Background The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. Methods We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. Results We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P=0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P=0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P=0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. Conclusions Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937 .)

Background: Immune checkpoint inhibitors (ICI) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events. Methods: The study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls, matched by age, a history of cardiovascular events and cancer type. In a second design, a case-crossover analysis was performed with an "at-risk period" defined as the two-year period after and the "control period" as the two-year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. Additionally, in an imaging sub-study (n=40), the rate of atherosclerotic plaque progression was compared from before and after starting an ICI. All study measures and outcomes were blindly adjudicated. Results: In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (HR, 3.3 [95% CI, 2.0-5.5]; P <0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at two years (adjusted HR, 4.8 [95% CI, 3.5-6.5]; P <0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/year pre-to 6.7%/year post). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids. Conclusions: Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk, prior to, during and after treatment, should be considered among patients on an ICI.

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Background Myocarditis attributable to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune‐related adverse event. Limited data have suggested an association between baseline and on‐treatment absolute lymphocyte count (ALC) and neutrophil/lymphocyte ratio (NLR) and the development of other immune‐related adverse events; there are no data characterizing the role of ALC and NLR in ICI‐associated myocarditis. Methods and Results This was a case control study of 55 patients with ICI myocarditis and 55 controls without any post‐ICI immune‐related adverse events. We leveraged clinical testing, where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events was also tested. In cases, there was a statistically significant decrease in ALC with myocarditis from baseline (1.6 thousands per cubic milliliter (K/μL); interquartile range, 1.1–1.9 K/μL) to admission (1.1 K/μL; interquartile range, 0.7–1.3 K/μL; P <0.001). Similarly, there was an increase in NLR from baseline (3.5; interquartile range, 2.3–5.4) to admission (6.6; interquartile range, 4.5–14.1; P <0.001). There was no statistically significant change in controls. In follow‐up, there were 20 events; larger decreases in ALC (44.6% versus 18.2%; P <0.001) or increases in NLR (156.5% versus 65.1%; P =0.019) were associated with major adverse cardiac events. Conclusions A reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR was associated with subsequent major adverse cardiac events.

Objectives Burnout is a psychophysiological syndrome, consisting of a triad of emotional and physical exhaustion, exhibition of impersonal attitude and loss of a sense of achievement for oneself. This study aimed to pinpoint its risk factors, measure its current prevalence in medical students of Karachi, Pakistan and accentuate the areas of focus to benefit the primary care-oriented community as a whole. Methods This cross-sectional study included responses from 600 medical students in Karachi (third to final year). A self-administered questionnaire using the Maslach Burnout Inventory-Human Services Survey (MBI-HSS), multi-dimensional mood state questionnaire and perceived stress scale was used, along with a section about burnout prevention assessment. Data were analyzed using SPSS version 24.0 (IBM Corp., Armonk, NY) and chi-square tests used to find significant associations. Results One-fifth (n=109, 18.2%) of our subjects were burned out. The syndrome was significantly observed in those who operated on insufficient sleep (p-value 0.028) and in those having anger management issues and non-dominating temperaments (p-value 0.05). Furthermore, it was statistically significant in those who gave up easily, in those who had no hobbies and had no time to exercise and pray (p-value <0.05). It was more prevalent in pupils of private medical colleges whereas two of its three constitutive factors, Emotional Exhaustion (p-value 0.03) and Personal Achievement (p-value <0.001) were significantly higher in pupils of public sector universities. Conclusion The deleterious repercussions of burnout syndrome warrant the need for extensive efforts towards the propagation of its awareness.

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BackgroundThere are limited data on the occurrence, associations and outcomes of pericardial effusions and pericarditis on or after treatment with immune checkpoint inhibitors (ICIs).MethodsThis was a retrospective study at a single academic center that compared 2842 consecutive patients who received ICIs with 2699 age- and cancer-type matched patients with metastatic disease who did not receive ICI. A pericardial event was defined as a composite outcome of pericarditis and new or worsening moderate or large pericardial effusion. The endpoints were obtained through chart review and were blindly adjudicated. To identify risk factors associated with a pericardial event, we compared patients who developed an event on an ICI with patients treated with an ICI who did not develop a pericardial event. Cox proportional-hazard model and logistical regression analysis were performed to study the association between ICI use and pericardial disease as well as pericardial disease and mortality. An additional 6-week landmark analysis was performed to account for lead-time bias.ResultsThere were 42 pericardial events in the patients treated with ICI (n=2842) over 193 days (IQR: 64–411), yielding an incidence rate of 1.57 events per 100 person-years. There was a more than fourfold increase in risk of pericarditis or a pericardial effusion among patients on an ICI compared with controls not treated with ICI after adjusting for potential confounders (HR 4.37, 95% CI 2.09 to 9.14, p<0.001). Patients who developed pericardial disease while on an ICI had a trend for increased all-cause mortality compared with patients who did not develop a pericardial event (HR 1.53, 95% CI 0.99 to 2.36, p=0.05). When comparing those who developed pericardial disease after ICI treatment with those who did not, a higher dose of corticosteroid pre-ICI (>0.7 mg/kg prednisone) was associated with increased risk of pericardial disease (HR 2.56, 95% CI 1.00 to 6.57, p=0.049).ConclusionsICI use was associated with an increased risk of development of pericardial disease among patients with cancer and a pericardial event on an ICI was associated with a trend towards increase in mortality.