Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions

International audienceAn antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Vulnérabilité des ressources en eau dans un contexte de changement climatique en milieu rural : le cas du delta du Saloum

International audienceThe Saloum delta faces a number of challenges that affect the living conditions of its populations and ecosystems. Edaphic factors combined with the climatic downturn of the 70s and 80s have greatly accentuated the vulnerability of water resources. This situation has led to the drying-up of surface waters, the lowering of water tables and the invasion of low-lying valleys by salt water. Recharge deficits and inadequate management of hydraulic infrastructures are affecting the availability of freshwater resources in the Saloum estuary. These increasingly acute hydraulic problems have led populations to resort to traditional sources (wells, ceans, etc.) of dubious quality. This research aims to analyze the vulnerability of water resources in the Saloum delta. To do this, we analyzed rainfall and piezometric data, and took in-situ measurements of well water quality. These data were supplemented by socio-economic surveys of households and interviews with well managers. The results show a correlation between rainfall variability and the static level of the water tables, as well as a deterioration of the hydraulic structures. The salinization of groundwater and the resilience of the local population to precarious hydraulic conditions were also noted.Le delta du Saloum, fait face à de nombreuses difficultés qui affectent les conditions de vie des populations et des écosystèmes. Les facteurs édaphiques combinés à la péjoration climatique des années 70-80 ont fortement accentué la vulnérabilité des ressources en eau. Cette situation a entrainé un assèchement des eaux superficielles, un abaissement des nappes et l’envahissement des basses vallées par les eaux salées. Le déficit de recharge et la gestion inadéquate des infrastructures hydrauliques affectent la disponibilité des ressources en eau douce dans l’estuaire du Saloum. Ces problèmes hydrauliques de plus en plus aigus ont poussé les populations à recourir aux sources traditionnelles (puits, céanes, etc.) aux qualités douteuses. Cette recherche vise à analyser la vulnérabilité des ressources en eau dans le delta du Saloum. Pour ce faire nous avons analyser les données pluviométriques, et piézométriques, des mesures in-situ de la qualité de l’eau des puits ont été effectuées. Ces données sont complétées par des enquêtes socio-économiques avec les ménages, des entretiens avec les gestionnaires des ouvrages. Les résultats mettent en évidence une corrélation entre la variabilité pluviométrique et le niveau statique des nappes mais également une dégradation des ouvrages hydrauliques. On note aussi une salinisation des eaux souterraines et une forte résilience de la population locale face à la précarité de leurs conditions hydraulique

Agriculture et gestion des ressources en eau dans un contexte de variabilité climatique: quel est l’impact du système transfert d’eau potable du Notto-Diosmone-Palmarin (NDP) dans la résilience des activités maraichères dans le bassin arachidier (Sénégal) ?

International audienceMarket gardening is one of the agricultural activities of the groundnut basin, practiced in the dry season after the harvest. However, over the course of the 70s, 80s and 90s, the region underwent environmental transformations that severely affected this activity. Prolonged drought and high rainfall variability led to the lowering of water tables, the drying-up of wetlands and the invasion of low-lying valleys by marine waters. The deep aquifers captured between 80 and 300 m are of poor physico-chemical quality, and poor governance of hydraulic infrastructures contributes to the precariousness of market gardening activities. However, the Notto-Diosmone-Palmarin (NDP) water transfer system, which was introduced as part of the rural hydraulic reforms and consists of transferring water from well-supplied areas to areas with severe hydraulic constraints, seems to be revitalizing this activity. The availability of more and better quality water has led to a significant reorganization of economic activities, particularly market gardening, which had disappeared from many villages. The aim of this article is to analyze the impact of the NDP water transfer network on the development of market gardening on the Thiès-Fatick axis in the central-western groundnut basin. To do this, we carried out socio-economic surveys and interviews with market gardeners, network managers, local authorities, etc. The results show a recovery in market gardening in the Thiès-Fatick area. The results show a resumption of market gardening in almost all the area covered by the network. Water control and sustainable management of the facilities have enabled the population to improve and diversify their income. However, the high cost of connections has prompted 46% of market gardeners to develop adaptive strategies to reduce their vulnerability.Le maraichage est l’une des activités agricoles du bassin arachidier, pratiqué en saison sèche après les récoltes. Cependant au cours des décennies 70, 80, et 90, la région a subi des transformations environnementales qui ont fortement éprouvé cette activité. La longue sécheresse et la forte variabilité pluviométriques ont entrainé l’abaissement du niveau des nappes, l’assèchement des zones humides, l’envahissement des basses vallées par les eaux marines. Les nappes profondes captées entre 80 et 300m sont de mauvaise qualité physico-chimique et la mauvaise gouvernance des infrastructures hydrauliques contribue à la précarité de l’activité de maraichage. Par ailleurs, le système de transfert d’eau du Notto-Diosmone-Palmarin (NDP) intervenu dans le cadre des réformes de l’hydraulique rurale, consistant à transférer de l’eau des zones pourvues vers les zones à fortes contraintes hydrauliques semble redonner vie à cette activité. La disponibilité d’une eau en quantité et de meilleure qualité a entrainé une forte recomposition des activités économiques, particulièrement le maraichage qui avait disparu dans de nombreux villages. L’objectif de cet article est d’analyser l’impact du réseau de transfert d’eau du NDP dans le développement du maraichage sur l’axe Thiès-Fatick dans le centre-ouest du bassin arachidier. Pour ce faire, nous avons effectué des enquêtes socio-économiques et des entretiens avec les maraîchers, les gestionnaires du réseau, et les autorités locales etc. Les résultats mettent en évidence une reprise du maraichage dans presque toute la zone couverte par le réseau. La maitrise de l’eau et la gestion durable des ouvrages ont permis à la population d’améliorer et de diversifier leurs revenus. Toutefois, la cherté des branchements a poussé 46 % maraichers à développer des stratégies d’adaptations afin de réduire leurs vulnérabilités

The ASOS Surgical Risk Calculator: development and validation of a tool for identifying African surgical patients at risk of severe postoperative complications

Background: The African Surgical Outcomes Study (ASOS) showed that surgical patients in Africa have a mortality twice the global average. Existing risk assessment tools are not valid for use in this population because the pattern of risk for poor outcomes differs from high-income countries. The objective of this study was to derive and validate a simple, preoperative risk stratification tool to identify African surgical patients at risk for in-hospital postoperative mortality and severe complications. Methods: ASOS was a 7-day prospective cohort study of adult patients undergoing surgery in Africa. The ASOS Surgical Risk Calculator was constructed with a multivariable logistic regression model for the outcome of in-hospital mortality and severe postoperative complications. The following preoperative risk factors were entered into the model; age, sex, smoking status, ASA physical status, preoperative chronic comorbid conditions, indication for surgery, urgency, severity, and type of surgery. Results: The model was derived from 8799 patients from 168 African hospitals. The composite outcome of severe postoperative complications and death occurred in 423/8799 (4.8%) patients. The ASOS Surgical Risk Calculator includes the following risk factors: age, ASA physical status, indication for surgery, urgency, severity, and type of surgery. The model showed good discrimination with an area under the receiver operating characteristic curve of 0.805 and good calibration with c-statistic corrected for optimism of 0.784. Conclusions: This simple preoperative risk calculator could be used to identify high-risk surgical patients in African hospitals and facilitate increased postoperative surveillance. © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.Medical Research Council of South Africa gran

Maternal and neonatal outcomes after caesarean delivery in the African Surgical Outcomes Study: a 7-day prospective observational cohort study.

BACKGROUND: Maternal and neonatal mortality is high in Africa, but few large, prospective studies have been done to investigate the risk factors associated with these poor maternal and neonatal outcomes. METHODS: A 7-day, international, prospective, observational cohort study was done in patients having caesarean delivery in 183 hospitals across 22 countries in Africa. The inclusion criteria were all consecutive patients (aged ≥18 years) admitted to participating centres having elective and non-elective caesarean delivery during the 7-day study cohort period. To ensure a representative sample, each hospital had to provide data for 90% of the eligible patients during the recruitment week. The primary outcome was in-hospital maternal mortality and complications, which were assessed by local investigators. The study was registered on the South African National Health Research Database, number KZ_2015RP7_22, and on ClinicalTrials.gov, number NCT03044899. FINDINGS: Between February, 2016, and May, 2016, 3792 patients were recruited from hospitals across Africa. 3685 were included in the postoperative complications analysis (107 missing data) and 3684 were included in the maternal mortality analysis (108 missing data). These hospitals had a combined number of specialist surgeons, obstetricians, and anaesthetists totalling 0·7 per 100 000 population (IQR 0·2-2·0). Maternal mortality was 20 (0·5%) of 3684 patients (95% CI 0·3-0·8). Complications occurred in 633 (17·4%) of 3636 mothers (16·2-18·6), which were predominantly severe intraoperative and postoperative bleeding (136 [3·8%] of 3612 mothers). Maternal mortality was independently associated with a preoperative presentation of placenta praevia, placental abruption, ruptured uterus, antepartum haemorrhage (odds ratio 4·47 [95% CI 1·46-13·65]), and perioperative severe obstetric haemorrhage (5·87 [1·99-17·34]) or anaesthesia complications (11·47 (1·20-109·20]). Neonatal mortality was 153 (4·4%) of 3506 infants (95% CI 3·7-5·0). INTERPRETATION: Maternal mortality after caesarean delivery in Africa is 50 times higher than that of high-income countries and is driven by peripartum haemorrhage and anaesthesia complications. Neonatal mortality is double the global average. Early identification and appropriate management of mothers at risk of peripartum haemorrhage might improve maternal and neonatal outcomes in Africa. FUNDING: Medical Research Council of South Africa.Medical Research Council of South Africa