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ObjectiveWe aimed to investigate sociodemographic factors associated with self-reported COVID-19 infection.MethodsThe study population was a prospective multicenter cohort of adult volunteers recruited from healthcare systems located in the mid-Atlantic and southern United States. Between April 2020 and October 2021, participants completed daily online questionnaires about symptoms, exposures, and risk behaviors related to COVID-19, including self-reports of positive SARS CoV-2 detection tests and COVID-19 vaccination. Analysis of time from study enrollment to self-reported COVID-19 infection used a time-varying mixed effects Cox-proportional hazards framework.ResultsOverall, 1,603 of 27,214 study participants (5.9%) reported a positive COVID-19 test during the study period. The adjusted hazard ratio demonstrated lower risk for women, those with a graduate level degree, and smokers. A higher risk was observed for healthcare workers, those aged 18-34, those in rural areas, those from households where a member attends school or interacts with the public, and those who visited a health provider in the last year.ConclusionsWe identified subgroups within healthcare network populations defined by age, occupational exposure, and rural location reporting higher than average rates of COVID-19 infection for our surveillance population. These subgroups should be monitored closely in future epidemics of respiratory viral diseases.

We determined weights for a multi-criteria tool for assessing the relative merits of clinical-trial research proposals, and investigated whether the weights vary across relevant stakeholder groups. A cross-sectional, adaptive discrete choice experiment using 1000minds online software was administered to consumers, researchers and funders affiliated with the Australian Clinical Trials Alliance (ACTA). We identified weights for four criteria-Appropriateness, Significance, Relevance, Feasibility-and their levels, representing their relative importance, so that research proposals can be scored between 0% (nil or very low merit) and 100% (very high merit). From 220 complete survey responses, the most important criterion was Appropriateness (adjusted for differences between stakeholder groups, mean weight 28.9%) and the least important was Feasibility (adjusted mean weight 19.5%). Consumers tended to weight Relevance more highly (2.7% points difference) and Feasibility less highly (3.1% points difference) than researchers. The research or grant writing experience of researchers or consumers was not associated with the weights. A multi-criteria tool for evaluating research proposals that reflects stakeholders' preferences was created. The tool can be used to assess the relative merits of clinical trial research proposals and rank them, to help identify the best proposals for funding.

Background and aimsHigh quality clinical research that addresses important questions requires significant resources. In resource-constrained environments, projects will therefore need to be prioritized. The Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trials Network aimed to develop a stakeholder-based, transparent, easily implementable tool that provides a score for the 'importance' of a research question which could be used to rank research projects in order of importance.MethodsUsing a mixed-methods, multi-stage approach that included a Delphi survey, consensus workshop, inter-rater reliability testing, validity testing and calibration using a discrete-choice methodology, the Research Question Importance Tool (ANZMUSC-RQIT) was developed. The tool incorporated broad stakeholder opinion, including consumers, at each stage and is designed for scoring by committee consensus.ResultsThe ANZMUSC-RQIT tool consists of 5 dimensions (compared to 6 dimensions for an earlier version of RQIT): (1) extent of stakeholder consensus, (2) social burden of health condition, (3) patient burden of health condition, (4) anticipated effectiveness of proposed intervention, and (5) extent to which health equity is addressed by the research. Each dimension is assessed by defining ordered levels of a relevant attribute and by assigning a score to each level. The scores for the dimensions are then summed to obtain an overall ANZMUSC-RQIT score, which represents the importance of the research question. The result is a score on an interval scale with an arbitrary unit, ranging from 0 (minimal importance) to 1000. The ANZMUSC-RQIT dimensions can be reliably ordered by committee consensus (ICC 0.73-0.93) and the overall score is positively associated with citation count (standardised regression coefficient 0.33, pConclusionWe propose that the ANZMUSC-RQIT is a useful tool for prioritising the importance of a research question.

IntroductionFracture configuration is often more complex than is radiographically appreciable. The objective of this study is to describe the influence of pre-operative computed tomography (CT) for surgical planning in a variety of fracture types. This has not been described in previous studies.Materials and methodsAll cases with pre-operative radiographs, admitted for CT and surgical repair of a suspected limb fracture from January 2010-December 2020 were reviewed. CT was acquired under general anaesthesia in a multi-slice helical scanner; any surgery was then performed immediately. Three diplomates (two surgical; one diagnostic imaging) performed a blinded retrospective review of the radiographs and CT for each horse. A consensus decision was made on any change in surgical plan prior to and after CT review, and cases divided into three categories: CT of major, intermediate or minor relevance, as previously described by Genton et al, 2019.Results55 cases were collated. Thoroughbred racehorses predominated. The median age was 3 years. A diverse range of fractures were presented: proximal phalanx (18/55), carpal (17/55), metacarpal/tarsal (11/55), sesamoid (5/55), tarsal (3/55), and middle phalanx (1/55). In 13 of 55 cases (23.6%, 95% CI[12%,35%]) CT was of major relevance. In 21 of 55 cases CT was of intermediate relevance (38.2%, 95% CI[25%,51%]). In 21 of 55 cases CT was of minor relevance (38.2%, 95% CI[25%,51%]). A Fisher's exact test demonstrated no statistical difference in CT relevance between fracture types (pDiscussion/conclusionsThis study demonstrates that CT has a significant role in surgical planning, and in the majority (61.8%) of cases added additional information or significantly changed the surgical plan. In all cases CT ensured confidence in surgical planning.

Background Quality of life (QoL) is an important measure of disease burden and general health perception. The relationship between early chronic kidney disease (CKD) and QoL remains poorly understood. The Oxford Renal Study (OxRen) cohort comprises 1063 adults aged ≥60 years from UK primary care practices screened for early CKD, grouped according to existing or screen-detected CKD diagnoses, or biochemistry results indicative of reduced renal function (referred to as transient estimated glomerular filtration rate (eGFR) reduction). Objectives This study aimed to compare QoL in participants known to have CKD at recruitment to those identified as having CKD through a screening programme. Methods Health profile data and multi-attribute utility scores were reported for two generic questionnaires: 5-level EuroQol-5 Dimension (EQ-5D-5L) and ICEpop CAPability measure for Adults (ICECAP-A). QoL was compared between patients with existing and screen-detected CKD; those with transient eGFR reduction served as the reference group in univariable and multivariable linear regression. Results Mean and standard deviation utility scores were not significantly different between the subgroups for EQ-5D-5L (screen-detected:0.785±0.156, n = 480, transient:0.779±0.157, n = 261, existing CKD:0.763±0.171, n = 322, p = 0.216) or ICECAP-A (screen-detected:0.909±0.094, transient:0.904±0.110, existing CKD:0.894±0.115, p = 0.200). Age, smoking status, and number of comorbidities were identified as independent predictors of QoL in this cohort. Conclusion QoL of participants with existing CKD diagnoses was not significantly different from those with screen-detected CKD or transient eGFR reduction and was similar to UK mean scores for the same age, suggesting that patient burden of early CKD is minor. Moreover, CKD-related comorbidities contribute more significantly to disease burden in earlier stages of CKD than renal function per se. Larger prospective studies are required to define the relationship between QoL and CKD progression more precisely. These data also confirm the essentially asymptomatic nature of CKD, implying that routine screening or case finding are required to diagnose it.

Elevated serum urate is the most important causal risk factor for developing gout. However, in longitudinal cohort studies, a small proportion of people with normal urate levels develop gout and the majority of those with high urate levels do not. These observations may be due to subsequent variations in serum urate over time. Our analysis examined whether single or repeat testing of serum urate more accurately predicts incident gout over time. Individual participant data from three publicly-available cohorts were included. Data from paired serum urate measures 3–5 years apart, followed by an assessment of gout incidence 5–6 years from the second urate measure were used to calculate the predictive ability of four measures of serum urate on incident gout: the first measure, the second measure, the average of the two measures, and the highest of the two measures. Participants with prevalent gout prior to the second measure were excluded. Receiver operator characteristic (ROC) curves and area under the curve (AUC) statistics were computed to compare the four measures. A total of 16,017 participants were included across the three cohorts, with a mean follow-up from the first serum urate test of 9.3 years (range 8.9–10.1 years). Overall, there was a small increase in the mean serum urate between the first and second measures (322 μmol/L (5.42 mg/dL) vs. 340 μmol/L (5.71 mg/dL), P

Elevated cadmium (Cd) concentrations in cacao and cocoa-based products (e.g., chocolate) present a potentially serious human health risk. While recent regulatory changes have established a threshold of 0.8 mg kg-1 for Cd content of cocoa-based products, the biophysical factors (e.g., climatic or edaphic conditions) that determine the amount of soil-derived Cd in the cacao bean are poorly understood and have yet to be quantitatively assessed across diverse production contexts. To determine the primary drivers of cacao bean Cd, we used the scientific literature to systematically compile a database of climatic, edaphic, and plant data from across the Cacao Belt, which is approximately 20 degrees latitude on either side of the equator. From this compiled dataset, we then used boosted regression trees to quantitatively synthesize and evaluate these drivers of cacao bean Cd. Total soil Cd concentration, soil pH, and leaf Cd were the best predictors of bean Cd content. Notably, we found that both available soil Cd and soil organic carbon (SOC) content had negligible effects on bean Cd. However, soil pH and SOC decreased the degree of bioconcentration of total soil Cd in the bean Cd concentration. Thus, given the difficulty in remediating soil Cd enriched soils, our results suggest that Cd mitigation strategies targeting plant physiology-based approaches (e.g., breeding, rootstocks) have a higher probability of success than soil-based strategies (e.g., remediation).

Aims This study aims to identify critically important features of digital type two diabetes mellitus (T2DM) prevention interventions. Methods A stakeholder mapping exercise was undertaken to identify key end-user and professional stakeholders, followed by a three-round Delphi procedure to generate and evaluate evidence statements related to the critical elements of digital T2DM prevention interventions in terms of product (intervention), price (funding models/financial cost), place (distribution/delivery channels), and promotion (target audiences). Results End-user (n = 38) and professional (n = 38) stakeholders including patients, dietitians, credentialed diabetes educators, nurses, medical doctors, research scientists, and exercise physiologists participated in the Delphi study. Fifty-two critical intervention characteristics were identified. Future interventions should address diet, physical activity, mental health (e.g. stress, diabetes-related distress), and functional health literacy, while advancing behaviour change support. Programs should be delivered digitally or used multiple delivery modes, target a range of population subgroups including children, and be based on collaborative efforts between national and local and government and non-government funded organisations. Conclusions Our findings highlight strong support for digital health to address T2DM in Australia and identify future directions for T2DM prevention interventions. The study also demonstrates the feasibility and value of stakeholder-led intervention development processes.

ObjectivesTo establish the prevalence of multimorbidity in people with chronic kidney disease (CKD) stages 1-5 and transiently impaired renal function and identify factors associated with multimorbidity.Design and settingProspective cohort study in UK primary care.Participants861 participants aged 60 and older with decreased renal function of whom, 584 (65.8%) had CKD and 277 (32.2%) did not have CKD.InterventionsParticipants underwent medical history and clinical assessment, and blood and urine sampling.Primary and secondary outcome measuresMultimorbidity was defined as presence of ≥2 chronic conditions including CKD. Prevalence of each condition, co-existing conditions and multimorbidity were described and logistic regression was used to identify predictors of multimorbidity.ResultsThe mean (±SD) age of participants was 74±7 years, 54% were women and 98% were white. After CKD, the next most prevalent condition was hypertension (n = 511, 59.3%), followed by obesity (n = 265, 30.8%) ischemic heart disease (n = 145, 16.8%) and diabetes (n = 133, 15.4%). Having two co-existing conditions was most common (27%), the most common combination of which was hypertension and obesity (29%). One or three conditions was the next most prevalent combination (20% and 21% respectively). The prevalence of multimorbidity was 73.9% (95%CI 70.9-76.8) in all participants and 86.6% (95%CI 83.9-89.3) in those with any-stage CKD. Logistic regression found a significant association between increasing age (OR 1.07, 95%CI 1.04-0.10), increasing BMI (OR 1.15, 95%CI 1.10-1.20) and decreasing eGFR (OR 0.99, 95%CI 0.98-1.00) with multimorbidity.ConclusionsThis analysis is the first to provide an accurate estimate of the prevalence of multimorbidity in a screened older primary care population living with or at risk of CKD across all stages. Hypertension and obesity were the most common combination of conditions other than CKD that people were living with, suggesting that there may be multiple reasons for closely monitoring health status in individuals with CKD.

IntroductionAt the population level, Black and Hispanic adults in the United States have increased risk of dying from COVID-19, yet whether race and ethnicity impact on risk of mortality among those hospitalized for COVID-19 is unclear.MethodsRetrospective cohort study using data on adults hospitalized with COVID-19 from the electronic health record from 52 health systems across the United States contributing data to Cerner Real World DataTM. In-hospital mortality was evaluated by race first in unadjusted analysis then sequentially adjusting for demographics and clinical characteristics using logistic regression.ResultsThrough August 2020, 19,584 patients with median age 52 years were hospitalized with COVID-19, including n = 4,215 (21.5%) Black and n = 5,761 (29.4%) Hispanic patients. Relative to white patients, crude mortality was slightly higher in Black adults [22.7% vs 20.8%, unadjusted OR 1.12 (95% CI 1.02-1.22)]. Mortality remained higher among Black adults after adjusting for demographic factors including age, sex, date, region, and insurance status (OR 1.13, 95% CI 1.01-1.27), but not after including comorbidities and body mass index (OR 1.07, 95% CI 0.93-1.23). Compared with non-Hispanic patients, Hispanic patients had lower mortality both in unadjusted and adjusted models [mortality 12.7 vs 25.0%, unadjusted OR 0.44(95% CI 0.40-0.48), fully adjusted OR 0.71 (95% CI 0.59-0.86)].DiscussionIn this large, multicenter, EHR-based analysis, Black adults hospitalized with COVID-19 had higher observed mortality than white patients due to a higher burden of comorbidities in Black adults. In contrast, Hispanic ethnicity was associated with lower mortality, even in fully adjusted models.

Maternal smoking is established to cause adverse birth outcomes, but evidence considering maternal smoking change across successive pregnancies is sparse. We examined the association between self-reported maternal smoking during and between the first two pregnancies with the odds of small for gestational age (SGA) birth (

Endogenous FLOWERING LOCUS T homolog MeFT1 was transgenically overexpressed under control of a strong constitutive promoter in cassava cultivar 60444 to determine its role in regulation of flowering and as a potential tool to accelerate cassava breeding. Early profuse flowering was recorded in-vitro in all ten transgenic plant lines recovered, causing eight lines to die within 21 days of culture. The two surviving transgenic plant lines flowered early and profusely commencing as soon as 14 days after establishment in soil in the greenhouse. Both transgenic lines sustained early flowering across the vegetative propagation cycle, with first flowering recorded 30-50 days after planting stakes compared to 90 days for non-transgenic controls. Transgenic plant lines completed five flowering cycles within 200 days in the greenhouse as opposed to twice flowering event in the controls. Constitutive overexpression of MeFT1 generated fully mature male and female flowers and produced a bushy phenotype due to significantly increased flowering-induced branching. Flower induction by MeFT1 overexpression was not graft-transmissible and negatively affected storage root development. Accelerated flowering in transgenic plants was associated with significantly increased mRNA levels of MeFT1 and the three floral meristem identity genes MeAP1, MeLFY and MeSOC1 in shoot apical tissues. These findings imply that MeFT1 encodes flower induction and triggers flowering by recruiting downstream floral meristem identity genes.

BACKGROUND:The World Health Organisation previously recommended routine screening in school-aged children in countries with a high prevalence of rheumatic heart disease (RHD); however, it is unclear if screening-detected (latent) valve disease will inevitably evolve to a pathological lesion. Understanding the natural history of latent RHD is essential prior to recommendation of screening in endemic areas. Studies documenting the progression of latent RHD have had contrasting conclusions about the pathogenicity of latent valvular lesions. This review provides estimates of rates of progression of latent RHD. METHODS AND FINDINGS:In this systematic review and meta-analysis, we searched EMBASE, MEDLINE, Global Index Medicus, Africa Wide, Cochrane Database of Systematic Reviews and Global Health Database for studies published before April 30, 2019. Study data were extracted from all studies which reported follow-up data on progression of latent valve lesions. Studies with control cohorts were used to calculate comparative prevalence ratios. This study is registered with PROSPERO, number CRD42019119427. We identified 12 studies reporting follow-up data on latent RHD for 950 people in 9 countries. The estimated pooled prevalence rate for progression per year of latent RHD was 5%/year (95% CI 2-8). Eight studies reported on the progression of borderline latent RHD with an estimated pooled prevalence of 2%/year (95% CI 0-4). Three studies included control groups. There was a significant increase in the risk of progression of valvular disease in the latent group compared with controls (RR = 3.57 (95%CI = 1.65-7.70, P = 0.001). The overall risk of bias was low. Given most studies included penicillin administration we were unable to document the natural history of latent RHD. Furthermore, we were unable to perform a sensitivity analysis to determine the effect of administering penicillin prophylaxis on progression of valve disease given prescription of penicillin was not standardised. CONCLUSION:Latent RHD has a slow rate of progression but it is significantly higher compared to controls, with definite latent RHD having a higher rate of progression compared with borderline latent disease. There are a massive number of individuals at risk for RHD in the developing world as well as logistical challenges of screening and delivering penicillin prophylaxis. The low rate of progression from untargeted screening may be an important consideration in resource-constrained environments.

PurposeTo test the hypothesis that the performance in novel computer-based tasks of everyday visual function worsens with disease severity in people with non-neovascular age-related macular degeneration.MethodsParticipants with and without non-neovascular age-related macular degeneration (≥60 years, minimum logMAR binocular visual acuity 0.7) performed a series of standard visual function tests and two novel computer-based tasks. In a visual search task, participants had to locate an image of a single real-world object within an array of 49 distractor images. Next, in a series of simulated dynamic driving scenes, participants were asked to identify one or two approaching real-world road signs and then select these road signs from four options. Outcome measures were median response times and total correct responses.ResultsForty-nine participants had no macular disease (n = 11), early/intermediate age-related macular degeneration (n = 16) or geographic atrophy (n = 22). Groups were age-similar with median (interquartile range) logMAR visual acuity of 0.00 (-0.08,0.12), 0.13 (-0.08,0.70) and 0.32 (0.12,0.70) respectively. Median (interquartile range) visual search response times were 1.9 (1.0,2.4), 1.8 (1.1,3.7) and 2.4 (1.2,6.0) seconds respectively. Median (interquartile range) road sign response times (single road signs) were 1.2 (0.4,1.7), 1.5 (0.9,2.8) and 1.8 (1.0,5.5) seconds respectively. Median (interquartile range) road sign response times (double road signs) were 1.7 (0.7,2.4), 2.3 (1.2,3.1) and 2.5 (1.7,6) seconds respectively. Participants with geographic atrophy recorded slower response times in all tasks and over 50% performed outside the normative limit for task performance. There were no significant differences between groups in total correct responses across all tasks.ConclusionsIn a novel computer-based assessment, people with increasing severity of age-related macular degeneration take longer to perform visual search of everyday objects and take longer to identify road signs than those with no age-related macular degeneration. These novel assessments could be useful as patient-relevant, secondary outcomes for clinical trials.

BackgroundMelanoma causes the vast majority of deaths attributable to skin cancer, largely due to its propensity for metastasis. To date, few studies have examined molecular changes between primary cutaneous melanoma and adjacent putatively normal skin. To broaden temporal inferences related to initiation of disease, we performed a metabolomics investigation of primary melanoma and matched extratumoral microenvironment (EM) tissues; and, to make inferences about progressive disease, we also compared unmatched metastatic melanoma tissues to EM tissues.MethodsUltra-high performance liquid chromatography-mass spectrometry-based metabolic profiling was performed on frozen human tissues.ResultsWe observed 824 metabolites as differentially abundant among 33 matched tissue samples, and 1,118 metabolites as differentially abundant between metastatic melanoma (n = 46) and EM (n = 34) after false discovery rate (FDR) adjustment (pConclusionsOverall, pathway-based results significantly distinguished melanoma tissues from EM in the metabolism of: ascorbate and aldarate, propanoate, tryptophan, histidine, and pyrimidine. Within pathways, the majority of individual metabolite abundances observed in comparisons of primary melanoma vs. EM and metastatic melanoma vs. EM were directionally consistent. This observed concordance suggests most identified compounds are implicated in the initiation or maintenance of melanoma.

Colletotrichum tanaceti is an emerging foliar fungal pathogen of commercially grown pyrethrum (Tanacetum cinerariifolium). Despite being reported consistently from field surveys in Australia, the molecular basis of pathogenicity of C. tanaceti on pyrethrum is unknown. Herein, the genome of C. tanaceti (isolate BRIP57314) was assembled de novo and annotated using transcriptomic evidence. The inferred putative pathogenicity gene suite of C. tanaceti comprised a large array of genes encoding secreted effectors, proteases, CAZymes and secondary metabolites. Comparative analysis of its putative pathogenicity gene profiles with those of closely related species suggested that C. tanaceti likely has additional hosts to pyrethrum. The genome of C. tanaceti had a high repeat content and repetitive elements were located significantly closer to genes inferred to influence pathogenicity than other genes. These repeats are likely to have accelerated mutational and transposition rates in the genome, resulting in a rapid evolution of certain CAZyme families in this species. The C. tanaceti genome showed strong signals of Repeat Induced Point (RIP) mutation which likely caused its bipartite nature consisting of distinct gene-sparse, repeat and A-T rich regions. Pathogenicity genes within these RIP affected regions were likely to have a higher evolutionary rate than the rest of the genome. This "two-speed" genome phenomenon in certain Colletotrichum spp. was hypothesized to have caused the clustering of species based on the pathogenicity genes, to deviate from taxonomic relationships. The large repertoire of pathogenicity factors that potentially evolve rapidly due to the plasticity of the genome, indicated that C. tanaceti has a high evolutionary potential. Therefore, C. tanaceti poses a high-risk to the pyrethrum industry. Knowledge of the evolution and diversity of the putative pathogenicity genes will facilitate future research in disease management of C. tanaceti and other Colletotrichum spp.

The biological significance of regional cladoceran morphotypes in the montane regions of the central Palearctic remains poorly understood. In the Holarctic Daphnia longispina complex (Cladocera: Daphniidae), several variants, lineages and species have been proposed as endemic for Southern Siberia. Daphnia turbinata Sars, for example, named after its unusual head shape, is known only from Southern Siberia. Here we sequence DNA of Daphnia from three mitochondrial genes (12S rRNA, 16S rRNA, and NADH dehydrogenase subunit 2, ND2) from 57 localities in Russia and Mongolia (the majority being from Southern Siberia) and place them in evolutionary context with existing data. Our aim was to examine regional endemism of the Daphnia longispina complex in Southern Siberian; to improve the phylogenetic understanding with improved taxonomic and regional sampling, and to better understand the influence of Pleistocene glaciation on the biogeography of these lineages. At least three lineages showed genetic evidence for endemism in Southern Siberia. There was strong support for D. turbinata as a sister lineage to to D. longispina/D. dentifera. Another endemic, Siberian D. cf. longispina, is a sister group to the longispina group in general. Within D. longispina s. str. there was an endemic Siberian clade with a western range boundary near the Yenisei River Basin. Gene flow estimates among populations (based on FST values) were very low for clades of D. longispina on a regional (the original 12S dataset), and on a pan-Eurasian (the extended 12S dataset) scale. Negative values of Fu's FS and Tajima's D tests prevailed for the species examined with significant values found for two D. longispina clades, D. dentifera, D. galeata and D. cristata. Our results support the notion that Southern Siberia is an important biogeographic region for cladocerans as it contained unexpected diversity of endemics (such as D. turbinata, D. cf. longispina and lineages of D. umbra and D. longsipina s.str.) and from being the geographic meeting place of expanding postglacial lineages from eastern and western refugia.

OBJECTIVES:Footwear management aims to preserve foot function, reduce the burden of foot pain and maintain joint mobility in women with rheumatoid arthritis (RA). Whilst retail footwear is commonly recommended by health professionals, there is no current consensus on recommended features of retail footwear for women with RA. This study aimed to determine consensus from health professionals about the important features of retail footwear for women with RA. METHODS:An international Delphi exercise using online survey software was conducted with 39 participants from health care backgrounds. Three iterative rounds were conducted. In the first round, participants listed features of retail footwear that would be important for women with RA. Responses of the first round, combined with results of a scoping review of patient-reported outcome measures used in assessing footwear in arthritis and a qualitative analysis of female patients' perspectives of retail footwear in RA were used to create items for the second round. Items were scored by a 9-point rating scale with consensus defined by the RAND/UCLA disagreement index. The third round consisted of items which did not reach consensus or scored >1 on the RAND/UCLA disagreement index from round two. RESULTS:Fifty-eight items (n = 58) were generated for rating and at the end of three iterative rounds, there was agreement that thirty-eight items were important, that two were not important, and there was no agreement for a further eighteen items. Item themes reaching consensus included footwear characteristics and acceptability and psychosocial aspects of footwear. Footwear characteristics related to heel height, shape, cushioning, toe box size, adjustable fastening, removable insoles, mid-foot support and soft accommodative uppers. Acceptability and psychosocial aspects included affordability, comfort, aesthetic, style, colour and impact on femininity. CONCLUSION:This consensus exercise has identified the important features of retail footwear for women with RA.

We present a new signal for detecting deception: full body motion. Previous work on detecting deception from body movement has relied either on human judges or on specific gestures (such as fidgeting or gaze aversion) that are coded by humans. While this research has helped to build the foundation of the field, results are often characterized by inconsistent and contradictory findings, with small-stakes lies under lab conditions detected at rates little better than guessing. We examine whether a full body motion capture suit, which records the position, velocity, and orientation of 23 points in the subject's body, could yield a better signal of deception. Interviewees of South Asian (n = 60) or White British culture (n = 30) were required to either tell the truth or lie about two experienced tasks while being interviewed by somebody from their own (n = 60) or different culture (n = 30). We discovered that full body motion-the sum of joint displacements-was indicative of lying 74.4% of the time. Further analyses indicated that including individual limb data in our full body motion measurements can increase its discriminatory power to 82.2%. Furthermore, movement was guilt- and penitential-related, and occurred independently of anxiety, cognitive load, and cultural background. It appears that full body motion can be an objective nonverbal indicator of deceit, showing that lying does not cause people to freeze.

Food choice is critical for survival because organisms must choose food that is edible and nutritious and avoid pathogenic food. Many organisms, including the nematode C. elegans, use olfaction to detect and distinguish among food sources. C. elegans exhibits innate preferences for the odors of different bacterial species. However, little is known about the preferences of C. elegans for bacterial strains isolated from their natural environment as well as the attractive volatile compounds released by preferred natural bacteria isolates. We tested food odor preferences of C. elegans for non-pathogenic bacteria found in their natural habitats. We found that C. elegans showed a preference for the odor of six of the eight tested bacterial isolates over its standard food source, E. coli HB101. Using solid-phase microextraction and gas chromatography coupled with mass spectrometry, we found that four of six attractive bacterial isolates (Alcaligenes sp. JUb4, Providenica sp. JUb5, Providencia sp. JUb39, and Flavobacteria sp. JUb43) released isoamyl alcohol, a well-studied C. elegans attractant, while both non-attractive isolates (Raoultella sp. JUb38 and Acinetobacter sp. JUb68) released very low or non-detectable amounts of isoamyl alcohol. In conclusion, we find that isoamyl alcohol is likely an ethologically relevant odor that is released by some attractive bacterial isolates in the natural environment of C. elegans.

Intermittent water supplies (IWS) deliver piped water to one billion people; this water is often microbially contaminated. Contaminants that accumulate while IWS are depressurized are flushed into customers' homes when these systems become pressurized. In addition, during the steady-state phase of IWS, contaminants from higher-pressure sources (e.g., sewers) may continue to intrude where pipe pressure is low. To guide the operation and improvement of IWS, this paper proposes an analytic model relating supply pressure, supply duration, leakage, and the volume of intruded, potentially-contaminated, fluids present during flushing and steady-state. The proposed model suggests that increasing the supply duration may improve water quality during the flushing phase, but decrease the subsequent steady-state water quality. As such, regulators and academics should take more care in reporting if water quality samples are taken during flushing or steady-state operational conditions. Pipe leakage increases with increased supply pressure and/or duration. We propose using an equivalent orifice area (EOA) to quantify pipe quality. This provides a more stable metric for regulators and utilities tracking pipe repairs. Finally, we show that the volume of intruded fluid decreases in proportion to reductions in EOA. The proposed relationships are applied to self-reported performance indicators for IWS serving 108 million people described in the IBNET database and in the Benchmarking and Data Book of Water Utilities in India. This application shows that current high-pressure, continuous water supply targets will require extensive EOA reductions. For example, in order to achieve national targets, utilities in India will need to reduce their EOA by a median of at least 90%.

Umami taste perception is mediated by the heterodimeric G-protein coupled receptors (GPCRs), formed by the assembly of T1R1 and T1R3 subunits. T1R1 and T1R3 subunits are class C GPCRs whose members share common structural homologies including a long N-terminal domain (NTD) linked to a seven transmembrane domain by a short cysteine-rich region. The NTD of the T1R1 subunit contains the primary binding site for umami stimuli, such as L-glutamate (L-Glu) for humans. Inosine-5'-monophosphate (IMP) binds at a location close to the opening of the T1R1-NTD "flytrap", thus creating the observed synergistic response between L-Glu and IMP. T1R1/T1R3 binding studies have revealed species-dependent differences. While human T1R1/T1R3 is activated specifically by L-Glu, the T1R1/T1R3 in other species is a broadly tuned receptor, sensitive to a range of L-amino acids. Because domestic cats are obligate carnivores, they display strong preferences for some specific amino acids. To better understand the structural basis of umami stimuli recognition by non-human taste receptors, we measured the binding of selected amino acids to cat T1R1/T1R3 (cT1R1/cT1R3) umami taste receptor. For this purpose, we expressed cT1R1-NTD in bacteria as inclusion bodies. After purification, refolding of the protein was achieved. Circular dichroism spectroscopic studies revealed that cT1R1-NTD was well renatured with evidence of secondary structures. Using size-exclusion chromatography coupled to light scattering, we found that the cT1R1-NTD behaves as a monomer. Ligand binding quantified by intrinsic tryptophan fluorescence showed that cT1R1-NTD is capable of binding L-amino acids with Kd values in the micromolar range. We demonstrated that IMP potentiates L-amino acid binding onto renatured cT1R1-NTD. Interestingly, our results revealed that IMP binds the extracellular domain in the absence of L-amino acids. Thus, this study demonstrates that the feasibility to produce milligram quantities of cT1R1-NTD for functional and structural studies.

Despite the American Academy of Pediatrics (AAP) recommending that electronic media be avoided in children under two years of age, screen use is common in infants and toddlers. The aims of this study were to determine how parenting style, infant temperament, and family type are associated with television viewing in two-year-old children.Participants were from the Prevention of Overweight in Infancy (POI) randomized controlled trial (n = 802) (Dunedin, New Zealand). Demographic information was collected at baseline (late pregnancy), and television and other screen time assessed by questionnaire at 24 months of age. Parenting style (Parenting Practices Questionnaire), infant temperament (Colorado Childhood Temperament Inventory), and family type (7 categories) were reported by both parents.Data were available for 487 participants (61% of the original participants). Median television viewing was relatively low at 21 minutes per day, or 30 minutes in those watching television (82%). Children who watched television played with mobile phones (12% of children) or iPads/tablets (22% of children) more frequently than children who did not (6% of children). In terms of parenting style, children of more authoritarian mothers (β = 17, 95% CI: 6-27 minutes), more authoritarian partners (β = 14, 95% CI: 2-26 minutes), or more permissive mothers (β = 10, 95% CI: 3-17 minutes) watched significantly more television. No significant relationships were observed between child temperament and time watching television after adjustment for confounding variables. Children from "active" families (as rated by partners) watched 29 minutes less television each day (P = 0.002).Parenting style and family type were associated with television viewing time in young children, whereas child temperament was not.

Rodent pests are especially problematic in terms of agriculture and public health since they can inflict considerable economic damage associated with their abundance, diversity, generalist feeding habits and high reproductive rates. To quantify rodent pest impacts and identify trends in rodent pest research impacting on small-holder agriculture in the Afro-Malagasy region we did a systematic review of research outputs from 1910 to 2015, by developing an a priori defined set of criteria to allow for replication of the review process. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We reviewed 162 publications, and while rodent pest research was spatially distributed across Africa (32 countries, including Madagascar), there was a disparity in number of studies per country with research biased towards four countries (Tanzania [25%], Nigeria [9%], Ethiopia [9%], Kenya [8%]) accounting for 51% of all rodent pest research in the Afro-Malagasy region. There was a disparity in the research themes addressed by Tanzanian publications compared to publications from the rest of the Afro-Malagasy region where research in Tanzania had a much more applied focus (50%) compared to a more basic research approach (92%) in the rest of the Afro-Malagasy region. We found that pest rodents have a significant negative effect on the Afro-Malagasy small-holder farming communities. Crop losses varied between cropping stages, storage and crops and the highest losses occurred during early cropping stages (46% median loss during seedling stage) and the mature stage (15% median loss). There was a scarcity of studies investigating the effectiveness of various management actions on rodent pest damage and population abundance. Our analysis highlights that there are inadequate empirical studies focused on developing sustainable control methods for rodent pests and rodent pests in the Africa-Malagasy context is generally ignored as a research topic.

A solution for the nuclear waste problem is the key challenge for an extensive use of nuclear reactors as a major carbon free, sustainable, and applied highly reliable energy source. Partitioning and Transmutation (P&T) promises a solution for improved waste management. Current strategies rely on systems designed in the 60's for the massive production of plutonium. We propose an innovative strategic development plan based on invention and innovation described with the concept of developments in s-curves identifying the current boundary conditions, and the evolvable objectives. This leads to the ultimate, universal vision for energy production characterized by minimal use of resources and production of waste, while being economically affordable and safe, secure and reliable in operation. This vision is transformed into a mission for a disruptive development of the future nuclear energy system operated by burning of existing spent nuclear fuel (SNF) without prior reprocessing. This highly innovative approach fulfils the sustainability goals and creates new options for P&T. A proof on the feasibility from neutronic point of view is given demonstrating sufficient breeding of fissile material from the inserted SNF. The system does neither require new resources nor produce additional waste, thus it provides a highly sustainable option for a future nuclear system fulfilling the requests of P&T as side effect. In addition, this nuclear system provides enhanced resistance against misuse of Pu and a significantly reduced fuel cycle. However, the new system requires a demand driven rethinking of the separation process to be efficient.

Lung Clearance Index (LCI) is recognised as an early marker of cystic fibrosis (CF) lung disease. The effect of posture on LCI however is important when considering longitudinal measurements from infancy and when comparing LCI to imaging studies.35 children with CF and 28 healthy controls (HC) were assessed. Multiple breath washout (MBW) was performed both sitting and supine in triplicate and analysed for LCI, Scond, Sacin, and lung volumes. These values were also corrected for the Fowler dead-space to create 'alveolar' indices.From sitting to supine there was a significant increase in LCI and a significant decrease in FRC for both CF and HC (p

[This corrects the article DOI: 10.1371/journal.pone.0174554.].

Due to low fluorine background signal in vivo, 19F is a good marker to study the fate of exogenous molecules by magnetic resonance imaging (MRI) using equilibrium nuclear spin polarization schemes. Since 19F MRI applications require high sensitivity, it can be important to assess experimental feasibility during the design stage already by estimating the minimum detectable fluorine concentration. Here we propose a simple method for the calibration of MRI hardware, providing sensitivity estimates for a given scanner and coil configuration. An experimental "calibration factor" to account for variations in coil configuration and hardware set-up is specified. Once it has been determined in a calibration experiment, the sensitivity of an experiment or, alternatively, the minimum number of required spins or the minimum marker concentration can be estimated without the need for a pilot experiment. The definition of this calibration factor is derived based on standard equations for the sensitivity in magnetic resonance, yet the method is not restricted by the limited validity of these equations, since additional instrument-dependent factors are implicitly included during calibration. The method is demonstrated using MR spectroscopy and imaging experiments with different 19F samples, both paramagnetically and susceptibility broadened, to approximate a range of realistic environments.

The biodiversity and the biogeography are still poorly understood for freshwater invertebrates. The crustacean Chydorus sphaericus-brevilabris complex (Cladocera: Chydoridae) is composed of species that are important components of Holarctic freshwater food webs. Recent morphological and genetic study of the complex has indicated a substantial species diversity in the northern hemisphere. However, we know little of the geographic boundaries of these novel lineages. Moreover, a large section of the Palearctic remains unexamined at the genetic level. Here we attempt to address the biodiversity knowledge gap for the Chydorus sphaericus group in the central Palearctic and assess its diversity and biogeographic boundaries. We sequenced nuclear (ITS-2) and mitochondrial (COI) gene regions of Chydorus specimens across the Palearctic and compared them with already available Holarctic sequences. We detected six main clades in the C. sphaericus group in the Palearctic, of which two of the groups are novel. Three of the more divergent clades are geographically widespread. The central portion of Eurasia (the Yenisey River basin) appears to be a narrow zone of secondary contact for phylogroups that expanded from European and Beringian refugia. As such, the previously unsampled central Palearctic represents an important region for understanding the evolutionary consequences of Pleistocene climatic oscillations on the Chydorus sphaericus group.

Epidemiological modeling for infectious disease is important for disease management and its routine implementation needs to be facilitated through better description of models in an operational context. A standardized model characterization process that allows selection or making manual comparisons of available models and their results is currently lacking. A key need is a universal framework to facilitate model description and understanding of its features. Los Alamos National Laboratory (LANL) has developed a comprehensive framework that can be used to characterize an infectious disease model in an operational context. The framework was developed through a consensus among a panel of subject matter experts. In this paper, we describe the framework, its application to model characterization, and the development of the Biosurveillance Analytics Resource Directory (BARD; http://brd.bsvgateway.org/brd/), to facilitate the rapid selection of operational models for specific infectious/communicable diseases. We offer this framework and associated database to stakeholders of the infectious disease modeling field as a tool for standardizing model description and facilitating the use of epidemiological models.

Gingival fibroblast-mediated extracellular matrix remodelling is implicated in the pathogenesis of periodontitis, yet the stimuli that regulate this response are not fully understood. The immunoregulatory adipokine leptin is detectable in the gingiva, human gingival fibroblasts express functional leptin receptor mRNA and leptin is known to regulate extracellular matrix remodelling responses in cardiac fibroblasts. We therefore hypothesised that leptin would enhance matrix metalloproteinase secretion in human gingival fibroblasts.We used in vitro cell culture to investigate leptin signalling and the effect of leptin on mRNA and protein expression in human gingival fibroblasts. We confirmed human gingival fibroblasts expressed cell surface leptin receptor, found leptin increased matrix metalloproteinase-1, -3, -8 and -14 expression in human gingival fibroblasts compared to unstimulated cells, and observed that leptin stimulation activated MAPK, STAT1/3 and Akt signalling in human gingival fibroblasts. Furthermore, leptin synergised with IL-1 or the TLR2 agonist pam2CSK4 to markedly enhance matrix metalloproteinase-1 and -3 production by human gingival fibroblasts. Signalling pathway inhibition demonstrated ERK was required for leptin-stimulated matrix metalloproteinase-1 expression in human gingival fibroblasts; whilst ERK, JNK, p38 and STAT3 were required for leptin+IL-1- and leptin+pam2CSK4-induced matrix metalloproteinase-1 expression. A genome-wide expression array and gene ontology analysis confirmed genes differentially expressed in leptin+IL-1-stimulated human gingival fibroblasts (compared to unstimulated cells) were enriched for extracellular matrix organisation and disassembly, and revealed that matrix metalloproteinase-8 and -12 were also synergistically upregulated by leptin+IL-1 in human gingival fibroblasts.We conclude that leptin selectively enhances the expression and secretion of certain matrix metalloproteinases in human gingival fibroblasts, and suggest that gingival fibroblasts may have an ECM-degrading phenotype during conditions of hyperleptinaemia (e.g., obesity, type 2 diabetes mellitus, exogenous leptin therapy).

Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent protein kinase A (PKA) and ATP-regulated chloride channel. Here, we demonstrate that nucleoside diphosphate kinase B (NDPK-B, NM23-H2) forms a functional complex with CFTR. In airway epithelia forskolin/IBMX significantly increases NDPK-B co-localisation with CFTR whereas PKA inhibitors attenuate complex formation. Furthermore, an NDPK-B derived peptide (but not its NDPK-A equivalent) disrupts the NDPK-B/CFTR complex in vitro (19-mers comprising amino acids 36-54 from NDPK-B or NDPK-A). Overlay (Far-Western) and Surface Plasmon Resonance (SPR) analysis both demonstrate that NDPK-B binds CFTR within its first nucleotide binding domain (NBD1, CFTR amino acids 351-727). Analysis of chloride currents reflective of CFTR or outwardly rectifying chloride channels (ORCC, DIDS-sensitive) showed that the 19-mer NDPK-B peptide (but not its NDPK-A equivalent) reduced both chloride conductances. Additionally, the NDPK-B (but not NDPK-A) peptide also attenuated acetylcholine-induced intestinal short circuit currents. In silico analysis of the NBD1/NDPK-B complex reveals an extended interaction surface between the two proteins. This binding zone is also target of the 19-mer NDPK-B peptide, thus confirming its capability to disrupt NDPK-B/CFTR complex. We propose that NDPK-B forms part of the complex that controls chloride currents in epithelia.

Changes in appetite occur during the ovarian cycle in female mammals. Research on appetite-regulatory gastrointestinal peptides in females is limited, because reproductive changes in steroid hormones present additional experimental factors to control for. This study aimed to explore possible changes in the orexigenic (appetite-stimulating) gastrointestinal peptide hormone ghrelin during the rodent oestrous cycle. Fed and fasted plasma and stomach tissue samples were taken from female Wistar rats (32-44 weeks of age) at each stage of the oestrous cycle for total ghrelin quantification using radioimmunoassay. Sampling occurred during the dark phase when most eating takes place in rats. Statistical analysis was by paired-samples t-test, one-way ANOVA on normally distributed data, with Tukey post-hoc tests, or Kruskal-Wallis if not. GLM univariate analysis was used to assess main effects and interactions in ghrelin concentrations in the fed or fasted state and during different stages of the ovarian cycle, with age as a covariate. No consistent fed to fasted ghrelin increases were measured in matched plasma samples from the same animals, contrary to expectations. Total ghrelin concentrations did not significantly change between cycle stages with ANOVA, in either fed or fasted plasma or in stomach tissue. This was despite significantly decreased fasted stomach contents at oestrus (P = 0.028), suggesting decreased food intake. There was however a significant interaction in ghrelin plasma concentrations between fed and fasted proestrus rats and a direct effect of age with rats over 37 weeks old having lower circulating concentrations of ghrelin in both fed and fasted states. The biological implications of altered ghrelin plasma concentrations from 37 weeks of age are as yet unknown, but warrant further investigation. Exploring peripheral ghrelin regulatory factor changes with increasing age in reproductively competent females may bring to light potential effects on offspring development and nutritional metabolic programming.

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function. The goal was to determine whether levels of plasma markers were altered in the SMNΔ7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers.SMNΔ7 and control mice were treated with antisense oligonucleotides (ASO) targeting ISS-N1 to increase SMN protein from SMN2 or scramble ASO (sham treatment) via intracerebroventricular injection on postnatal day 1 (P1). Brain, spinal cord, quadriceps muscle, and liver were analyzed for SMN protein levels at P12 and P90. Ten plasma biomarkers (a subset of biomarkers in the SMA-MAP panel available for analysis in mice) were analyzed in plasma obtained at P12, P30, and P90.Of the eight plasma biomarkers assessed, 5 were significantly changed in sham treated SMNΔ7 mice compared to control mice and were normalized in SMNΔ7 mice treated with ASO.This study defines a subset of the SMA-MAP plasma biomarker panel that is abnormal in the most commonly used mouse model of SMA. Furthermore, some of these markers are responsive to postnatal SMN restoration. These findings support continued clinical development of these potential prognostic and pharmacodynamic biomarkers.

Ten strains representing four lineages of the Pseudomonas fluorescens group (P. chlororaphis, P. corrugata, P. koreensis, and P. fluorescens subgroups) were evaluated for toxicity to the tobacco hornworm Manduca sexta and the common fruit fly Drosophila melanogaster. The three strains within the P. chlororaphis subgroup exhibited both oral and injectable toxicity to the lepidopteran M. sexta. All three strains have the gene cluster encoding the FitD insect toxin and a ΔfitD mutant of P. protegens strain Pf-5 exhibited diminished oral toxicity compared to the wildtype strain. Only one of the three strains, P. protegens Pf-5, exhibited substantial levels of oral toxicity against the dipteran D. melanogaster. Three strains in the P. fluorescens subgroup, which lack fitD, consistently showed significant levels of injectable toxicity against M. sexta. In contrast, the oral toxicity of these strains against D. melanogaster was variable between experiments, with only one strain, Pseudomonas sp. BG33R, causing significant levels of mortality in repeated experiments. Toxin complex (Tc) gene clusters, which encode insecticidal properties in Photorhabdus luminescens, were identified in the genomes of seven of the ten strains evaluated in this study. Within those seven genomes, six types of Tc gene clusters were identified, distinguished by gene content, organization and genomic location, but no correlation was observed between the presence of Tc genes and insect toxicity of the evaluated strains. Our results demonstrate that members of the P. fluorescens group have the capacity to kill insects by both FitD-dependent and independent mechanisms.

Post-traumatic stress disorder (PTSD) is a mental health injury characterised by re-experiencing, avoidance, numbing and hyperarousal. Whilst the aetiology of the disorder is relatively well understood, there is debate about the prevalence of cognitive sequelae that manifest in PTSD. In particular, there are conflicting reports about deficits in executive function and mental flexibility. Even less is known about the neural changes that underlie such deficits. Here, we used magnetoencephalography to study differences in functional connectivity during a mental flexibility task in combat-related PTSD (all males, mean age = 37.4, n = 18) versus a military control (all males, mean age = 33.05, n = 19) group. We observed large-scale increases in theta connectivity in the PTSD group compared to controls. The PTSD group performance was compromised in the more attentionally-demanding task and this was characterised by 'late-stage' theta hyperconnectivity, concentrated in network connections involving right parietal cortex. Furthermore, we observed significant correlations with the connectivity strength in this region with a number of cognitive-behavioural outcomes, including measures of attention, depression and anxiety. These findings suggest atypical coordination of neural synchronisation in large scale networks contributes to deficits in mental flexibility for PTSD populations in timed, attentionally-demanding tasks, and this propensity toward network hyperconnectivity may play a more general role in the cognitive sequelae evident in this disorder.

Variation in the melanocortin-1receptor (MC1R) gene is associated with pigmentary phenotypes and risk of malignant melanoma. Few studies have reported on MC1R variation with respect to tumor characteristics, especially clinically important prognostic features. We examined associations between MC1R variants and histopathological melanoma characteristics. Study participants were enrolled from nine geographic regions in Australia, Canada, Italy and the United States and were genotyped for MC1R variants classified as high-risk [R] (D84E, R142H, R151C, R160W, and D294H, all nonsense and insertion/deletion) or low-risk [r] (all other nonsynonymous) variants. Tissue was available for 2,160 white participants of the Genes, Environment and Melanoma (GEM) Study with a first incident primary melanoma diagnosis, and underwent centralized pathologic review. No statistically significant associations were observed between MC1R variants and AJCC established prognostic tumor characteristics: Breslow thickness, presence of mitoses or presence of ulceration. However, MC1R was significantly associated with anatomic site of melanoma (p = 0.002) and a positive association was observed between carriage of more than one [R] variant and melanomas arising on the arms (OR = 2.39; 95% CI: 1.40, 4.09). We also observed statistically significant differences between sun-sensitive and sun-resistant individuals with respect to associations between MC1R genotype and AJCC prognostic tumor characteristics. Our results suggest inherited variation in MC1R may play an influential role in anatomic site presentation of melanomas and may differ with respect to skin pigmentation phenotype.

Multi-walled carbon nanotubes (MWCNTs) represent a human health risk as mice exposed by inhalation display pulmonary fibrosis. Production of IL-1β via inflammasome activation is a mechanism of MWCNT-induced acute inflammation and has been implicated in chronic fibrogenesis. Mice sensitized to allergens have elevated T-helper 2 (Th2) cytokines, IL-4 and IL-13, and are susceptible to MWCNT-induced airway fibrosis. We postulated that Th2 cytokines would modulate MWCNT-induced inflammasome activation and IL-1β release in vitro and in vivo during allergic inflammation.THP-1 macrophages were primed with LPS, exposed to MWCNTs and/or IL-4 or IL-13 for 24 hours, and analyzed for indicators of inflammasome activation. C57BL6 mice were sensitized to house dust mite (HDM) allergen and MWCNTs were delivered to the lungs by oropharyngeal aspiration. Mice were euthanized 1 or 21 days post-MWCNT exposure and evaluated for lung inflammasome components and allergic inflammatory responses.Priming of THP-1 macrophages with LPS increased pro-IL-1β and subsequent exposure to MWCNTs induced IL-1β secretion. IL-4 or IL-13 decreased MWCNT-induced IL-1β secretion by THP-1 cells and reduced pro-caspase-1 but not pro-IL-1β. Treatment of THP-1 cells with STAT6 inhibitors, either Leflunomide or JAK I inhibitor, blocked suppression of caspase activity by IL-4 and IL-13. In vivo, MWCNTs alone caused neutrophilic infiltration into the lungs of mice 1 day post-exposure and increased IL-1β in bronchoalveolar lavage fluid (BALF) and pro-caspase-1 immuno-staining in macrophages and airway epithelium. HDM sensitization alone caused eosinophilic inflammation with increased IL-13. MWCNT exposure after HDM sensitization increased total cell numbers in BALF, but decreased numbers of neutrophils and IL-1β in BALF as well as reduced pro-caspase-1 in lung tissue. Despite reduced IL-1β mice exposed to MWCNTs after HDM developed more severe airway fibrosis by 21 days and had increased pro-fibrogenic cytokine mRNAs.These data indicate that Th2 cytokines suppress MWCNT-induced inflammasome activation via STAT6-dependent down-regulation of pro-caspase-1 and suggest that suppression of inflammasome activation and IL-1β by an allergic lung microenvironment is a mechanism through which MWCNTs exacerbate allergen-induced airway fibrosis.

Effective conservation management for climate adaptation rests on understanding the factors driving species' vulnerability in a spatially explicit manner so as to direct on-ground action. However, there have been only few attempts to map the spatial distribution of the factors driving vulnerability to climate change. Here we conduct a species-level assessment of climate change vulnerability for a sample of Australia's threatened species and map the distribution of species affected by each factor driving climate change vulnerability across the continent. Almost half of the threatened species assessed were considered vulnerable to the impacts of climate change: amphibians being the most vulnerable group, followed by plants, reptiles, mammals and birds. Species with more restricted distributions were more likely to show high climate change vulnerability than widespread species. The main factors driving climate change vulnerability were low genetic variation, dependence on a particular disturbance regime and reliance on a particular moisture regime or habitat. The geographic distribution of the species impacted by each driver varies markedly across the continent, for example species impacted by low genetic variation are prevalent across the human-dominated south-east of the country, while reliance on particular moisture regimes is prevalent across northern Australia. Our results show that actions to address climate adaptation will need to be spatially appropriate, and that in some regions a complex suite of factors driving climate change vulnerability will need to be addressed. Taxonomic and geographic variation in the factors driving climate change vulnerability highlights an urgent need for a spatial prioritisation of climate adaptation actions for threatened species.

Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines.Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy.Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration.The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI.clinicaltrials.gov NCT01205503.

BackgroundUser-friendly, accurate, point-of-care rapid tests to detect glucose-6-phosphate dehydrogenase deficiency (G6PDd) are urgently needed at peripheral level to safely recommend primaquine for malaria elimination.MethodsThe CareStart G6PD RDT (AccessBio, New Jersey, USA), a novel rapid diagnostic test and the most commonly used test, the fluorescent spot test (FST) were assessed against the quantitatively measured G6PD enzyme activity for detecting G6PDd. Subjects were healthy males and non-pregnant females aged 18 years or older residing in six villages in Pailin Province, western Cambodia.FindingsOf the 938 subjects recruited, 74 (7.9%) were severe and moderately severe G6PD deficient (enzyme activity ConclusionsThe CareStart G6PD RDT reliably detected moderate and severe G6PD deficient individuals (enzyme activity

The National Strategy for Biosurveillance defines biosurveillance as "the process of gathering, integrating, interpreting, and communicating essential information related to all-hazards threats or disease activity affecting human, animal, or plant health to achieve early detection and warning, contribute to overall situational awareness of the health aspects of an incident, and to enable better decision-making at all levels." However, the strategy does not specify how "essential information" is to be identified and integrated into the current biosurveillance enterprise, or what the metrics qualify information as being "essential". The question of data stream identification and selection requires a structured methodology that can systematically evaluate the tradeoffs between the many criteria that need to be taken in account. Multi-Attribute Utility Theory, a type of multi-criteria decision analysis, can provide a well-defined, structured approach that can offer solutions to this problem. While the use of Multi-Attribute Utility Theoryas a practical method to apply formal scientific decision theoretical approaches to complex, multi-criteria problems has been demonstrated in a variety of fields, this method has never been applied to decision support in biosurveillance.We have developed a formalized decision support analytic framework that can facilitate identification of "essential information" for use in biosurveillance systems or processes and we offer this framework to the global BSV community as a tool for optimizing the BSV enterprise. To demonstrate utility, we applied the framework to the problem of evaluating data streams for use in an integrated global infectious disease surveillance system.

AimTo determine whether levels of daytime physical activity are associated with sleep duration and night waking in children assessed using accelerometry, and if these associations change over time.Methods24-hour accelerometry data were obtained from 234 children at 3, 5 and 7 years of age for at least 5 days at each time. Sleep duration was estimated using the Sadeh algorithm. Time spent in sedentary, light and moderate-vigorous (MVPA) activity was established using published cut-points. Appropriate statistical techniques were utilised to account for the closed nature of the data (24-hour periods).ResultsTime spent asleep was related more to sedentary or light activity and not to MVPA. The most active (95th percentile) children spent 55-84 fewer minutes asleep and 16-19 more minutes awake at night compared to the least active (5th percentile) children. Children with later bedtimes slept less at night (30-40 minutes) and undertook more sedentary (10-15 minutes) but also more light (18-23 minutes) activity during the day. However, no differences in MVPA were apparent according to bedtime. Children slept slightly less on weekend nights (11 minutes) compared with week-nights, but only at 3 years of age. Most relationships were broadly similar at 3, 5 and 7 years of age.ConclusionChildren who are more physically active during the day have shorter total sleep time and are more awake at night than less active children. The protective effect of sleep on obesity does not appear to be mediated by increased physical activity.

In recent years, biosurveillance has become the buzzword under which a diverse set of ideas and activities regarding detecting and mitigating biological threats are incorporated depending on context and perspective. Increasingly, biosurveillance practice has become global and interdisciplinary, requiring information and resources across public health, One Health, and biothreat domains. Even within the scope of infectious disease surveillance, multiple systems, data sources, and tools are used with varying and often unknown effectiveness. Evaluating the impact and utility of state-of-the-art biosurveillance is, in part, confounded by the complexity of the systems and the information derived from them. We present a novel approach conceptualizing biosurveillance from the perspective of the fundamental data streams that have been or could be used for biosurveillance and to systematically structure a framework that can be universally applicable for use in evaluating and understanding a wide range of biosurveillance activities. Moreover, the Biosurveillance Data Stream Framework and associated definitions are proposed as a starting point to facilitate the development of a standardized lexicon for biosurveillance and characterization of currently used and newly emerging data streams. Criteria for building the data stream framework were developed from an examination of the literature, analysis of information on operational infectious disease biosurveillance systems, and consultation with experts in the area of biosurveillance. To demonstrate utility, the framework and definitions were used as the basis for a schema of a relational database for biosurveillance resources and in the development and use of a decision support tool for data stream evaluation.

Interactions of the Th2 cytokine IL-33 with its receptor ST2 lead to amplified Type 2 immune responses. As Type 2 immune responses are known to mediate protection against helminth infections we hypothesized that the lack of ST2 would lead to an increased susceptibility to filarial infections.ST2 deficient and immunocompetent BALB/c mice were infected with the filarial nematode Litomosoides sigmodontis. At different time points after infection mice were analyzed for worm burden and their immune responses were examined within the thoracic cavity, the site of infection, and systemically using spleen cells and plasma. Absence of ST2 led to significantly increased levels of peripheral blood microfilariae, the filarial progeny, whereas L. sigmodontis adult worm burden was not affected. Development of local and systemic Type 2 immune responses were not impaired in ST2 deficient mice after the onset of microfilaremia, but L. sigmodontis infected ST2-ko mice had significantly reduced total numbers of cells within the thoracic cavity and spleen compared to infected immunocompetent controls. Pronounced microfilaremia in ST2-ko mice did not result from an increased microfilariae release by adult female worms, but an impaired splenic clearance of microfilariae.Our findings suggest that the absence of ST2 does not impair the establishment of adult L. sigmodontis worms, but is important for the splenic clearance of microfilariae from peripheral blood. Thus, ST2 interactions may be important for therapies that intend to block the transmission of filarial disease.

It is well known that we continuously filter incoming sensory information, selectively allocating attention to what is important while suppressing distracting or irrelevant information. Yet questions remain about spatiotemporal patterns of neural processes underlying attentional biases toward emotionally significant aspects of the world. One index of affectively biased attention is an emotional variant of an attentional blink (AB) paradigm, which reveals enhanced perceptual encoding for emotionally salient over neutral stimuli under conditions of limited executive attention. The present study took advantage of the high spatial and temporal resolution of magnetoencephalography (MEG) to investigate neural activation related to emotional and neutral targets in an AB task. MEG data were collected while participants performed a rapid stimulus visual presentation task in which two target stimuli were embedded in a stream of distractor words. The first target (T1) was a number and the second (T2) either an emotionally salient or neutral word. Behavioural results replicated previous findings of greater accuracy for emotionally salient than neutral T2 words. MEG source analyses showed that activation in orbitofrontal cortex, characterized by greater power in the theta and alpha bands, and dorsolateral prefrontal activation were associated with successful perceptual encoding of emotionally salient relative to neutral words. These effects were observed between 250 and 550 ms, latencies associated with discrimination of perceived from unperceived stimuli. These data suggest that important nodes of both emotional salience and frontoparietal executive systems are associated with the emotional modulation of the attentional blink.

We evaluate the intra- and interspecific diversity in the four South African rodent species of the genus Dendromus. The molecular phylogenetic analysis on twenty-three individuals have been conducted on a combined dataset of nuclear and mitochondrial markers. Moreover, the extent and processes underlying chromosomal variation, have been investigated on three species by mean of G-, C-bands, NORs and Zoo-FISH analysis. The molecular analysis shows the presence of six monophyletic lineages corresponding to D. mesomelas, D. mystacalis and four lineages within D. cfr. melanotis with high divergence values (ranges: 10.6% - 18.3%) that raises the question of the possible presence of cryptic species. The first description of the karyotype for D. mesomelas and D. mystacalis and C- and G- banding for one lineage of D. cfr. melanotis are reported highlighting an extended karyotype reorganization in the genus. Furthermore, the G-banding and Zoo-FISH evidenced an autosome-sex chromosome translocation characterizing all the species and our timing estimates this mutation date back 7.4 mya (Late Miocene). Finally, the molecular clock suggests that cladogenesis took place since the end of Miocene to Plio-Pleistocene, probably due to ecological factors, isolation in refugia followed by differential adaptation to the mesic or dry habitat.

This study aimed to determine whether the multi-kinase inhibitor dasatinib would provide an effective therapy for myeloproliferative diseases (MPDs) involving c-Cbl mutations. These mutations, which occur in the RING finger and linker domains, abolish the ability of c-Cbl to function as an E3 ubiquitin ligase and downregulate activated protein tyrosine kinases. Here we analyzed the effects of dasatinib in a c-Cbl RING finger mutant mouse that develops an MPD with a phenotype similar to the human MPDs. The mice are characterized by enhanced tyrosine kinase signaling resulting in an expansion of hematopoietic stem cells, multipotent progenitors and cells within the myeloid lineage. Since c-Cbl is a negative regulator of c-Kit and Src signaling we reasoned that dasatinib, which targets these kinases, would be an effective therapy. Furthermore, two recent studies showed dasatinib to be effective in inhibiting the in vitro growth of cells from leukemia patients with c-Cbl RING finger and linker domain mutations. Surprisingly we found that dasatinib did not provide an effective therapy for c-Cbl RING finger mutant mice since it did not suppress any of the hematopoietic lineages that promote MPD development. Thus we conclude that dasatinib may not be an appropriate therapy for leukemia patients with c-Cbl mutations. We did however find that dasatinib caused a marked reduction of pre-B cells and immature B cells which correlated with a loss of Src activity. This study is therefore the first to provide a detailed characterization of in vivo effects of dasatinib in a hematopoietic disorder that is driven by protein tyrosine kinases other than BCR-ABL.

Multi-walled carbon nanotubes (MWCNTs) pose a possible human health risk for lung disease as a result of inhalation exposure. Mice exposed to MWCNTs develop pulmonary fibrosis. Lung macrophages engulf MWCNTs and produce pro-fibrogenic cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and osteopontin (OPN). Atomic layer deposition (ALD) is a novel process used to enhance functional properties of MWCNTs, yet the consequence of ALD-modified MWCNTs on macrophage biology and fibrosis is unknown.The purpose of this study was to determine whether ALD coating with aluminum oxide (Al2O3) would alter the fibrogenic response to MWCNTs and whether cytokine expression in human macrophage/monocytes exposed to MWCNTs in vitro would predict the severity of lung fibrosis in mice. Uncoated (U)-MWCNTs or ALD-coated (A)-MWCNTs were incubated with THP-1 macrophages or human peripheral blood mononuclear cells (PBMC) and cell supernatants assayed for cytokines by ELISA. C57BL6 mice were exposed to a single dose of A- or U-MWCNTs by oropharyngeal aspiration (4 mg/kg) followed by evaluation of histopathology, lung inflammatory cell counts, and cytokine levels at day 1 and 28 post-exposure.ALD coating of MWCNTs with Al2O3 enhanced IL-1β secretion by THP-1 and PBMC in vitro, yet reduced protein levels of IL-6, TNF-α, and OPN production by THP-1 cells. Moreover, Al2O3 nanoparticles, but not carbon black NPs, increased IL-1β but decreased OPN and IL-6 in THP-1 and PBMC. Mice exposed to U-MWCNT had increased levels of all four cytokines assayed and developed pulmonary fibrosis by 28 days, whereas ALD-coating significantly reduced fibrosis and cytokine levels at the mRNA or protein level.These findings indicate that ALD thin film coating of MWCNTs with Al2O3 reduces fibrosis in mice and that in vitro phagocyte expression of IL-6, TNF-α, and OPN, but not IL-1β, predict MWCNT-induced fibrosis in the lungs of mice in vivo.