T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations

Evidence-based medical leadership development: a systematic review

Health systems invest significant resources in leadership development for physicians and other health professionals. Competent leadership is considered vital for maintaining and improving quality and patient safety. We carried out this systematic review to synthesise new empirical evidence regarding medical leadership development programme factors which are associated with outcomes at the clinical and organisational levels. Using Ovid MEDLINE, we conducted a database search using both free text and Medical Subject Headings. We then conducted an extensive hand-search of references and of citations in known healthcare leadership development reviews. We applied the Medical Education Research Study Quality Indicator (MERSQI) and the Joanna Briggs Institute (JBI) Critical Appraisal Tool to determine study reliability, and synthesised results using a meta-aggregation approach. 117 studies were included in this systematic review. 28 studies met criteria for higher reliability studies. The median critical appraisal score according to the MERSQI was 8.5/18 and the median critical appraisal score according to the JBI was 3/10. There were recurring causes of low study quality scores related to study design, data analysis and reporting. There was considerable heterogeneity in intervention design and evaluation design. Programmes with internal or mixed faculty were significantly more likely to report organisational outcomes than programmes with external faculty only (p=0.049). Project work and mentoring increased the likelihood of organisational outcomes. No leadership development content area was particularly associated with organisational outcomes. In leadership development programmes in healthcare, external faculty should be used to supplement in-house faculty and not be a replacement for in-house expertise. To facilitate organisational outcomes, interventions should include project work and mentoring. Educational methods appear to be more important for organisational outcomes than specific curriculum content. Improving evaluation design will allow educators and evaluators to more effectively understand factors which are reliably associated with organisational outcomes of leadership development

Evidence-based medical leadership development: a systematic review

Health systems invest significant resources in leadership development for physicians and other health professionals. Competent leadership is considered vital for maintaining and improving quality and patient safety. We carried out this systematic review to synthesise new empirical evidence regarding medical leadership development programme factors which are associated with outcomes at the clinical and organisational levels. Using Ovid MEDLINE, we conducted a database search using both free text and Medical Subject Headings. We then conducted an extensive hand-search of references and of citations in known healthcare leadership development reviews. We applied the Medical Education Research Study Quality Indicator (MERSQI) and the Joanna Briggs Institute (JBI) Critical Appraisal Tool to determine study reliability, and synthesised results using a meta-aggregation approach. 117 studies were included in this systematic review. 28 studies met criteria for higher reliability studies. The median critical appraisal score according to the MERSQI was 8.5/18 and the median critical appraisal score according to the JBI was 3/10. There were recurring causes of low study quality scores related to study design, data analysis and reporting. There was considerable heterogeneity in intervention design and evaluation design. Programmes with internal or mixed faculty were significantly more likely to report organisational outcomes than programmes with external faculty only (p=0.049). Project work and mentoring increased the likelihood of organisational outcomes. No leadership development content area was particularly associated with organisational outcomes. In leadership development programmes in healthcare, external faculty should be used to supplement in-house faculty and not be a replacement for in-house expertise. To facilitate organisational outcomes, interventions should include project work and mentoring. Educational methods appear to be more important for organisational outcomes than specific curriculum content. Improving evaluation design will allow educators and evaluators to more effectively understand factors which are reliably associated with organisational outcomes of leadership development

Performance characteristics of five immunoassays for SARS-CoV-2: a head-to-head benchmark comparison

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic in 2020. Testing is crucial for mitigating public health and economic effects. Serology is considered key to population-level surveillance and potentially individual-level risk assessment. However, immunoassay performance has not been compared on large, identical sample sets. We aimed to investigate the performance of four high-throughput commercial SARS-CoV-2 antibody immunoassays and a novel 384-well ELISA.We did a head-to-head assessment of SARS-CoV-2 IgG assay (Abbott, Chicago, IL, USA), LIAISON SARS-CoV-2 S1/S2 IgG assay (DiaSorin, Saluggia, Italy), Elecsys Anti-SARS-CoV-2 assay (Roche, Basel, Switzerland), SARS-CoV-2 Total assay (Siemens, Munich, Germany), and a novel 384-well ELISA (the Oxford immunoassay). We derived sensitivity and specificity from 976 pre-pandemic blood samples (collected between Sept 4, 2014, and Oct 4, 2016) and 536 blood samples from patients with laboratory-confirmed SARS-CoV-2 infection, collected at least 20 days post symptom onset (collected between Feb 1, 2020, and May 31, 2020). Receiver operating characteristic (ROC) curves were used to assess assay thresholds.At the manufacturers' thresholds, for the Abbott assay sensitivity was 92·7% (95% CI 90·2–94·8) and specificity was 99·9% (99·4–100%); for the DiaSorin assay sensitivity was 96·2% (94·2–97·7) and specificity was 98·9% (98·0–99·4); for the Oxford immunoassay sensitivity was 99·1% (97·8–99·7) and specificity was 99·0% (98·1–99·5); for the Roche assay sensitivity was 97·2% (95·4–98·4) and specificity was 99·8% (99·3–100); and for the Siemens assay sensitivity was 98·1% (96·6–99·1) and specificity was 99·9% (99·4–100%). All assays achieved a sensitivity of at least 98% with thresholds optimised to achieve a specificity of at least 98% on samples taken 30 days or more post symptom onset.Four commercial, widely available assays and a scalable 384-well ELISA can be used for SARS-CoV-2 serological testing to achieve sensitivity and specificity of at least 98%. The Siemens assay and Oxford immunoassay achieved these metrics without further optimisation. This benchmark study in immunoassay assessment should enable refinements of testing strategies and the best use of serological testing resource to benefit individuals and population health.Public Health England and UK National Institute for Health Research

Divergent trajectories of antiviral memory after SARS-CoV-2 infection

The trajectories of acquired immunity to severe acute respiratory syndrome coronavirus 2 infection are not fully understood. We present a detailed longitudinal cohort study of UK healthcare workers prior to vaccination, presenting April-June 2020 with asymptomatic or symptomatic infection. Here we show a highly variable range of responses, some of which (T cell interferon-gamma ELISpot, N-specific antibody) wane over time, while others (spike-specific antibody, B cell memory ELISpot) are stable. We use integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling OverNight) to explore this heterogeneity. We identify a subgroup of participants with higher antibody responses and interferon-gamma ELISpot T cell responses, and a robust trajectory for longer term immunity associates with higher levels of neutralising antibodies against the infecting (Victoria) strain and also against variants B.1.1.7 (alpha) and B.1.351 (beta). These variable trajectories following early priming may define subsequent protection from severe disease from novel variants