AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Epidémiologie génétique de la réponse à Mycobacterium tuberculosis (études de phénotypes cliniques et immunologiques)

La tuberculose (TB) demeure un problème majeur de la santé publique mondiale et il est connu que des facteurs génétiques influencent la susceptibilité de l'hôte à l'infection par M. tuberculosis. Nous avons étudié les gènes NRAMP1, qui a été associé à la susceptibilité à la tuberculose dans plusieurs groupes ethniques, etIL12RBl, qui joue un rôle majeur dans la susceptibilité Mendélienne aux infections mycobactériennes (MSMD), et nous n'avons pas trouvé une association avec la TB pulmonaire dans une population adulte Marocaine. Par conséquent, la susceptibilité complexe à la TB maladie dans cette population semble être régie par d'autres mécanismes que la susceptibilité Mendélienne chez les enfants, ce qui pourrait expliquer les différentes présentations cliniques et mécanismes physiopathologiques dans ces différents groupes d'âge. Nous avons ensuite analysé les corrélations familiales de la réponse immunitaire à l'infection en étudiant la taille de l'intradermo réaction (IDR) à la tuberculine et la production d'IFNy de PBMC après stimulation avec des antigènes mycobactériennes dans in population d'une région d'incidence faible à modéré proche de Paris (Val de Marne). Nous avons observé une forte corrélation familiale pour la taille d'IDR, et après limitation de la population à des personnes non infectées, les corrélations de l'ESATô ont été à la limite significative (p = 0.047). Ces études ont à la fois des implications scientifiques car ils améliorent la compréhension des mécanismes de contrôle immunitaire de l'infection, et des implications médicales, et permettent ainsi d'ouvrir la voie à de nouvelles stratégies de prévention et de thérapie.Tuberculosis (TB) remains a major global public health threat and host genetic factors are known to modulate the outcome of exposure to M. tuberculosis. We studied the genes NRAMP1, which has been associated with TB susceptibility in several ethnic groups, and IL12RB1, that plays a major role in Mendelian Susceptibility to Mycobacterial Disease (MSMD) and found no evidence for association with pulmonary TB in an adult Moroccan population. Thus, complex susceptibility to TB disease in this population seems to be governed by other mechanisms than Mendelian susceptibility in children, which might explain the different clinical presentations and physiopathological pathways in these different age groups. We then analysed familial correlations of the immune response to infection studying the tuberculin skin test (TST) size and IFNy-production of PBMC's after stimulation with mycobacterial antigens in a population from a low to moderate incidence region near Paris (Val de Marne). We observed strong familial correlations for the TST, and after restriction of the study population to non-infected individuals, correlations for the ESAT6 trait were borderline significant (p=0.047). These studies have both scientific implications, as they will enhance understanding of immune mechanisms controlling infection, and medical implications, as they will open the way for new preventive and therapeutic strategies.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Unsolved severe chronic rhinosinusitis elucidated by extensive CFTR

International audienceSevere chronic rhinosinusitis in children should alert clinicians and extensive CFTR genotyping should be performed. We propose that thorough clinical and functional assessment in severe chronic rhinosinusitis is valuable to discover rare mutations which could be treated by CFTR correctors to postpone pulmonary infection

Major Loci on Chromosomes 8q and 3q Control Interferon γ Production Triggered by Bacillus Calmette-Guerin and 6-kDa Early Secretory Antigen Target, Respectively, in Various Populations

Background. Interferon γ (IFN-γ) release assays (IGRAs) provide an in vitro measurement of antimycobacterial immunity that is widely used as a test for Mycobacterium tuberculosis infection. IGRA outcomes are highly heritable in various populations, but the nature of the involved genetic factors remains unknown. Methods. We conducted a genome-wide linkage analysis of IGRA phenotypes in families from a tuberculosis household contact study in France and a replication study in families from South Africa to confirm the loci identified. Results. We identified a major locus on chromosome 8q controlling IFN-γ production in response to stimulation with live bacillus Calmette-Guerin (BCG; LOD score, 3.81; P = 1.40 × 10(−5)). We also detected a second locus, on chromosome 3q, that controlled IFN-γ levels in response to stimulation with 6-kDa early secretory antigen target, when accounting for the IFN-γ production shared with that induced by BCG (LOD score, 3.72; P = 1.8 × 10(−5)). Both loci were replicated in South African families, where tuberculosis is hyperendemic. These loci differ from those previously identified as controlling the response to the tuberculin skin test (TST1 and TST2) and the production of TNF-α (TNF1). Conclusions. The identification of 2 new linkage signals in populations of various ethnic origins living in different M. tuberculosis exposure settings provides new clues about the genetic control of human antimycobacterial immunity

Reclassifying inconclusive diagnosis for cystic fibrosis with new generation sweat test

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Impact of the COVID-19 pandemic and associated lockdown measures on the management, health, and behavior of the cystic fibrosis population in France during 2020 (MUCONFIN)

International audienceBackground Most of the studies on cystic fibrosis (CF) focused on SARS-CoV-2 prevalence and suggested a low incidence of infection in this population. We aimed to assess the impact of the pandemic and related lockdown measures implemented in May 2020 in response to the first wave of SARS-CoV-2 infection on healthcare access, health, and behavior in CF patients. Methods A national questionnaire opened online from May 15th, 2020 to June 11 th , 2020 was completed by 751 CF-patients, aged 14 years and over. It comprised questions about access to healthcare, anxiety and depression, smoking, alcohol, drug and psychotropic drug consumption, adherence to CF treatment, and constraints. A semi-structured comprehensive interview was performed no later than 1 month after the end of the lockdown in 16 CF-patients. Results The mean age of the population was 28.0 [interquartile range (IQR) 20.0–37.0] years old. More than 75% of in-person consultations scheduled during the lockdown were canceled. Alternatively, 27% were postponed, and telehealth consultations were proposed and accepted in almost 40% of cases. More than 75% of the scheduled physiotherapy sessions were canceled and replaced mainly by self-drainage. Annual follow-up clinic visits were consistently postponed whereas required hospitalizations at CF centers for exacerbation were maintained in most cases. While 43.2% CF-patients had signs of anxiety, 51.0% presented symptoms of depression, both associated with increased use of psychotic medications and inversely correlated to COVID-19 prevalence. Among the lower and lower middle classes, very little medical information was obtained or requested by the patient, participation to sports or other activities was low, while excessive home confinement and isolation were more frequent. In contrast, in the upper middle and upper classes, individuals solicitated help to their CF centre, had more physical activities, and maintained contact with friends or families. Conclusion The first lockdown in France had only minimal impact on the management care of CF-patients but was associated with increased symptoms of anxiety and depression, together with behavioral changes that varied with social class. Trial registration NCT04463628

Cardiopulmonary exercise testing provides prognostic information in advanced cystic fibrosis lung disease

Rationale: cardiopulmonary exercise testing (CPET) provides prognostic information in cystic fibrosis (CF); however, its prognostic value for patients with advanced CF lung disease (ACFLD) is unknown. Objectives: to determine the prognostic value of CPET on the risk of death or lung transplant (LTX) within 2-years. Methods: we retrospectively collected data from 20 CF centers in Asia, Australia, Europe, and North America on patients with a forced expiratory volume in 1s (FEV1) ≤40% predicted who performed a cycle ergometer CPET between January 2008 and December 2017. Time to death/LTX was analyzed using mixed Cox proportional hazards regression. Conditional inference trees were modelled to identify subgroups with increased risk of death/LTX. Results: In total, 174 patients (FEV1, 30.9% ± 5.8% predicted) were included. Forty-four patients (25.5%) died or underwent LTX. Cox regression analysis adjusted for age, sex, and FEV1 revealed percentage predicted peak oxygen uptake (Vo2peak) and peak work rate (Wpeak) as significant predictors of death/LTX: adjusted hazard ratios per each additional 10% predicted were 0.60 (95% confidence interval, 0.43–0.90; P = 0.008) and 0.60 (0.48–0.82; P < 0.001). Tree-structured regression models, including a set of 11 prognostic factors for survival, identified Wpeak to be most strongly associated with 2-year risk of death/LTX. Probability of death/LTX was 45.2% for those with a Wpeak ⩽ 49.2% predicted versus 10.9% for those with a Wpeak > 49.2% predicted (P < 0.001).Conclusions: CPET provides prognostic information in advanced CF lung disease, and Wpeak appears to be a promising marker for LTX referral and candidate selection

Rapid Improvement after Starting Elexacaftor–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease

International audienceRationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1) <40 who initiated elexacaftor-tezacaftor-ivacaftor from December 2019 to August 2020 in France was conducted. Clinical characteristics were collected at initiation and at 1 and 3 months. Safety and effectiveness were evaluated by September 2020. National-level transplantation and mortality figures for 2020 were obtained from the French CF and transplant centers and registries. Measurements and Main Results: Elexacaftor-tezacaftor- ivacaftor was initiated in 245 patients with a median (interquartile range) ppFEV1 = 29 (24-34). The mean (95% confidence interval) absolute increase in the ppFEV1 was +15.1 (+13.8 to +16.4; P < 0.0001), and the mean (95% confidence interval) in weight was +4.2 kg (+3.9 to +4.6; P < 0.0001). The number of patients requiring long-term oxygen, noninvasive ventilation, and/or enteral tube feeding decreased by 50%, 30%, and 50%, respectively (P < 0.01). Although 16 patients were on the transplant waiting list and 37 were undergoing transplantation evaluation at treatment initiation, only 2 received a transplant, and 1 died. By September 2020, only five patients were still on the transplantation path. Compared with the previous 2 years, a twofold decrease in the number of lung transplantations in patients with CF was observed in 2020, whereas the number of deaths without transplantation remained stable. Conclusions: In patients with advanced disease, elexacaftor-tezacaftor-ivacaftor is associated with rapid clinical improvement, often leading to the indication for lung transplantation being suspended