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Aims Functional tricuspid regurgitation (TR) is a turning point in cardiac diseases. Symptoms typically appear late. The optimal timing for proposing a valve repair remains a challenge. We sought to analyse the characteristics of right heart remodelling in patients with significant functional TR to identify the parameters that could be used in a simple prognostic model predicting clinical events. Methods and results We designed a prospective observational French multicentre study including 160 patients with significant functional TR (effective regurgitant orifice area > 30 mm2) and left ventricular ejection fraction > 40%. Clinical, echocardiographic, and electrocardiogram data were collected at baseline and at the 1 and 2 year follow‐up. The primary outcome was all‐cause death or hospitalization for heart failure. At 2 years, 56 patients (35%) achieved the primary outcome. The subset with events showed more advanced right heart remodelling at baseline, but similar TR severity. Right atrial volume index (RAVI) and the tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure (TAPSE/sPAP) ratio, reflecting right ventricular–pulmonary arterial coupling, were 73 mL/m2 and 0.40 vs. 64.7 mL/m2 and 0.50 in the event vs. event‐free groups, respectively (both P < 0.05). None among all the clinical and imaging parameters tested had a significant group × time interaction. The multivariable analysis leads to a model including TAPSE/sPAP ratio > 0.4 (odds ratio = 0.41, 95% confidence limit 0.2 to 0.82) and RAVI > 60 mL/m2 (odds ratio = 2.13, 95% confidence limit 0.96 to 4.75), providing a clinically valid prognostic evaluation. Conclusions RAVI and TAPSE/sPAP are relevant for predicting the risk for event at 2 year follow‐up in patients with an isolated functional TR.

Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic 1 . The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes 1 . Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a–C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a–C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19. Blockade of the C5a–C5aR1 axis using anti-C5aR1 monoclonal antibodies prevented inflammation associated with COVID-19.

Purpose CTLA4 deficiency is an inborn error of immunity (IEI) due to heterozygosity for germline loss-of-function variants of the CTLA4 gene located on chromosome 2q33.2. CTLA4 deficiency underlies pleiotropic immune and lymphoproliferation-mediated features with incomplete penetrance. It has been identified in hundreds of patients but copy number variants (CNVs) have been reported in only 12 kindreds, including nine which displayed large 2q33.1-2q33.2 deletions encompassing CTLA4 . Methods We conducted a nationwide study in France to identify patients with 2q33 deletions encompassing CTLA4 . We investigated the clinical and immunological phenotypes and genotypes of these patients. Results We identified 12 patients across six unrelated kindreds with clinical immunodeficiency. Neurological features were recorded in three patients, including one with syndromic neurodevelopmental disorder. Single-nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) array analysis, and targeted high-throughput sequencing revealed five different heterozygous 2q33 deletions of 26 kilobases to 7.12 megabases in size and encompassing one to 41 genes. We identified a contiguous gene syndrome (CGS) due to associated KLF7 deficiency in a kindred with a neurodevelopmental phenotype. Conclusion Deletions within the 2q33 region encompassing CTLA4 are rare and not extensively explored, and are probably underdiagnosed in cytogenetic practice. A literature review identified 14 different CGS loci including at least one gene responsible for an IEI. The deletions involved in IEIs should be systematically delimited, to facilitate screening for CGS.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is part of the treatment strategy for some patients with high-risk lymphoma by improving survival with an acceptable toxicity profile. Although the BEAM (BCNU, etoposide, cytarabine, and melphalan) intensification regimen is the most used, the optimal dosing for each drug is unclear. Here, we retrospectively compared the outcome of 110 patients receiving higher (400 mg/m2, n = 69) or lower (200 mg/m2, n = 41) etoposide and cytarabine doses in our institution between 2012 and 2019. Patients in the BEAM 200 group experienced less toxicity with reduced fever duration (P < 0.001), number of platelet transfusions (P = 0.008), antibiotic duration (P < 0.001), antifungal therapy (P < 0.001), and mucositis (P < 0.001) whereas length of stay, admission to the intensive care unit, and in-hospital mortality were not different between groups. Progression-free survival (PFS) was non-significantly lower in the BEAM 200 group (36-month PFS, 68% vs. 80%, P = 0.053) whereas OS was similar between the two groups (36-month OS, 87% vs. 91%, respectively, P = 0.12). Albeit a non-significant reduction in PFS, BEAM 200 conditioning intensity was associated with a reduced toxicity profile.