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Early-life microbial exposure is of particular importance to growth, immune system development and long-lasting health. Hence, early microbiota composition is a promising predictive biomarker for health and disease but still remains poorly characterized in regards to susceptibility to diarrhoea. In the present study, we aimed to assess if gut bacterial community diversity and composition during the suckling period were associated with differences in susceptibility of pigs to post-weaning diarrhoea. Twenty piglets from 5 sows (4 piglets / litter) were weaned in poor housing conditions to challenge their susceptibility to post-weaning diarrhoea. Two weeks after weaning, 13 pigs exhibited liquid faeces during 2 or 3 days and were defined as diarrhoeic (D) pigs. The other 7 pigs did not have diarrhea during the whole post-weaning experimental periodand were defined as healthy (H) pigs. Using a molecular characterisation of fecal microbiota with CE-SSCP fingerprint, Next Generation Sequencing and qPCR, we show that D and H pigs were mainly discriminated as early as postnatal day (PND) 7, i.e. 4 weeks before post-weaning diarrhoea occurence. At PND 7 H pigs displayed a lower evenness and a higher abundance of Prevotellaceae, Lachnospiraceae, Ruminocacaceae and Lactobacillaceae compared to D pigs. The sPLS regression method indicates that these bacterial families were strongly correlated to a higher Bacteroidetes abundance observed in PND 30 H pigs one week before diarrhoea. These results emphasize the potential of early microbiota diversity and composition as being an indicator of susceptibility to post-weaning diarrhoea. Furthermore, they support the health promoting strategies of pig herds through gut microbiota engineering.

RésuméEn Afrique, les droits des adolescentes et des jeunes femmes en matière de santé sexuelle et reproductive sont fortement influencés par les normes sociales. Cet article se penche sur le rôle crucial que jouent ces normes dans les décisions et les parcours d’avortement des jeunes femmes âgées de 15 à 24 ans au Bénin. Une approche ethnographique a été adoptée pour la collecte des données auprès des jeunes femmes ayant eu recours à l’avortement, de leurs proches, ainsi que d’autres membres de la communauté.Les résultats révèlent que ces jeunes femmes se retrouvent confrontées à une triple charge normative dans leur environnement social. Elles doivent jongler avec des normes contradictoires qui stigmatisent à la fois les grossesses précoces, entravent une éducation sexuelle adéquate, et condamnent fermement l’avortement. Ces pressions normatives sont souvent le moteur de leur recours à des avortements, généralement effectués dans des conditions précaires. L’étude met également en évidence le rôle majeur des parents dans les décisions et les démarches d’avortement des adolescentes de moins de 20 ans. Lorsque les hommes sont impliqués dans la recherche de soins pour l’avortement, les adolescentes et les jeunes femmes ont généralement accès à des procédures sécurisées. Cependant, leur accès aux soins de suivi et à la contraception après un avortement est entravé par les normes sociales des professionnels de la santé.En plus de l’élargissement des conditions d’accès à l’avortement au Bénin en octobre 2021, il est impératif de mettre en œuvre des interventions axées sur la clarification des valeurs, la sensibilisation aux droits des adolescentes, la lutte contre les violences obstétricales et la stigmatisation sociale. Ces mesures sont essentielles pour alléger le poids des normes sociales qui pèsent sur ces jeunes femmes.

This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC. Immune checkpoint blockade could improve the complete cytoreduction rate with standard-of-care neoadjuvant chemotherapy (NACT) in patients with ovarian cancer. Here the authors report the results of a randomized phase II trial of NACT alone or in combination with pembrolizumab (anti-PD1) in patients with advanced high-grade serous carcinoma.

Data are needed to assess the relationships between urbanization and biodiversity to establish conservation priorities. However, many of these relationships are difficult to fully assess using traditional research methods. To address this gap and evaluate new acoustic sensors and associated data, we conducted a multimethod analysis of biodiversity in a rapidly urbanizing county: Greenville, South Carolina, USA. We conducted audio recordings at 25 points along a development gradient. At the same locations, we used refugia tubes, visual assessments, and an online database. Analysis focused on species identification of both audio and visual data at each point along the trail to determine relationships between both herpetofauna and acoustic indices (as proxies for biodiversity) and environmental gradient of land use and land cover. Our analysis suggests the use of a multitude of different sampling methods to be conducive to the completion of a more comprehensive occupancy measure. Moving forward, this research protocol can potentially be useful in the establishment of more effective wildlife occupancy indices using acoustic sensors to move toward future conservation policies and efforts concerning urbanization, forest fragmentation, and biodiversity in natural, particularly forested, ecosystems.

Background Healthcare associated infections (HAIs) are the most frequent adverse outcome in healthcare delivery worldwide. In conflict-affected settings HAIs, in particular surgical site infections, are prevalent. Effective infection prevention and control (IPC) is crucial to ending avoidable HAIs and an integral part of safe, effective, high quality health service delivery. However, armed conflict and widespread violence can negatively affect the quality of health care through workforce shortages, supply chain disruptions and attacks on health facilities and staff. To improve IPC in these settings it is necessary to understand the specific barriers and facilitators experienced locally. Methods In January and February of 2020, we conducted semi-structured interviews with hospital staff working for the International Committee of the Red Cross across eight conflict-affected countries (Central African Republic, South Sudan, Democratic Republic of the Congo, Mali, Nigeria, Lebanon, Yemen and Afghanistan). We explored barriers and facilitators to IPC, as well as the direct impact of conflict on the hospital and its’ IPC programme. Data was analysed thematically. Results We found that inadequate hospital infrastructure, resource and workforce shortages, education of staff, inadequate in-service IPC training and supervision and large visitor numbers are barriers to IPC in hospitals in this study, similar to barriers seen in other resource-limited settings. High patient numbers, supply chain disruptions, high infection rates and attacks on healthcare infrastructures, all as a direct result of conflict, exacerbated existing challenges and imposed an additional burden on hospitals and their IPC programmes. We also found examples of local strategies for improving IPC in the face of limited resources, including departmental IPC champions and illustrated guidelines for in-service training. Conclusions Hospitals included in this study demonstrated how they overcame certain challenges in the face of limited resources and funding. These strategies present opportunities for learning and knowledge exchange across contexts, particularly in the face of the current global coronavirus pandemic. The findings are increasingly relevant today as they provide evidence of the fragility of IPC programmes in these settings. More research is required on tailoring IPC programmes so that they can be feasible and sustainable in unstable settings.

Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators. Here we show that GR and the lysine-specific demethylase 1 (LSD1) interact in myofibers of male mice, and that LSD1 connects GR-bound enhancers with NRF1-associated promoters to stimulate target gene expression. In addition, we unravel that LSD1 demethylase activity is required for triggering starvation- and dexamethasone-induced skeletal muscle proteolysis in collaboration with GR. Importantly, inhibition of LSD1 circumvents muscle wasting induced by pharmacological levels of dexamethasone, without affecting their anti-inflammatory activities. Thus, our findings provide mechanistic insights into the muscle-specific GC activities, and highlight the therapeutic potential of targeting GR co-regulators to limit corticotherapy-induced side effects. Even though glucocorticoids are potent anti-inflammatory agents, they can cause muscle wasting. Here, the authors show that targeting the glucocorticoid receptor coactivator LSD1 limits muscle loss without reducing the drugs’ efficiency on the immune system.

The glucocorticoid receptor (GR) is a ligand-activated transcription factor that binds DNA and assembles co-regulator complexes to regulate gene transcription. GR agonists are widely prescribed to people with inflammatory and autoimmune diseases. Here we present high-resolution, multidomain structures of GR in complex with ligand, DNA and co-regulator peptide. The structures reveal how the receptor forms an asymmetric dimer on the DNA and provide a detailed view of the domain interactions within and across the two monomers. Hydrogen–deuterium exchange and DNA-binding experiments demonstrate that ligand-dependent structural changes are communicated across the different domains in the full-length receptor. This study demonstrates how GR forms a distinct architecture on DNA and how signal transmission can be modulated by the ligand pharmacophore, provides a platform to build a new level of understanding of how receptor modifications can drive disease progression and offers key insight for future drug design. Postel et al. have determined a multidomain structure of GR in complex with ligand, DNA and a co-regulator peptide that demonstrates how GR forms a distinct architecture on DNA and how signal transmission can be modulated by the ligand pharmacophore.

Background Hypertension, itself a cardiovascular condition, is a significant risk factor for other cardiovascular diseases. Hypertension is recognized as a major public health challenge in Ghana. Beginning in 2014, a collaborative team launched the community-based hypertension improvement program (ComHIP) in one health district in Ghana. The ComHIP project, a public-private partnership, tests a community-based model that engages the private sector and utilizes information and communication technology (ICT) to control hypertension. This paper, focuses on the various challenges associated with managing hypertension in Ghana, as reported by ComHIP stakeholders. Methods A total of 55 informants – comprising patients, health care professionals, licensed chemical sellers (LCS), national and sub-national policymakers – were purposively selected for interview and focus group discussions (FGDs). Interviews were audio-recorded and transcribed verbatim. Where applicable, transcriptions were translated directly from local language to English. The data were then analysed using two-step thematic analysis. The protocol was approved by the two ethics review committees based in Ghana and the third, based in the United Kingdom. All participants were interviewed after giving informed consent. Results Our data have implications for the on-going implementation of ComHIP, especially the importance of policy maker buy-in, and the benefits, as well as drawbacks, of the program to different stakeholders. While our data show that the ComHIP initiative is acceptable to patients and healthcare providers – increasing providers’ knowledge on hypertension and patients’ awareness of same- there were implementation challenges identified by both patients and providers. Policy level challenges relate to task-sharing bottlenecks, which precluded nurses from prescribing or dispensing antihypertensives, and LCS from stocking same. Medication adherence and the phenomenon of medical pluralism in Ghana were identified challenges. The perspectives from the national level stakeholders enable elucidation of whole of health system challenges to ComHIP and similarly designed programmes. Conclusions This paper sheds important light on the patient/individual, and system level challenges to hypertension and related non-communicable disease prevention and treatment in Ghana. The data show that although the ComHIP initiative is acceptable to patients and healthcare providers, policy level task-sharing bottlenecks preclude optimal implementation of ComHIP.