A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Microbiota educates innate immune response to Toll-like receptors ligands and RSV infection in lung

International audienceSince the apparition of new technologies permitting the precise characterization of microorganisms, studies involving microbiotas’ influence swarmed in the literature. It has also brought evidences to raise the emerging concept that the lung is not a sterile compartment and possesses its own microbiota. It has been shown that the lung microbiota could be altered in patients suffering of respiratory diseases, such as asthma or bronchiolitis induced by respiratory syncytial virus (RSV). However, we still don’t know if it is pathologies that influences the dysbiosis or the reverse. Despite this fundamental question, we know that microbiota is able to affect the immune response. But, the manner by which this phenomenon occurs remains elusive. First, using lung explants from specific pathogen free (SPF) and germ-free (GF) mice exposed to Toll-like receptors (TLRs) ligands or RSV, we show a higher production of pro-inflammatory cytokines, notably IL-6 and TNF by lung explants from GF mice compared to SPF mice. These data suggest that microbiota educates innate immune response in lung by reducing pro-inflammatory pathways. We have also observed a more abundant expression of TLR4 in the lungs of GF mice compared to SPF mice, which could predispose the innate immune system of GF mice to react strongly to environmental stimuli. In this context, the microbiota seems to modulate innate immune receptors expression. Not only these data partially explain how the microbiota educates the immune system, but they also allow to strengthen the emerging concept of immunomodulation by probiotics bacteria to prevent respiratory pathology development

Microbiota educates innate immune response to Toll-like receptors ligands and RSV infection in lung

Since the apparition of new technologies permitting the precise characterization of microorganisms, studies involving microbiotas’ influence swarmed in the literature. It has also brought evidences to raise the emerging concept that the lung is not a sterile compartment and possesses its own microbiota. It has been shown that the lung microbiota could be altered in patients suffering of respiratory diseases, such as asthma or bronchiolitis induced by respiratory syncytial virus (RSV). However, we still don’t know if it is pathologies that influences the dysbiosis or the reverse. Despite this fundamental question, we know that microbiota is able to affect the immune response. But, the manner by which this phenomenon occurs remains elusive. First, using lung explants from specific pathogen free (SPF) and germ-free (GF) mice exposed to Toll-like receptors (TLRs) ligands or RSV, we show a higher production of pro-inflammatory cytokines, notably IL-6 and TNF by lung explants from GF mice compared to SPF mice. These data suggest that microbiota educates innate immune response in lung by reducing pro-inflammatory pathways. We have also observed a more abundant expression of TLR4 in the lungs of GF mice compared to SPF mice, which could predispose the innate immune system of GF mice to react strongly to environmental stimuli. In this context, the microbiota seems to modulate innate immune receptors expression. Not only these data partially explain how the microbiota educates the immune system, but they also allow to strengthen the emerging concept of immunomodulation by probiotics bacteria to prevent respiratory pathology development

Impact of the first wave of COVID-19 epidemy on the surgical management of sigmoid diverticular disease in France: National French retrospective study

International audienceObjective: To analyze the surgical management of sigmoid diverticular disease (SDD) before, during, and after the first containment rules (CR) for the first wave of COVID-19.Methods: From the French Surgical Association multicenter series, this study included all patients operated on between January 2018 and September 2021. Three groups were compared: A (before CR period: 01/01/18-03/16/20), B (CR period: 03/17/20-05/03/20), and C (post CR period: 05/04/20-09/30/21).Results: A total of 1965 patients (A n = 1517, B n = 52, C n = 396) were included. The A group had significantly more previous SDD compared to the two other groups (p = 0.007), especially complicated (p = 0.0004). The rate of peritonitis was significantly higher in the B (46.1%) and C (38.4%) groups compared to the A group (31.7%) (p = 0.034 and p = 0.014). As regards surgical treatment, Hartmann's procedure was more often performed in the B group (44.2%, vs A 25.5% and C 26.8%, p = 0.01). Mortality at 90 days was significantly higher in the B group (9.6%, vs A 4% and C 6.3%, p = 0.034). This difference was also significant between the A and B groups (p = 0.048), as well as between the A and C groups (p = 0.05). There was no significant difference between the three groups in terms of postoperative morbidity.Conclusion: This study shows that the management of SDD was impacted by COVID-19 at CR, but also after and until September 2021, both on the initial clinical presentation and on postoperative mortality

Risk factors for emergency surgery for diverticulitis: A retrospective multicentric French study at 41 hospitals

International audienceBackgroundThe observed increase in the incidence of complicated diverticulitis may lead to the performance of more emergency surgeries. This study aimed to assess the rate and risk factors of emergency surgery for sigmoid diverticulitis.MethodThe primary outcomes were the rate of emergency surgery for sigmoid diverticulitis and its associated risk factors. The urgent or elective nature of the surgical intervention was provided by the surgeon and in accordance with the indication for surgical treatment. A mixed logistic regression with a random intercept after multiple imputations by the chained equation was performed to consider the influence of missing data on the results.ResultsBetween 2010 and 2021, 6,867 patients underwent surgery for sigmoid diverticulitis in the participating centers, of which one-third (n = 2317) were emergency cases. In multivariate regression analysis with multiple imputation by chained equation, increasing age, body mass index <18.5 kg/m2, neurologic and pulmonary comorbidities, use of anticoagulant drugs, immunocompromised status, and first attack of sigmoid diverticulitis were independent risk factors for emergency surgery. The likelihood of emergency surgery was significantly more frequent after national guidelines, which were implemented in 2017, only in patients with a history of sigmoid diverticulitis attacks.ConclusionThe present study highlights a high rate (33%) of emergency surgery for sigmoid diverticulitis in France, which was significantly associated with patient features and the first attack of diverticulitis