Capacity Building in Sub-Saharan Africa as Part of the INTENSE-TBM Project During the COVID-19 Pandemic.

Tuberculous meningitis (TBM) is the most severe and disabling form of tuberculosis (TB), with at least 100,000 cases per year and a mortality rate of up to 50% in individuals co-infected with human immunodeficiency virus type 1 (HIV-1). To evaluate the efficacy and safety of an intensified anti-tubercular regimen and an anti-inflammatory treatment, the INTENSE-TBM project includes a phase III randomised clinical trial (TBM-RCT) in four countries in sub-Saharan Africa (SSA). Within this framework, we designed a comprehensive capacity-building work package ensuring all centres had, or would acquire, the ability to conduct the TBM-RCT and developing a network of skilled researchers, clinical centres and microbiology laboratories. Here, we describe these activities, identify strengths/challenges and share tools adaptable to other projects, particularly in low- and lower-middle income countries with heterogeneous settings and during the coronavirus disease 2019 (COVID-19) pandemic. Despite major challenges, TBM-RCT initiation was achieved in all sites, promoting enhanced local healthcare systems and encouraging further clinical research in SSA. In terms of certified trainings, the achievement levels were 95% (124/131) for good clinical practice, 91% (39/43) for good clinical laboratory practice and 91% (48/53) for infection prevention and control. Platform-based research, developed as part of capacity-building activities for specific projects, may be a valuable tool in fighting future infectious diseases and in developing high-level research in Africa.

The INTENSE-TBM project aimed to design a comprehensive work-package on capacity building, ensuring all centres would acquire the ability to conduct a phase III randomised clinical trial on TBM in sub-Saharan Africa, to reduce tuberculous meningitis mortality and morbidity in patients with/without HIV-1 co-infection. Therefore, the INTENSE-TBM project is an example of how an international clinical research consortium can provide opportunities to enhance local capacity building and promote centres without previous experience in clinical research. This article provides practical approaches for implementing effective capacity-building programmes. We highlight how to overcome limitations imposed by the COVID-19 pandemic to successfully complete clinics, laboratory set-ups and personnel training, so as to optimise resources and empower African institutions on a local level. At the same time, our experience shows how capacity-building programmes can deliver long-lasting impact that extends beyond the original aims of the project (e.g. HIV and TB), and support local health systems in fighting other infectious disease (e.g. COVID-19). Research projects in low- and lower-middle income countries with heterogeneous settings could stand to benefit the most.

Increased incidence of pathogenic variants in ATM in the context of testing for breast and ovarian cancer predisposition.

Pathogenic Variants (PV) in major cancer predisposition genes are only identified in approximately 10% of patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Next Generation Sequencing (NGS) leads to the characterization of incidental variants in genes other than those known to be associated with HBOC syndrome. The aim of this study was to determine if such incidental PV were specific to a phenotype. The detection rates of HBOC-associated and incidental PV in 1812 patients who underwent genetic testing were compared with rates in control groups FLOSSIES and ExAC. The rates of incidental PV in the PALB2, ATM and CHEK2 genes were significantly increased in the HBOC group compared to controls with, respective odds ratios of 15.2 (95% CI = 5.6-47.6), 9.6 (95% CI = 4.8-19.6) and 2.7 (95% CI = 1.3-5.5). Unsupervised Hierarchical Clustering on Principle Components characterized 3 clusters: by HBOC (P = 0.01); by ExAC and FLOSSIES (P = 0.01 and 0.02 respectively); and by HBOC, ExAC and FLOSSIES (P = 0.01, 0.04 and 0.04 respectively). Interestingly, PALB2 and ATM were grouped in the same statistical cluster defined by the HBOC group, whereas CHEK2 was in a different cluster. We identified co-occurrences of PV in ATM and BRCA genes and confirmed the Manchester Scoring System as a reliable PV predictor tool for BRCA genes but not for ATM or PALB2. This study demonstrates that ATM PV, and to a lesser extent CHEK2 PV, are associated with HBOC syndrome. The co-occurrence of ATM PV with BRCA PV suggests that such ATM variants are not sufficient alone to induce cancer, supporting a multigenism hypothesis.

PROSPECT guidelines for video-assisted thoracoscopic surgery: a systematic review and procedure-specific postoperative pain management recommendations.

Video-assisted thoracoscopic surgery has become increasingly popular due to faster recovery times and reduced postoperative pain compared with thoracotomy. However, analgesic regimens for video-assisted thoracoscopic surgery vary significantly. The goal of this systematic review was to evaluate the available literature and develop recommendations for optimal pain management after video-assisted thoracoscopic surgery. A systematic review was undertaken using procedure-specific postoperative pain management (PROSPECT) methodology. Randomised controlled trials published in the English language, between January 2010 and January 2021 assessing the effect of analgesic, anaesthetic or surgical interventions were identified. We retrieved 1070 studies of which 69 randomised controlled trials and two reviews met inclusion criteria. We recommend the administration of basic analgesia including paracetamol and non-steroidal anti-inflammatory drugs or cyclo-oxygenase-2-specific inhibitors pre-operatively or intra-operatively and continued postoperatively. Intra-operative intravenous dexmedetomidine infusion may be used, specifically when basic analgesia and regional analgesic techniques could not be given. In addition, a paravertebral block or erector spinae plane block is recommended as a first-choice option. A serratus anterior plane block could also be administered as a second-choice option. Opioids should be reserved as rescue analgesics in the postoperative period.

Anti-Müllerian hormone: A function beyond the Müllerian structures.

The anti-Müllerian hormone (AMH) is a heterodimeric glycoprotein belonging to the TGFb superfamily implicated in human embryonic development. This hormone was first described as allowing regression of the epithelial embryonic Müllerian structures in males, which would otherwise differentiate into the uterus and fallopian tubes. It activates a signaling pathway mediated by two transmembrane receptors. Binding of AMH to its receptor induces morphological changes leading to the degeneration of Müllerian ducts. Recently, new data has shown the role played by this hormone on structures other than the genital tract. If testicular AMH expression decreases in humans over the course of a lifetime, synthesis may persist in other tissues in adulthood. The mechanisms underlying its production have been unveiled. The aim of this review is to describe the different pathways in which AMH has been identified and plays a pivotal role.

Irinotecan and its metabolite SN38 inhibits procollagen I production of dermal fibroblasts from Systemic Sclerosis patients.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by a microangiopathy and fibrosis of the skin and internal organs. No treatment has been proved to be efficient in case of early or advanced SSc to prevent or reduce fibrosis. There are strong arguments for a key role of topo-I in the pathogenesis of diffuse SSc. Irinotecan, a semisynthetic derivative of Camptothecin, specifically target topo-I. This study was undertaken to evaluate the effects of noncytotoxic doses of irinotecan or its active metabolite SN38 on collagen production in SSc fibroblasts. Dermal fibroblasts from 4 patients with SSc and 2 healthy donors were cultured in the presence or absence of irinotecan or SN38. Procollagen I release was determined by ELISA and expression of a panel of genes involved in fibrosis was evaluated by qRT-PCR. Subcytotoxic doses of irinotecan and SN38 caused a significant and dose-dependent decrease of the procollagen I production in dermal fibroblasts from SSc patients, respectively - 48 ± 3%, p < 0.0001 and - 37 ± 6.2%, p = 0.0097. Both irinotecan and SN38 led to a global downregulation of genes involved in fibrosis such as COL1A1, COL1A2, MMP1 and ACTA2 in dermal fibroblasts from SSc patients (respectively - 27; - 20.5; - 30.2 and - 30% for irinotecan and - 61; - 55; - 50 and - 54% for SN38). SN38 increased significantly CCL2 mRNA level (+ 163%). The inhibitory effect of irinotecan and its active metabolite SN38 on collagen production by SSc fibroblasts, which occurs through regulating the levels of expression of genes mRNA, suggests that topoisomerase I inhibitors may be effective in limiting fibrosis in such patients.

[Self-assessment of healthcare workers regarding the management of trans people in a university hospital]. / Auto-évaluation de professionnels de santé concernant la prise en charge des personnes trans dans un hôpital universitaire.

INTRODUCTION: Trans people face more barriers when seeking healthcare than the cisgender population probably due to a lack of knowledge, education and comfort of healthcare workers. The purpose of this study was to assess the knowledge and comfort felt by healthcare professionals in managing trans people in a French university hospital. METHODS: A self-questionnaire was emailed to healthcare professionals working in departments usually involved in the care of trans people in a French university hospital "not specialized" in medical and surgical gender transition. The questionnaire included demographic questions and Likert scales regarding their knowledge and comfort in taking care of trans people. Responses on the 7-point Likert scales were categorized into "low", "medium" and "high" groups, and responses on the 5-point Likert scales were categorized into "in favour", "neutral" and "against" groups. RESULTS: One hundred and two (29%) healthcare professionals answered the questionnaire. Half worked in surgical departments (urology, plastic surgery, gynecology), 24% worked in medical departments (endocrinology, reproductive medicine, cytogenetics) and 26% worked in psychiatry. The majority (60.3%) rated their level of knowledge as "low" and 39.7% as "medium". Sixteen percent rated their level of comfort in managing trans people as "low", 72.5% as "medium" and 11.5% as "high". A majority (77.5%) were in favor of having the costs of gender transition care covered by the national health insurance system, 16.4% were neutral and 6% were against this idea. Feelings about surgical and hormonal gender transition were overwhelmingly (96.4%) in favour or neutral and 91% were willing to get more training and education to manage trans people. CONCLUSION: The lack of comfort felt by healthcare professionals in university hospital in managing trans people seems to be related to a lack of knowledge and training in that field and not to a disagreement with the need of transgender healthcare. LEVEL OF EVIDENCE: 3.

[Aggressive tumor progression during immunosuppressive therapy with abatacept]. / Une progression tumorale fulgurante sous abatacept.

INTRODUCTION: Co-stimulatory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibits T-cell activation. Clinically, CTLA-4 has been targeted in opposite ways: its blockade enhances antitumor immunity in the field of oncology, whereas CTLA-4 agonists such as abatacept are used for the treatment of immuno-inflammatory diseases as rheumatoid arthritis (RA). OBSERVATION: We herein report the case of a 69-year-old man with a history of severe RA successfully treated with abatacept, who showed unusually rapid progression of undifferentiated multi-metastatic carcinoma. DISCUSSION: Although no significant increase in malignancy has been reported in abatacept-treated patients, several case reports have documented the possible association with the acceleration of the progression of malignancy. Here, abatacept may have altered immune surveillance and hence allowed tumor growth.

Association between increased plasma ceramides and chronic kidney disease in patients with and without ischemic heart disease.

AIM: Plasma levels of certain ceramides are increased in patients with ischemic heart disease (IHD). Many risk factors for IHD are also risk factors for chronic kidney disease (CKD), but it is currently uncertain whether plasma ceramide levels are increased in patients with CKD. METHODS: We measured six previously identified high-risk plasma ceramide concentrations [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] in 415 middle-aged individuals who attended our clinical Cardiology and Diabetes services over a period of 9 months. RESULTS: A total of 97 patients had CKD (defined as e-GFRCKD-EPI<60ml/min/1.73m2 and/or urinary albumin-to-creatinine ratio≥30mg/g), 117 had established IHD and 242 had type 2 diabetes. Patients with CKD had significantly (P=0.005 or less) higher levels of plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1) compared to those without CKD. The presence of CKD remained significantly associated with higher levels of plasma ceramides (standardized beta coefficients ranging from 0.124 to 0.227, P<0.001) even after adjustment for body mass index, smoking, hypertension, diabetes, prior IHD, plasma LDL-cholesterol, hs-C-reactive protein levels and use of any lipid-lowering medications. Notably, more advanced stages of CKD and abnormal albuminuria were both associated (independently of each other) with increased levels of plasma ceramides. These results were consistent in all subgroups considered, including patients with and without established IHD or those with and without diabetes. CONCLUSION: Increased levels of plasma ceramides are associated with CKD independently of pre-existing IHD, diabetes and other established cardiovascular risk factors.

Cerebral alterations in West African HIV and non-HIV adults aged ≥50: An MRI study.

OBJECTIVES: To cross-sectionally describe brain alterations in PLHIV aged above 50 years old, receiving antiretroviral treatment (ART) and living in Senegal compared to HIV-negative subjects. METHODS: Twenty PLHIV and 26 HIV-negative subjects with comparable socio-demographic and clinical characteristics underwent an MRI exam (3D-T1 and FLAIR sequences). Global atrophy and White Matter Hyperintensities (WMH) were evaluated. After assessing the feasibility and acceptability of MRI scans in this population, we described atrophy and WHM prevalence and associated factors using logistic regressions. RESULTS: Overall, 43.5% of the study sample were aged ≥60 years, 58.7% were women, and 28.3% had hypertension. The overall prevalence of atrophy and WMH was 19.6% [95% CI: 8.1-31.1] and 30.4% [95% CI: 17.1-43.7]. HIV status had no significant effect on atrophy or WMH. Unemployment and hypertension were significantly associated with atrophy, whereas women were less likely to present atrophy. Aged ≥60 years was the only factor associated with WMH. CONCLUSIONS: A high prevalence of atrophy and WMH was observed in West African adults aged over 50 years without a clear HIV impact. As brain MRI studies are critical to better understand cognitive and emotional outcomes, we encourage those studies in older PLHIV in West Africa.

Evolution of comorbidities in people living with HIV between 2004 and 2014: cross-sectional analyses from ANRS CO3 Aquitaine cohort.

BACKGROUND: The objective of the study was to describe the evolution of chronic non-AIDS related diseases and their risk factors, in patients living with HIV (PLHIV) in the French ANRS CO3 Aquitaine prospective cohort, observed both in 2004 and in 2014 in order to improve long-term healthcare management. METHODS: The ANRS CO3 Aquitaine cohort prospectively collects epidemiological, clinical, biological and therapeutic data on PLHIV in the French Aquitaine region. Two cross sectional analyses were performed in 2004 and 2014, to investigate the patient characteristics, HIV RNA, CD4 counts and prevalence of some common comorbidities and treatment. RESULTS: 2138 PLHIV (71% male, median age 52.2 years in 2014) were identified for inclusion in the study, including participants who were registered in the cohort with at least one hospital visit recorded in both 2004 and 2014. Significant increases in the prevalence of diagnosed chronic kidney disease (CKD), bone fractures, cardiovascular events (CVE), hypertension, diabetes and dyslipidaemia, as well as an increase in treatment or prevention for these conditions (statins, clopidogrel, aspirin) were observed. It was also reflected in the increase in the proportion of patients in the "high" or "very high" risk groups of the disease risk scores for CKD, CVE and bone fracture score. CONCLUSIONS: Between 2004 and 2014, the aging PLHIV population identified in the French ANRS CO3 Aquitaine prospective cohort experienced an overall higher prevalence of non-HIV related comorbidities, including CKD and CVD. Long-term healthcare management and long-term health outcomes could be improved for PLHIV by: careful HIV management according to current recommendations with optimal selection of antiretrovirals, and early management of comorbidities through recommended lifestyle improvements and preventative measures.

What do the changing patterns of comorbidity burden in people living with HIV mean for long-term management? Perspectives from European HIV cohorts.

Undoubtedly, comorbidities complicate long-term HIV management and have significant cost implications for healthcare systems. A better understanding of these comorbidities and underlying causes would allow for a more considered and proactive approach to the long-term management of HIV. This review examines cross-sectional analyses of six European cohort studies (Athens Multicenter AIDS Cohort Study, Aquitaine Cohort, EuroSIDA Cohort study, French claims EGB, German InGef Cohort and the Italian Cohort of Individuals, Naïve for Antiretrovirals), which included individuals with HIV followed over a certain period of time. Based on these cohorts, we examined how comorbidities have changed over time; how they compromise HIV management; and how much of a financial burden they impart. These data also provided a framework to explore the major issues of ageing and HIV and the practical implications of managing such issues in real-life practice.

A data-driven method for reconstructing and modelling social interactions in moving animal groups.

Group-living organisms that collectively migrate range from cells and bacteria to human crowds, and include swarms of insects, schools of fish, and flocks of birds or ungulates. Unveiling the behavioural and cognitive mechanisms by which these groups coordinate their movements is a challenging task. These mechanisms take place at the individual scale and can be described as a combination of interactions between individuals and interactions between these individuals and the physical obstacles in the environment. Thanks to the development of novel tracking techniques that provide large and accurate datasets, the main characteristics of individual and collective behavioural patterns can be quantified with an unprecedented level of precision. However, in a large number of studies, social interactions are usually described by force map methods that only have a limited capacity of explanation and prediction, being rarely suitable for a direct implementation in a concise and explicit mathematical model. Here, we present a general method to extract the interactions between individuals that are involved in the coordination of collective movements in groups of organisms. We then apply this method to characterize social interactions in two species of shoaling fish, the rummy-nose tetra (Hemigrammus rhodostomus) and the zebrafish (Danio rerio), which both present a burst-and-coast motion. From the detailed quantitative description of individual-level interactions, it is thus possible to develop a quantitative model of the emergent dynamics observed at the group level, whose predictions can be checked against experimental results. This method can be applied to a wide range of biological and social systems. This article is part of the theme issue 'Multi-scale analysis and modelling of collective migration in biological systems'.

Increased risk of type 2 diabetes in antidepressant users: evidence from a 6-year longitudinal study in the E3N cohort.

AIM: To examine the association between antidepressant medication use and the risk of type 2 diabetes. METHODS: Data were obtained from the E3N study (Étude Épidémiologique de Femmes de la Mutuelle Générale de l'Éducation Nationale), a French cohort study initiated in 1990, with questionnaire-based follow-up every 2 or 3 years. Exposure to antidepressants was obtained from drug reimbursement files available from 2004 onwards, and individually matched with questionnaire data. Cases of type 2 diabetes were identified from drug reimbursements. Cox proportional-hazard regression models were used, with drug exposure considered as a time-varying parameter. RESULTS: Of the 63 999 women who were free of drug-treated type 2 diabetes at baseline in 2005, 1124 developed type 2 diabetes over the 6-year follow-up. Current use of antidepressants was associated with an increased risk of type 2 diabetes [hazard ratio 1.34 (95% CI 1.12, 1.61)] compared to non-users. When the different types of antidepressants were considered, women who currently used selective serotonin reuptake inhibitors, imipramine-type, 'other' or 'mixed' antidepressants had a 1.25-fold (95% CI 0.99, 1.57), 1.66-fold (95% CI 1.12, 2.46), 1.35-fold (95% CI 1.00, 1.84) and 1.82-fold (95% CI 0.85, 3.86) increase in risk of type 2 diabetes compared to non-users, respectively. CONCLUSION: Our study suggests a positive association between antidepressant use and the risk of type 2 diabetes among women. If this association is confirmed, screening and surveillance of glucose levels should be considered in the context of antidepressant therapy. Further studies assessing the underlying mechanisms of this association are needed. (ClinicalTrials.gov identifier: NCT03285230).