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BackgroundElectrolytes (sodium, potassium, calcium, magnesium, chloride, phosphate) are required in specific amounts for proper functioning of the human body. Although the body has different organ systems, such as the kidneys, that regulate electrolyte levels in the blood, electrolyte abnormalities occur frequently in people with eating disorders. The objective of this review will be to examine the association between electrolyte imbalances and adverse outcomes in people with eating disorders.MethodsA systematic review of studies on eating and electrolyte disorders shall be conducted. Electronic searches shall be done in the Ovid MEDLINE, EMBASE, and PsycINFO databases. Selected studies shall include randomized control trials (RCTs), non-randomized controlled trials, and cross-sectional studies published in English or French. Quality appraisal of studies and a narrative synthesis of extracted data shall be conducted.DiscussionThis review will synthesize existing evidence on electrolyte abnormalities in people with eating disorders. It will identify the type of electrolyte imbalances, their impact, and outcomes in people with eating disorders. We anticipate that information that will be useful to policy makers and clinicians in designing better policies to prevent eating disorders and or manage people with eating disorders shall be elucidated in this study.DisseminationThe final manuscript will be submitted for publication in a journal.Review registrationThis protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO); registration number CRD42023477497.

This study evaluated the effect of Momentum-an integrated family planning, maternal and newborn health, and nutrition intervention-on postpartum family planning norms and behaviors among ever married and never-married first-time mothers age 15-24 in Kinshasa, Democratic Republic of the Congo. Using data collected in 2018 and 2020, we conducted an intent-to-treat analysis among 1,927 first-time mothers who were about six-months pregnant at enrollment. Difference-in-differences models were run for panel data and treatment effects models with inverse-probability weighting for endline-only outcomes. Average treatment effects (ATE) were estimated. Momentum had positive effects on partner discussion of family planning in the early postpartum period (ever married 15-19: ATE = 0.179, 95% CI = 0.098, 0.261; never married 15-19: ATE = 0.131, 95% CI = 0.029, 0.232; ever married 20-24: ATE = 0.233, 95% CI = 0.164, 0.302; never married 20-24: ATE = 0.241, 95% CI = 0.121, 0.362) and discussion with a health worker, and on obtaining a contraceptive method in the early postpartum period, except among never married adolescents. Among adolescents, intervention effects on modern contraceptive use within 12 months of childbirth/pregnancy loss were larger for the never married (ATE = 0.251, 95% CI = 0.122, 0.380) than the ever married (ATE = 0.114, 95% CI = 0.020, 0.208). Full intervention exposure had consistently larger effects on contraceptive behaviors than partial exposure, except among ever married adolescents. Momentum had no effect on normative expectations about postpartum family planning use among adolescents, and on descriptive norms and personal agency among those who were never married. Results for normative outcomes and personal agency underscored the intersectionality between young maternal age and marital status. Future programs should improve personal agency and foster normative change in support of postpartum family planning uptake and tailor interventions to different age and marital status subsets of first-time mothers.

For the Early Neolithic lithic industry in Western Europe (5500–4800 BCE), the study of technical behaviors, recognition of technical traditions, and even more so, idiosyncratic manifestations are not widespread. In this study, we propose an original approach to lithic industries based on the identification of "communities of practice" and individuals within housing units. The comparison of lithic series from the Meuse, Rhine and Seine basins allowed us to identify different technical traditions in the Early Neolithic. The study of three dwelling units at two sites in the Aisne Valley in France shows that it is possible to distinguish different flint blade debitages, which we interpreted as the work of different knappers. This novel study of hand-finding in the villages of the first agro-pastoralists populations proves stimulating for the renewal of perspectives on the interpretation of the organization of activities within villages.

Allograft bone tissue has a long history of use. There are two main ways of preserving allografts: by cold (freezing), or at room temperature after an additional cleaning treatment using chemicals. These chemicals are considered potentially harmful to humans. The aim of the study was (i) to assess the presence of chemical residues on processed bone allografts and (ii) to compare the in vitro biocompatibility of such allografts with that of frozen allografts. The presence of chemical residues on industrially chemically treated bone was assessed by high performance liquid chromatography (HPLC) after extraction. Biocompatibility analysis was performed on primary osteoblast cultures from Wistar rats grown on bone disks, either frozen (F-bone group) or treated with supercritical carbon dioxide with no added chemical (scCO2-bone group) or industrially treated with chemicals (CT-bone group). Cell viability (XTT) was measured after one week of culture. Osteoblastic differentiation was assessed after 1, 7 and 14 days of culture by measuring alkaline phosphatase (ALP) activity directly on the bone discs and indirectly on the cell mat in the vicinity of the bone discs. Residues of all the chemicals used were found in the CT-bone group. There was no significant difference in cell viability between the three bone groups. Direct and indirect ALP activities were significantly lower (−40% to −80%) in the CT-bone group after 7 and 14 days of culture (p < 0.05). Residues of chemical substances used in the cleaning of bone allografts cause an in vitro decrease in their biocompatibility. Tissue cleaning processes must be developed that limit or replace these chemicals to favor biocompatibility.

Determination of the self-reported walking capacity by interview or standardized questionnaire is important. However, the existing questionnaires require the patient to be able to read and write in a specific language. We recently proposed the WELSH (Walking Estimated Limitation Stated by History) tool to be administrable to illiterate people. The main objective was to assess the applicability of WELSH tool in the community and in a large group. We performed a prospective study in the city of Bobo-Dioulasso in Burkina Faso during June 2020. We recruited 630 interviewers among medical students. They were trained to administer the WELSH, and to conduct a 6-minute walk test. We performed a Pearson's "r" correlation between the WELSH and maximal walking distance (MWD). Of the 1723 participants available for the analysis, 757 (43.9%: 41.6-46.3) never went to school or attended only elementary school. The percentage of questionnaires with participant filling-in errors corrected by the investigator decreased with the decrease in educational level (p

This paper presents new updated evidence on the initial public offering (IPO) aftermarket performance for 144 public listed firms on the Colombo Stock Exchange from 1991 to 2017. We found that average aftermarket returns are always lower than 1%. On average, buy and hold abnormal returns are negative in a short period, and abnormal returns gradually become positive over a longer period (12.46% in 3 years). Further, aftermarket returns are positively related to investor sentiment and the annual volume of listings while being negatively related to initial returns, which is consistent with the divergence of opinion hypothesis. We suggest that investors should hold their subscriptions of IPO shares for a prolonged time, usually exceeding two years, as the dynamic of shares rewards the investors with positive abnormal returns in the long run.

Laryngeal paralysis is a well-documented cause of upper respiratory tract obstruction in canines. Diagnosis of laryngeal paralysis is usually made by visual evaluation of laryngeal motion whilst patients are under a light-plane of anesthesia. However, in human studies of laryngeal function evaluation, it has been shown that subjective scoring can lead to significant interobserver variance, which may cause false diagnosis. In this study, we propose to introduce a more objective method of assessing laryngeal function using GlotAnTools and Tracker software to directly measure laryngeal motion in anaesthetized patients. Additionally, two anesthetic agents, alfaxalone and propofol, were compared in this study to assess their relative effect on laryngeal motion and thus their suitability for use in this diagnostic process. This study was a two-stage, cross-over, 1:1 randomization, with two active treatment arms. Ten beagles (10-18 months, five males and five females) were exposed to both anesthetic agents and laryngeal motion was recorded using videoendoscopy. GlotAnTools and Tracker software were applied to the recorded images to measure glottal gap area (A) and length (L). A normalized measure of laryngeal function-computed as A/L-was created, representing the "elongatedness" of the rima glottidis. The glottal gap area was significantly reduced in dogs receiving alfaxalone. This study objectively establishes that alfaxalone impacted laryngeal motion significantly more than propofol and confirms the capability of these computational methods to detect differences in laryngeal motion.

BackgroundData on microcirculatory pattern of COVID-19 critically ill patients are scarce. The objective was to compare sublingual microcirculation parameters of critically ill patients according to the severity of the disease.MethodsThe study is a single-center prospective study with critically ill COVID-19 patients admitted in ICU. Sublingual microcirculation was assessed by IDF microscopy within 48 hours of ICU admission. Microcirculatory flow index (MFI), proportion of perfused vessel (PPV), total vessel density (TVD), De Backer score (DBS), perfused vessel density (PVD) and heterogeneity index (HI) were assessed. Patients were divided in 2 groups (severe and critical) according to the World health organization definition.FindingsFrom 19th of March to 7th of April 2020, 43 patients were included. Fourteen patients (33%) were in the severe group and twenty-nine patients (67%) in the critical group. Patients in the critical group were all mechanically ventilated. The critical group had significantly higher values of MFI, DBS and PVD in comparison to severe group (respectively, PaCO2: 49 [44-45] vs 36 [33-37] mmHg; pConclusionCritical COVID-19 patients under mechanical ventilation seem to have higher red blood cell velocity than severe non-ventilated patients.

BackgroundWomen who start using contraception ("adopters") are a key population for family planning goals, but little is known about characteristics that predict the adoption of contraception as opposed to current use. We used prospective data from women and facilities for five countries, (Democratic Republic of Congo, India, Kenya, Nigeria, and Burkina Faso) and identified baseline characteristics that predicted adoption of modern contraception in the short term.MethodsWe used data from the Performance Monitoring for Action (PMA) Agile Project. PMA Agile administered service delivery point (SDP) client exit interview (CEI) surveys in urban sites of these five countries. Female clients responding to the CEI were asked for phone numbers that were used for a phone follow-up survey approximately four months later. For our analysis, we used data from the SDP and CEI baseline surveys, and the phone follow up to compare women who start using contraception during this period with those who remain non-users. We used characteristics of the facility and the woman at baseline to predict her contraception adoption in the future.ResultsDiscussing FP with a partner at baseline was associated with greater odds of adoption in DRC (OR 2.34; 95% CI 0.97-5.66), India (OR 2.27; 95% CI 1.05-4.93), and Kenya (OR 1.65; 95% CI 1.16-2.35). Women who discussed family planning with any staff member at the health facility had 1.72 greater odds (95% CI 1.13-2.67) of becoming an adopter in Nigeria. The odds of adoption were lower in Nigerian facilities that had a stockout (OR 0.66 95% CI 0.44-1.00) at baseline. Other characteristics associated with contraception adoption across settings were education, age, wealth, parity, and marital status.ConclusionsCharacteristics of both the woman and the health facility were associated with adoption of modern contraception in the future. Some characteristics, like discussing family planning with a spouse, education, and parity, were associated with contraceptive adoption across settings. Other characteristics that predict contraceptive use, such as health facility measures, varied across countries.

Coastally distributed dolphin species are vulnerable to a variety of anthropogenic pressures, yet a lack of abundance data often prevents data-driven conservation management strategies from being implemented. We investigated the abundance of Indo-Pacific bottlenose dolphins (Tursiops aduncus) along the south coast of South Africa, from the Goukamma Marine Protected Area (MPA) to the Tsitsikamma MPA, between 2014 and 2016. During this period, 662.3h of boat-based photo-identification survey effort was carried out during 189 surveys. The sighting histories of 817 identified individuals were used to estimate abundance using capture-recapture modelling. Using open population (POPAN) models, we estimated that 2,155 individuals (95% CI: 1,873-2,479) occurred in the study area, although many individuals appeared to be transients. We recorded smaller group sizes and an apparent decline in abundance in a subset of the study area (Plettenberg Bay) compared to estimates obtained in 2002-2003 at this location. We recorded declines of more than 70% in both abundance and group size for a subset of the study area (Plettenberg Bay), in relation to estimates obtained in 2002-2003 at this location. We discuss plausible hypotheses for causes of the declines, including anthropogenic pressure, ecosystem change, and methodological inconsistencies. Our study highlights the importance of assessing trends in abundance at other locations to inform data-driven conservation management strategies of T. aduncus in South Africa.

Aortic valve stenosis (AVS) is a prevalent condition among the elderly population that eventually requires aortic valve replacement. The lack of reliable biomarkers for AVS poses a challenge for its early diagnosis and the application of preventive measures. Untargeted gas chromatography mass spectrometry (GC-MS) metabolomics was applied in 46 AVS cases and 46 controls to identify plasma and urine metabolites underlying AVS risk. Multivariate data analyses were performed on pre-processed data (e.g. spectral peak alignment), in order to detect changes in metabolite levels in AVS patients and to evaluate their performance in group separation and sensitivity of AVS prediction, followed by regression analyses to test for their association with AVS. Through untargeted analysis of 190 urine and 130 plasma features that could be detected and quantified in the GC-MS spectra, we identified contrasting levels of 22 urine and 21 plasma features between AVS patients and control subjects. Following metabolite assignment, we observed significant changes in the concentration of known metabolites in urine (n = 14) and plasma (n = 15) that distinguish the metabolomic profiles of AVS patients from healthy controls. Associations with AVS were replicated in both plasma and urine for about half of these metabolites. Among these, 2-Oxovaleric acid, elaidic acid, myristic acid, palmitic acid, estrone, myo-inositol showed contrasting trends of regulation in the two biofluids. Only trans-Aconitic acid and 2,4-Di-tert-butylphenol showed consistent patterns of regulation in both plasma and urine. These results illustrate the power of metabolomics in identifying potential disease-associated biomarkers and provide a foundation for further studies towards early diagnostic applications in severe heart conditions that may prevent surgery in the elderly.

Lead and malaria both present significant health risks to children in Sub-Saharan Africa. Previous studies have shown that high blood lead levels in children act as a protective factor against subsequent malaria incidence. The main objective of this study was to investigate associations between blood lead level and malaria outcomes prospectively in Beninese children from 12 to 24 months of age. Two-hundred and four children were assessed for lead at 12 months and closely followed until 24 months for malaria; when symptoms and parasite density were also recorded. Univariate and multivariate negative binomial and linear regression models tested associations between blood lead level quartile and total episodes of malaria (total symptomatic and asymptomatic episodes) and parasite density, respectively. Median blood lead level among children measured at 12 months was 56.50 (4.81-578) μg/L. During the 12-month follow-up, 172 (84.31%) children had at least one malaria episode. Univariate and multivariate negative binomial and linear regressions did not reveal significant associations between blood lead level quartile and malaria outcomes. Iron deficiency was not found to be an effect modifier. Results from this prospective child-cohort study investigating associations between blood lead level and malaria did not confirm results from previous cross-sectional studies. Further research is needed to further explore this relationship and other co-morbidities due to malaria and lead.

Antiphospholipid antibodies (aPL) promote endothelial dysfunction, inflammation and procoagulant state. We investigated the effect of hydroxychloroquine (HCQ) on prothrombotic state and endothelial function in mice and in human aortic endothelial cells (HAEC). Human aPL were injected to C57BL/6 mice treated or not with HCQ. Vascular endothelial function and eNOS were assessed in isolated mesenteric arteries. Thrombosis was assessed both in vitro by measuring thrombin generation time (TGT) and tissue factor (TF) expression and in vivo by the measurement of the time to occlusion in carotid and the total thrombosis area in mesenteric arteries. TGT, TF, and VCAM1 expression were evaluated in HAEC. aPL increased VCAM-1 expression and reduced endothelium dependent relaxation to acetylcholine. In parallel, aPL shortened the time to occlusion and extended thrombus area in mice. This was associated with an overexpression of TF and an increased TGT in mice and in HAEC. HCQ reduced clot formation as well as TGT, and improved endothelial-dependent relaxations. Finally, HCQ increased the p-eNOS/eNOS ratio. This study provides new evidence that HCQ improves procoagulant status and vascular function in APS by modulating eNOS, leading to an improvement in the production of NO.

IntroductionThe subventricular zone (SVZ) in the brain is associated with gliomagenesis and resistance to treatment in glioblastoma. In this study, we investigate the prognostic role and biological characteristics of subventricular zone (SVZ) involvement in glioblastoma.MethodsWe analyzed T1-weighted, gadolinium-enhanced MR images of a retrospective cohort of 647 primary glioblastoma patients diagnosed between 2005-2013, and performed a multivariable Cox regression analysis to adjust the prognostic effect of SVZ involvement for clinical patient- and tumor-related factors. Protein expression patterns of a.o. markers of neural stem cellness (CD133 and GFAP-δ) and (epithelial-) mesenchymal transition (NF-κB, C/EBP-β and STAT3) were determined with immunohistochemistry on tissue microarrays containing 220 of the tumors. Molecular classification and mRNA expression-based gene set enrichment analyses, miRNA expression and SNP copy number analyses were performed on fresh frozen tissue obtained from 76 tumors. Confirmatory analyses were performed on glioblastoma TCGA/TCIA data.ResultsInvolvement of the SVZ was a significant adverse prognostic factor in glioblastoma, independent of age, KPS, surgery type and postoperative treatment. Tumor volume and postoperative complications did not explain this prognostic effect. SVZ contact was associated with increased nuclear expression of the (epithelial-) mesenchymal transition markers C/EBP-β and phospho-STAT3. SVZ contact was not associated with molecular subtype, distinct gene expression patterns, or markers of stem cellness. Our main findings were confirmed in a cohort of 229 TCGA/TCIA glioblastomas.ConclusionIn conclusion, involvement of the SVZ is an independent prognostic factor in glioblastoma, and associates with increased expression of key markers of (epithelial-) mesenchymal transformation, but does not correlate with stem cellness, molecular subtype, or specific (mi)RNA expression patterns.

This study evaluated the effect of Momentum-an integrated family planning, maternal and newborn health, and nutrition intervention-on postpartum family planning norms and behaviors among ever married and never-married first-time mothers age 15-24 in Kinshasa, Democratic Republic of the Congo. Using data collected in 2018 and 2020, we conducted an intent-to-treat analysis among 1,927 first-time mothers who were about six-months pregnant at enrollment. Difference-in-differences models were run for panel data and treatment effects models with inverse-probability weighting for endline-only outcomes. Average treatment effects (ATE) were estimated. Momentum had positive effects on partner discussion of family planning in the early postpartum period (ever married 15-19: ATE = 0.179, 95% CI = 0.098, 0.261; never married 15-19: ATE = 0.131, 95% CI = 0.029, 0.232; ever married 20-24: ATE = 0.233, 95% CI = 0.164, 0.302; never married 20-24: ATE = 0.241, 95% CI = 0.121, 0.362) and discussion with a health worker, and on obtaining a contraceptive method in the early postpartum period, except among never married adolescents. Among adolescents, intervention effects on modern contraceptive use within 12 months of childbirth/pregnancy loss were larger for the never married (ATE = 0.251, 95% CI = 0.122, 0.380) than the ever married (ATE = 0.114, 95% CI = 0.020, 0.208). Full intervention exposure had consistently larger effects on contraceptive behaviors than partial exposure, except among ever married adolescents. Momentum had no effect on normative expectations about postpartum family planning use among adolescents, and on descriptive norms and personal agency among those who were never married. Results for normative outcomes and personal agency underscored the intersectionality between young maternal age and marital status. Future programs should improve personal agency and foster normative change in support of postpartum family planning uptake and tailor interventions to different age and marital status subsets of first-time mothers.

The Northern California Current is a highly productive marine upwelling ecosystem that is economically and ecologically important. It is home to both commercially harvested species and those that are federally listed under the U.S. Endangered Species Act. Recently, there has been a global shift from single-species fisheries management to ecosystem-based fisheries management, which acknowledges that more complex dynamics can reverberate through a food web. Here, we have integrated new research into an end-to-end ecosystem model (i.e., physics to fisheries) using data from long-term ocean surveys, phytoplankton satellite imagery paired with a vertically generalized production model, a recently assembled diet database, fishery catch information, species distribution models, and existing literature. This spatially-explicit model includes 90 living and detrital functional groups ranging from phytoplankton, krill, and forage fish to salmon, seabirds, and marine mammals, and nine fisheries that occur off the coast of Washington, Oregon, and Northern California. This model was updated from previous regional models to account for more recent changes in the Northern California Current (e.g., increases in market squid and some gelatinous zooplankton such as pyrosomes and salps), to expand the previous domain to increase the spatial resolution, to include data from previously unincorporated surveys, and to add improved characterization of endangered species, such as Chinook salmon (Oncorhynchus tshawytscha) and southern resident killer whales (Orcinus orca). Our model is mass-balanced, ecologically plausible, without extinctions, and stable over 150-year simulations. Ammonium and nitrate availability, total primary production rates, and model-derived phytoplankton time series are within realistic ranges. As we move towards holistic ecosystem-based fisheries management, we must continue to openly and collaboratively integrate our disparate datasets and collective knowledge to solve the intricate problems we face. As a tool for future research, we provide the data and code to use our ecosystem model.

INTRODUCTION:To examine the relationship between chronic health conditions and out-of-pocket costs (OOPC) and medical debt. METHODS:Secondary data from the 2013 Panel Study of Income Dynamics (PSID) was used. Households whose head of household and spouse (for married households) were 18 to 64 years old were included. RESULTS:Households with 1 to 3 chronic conditions had higher odds of having any OOPC compared to households with no chronic conditions (AOR 1.74, 95% CI 1.39, 2.17) (p < .01). Households with 1 to 3 and 4 or more chronic health conditions were associated with higher odds of having any medical debt (AOR 2.24, 95% CI 1.75 to 2.87; AOR 5.04, 95% CI 3.04 to 8.34) compared to those with no chronic conditions (p < 0.01). Similarly, 1 to 3 and 4 or more chronic health conditions was associated with higher amounts of OOPC (Exponentiated Coefficient 1.18, 95% CI 1.03 to 1.36; Exponentiated Coefficient 1.56, 95% CI 1.17 to 2.07) and medical debt (Exponentiated Coefficient 1.69, 95% CI 1.23 to 2.34; Exponentiated Coefficient 2.73, 95% CI 1.19 to 6.25) compared to households with no chronic conditions (p < 0.05). CONCLUSIONS:Findings from this study show that the presence of chronic health conditions impose a large financial burden on some households.

The Kidney Failure Risk Equation (KFRE) predicts the need for dialysis or transplantation using age, sex, estimated glomerular filtration rate (eGFR), and urine albumin to creatinine ratio (ACR). The eGFR and ACR have known biological and analytical variability. We examined the effect of biological and analytical variability of eGFR and ACR on the 2-year KFRE predicted kidney failure probabilities using single measure and the average of repeat measures of simulated eGFR and ACR. Previously reported values for coefficient of variation (CV) for ACR and eGFR were used to calculate day to day variability. Variation was also examined with outpatient laboratory data from patients with an eGFR between 15 and 50 mL/min/1.72 m2. A web application was developed to calculate and model day to day variation in risk. The biological and analytical variability related to ACR and eGFR lead to variation in the predicted probability of kidney failure. A male patient age 50, ACR 30 mg/mmol and eGFR 25, had a day to day variation in risk of 7% (KFRE point estimate: 17%, variability range 14% to 21%). The addition of inter laboratory variation due to different instrumentation increased the variability to 9% (KFRE point estimate 17%, variability range 13% to 22%). Averaging of repeated measures of eGFR and ACR significantly decreased the variability (KFRE point estimate 17%, variability range 15% to 19%). These findings were consistent when using outpatient laboratory data which showed that most patients had a KFRE 2-year risk variability of ≤ 5% (79% of patients). Approximately 13% of patients had variability from 5-10% and 8% had variability > 10%. The mean age (SD) of this cohort was 64 (15) years, 36% were females, the mean (SD) eGFR was 32 (10) ml/min/1.73m2 and median (IQR) ACR was 22.7 (110). Biological and analytical variation intrinsic to the eGFR and ACR may lead to a substantial degree of variability that decreases with repeat measures. Use of a web application may help physicians and patients understand individual patient's risk variability and communicate risk (https://mccudden.shinyapps.io/kfre_app/). The web application allows the user to alter age, gender, eGFR, ACR, CV (for both eGFR and ACR) as well as units of measurements for ACR (g/mol versus mg/g).

Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g. BRAFV600E). These features may serve as diagnostic and prognostic markers, and also facilitate development of targeted therapy. The aims of this study were to characterize the genetic alterations underlying the development of PA in six tumor cases, and evaluate methods for fusion oncogene detection. Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5' gene fusion partner GTF2I (7q11.23), not previously described in PA. The new GTF2I-BRAF 19-10 fusion was found in one case, while the other five cases harbored the frequent KIAA1549-BRAF 16-9 fusion gene. Similar to other BRAF fusions, the GTF2I-BRAF fusion retains an intact BRAF kinase domain while the inhibitory N-terminal domain is lost. Functional studies on GTF2I-BRAF showed elevated MAPK pathway activation compared to BRAFWT. Comparing fusion detection methods, we found Fluorescence in situ hybridization with BRAF break apart probe as the most sensitive method for detection of different BRAF rearrangements (GTF2I-BRAF and KIAA1549-BRAF). Our finding of a new BRAF fusion in PA further emphasis the important role of B-Raf in tumorigenesis of these tumor types. Moreover, the consistency and growing list of BRAF/RAF gene fusions suggests these rearrangements to be informative tumor markers in molecular diagnostics, which could guide future treatment strategies.

Although numerous studies have demonstrated the key role of bacterial diversity in soil functions and ecosystem services, little is known about the variations and determinants of such diversity on a nationwide scale. The overall objectives of this study were i) to describe the bacterial taxonomic richness variations across France, ii) to identify the ecological processes (i.e. selection by the environment and dispersal limitation) influencing this distribution, and iii) to develop a statistical predictive model of soil bacterial richness. We used the French Soil Quality Monitoring Network (RMQS), which covers all of France with 2,173 sites. The soil bacterial richness (i.e. OTU number) was determined by pyrosequencing 16S rRNA genes and related to the soil characteristics, climatic conditions, geomorphology, land use and space. Mapping of bacterial richness revealed a heterogeneous spatial distribution, structured into patches of about 111km, where the main drivers were the soil physico-chemical properties (18% of explained variance), the spatial descriptors (5.25%, 1.89% and 1.02% for the fine, medium and coarse scales, respectively), and the land use (1.4%). Based on these drivers, a predictive model was developed, which allows a good prediction of the bacterial richness (R2adj of 0.56) and provides a reference value for a given pedoclimatic condition.

[This corrects the article DOI: 10.1371/journal.pone.0186766.].

Fabry disease (FD) is a lysosomal storage disorder leading to decreased α-galactosidase A enzyme activity and subsequent abnormal accumulation of glycosphingolipids in various organs. Although histological evidence of lung involvement has been demonstrated, the functional impact of these changes is less clear.Adult patients with FD who had yearly pulmonary function tests (PFT) at two centers from 1999 thru 2015 were eligible for this observational study. Primary outcome measures were the change in forced expiratory volume in the first second (FEV1) and FEV1/FVC over time. As secondary outcome we investigated sex, smoking, enzyme replacement therapy (ERT), residual enzyme activity, and Mainz Severity Score Index as possible predictors.95 patients (41% male, 38.2 ± 14.5 years) were included. The overall prevalence of bronchial obstruction (BO, (FEV1/FVC < 70%)) was 46%, with male sex, age and smoking as significant predictors. FEV1 decreased 29 ml per year (95% CI -36, -22 ml, p

Clouds are key components in Earth's functioning. In addition of acting as obstacles to light radiations and chemical reactors, they are possible atmospheric oases for airborne microorganisms, providing water, nutrients and paths to the ground. Microbial activity was previously detected in clouds, but the microbial community that is active in situ remains unknown. Here, microbial communities in cloud water collected at puy de Dôme Mountain's meteorological station (1465 m altitude, France) were fixed upon sampling and examined by high-throughput sequencing from DNA and RNA extracts, so as to identify active species among community members. Communities consisted of ~103-104 bacteria and archaea mL-1 and ~102-103 eukaryote cells mL-1. They appeared extremely rich, with more than 28 000 distinct species detected in bacteria and 2 600 in eukaryotes. Proteobacteria and Bacteroidetes largely dominated in bacteria, while eukaryotes were essentially distributed among Fungi, Stramenopiles and Alveolata. Within these complex communities, the active members of cloud microbiota were identified as Alpha- (Sphingomonadales, Rhodospirillales and Rhizobiales), Beta- (Burkholderiales) and Gamma-Proteobacteria (Pseudomonadales). These groups of bacteria usually classified as epiphytic are probably the best candidates for interfering with abiotic chemical processes in clouds, and the most prone to successful aerial dispersion.

[This corrects the article DOI: 10.1371/journal.pone.0175638.].

In the context of limited marine resources, the exponential growth of aquaculture requires the substitution of fish oil and fishmeal, the traditional components of fish feeds by terrestrial plant ingredients. High levels of such substitution are known to negatively impact fish performance such as growth and survival in rainbow trout (Oncorhynchus mykiss) as in other salmonids. In this respect, genetic selection is a key enabler for improving those performances and hence for the further sustainable development of aquaculture. We selected a rainbow trout line over three generations for its ability to survive and grow on a 100% plant-based diet devoid of both fish oil and fishmeal (V diet) from the very first meal. In the present study, we compared the control line and the selected line after 3 generations of selection, both fed either the V diet or a marine resources-based diet (M diet). The objective of the study was to assess the efficiency of selection and the consequences on various correlated nutritional traits: feed intake, feed efficiency, digestibility, composition of whole fish, nutrient retention and fatty acid (FA) profile. We demonstrated that the genetic variability present in our rainbow trout population can be selected to improve survival and growth. The major result of the study is that after only three generations of selection, selected fish fed the V diet grew at the same rate as the control line fed the M diet, whilst the relative reduction of body weight was 36.8% before the selection. This enhanced performance on the V diet seems to be mostly linked to a higher feed intake for the selected fish.

In sports medicine, there is increasing interest in quantifying the elastic properties of skeletal muscle, especially during extreme muscular stimulation, to improve our understanding of the impact of alterations in skeletal muscle stiffness on resulting pain or injuries, as well as the mechanisms underlying the relationships between these parameters. Our main objective was to determine whether real-time shear-wave elastography (SWE) can monitor changes in quadriceps muscle elasticity during an extreme mountain ultra-marathon, a powerful mechanical stress model. Our study involved 50 volunteers participating in an extreme mountain marathon (distance: 330 km, elevation: +24,000 m). Quantitative SWE velocity and shear modulus measurements were performed in most superficial quadriceps muscle heads at the following 4 time points: before the race, halfway through the race, upon finishing the race and after recovery (+48 h). Blood biomarker levels were also measured. A significant decrease in the quadriceps shear modulus was observed upon finishing the race (3.31±0.61 kPa) (p

[This corrects the article DOI: 10.1371/journal.pone.0161855.].

INTRODUCTION:Elevated blood lead levels (BLL) and malaria carry an important burden of disease in West Africa. Both diseases might cause anemia and they might entail long-term consequences for the development and the health status of the child. Albeit the significant impact of malaria on lead levels described in Nigeria, no evaluation of the effect of elevated BLL on malaria risk has been investigated so far. MATERIALS AND METHODS:Between 2010 and 2012, blood lead levels of 203 Beninese infants from Allada, a semi-rural area 50km North from Cotonou, were assessed at 12 months of age. To assess lead levels, blood samples were analyzed by mass spectrometry. In parallel, clinical, microbiological and hematological data were collected. More precisely, hemoglobin, serum ferritin, CRP, vitamin B12, folate levels, and Plasmodium falciparum parasitemia were assessed and stool samples were also analyzed. RESULTS:At 12 months, the mean BLL of infants was 7.41 μg/dL (CI: 65.2; 83), and 128 infants (63%) had elevated blood lead levels, defined by the CDC as BLL>5 μg/dL. Lead poisoning, defined as BLL>10 μg/dL, was found in 39 infants (19%). Twenty-five infants (12.5%) had a positive blood smear at 12 months and 144 infants were anemic (71%, hemoglobin

Foraging behaviour of marine top predators is increasingly being used to identify areas of ecological importance. This is largely enabled by the ability of many such species to forage extensively in search of prey that is often concentrated in oceanographically productive areas. To identify important habitat in the Southern Indian Ocean within and around South Africa's Prince Edward Islands' Marine Protected Area (MPA), satellite transmitters were deployed on 12 lactating Subantarctic fur seals Arctocephalus tropicalis at Prince Edward Island (PEI) itself. Switching state space models were employed to correct ARGOS tracks and estimate behavioural states for locations along predicted tracks, namely travelling or area restricted search (ARS). A random forest model showed that distance from the study colony, longitude and distance from the Subantarctic Front were the most important predictors of suitable foraging habitat (inferred from ARS). Model-predicted suitable habitat occurred within the MPA in relatively close access to the colony during summer and autumn, but shifted northwards concurrently with frontal movements in winter and spring. The association of ARS with the MPA during summer-autumn was highly significant, highlighting the effectiveness of the recently declared reserve's design for capturing suitable foraging habitat for this and probably other marine top predator species.

MicroRNAs have emerged as important markers and regulators of cell identity. Precise measurements of cellular miRNA levels rely traditionally on RNA extraction and thus do not allow to follow miRNA expression dynamics at the level of single cells. Non-invasive miRNA sensors present an ideal solution but they critically depend on the performance of suitable ubiquitous promoters that reliably drive expression both in pluripotent and differentiated cell types. Here we describe the engineering of bidirectional promoters that drive the expression of precise ratiometric fluorescent miRNA sensors in single mouse embryonic stem cells (mESCs) and their differentiated derivatives. These promoters are based on combinations of the widely used CAG, EF1α and PGK promoters as well as the CMV and PGK enhancers. miR-142-3p, which is known to be bimodally expressed in mESCs, served as a model miRNA to gauge the precision of the sensors. The performance of the resulting miRNA sensors was assessed by flow cytometry in single stable transgenic mESCs undergoing self-renewal or differentiation. EF1α promoters arranged back-to-back failed to drive the robustly correlated expression of two transgenes. Back-to-back PGK promoters were shut down during mESC differentiation. However, we found that a back-to-back arrangement of CAG promoters with four CMV enhancers provided both robust expression in mESCs undergoing differentiation and the best signal-to-noise for measurement of miRNA activity in single cells among all the sensors we tested. Such a bidirectional promoter is therefore particularly well suited to study the dynamics of miRNA expression during cell fate transitions at the single cell level.

Many species of seabirds, including the only penguin species breeding on the African continent, are threatened with extinction. The world population of the endangered African penguin Spheniscus demersus has decreased from more than 1.5 million individuals in the early 1900s to c.a. 23 000 pairs in 2013. Determining the trophic interactions of species, especially those of conservation concern, is important when declining numbers are thought to be driven by food limitation. By and large, African penguin dietary studies have relied on the identification of prey remains from stomach contents. Despite all the advantages of this method, it has well known biases. We therefore assessed the African penguin's diet, using stable isotopes, at two colonies in Algoa Bay (south-east coast of South Africa). These represent over 50% of the world population. Various samples (blood, feathers, egg membranes) were collected for carbon and nitrogen stable isotope analyses. Results indicate that the trophic ecology of African penguins is influenced by colony, season and age class, but not adult sex. Isotopic niches identified by standard Bayesian ellipse areas and convex hulls, highlighted differences among groups and variability among individual penguins. Using Bayesian mixing models it was for the first time shown that adults target chokka squid Loligo reynaudii for self-provisioning during particular stages of their annual cycle, while concurrently feeding their chicks primarily with small pelagic fish. This has important ramifications and means that not only pelagic fish, but also squid stocks, need to be carefully managed in order to allow population recovery of African penguin.

It is commonly assumed that perfusion in a given cerebral territory can be inferred from Blood Flow Velocity (BFV) measurements in the corresponding stem artery. In order to test this hypothesis, we construct a cerebral blood flow (CBF) estimator based on transcranial Doppler (TCD) blood flow velocity and ten other easily available patient characteristics and clinical parameters. A total of 261 measurements were collected from 88 older patients. The estimator is based on local regression (Random Forest). Its performance is analyzed against baseline CBF from 3-D pseudocontinuous arterial spin labeling (pCASL) magnetic resonance imaging (MRI). Patient specific CBF predictions are of poor quality (r = 0.41 and p-value = 4.5 × 10-12); the hypothesis is thus not clearly supported by evidence.

OBJECTIVE:To test the hypothesis whether enriched air nitrox (EAN) breathing during simulated diving reduces decompression stress when compared to compressed air breathing as assessed by intravascular bubble formation after decompression. METHODS:Human volunteers underwent a first simulated dive breathing compressed air to include subjects prone to post-decompression venous gas bubbling. Twelve subjects prone to bubbling underwent a double-blind, randomized, cross-over trial including one simulated dive breathing compressed air, and one dive breathing EAN (36% O2) in a hyperbaric chamber, with identical diving profiles (28 msw for 55 minutes). Intravascular bubble formation was assessed after decompression using pulmonary artery pulsed Doppler. RESULTS:Twelve subjects showing high bubble production were included for the cross-over trial, and all completed the experimental protocol. In the randomized protocol, EAN significantly reduced the bubble score at all time points (cumulative bubble scores: 1 [0-3.5] vs. 8 [4.5-10]; P < 0.001). Three decompression incidents, all presenting as cutaneous itching, occurred in the air versus zero in the EAN group (P = 0.217). Weak correlations were observed between bubble scores and age or body mass index, respectively. CONCLUSION:EAN breathing markedly reduces venous gas bubble emboli after decompression in volunteers selected for susceptibility for intravascular bubble formation. When using similar diving profiles and avoiding oxygen toxicity limits, EAN increases safety of diving as compared to compressed air breathing. TRIAL REGISTRATION:ISRCTN 31681480.

[This corrects the article DOI: 10.1371/journal.pone.0154761.].

While Phoenician culture and trade networks had a significant impact on Western civilizations, we know little about the Phoenicians themselves. In 1994, a Punic burial crypt was discovered on Byrsa Hill, near the entry to the National Museum of Carthage in Tunisia. Inside this crypt were the remains of a young man along with a range of burial goods, all dating to the late 6th century BCE. Here we describe the complete mitochondrial genome recovered from the Young Man of Byrsa and identify that he carried a rare European haplogroup, likely linking his maternal ancestry to Phoenician influenced locations somewhere on the North Mediterranean coast, the islands of the Mediterranean or the Iberian Peninsula. This result not only provides the first direct ancient DNA evidence of a Phoenician individual but the earliest evidence of a European mitochondrial haplogroup, U5b2c1, in North Africa.

How animals respond to varying environmental conditions is fundamental to ecology and is a question that has gained impetus due to mounting evidence indicating negative effects of global change on biodiversity. Behavioural plasticity is one mechanism that enables individuals and species to deal with environmental changes, yet for many taxa information on behavioural parameters and their capacity to change are lacking or restricted to certain periods within the annual cycle. This is particularly true for seabirds where year-round behavioural information is intrinsically challenging to acquire due to their reliance on the marine environment where they are difficult to study. Using data from over 13,000 foraging trips throughout the annual cycle, acquired using new-generation automated VHF technology, we described sex-specific, year-round activity budgets in Cape gannets. Using these data we investigated the role of weather (wind and rain) on foraging activity and time allocated to nest attendance. Foraging activity was clearly influenced by wind speed, wind direction and rainfall during and outside the breeding season. Generally, strong wind conditions throughout the year resulted in relatively short foraging trips. Birds spent longer periods foraging when rainfall was moderate. Nest attendance, which was sex-specific outside of the breeding season, was also influenced by meteorological conditions. Large amounts of rainfall (> 2.5 mm per hour) and strong winds (> 13 m s-1) resulted in gannets spending shorter amounts of time at their nests. We discuss these findings in terms of life history strategies and implications for the use of seabirds as bio-indicators.

Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest trauma is due to the physical damage, the drop in alveolar PO2, and the consecutive hypoxemia and tissue hypoxia. Therefore, we tested the hypotheses that 1) CS exposure prior to blunt chest trauma causes more severe post-traumatic inflammation and thereby aggravates lung injury, and that 2) hyperoxia may attenuate this effect. Immediately after blast wave-induced blunt chest trauma, mice (n=32) with or without 3-4 weeks of CS exposure underwent 4 hours of pressure-controlled, thoraco-pulmonary compliance-titrated, lung-protective mechanical ventilation with air or 100% O2. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1 (HO-1), activated caspase-3, and hypoxia-inducible factor 1-α (HIF-1α) expression, nuclear factor-κB (NF-κB) activation, nitrotyrosine formation, purinergic receptor 2X4 (P2XR4) and 2X7 (P2XR7) expression, and histological scoring. CS exposure prior to chest trauma lead to higher pulmonary compliance and lower PaO2 and Horovitz-index, associated with increased tissue IL-18 and blood MCP-1 concentrations, a 2-4-fold higher inflammatory cell infiltration, and more pronounced alveolar membrane thickening. This effect coincided with increased activated caspase-3, nitrotyrosine, P2XR4, and P2XR7 expression, NF-κB activation, and reduced HIF-1α expression. Hyperoxia did not further affect lung mechanics, gas exchange, pulmonary and systemic cytokine and chemokine concentrations, or histological scoring, except for some patchy alveolar edema in CS exposed mice. However, hyperoxia attenuated tissue HIF-1α, nitrotyrosine, P2XR7, and P2XR4 expression, while it increased HO-1 formation in CS exposed mice. Overall, CS exposure aggravated post-traumatic inflammation, nitrosative stress and thereby organ dysfunction and injury; short-term, lung-protective, hyperoxic mechanical ventilation have no major beneficial effect despite attenuation of nitrosative stress, possibly due to compensation of by regional alveolar hypoxia and/or consecutive hypoxemia, resulting in down-regulation of HIF-1α expression.

The number of patients starting dialysis is increasing world wide. Unplanned dialysis starts (patients urgently starting dialysis in hospital) is associated with increased costs and high morbidity and mortality. Risk factors for starting dialysis urgently in hospital have not been well studied. The primary objective of this study was to identify risk factors for unplanned dialysis starts in patients followed in a multidisciplinary chronic kidney disease (CKD) clinic. We performed a retrospective cohort study of 649 advanced CKD patients followed in a multidisciplinary CKD clinic at a tertiary care hospital from January 01, 2010 to April 30, 2013. Patients were classified as unplanned start (in hospital) or elective start. Multivariable logistic regression was used to identify variables associated with unplanned dialysis initiation. 184 patients (28.4%) initiated dialysis, of which 76 patients (41.3%) initiated dialysis in an unplanned fashion and 108 (58.7%) starting electively. Unplanned start patients were more likely to have diabetes (68.4% versus 51.9%; p = 0.04), CAD (42.1% versus 24.1%; p = 0.02), congestive heart failure (36.8% versus 17.6%; p = 0.01), and were less likely to receive modality education (64.5% vs 89.8%; p < 0.01) or be assessed by a surgeon for access creation (40.8% vesrus 78.7% p < 0.01). On multivariable analysis, higher body mass index (OR 1.07, 95% CI 1.02, 1.13), and a history of congestive heart failure (OR 2.41, 95% CI 1.09, 5.41) were independently associated with an unplanned start. Unplanned dialysis initiation is common among advanced CKD patients, even if they are followed in a multidisciplinary chronic kidney disease clinic. Timely education and access creation in patients at risk may lead to lower costs and less morbidity and mortality.

To assess and compare cortical thickness (CTh) of patients with prodromal Dementia with Lewy bodies (pro-DLB), prodromal Alzheimer's disease (pro-AD), DLB dementia (DLB-d), AD dementia (AD-d) and normal ageing.Study participants(28 pro-DLB, 27 pro-AD, 31 DLB-d, 54 AD-d and 33 elderly controls) underwent 3Tesla T1 3D MRI and detailed clinical and cognitive assessments. We used FreeSurfer analysis package to measure CTh and investigate patterns of cortical thinning across groups.Comparison of CTh between pro-DLB and pro-AD (p

BACKGROUND AND PURPOSE: Different studies already demonstrated the benefits of 7T for precontrast TOF-MRA in the visualization of intracranial small vessels. The aim of this study was to assess the performance of high-resolution 7T TOF-MRA after the administration of a gadolinium-based contrast agent in visualizing intracranial perforating arteries. MATERIALS AND METHODS: Ten consecutive patients (7 male; mean age, 50.4 ± 9.9 years) who received TOF-MRA at 7T after contrast administration were retrospectively included in this study. Intracranial perforating arteries, branching from the parent arteries of the circle of Willis, were identified on all TOF-MRA images. Provided a TOF-MRA before contrast administration was present, a direct comparison between pre- and postcontrast TOF-MRA was made. RESULTS: It was possible to visualize intracranial perforating arteries branching off from the entire circle of Willis, and their proximal branches. The posterior cerebral artery (P1 and proximal segment of P2) appeared to have the largest number of visible perforating branches (mean of 5.1 in each patient, with a range of 2-7). The basilar artery and middle cerebral artery (M1 and proximal segment M2) followed with a mean number of 5.0 and 3.5 visible perforating branches (range of 1-9 and 1-8, respectively). Venous contamination in the postcontrast scans sometimes made it difficult to discern the arterial or venous nature of a vessel. CONCLUSION: High-resolution postcontrast TOF-MRA at 7T was able to visualize multiple intracranial perforators branching off from various parts of the circle of Willis and proximal intracranial arteries. Although confirmation in a larger study is needed, the administration of a contrast agent for high-resolution TOF-MRA at 7T seems to enable a better visualization of the distal segment of certain intracranial perforators.

Y-chromosomal haplogroup G1 is a minor component of the overall gene pool of South-West and Central Asia but reaches up to 80% frequency in some populations scattered within this area. We have genotyped the G1-defining marker M285 in 27 Eurasian populations (n= 5,346), analyzed 367 M285-positive samples using 17 Y-STRs, and sequenced ~11 Mb of the Y-chromosome in 20 of these samples to an average coverage of 67X. This allowed detailed phylogenetic reconstruction. We identified five branches, all with high geographical specificity: G1-L1323 in Kazakhs, the closely related G1-GG1 in Mongols, G1-GG265 in Armenians and its distant brother clade G1-GG162 in Bashkirs, and G1-GG362 in West Indians. The haplotype diversity, which decreased from West Iran to Central Asia, allows us to hypothesize that this rare haplogroup could have been carried by the expansion of Iranic speakers northwards to the Eurasian steppe and via founder effects became a predominant genetic component of some populations, including the Argyn tribe of the Kazakhs. The remarkable agreement between genetic and genealogical trees of Argyns allowed us to calibrate the molecular clock using a historical date (1405 AD) of the most recent common genealogical ancestor. The mutation rate for Y-chromosomal sequence data obtained was 0.78×10-9 per bp per year, falling within the range of published rates. The mutation rate for Y-chromosomal STRs was 0.0022 per locus per generation, very close to the so-called genealogical rate. The "clan-based" approach to estimating the mutation rate provides a third, middle way between direct farther-to-son comparisons and using archeologically known migrations, whose dates are subject to revision and of uncertain relationship to genetic events.

The continuous improvement of imaging technologies has driven the development of sophisticated reporters to monitor biological processes. Such constructs should ideally be assembled in a flexible enough way to allow for their optimization. Here we describe a highly reliable cloning method to efficiently assemble constructs for imaging or flow cytometry applications in mammalian cell culture systems. We bioinformatically identified a list of restriction enzymes whose sites are rarely found in human and mouse cDNA libraries. From the best candidates, we chose an enzyme combination (MluI, XhoI and SalI: MXS) that enables iterative chaining of individual building blocks. The ligation scar resulting from the compatible XhoI- and SalI-sticky ends can be translated and hence enables easy in-frame cloning of coding sequences. The robustness of the MXS-chaining approach was validated by assembling constructs up to 20 kb long and comprising up to 34 individual building blocks. By assessing the success rate of 400 ligation reactions, we determined cloning efficiency to be 90% on average. Large polycistronic constructs for single-cell imaging or flow cytometry applications were generated to demonstrate the versatility of the MXS-chaining approach. We devised several constructs that fluorescently label subcellular structures, an adapted version of FUCCI (fluorescent, ubiquitination-based cell cycle indicator) optimized to visualize cell cycle progression in mouse embryonic stem cells and an array of artificial promoters enabling dosage of doxycyline-inducible transgene expression. We made publicly available through the Addgene repository a comprehensive set of MXS-building blocks comprising custom vectors, a set of fluorescent proteins, constitutive promoters, polyadenylation signals, selection cassettes and tools for inducible gene expression. Finally, detailed guidelines describe how to chain together prebuilt MXS-building blocks and how to generate new customized MXS-building blocks.

Since 8th March 2020 up to the time of writing, we have been producing near real-time weekly estimates of SARS-CoV-2 transmissibility and forecasts of deaths due to COVID-19 for all countries with evidence of sustained transmission, shared online. We also developed a novel heuristic to combine weekly estimates of transmissibility to produce forecasts over a 4-week horizon. Here we present a retrospective evaluation of the forecasts produced between 8th March to 29th November 2020 for 81 countries. We evaluated the robustness of the forecasts produced in real-time using relative error, coverage probability, and comparisons with null models. During the 39-week period covered by this study, both the short- and medium-term forecasts captured well the epidemic trajectory across different waves of COVID-19 infections with small relative errors over the forecast horizon. The model was well calibrated with 56.3% and 45.6% of the observations lying in the 50% Credible Interval in 1-week and 4-week ahead forecasts respectively. The retrospective evaluation of our models shows that simple transmission models calibrated using routine disease surveillance data can reliably capture the epidemic trajectory in multiple countries. The medium-term forecasts can be used in conjunction with the short-term forecasts of COVID-19 mortality as a useful planning tool as countries continue to relax public health measures.

BACKGROUND: Androgens are critical in male external genital development. Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome (AIS). OBJECTIVE: The aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR. MATERIALS AND METHODS: Two hundred and ninety-two Caucasian children presenting with isolated hypospadias without micropenis or cryptorchidism and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1-8) was performed. In silico and luciferase functional assays were performed for unreported variants. RESULTS: Five missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n = 5), penile midshaft (n = 2) and penile posterior (n = 2) hypospadias, i.e., 3%: p.Q58L (c.173A>T), 4 cases of p.P392S (c.1174C>T), 2 cases of p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G). None of these mutations was present in the control group. One mutation has never been reported to date (p.D551H). It was predicted to be damaging based on 6 in silico models, and in vitro functional studies confirmed the lowered transactivation function of the mutated protein. Three mutations have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patient. CONCLUSION: AR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration may be important for proper diagnosis and longer follow-up is necessary to find out if the mutations cause differences in sexual function and fertility later in life.

Background and purposeThe aim of our study was to validate in an independent cohort the MRI-DRAGON score, an adaptation of the (CT-) DRAGON score to predict 3-month outcome in acute ischemic stroke patients undergoing MRI before intravenous thrombolysis (IV-tPA).MethodsWe reviewed consecutive (2009-2013) anterior circulation stroke patients treated within 4.5 hours by IV-tPA in the Lille stroke unit (France), where MRI is the first-line pretherapeutic work-up. We assessed the discrimination and calibration of the MRI-DRAGON score to predict poor 3-month outcome, defined as modified Rankin Score >2, using c-statistic and the Hosmer-Lemeshow test, respectively.ResultsWe included 230 patients (mean ±SD age 70.4±16.0 years, median [IQR] baseline NIHSS 8 [5]-[14]; poor outcome in 78(34%) patients). The c-statistic was 0.81 (95%CI 0.75-0.87), and the Hosmer-Lemeshow test was not significant (p = 0.54).ConclusionsThe MRI-DRAGON score showed good prognostic performance in the external validation cohort. It could therefore be used to inform the patient's relatives about long-term prognosis and help to identify poor responders to IV-tPA alone, who may be candidates for additional therapeutic strategies, if they are otherwise eligible for such procedures based on the institutional criteria.

Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up a screen to identify new regulators of adaptation to fasting using the serum Vanin-1 as a marker of PPARalpha activation. Mutagenized mice were screened for low serum Vanin-1 expression. Functional interactions with PPARalpha were investigated by combining transcriptomic, biochemical and metabolic approaches. We characterized a new mutant mouse in which hepatic and serum expression of Vanin-1 is depressed. This mouse carries a mutation in the HMG domain of the Sox17 transcription factor. Mutant mice display a metabolic phenotype featuring lipid abnormalities and inefficient adaptation to fasting. Upon fasting, a fraction of the PPARα-driven transcriptional program is no longer induced and associated with impaired fatty acid oxidation. The transcriptional phenotype is partially observed in heterozygous Sox17+/- mice. In mutant mice, the fasting phenotype but not all transcriptomic signature is rescued by the administration of the PPARalpha agonist fenofibrate. These results identify a novel role for Sox17 in adult liver as a modulator of the metabolic adaptation to fasting.

Members of the P2X family of ligand-gated cation channels (P2RX) are expressed by various cell types including neurons, smooth- and cardiac muscle cells, and leukocytes. The channels mediate signalling in response to extracellular ATP. Seven subunit isoforms (P2RX1-P2RX7) have been identified and these can assemble as homo- and heterotrimeric molecules. In humans, P2RX5 exists as a natural deletion mutant lacking amino acids 328-349 of exon 10, which are part of transmembrane (TM) 2 and pre-TM2 regions in other organisms like rat, chicken and zebrafish. We show that P2RX5 gene expression of human T lymphocytes is upregulated during activation. P2RX5 is recruited to the cell surface. P2RX5-siRNA-transfected CD4+ T cells produced twofold more IL-10 than controls. Surface and intracellular P2RX5 expression was upregulated in activated antigen-specific CD4+ T cell clones. These data indicate a functional role of the human P2RX5 splice variant in T cell activation and immunoregulation.

The contribution of arterial calcification (AC) in peripheral arterial disease (PAD) and arterial wall compressibility is a matter of debate. Pseudoxanthoma elasticum (PXE), an inherited metabolic disease due to ABCC6 gene mutations, combines elastic fiber fragmentation and calcification in various soft tissues including the arterial wall. Since AC is associated with PAD, a frequent complication of PXE, we sought to determine the role of AC in PAD and arterial wall compressibility in this group of patients.Arterial compressibility and patency were determined by ankle-brachial pressure index (ABI) in a cohort of 71 PXE patients (mean age 48 ± SD 14 yrs, 45 women) and compared to 30 controls without PAD. Lower limb arterial calcification (LLAC) was determined by non-contrast enhanced helicoidal CT-scan. A calcification score (Ca-score) was computed for the femoral, popliteal and sub-popliteal artery segments of both legs. Forty patients with PXE had an ABI1.40. LLAC increased with age, significantly more in PXE subjects than controls. A negative association was found between LLAC and ABI (r = -0.363, p = 0.002). The LLAC was independently associated with PXE and age, and ABI was not linked to cardiovascular risk factors.The presence of AC was associated with PAD and PXE without affecting arterial compressibility. PAD in PXE patients is probably due to proximal obstructive lesions developing independently from cardiovascular risk factors.