The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. OBJECTIVE To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (PaO 2 /FIO 2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. INTERVENTIONS Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. MAIN OUTCOME AND MEASURES The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a PaO 2 /FIO 2 ratio less than 150 mm Hg, whichever came first. RESULTS A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. CONCLUSIONS AND RELEVANCE In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and PaO 2 /FIO 2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease.

Summary Cases of B‐cell chronic lymphocytic leukaemia (B‐CLL) with mutated (M) IgVH genes have a better prognosis than unmutated (UM) cases. We analysed the IgVH mutational status of B‐CLL according to the features of a canonical somatic hypermutation (SHM) process, correlating this data with survival. In a series of 141 B‐CLLs, 124 cases were examined for IgVH gene per cent mutations and skewing of replacement/silent mutations in the framework/complementarity‐determining regions as evidence of antigen‐driven selection; this identified three B‐CLL subsets: significantly mutated (sM), with evidence of antigen‐driven selection, not significantly mutated (nsM) and UM, without such evidence and IgVH gene per cent mutations above or below the 2% cut‐off. sM B‐CLL patients had longer survival within the good prognosis subgroup that had more than 2% mutations of IgVH genes. sM, nsM and UM B‐CLL were also characterized for the biased usage of IgVH families, intraclonal IgVH gene diversification, preference of mutations to target‐specific nucleotides or hotspots, and for the expression of enzymes involved in SHM (translesion DNA polymerase ζ and η and activation‐induced cytidine deaminase). These findings indicate the activation of a canonical SHM process in nsM and sM B‐CLLs and underscore the role of the antigen in defining the specific clinical and biological features of B‐CLL.

Both regimes showed good tolerability and appealing response rates. FFS was more prolonged in R-GEMOX, but patients continuously relapsed without a clear plateau on survival curves.

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on behalf of the HARVEST Investigators Summary Background and objectives Whether glomerular hyperfiltration is implicated in the development of microalbuminuria in hypertension is not well known. This prospective study investigated the relationship between changes in GFR and microalbuminuria in hypertension.Design, setting, participants, & measurements This study assessed 534 stage 1 hypertensive participants from the Hypertension and Ambulatory Recording Venetia Study (n=386 men) without microalbuminuria at baseline, who were recruited from 1990 to 1995 and followed for a median of 8.5 years. Mean age was 33.968.6 years and mean BP was 146.6610.5/94.065.0 mmHg. Creatinine clearance and 24-hour urinary albumin were measured at study entry and end. Participants were defined as normofilterers (normo) or hyperfilterers (hyper) according to whether GFR was ,150 or $150 ml/min per 1.73 m 2 , respectively. Participants were divided into four groups based on GFR changes from baseline to follow-up end: normo→normo (n=395), normo→hyper (n=31), hyper→hyper (n=61), and hyper→normo (n=47).Results Microalbuminuria progressively increased across the four groups and was 5.3% in normo→normo, 9.7% in normo→hyper, 16.4% in hyper→hyper, and 36.2% in hyper→normo (P,0.001). This association held true in a multivariable logistic regression in which several confounders, ambulatory BP, and other risk factors were taken into account (P,0.001). In particular, hyperfilterers whose GFR decreased to normal at study end had an adjusted odds ratio of 7.8 (95% confidence interval, 3.3-18.2) for development of microalbuminuria compared with participants with normal GFR throughout the study.Conclusions These data support the hypothesis for a parabolic association between GFR and urinary albumin in the early stage of hypertension.