Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.

Taylor et al. show that PD1 negatively regulates KLRG1+ ILC-2s by attenuating STAT5 activation. Blocking PD1 signaling significantly enhances the protective function of ILC-2s in helminthic infection.

BackgroundTo counteract microgravity (µG)-induced adaptation, European Space Agency (ESA) astronauts on long-duration missions (LDMs) to the International Space Station (ISS) perform a daily physical exercise countermeasure program. Since the first ESA crewmember completed an LDM in 2006, the ESA countermeasure program has strived to provide efficient protection against decreases in body mass, muscle strength, bone mass, and aerobic capacity within the operational constraints of the ISS environment and the changing availability of on-board exercise devices. The purpose of this paper is to provide a description of ESA’s individualised approach to in-flight exercise countermeasures and an up-to-date picture of how exercise is used to counteract physiological changes resulting from µG-induced adaptation. Changes in the absolute workload for resistive exercise, treadmill running and cycle ergometry throughout ESA’s eight LDMs are also presented, and aspects of pre-flight physical preparation and post-flight reconditioning outlined.ResultsWith the introduction of the advanced resistive exercise device (ARED) in 2009, the relative contribution of resistance exercise to total in-flight exercise increased (33–46 %), whilst treadmill running (42–33 %) and cycle ergometry (26–20 %) decreased. All eight ESA crewmembers increased their in-flight absolute workload during their LDMs for resistance exercise and treadmill running (running speed and vertical loading through the harness), while cycle ergometer workload was unchanged across missions.ConclusionIncreased or unchanged absolute exercise workloads in-flight would appear contradictory to typical post-flight reductions in muscle mass and strength, and cardiovascular capacity following LDMs. However, increased absolute in-flight workloads are not directly linked to changes in exercise capacity as they likely also reflect the planned, conservative loading early in the mission to allow adaption to µG exercise, including personal comfort issues with novel exercise hardware (e.g. the treadmill harness). Inconsistency in hardware and individualised support concepts across time limit the comparability of results from different crewmembers, and questions regarding the difference between cycling and running in µG versus identical exercise here on Earth, and other factors that might influence in-flight exercise performance, still require further investigation.

Scott JP, Sale C, Greeves JP, Casey A, Dutton J, Fraser WD. The role of exercise intensity in the bone metabolic response to an acute bout of weight-bearing exercise. J Appl Physiol 110: 423-432, 2011. First published December 2, 2010 doi:10.1152/japplphysiol.00764.2010.-We compared the effects of exercise intensity (EI) on bone metabolism during and for 4 days after acute, weight-bearing endurance exercise. Ten males [mean Ϯ SD maximum oxygen uptake (V O2max): 56.2 Ϯ 8.1 ml·min Ϫ1 ·kg Ϫ1 ] completed three counterbalanced 8-day trials. Following three control days, on day 4, subjects completed 60 min of running at 55%, 65%, and 75% V O2max. Markers of bone resorption [COOH-terminal telopeptide region of collagen type 1 (␤-CTX)] and formation [NH2-terminal propeptides of procollagen type 1 (P1NP), osteocalcin (OC), bone-alkaline phosphatase (ALP)], osteoprotegerin (OPG), parathyroid hormone (PTH), albumin-adjusted calcium (ACa), phosphate (PO4), and cortisol were measured during and for 3 h after exercise and on four follow-up days (FU1-FU4). At 75% V O2max, ␤-CTX was not significantly increased from baseline by exercise but was higher compared with 55% (17-19%, P Ͻ 0.01) and 65% (11-13%, P Ͻ 0.05) V O2max in the first hour postexercise. Concentrations were decreased from baseline in all three groups by 39 -42% (P Ͻ 0.001) at 3 h postexercise but not thereafter. P1NP increased (P Ͻ 0.001) during exercise only, while bone-ALP was increased (P Ͻ 0.01) at FU3 and FU4, but neither were affected by EI. PTH and cortisol increased (P Ͻ 0.001) with exercise at 75% V O2max only and were higher (P Ͻ 0.05) than at 55% and 65% V O2max during and immediately after exercise. The increases (P Ͻ 0.001) in OPG, ACa, and PO4 with exercise were not affected by EI. Increasing EI from 55% to 75% V O2max during 60 min of running resulted in higher ␤-CTX concentrations in the first hour postexercise but had no effect on bone formation markers. Increased bone-ALP concentrations at 3 and 4 days postexercise suggest a beneficial effect of this type of exercise on bone mineralization. The increase in OPG was not influenced by exercise intensity, whereas PTH was increased at 75% V O2max only, which cannot be fully explained by changes in serum calcium or PO 4 concentrations. treadmill running; bone turnover markers; osteoprotegerin; parathyroid hormone EXERCISE is associated with improvements in bone mineral density (BMD), particularly at load-bearing sites (9,11,22,60), and might play a role in reducing fragility fractures associated with osteoporosis (19, 24), either by increasing the accumulation of bone mass during childhood growth (9, 68) or by decreasing the rate of bone loss following the attainment of peak bone mass (37,60). Despite this, the specific mechanisms by which exercise exerts its effects on bone remain to be fully determined, as does the most effective form of exercise to increase BMD.Mechanical loads imposed by muscle contractions and gravity that are in excess of those habitually encountered can positively influence th...

Background Ventilator-associated pneumonia is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1β and IL-8 in bronchoalveolar lavage fluid have been validated as effective markers for exclusion of ventilator-associated pneumonia. The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1β and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia. Methods VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to 24 ICUs from 17 National Health Service hospital trusts across England, Scotland, and Northern Ireland. Patients were screened for eligibility and included if they were 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Clinicians were masked to patient assignment for an initial period until biomarker results were reported. Bronchoalveolar lavage was done in all patients, with concentrations of IL-1β and IL-8 rapidly determined in bronchoalveolar lavage fluid from patients randomised to the biomarker-based antibiotic recommendation group. If concentrations were below a previously validated cutoff, clinicians were advised that ventilator-associated pneumonia was unlikely and to consider discontinuing antibiotics. Patients in the routine use of antibiotics group received antibiotics according to usual practice at sites. Microbiology was done on bronchoalveolar lavage fluid from all patients and ventilator-associated pneumonia was confirmed by at least 10⁴ colony forming units per mL of bronchoalveolar lavage fluid. The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomly assigned to the intervention group who defaulted to routine use of antibiotics because of failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment, and decision making. This study is registered with ISRCTN, ISRCTN65937227, and ClinicalTrials.gov, NCT01972425. Findings Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine us...