Background: Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection has disproportionately affected older individuals and those with underlying medical conditions. Research has focused on short-term outcomes in hospital, and single organ involvement. Consequently, impact of long COVID (persistent symptoms three months post-infection) across multiple organs in low-risk individuals is yet to be assessed. Methods: An ongoing prospective, longitudinal, two-centre, observational study was performed in individuals symptomatic after recovery from acute SARS-CoV-2 infection. Symptoms and organ function (heart, lungs, kidneys, liver, pancreas, spleen) were assessed by standardised questionnaires (EQ-5D-5L, Dyspnoea-12), blood investigations and quantitative magnetic resonance imaging, defining single and multi-organ impairment by consensus definitions. Findings: Between April and September 2020, 201 individuals (mean age 44 (SD 11.0) years, 70% female, 87% white, 31% healthcare workers) completed assessments following SARS-CoV-2 infection (median 140, IQR 105-160 days after initial symptoms). The prevalence of pre-existing conditions (obesity: 20%, hypertension: 6%; diabetes: 2%; heart disease: 4%) was low, and only 18% of individuals had been hospitalised with COVID-19. Fatigue (98%), muscle aches (88%), breathlessness (87%), and headaches (83%) were the most frequently reported symptoms. Ongoing cardiorespiratory (92%) and gastrointestinal (73%) symptoms were common, and 42% of individuals had ten or more symptoms. There was evidence of mild organ impairment in heart (32%), lungs (33%), kidneys (12%), liver (10%), pancreas (17%), and spleen (6%). Single (66%) and multi-organ (25%) impairment was observed, and was significantly associated with risk of prior COVID-19 hospitalisation (p<0.05). Interpretation: In a young, low-risk population with ongoing symptoms, almost 70% of individuals have impairment in one or more organs four months after initial symptoms of SARS-CoV-2 infection. There are implications not only for burden of long COVID but also public health approaches which have assumed low risk in young people with no comorbidities.

Background Two FDA-authorized mRNA COVID-19 vaccines, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna), have demonstrated high efficacies in large Phase 3 randomized clinical trials. It is important to assess their effectiveness in a real-world setting. Methods This is a retrospective analysis of 136,532 individuals in the Mayo Clinic health system (Arizona, Florida, Iowa, Minnesota, Wisconsin) with PCR testing data between December 1, 2020 and April 20, 2021. We compared clinical outcomes for a vaccinated cohort of 68,266 individuals who received at least one dose of either vaccine (n BNT162b2 = 51,795; n mRNA-1273 = 16,471) and an unvaccinated control cohort of 68,266 individuals propensity-matched based on relevant demographic, clinical, and geographic features. We estimated real-world vaccine effectiveness by comparing incidence rates of positive SARS-CoV-2 PCR testing and COVID-19 associated hospitalization and ICU admission starting 7 days after the second vaccine dose. Findings The real-world vaccine effectiveness in preventing SARS-CoV-2 infection was 86.1% (95% CI: 82.4-89.1%) for BNT162b2 and 93.3% (95% CI: 85.7-97.4%) for mRNA-1273. BNT162b2 and mRNA-1273 were 88.8% (95% CI: 75.5-95.7%) and 86.0% (95% CI: 71.6-93.9%) effective in preventing COVID-19 associated hospitalization. Both vaccines were 100% effective (95% CI BNT162b2 : 51.4-100%; 95% CI mRNA-1273 : 43.3-100%) in preventing COVID-19 associated ICU admission. Conclusions BNT162b2 and mRNA-1273 are both effective in a real-world setting and are associated with reduced rates of SARS-CoV-2 infection and decreased burden of COVID-19 on the healthcare system.

Infection with the human immunodeficiency virus (HIV) is associated with a progressive decrease in CD4 T-cell number and a consequent impairment in host immune defenses. Analysis of T cells from patients infected with HIV, or of T cells infected in vitro with HIV, demonstrates a significant fraction of both infected and uninfected cells dying by apoptosis. The many mechanisms that contribute to HIV-associated lymphocyte apoptosis include chronic immunologic activation; gp120/160 ligation of the CD4 receptor; enhanced production of cytotoxic ligands or viral proteins by monocytes, macrophages, B cells, and CD8 T cells from HIV-infected patients that kill uninfected CD4 T cells; and direct infection of target cells by HIV, resulting in apoptosis. Although HIV infection results in T-cell apoptosis, under some circumstances HIV infection of resting T cells or macrophages does not result in apoptosis; this may be a critical step in the development of viral reservoirs. Recent therapies for HIV effectively reduce lymphoid and peripheral T-cell apoptosis, reduce viral replication, and enhance cellular immune competence; however, they do not alter viral reservoirs. Further understanding the regulation of apoptosis in HIV disease is required to develop novel immune-based therapies aimed at modifying HIV-induced apoptosis to the benefit of patients infected with HIV.

The absence of immune defects that occurs in the syndrome of long-term nonprogressive (LTNP) HIV infection offers insights into the pathophysiology of HIV-induced immune disease. The (H[F/S]RIG)2 domain of viral protein R (Vpr) induces apoptosis and may contribute to HIV-induced T cell depletion. We demonstrate a higher frequency of R77Q Vpr mutations in patients with LTNP than in patients with progressive disease. In addition, T cell infections using vesicular stomatitis virus G (VSV-G) pseudotyped HIV-1 Vpr R77Q result in less (P = 0.01) T cell death than infections using wild-type Vpr, despite similar levels of viral replication. Wild-type Vpr-associated events, including procaspase-8 and -3 cleavage, loss of mitochondrial transmembrane potential (Δψm), and DNA fragmentation factor activation are attenuated by R77Q Vpr. These data highlight the pathophysiologic role of Vpr in HIV-induced immune disease and suggest a novel mechanism of LTNP

Background The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT04351152 , and is completed. Findings Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with CO...