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Background Studies examining the relationship between serological status (rheumatoid factor and/or anticitrullinated antibody) and rituximab treatment outcome in rheumatoid arthritis (RA) have been hampered by limited numbers of seronegative patients. Objective To carry out a meta-analysis of trials from the rituximab RA clinical programme to investigate this relationship further. Methods This was a meta-analysis of four placebo-controlled, phase II or III clinical trials. The efficacy end point in all analyses was change from baseline in Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 24 weeks. Assay of serotype and missing data imputation methods were consistent across all studies. Results The population analysed comprised 2177 patients (rituximab, n=1416; placebo, n=761). Demographics and baseline disease characteristics were well balanced. When a fixed-effects meta-analysis approach was used, the overall-effect model indicated evidence of additional treatment benefit with rituximab in seropositive patients: reduction in DAS28-ESR at week 24 was on average 0.35 units (95% CI 0.12 to 0.84; n=1394) greater than in seronegative patients; this effect was not seen in placebo patients. Heterogeneity indices indicated significant uncertainty in the overall-effect model (Q=8.8, I=0.77; p=0.03 (χ2 test)). Baseline Health Assessment Questionnaire score, pain visual analogue scale, swollen joint counts of 28 joints and race were significant contributors to this heterogeneity, with additional analysis indicating that these effects may predominate in early RA (methotrexate-naïve) populations. A dominant effect was seen in patients for whom one or more tumour necrosis factor inhibitors had failed. Conclusion Although the difference was modest, the overall-effect model indicates that seropositive patients respond better to rituximab than seronegative patients.

ObjectivesThis process evaluation explores patient and healthcare professional acceptability of community-based monitoring versus hospital-based care for patients with quiescent neovascular age-related macular degeneration (QnAMD).DesignQualitative process evaluation was conducted as part of a randomised controlled trial.SettingSix hospitals and six community-based practices.Participants25 patients and 16 healthcare professionals (ophthalmologists and optometrists). This approach helped differentiate between common issues and those specific to community-based monitoring.InterventionThe Quality-Assured Follow-Up of QnAMD by non-medical practitioners trial aimed to examine whether non-medical practitioners follow-up patients with QnAMD in the community in a safe and clinically and cost-effective way. The process evaluation aimed to examine whether the intervention was acceptable by patients and professionals. The process evaluation was based on interviews which contained open-ended questions focused on patient experience and confidence in community-based care, issues concerning the practicalities of the organisation and management of the clinic, and resources including IT and digital equipment. The theory of acceptability framework was used to interpret the findings.ResultsPatients reported positively on the experience of receiving QnAMD services in the community and highlighted staff professionalism and clear communication. Key themes were the proximity of care provision for patients, IT interoperability and the real-world costs of running the service. Some patients randomised to the hospital showed preference for the intervention to take place in the hospital, mediated mainly by prior experience of hospital care and travel distance. The location of the clinic and transport routes affected the experience of attending appointments, with strong preference expressed for proximity to one’s home. Inaccessibility due to non-modifiable internal building structures in the community and parking in hospital eye services was reported by a small proportion of patients. Healthcare professionals reported positively about their ability to deliver QnAMD services in community settings but raised concerns about the compatibility of technological infrastructure that facilitates the sharing of optical coherence tomography image and video files. Some optometrists were also concerned about the financial sustainability of the intervention after the end of the trial due to the costs involved in the administration of QnAMD follow-up care.ConclusionsThe delivery of QnAMD services in the community by non-medical personnel was broadly accepted by both patients and practitioners. This implies that non-medical practitioners can follow up patients with QnAMD in the community in a safe way. Further research would be needed to establish whether similar results would be obtained during routine practice outside a research project and whether the long-term follow-up for QnAMD would be financially sustainable for independent as well as chain community optometry practices.Trial registration numberNCT03893474.

In north India, vitamin A deficiency (retinol <0·70 μmol/L) is common in pre-school children and 2–3% die at ages 1·0–6·0 years. We aimed to assess whether periodic vitamin A supplementation could reduce this mortality. Participants in this cluster-randomised trial were pre-school children in the defined catchment areas of 8338 state-staffed village child-care centres (under-5 population 1 million) in 72 administrative blocks. Groups of four neighbouring blocks (clusters) were cluster-randomly allocated in Oxford, UK, between 6-monthly vitamin A (retinol capsule of 200 000 IU retinyl acetate in oil, to be cut and dripped into the child's mouth every 6 months), albendazole (400 mg tablet every 6 months), both, or neither (open control). Analyses of retinol effects are by block (36 vs 36 clusters). The study spanned 5 calendar years, with 11 6-monthly mass-treatment days for all children then aged 6–72 months. Annually, one centre per block was randomly selected and visited by a study team 1–5 months after any trial vitamin A to sample blood (for retinol assay, technically reliable only after mid-study), examine eyes, and interview caregivers. Separately, all 8338 centres were visited every 6 months to monitor pre-school deaths (100 000 visits, 25 000 deaths at ages 1·0–6·0 years [the primary outcome]). This trial is registered at ClinicalTrials.gov, NCT00222547. Estimated compliance with 6-monthly retinol supplements was 86%. Among 2581 versus 2584 children surveyed during the second half of the study, mean plasma retinol was one-sixth higher (0·72 [SE 0·01] vs 0·62 [0·01] μmol/L, increase 0·10 [SE 0·01] μmol/L) and the prevalence of severe deficiency was halved (retinol <0·35 μmol/L 6%vs 13%, decrease 7% [SE 1%]), as was that of Bitot's spots (1·4%vs 3·5%, decrease 2·1% [SE 0·7%]). Comparing the 36 retinol-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1·0–6·0 years during the 5-year study were 3·01 retinol versus 3·15 control (absolute reduction 0·14 [SE 0·11], mortality ratio 0·96, 95% CI 0·89–1·03, p=0·22), suggesting absolute risks of death between ages 1·0 and 6·0 years of approximately 2·5% retinol versus 2·6% control. No specific cause of death was significantly affected. DEVTA contradicts the expectation from other trials that vitamin A supplementation would reduce child mortality by 20–30%, but cannot rule out some more modest effect. Meta-analysis of DEVTA plus eight previous randomised trials of supplementation (in various different populations) yielded a weighted average mortality reduction of 11% (95% CI 5–16, p=0·00015), reliably contradicting the hypothesis of no effect. UK Medical Research Council, USAID, World Bank (vitamin A donated by Roche).

Normalisation process theory reports the importance of contextual integration in successfully embedding novel interventions, with recent propositions detailing the role that 'plasticity' of intervention components and 'elasticity' of an intended setting contribute. We report on the introduction of a clinical pathway assessing patient non-responsiveness to treatment for glaucoma and ocular hypertension. The aim of this study was to assess the feasibility of implementing the Cardiff Model of Glaucoma Care into hospital eye services, identifying any issues of acceptability for staff through the filter of normalisation process theory. A prospective observational study was undertaken in four hospital eye services. This incorporated detailed qualitative semi-structured interviews with staff (n = 8) to gather their perceptions on the intervention's usefulness and practicality. In addition, observational field notes of patient and staff consultations (n = 88) were collected, as well as broader organisational observations from within the research sites (n = 52). Data collection and analysis was informed by the normalisation process theory framework. Staff reported the pathway led to beneficial knowledge on managing patient treatment, but the model was sometimes perceived as overly prescriptive. This perception varied significantly based on the composition of clinics in relation to staff experience, staff availability and pre-existing clinical structures. The most commonly recounted barrier came in contextually integrating into sites where wider administrative systems were inflexible to intervention components. Flexibility will be the key determinant of whether the clinical pathway can progress to wider implementation. Addressing the complexity and variation associated with practice between clinics required a remodelling of the pathway to maintain its central benefits but enhance its plasticity. Our study therefore helps to confirm propositions developed in relation to normalisation process theory, contextual integration, intervention plasticity, and setting elasticity. This enables the transferability of findings to healthcare settings other than ophthalmology, where any novel intervention is implemented.

In north India many pre-school children are underweight, many have intestinal worms, and 2–3% die at ages 1·0–6·0 years. We used the state-wide Integrated Child Development Service (ICDS) infrastructure to help to assess any effects of regular deworming on mortality. Participants in this cluster-randomised study were children in catchment areas of 8338 ICDS-staffed village child-care centres (under-5 population 1 million) in 72 administrative blocks. Groups of four neighbouring blocks were cluster-randomly allocated in Oxford between 6-monthly vitamin A (retinol capsule of 200 000 IU retinyl acetate in oil, to be cut and dripped into the child's mouth every 6 months), albendazole (400 mg tablet every 6 months), both, or neither (open control). Analyses of albendazole effects are by block (36 vs 36 clusters). The study spanned 5 calendar years, with 11 6-monthly mass-treatment days for all children then aged 6–72 months. Annually, one centre per block was randomly selected and visited by a study team 1–5 months after any trial deworming to sample faeces (for presence of worm eggs, reliably assessed only after mid-study), weigh children, and interview caregivers. Separately, all 8338 centres were visited every 6 months to monitor pre-school deaths (100 000 visits, 25 000 deaths at age 1·0–6·0 years [the primary outcome]). This trial is registered at ClinicalTrials.gov, NCT00222547. Estimated compliance with 6-monthly albendazole was 86%. Among 2589 versus 2576 children surveyed during the second half of the study, nematode egg prevalence was 16% versus 36%, and most infection was light. After at least 2 years of treatment, weight at ages 3·0–6·0 years (standardised to age 4·0 years, 50% male) was 12·72 kg albendazole versus 12·68 kg control (difference 0·04 kg, 95% CI −0·14 to 0·21, p=0·66). Comparing the 36 albendazole-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1·0–6·0 years during the 5-year study were 3·00 (SE 0·07) albendazole versus 3·16 (SE 0·09) control, difference 0·16 (SE 0·11, mortality ratio 0·95, 95% CI 0·89 to 1·02, p=0·16), suggesting absolute risks of dying between ages 1·0 and 6·0 years of roughly 2·5% albendazole versus 2·6% control. No specific cause of death was significantly affected. Existing ICDS village staff can be organised to deliver simple pre-school interventions sustainably for many years at low cost, but regular deworming had little effect on mortality in this lightly infected pre-school population. UK Medical Research Council, USAID, World Bank (albendazole donated by GlaxoSmithKline).

Prevention is becoming ever more central in UK care policy for older people, though precisely what this entails, and how it works most effectively in social care and support, remains ambiguous. Set against the “newness” of recent social care legislation in Wales, this article explores the perspectives of professionals on prevention and community development, particularly for older people. This draws on qualitative data collected from 11 Welsh local authorities, four NHS Wales health boards, and eight regional third-sector organisations, incorporating 64 interviews with directors, executives, and senior managers. Recent research has highlighted concerns over the slipperiness of prevention as a concept, resulting in multiple interpretations and activities operating under its banner. Consistent with this, our data suggested a kaleidoscopic picture of variously named community-based initiatives working to support the intricate web of connections that sustain older people, as well as provide practical or material help. Similarly, professionals highlighted varied agendas of community resilience, individual independence, and reducing the need for state-funded health and social care, as well as a range of viewpoints on the roles of the state, private sector, and the third sector. Analysis revealed fragments of familiar themes in community development; positive hopes for community initiatives, tensions between the mixed agendas of state-instigated activities, and the practical challenges arising from systems imbued with neo-liberal ideas. Realising the promise of prevention will require deft steering through these challenges.

The ecosystem services approach is based on the interdependencies between nature and human well‐being. However, while the ecosystem services aspect of this approach is well‐developed, the human well‐being aspect remains unstructured and vaguely defined. An integrated conceptual framework was developed by adapting and linking the UK National Ecosystem Assessment‐Follow On framework with human well‐being domains. As well as benefits, the notion of disbenefits was incorporated to recognise the potentially detrimental effects from interacting with nature. Benefits and disbenefits occur at the social–ecological interface and are classified by the seven domains of human well‐being they affect. The framework is applied to saltmarsh habitat as a case study, highlighting knowledge gaps and the potential applicability and usefulness of the framework. In saltmarsh, benefits mainly accrue at larger scales with a greater impact affecting local to global individuals, while disbenefits tend to occur at a smaller scale and impact in‐situ individuals. The framework provides in‐depth insight into links, trade‐offs and dichotomies between benefits and disbenefits and human well‐being, and improves accessibility to the complex research area of human well‐being. This research can be a useful tool to guide environmental and health policy and management, as well as stakeholder engagement. A free Plain Language Summary can be found within the Supporting Information of this article. A free Plain Language Summary can be found within the Supporting Information of this article.

Interleukin 6 (IL‐6) has previously been identified as playing a role in ulcerative colitis (UC) by activating the signal‐transducing element gp130 through ligation of either the membrane‐bound or soluble IL‐6 receptor (termed classic and trans‐signaling respectively). It has been proposed that selective inhibition of trans‐IL‐6 signaling could ameliorate the deleterious, pro‐inflammatory effects of IL‐6, while preserving the homeostatic activity of classic IL‐6 signaling. We developed an in silico, mechanistic model of UC in two stages to compare the biological effects that result from inhibition of classic and trans‐IL‐6 signaling. In the first stage, we developed a limited‐scope model of IL‐6 signaling to establish the quantitative properties of classic and trans‐signaling pathways on a short timescale following stimulation with IL‐6. The model included both a pan‐inhibitor of IL‐6 classic and trans‐signaling and a soluble gp130‐Fc that selectively inhibited trans‐signaling. In the second stage, we developed a multi‐scale model of UC to study the pharmacodynamic effects of cytokine signaling inhibition and optimize treatment regimens. Across three virtual experiments, both selective and global suppression of IL‐6 signaling were associated with a transition away from an inflammatory state in patients with moderate to severe inflammatory activity. In our multi‐scale model, we identified a dose–response relationship between selective inhibition of trans‐IL‐6 signaling and tissue regeneration. Moreover, selective inhibition of trans‐IL‐6 signaling effectively suppressed inflammation and induced faster gut tissue healing than global IL‐6 suppression. These findings suggest that global suppression of IL‐6 signaling could negatively affect IL‐6‐induced regeneration activity, whereas this effect is less likely for selective inhibition.

Recently there has been a chorus of demands to “re‐imagine” social care. Community and faith‐based organisations, policy, and academic communities are engaged in discussions on issues such as human rights for older populations, the future of residential care, how to better support family/community care, and strengthen local place‐based community development. Moreover, the Covid‐19 pandemic has added new urgency to this mission, galvanizing developments for change and collective action and exposing public troubles of endemic system failings, prevailing discourses of ageism, tensions with health systems, and limitations of market models of care and support. Prevention is a central social welfare principle in many countries. It is associated with policy and practices that aim to meet social care needs early and is explored in this thematic issue.