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BackgroundSnakebites is a serious public health issue but remains a neglected tropical disease. Data on antivenom effectiveness are urgently needed in Africa. We assessed effectiveness of Inoserp PAN-AFRICA (IPA), the recommended antivenom available in Cameroon.Methodology/principal findingsWe enrolled 447 patients presenting with snakebite in 14 health facilities across Cameroon. At presentation, cytotoxicity, coagulation troubles and neurotoxicity were graded. We administered two to four vials of antivenom to patients based on hemotoxic or neurotoxic signs. We renewed antivenom administration to patients with persistence of bleedings or neurotoxicity 2 hours after each injection. We defined early improvement as a reduction of the grade of envenomation symptoms 2 hours after first injection. Medium-term effectiveness was investigated looking at disappearance of symptoms during hospitalization. After hospital discharge, a home visit was planned to assess long-term outcomes. Between October 2019 and May 2021, we enrolled 447 (93.7%), including 72% from the savannah regions. The median [IQR] age was 25 [14-40]. Envenomation was diagnosed in 369 (82.6%) participants. The antivenom was administered to 356 patients (96.5%) of whom 256 (71.9%) received one administration. Among these patients, cytotoxic symptoms were observed in 336 (94.4%) participants, coagulation disorders in 234 (65.7%) participants and neurotoxicity in 23 (6.5%) participants. Two hours after the first administration of antivenom, we observed a decrease in coagulation disorders or neurotoxicity in 75.2% and 39.1% of patients, respectively. Complete cessation of bleedings and neurotoxicity occurred in 96% and 93% of patients within 24 hours, respectively. Sequelae have been observed in 9 (3%) patients at the home visit 15 days after hospital admission and 11 (3%) died including one before antivenom injection.Conclusions/significanceWe confirmed good effectiveness of the IPA and highlighted the rapid improvement in bleeding or neurotoxicity after the first administration. Sequential administrations of low doses of antivenom, rigorously assessed at short intervals for an eventual renewal, can preserve patient safety and save antivenom.Trial registrationNCT03326492.

Snakebite envenomation (SBE) is a public health issue in sub-Saharan countries. Antivenom is the only etiological treatment. Excellent tolerance is essential in managing SBE successfully. This study aimed to evaluate tolerance of InoserpTM PAN-AFRICA (IPA). It was conducted on fourteen sites across Cameroon. IPA was administered intravenously and repeated at the same dose every two hours if needed. Early and late tolerance was assessed by the onset of clinical signs within two hours and at a visit two weeks or more after the first IPA administration, respectively. Over 20 months, 447 patients presenting with a snakebite were included. One dose of IPA was administered to 361 patients and repeated at least once in 106 patients. No significant difference was shown between the proportion of adverse events in patients who received IPA (266/361, 73.7%) and those who did not (69/85, 81.2%) (p = 0.95). Adverse reactions, probably attributable to IPA, were identified in four (1.1%) patients, including one severe (angioedema) and three mild. All these reactions resolved favorably. None of the serious adverse events observed in twelve patients were attributed to IPA. No signs of late intolerance were observed in 302 patients. Tolerance appears to be satisfactory. The availability of effective and well-tolerated antivenoms would reduce the duration of treatment and prevent most disabilities and/or deaths.

BackgroundWhile Latin America has been heavily affected by the pandemic, only a few seroprevalence studies have been conducted there during the first epidemic wave in the first half of 2020.Methodology/principal findingsA cross-sectional survey was performed between 15 July 2020 and 23 July 2020 among individuals who visited 4 medical laboratories or 5 health centers for routine screening or clinical management, with the exception of symptomatic suggestive cases of covid-19. Samples were screened for the presence of anti-SARS-CoV-2 IgG directed against domain S1 of the SARS-CoV-2 spike protein using the anti-SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) from Euroimmun.Conclusions/significanceThe overall seroprevalence was 15.4% [9.3%-24.4%] among 480 participants, ranging from 4.0% to 25.5% across the different municipalities. The seroprevalence did not differ according to gender (p = 0.19) or age (p = 0.51). Among SARS-CoV-2 positive individuals, we found that 24.6% [11.5%-45.2%] reported symptoms consistent with COVID-19. Our findings revealed high levels of infection across the territory but a low number of resulting deaths, which can be explained by French Guiana's young population structure.

Snakebite envenomation (SBE) is a public health issue in sub-Saharan countries. Antivenom is the only etiological treatment. Excellent tolerance is essential in managing SBE successfully. This study aimed to evaluate tolerance of InoserpTM PAN-AFRICA (IPA). It was conducted on fourteen sites across Cameroon. IPA was administered intravenously and repeated at the same dose every two hours if needed. Early and late tolerance was assessed by the onset of clinical signs within two hours and at a visit two weeks or more after the first IPA administration, respectively. Over 20 months, 447 patients presenting with a snakebite were included. One dose of IPA was administered to 361 patients and repeated at least once in 106 patients. No significant difference was shown between the proportion of adverse events in patients who received IPA (266/361, 73.7%) and those who did not (69/85, 81.2%) (p = 0.95). Adverse reactions, probably attributable to IPA, were identified in four (1.1%) patients, including one severe (angioedema) and three mild. All these reactions resolved favorably. None of the serious adverse events observed in twelve patients were attributed to IPA. No signs of late intolerance were observed in 302 patients. Tolerance appears to be satisfactory. The availability of effective and well-tolerated antivenoms would reduce the duration of treatment and prevent most disabilities and/or deaths. [ABSTRACT FROM AUTHOR]

Background: Snakebites is a serious public health issue but remains a neglected tropical disease. Data on antivenom effectiveness are urgently needed in Africa. We assessed effectiveness of Inoserp PAN-AFRICA (IPA), the recommended antivenom available in Cameroon. Methodology/Principal findings: We enrolled 447 patients presenting with snakebite in 14 health facilities across Cameroon. At presentation, cytotoxicity, coagulation troubles and neurotoxicity were graded. We administered two to four vials of antivenom to patients based on hemotoxic or neurotoxic signs. We renewed antivenom administration to patients with persistence of bleedings or neurotoxicity 2 hours after each injection. We defined early improvement as a reduction of the grade of envenomation symptoms 2 hours after first injection. Medium-term effectiveness was investigated looking at disappearance of symptoms during hospitalization. After hospital discharge, a home visit was planned to assess long-term outcomes. Between October 2019 and May 2021, we enrolled 447 (93.7%), including 72% from the savannah regions. The median [IQR] age was 25 [14–40]. Envenomation was diagnosed in 369 (82.6%) participants. The antivenom was administered to 356 patients (96.5%) of whom 256 (71.9%) received one administration. Among these patients, cytotoxic symptoms were observed in 336 (94.4%) participants, coagulation disorders in 234 (65.7%) participants and neurotoxicity in 23 (6.5%) participants. Two hours after the first administration of antivenom, we observed a decrease in coagulation disorders or neurotoxicity in 75.2% and 39.1% of patients, respectively. Complete cessation of bleedings and neurotoxicity occurred in 96% and 93% of patients within 24 hours, respectively. Sequelae have been observed in 9 (3%) patients at the home visit 15 days after hospital admission and 11 (3%) died including one before antivenom injection. Conclusions/Significance: We confirmed good effectiveness of the IPA and highlighted the rapid improvement in bleeding or neurotoxicity after the first administration. Sequential administrations of low doses of antivenom, rigorously assessed at short intervals for an eventual renewal, can preserve patient safety and save antivenom. Trial registration: NCT03326492. Author summary: Snakebite envenomation is a public health issue in all sub-Saharan countries. Their management remains a challenge due to the high cost of antivenom and complex treatment-seeking behavior. The objective of this study was to evaluate the tolerance and effectiveness of a commonly used antivenom in Cameroon, in 14 sites representative of the diversity of common epidemiological situations in sub-Saharan Africa. The treatment protocol was that recommended by the Cameroonian Ministry of Health. We reported in the present manuscript results on antivenom effectiveness. Administration of IPA (at least two vials) was decided in all patients presenting with any symptoms of envenomation (cytotoxicity, bleeding, neurotoxicity) regardless of severity. Two to four vials of antivenom were administered to patients depending on whether they had coagulopathy or neurotoxic disorders, respectively. We repeated the administration of antivenom at the same dose to patients if hemorrhagic or neurotoxic signs persisted 2 hours after each injection. During 20 months, we examined 477 patients and enrolled 447 (94%). Three hundred fifty-six patients presenting envenomation signs have received at least one dose of antivenom. Envenomation was diagnosed in 369 (83%) participants, out of which, 9 (3%) kept sequelae of varying severity, and 11 (3%) died, including one before the antivenom injection. Cytotoxic symptoms were observed in 336 (94.4%) participants, coagulation disorders in 234 (65.7%) participants and neurotoxic syndrome in 23 (6.5%) participants. A single antivenom administration was performed for 256 (71.9%) patients. Two hours after the first administration of antivenom, coagulation disorders and neurotoxicity decreased in 75.2% and 39.1% of patients, respectively. Complete stop bleedings and neurotoxicity occurred in 96% and 93% of patients within 24 hours, respectively. We confirmed the good effectiveness of IPA and highlighted the rapid improvement in bleedings or neurotoxicity after its first administration. [ABSTRACT FROM AUTHOR]

Arthrospira platensis (Spirulina) is the most cultivated microalga worldwide. Improving its cultivation in terms of biomass productivity, quality, or production cost could significantly impact the Spirulina industry. The objectives of this paper were defined as to contribute to this goal. Spirulina biomass productivity was investigated through medium choice. A modified Zarrouk’s medium was selected as it gave higher final dry weights and longer sustained growth than Hiri’s and Jourdan’s media. Then, in order to reduce Spirulina production cost, modified Zarrouk’s medium was rationalized by testing different dilutions. It was found that modified Zarrouk’s medium could be diluted up to five times without impacting the growth rates in a 28-days batch cultivation. Higher dry weights were even observed after 21 days of batch cultivation (1.21 g/L for 20%-modified Zarrouk’s medium in comparison to 0.84 g/L for modified Zarrouk’s medium). Iron uptake was then investigated as one of the major contributors to Spirulina nutritional quality. An increase in iron content was obtained by replacing iron sulfate by iron EDTA at a concentration of 10 mgFe/L (2.11 ± 0.13 mgFe/gbiomass for EDTA-FeNa, 3 H2O at 10 mgFe/L compared to 0.18 ± 0.13 for FeSO4,6H2O at 2 mgFe/L). Impact of light intensity on Spirulina biomass productivity was also investigated in a 2 L Photobioreactor (PBR). Specific growth rates were calculated for Photosynthetically Photon Flux Densities (PPFD) from 85 to 430 µmol/m2/s. At 430 µmol/m2/s, photoinhibition was not observed and the specific growth rate was maximum (0.12/day). Finally, a 40-day cultivation experiment was conducted in a 1000 L PBR giving a maximum daily areal productivity of 58.4 g/m2/day. A techno-economic analysis gave production cost two to 20 times higher for PBR (from 18.71 to 74.29 €/kg) than for open ponds (from 3.86 to 9.59 €/kg) depending on Spirulina productivity.

The Nuclear Receptor 2F2 (NR2F2/COUP-TFII) heterozygous knockout mice display low basal insulinemia and enhanced insulin sensitivity. We previously established that insulin represses NR2F2 gene expression in pancreatic β-cells. The cis-regulatory region of the NR2F2 promoter is unknown and its influence on metabolism in humans is poorly understood. The present study aimed to identify the regulatory regions that control NR2F2 gene transcription and to evaluate the effect of NR2F2 promoter variation on glucose homeostasis in humans.Regulation of the NR2F2 promoter was assessed using gene reporter assays, ChIP and gel shift experiments. The effects of variation at SNP rs3743462 in NR2F2 on quantitative metabolic traits were studied in two European prospective cohorts. We identified a minimal promoter region that down-regulates NR2F2 expression by attenuating HNF4α activation in response to high glucose concentrations. Subjects of the French DESIR population, who carried the rs3743462 T-to-C polymorphism, located in the distal glucose-responsive promoter, displayed lower basal insulin levels and lower HOMA-IR index. The C-allele at rs3743462 was associated with increased NR2F2 binding and decreased NR2F2 gene expression.The rs3743462 polymorphism affects glucose-responsive NR2F2 promoter regulation and thereby may influence whole-body insulin sensitivity, suggesting a role of NR2F2 in the control of glucose homeostasis in humans.

Background: While Latin America has been heavily affected by the pandemic, only a few seroprevalence studies have been conducted there during the first epidemic wave in the first half of 2020. Methodology/Principal findings: A cross-sectional survey was performed between 15 July 2020 and 23 July 2020 among individuals who visited 4 medical laboratories or 5 health centers for routine screening or clinical management, with the exception of symptomatic suggestive cases of covid-19. Samples were screened for the presence of anti-SARS-CoV-2 IgG directed against domain S1 of the SARS-CoV-2 spike protein using the anti-SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) from Euroimmun. Conclusions/Significance: The overall seroprevalence was 15.4% [9.3%-24.4%] among 480 participants, ranging from 4.0% to 25.5% across the different municipalities. The seroprevalence did not differ according to gender (p = 0.19) or age (p = 0.51). Among SARS-CoV-2 positive individuals, we found that 24.6% [11.5%-45.2%] reported symptoms consistent with COVID-19. Our findings revealed high levels of infection across the territory but a low number of resulting deaths, which can be explained by French Guiana's young population structure. Author summary: While Latin America has been heavily affected by the pandemic, only a few seroprevalence studies have been conducted there during the first epidemic wave in the first half of 2020. A cross-sectional survey was performed between 15 July 2020 and 23 July 2020 among individuals who visited 4 medical laboratories or 5 health centers for routine screening or clinical management, with the exception of symptomatic suggestive cases of covid-19. Samples were screened for the presence of anti-SARS-CoV-2 IgG using the anti-SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) from Euroimmun. The overall seroprevalence was 15.4% [9.3%-24.4%] among 480 participants, ranging from 4.0% to 25.5% across the different municipalities. The seroprevalence did not differ according to gender (p = 0.19) or age (p = 0.51). Among SARS-CoV-2 positive individuals, we found that 24.6% [11.5%-45.2%] reported symptoms consistent with COVID-19. Our findings revealed high levels of infection across the territory but a low number of resulting deaths, which can be explained by French Guiana's young population structure. [ABSTRACT FROM AUTHOR]

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) has been implicated in the control of blood glucose by its potent effect on expression and signaling of various nuclear receptors. To understand the role of COUP-TFII in glucose homeostasis, conditional COUP-TFII-deficient mice were generated and crossed with mice expressing Cre under the control of rat insulin II gene promoter, resulting in deletion of COUP-TFII in pancreatic beta-cells. Homozygous mutants died before birth for yet undetermined reasons. Heterozygous mice appeared healthy at birth and showed normal growth and fertility. When challenged intraperitoneally, the animals had glucose intolerance associated with reduced glucose-stimulated insulin secretion. Moreover, these heterozygous mice presented a mild increase in fasting and random-fed circulating insulin levels. In accordance, islets isolated from these animals exhibited higher insulin secretion in low glucose conditions and markedly decreased glucose-stimulated insulin secretion. Their pancreata presented normal microscopic architecture and insulin content up to 16 weeks of study. Altered insulin secretion was associated with peripheral insulin resistance in whole animals. It can be concluded that COUP-TFII is a new, important regulator of glucose homeostasis and insulin sensitivity. [ABSTRACT FROM AUTHOR]

The risk of serious bacterial infection in human immunodeficiency virus–exposed but uninfected infants is inverse to the mother's CD4 count. This association remains significant during the first year of life.Background. Morbidity and mortality are higher among human immunodeficiency virus (HIV) exposed but uninfected (HEU) infants than unexposed infants, particularly if the mother had a low CD4 count. We investigated the possible association between maternal immune depression during pregnancy and the risk of infection in HEU infants in the national French Perinatal Cohort (EPF).Methods. All neonates, born alive, to HIV-1–infected women enrolled in the EPF between 2002 and 2010 were included. The primary outcome was the first serious (hospitalization or death) infection during the first year of life. The main exposure variable was maternal CD4 cell count near delivery. The Kaplan–Meier method and multivariate Cox models were applied, with the different types of infections managed as competing events.Results. Among 7638 HEU neonates, 699 had at least 1 serious infection (of which 159 were bacterial) with a Kaplan–Meier probability of 9.3% (95% confidence interval, 8.7–10.0) at 1 year. The risk of serious bacterial infection during the first year of life significantly increased with lower maternal CD4 cell count, before and after adjustment for maternal CD4 cell count <350 and 350–499 CD4/mm3 (adjusted hazard ratio = 1.7 [1.2–2.6] and 1.2 [0.8–1.9], respectively; P = .03). This association mainly concerned infections involving encapsulated bacteria (P = .03). The risk of serious viral infection was, by contrast, independent of the mother's CD4 cell count.Conclusions. Maternal CD4 count is significantly and specifically associated with the risk of serious infections with encapsulated bacteria in HEU infants. [ABSTRACT FROM AUTHOR]

Background: The Nuclear Receptor 2F2 (NR2F2/COUP-TFII) heterozygous knockout mice display low basal insulinemia and enhanced insulin sensitivity. We previously established that insulin represses NR2F2 gene expression in pancreatic b-cells. The cis-regulatory region of the NR2F2 promoter is unknown and its influence on metabolism in humans is poorly understood. The present study aimed to identify the regulatory regions that control NR2F2 gene transcription and to evaluate the effect of NR2F2 promoter variation on glucose homeostasis in humans. Methodology/Principal Findings: RegulationoftheNR2F2promoterwasassessedusinggenereporterassays,ChIPandgelshift experiments. The effects of variation at SNP rs3743462 in NR2F2 on quantitative metabolic traits were studied in two European prospective cohorts. We identified a minimal promoter region that down-regulates NR2F2 expression by attenuating HNF4a activation in response to high glucose concentrations. Subjects of the French DESIR population, who carried thers 3743462T-to-C polymorphism, located in the distal glucose-responsive promoter, displayed lower basal insulin levelsand lowerHOMA-IRindex. The C-allele at rs3743462 was associated with increased NR2F2 binding and decreased NR2F2 gene expression. Conclusions/Significance: The rs3743462 polymorphism affects glucose-responsive NR2F2 promoter regulation and thereby may influence whole-body insulin sensitivity, suggesting a role of NR2F2 in the control of glucose homeostasis in humans. [ABSTRACT FROM AUTHOR]

COUP-TFII has an important role in regulating metabolism in vivo. We showed this previously by deleting COUP-TFII from pancreatic beta cells in heterozygous mutant mice, which led to abnormal insulin secretion. Here, we report that COUP-TFII expression is reduced in the pancreas and liver of mice refed with a carbohydrate-rich diet and in the pancreas and liver of hyperinsulinemic and hyperglycemic mice. In pancreatic beta cells, COUP-TFII gene expression is repressed by secreted insulin in response to glucose through Foxo1 signaling. Ex vivo COUP-TFII reduces insulin production and secretion. Our results suggest that beta cell insulin secretion is under the control of an autocrine positive feedback loop by alleviating COUP-TFII repression. In hepatocytes, both insulin, through Foxo1, and high glucose concentrations repress COUP-TFII expression. We demonstrate that this negative glucose effect involves ChREBP expression. We propose that COUP-TFII acts in a coordinate fashion to control insulin secretion and glucose metabolism. [ABSTRACT FROM AUTHOR]

Introduction: De nombreuses études montrent que l’hypothalamus est un organe impliqué dans le contrôle de l’homéostasie énergétique. Toute perturbation de la détection des signaux émis par les nutriments et/ou les hormones par cet organe peut conduire en périphérie à une insulino-résistance et/ou à l’obésité. Notre équipe travaille sur le facteur de transcription Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII). Des données obtenues à partir de nos différents modèles de souris transgéniques avec une spécificité cellulaire de la délétion de ce gène suggèrent fortement que son expression dans le système nerveux central pourrait être liée au maintien d’une sensibilité périphérique à l’insuline. Résultats: Par des techniques d’immunofluorescence, nous avons observé que l’expression de la protéine COUP-TFII est restreinte au noyau ventromédian de l’hypothalamus (VMN). Elle est présente dans des neurones exprimant le récepteur à la mélanocortine MC4-R, cellules impliquées dans l’homéostasie énergétique et co-localise avec la protéine Stéroidogenic Factor 1 (SF1) un marqueur du noyau ventromédian. Afin d’étudier la fonction de ce facteur, nous générons une lignée de souris inactivée pour le gène COUP-TFII dans les neurones SF1 de l’hypothalamus. Parallèlement, nous étudions la régulation de l’expression de COUP-TFII en réponse au statut nutritionnel et hormonal dans différents modèles murins. Une augmentation de l’insulinémie active in vivo l’expression des messagers COUP-TFII dans l’hypothalamus. Cependant, l’étude de sa régulation dans une lignée de cellules dérivées de l’hypothalamus suggère fortement que les effets de l’insuline sur l’expression de COUP-TFII dans le VMN pourraient être indirectement liés à une augmentation de la production locale du ligand du récepteur MC-4R. Ex vivo des expériences utilisant un agoniste du récepteur MC-4R montrent une augmentation de l’expression des messagers COUP-TFII. Nous testons les effets de cet agoniste chez la souris par des injections intra-cérébroventriculaires. Conclusion: De par ces observations, COUP-TFII pourrait être un nouvel acteur du contrôle central de l’homéostasie glucidique. [Copyright &y& Elsevier]

Pancreatic islet beta cell differentiation and function are dependent upon a group of transcription factors that maintain the expression of key genes and suppress others. Knockout mice with the heterozygous deletion of the gene for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) or the complete disruption of the gene for hepatocyte nuclear factor 4{alpha} (HNF4{alpha}) in pancreatic beta cells have similar insulin secretion defects, leading us to hypothesize that there is transcriptional cross talk between these two nuclear receptors. Here, we demonstrate specific HNF4{alpha} activation of a reporter plasmid containing the COUP-TFII gene promoter region in transfected pancreatic beta cells. The stable association of the endogenous HNF4{alpha} with a region of the COUP-TFII gene promoter that contains a direct repeat 1 (DR-1) binding site was revealed by chromatin immunoprecipitation. Mutation experiments showed that this DR-1 site is essential for HNF4{alpha} transactivation of COUP-TFII. The dominant negative suppression of HNF4{alpha} function decreased endogenous COUP-TFII expression, and the specific inactivation of COUP-TFII by small interfering RNA caused HNF4{alpha} mRNA levels in 832/13 INS-1 cells to decrease. This positive regulation of HNF4{alpha} by COUP-TFII was confirmed by the adenovirus-mediated overexpression of human COUP-TFII (hCOUP-TFII), which increased HNF4{alpha} mRNA levels in 832/13 INS-1 cells and in mouse pancreatic islets. Finally, hCOUP-TFII overexpression showed that there is direct COUP-TFII autorepression, as COUP-TFII occupies the proximal DR-1 binding site of its own gene in vivo. Therefore, COUP-TFII may contribute to the control of insulin secretion through the complex HNF4{alpha}/maturity-onset diabetes of the young 1 (MODY1) transcription factor network operating in beta cells. [ABSTRACT FROM AUTHOR]