COVID-19 affects millions of patients worldwide with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens and can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n=33) with age- and sex-matched controls (n=17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), Platelet Factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-Inhibitory Factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19 with intubation (P<0.0001) and death as outcome (P<0.0005). Illness severity correlated directly with plasma MPO-DNA complexes (P=0.0360), while PaO2/FiO2 correlated inversely(P=0.0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19 and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline and COVID-19 plasma triggered NET formation which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19 and NETs may represent targets for therapeutic intervention.

There is an urgent need to understand the pathogenesis of coronavirus disease 2019 (COVID-19). In particular, thrombotic complications in patients with COVID-19 are common and contribute to organ failure and mortality. Patients with severe COVID-19 present with hemostatic abnormalities that mimic disseminated intravascular coagulopathy associated with sepsis with the major difference being increased risk of thrombosis rather than bleeding. However, whether SARS-CoV-2 infection alters platelet function to contribute to the pathophysiology of COVID-19 remains unknown. In this study, we report altered platelet gene expression and functional responses in patients infected with SARS-CoV-2. RNA sequencing demonstrated distinct changes in the gene expression profile of circulating platelets of COVID-19 patients. Pathway analysis revealed differential gene expression changes in pathways associated with protein ubiquitination, antigen presentation and mitochondrial dysfunction. The receptor for SARS-CoV-2 binding, ACE2, was not detected by mRNA or protein in platelets. Surprisingly, mRNA from the SARS-CoV-2 N1 gene was detected in platelets from 2/25 COVID-19 patients, suggesting platelets may take-up SARS-COV-2 mRNA independent of ACE2. Resting platelets from COVID-19 patients had increased P-selectin expression basally and upon activation. Circulating platelet-neutrophil, -monocyte, and -T-cell aggregates were all significantly elevated in COVID-19 patients compared to healthy donors. Furthermore, platelets from COVID-19 patients aggregated faster and showed increased spreading on both fibrinogen and collagen. The increase in platelet activation and aggregation could partially be attributed to increased MAPK pathway activation and thromboxane generation. These findings demonstrate that SARS-CoV-2 infection is associated with platelet hyperreactivity which may contribute to COVID-19 pathophysiology.

Objective: Supporting patients' self care could have a major effect on the management of long-term conditions, which has led to worldwide interest in effective self care interventions. In England, self care support is being developed through the ''Expert Patients Programme'', which provides lay-led generic courses to improve patients' self care skills. However, the clinical and cost effectiveness of such courses remains unclear. Methods: Two-arm pragmatic randomised controlled trial design with waiting list control in community settings in England. 629 patients with a wide range of self-defined long-term conditions were studied. The lay-led self care support group involved 6-weekly sessions to teach self care skills. Primary outcomes were self-efficacy, reported energy and routine health services utilisation at 6 months. A cost-effectiveness analysis was also conducted. Results: Patients receiving immediate course access reported considerably greater self-efficacy and energy at 6-month follow-up, but reported no statistically significant reductions in routine health services utilisation over the same time period. The cost-effectiveness analysis showed that patients receiving immediate course access reported considerably greater health related quality of life, and a small reduction in costs. If a quality adjusted life year was valued at £20 000 ($39 191; J30 282), there was a 70% probability that the intervention was cost effective. Conclusions: Lay-led self care support groups are effective in improving self-efficacy and energy levels among patients with long-term conditions, and are likely to be cost effective over 6 months at conventional values of a decision-maker's willingness to pay. They may be a useful addition to current services in the management of long-term conditions.

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Platelets are essential for physiological hemostasis and are central in pathological thrombosis. These are their traditional and best known activities in health and disease. In addition, however, platelets have specializations that broaden their functional repertoire considerably. These functional capabilities, some of which are recently discovered, include the ability to sense and respond to infectious and immune signals and to act as inflammatory effector cells. Human platelets and platelets from mice and other experimental animals can link the innate and adaptive limbs of the immune system and act across the immune continuum, often also linking immune and hemostatic functions. Traditional and newly recognized facets of the biology of platelets are relevant to defensive, physiological immune responses of the lungs and to inflammatory lung diseases. The emerging view of platelets as blood cells that are much more diverse and versatile than previously thought further predicts that additional features of the biology of platelets and of megakaryocytes, the precursors of platelets, will be discovered and that some of these will also influence pulmonary immune defenses and inflammatory injury.

In a Plenary Paper, Middleton and colleagues describe important transcriptional and translational changes in murine and human platelets during sepsis, elucidating the emerging role of platelets in the complications of systemic inflammatory illness.

Objective To measure changes in quality of care for three major chronic diseases (coronary heart disease, asthma, and type 2 diabetes) between 1998 and 2003. Design Longitudinal cohort study. Setting 42 general practices in six geographical areas of England (Avon, Bury/Rochdale, Enfield, Oldham, Somerset, South Essex). Participants Medical record data for 2300 patients with diabetes, asthma, or coronary heart disease in 1998, and 1495 patients in 2003. Main outcome measure Quality of care assessed against predefined evidence based review criteria. Results Between 1998 and 2003, quality of care improved markedly in terms of maximum possible scores on the review criteria, from 60.5% to 78.1% for coronary heart disease (change = 17.6, 95% confidence interval 13.9 to 21.4; P < 0.001), 60.1% to 70.3% for asthma (10.2, 4.6 to 15.8; P = 0.001), and 70.4% to 77.7% for diabetes (7.3, 3.5 to 11.1; P = 0.001). Important changes occurred to several indicators potentially related to improved health outcomes. These included improved control of serum cholesterol (to ≤ 5 mmol/l) from 17.6% to 61.4% in coronary heart disease and from 21.5% to 52% in diabetes and control of blood pressure to ≤ 150/90 in coronary heart disease from 47.3% to 72.2% and to ≤ 145/85 in diabetes from 21.8% to 35.8%. A small, non-significant improvement in glycaemic control occurred among diabetic patients (37.9% to 39.7% with HbA 1c < 7.4%). Significant improvements also occurred in the recording of exercise capacity and diet and weight advice for patients with coronary heart disease; of smoking advice, peak flow, and symptoms for patients with asthma; and of creatinine, weight, and HbA 1c for patients with diabetes. Over the five years, more improvement in coronary heart disease care occurred in large practices and practices in affluent areas. Conclusions Substantial improvements were seen in quality of care for the three conditions studied between 1998 and 2003, a time of systematic quality improvement initiatives in the NHS. The changes were most marked for coronary heart disease. English general practices could be expected to achieve high clinical quality scores in the initial year of a new contact, which provides financial incentives for high quality care from 2004.

Study objectives: To examine changing inequality in the coverage of cervical screening and its relation to organisational aspects of primary care and to inequality in cervical cancer incidence and mortality. Design: Retrospective time trends analysis (1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001) of screening coverage and cervical cancer incidence and mortality in England. Setting: The 99 district health authorities in England, as defined by 1999 boundaries were used to create a time series of incidence and mortality rates from cervical cancer per 100 000 population. A subset of 60 district health authorities were used to construct a time series of screening coverage data and GP and practice characteristics. Health authorities were categorised into one of three "deprivation" groups using the Townsend Deprivation Index. Participants: Women aged <35 and 35-64 were selected from health authority populations as the main focus of the study. Results: Cervical cancer screening coverage was consistently higher in affluent areas from 1991-9 but ratio rates of inequality between affluent and deprived health authorities narrowed over time. The increase in coverage in deprived areas was most closely associated with an increase in the number of practice nurses. Cervical cancer incidence and mortality rates were consistently higher in deprived health authorities, but inequality decreased. Screening coverage and cervical cancer rates were highly negatively correlated in deprived health authorities. Conclusion: A primary health care intervention such as an organised programme of cervical screening can contribute to reducing inequality in population health.