs to be paid in collectivistic countries, as emotionally-driven prostheses may enhance users’ stigmatisation.
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Vlachaki, Anna (2020): Emotionally-driven prostheses: exploring the effects on users’ lives and societies’ attitudes in the UK and Greece. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Type
Conference Paper
Themes
Assistive & Accessible Technology
Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People
Maryam Bandukda,Catherine Holloway, Aneesha Singh,Giulia Barbareschi, Nadia Berthouze
We conducted semi-structured interviews with 20 BPS people and 8 Mobility and Orientation Trainers (MOT). The interviews were thematically analysed and organised into four overarching themes discussing factors influencing the self-efficacy belief of BPS people: Tools and Strategies for O&M training, Technology Use in O&M Training, Changing Personal and Social Circumstances, and Social Influences. We further highlight opportunities for combinations of multimodal technologies to increase access to and effectiveness of O&M training.
ASSETS '21: Proceedings of the 23rd International ACM SIGACCESS Conference on Computers and Accessibility
Abstract
Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People
Orientation and mobility (O&M) training provides essential skills and techniques for safe and independent mobility for blind and partially sighted (BPS) people. The demand for O&M training is increasing as the number of people living with vision impairment increases. Despite the growing portfolio of HCI research on assistive technologies (AT), few studies have examined the experiences of BPS people during O&M training, including the use of technology to aid O&M training. To address this gap, we conducted semi-structured interviews with 20 BPS people and 8 Mobility and Orientation Trainers (MOT). The interviews were thematically analysed and organised into four overarching themes discussing factors influencing the self-efficacy belief of BPS people: Tools and Strategies for O&M training, Technology Use in O&M Training, Changing Personal and Social Circumstances, and Social Influences. We further highlight opportunities for combinations of multimodal technologies to increase access to and effectiveness of O&M training.
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Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People
Type
Conference Paper
Themes
Assistive & Accessible Technology
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Giulia Barbareschi, Norah Shitawa Kopi,Ben Oldfrey,Catherine Holloway
In this paper, we examine how young Kenyans without disabilities view people with disabilities and AT users. Findings show that while the portrayal of disability is often shaped by negative emotion, participants felt that many of the barriers affecting people with disabilities were created by society. Perceptions of AT differed –devices were not only seen as a mark of disability but also as a sign of access to resources. Therefore, what we see is an emergent picture where social barriers can be reinforced by poverty, and where poverty reinforces social barriers faced by people with disabilities. We conclude that access to appropriate technology alongside societal interventions tackling incorrect beliefs about disability can help to overcome the stigma faced by people with disabilities.
ASSETS '21: Proceedings of the 23rd International ACM SIGACCESS Conference on Computers and Accessibility
Abstract
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Most research which investigates stigma towards with people with disabilities and the use of Assistive Technology (AT) are based in the Global North and focus on the experiences of people with disabilities and the consequences that stigma has on choices surrounding AT. However, stigma is a societal construct rooted in the attitude and beliefs that people without disabilities hold on disability and AT. Furthermore, the portrayal of people with disabilities and AT is dependent on the social context. In this paper, we examine how young Kenyans without disabilities view people with disabilities and AT users. Findings show that while the portrayal of disability is often shaped by negative emotion, participants felt that many of the barriers affecting people with disabilities were created by society. Perceptions of AT differed –devices were not only seen as a mark of disability but also as a sign of access to resources. Therefore, what we see is an emergent picture where social barriers can be reinforced by poverty, and where poverty reinforces social barriers faced by people with disabilities. We conclude that access to appropriate technology alongside societal interventions tackling incorrect beliefs about disability can help to overcome the stigma faced by people with disabilities.
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Giulia Barbareschi, Norah Shitawa Kopi, Ben Oldfrey, and Catherine Holloway. 2021. What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT. In The 23rd International ACM SIGACCESS Conference on Computers and Accessibility( ASSETS '21). Association for Computing Machinery, New York, NY, USA, Article 18, 1–13. DOI:https://doi.org/10.1145/3441852.3471226
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Type
Editorial
Themes
Assistive & Accessible Technology
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Giulia Barbareschi& Tom Shakespeare
Assistive products (APs) are broadly defined as “ any product (including devices, equipment, instruments, and software), either specially designed and produced or generally available, whose primary purpose is to maintain or improve an individual’s functioning and independence and thereby promote their wellbeing” (Khasnabis et al.,2015). Although the concept of wellbeing is extremely slippery and researchers have yet to agree on a single definition for it, as individuals we instinctively develop mental models about what does, and does not, promote our happiness and wellbeing. Considerations about values, wellbeing and happiness are extremely personal and are shaped by a variety of factors ranging from our age and socio-cultural background to our life experiences (Schwartz & Bardi,2001).
RESNA
Abstract
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Assistive products (APs) are broadly defined as “ any product (including devices, equipment, instruments, and software), either specially designed and produced or generally available, whose primary purpose is to maintain or improve an individual’s functioning and independence and thereby promote their wellbeing” (Khasnabis et al.,2015). Although the concept of wellbeing is extremely slippery and researchers have yet to agree on a single definition for it, as individuals we instinctively develop mental models about what does, and does not, promote our happiness and wellbeing. Considerations about values, wellbeing and happiness are extremely personal and are shaped by a variety of factors ranging from our age and socio-cultural background to our life experiences (Schwartz & Bardi,2001).
However, when it comes to assistive technology (AT) research, our focus seems to be primarily geared toward values and activities in the domains of education, employment, transport or health, often framed according to an outcome driven perspective that is heavily influenced by what is seen as useful (often what is measurable), vs what is frivolous (less tangible social or emotional aspects).
This disparity parallels the priorities of the disability rights movement and disability studies research that have helped to shape the research agenda around disability and AT. Often influenced by labor movement politics, or feminism, there appears to have been more concern with public and practical aspects of social life as opposed to the more private and sensitive ones (Shakespeare,2014). The focus on the public utilitarian function of AT becomes even more evident when we consider AT research carried out in the Global South. In this context the success of an intervention is usually assessed using measures of outcome and impact which can be somehow linked to economic improvement (Alkire,2016).
In this editorial, we are not suggesting that enabling people with disabilities to gain a good education, obtain a fulfilling job or be able to vote are not important goals for the APs we develop and research. But are those the only worthwhile goals? Should we not also enquire whether existing and future APs could help people with disabilities to develop meaningful friendships, enjoy fulfilling sex lives with their partners of choice, cook sociable dinners, or engage in their favorite hobbies? Although sporadic publications focus on the role of APs in the context of personal relationships, sexuality, or fun and play for people with disabilities do exist, these are rare, and often framed around utilitarian goals. For example, research around AT and play is largely focused on children and often examined in connection to learning outcomes. Similarly, sex and sexuality are often explored solely in connection to dysfunction, abuse or sexual health (Shakespeare & Richardson,2018).
These unbalanced narratives show how the AT research agenda is dictated by a set of universal priorities that are largely focused on global measurable goals that do not necessarily match the everyday values of people with disabilities. We invite researchers and practitioners to consider ways to find a better balance between public and private aspects of life, and between utilitarian and emotional values. Both approaches have a significant impact on the lives of people with disabilities.
Ultimately, as AT researchers we need to actively engage with people with disabilities to uncover their priorities, understand what different people with disabilities most value in life, and identify how current and future APs might help to make a positive impact on wellbeing. Aspects of life such as friendship, socialization, sexuality, love and play might indeed be more frivolous than practical ones such as education, health, employment and civil rights, but they are inherent to our shared humanity and fundamental to our happiness.
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Giulia Barbareschi & Tom Shakespeare (2021) A right to the frivolous? Renegotiating a wellbeing agenda for AT research, Assistive Technology, 33:5, 237, DOI:10.1080/10400435.2021.1984112
Type
Conference Paper
Themes
Assistive & Accessible Technology
Inclusive Educational Technology
Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
Tigmanshu Bhatnagar, Nicolai Marquardt, Mark Miodownik,Catherine Holloway
Shape changing materials create a unique opportunity to design reconfigurable tactile display actuators. In this paper, we present a method that transforms a single thin monolithic sheet of Nitinol into a passive reconfigurable tactile pixel array at Braille resolution. We have designed a 27x27 tactile pixel array in which each pixel can be selectively actuated with an external source of heat. The pixels rise 0.4mm vertically with a peak blocked force of 0.28kg and have an average blocked force of 0.23kg at room temperature. After cooling, the pixels can be mechanically reconfigured back to their flat state for repeatable actuation. We demonstrate this actuator’s interactive capabilities through a novel erasable tactile drawing interface.
IEEE World Haptics Conference; 2021
Abstract
Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
Shape changing materials create a unique opportunity to design reconfigurable tactile display actuators. In this paper, we present a method that transforms a single thin monolithic sheet of Nitinol into a passive reconfigurable tactile pixel array at Braille resolution. We have designed a 27x27 tactile pixel array in which each pixel can be selectively actuated with an external source of heat. The pixels rise 0.4mm vertically with a peak blocked force of 0.28kg and have an average blocked force of 0.23kg at room temperature. After cooling, the pixels can be mechanically reconfigured back to their flat state for repeatable actuation. We demonstrate this actuator’s interactive capabilities through a novel erasable tactile drawing interface.
Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
T. Bhatnagar, N. Marquardt, M. Miodownik and C. Holloway, "Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution," 2021 IEEE World Haptics Conference (WHC), 2021, pp. 409-414, doi: 10.1109/WHC49131.2021.9517239.
Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
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Determinants of Diagnostic Imaging Utilization in Primary Care
We examine and quantify patient and physician factors that affect the utilization of outpatient imaging by primary care physicians caring for adult patients.
Determinants of Diagnostic Imaging Utilization in Primary Care
By Chris Sistrom, MD, MPH, PhD Niccie L. McKay, PhD Jeffrey B. Weilburg, MD Steven J. Atlas, MD, MPH Timothy G. Ferris, MD View All
The American Journal of Managed Care April 2012 Volume 18 Issue 4
We examine and quantify patient and physician factors that affect the utilization of outpatient imaging by primary care physicians caring for adult patients.
Objectives:
To examine patient and physician factors affecting utilization of diagnostic imaging in primary care.
Articles in this issue
Factors of Hyperlipidemia Medication Adherence in a Nationwide Health Plan Predictors of Physician Use of Inpatient Electronic Health Records Evaluation of Human Immunodeficiency Virus and Hepatitis C Telemedicine Clinics Predicting Costs With Diabetes Complications Severity Index in Claims Data Chasing High Performance: Best Business Practices for Using Health Information Technology to Advance Patient Safety Association Between Physician Quality Improvement Incentives and Ambulatory Quality Measures Determinants of Diagnostic Imaging Utilization in Primary Care Cost-Effectiveness of Pharmacist-Provided Treatment of Adult Pharyngitis Primary Care Physicians' Experiences With Case Finding for Practice-Based Care Management
Data Sources/Study Setting:
Study Design:
This is a retrospective cohort study of 85,277 patients cared for by 148 primary care physicians (PCPs). The dependent variable is the number of outpatient imaging exams ordered by each patient’s PCP over the study period. Independent variables include 17 patient factorsdescribing both clinical need and demographic characteristics and 7 physician factors.
Better Together? Costs of First-line Chemoimmunotherapy for Advanced Non–Small Cell Lung Cancer
Data Collection:
Data were collected from the electronic medical record and associated administrative databases.
Principal Findings:
Better Together? Costs of First-line Chemoimmunotherapy for Advanced Non–Small Cell Lung Cancer May 18th 2023
Chronic Overlapping Pain Conditions and Long-term Opioid Treatment May 17th 2023
Association Between Low-Income Subsidies and Inequities in Orally Administered Antimyeloma Therapy Use May 16th 2023
Tacking Upwind: Reducing Spending Among High-risk Commercially Insured Patients May 15th 2023
Cost-effectiveness of a 3-Year Tele-Messaging Intervention for Positive Airway Pressure Use May 4th 2023
Time to Publication of Cost-effectiveness Analyses for Medical Devices May 3rd 2023
Better Together? Costs of First-line Chemoimmunotherapy for Advanced Non–Small Cell Lung Cancer May 18th 2023
Chronic Overlapping Pain Conditions and Long-term Opioid Treatment May 17th 2023
Association Between Low-Income Subsidies and Inequities in Orally Administered Antimyeloma Therapy Use May 16th 2023
Tacking Upwind: Reducing Spending Among High-risk Commercially Insured Patients May 15th 2023
Cost-effectiveness of a 3-Year Tele-Messaging Intervention for Positive Airway Pressure Use May 4th 2023
Time to Publication of Cost-effectiveness Analyses for Medical Devices May 3rd 2023
Better Together? Costs of First-line Chemoimmunotherapy for Advanced Non–Small Cell Lung Cancer May 18th 2023
Chronic Overlapping Pain Conditions and Long-term Opioid Treatment May 17th 2023
Association Between Low-Income Subsidies and Inequities in Orally Administered Antimyeloma Therapy Use May 16th 2023
Tacking Upwind: Reducing Spending Among High-risk Commercially Insured Patients May 15th 2023
Cost-effectiveness of a 3-Year Tele-Messaging Intervention for Positive Airway Pressure Use May 4th 2023
Time to Publication of Cost-effectiveness Analyses for Medical Devices May 3rd 2023
Conclusions:
Both patient and physician factors have a substantial effect on primary care outpatient diagnostic imaging utilization. Several of these significantly influence both the probability that any images will be ordered and the intensity (number) of imaging.
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(Am J Manag Care. 2012;18(4):e135-e144)
Primary care providers caring for adult patients order from 0 (63%) to 15 images per patient over 2 years, with the average being 0.72.
Multivariable modeling of outpatient imaging utilization should take into account the observed distribution of per patient counts, which is 0 inflated and skewed to the right.
Nine of 17 patient factors influence both the probability of any imaging and the amount of imaging performed.
Three of 7 provider factors influence both the probability of any imaging and the amount of imaging performed.
A central problem facing health policy makers is how to control the costs of medical services while maintaining the quality of care. Given that costs depend on utilization and unit costs, an understanding of factors driving utilization is fundamental to developing feasible and effective recommendations for cost control. Diagnostic imaging utilization is of particular interest because medical technology is often mentioned as a major driver of costs, with radiology in particular experiencing rapid growth. For example, in their 2006 report to Congress, MedPAC noted that from 1999 through 2004 growth in Medicare claims for diagnostic imaging was the highest of all physician services, at 62%.
Much of the research on utilization of health services stems from the large body of work that has demonstrated considerable variation in their use at various levels of geographic comparison. 1-3Much of this variation in the use of medical services is not explained by differences in health status, disease-specific population health indicators, or other measures of health outcomes. This raises the question of what other factors influence utilization.
Although there is a large literature on the general topic of utilization of healthcare services, less attention has been paid to diagnostic imaging. Some studies focused on diagnostic services in general 4or ambulatory test utilization. 5-7Rosen, Davis, and Lesky 8examined utilization of outpatient diagnostic imaging and found that the probability of a diagnostic imaging study being ordered was significantly affected by patient age, urgent visits, visit frequency, and physician gender. A study by Grytten and Sorensen 9examined the use of diagnostic tests (including imaging) among Norwegian primary care physicians (PCPs); after controlling for patient age, gender, and reason for visit, the remaining variation in diagnostic test use ranged from 47% to 66%. Other studies have examined computed tomography (CT) scans and magnetic resonance imaging (MRI) only. 10-12
The objective of this study is to examine patient and physician factors determining utilization of diagnostic imaging in primary care. Detailed patient-level data come from the physician organization associated with a large, urban academic medical center over a 2-year period. A patient-provider connectedness algorithm identifies a cohort of patients each linked to a single PCP based on outpatient visits over the previous 3 years. The analysis uses a 2-part model, which distinguishes between the probability of any imaging utilization (yes or no) and, conditional on any imaging, the amount of imaging utilization (number of exams). Multivariate regression is performed using maximum likelihood methods and zero-inflated Poisson distribution, which allows simultaneous estimation of coefficients for the 2-part model.
The study contributes to the literature by providing a deeper understanding of factors that influence the utilization of diagnostic imaging in primary care. The data used in the study are rich in detail and depth; the analysis includes 17 patient factors describing both clinical need and demographic characteristics as well as 7 physician factors, including gender, experience (years after MD degree), panel size, and having been sued for malpractice. Also, previous research on imaging utilization typically has focused solely on the amount of utilization, whereas this study applies the 2-part model in order to distinguish between the probability of any utilization and the amount of utilization, and the methodology used jointly estimates coefficients for the 2-part model.
CONCEPTUAL FRAMEWORK
This study examines the utilization of outpatient diagnostic imaging by PCPs caring for adult patients. We will not discuss imaging that occurs as part of disease screening programs, such as mammography and CT colonography, because the factors affecting utilization are likely to differ between imaging for screening and imaging for diagnostic purposes. Factors influencing the utilization of outpatient diagnostic imaging can be divided into 4 major classes: patient, physician, organization, and community. Because this study uses data from a single large physician organization in a single community, the focus is limited to patient and physician factors.
Patient factors affecting imaging utilization stem from clinical need as modified by demographic and socioeconomic characteristics. The physician orders imaging to address clinical uncertainty that arises about an existing medical condition or clinical event. Under ideal conditions of evidence-based practice, the mixture and amount of imaging that patients received would depend only on their existing diagnoses, disease status, and clinical events. However, the current state of medical knowledge and the consistency with which it is applied in actual practice is such that physicians’ decisions about intensity and mixture of diagnostic imaging are quite variable even when faced with identical clinical scenarios. Consequently, utilization decisions also are influenced by patient factors other than clinical need as well as by physician factors.
Patient demographics such as gender and age strongly correlate with the amount and type of clinical need based on their complex relationships with many diseases and health states. However, these same demographic factors also exert social and psychological effects on the patient’s likelihood to undergo diagnostic testing under various scenarios. Other patient factors such as ethnicity, level of education, and income also may affect individual patient tendencies to seek care and comply with provider recommendations. In addition to patient factors, physician characteristics may affect a doctor’s tendency to order diagnostic imaging tests. Physician training has direct effects on test-ordering behavior in primary care. Because the majority of training and experience about radiology is gained during residency, the relative intensity of imaging utilization at the training institution strongly influences subsequent decision making about imaging during practice. Previous research has found that physicians trained in high-use regions and at large academic centers tend to order diagnostic imaging more frequently than those trained in smaller centers and low-use regions. 2,5,9,13,14Physician experience is also relevant, with empirical evidence indicating that physicians having greater experience tend to order fewer imaging tests in identical scenarios. 4,6,7,10,11,15
Physician gender also may have an effect on use of imaging independent of experience and training, although, with the recent and substantial increase in the fraction of women trained in and practicing medicine in the United States, it may be difficult to measure, since women physicians tend to be younger and trained later. Empirical evidence about physician gender has been mixed, with studies showing both increased and decreased tendency to order imaging and other diagnostic tests between male and female doctors in primary care. 7,8,16
Malpractice deserves special mention because the term “defensive medicine” is often used to describe the phenomenon of physicians’ increased ordering of imaging and other diagnostic tests based on fear of being sued for failure to diagnose. 7,17Being sued for malpractice is an extremely negative and unsettling event that induces a strong desire to avoid repeat occurrences. 18Thus, if physicians have been sued for malpractice, the expectation is that they will alter future practice toward more diagnostic testing.
For purposes of the empirical analysis, the conceptual framework can be summarized as: imaging utilization = f [patient factors (clinical need, demographic characteristics), physician factors].
METHODS
This study was conducted at Massachusetts General Hospital (MGH) and the associated Mass General Physician Organization (MGPO). The Institutional Review Board (IRB) and privacy office approved the study and deemed it to be Health Insurance Portability and Accountability Act compliant. Within the MGPO, the Primary Care Operations Improvement Group conducts analyses of the practice for internal quality assessment and improvement. In support of these efforts they have devised and validated a method for identifying a group of patients and PCPs with stable relationships to each other. The result is termed a connectedness (“loyalty”) cohort. Each cohort is identified by year and comprises a list of patients who are considered to be linked to a single PCP by virtue of their outpatient visits as documented in the electronic medical record (EMR) over the 3 years ending in the “cohort” year. All patients seen in the primary care practice are initially eligible for inclusion in the cohort. Assertions about connectedness for patientdoctor pairs are calculated probabilistically from office visit history. 19-21During the validation studies of the algorithm, cutoff probabilities were selected to produce sensitivity of 80.4%, specificity of 93.7%, and positive predictive value of 96.5%. The original goal of the method was to achieve a positive predictive value of 90% for any given provider’s linked patients. 20,21
The Radiology Department at MGH provides a full range of imaging services for inpatient, emergency department, and outpatient practices. The main department is located at the MGH campus, with several ancillary outpatient sites in the Boston, Massachusetts, area. The whole department is linked via a robust electronic infrastructure with records of all imaging tests housed in a data warehouse. In total, almost 100 items of information are stored about each test, including the identity of the ordering physician, dates of order and completion, modality, body area, and setting.
Data Collection
The 2008 primary care connectedness cohort contained 87,568 patients flagged as being linked to a PCP. There were 804 patients who were linked to 26 providers with less than 100 patients in their practices. These were excluded, leaving 86,764 patients. Of these, 1483 were linked to 4 providers who had left the MGPO in late 2008 or the first or second quarters of 2009. Therefore the analytic sample includes 85,277 patients, linked to 1 of 148 PCPs. These physicians practice in 1 of 15 clinics distributed through the greater Boston area. The unit of observation for this study is the patient. The 85,277 patient medical record numbers were queried against the clinical radiology system to return all diagnostic imaging exams performed during the study interval (July 1, 2007, through June 30, 2009). The query specifically excluded interventional procedures and mammograms. Table 1 shows the total number of outpatient diagnostic imaging exams performed on the study cohort during the study period. The dependent variable for the study was constructed by aggregating and summing (by patient) the 60,983 outpatient imaging procedures ordered by the PCP to whom the patients were linked (outpatient ordered by PCP in Table 1). The remaining diagnostic imaging procedures were performed while patients were in the emergency department (N = 34,345), were completed while patients were in the hospital (N = 29,763), or were outpatient exams ordered by specialists (N = 96,525). These other categories of imaging utilization were also aggregated by patient and summed to produce 3 patient-level imaging utilization independent variables as described below.
The EMR system was used to obtain counts of various clinical events for each patient over the study period. Hospital activity variables included visits to the emergency department (ED), inpatient hospital stays, intensive care unit (ICU) days, and inpatient observation days. Records of outpatient visits for each patient during the study period were used to sum the professional relative value units (RVUs; obtained from Centers for Medicare & Medicaid Services as of 2008) for visits to the linked PCP and to specialists.
The EMR system was used to develop an active medical problem list for each patient. The coded problems were mapped into the following broad categories: diabetes, hypertension, heart failure, coronary artery disease, renal failure, cancer, trauma, obesity, and substance abuse. For each of the major categories, a binary variable was constructed when the patient had at least 1 active problem listed falling into that category. The counts of unmapped problem codes were placed into a separate variable of other problems.
The EMR system also provided data on the number of outpatient medications each patient was taking during 2008. The queries did not count refills of the same drug and dose as new prescriptions. However, switches within a drug class and/or dose changes were counted as new prescriptions, which could result in over-counting and rendering small differences in the discrete number less meaningful than the general amount each patient was taking. Therefore, we stratified the count of outpatient medications into 4 categories.
The MGH registrars’ database was used to obtain relevant information pertaining to the 148 PCPs in the study, including gender, birth year, medical school graduation year, and medical school state (or country for foreign medical graduates). All were licensed in the state of Massachusetts, and the publicly available website for the Massachusetts Board of Medicine was queried to determine whether or not each physician had been sued for medical malpractice in the past 10 years.
Variables
Table 2
presents descriptive statistics for the variables used in the analysis, with frequency and percent shown for categorical variables and mean and standard deviation shown for numeric variables. The dependent variable is the per patient number of outpatient imaging tests ordered by the patient’s PCP over the study period. The value of this variable ranged from zero (for 53,617 = 62.9% of the patients) to 15, with a mean of 0.715 and a standard deviation of 1.26.
The independent variables fall into 2 categories—patient factors (measured on a per patient basis) and physician factors (measured on a per physician basis, then linked to loyal patients of the given physician). Patient factors expected to influence outpatient imaging utilization include demographic characteristics (age, race, and gender), indicators of clinical problems (number of medications, medical problems, hospital readmission within 30 days), utilization of other medical services (PCP visits, specialist visits, ED visits, observation days, inpatient stays, inpatient length of stay [LOS], and inpatient ICU), and other imaging utilization (outpatient imaging ordered by specialists, ED imaging, and inpatient imaging). Physician factors expected to influence utilization include gender, experience (years since graduating medical school), foreign medical graduate status, having an additional degree, having been sued for malpractice, size of panel, and size of clinic.
Statistical Analysis
For the regression analysis, a zero-inflated Poisson (loglink) model was estimated using PROC GENMOD (SAS Version 9.3, SAS Institute Inc, Cary, North Carolina) with all independent variables included in both the zero-model and count portions of the regression. 22-24This method is appropriate for a 2-level utilization model, which jointly estimates the effect of each independent variable on the probability of any imaging utilization (the zero-model portion) and on the amount of imaging utilization (count portion). The significance of each of the independent variables was determined from the type 3 table of Wald c2 statistics. To quantify the direction and size of the independent variable effects, explicit reference levels for the categorical variables were specified (using the PARAMETER = REFERENCE option).
RESULTS
Table 3
Factors Affecting Probability of Any Imagingpresents the regression results; the zero-model coefficients are listed in the middle column. The coefficients were transformed by exponentiation for clarity and can be interpreted similarly to odds ratios in logistic regression. Thus, a value of 1.1 would indicate a 10% higher probability of any imaging being ordered by the patient’s linked PCP compared with reference for categorical predictors or a unit increase for quantitative ones. Conversely, a coefficient of 0.9 would indicate a 10% lower probability of any imaging being ordered by the patient’s linked PCP.
Patient factors that had a statistically significant effect on the probability of any imaging included race, more than 10 medications, cancer, congestive heart failure, diabetes, hypertension, trauma, other problems, visits to the linked PCP, visits to specialists, imaging exams ordered by specialists, and imaging exams ordered during observation days in the hospital. The effect on the probability of any imaging was positive for race, trauma, other problems, visits to the linked PCP, visits to specialists, imaging exams ordered by specialists, and imaging exams ordered during observation days in the hospital. For example, the probability of any imaging utilization was approximately 0.5% higher for each additional visit to the linked PCP. For more than 10 medications, cancer, congestive heart failure, diabetes, and hypertension, the effect on the probability of any imaging was negative. For example, patients taking more than 10 medications had a probability of any imaging utilization that was approximately 17% less than for patients taking no medications. Although this may seem counterintuitive, the results for more than 10 medications,
cancer, congestive heart failure, diabetes, and hypertension may reflect the fact that patients with serious medical problems are more likely to have their imaging exams ordered by specialists than by their respective PCPs.
The physician factors having a statistically significant effect on the probability of any imaging utilization included years of experience, gender, foreign medical graduate status, and possession of another graduate degree in addition to the MD. All of these factors had a positive effect on the probability of any imaging. For example, patients of PCPs who were female had a probability of any imaging utilization that was approximately 6% higher than comparable patients of PCPs who were male.
Factors Affecting Intensity of Imaging
The coefficients from the count (intensity) of imaging utilization portion of the model measure the effect of a given factor on the number of imaging exams ordered over the study period by the patient’s linked PCP. These are shown in the far right column of Table 3 and have been transformed (by exponentiation) to incident rate ratios. Analogous to the probability of any imaging, for a given factor, a value of 1.1 would indicate 10% greater number of images ordered by the PCP, whereas a value of 0.9 would indicate 10% fewer images. The patient factors having a statistically significant and positive effect on the intensity of imaging utilization included age, gender, race, more than 10 medications, obesity, other problems, visits to the linked PCP, visits to specialists, imaging exams ordered by specialists, and imaging exams ordered while in the hospital. For example, patients who were female had approximately 6% more imaging exams ordered by their PCPs than comparable patients who were male. Factors that had a statistically significant and negative effect on the amount of imaging utilization included congestive heart failure, renal failure, diabetes, hypertension, days as inpatient, and days in ICU. Patients with congestive heart failure, for example, had approximately 8% fewer imaging exams ordered by their respective PCPs than those without this medical condition.
In terms of provider factors, gender, having another degree, panel size, and clinic size had a statistically significant and positive effect on the amount of imaging utilization. Patients of PCPs who were female, for example, had approximately 11% more imaging exams ordered than comparable patients of PCPs who were male. Provider years of experience, on the other hand, had a negative effect, such that patients of PCPs with an additional year of experience had approximately 1% fewer imaging exams ordered.
Factors Affecting Both Probability and Intensity of Imaging
Figure
Of the variables included in Table 3, some factors significantly affected the probability of any imaging and not intensity of imaging ordered by the linked PCP, some affected intensity and not probability, and some affected both probability and intensity. Thepresents results for factors that are statistically significant in both portions of the model. Due to the difference in scale, Panel A shows the results for the categorical variables and Panel B for the numeric variables.
Patient factors that were statistically significant in both portions of the model include race (black), more than 10 medications, congestive heart failure, diabetes, hypertension, other problems, visits to the linked PCP, visits to specialists, and imaging exams ordered by specialists. With the exception of more than 10 medications, these patient factors have effects in the same direction on both probability of any imaging and intensity of imaging. For patients taking more than 10 medications, however, the probability of any imaging is less than for patients taking no medications while the intensity of imaging is higher than for patients taking no medications.
For physician factors, experience, gender, and having an extra degree were statistically significant in both portions of the model. Gender and having an extra degree had a positive effect on both probability of any imaging and intensity of imaging, while physician experience had a very small positive effect on the probability of any imaging but a negative effect on imaging intensity.
DISCUSSION
This study examined patient and physician factors affecting utilization of outpatient diagnostic imaging ordered by PCPs caring for a stable cohort of patients. The data came from a practice associated with a large, urban academic medical center over a 2-year period. Variables related to a patient’s clinical need tended to be significantly associated with imaging utilization, as would be expected. For example, the amount of visits to the linked PCP strongly influenced both the probability of any imaging and the amount of imaging. This positive relationship was also true for visits to specialists and outpatient imaging ordered by specialists.
Among the demographic patient factors, age and gender had a statistically significant and positive effect only on the amount of imaging ordered by the patient’s PCP. Race, on the other hand, affected both the probability of any imaging and the amount of imaging. Specifically, black patients had a probability of any imaging utilization ordered by their PCPs that was approximately 19% higher than for comparable whites, and black patients had approximately 9% more imaging exams ordered by their PCPs than comparable patients who were white. We can only speculate about the etiology of this apparent ethnic disparity. Perhaps the PCPs elected to order imaging tests themselves rather than refer black patients having comparable problems on to specialists.
Physician factors contributed significantly and substantially to imaging utilization. Physician years of experience, gender, foreign medical graduate status, and having another degree had a positive effect on the probability of any imaging. Physician years of experience had a negative effect, while gender, having another degree, panel size, and clinic size had a positive effect on the amount of imaging. One notable factor that did not reach statistical significance for either probability or intensity of imaging was our physician-level, binary malpractice variable.
Limitations
One limitation of the study is that it did not examine imaging utilization that occurs as part of disease-screening programs. While important for population health and public policy, fundamental differences exist between imaging for screening and imaging for diagnostic purposes. For example, given agreement on the appropriate level of screening, policy makers are primarily concerned with under-utilization of imaging for screening, whereas the extent and nature of overutilization tend to be the key issues for diagnostic imaging. Another limitation is that the dependent variable, outpatient imaging utilization, was quantified by number of imaging exams. However, some imaging exams cost considerably more than others. Thus, if cost were the only focus of the analysis,summed RVUs for the imaging exams would be a preferable outcome measure.
The patient population examined was specifically selected by evidence of a stable relationship with a PCP. New patients or those with irregular attendance might have more imaging due to lack of PCP familiarity with their clinical situation. All physicians in the practice are salaried employees. Consequently, providers in this setting may be subject to less influence from other incentives affecting utilization than would be the case in a private practice that owns or leases imaging equipment and thus profits from technical component reimbursements. 25Therefore, our results may not generalize to other primary care practice settings.
As mentioned in the introductory material, physician training after medical school (residency and/or fellowship) likely has influence on test ordering behavior (in this case imaging). We did not have consistent and reliable data about place, type, and timing of residency/fellowship training for the PCPs studied. Therefore, we cannot make any assertions about these effects or their interaction with the other physician- level variables studied.
In terms of imaging utilization management, the outpatient multispecialty group used in the study is arguably a “best practice” setting, having used EMRs since 1995 and a computerized outpatient radiology order entry (ROE) system since 2004. In addition, starting in 2005 a decision support (DS) component was added to the system that is triggered with all orders for CT, MRI, and nuclear medicine studies. A retrospective study in the same setting over 7 years ending in 2009 found that, after correction for overall practice activity, there were substantial reductions in imaging utilization growth rates, especially for CT scans, which were attributed to the ROE-DS system. 26Although the aforementioned ROEDS system does render and record “appropriateness scores” for high-cost outpatient studies, these were not analyzed or used as control variables in the current study. We plan to extend this research in several directions including correlation of appropriateness with variations in utilization by provider, specialty, and over time.
Policy Implications
The key policy concern related to diagnostic imaging stems from substantial and rapidly rising costs. However, any attempts to control imaging utilization growth in general or to target “high users” for special attention must be informed by proper modeling of the factors driving imaging utilization. In discussing policy implications, it is important to emphasize that the focus of this study is not what is often called physician profiling, with the accompanying debate over appropriate risk adjustment. 27Rather, this study examines all factors thought to influence utilization. These findings thus should be useful in decisions about what factors to include in risk adjustment.
A major implication of the study is that physician factors have a substantial effect on outpatient diagnostic imaging utilization, even after controlling for a host of patient factors. This contrasts with the presumed outcome under ideal conditions of evidence-based practice, in which imaging utilization would depend only on a patient’s medical condition, with a certain level of randomness due to clinical uncertainty. Caution is warranted, though, due to the lack of a “gold standard” against which to measure “appropriate” utilization. 28
An important next step in understanding utilization of medical services will be to examine physician factors and how they combine with patient need variables to influence utilization. An interesting question is why a physician’s years of experience has a small positive effect on the probability of any imaging, but a negative effect on the amount of imaging ordered. Another question is why, as a physician’s panel size increases, the amount of imaging ordered per patient also increases (but not the probability of any imaging). One possibility is that this stems from time pressure on the physician. For instance, an initial visit to a PCP for headache that occurs at the end of a busy day in clinic might be more likely to include an imaging test than otherwise. Again, however, judgments about under- or over-utilization are only valid given an established standard of comparison.
For this data set, outpatient imaging ordered by a patient’s PCP accounted for 27.5% of all diagnostic imaging, with 43.6% of all imaging exams being ordered by specialists (Table 1). An important topic for future research thus will be the consideration of imaging utilization by specialists and the relationship between imaging exams ordered by PCPs and those ordered by specialists for similar patients. It may be, for example, that some PCPs who order fewer imaging exams themselves also refer more often to specialists; such a pattern of behavior could ultimately be more costly overall than PCPs who order more imaging exams but refer to specialists As mentioned above, we are seeking to combine these sorts of population-level imaging utilization studies and variation analyses with normative assertions about the appropriateness of the examinations being enumerated.
Author Affiliations:From Department of Radiology (CS), University of Florida Health Center, Gainesville, FL; Department of Health Services Research (NLM), Management and Policy, University of Florida, Gainesville, FL; Department of Psychiatry (JBW), Department of Medicine (SJA, TGF), Massachusetts General Hospital, Boston, MA.
Funding Source:None.
Author Disclosures:The authors (CS, NLM, JBW, SJA, TGF) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information:Concept and design (CS, NLM, JBW, SJA, TGF); acquisition of data (CS, JBW, SJA, TGF); analysis and interpretation of data (CS, NLM, JBW, TGF); drafting of the manuscript (CS, NLM, JBW); critical revision of the manuscript for important intellectual content (CS, NLM, JBW, SJA); statistical analysis (CS, NLM); provision of study materials or patients (SJA); administrative, technical, or logistic support (CS); and supervision (CS, TGF).
Address correspondence to:Chris Sistrom, MD, MPH, PhD, Department of Radiology, University of Florida Health Center, PO Box 100374, Gainesville, FL 32610-0374. E-mail: [email protected]. Wennberg J, Gittelsohn. Small area variations in health care delivery. Science. 1973;182(117):1102-1108.
2. Folland S, Stano M. Small area variations: a critical review of propositions, methods, and evidence. Med Care Rev. 1990;47(4):419-465.
3. Leape LL, Park RE, Solomon DH, et al. Does inappropriate use explain small-area variations in the use of health care services? JAMA. 1990; 263(5):669-672.
4. Eisenberg JM, Nicklin D. Use of diagnostic services by physicians in community practice. Med Care. 1981;19(3):297-309.
5. Epstein AM, McNeil BJ. The effects of patient characteristics on ambulatory test ordering. Soc Sci Med. 1985;21(10):1071-1075.
6. Bugter-Maessen AM, Winkens RA, Grol RP, et al. Factors predicting differences among general practitioners in test ordering behaviour and in the response to feedback on test requests. Fam Pract. 1996;13(3): 254-258.
7. Sood R, Sood A, Ghosh AK. Non-evidence-based variables affecting physicians’ test-ordering tendencies: a systematic review. Neth J Med. 2007;65(5):167-177.
8. Rosen MP, Davis RB, Lesky LG. Utilization of outpatient diagnostic imaging: does the physician’s gender play a role? J Gen Intern Med. 1997;12(7):407-411.
9. Grytten J, Sorensen R. Practice variation and physician-specific effects. J Health Econ. 2003;22(3):403-418.
10. Couchman GR, Forjuoh SN, Rajab MH, Phillips CD, Yu J. Nonclinical factors associated with primary care physicians’ ordering patterns of magnetic resonance imaging/computed tomography for headache. Acad Radiol. 2004;11(7):735-740.
11. Couchman GR, Forjuoh SN, Reis MD, Bartels G, Lindzey D. Variation in MRI/CT utilization among family physicians and general internists in a multi-specialty group practice. Med Sci Monit. 2005;11(3):MT19-MT25.
12. Kung PT, Tsai WC, Yaung CL, Liao KP. Determinants of computed tomography and magnetic resonance imaging utilization in Taiwan. Int J Technol Assess Health Care. 2005;21(1):81-88.
13. Chassin MR. Explaining geographic variations: the enthusiasm hypothesis. Med Care. 1993;31(5) (suppl):YS37-YS44.
14. O’Neill L, Kuder J. Explaining variation in physician practice patterns and their propensities to recommend services. Med Care Res Rev. 2005;62(3):339-357.
15. Childs AW, Hunter ED. Non-medical factors influencing use of diagnostic x-ray by physicians. Med Care. 1972;10(4):323-335.
16. Britt H, Bhasale A, Miles DA, Meza A, Sayer GP, Angelis M. The sex of the general practitioner: a comparison of characteristics, patients, and medical conditions managed. Med Care. 1996;34(5):403-415.
17. DeKay ML, Asch DA. Is the defensive use of diagnostic tests good for patients, or bad? Med Decis Making. 1998;18(1):19-28.
18. Hermer LD, Brody H. Defensive medicine, cost containment, and reform. J Gen Intern Med. 2010;25(5):470-473.
19. Atlas SJ, Grant RW, Ferris TG, Chang Y, Barry MJ. Patient-physician connectedness and quality of primary care. Ann Intern Med. 2009; 150(5):325-335.
20. Atlas SJ, Chang Y, Lasko TA, et al. Is this “my” patient? development and validation of a predictive model to link patients to primary care providers. J Gen Intern Med. 2006;21(9):973-978.
21. Lasko TA, Atlas SJ, Barry MJ, Chueh HC. Automated identification of a physician’s primary patients. J Am Med Inform Assoc. 2006;13(1): 74-79.
22. Lambert D. Zero-inflated Poisson regression, with an application to defects in manufacturing. Technometrics. 1992;34(1):1-14.
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26. Sistrom CL, Dang PA, Weilburg JB, Dreyer KJ, Rosenthal DI, Thrall JH. Effect of computerized order entry with integrated decision support on the growth of outpatient procedure volumes: seven-year time series analysis. Radiology. 2009;251(1):147-155.
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Download PDF: Determinants of Diagnostic Imaging Utilization in Primary Care
Compared with first-line immunotherapy or chemotherapy alone, combination chemoimmunotherapy for advanced/metastatic non–small cell lung cancer has significantly higher antineoplastic drug and associated medical costs.
ABSTRACT
Objectives:Recent advances have created options for first-line (1L) treatment of advanced/metastatic non–small cell lung cancer (aNSCLC). The study objectives were to describe the utilization of 3 classes of 1L treatment—chemotherapy (CT), immunotherapy (IO), and chemoimmunotherapy (IO+CT)—and the total, third-party payer, direct health care costs.
Study Design:Retrospective, administrative claims database analysis of patients with aNSCLC who initiated 1L treatment between January 1, 2017, and May 31, 2019, with IO, CT, or IO+CT.
Methods:Microcosting enumerated health care resource utilization, including antineoplastic drug costs, using standardized costs. Generalized linear models estimated per-patient per-month (PPPM) costs during 1L treatment, and adjusted cost differences in 1L among treatment cohorts were calculated using recycled predictions.
Results:A total of 1317 IO-, 5315 CT-, and 1522 IO+CT-treated patients were identified. Utilization of CT declined from 72.3% to 47.6% between 2017 and 2019, replaced by use of IO+CT, which increased from 1.8% to 29.8%. Total PPPM costs in 1L were highest with IO+CT at $32,436, compared with $19,000 and $17,763 in the CT and IO cohorts, respectively. Adjusted analyses showed that PPPM costs were $13,933 (95% CI, $11,760-$16,105) higher in the IO+CT vs IO cohort ( P< .001) and IO costs were $1024 (95% CI, $67-$1980) lower than CT ( P= .04).
Conclusions:IO+CT accounts for almost one-third of 1L aNSCLC treatment modalities, coinciding with a reduction in treatment with CT. Costs for patients treated with IO were lower than those for patients treated with both IO+CT and CT alone, driven primarily by antineoplastic drug and associated medical costs.
Takeaway Points
Until recently, cytotoxic chemotherapy was the standard of care for patients with non–small cell lung cancer. Costs of cancer care, particularly for lung cancer, continue to rise with the introduction of novel therapies such as chemoimmunotherapy, the use of which has increased substantially since 2017.
This cost and health care resource utilization analysis study provides the first estimates of the real-world, third-party payer costs comparing chemotherapy, immunotherapy, and chemoimmunotherapy to inform comparative value-based decision-making in earlier therapeutic settings.
Compared with first-line immunotherapy or chemotherapy alone, combination chemoimmunotherapy for advanced/metastatic non–small cell lung cancer has significantly higher antineoplastic drug and associated medical costs.
Although reductions in smoking, along with diagnostic and therapeutic advances, have resulted in a recent decline of lung cancer mortality rates of 5%, the 5-year survival rate among patients with newly diagnosed disease remains around 20%. 2In 2015, the approval of the first immunotherapy (IO) drug, nivolumab, ushered in a new era of treatment for advanced non–small cell lung cancer (aNSCLC) with its indication as a second-line treatment. 3This approval was shortly followed by the approval of pembrolizumab, which in October 2016 became the first IO agent approved in the first-line (1L) therapeutic setting for patients with a PD-L1 expression level of 50% or more. 4Less than a year later in May 2017, the chemoimmunotherapy (IO+CT) regimen of pembrolizumab plus chemotherapy (CT) was approved for the 1L setting regardless of PD-L1 expression level. 5Today, the landscape continues to evolve, including novel approved IO agents and combination IO therapies with and without a CT component. 6,7In May 2020, nivolumab plus ipilimumab became the first combination IO+IO treatment approved for aNSCLC. 8
The US health care system has historically imposed no restrictions on the reimbursement of cancer therapies based on cost-effectiveness. However, growing attention is being paid to treatment costs as a result of value-based care (VBC) initiatives such as the Oncology Care Model (OCM) and its replacement initiative, the Enhanced Oncology Model (EOM), which impose shared financial risk between providers and payers. 9Moreover, the rapid expansion of high-cost, novel agents such as IO into the 1L setting for aNSCLC raises concerns about affordability, especially given the trend toward combination therapy. Drug price is typically the most important factor in sensitivity analyses of cost-effectiveness, yet other aspects of care such as office visits, infused drug administration, supportive care agents, and emergency and hospital care for adverse events (AEs) may contribute substantially to the economic burden of particular therapies.
Data Source
Medical and pharmacy claims from the Ability Patient Complete (APC) database were used to identify US patients 18 years or older who received aNSCLC diagnoses and initiated 1L systemic therapy with IO monotherapy, CT alone, or IO+CT agents between January 1, 2017, and May 31, 2019. The APC database is nationally representative, including claims during the past 5 years on 160 million covered patients from more than 150 payers across all states representing commercial health plan (~50%), Medicaid (~40%), and Medicare Advantage/supplemental sources. Claims-based selection criteria are described inFigure 1. Patients were required to have had a lung cancer diagnosis, have received a diagnosis of advanced/metastatic disease, and have initiated 1L systemic therapy with any IO monotherapy, CT alone, IO+CT, or targeted regimen approved for treatment of aNSCLC on or after January 1, 2017. Although patients who received a targeted treatment (eg, VEGF inhibitor, monoclonal antibody) were initially selected, only the frequency of use over time was reported for these agents, and this study did not specify HCRU or cost-of-care analyses for them. Patients were identified as having aNSCLC if any claim included a diagnosis code for a distant lymph node or distant metastatic site. The database included the patients’ full claims history through May 30, 2019.
Line of Therapy and Study Cohorts
Line of therapy (LOT) assignment was made by grouping agents that were administered within 30 days of each other. Use of a new or additional agent, discontinuation of an agent for at least 120 days, or a gap in the administration of an agent for more than 120 days formed a new LOT. Maintenance therapy was defined as the continuation of an IO agent (eg, pembrolizumab) following combination IO+CT, provided that the last claim for CT occurred within 120 days of the next claim for the IO agent. As such, maintenance therapy was not considered a new LOT, but a continuation of 1L therapy. Following LOT assignment, patients were categorized into 4 mutually exclusive cohorts based on the 1L treatment regimen received: (1) IO monotherapy, (2) IO+CT, (3) CT only, and (4) all other regimens (including targeted therapy).
HCRU and Costs
The study objectives were to estimate and compare the total costs of care during 1L therapy for patients by treatment cohort. Only patients treated with IO monotherapy, IO+CT, or CT alone were included in this portion of the analysis, as it was assumed that many patients treated with other regimens likely had ALKor EGFRmutations, and therefore their disease was not comparable with that of patients treated with IO or CT. For the 3 cohorts of interest, HCRU was first estimated per 1L therapy cohort based on the Current Procedural Terminologycodes listed in the claims, which indicated the site of care where services were rendered. First, all hospital stays were identified, followed by emergency department (ED) visits, and the remainder of care was assigned to the outpatient/office setting. Next, a microcosting approach was taken to enumerate the per-patient costs of each medical or pharmaceutical service or product rendered in each setting during 1L therapy. Standardized unit costs from CMS fee schedules for medical services and average wholesale price (AWP) for pharmaceutical agents, including antineoplastics, were applied to each service. 11-13Because units (ie, dose administered in mg/kg) were not uniformly available from the claims for IO therapies and other infused drugs, a standard dosage was applied to each antineoplastic drug claim (ie, mg/kg or mg/m 2per schedule of administration using the average weight/height of US men/women). The cost was calculated as the standard dosage multiplied by the AWP. All costs were adjusted to an average of the Consumer Price Index for the United States in 2020.
Statistical Analysis
Patient demographics and clinical characteristics were estimated in each cohort using descriptive statistical techniques including mean, SD, and median for continuous variables and counts and proportions for categorical variables. Statistical comparisons of demographics and clinical characteristics were not made among the cohorts, as it was not an objective of this research. Due to the potential variability in follow-up time (no minimum was required), exposure-adjusted estimates of HCRU and costs in the 1L setting were calculated as per-patient per-month (PPPM). For HCRU and costs, the numbers of events (eg, inpatient admissions) or total dollars were divided by the total days of therapy and then multiplied by 30. Given that a cycle of systemic therapy (IO or CT) is 1 infusion every 2, 3, or 4 weeks, the total days of therapy value for patients with less than 1 month of follow-up was extrapolated to 30 in order to not artificially inflate PPPM estimates in cases where a patient had only 1 claim for systemic therapy.
Using the PPPM approach, 2 estimates of costs were calculated: (1) mean unadjusted PPPM, and (2) mean adjusted difference in costs among the 3 cohorts. First, the adjusted PPPM costs were estimated using a generalized linear model (GLM) with γ distribution and log-link function based on goodness-of-fit testing adjusted for sex, age at 1L initiation, insurance payer type, US geographical region, time from first diagnosis to 1L initiation, and Charlson Comorbidity Index (CCI) score. Next, the incremental adjusted mean differences in PPPM total health care costs and the respective individual component costs (eg, inpatient hospitalization, ED visit, office visit, and pharmacy) among the cohorts were calculated (ie, IO monotherapy vs IO+CT, IO monotherapy vs CT, and IO+CT vs CT) using the recycled predictions method. 14Briefly, it isolates the effect of the treatment class on the outcome by holding constant the values for all other covariates, which in this case were sex, age at 1L therapy initiation, payer, US region of residence, and CCI score. To obtain the mean values for the covariates, a probabilistic sampling technique was repeated 100 times in the patient population and a GLM was used to predict the PPPM costs. Next, the mean estimates were used as covariate parameters to calculate the incremental cost differences among the cohorts.
RESULTS
Overall, 125,269 individuals were initially selected and 9062 (7.2%) met the study inclusion/exclusion criteria (Figure 1). The 1L therapy distribution of patients during the entire period was 14.5% receiving IO (n = 1317), 16.8% receiving IO+CT (n = 1522), 58.7% receiving CT (n = 5315), and 10.0% receiving other therapies (n = 908). The proportion of patients receiving CT declined from 72.3% in January through May 2017 to 47.6% during the corresponding months of 2019 (Figure 2). Use of IO+CT increased from 1.8% to 29.8% over the same interval, whereas use of IO therapies declined from 16.4% to 12.0% and use of other 1L therapies increased from 9.5% to 10.7%.
Patient characteristics were similar among those who received IO, IO+CT, and CT in 1L (Table 1). A slightly higher proportion of patients treated with IO+CT were male (54.7% vs 51.5% for IO and 50.9% for CT), whereas patients receiving IO were slightly older (median, 64 years) compared with those receiving IO+CT (62 years), and CT (63 years). Patients who received IO+CT had a lower CCI score (mean of 1.8) compared with those who received IO or CT (mean of 2.1 for each).
The mean (SD) duration of 1L treatment (Table 1) was longest for IO-treated patients at 6.5 (7.3) months compared with IO+CT-treated patients at 5.6 (5.1) months and CT-treated patients at 3.0 (1.6) months. Treatment duration did vary according to the time of initiation (as follow-up time varied) but did so consistently across cohorts. Mean PPPM inpatient hospital admission and ED visit rates during 1L therapy were similar across the cohorts, at 0.23 and 0.34, respectively, for IO-treated patients, 0.24 and 0.37 for IO+CT–treated patients, and 0.23 and 0.35 for CT-treated patients. Mean PPPM outpatient physician office visits were 2.1 for the IO cohort, 2.5 for the IO+CT cohort, and 2.6 for the CT cohort (Table 1).
The mean unadjusted total health care PPPM costs during 1L therapy are shown inFigure 3(including estimates for medical, pharmacy, and antineoplastic drug costs). The highest PPPM costs during 1L therapy were in the IO+CT cohort at $32,436, compared with $19,000 and $17,763 in the CT and IO cohorts, respectively. Mean PPPM antineoplastic drug costs were highest in the IO+CT cohort at $20,234, compared with $2040 in the CT cohort and $12,116 in the IO cohort. Associated medical costs (eg, office visits, hospitalizations, supportive care) were highest in the CT cohort at $13,178 and lowest in the IO cohort at $2743.
Cost differences comparing each cohort are shown inTable 2. Adjusted analyses showed that PPPM costs were $13,933 (95% CI, $11,760-$16,105) higher in the IO+CT cohort vs the IO cohort ( P< .0001). Further, PPPM medical costs were $5876 higher and antineoplastic drug costs were $7596 higher. Compared with CT costs, IO costs were $1024 lower (95% CI, $67-$1980) ( P= .04), driven by substantially ($10,265) lower medical costs notwithstanding substantially ($10,025) higher antineoplastic drug costs for IO. As such, total health care PPPM costs in the IO+CT cohort were also higher by $13,131 (95% CI, $11,286-$14,437) compared with those in the CT cohort.
DISCUSSION
The last 5 years have seen expansive growth in the approved indications for IO in aNSCLC, which has led to meaningful improvements in clinical outcomes for patients. However, these improvements impose a cost on health care payers, patients, and society through government-subsidized health care plans. Research has demonstrated that at locally relevant willingness-to-pay thresholds, IO agents are cost-effective. 10Studies comparing IO+CT regimens with CT alone have reported similar findings and conclusions (albeit at varying levels of willingness-to-pay thresholds and quality-adjusted life-years), 4,15,16but as far as we are aware, this research represents the first nationally representative real-world data study to estimate and compare the direct total health care costs to payers among IO, CT, and IO+CT regimens for 1L treatment of aNSCLC since the approval of IO in the 1L therapeutic setting.
We observed the direct impact of the introduction of IO therapy by first assessing its rate of adoption. Although the use of IO monotherapy in the 1L setting has remained relatively constant, the use of IO+CT has increased at a rate of more than 5% every 6 months between 2018 and 2019. Our data mirror the timing of the August 2018 approval of pembrolizumab plus CT for 1L treatment of aNSCLC, with a near doubling of the proportion of patients initiating 1L IO+CT between the first and second half of 2018 (99% of patients in the study sample had received pembrolizumab-containing regimens). 4The observation that IO monotherapy use remained relatively constant may be explained by its preferred use in patients with high PD-L1 expression (although PD-L1 data were not available for analysis in this study), cost concerns for combination therapy (especially among providers participating in VBC initiatives such as OCM), and/or the inability of certain patients to tolerate CT. Consequently, IO monotherapy remains a relevant treatment approach for appropriate patients with aNSCLC (eg, those with ≥ 50% PD-L1 expression).
Next, we found that IO+CT–treated patients had the highest total PPPM health care costs in the 1L setting, which were significantly higher than those of patients treated with IO or CT. These findings were not explained by HCRU differences, as no statistically significant differences in hospitalizations or ED visits were found among the 3 cohorts. Instead, higher antineoplastic drug costs likely explain a large proportion of this difference, a phenomenon that has previously been reported with novel aNSCLC agents such as osimertinib, which was adopted into routine clinical practice and led to a 100% increase in total health care costs. 17In addition, a possible explanation for the greater antineoplastic drug costs for the IO+CT cohort compared with IO monotherapy or CT alone may be driven by the use of pemetrexed, which remains unavailable in generic formulation in the United States. In the IO+CT cohort, more than 80% of individuals received pembrolizumab in combination with pemetrexed, compared with less than 25% of patients in the CT cohort. In addition to the higher drug costs of pembrolizumab and pemetrexed, substantially ($8860) higher PPPM medical costs for IO+CT were observed compared with the total PPPM medical costs for IO of $2743. The difference may result at least in part from the association of CT with costs for the management of AEs, which may require supportive care interventions. The declining duration of 1L therapy over time in all cohorts may have been associated with fewer patients in each category over time, shortened length of follow-up, or switches to different types of therapy if the current therapy was not efficacious as time continued.
Finally, we observed significantly higher medical costs for patients who received CT alone vs either IO or IO+CT. Further research is warranted to examine whether higher medical costs of CT alone may be related to inferior clinical outcomes for patients or whether these differences could be explained by systematic clinical differences among the cohorts. Patients in the end-of-life phase of cancer care, during which treatment with CT alone may be more frequent, incur direct medical costs substantially higher than those of patients in the continuing phase of treatment. 18
Limitations
There are several limitations to the current study specifically and inherent to administrative claims–based analyses. First, HCRU and total PPPM cost estimates may be prone to error due to lack of complete follow-up. Second, paid costs were not available, and drug reimbursement rates may vary by payer. Third, LOT assignment was based on an algorithm, and as such may be subject to misclassification. Strengths of this study include the large sample size and the representation of Medicaid patients in the APC database, which is higher than in other commercial claims-based databases.
CONCLUSIONS
IO+CT in the 1L therapeutic setting now accounts for nearly a third of 1L aNSCLC treatment modalities, a shift that has coincided with a 25% reduction in the proportion of patients treated with 1L CT from 2017 to 2019. Additionally, the use of IO monotherapy has remained relatively constant at 12% to 16% during this interval. Patients treated with IO monotherapy had fewer outpatient visits PPPM, but no differences in hospital admissions or ED visits were observed among the 1L therapy cohorts. Further, CT-containing regimens were associated with higher nonantineoplastic health care costs than were IO monotherapy regimens. The transition to a VBC framework and shared financial risk payment models such as OCM warrants continued analyses of cost-effectiveness to provide patients, providers, payers, and policymakers the data needed to inform the design of benefit plans, shared decision-making, and optimized health care outcomes, both clinically and financially. Further research will help to stratify cost-effectiveness of the increasingly myriad therapeutic options for aNSCLC, which include CT, IO, and targeted therapies alone and in combination.
Acknowledgments
The authors would like to acknowledge Alexandrina Balanean and Danielle Gentile of Cardinal Health for manuscript editing.
Author Affiliations:Cardinal Health (JK, DL, DC, BF), Dublin, OH; Bristol Myers Squibb (JH, SJL), Lawrenceville, NJ.
Source of Funding:This research was sponsored by Bristol Myers Squibb.
Author Disclosures:Dr Kish reports former employment and stock ownership in Cardinal Health. Mr Liassou reports employment at Cardinal Health. Dr Hartman reports employment and stock ownership in Bristol Myers Squibb, which is the manufacturer and patent owner of a competitor regimen. Dr Lubinga reports employment and stock ownership in Bristol Myers Squibb. Mr Chopra reports employment at Cardinal Health. Dr Feinberg reports employment and stock ownership in Cardinal Health.
Authorship Information:Concept and design (JK, JDH, SJL, DC, BF); acquisition of data (JK, DC); analysis and interpretation of data (JK, DL, JDH, SJL, DC, BF); drafting of the manuscript (JK, BF); critical revision of the manuscript for important intellectual content (JK, DL, JDH, SJL, BF); statistical analysis (JK, DL); obtaining funding (JDH); administrative, technical, or logistic support (SJL); and supervision (JK, JDH).
Address Correspondence to:Bruce Feinberg, DO, Cardinal Health, 7000 Cardinal Pl, Dublin, OH 43017. Email: [email protected].
REFERENCES
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30. doi:10.3322/caac.21590
2. Cancer stat facts: lung and bronchus cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed September 17, 2022. https://seer.cancer.gov/statfacts/html/lungb.html
3. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. doi:10.1056/NEJMoa1507643
4. Pai-Scherf L, Blumenthal G, Li H, et al. FDA approval summary: pembrolizumab for treatment of metastatic non-small cell lung cancer: first-line therapy and beyond. Oncologist. 2017;22(11):1392-1399. doi:10.1634/theoncologist.2017-0078
5. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865
6. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948
7. Wang C, Kulkarni P, Salgia R. Combined checkpoint inhibition and chemotherapy: new era of 1st-line treatment for non-small-cell lung cancer. Mol Ther Oncolytics. 2019;13:1-6. doi:10.1016/j.omto.2019.02.001
8. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019:381(21):2020-2031. doi:10.1056/NEJMoa1910231
9. Aviki EM, Schleicher SM, Mullangi S. The Oncology Care Model and other value-based payment models in cancer care. JAMA Oncol. 2019;5(3):298-299. doi:10.1001/jamaoncol.2018.5735
10. Dacosta Byfield S, Chastek B, Korrer S, Horstman T, Malin J, Newcomer L. Real-world outcomes and value of first-line therapy for metastatic non-small cell lung cancer. Cancer Invest. 2020;38(10):608-617. doi:10.1080/07357907.2020.1827415
11. Physician fee schedule: CY 2021 physician fee schedule update. CMS. Updated November 2, 2022. Accessed August 5, 2022. https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/PhysicianFeeSched
12. Medicare Part B drug average sales price. CMS. Updated March 15, 2023. Accessed August 12, 2022. https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice
13. Medi-Span Price Rx: online drug pricing tool. Wolters Kluwer. Accessed July 10, 2022. https://www.wolterskluwercdi.com/cdi/ppc/pricerx/
14. Li Z, Mahendra G. Using “recycled predictions” for computing marginal effects. Lex Jansen. Accessed October 26, 2022. https://www.lexjansen.com/wuss/2009/hor/HOR-Li.pdf
15. Courtney PT, Yip AT, Cherry DR, Salans MA, Kumar A, Murphy JD. Cost-effectiveness of nivolumab-ipilimumab combination therapy for the treatment of advanced non-small cell lung cancer. JAMA Netw Open. 2021;4(5):e218787. doi:10.1001/jamanetworkopen.2021.8787
16. Wan X, Zeng X, Peng L, et al. Cost-effectiveness analysis of nivolumab plus ipilimumab for advanced non-small-cell lung cancer. Front Pharmacol. 2021;12:580459. doi:10.3389/fphar.2021.580459
17. Whalen JJ, Eckwright DJ, Burke JP, Gleason PP. Osimertinib first-line approval in epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small cell lung cancer (NSCLC): impact on utilization and total cost of care among 15 million commercially insured members. J Manag Care Spec Pharm. 2019;29(suppl 10-a):S30. doi:10.18553/jmcp.2019.25.10-a.s1
18. Kaye DR, Sung Min H, Herrel LA, Dupree JM, Ellimoottil C, Miller DC. Costs of cancer care across the disease continuum. Oncologist. 2018;23(7):798-805. doi:10.1634/theoncologist.2017-0481
Association Between Low-Income Subsidies and Inequities in Orally Administered Antimyeloma Therapy Use May 16th 2023
© 2023 MJH Life Sciences ™ . All rights reserved.
| https://www.ajmc.com/view/determinants-of-diagnostic-imaging-utilization-in-primary-care |
Metropen: Uses, Price, Dosage, Side Effects, Substitute, Buy Online
Find out about Metropen benefits, side effects, price, dose, how to use Metropen, interactions and contraindications
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Metropen
☆ ☆ ☆ ☆ ☆ 5.0/5.0 (1 Ratings & 0 Reviews)
10 Tablet in 1 Strip
₹ 7
Metropen Tablet 10 TABLET 1 Strip ₹ 7
Out of Stock
Manufactured by: Pfizer Ltd
Contains / Salt: Metronidazole (400 mg)
Metropen Information
Metropen is a prescription medicine that is available as a Tablet. Bacterial Infections, Stomach Infection, Amebiasis are some of its major therapeutic uses. The alternative uses of Metropen have also been explained below.
Medical history of the patient along with age and gender determines the dosage of Metropen. Dosage also depends on the route of administration and your chief complaint for which the drug is prescribed. Refer to the dosage section for a detailed discussion.
The side effects typically associated with Metropen include Nausea or vomiting, Headache. Besides the aforementioned side effects, there are other adverse effects of Metropen as well, which are listed below. These side effects of Metropen are usually temporary and subside with the completion of treatment. Please speak with your doctor if these side effects worsen or persist for a longer duration.
It is also important to note that Metropen has a Safe effect for pregnant women and Moderate effect on lactating mothers. It is important to know if Metropen has any effect on the kidney, liver and heart. Information on such adverse effects, if any, has been given in the Metropen related warnings section.
Metropen is not recommended if you suffer from certain medical conditions as it can have adverse effects. Liver Disease, Heart Disease, Peripheral Neuropathy are examples of such conditions. The section on Metropen contraindications lists all such conditions.
Additionally, Metropen may also adversely react with other medicines. A complete list of these interactions is given below.
In addition to these precautions, you may also note that Metropen is not safe while driving, and is is not addictive in nature.
Metropen Benefits & Uses
Metropen Dosage & How to Take
Metropen Side Effects
Metropen Related Warnings
Severe Interaction of Metropen with Other Drugs
Metropen Contraindications
Frequently asked Questions about Metropen
Metropen Interactions with Food and Alcohol
Metropen Benefits & Uses
Metropen is used to treat the following -
Main Benefits
Bacterial Infections
Stomach Infection
Amebiasis
Giardiasis
Diarrhoea(Read More -Home Remedies for Diarrhoea)
Parasitic Infections
Other Benefits
Brain Infection
Skin Infections
Reproductive System Infection
Peptic Ulcer
Rosacea
Endocarditis
White Discharge(Read More -Leucorrhoea home remedies)
Blood in Stool
Toothache(Read More -Home remedies for toothache)
Bleeding Gums(Read More -Home remedies for bleeding gums)
Dysentery
Bacterial Vaginosis
Trichomoniasis
Peritonitis
Pneumonia
H. Pylori
Intestinal Worms
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Metropen Dosage & How to Take
This is the usual dosage recommended in most common treatment cases. Please remember that every patient and their case is different, so the dosage can be different based on the disease, route of administration, patient's age and medical history.
<table><tbody><tr><td> Age Group</td><td> Dosage</td></tr><tr><td>Adult</td><td> Disease:Bacterial Infections Before or After Meal:After Meal Single Maximum Dose:7.5
mg/kg Dosage Form:Tablet (Immediate Release) Dosage Route:Oral Frequency:6
hourly Course Duration:10 days Special Instructions:As prescribed by the doctor</td></tr><tr><td>Adult(Female)</td><td> Disease:Endocarditis Before or After Meal:After Meal Single Maximum Dose:7.5
mg/kg Dosage Form:Tablet (Immediate Release) Dosage Route:Oral Frequency:6
hourly Course Duration:10 days Special Instructions:As prescribed by the doctor</td></tr><tr><td>Geriatric</td><td> Disease:Bacterial Infections Before or After Meal:After Meal Single Maximum Dose:7.5
mg/kg Dosage Form:Tablet (Immediate Release) Dosage Route:Oral Frequency:6
hourly Course Duration:10 days Special Instructions:As prescribed by the doctor</td></tr><tr><td>13 - 18 years (Adolescent)</td><td> Disease:Bacterial Infections Before or After Meal:After Meal Single Maximum Dose:750
mg Dosage Form:Tablet (Immediate Release) Dosage Route:Oral Frequency:8
hourly Course Duration:10 days Special Instructions:As prescribed by the doctor</td></tr><tr><td>2 - 12 years (Child)</td><td> Disease:Bacterial Infections Before or After Meal:After Meal Single Maximum Dose:750
mg Dosage Form:Tablet (Immediate Release) Dosage Route:Oral Frequency:8
hourly Course Duration:10 days Special Instructions:As prescribed by the doctor</td></tr><tr><td>Neonates (0 to 1 month)</td><td> Disease:Bacterial Infections Before or After Meal:After Meal Single Maximum Dose:7.5
mg/kg Dosage Form:Tablet (Immediate Release) Dosage Route:Oral Frequency:8
hourly Course Duration:10 days Special Instructions:As prescribed by the doctor</td></tr><tr><td>Infant (1 month to 2 years)</td><td> Disease:Bacterial Infections Before or After Meal:After Meal Single Maximum Dose:750
mg Dosage Form:Tablet (Immediate Release) Dosage Route:Oral Frequency:8
hourly Course Duration:10 days Special Instructions:As prescribed by the doctor</td></tr></tbody></table>
Metropen Side Effects
Based on research, the following side effects have been observed when Metropen is used -
Severe
Skin redness
Skin Burning
Skin irritation
Agitation
Loss of appetite
Moderate
Erythema
Mild
Metallic taste in mouth
Common
Nausea or vomiting
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Metropen Related Warnings
Is the use of Metropen safe for pregnant women?
There are no side effects of Metropen in pregnant women.
Safe
Is the use of Metropen safe during breastfeeding?
If you are breastfeeding, you may experience some harmful effects of Metropen. In case you experience any of these, discontinue its use until you consult your doctor.
Moderate
What is the effect of Metropen on the Kidneys?
Metropen rarely harms the kidneys.
Mild
What is the effect of Metropen on the Liver?
Metropen is rarely harmful for the liver.
Mild
What is the effect of Metropen on the Heart?
Very few cases of side effects of Metropen on the heart have been reported.
Mild
Severe Interaction of Metropen with Other Drugs
Metropen should not be taken with following medicines due to severe side effects it may cause to patients -
Life Threatening
Disulfiram
Esperal Tablet
Deadict 500 Tablet
Metropen Contraindications
If you are suffering from any of the following diseases, you should not take Metropen unless your doctor advises you to do so -
Liver Disease
Kidney Disease
Heart Disease
Diabetes
Peripheral Neuropathy
Calcium Deficiency
Potassium Deficiency
Coronary Artery Disease (CAD)
Frequently asked Questions about Metropen
Is this Metropen habit forming or addictive?
No, you will not get addicted to Metropen.
No
Is it safe to drive or operate heavy machinery when consuming?
After taking Metropen you may feel sleepy. So it is not advised to perform these activities.
Dangerous
Is it safe?
Yes, but consume Metropen only on doctor's advice.
Safe, but take only on Doctor's advise
Is it able to treat mental disorders?
No, Metropen is not used to treat mental disorders.
No
Metropen Interactions with Food and Alcohol
Interaction between Food and Metropen
Taking Metropen with food does not harm your health.
Safe
Interaction between Alcohol and Metropen
Consult your doctor before consuming alcohol while taking Metropen as it can have severe side effects.
Severe
Frequently asked Questions about Metropen
How long can I safely take Metropen?
Dr. Rahul Poddar MBBS, DNB, MBBS, DNB , General Surgery
Take Metropen as directed by your doctor. Do not discontinue the drug suddenly or take it longer than prescribed.
How does Metropen work?
Metropen acts on the DNA structure of bacterial and protozoan cells and disrupts its helical structure resulting in the death of bacteria and protozoa. Infections caused due to pathogens are eradicated completely when taken in prescribed dosage and duration.
Can I discontinue Metropen on my own without doctors advice?
Dr. Kuldeep Meena MBBS, MD , Cardiology, Neurology, Pediatrics, Dermatology, Pulmonology, Nephrology, General Physician, Other, Infectious Disease, Emergency Medicine, Allergy and Immunology, Internal Medicine, Multispeciality
Discontinuation of Metropen on your own can cause unwanted side effects. You are recommended to always consult a doctor before discontinuing this medicine.
Can I take Metropen without consulting a doctor?
Metropen is a prescription drug so do not take it without consulting a doctor. It can be harmful to consume this medicine if you don't require it.
Is Metropen carcinogenic?
Yes, Metropen may be carcinogenic (cancer-causing) if taken beyond prescribed dosage. As per FDA reports, it has shown cancer-causing properties in rats and mice in clinical trials. Therefore, take this medicine strictly as per instructions and do not use it unnecessarily.
This medicine data has been created by -
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Vikas Chauhan
B.Pharma, Pharmacy5 Years of Experience
References
US Food and Drug Administration (FDA) [Internet]. Maryland. USA;Package leaflet information for the user; Flagyl® Metronidazole
KD Tripathi. [link]. Seventh Edition. New Delhi, India: Jaypee Brothers Medical Publishers; 2013: Page No 837-839
April Hazard Vallerand, Cynthia A. Sanoski. [link]. Sixteenth Edition. Philadelphia, China: F. A. Davis Company; 2019: Page No 850-851
In stock alternatives of Metropen (based on Metronidazole (400 mg))
| https://www.myupchar.com/en/medicine/metropen-p37098878?ref=linkstock |
EudraCT Number 2011-003731-63 - Clinical trial results - EU Clinical Trials Register
Clinical trials
The European Union Clinical Trials Register allows you to search for protocol and results information on: interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development
EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the Clinical Trials Information System (CTIS).
The EU Clinical Trials Register currently displays 43616 clinical trials with a EudraCT protocol, of which 7207 are clinical trials conducted with subjects less than 18 years old.
The register also displays information on 18700 older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).
Clinical Trial Results: A phase IV, open, multi-centre study to assess the immunogenicity, reactogenicity and safety of two doses of GSK Biologicals’ oral live attenuated human rotavirus (HRV) vaccine in healthy Taiwanese infants who received hepatitis B immunoglobulin after birth.
Summary EudraCT number 2011-003731-63 Trial protocol Outside EU/EEA Global end of trial date 18 Apr 2011 Results information Results version number v2(current) This version publication date 05 Mar 2023 First version publication date 12 Jun 2015 Other versions v1 Version creation reason Correction of full data set Correction of full data set and alignment between registries.
Trial information Top of page
Trial identification
Sponsor protocol code 114351
Additional study identifiers
ISRCTN number -
US NCT number NCT01198769
WHO universal trial number (UTN) -
Sponsors
Sponsor organisation name GlaxoSmithKline Biologicals
Sponsor organisation address Rue de l’Institut 89, Rixensart, Belgium, B-1330
Public contact Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089904466, [email protected]
Scientific contact Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089904466, [email protected]
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP) No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? Yes
Results analysis stage
Analysis stage Final
Date of interim/final analysis 18 Apr 2011
Is this the analysis of the primary completion data? Yes
Primary completion date 18 Apr 2011
Global end of trial date 18 Apr 2011
Was the trial ended prematurely? No
General information about the trial
Main objective of the trial
To assess the immunogenicity of GSK Biologicals' HRV vaccine in terms of serum anti-rotavirus (anti-RV) immunoglobulin A (IgA) antibody seroconversion rate (SCR), 2 months post-Dose 2 (i.e. at study Month 4) of the HRV vaccine.
Protection of trial subjects All the subjects were observed closely for at least 30 minutes, with appropriate medical treatment readily available in case of anaphylaxis following the administration of vaccine.
Background therapy -
Evidence for comparator -
Actual start date of recruitment 11 Nov 2010
Long term follow-up planned No
Independent data monitoring committee (IDMC) involvement? No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled Taiwan: 15
Worldwide total number of subjects 15
EEA total number of subjects 0
Number of subjects enrolled per age group
In utero 0
Preterm newborn - gestational age < 37 wk 0
Newborns (0-27 days) 0
Infants and toddlers (28 days-23 months) 15
Children (2-11 years) 0
Adults (18-64 years) 0
From 65 to 84 years 0
85 years and over 0
Subject disposition Top of page
Recruitment
Recruitment details -
Pre-assignment
Screening details During the screening the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms.
Period 1
Period 1 title Overall Trial (overall period)
Is this the baseline period? Yes
Allocation method Not applicable
Blinding used Not blinded
Arms
Arm title Rotarix Group
Arm description Subjects received 2 oral doses of Rotarix vaccine at 2 and 4 months of age.
Arm type Experimental
Investigational medicinal product name Rotarix
Investigational medicinal product code
Other name
Pharmaceutical forms Oral suspension
Dosage and administration details Subjects received 2 oral doses of Rotarix (HRV) vaccine at 2 and 4 months of age.
Number of subjects in period 1 Rotarix Group Started 15 Completed 15
Baseline characteristics Top of page Baseline characteristics reporting groups Reporting group title Rotarix Group Reporting group description Subjects received 2 oral doses of Rotarix vaccine at 2 and 4 months of age. Reporting group values Rotarix Group Total Number of subjects 15 15 Age categorical Units: Subjects In utero 0 0 Preterm newborn infants (gestational age < 37 wks) 0 0 Newborns (0-27 days) 0 0 Infants and toddlers (28 days-23 months) 15 15 Children (2-11 years) 0 0 Adolescents (12-17 years) 0 0 Adults (18-64 years) 0 0 From 65-84 years 0 0 85 years and over 0 0 Age continuous Units: weeks arithmetic mean (standard deviation) 8.9 ± 0.8 - Gender categorical Units: Subjects Female 8 8 Male 7 7
End points Top of page End points reporting groups Reporting group title Rotarix Group Reporting group description Subjects received 2 oral doses of Rotarix vaccine at 2 and 4 months of age.
Primary: Number of seroconverted subjects for serum anti-rotavirus immunoglobulin A (igA) antibody Top of page
End point title Number of seroconverted subjects for serum anti-rotavirus immunoglobulin A (igA) antibody [1]
End point description
Seroconversion is defined as the appearance of IgA antibody concentration equal to or above (≥) 20 Units per millilitre (U/mL) in the serum of subjects who were seronegative before vaccination. A seronegative subject is a subject with anti-rotavirus IgA antibody concentration below (<) 20 U/mL.
The According-To-Protocol cohort for immunogenicity included subjects who received Hepatitis B immunoglobulin after birth, who were seronegative for serum anti-RV IgA antibody at Day 0, who complied with vaccination schedule for the Rotarix vaccine, who had no RV other than the vaccine strain in gastroenteritis stool sample up to Month 4.
End point type Primary
End point timeframe 2 months post-Dose 2 (at study Month 4)
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
End point values Rotarix Group Number of subjects analysed 15 Units: Subjects ≥20 U/mL 15
No statistical analyses for this end point
Primary: Number of seroconverted subjects for serum anti-rotavirus immunoglobulin A (igA) antibody Top of page
Secondary: Serum anti-rotavirus IgA antibody concentrations Top of page
End point title Serum anti-rotavirus IgA antibody concentrations
End point description
Concentrations were expressed as geometric mean antibody concentration in units per millilitre (U/mL), calculated on all subjects.
The According-To-Protocol cohort for immunogenicity included subjects who received Hepatitis B immunoglobulin after birth, who were seronegative for serum anti-RV IgA antibody at Day 0, who complied with vaccination schedule for the Rotarix vaccine, who had no RV other than the vaccine strain in gastroenteritis stool sample up to Month 4.
End point type Secondary
End point values Rotarix Group Number of subjects analysed 15 Units: U/mL geometric mean (confidence interval 95%) GMC (U/mL) 254.7 (145 to 447.7)
No statistical analyses for this end point
Secondary: Serum anti-rotavirus IgA antibody concentrations Top of page
Secondary: Number of subjects reporting solicited general symptoms Top of page End point title Number of subjects reporting solicited general symptoms End point description Solicited general symptoms assessed were cough, diarrhoea, irritability, loss of appetite, temperature (any temperature was defined as a tympanic on rectal setting temperature ≥ 38.0 degrees Celsius) and vomiting.
The Total vaccinated cohort included all subjects with at least one vaccine administration documented. End point type Secondary End point timeframe During the 8-day (Days 0-7) post-vaccination period End point values Rotarix Group Number of subjects analysed 15 Units: Subjects Cough 6 Diarrhoea 1 Irritability 11 Loss of appetite 10 Temperature (Tympanic on rectal seting (≥38.0°C)) 5 Vomiting 2 No statistical analyses for this end point
Secondary: Number of subjects reporting solicited general symptoms Top of page
Secondary: Number of subjects with rotavirus (RV) present in the gastroenteritis (GE) stool sample Top of page
End point title Number of subjects with rotavirus (RV) present in the gastroenteritis (GE) stool sample
End point description
RV was not identified in the one GE stool sample collected in the study. Two subjects reported GE episode between vaccination Dose 1 and before vaccination Dose 2. For one of them, GE stool sample was not collected and for the other subject no RV was identified in the GE stool sample. GE symptoms were defined as diarrhoea with or without vomiting. A GE stool sample was collected as soon as possible after the illness began by the parent/guardian of the subject. Presence of RV antigen was detected by Enzyme-linked immunosorbent assay (ELISA).
The Total vaccinated cohort included all subjects with at least one vaccine administration documented.
End point type Secondary
End point timeframe From Day 0 (first vaccine dose) to study Month 4 (2 months post-Dose 2)
End point values Rotarix Group Number of subjects analysed 15 Units: Subjects RV present in the GE stool samples 0
No statistical analyses for this end point
Secondary: Number of subjects with rotavirus (RV) present in the gastroenteritis (GE) stool sample Top of page
Secondary: Number of subjects reporting unsolicited adverse events (AEs) Top of page
End point title Number of subjects reporting unsolicited adverse events (AEs)
End point description
An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.
The Total vaccinated cohort included all subjects with at least one vaccine administration documented.
End point type Secondary
End point timeframe Within the 31-day (Days 0-30) follow-up period after vaccination
End point values Rotarix Group Number of subjects analysed 15 Units: Subjects Unsolicited AEs 4
No statistical analyses for this end point
Secondary: Number of subjects reporting serious adverse events (SAEs) Top of page End point title Number of subjects reporting serious adverse events (SAEs) End point description SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects.
The Total vaccinated cohort included all subjects with at least one vaccine administration documented. End point type Secondary End point timeframe During the entire study period (from Dose 1 at Day 0 up to Month 4) End point values Rotarix Group Number of subjects analysed 15 Units: Subjects SAEs 1 No statistical analyses for this end point
Adverse events information
| https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-003731-63/results |
Diagnostic impact of 18F-FDG PET/CT imaging on the detection of immune-related adverse events in patients treated with immunotherapy | Request PDF
Request PDF | Diagnostic impact of 18F-FDG PET/CT imaging on the detection of immune-related adverse events in patients treated with immunotherapy | Introduction: Immunotherapy is an effective treatment method for cancer cells with humoral and cellular immune mechanisms of action but triggers... | Find, read and cite all the research you need on ResearchGate
Article
Diagnostic impact of 18F-FDG PET/CT imaging on the detection of immune-related adverse events in patients treated with immunotherapy
May 2022
Clinical and Translational Oncology
DOI: 10.1007/s12094-022-02840-9
Authors:
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Gamze Tatar
Hitit University Çorum Erol Olçok Training And Research Hospital
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Göksel Alçın
Istanbul Training and Research Hospital
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Nilay Sengul Samanci
İstanbul University-Cerrahpaşa
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Özge Erol Fenercioğlu
Istanbul Training and Research Hospital
Abstract
Introduction:
Immunotherapy is an effective treatment method for cancer cells with humoral and cellular immune mechanisms of action but triggers an inflammatory response and disrupts standard protective immune tolerance. Early detection of immune-related adverse events (irAEs) on PET/CT is crucial for patient management and subsequent therapy decisions. In this study, we aimed to evaluate the impact of 18F-FDG PET/CT on detecting of irAEs in patients receiving immunotherapy.
Patients and methods:
Forty-six patients with advanced RCC (n: 32), malign melanoma (n: 9), lung cancer (n: 4), and laryngeal carcinoma (n: 1), who underwent 18F-FDG PET/CT imaging for response assessment after immunotherapy, were enrolled in the study. Newly detected findings associated with irAEs on posttreatment PET/CT images were compared with the pretreatment PET/CT, both qualitatively and semi-quantitatively.
Results:
Twenty-eight (61%) patients developed irAEs as observed on PET/CT. Enteritis/colitis was the most frequent irAE visualized on PET/CT with 13 patients (28.2%), followed by gastritis (17.3%), thyroiditis (13%), and myositis/arthritis (13%). Hepatitis (6.5%), pneumonitis (6.5%), sarcoid-like reaction (4.3%), and hypophysitis (4.3%) were observed to a lesser extent. The median time between the appearance of irAEs on PET/CT and the initiation of immunotherapy was 4.3 months. There were no significant differences in age, sex, and treatment response status of patients with and without irAEs.
Conclusion:
18F-FDG PET/CT plays a fundamental role in cancer immunotherapy with the potential to show significant irAEs both in the diagnosis and in follow-up of irAEs. IrAEs were present on PET/CT images of more than half of the patients who received immunotherapy in our study.
... Tatar et al. studied [18F]-fluoro-2-deoxy-D-glucose (F-FDG) PET/CT for detecting immune-related adverse events (irAEs) in immune checkpoint inhibitor patients in 2022 (ICIs). The study enrolled 46 patients with diverse forms of advanced cancer, and their treatment responses were monitored using PET/CT scanning
[24]
. The study found that among the most frequently observed adverse effects, colitis (28.1%) stood out, while among the least often observed adverse effects, thyroiditis and myositis/ arthritis (13.0%) affected only about six individuals. ...
... The study's results suggest that F-FDG PET/ CT is an important aspect of cancer immunotherapy, as it can detect serious irAEs during diagnosis and followup. irAEs were detected on PET/CT scans in more than 50% of the trial patients
[24]
. The study concludes that implementing F-FDG PET/CT scans in the management and follow-up of patients receiving ICIs is essential for the early detection and management of irAEs [24]. ...
... irAEs were detected on PET/CT scans in more than 50% of the trial patients [24]. The study concludes that implementing F-FDG PET/CT scans in the management and follow-up of patients receiving ICIs is essential for the early detection and management of irAEs
[24]
. ...
Immunotherapy-induced thyroid dysfunction: an updated review
Article
Full-text available
Jun 2023
<here is a image 0d80ea7b12b92480-8929df4fa182dc36> Mahmoud Nassar
<here is a image bccf865f8b27979f-033ec8e67108c299> Hazem Abosheaishaa
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Bahaaeldin Baraka
Immunotherapy medicines (immune checkpoint inhibitors, ICIs) that work directly on the immune system have shown vastly increased survival for people with cancer in phases 2 and 3 clinical studies during the past few years. Nevertheless, ICI treatment (irAEs) may trigger immune-related adverse effects. An underactive thyroid is among the most frequent endocrine irAE, affecting about 40% of individuals who received ICIs. Our review aims to collect and organize the most recent data on immunotherapy-induced thyroid dysfunction in cancer patients, including its prevalence, diagnostic criteria, and treatment options and to summarize those findings in a comprehensive review article. The incidence of irAEs varies depending on the type of cancer and the treatment regimen. Thyroid ultrasound, radioactive uptake scan, and PET CT scan can aid in diagnosing thyroid dysfunction. Thyroid dysfunction treatment necessitates collaboration between specialists in oncology, endocrinology, and primary care in a multidisciplinary team discussion. The prognosis of patients who suffered from thyroid dysfunction while on ICIs treatment is reasonably good. Suboptimal baseline thyroid function was linked with decreased overall survival (OS) among ICI-treated patients, but initiating replacement hormonal therapy after ICI initiation was associated with enhanced OS. More research work is required to identify these links and mechanisms of action.
Severe Late-Onset Grade III-IV Adverse Events under Immunotherapy: A Retrospective Study of 79 Cases
Background: For several decades, PD‐1 has been a target in malignant melanoma (MM). PD‐1 inhibitors (nivolumab, pembrolizumab) and anti‐CTLA‐4 (CD152) (ipilimumab) have revolutionized cancer therapy. PD‐1 and CTLA‐4 inhibition leads to prolonged lymphocyte effects, which explains the cytotoxicity underlying immune‐reaction‐based adverse events (irAEs). Most irAEs occurin the first cycle of treatment at a median of 40 days. IrAEs of any grade have been observed in 68.2% of patients, with 10% of patients experiencing severe grade III/IV irAEs. Data on late‐onset irAEs are lacking. Methods: Data on patients with advanced melanoma (N = 1862) from March 2016 to March 2021 were obtained from the RicMel database, a French national multicentric biobank dedicated to the follow‐up of MM patients. Patients who received anti‐PD‐1 therapy or a combination therapy and experienced grade III‐IV irAEs were selected and analyzed at 7 months, one year and two years after treatment was initiated. Results: Superficial spreading melanoma (SSM) and previous oncological drug administration before immunotherapy are significant risk factors for lateonset irAEs over 2 years after beginning immunotherapy in the univariate and multivariate analysis. The other parameters—sex, mutational status, association of immunotherapy (PD‐1i and CTLA‐4i) and overall response—were not significantly associated with late‐onset irAEs. In our real‐life data study, the median onset time of grade III‐IV irAES was 128 days after the initiation of immune checkpoint inhibitors (ICI) therapy. Conclusions: Our study, using real‐life data, suggests that patients with SSM and those who have received previous oncological treatments are more likely to experience late‐onset grade III‐IV irAES. Further multicentric studies with wider recruitment of patients should be performed to confirm our findings, potentially leading to changes in the recommended treatment for carefully monitored at‐risk patients.
Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors
Expanding the US Food and Drug Administration–approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%–12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.
Cardiac Toxicities Associated with Immune Checkpoints Inhibitors: Mechanisms, Manifestations and Management
Article
| https://www.researchgate.net/publication/360746414_Diagnostic_impact_of_18F-FDG_PETCT_imaging_on_the_detection_of_immune-related_adverse_events_in_patients_treated_with_immunotherapy |
SPECIAL SECTION/BRICK & CLAY RECORD: Energy-Efficient Dust Collection
Optimizing factors such as a dust collection system's hood and ducting can enable the use of smaller, more energy-efficient motors.
Optimizing factors such as a dust collection system's
hood and ducting can enable the use of smaller, more energy-efficient motors.
For environmental and worker safety reasons, among
others, effective dust collection is a must. Mechanical and media filtration
dust collectors are designed primarily for "dry" industrial dusts,
but some tolerate a minimal amount of liquid contaminants. The most common
mechanical dust collector is the cyclone collector. Typical media filtration
collector types include media fan/filter, cartridge filter and bag house.
Cyclones are the oldest type of dust collection device.
They operate by spinning the collected material within the device using
centrifugal force to direct the dust to the outside wall of the separator.
Gravity and mechanical internal deflectors direct the dust-laden air in a
downward spiral and discharge the dust through the cone bottom. Cyclones can
also be used as pre-separators for heavy concentration levels.
A self-contained media fan/filter unit is the simplest
form of industrial filtration device. It works by passing contaminated air
through a pre-filter, which collects larger particles, then through a primary
filter where smaller particles can be captured. The clean air is then returned
to the workplace.
Continuous cleaning cartridge filter units use pleated
paper or polyester cartridge filters. The filter elements are cleaned on-line
during the dust collection process. Cartridge units offer high filtration
efficiency and are capable of trapping up to 99% of sub-micronic materials and
virtually 100% of larger dust particles.A bag house dust collector is a tubular bag device that,
like cartridge filter units, can be cleaned on-line during the dust collection
process. This results in a relatively constant airflow, as well as energy
savings. Bag house dust collectors are highly efficient in the collection of
fibrous and other large-size process particulate at relatively high
concentration levels.The design and location of a dust collection system's
hood, ducting, collector and fan can collectively add sufficient static
pressure requirements to the point where larger, more expensive-to-operate
motors are necessary to maintain effectiveness. However, optimizing these areas
can make it possible to use smaller, more energy-efficient brake horsepower
motors. The electrical savings potential for a simple dust control system can
be at least $2000 per year, and the savings increase significantly for larger
systems.
Figure 1. A plain, or raw edge, collection orifice.
Hood Design/Location
When a duct is under suction with a plain end opening
acting as a hood, air is pulled into the opening from the front, sides and even
behind the opening. The plain end, also known as a raw edge orifice (see Figure
1), has a lot of resistance associated with the opening. Specifically, this
resistance measures 0.93 velocity pressure (VP). Ideally, air should be pulled
in from the front. Placing a flange around the plain opening also allows air to
be drawn from a further distance, which lowers the resistance to 0.50 VP. The
perfect hood, in terms of energy savings, is a bell mouth-shaped fitting with a
resistance factor of 0.04 VP (see Figure 2).
Figure 2. Bell
mouth-shaped hoods are ideal for energy savings.
The VP in a duct comes from the actual velocity in the
duct; 4005 feet per minute (fpm) velocity equals 1.0 VP. Energy is required to
make the contaminated air flow into the hood opening, and this is always
calculated with a factor of 1.0 VP (duct). When multiplied by the actual duct
VP, this 1.0 VP will equal the static pressure (SP), which is measured in
inches water gauge (wg, defined as pressure equal to that which is exerted by a
column of water of the same height). Static pressure is a measure of the
differential air pressure between the air pressures inside a duct and the
ambient air pressure outside the duct. As static pressure increases, airflow
decreases, and larger motors are required to maintain effectiveness.
The hood static pressure equals the hood VP multiplied by
the actual duct VP, plus the energy loss to make air flow into the hood. The
static pressure requirement of a bell mouth-shaped hood is 1.04 in. wgSP. In
comparison, the plain opening design requires 1.93 in. wgSP, for an increase of
0.89 in. wgSP.
Further energy savings result when the collection hood is
located as close as possible to the point of dust generation. This reduces the
volume of air required to collect the dust. If the dust generated is 12 in.
from the hood opening, a volume of 1000 cu ft per minute (cfm) might be
required. But, if the hood opening is 24 in. away, the required cfm volume
increases as the square of the distance to 4000 cfm.
Duct Design
The air velocity required to carry collected dust through
the ducting is another important consideration. If the collected dust can be
conveyed at 3500 fpm when VP = 0.76, it is disadvantageous to convey the dust
at 4500 fpm when VP = 1.26. At 3500 fpm, the duct friction factor (the friction
created by the duct itself) is 0.018 VP per foot of duct (0.018 VP x 100 ft =
1.8 VP x 0.76 = 1.37 in. SP). At 4500 fpm, however, the duct friction factor is
0.02 VP per foot of duct (0.02 x 100 ft = 2.0 VP x 1.26 = 2.52 in. SP). The slower
speed saves 1.15 in. of wgSP.
In addition, duct elbows with a 1.5 diameter radius can
have a duct friction factor of 0.24, and a 2.0 duct elbow radius can have a
factor of 0.19. Using the same factors as above, the 2.0 diameter radius will
save 0.05 in. wgSP. The total savings gained from well-designed ducting for a
simple dust collection system is 1.15 + 0.10 + 0.05 in., for a total of 1.30
in. wgSP.
Dust Collector Operation
Additional energy savings can be obtained by using a Photohelic
®
gauge to control the pulsejet cleaning cycle in place of the traditional
Magnehelic
®
gauge. A Magnehelic gauge simply measures SP
in inches wg. In a system with this type of gauge, the compressed air is always
on.
A Photohelic gauge is a Magnehelic gauge with the added
benefit of electrical contacts that control the pulsejet cleaning cycle, which
gives operators the flexibility to set the high and low static pressure points
at which the unit pulses. If a dust collector is set to operate with nominally
dirty filters at 4 in. wgSP instead of the more common 5 in. wgSP, a savings of
1.0 in. wgSP can be achieved. Controlled cleaning with a Photohelic gauge not
only saves compressed air and its associated energy costs, it also extends
filter media life.
Fan Ducting
Air has weight, and if the ducting in and out of the fan
is not properly designed and installed, the weight of the air loads the fan
unevenly. This can cause the fan to pulse, or surge, and adversely affect
performance. Fan pulsing must be overcome by adding extra static pressure. If
the SP goes up on a fan performance curve and is not accounted for, cfm
performance will go down. As cfm performance lessens, the hood performance will
suffer and possibly allow contaminants to enter the workers' breathing zone.
One relatively common design includes the installation of
a two-diameter 90°-radius duct elbow right at the fan inlet. This only serves
to add 1.0 in. VP and (with inlet velocity at 4000 fpm) 1.0 in. wgSP. To
improve efficiency, fan ducting designs should incorporate 7-10 duct diameters
of straight ducting between the elbow and the fan inlet.
Table 1. Static pressure loss resulting from poor design (in. SP).
Potential Savings
The accumulated SP losses from poor design on a small cfm
system can add approximately 4.20 in. SP (see Table 1). If a small dust
collection system has a system static pressure (SSP) of 9.0 in. wg, poor design
can add an additional 4.19 in. SSP, for a total of 13.19 in. wg. Assuming 2000
cfm, the brake horsepower (BHP) requirement for the 9.0 in. wg system would be
5.43. At 13.19 in. SSP, 7.65 BHP would be required.
Assuming the use of motors having the same efficiency and
operating 8760 hours per year at a cost of $0.11 per kilowatt-hour, the annual
operating cost of the larger 7.65 BHP motor would be $6706. In comparison, the
annual operating cost for the smaller 5.43 BHP motor in a simple dust control
system would be $4760, for an overall electrical energy cost savings of approximately
$2000 per year.
The energy cost savings potential increases in direct
proportion to the size and complexity of the dust collection system, and will
depend on individual dust collection situations and requirements. For this
reason, it is recommended that manufacturers consult an expert to evaluate
their specific dust collection system requirements and the design approaches
that will make the most sense in terms of economics and energy efficiency.
| https://www.ceramicindustry.com/articles/88465-special-section-brick-clay-record-energy-efficient-dust-collection/ |