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Following Toll-like receptor 4 (TLR4) stimulation of macrophages, negative feedback mediated by the anti-inflammatory cytokine interleukin-10 (IL-10) limits the inflammatory response. However, extensive cell-to-cell variability in TLR4-stimulated cytokine secretion raises questions about how negative feedback is robustly implemented. To explore this, we characterize the TLR4-stimulated secretion program in primary murine macrophages using a single-cell microwell assay that enables evaluation of functional autocrine IL-10 signaling. High-dimensional analysis of single-cell data reveals three tiers of TLR4-induced proinflammatory activation based on levels of cytokine secretion. Surprisingly, while IL-10 inhibits TLR4-induced activation in the highest tier, it also contributes to the TLR4-induced activation threshold by regulating which cells transition from non-secreting to secreting states. This role for IL-10 in restraining TLR4 inflammatory activation is largely mediated by intermediate interferon (IFN)-ß signaling, while TNF likely mediates response resolution by IL-10. Thus, cell-to-cell variability in cytokine regulatory motifs provides a means to tailor the TLR4-induced inflammatory response.

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BACKGROUND: For the last few years, English general practices - which are, traditionally, small - have been encouraged to serve larger populations of registered patients by merging or collaborating with each other. Meanwhile, patient surveys have suggested that continuity of care and access to care are worsening. AIM: To explore whether increasing the size of the practice population and working collaboratively are linked to changes in continuity of care or access to care. DESIGN AND SETTING: This observational study in English general practice used data on patient experience, practice size, and collaborative working. Data were drawn from the English GP Patient Survey, NHS Digital, and from a previous study. METHOD: The main outcome measures were the proportions of patients at practice level reporting positive experiences of both access and relationship continuity of care in the GP Patient Survey. Changes in proportions between 2013 and 2018 among practices that had grown and those that had, roughly, stayed the same size were compared, as were patients' experiences, categorised by whether or not practices were working in close collaborations in 2018. RESULTS: Practices that had grown in population size had a greater fall in continuity of care (by 6.6%, 95% confidence interval = 4.3% to 8.9%), than practices that had roughly stayed the same size, after controlling for other factors. Differences in falls in access to care were smaller (4.3% difference for being able to get through easily on the telephone; 1.5% for being able to get an appointment; 0.9% in satisfaction with opening hours), but were statistically significant. Practices collaborating closely with others had marginally worse continuity of care than those not working in collaboration, and no differences in access. CONCLUSION: Larger general practice size in England may be associated with slightly poorer continuity of care and may not improve patient access. Close collaborative working did not have any demonstrable effect on patient experience.

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OBJECTIVES: Glaucoma filtering schemes such as the Manchester Glaucoma Enhanced Referral Scheme (GERS) aim to reduce the number of false positive cases referred to Hospital Eye Services. Such schemes can also have wider system benefits, as they may reduce waiting times for other patients. However, previous studies of the cost consequences and wider system benefits of glaucoma filtering schemes are inconclusive. We investigate the cost consequences of the Manchester GERS. DESIGN: Observational study. METHODS: A cost analysis from the perspective of the National Health Service (NHS) was conducted using audit data from the Manchester GERS. RESULTS: 2405 patients passed through the Manchester GERS from April 2013 to November 2016. 53.3% were not referred on to Manchester Royal Eye Hospital (MREH). Assuming an average of 2.3 outpatient visits to MREH were avoided for each filtered patient, the scheme saved the NHS approximately £2.76 per patient passing through the scheme. CONCLUSION: Our results indicate that glaucoma filtering schemes have the potential to reduce false positive referrals and costs to the NHS.

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BACKGROUND: Over the last 5 years, national policy has encouraged general practices to serve populations of >30 000 people (called 'working at scale') by collaborating with other practices. AIM: To describe the number of English general practices working at scale, and their patient populations. DESIGN AND SETTING: Observational study of general practices in England. METHOD: Data published by the NHS on practices' self-reports of working in groups were supplemented with data from reports by various organisations and practice group websites. Practices were categorised by the extent to which they were working at scale; within these categories, the age distribution of the practice population, level of socioeconomic deprivation, rurality, and prevalence of longstanding illness were then examined. RESULTS: Approximately 55% of English practices (serving 33.5 million patients) were working at scale, individually or collectively serving populations of >30 000 people. Organisational models representing close collaboration for the purposes of core general practice services were identifiable for approximately 5% of practices; these comprised large practices, superpartnerships, and multisite organisations. Approximately 50% of practices were working in looser forms of collaboration, focusing on services beyond core general practice; for example, primary care in the evenings and at weekends. Data on organisational models and the purpose of the collaboration were very limited for this group. CONCLUSION: In early 2018, approximately 5% of general practices were working closely at scale; approximately half of practices were working more loosely at scale. However, data were incomplete. Better records of what is happening at practice level should be collected so that the effect of working at scale on patient care can be evaluated.

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Better management by individuals of their long-term conditions is promoted to improve health and reduce healthcare expenditure. However, there is limited evidence on the determinants and consequences of self-management activity. We investigate the determinants of two forms of self-management, exercise and relaxation, and their impact on the health and wellbeing of 3472 individuals with long-term health conditions over a 1-year period. We use simultaneous recursive trivariate models to estimate the effects of these two inputs on three health and wellbeing outcomes: the EuroQol five-dimensional (EQ-5D) score, self-assessed health and happiness. We reflect the opportunity cost of time and knowledge with employment status and education and find that employment reduces relaxation and education increases exercise. We find that neither exercise nor relaxation affects the EuroQol five-dimensional score, but exercise increases self-assessed health and relaxation increases happiness. Our findings show that individuals tailor their self-management activities to their economic constraints, with effects on different aspects of their utility. Interventions to encourage self-management should take account of heterogeneous effects and constraints. © 2017 The Authors. Health Economics Published by John Wiley & Sons, Ltd.

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PURPOSE: More input from the individual into the management of their health has the potential to reduce demand on the formal care system and improve health outcomes. A variety of interventions have been developed to encourage such 'self-care', particularly for populations with long-term conditions. However the equity consequences of such initiatives are relatively unknown as there is little evidence on the social and economic determinants of time spent on self-care. KEY METHODS: We estimate the social and economic determinants of time spent on self-care. We also examine whether patients spend time on self-care because they are compensating for lack of access to formal health care. We undertook regression analyses of eight self-care and formal care measures from a dedicated survey of 300 patients with long-term conditions. MAIN RESULTS: We found that higher income is associated with less time spent on self-care. Various measures of access to formal health care are found to not be associated with time spent on self-care. MAIN CONCLUSION: People from a lower socioeconomic position spend more time managing their condition even when there is universal entitlement to health care.

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