Exploring changes in patient experience with increasing practice size: observational study using data from the General Practice Patient Survey

Background For the last few years, English general practices, which are traditionally small, have been encouraged to work together to serve larger populations of registered patients, by merging or collaborating with each other. Meanwhile, patient surveys suggest worsening continuity of care and access to care. Aim To explore whether increasing size of practice population and working collaboratively are linked to changes in continuity of care or access to care. Design and setting Observational study in English general practice using data on patient experience, practice size and collaborative working Methods The main outcome measures were General Practice Patient Survey practice-level proportions of patients reporting positive experiences of access and relationship continuity of care. We compared change in proportions 2013-2018 among practices that had grown and those that had stayed about the same size. We also compared patients’ experiences by whether practices were working in close collaborations or not in 2018. Results. Practices that had grown in population size had a greater percentage fall in continuity of care, by 6.6% (95% confidence interval 4.3% to 8.9%) than practices that had stayed about the same size, after controlling for other factors. There was no similar difference in relation to access to care. Practices collaborating closely with others had marginally worse continuity of care than those not working in collaboration and no important differences in access. Conclusion Concerns that larger general practice size threatens continuity of care may be justified

Gender-Diverse Inclusion in Immunological Research: Benefits to Science and Health

The differences between male and female immune systems are an under-researched field, ripe for discovery. This is evidenced by the stark sex biases seen in autoimmunity and infectious disease. Both the sex hormones (oestrogen and testosterone), as well as the sex chromosomes have been demonstrated to impact immune responses, in multiple ways. Historical shortcomings in reporting basic and clinical scientific findings in a sex-disaggregated manner have led not only to limited discovery of disease aetiology, but to potential inaccuracies in the estimation of the effects of diseases or interventions on females and gender-diverse groups. Here we propose not only that research subjects should include both cis-gender men and cis-gender women, but also transgender and gender-diverse people alongside them. The known interaction between the hormonal milieu and the sex chromosomes is inseparable in cis-gender human research, without the confounders of puberty and age. By inclusion of those pursuing hormonal affirmation of their gender identity- the individual and interactive investigation of hormones and chromosomes is permitted. Not only does this allow for a fine-tuned dissection of these individual effects, but it allows for discovery that is both pertinent and relevant to a far wider portion of the population. There is an unmet need for detailed treatment follow-up of the transgender community- little is known of the potential benefits and risks of hormonal supplementation on the immune system, nor indeed on many other health and disease outcomes. Our research team has pioneered the inclusion of gender-diverse persons in our basic research in adolescent autoimmune rheumatic diseases. We review here the many avenues that remain unexplored, and suggest ways in which other groups and teams can broaden their horizons and invest in a future for medicine that is both fruitful and inclusive

Investigating sex differences in T regulatory cells from cisgender and transgender healthy individuals and patients with autoimmune inflammatory disease: a cross-sectional study

Summary Background Sexual dimorphisms, which vary depending on age group and pubertal status, have been described across both the innate and adaptive immune system. We explored the influence of sex hormones on immune phenotype in the context of adolescent health and autoimmunity. Methods In this cross-sectional study, healthy, post-pubertal cisgender individuals (aged 16–25 years); healthy, pre-pubertal cisgender individuals (aged 6–11 years); transgender individuals (aged 18–19 years) undergoing gender-affirming treatment (testosterone in individuals assigned female sex at birth and oestradiol in individuals assigned male sex at birth); and post-pubertal cisgender individuals (aged 14–25 years) with juvenile-onset systemic lupus erythematosus (SLE) age-matched to cisgender individuals without juvenile-onset SLE were eligible for inclusion. Frequencies of 28 immune-cell subsets (including different T cell, B cell, and monocyte subsets) from each participant were measured in peripheral blood mononuclear cells by flow cytometry and analysed by balanced random forest machine learning. RNA-sequencing was used to compare sex and gender differences in regulatory T (Treg) cell phenotype between participants with juvenile-onset SLE, age-matched cis-gender participants without the disease, and age matched transgender individuals on gender-affirming sex hormone treatment. Differentially expressed genes were analysed by cluster and pathway analysis. Suppression assays assessed the anti-inflammatory function of Treg cells in vitro. Findings Between Sept 5, 2012, and Nov 6, 2019, peripheral blood was collected from 39 individuals in the post-pubertal group (17 [44%] cisgender men, mean age 18·76 years [SD 2·66]; 22 [56%] cisgender women, mean age 18·59 years [2·81]), 14 children in the cisgender pre-pubertal group (seven [50%] cisgender boys, mean age 8·90 [1·66]; seven [50%] cisgender girls, mean age 8·40 [1·58]), ten people in the transgender group (five [50%] transgender men, mean age 18·20 years [0·47]; five [50%] transgender women, mean age 18·70 years [0·55]), and 35 people in the juvenile-onset SLE group (12 [34%] cisgender men, mean age 18·58 years [2·35]; 23 [66%] cisgender women, mean age 19·48 [3·08]). Statistically significantly elevated frequencies of Treg cells were one of the top immune-cell features differentiating young post-pubertal cisgender men from similarly aged cisgender women (p=0·0097). Treg cells from young cisgender men had a statistically significantly increased suppressive capacity in vitro compared with those from cisgender women and a distinct transcriptomic signature significantly enriched for genes in the PI3K–AKT signalling pathway. Gender-affirming sex hormones in transgender men and transgender women induced multiple statistically significant changes in the Treg-cell transcriptome, many of which enriched functional pathways that overlapped with those altered between cisgender men and cisgender women, highlighting a hormonal influence on Treg-cell function by gender. Finally, sex differences in Treg-cell frequency were absent and suppressive capacity was reversed in patients with juvenile-onset SLE, but sex differences in Treg-cell transcriptional signatures were significantly more pronounced in patients with juvenile-onset SLE compared with individuals without juvenile-onset SLE, suggesting that sex hormone signalling could be dysregulated in autoimmunity. Interpretation Sex-chromosomes and hormones might drive changes in Treg-cell frequency and function. Young post-pubertal men have a more anti-inflammatory Treg-cell profile, which could explain inflammatory disease susceptibilities, and inform sex-tailored therapeutic strategies. Funding Versus Arthritis, UK National Institute for Health Research University College London Hospital Biomedical Research Centre, Lupus UK, and The Rosetrees Trust

Differential impact of sex steroid hormones on B cell class switching, dependant upon sex chromosomal complement

Cis-gender females mount stronger humoral immune responses than cis-gender males in response to infection/vaccination, but are more likely to develop B-cell-driven autoimmune disorders. Murine work suggests a complex interplay between sex chromosomes and hormones creates this sex-bias. Oestrogen has been shown to enhance class-switch recombination(CSR)- the process by which B-cells ‘switch’ to IgG/A/E immunoglobulin isotypes. This study utilises a unique in vivo human model, with samples from both cis-gender and trans-gender age-matched young healthy volunteers, to investigate the impact of sex-chromosomal complement and hormonal milieu on CSR. Peripheral blood samples were collected from cis-male(n=43) and -female(n=62) volunteers(14-31yrs), and trans-male(n=25) and trans-female(n=23) volunteers(15-19yrs) on GnRH-analogue(“puberty blockers”), +/- testosterone or oestrogen treatment, respectively. PBMC/serum phenotyping was performed using flow cytometry and LEGENDplex™ immunoassay. Sorted CD19+ cells from a representative subset(n=22) were sent for RNAseq analysis. Post-pubertal cis-males had lower percentages of class-switched(IgD-CD27+) B-cells than cis-females(p=0.002), specifically pertaining to decreased IgG+ B-cells(p=0.009). Whilst IgG subclasses 1-3 are implicated in infection responses and the bulk of pathogenic autoantibodies, IgG4 is purported to be immunoregulatory. Cis-males demonstrated a higher IgG4:IgG1 serum antibody ratio than cis-females(p=0.003). Oestrogen blockade on an XX background in trans-males resulted in a reduced proportion of class-switched B-cells compared to cis-females(p=0.005), in-line with the cis-male profile. The ratio of IgG1:IgG4 subclasses was unaffected. Interestingly, oestrogen treatment on the XY background of trans-females demonstrated no overall effect on class-switching(p=0.250) but IgG4:IgG1 ratios were decreased significantly(p=0.015). Preliminary mechanistic analysis showed that AICDA(Activation-induced cytidine deaminase, an enzyme essential for CSR DNA mutations) expression was decreased in cis-males(p=0.038), and that oestrogen blockade in trans-males(p=0.125) was associated with a potential reduction, compared to cis-females. No differences were observed following oestrogen treatment in trans-females compared to cis-males(p=0.230). Oestrogen differentially affected B-cell CSR on XX and XY chromosomal backgrounds. Further work is implicated to establish the mechanisms behind this

How Widespread Is Working at Scale in English General Practice? an Observational Study

Background Over the last five years, national policy has encouraged 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 practice in England Methods We supplemented data published by the National Health Service on practices' self-reports of working in groups with data from reports by various organisations and websites of practice groups. We categorised practices by the extent to which they were working at scale, and examined age distribution of practice population, level of socioeconomic deprivation, rurality and prevalence of longstanding illness by these categories. Results About 55% English practices (serving 33 million patients) were working at scale, individually or collectively serving populations of >30,000 people. Organisations models representing close collaboration for the purposes of core general practice services were identifiable for ~5% of practices; these were: large practices; superpartnerships, and multisite organisations. About 50% of practices were working in looser forms of collaboration focusing on services beyond core general practice, e.g. primary care in the evenings and weekends. Data on organisations models and purpose of the collaboration were very limited for this group. Conclusions In early 2018, <5% of general practices were working closely at scale; about half of practices were working more loosely at scale. Data were, however, incomplete. Understanding what is happening at practice level is needed so that we can evaluate benefits and harms

Successful recruitment to trials : findings from the SCIMITAR+ Trial

BACKGROUND: Randomised controlled trials (RCT) can struggle to recruit to target on time. This is especially the case with hard to reach populations such as those with severe mental ill health. The SCIMITAR+ trial, a trial of a bespoke smoking cessation intervention for people with severe mental ill health achieved their recruitment ahead of time and target. This article reports strategies that helped us to achieve this with the aim of aiding others recruiting from similar populations. METHODS: SCIMITAR+ is a multi-centre pragmatic two-arm parallel-group RCT, which aimed to recruit 400 participants with severe mental ill health who smoke and would like to cut down or quit. The study recruited primarily in secondary care through community mental health teams and psychiatrists with a smaller number of participants recruited through primary care. Recruitment opened in October 2015 and closed in December 2016, by which point 526 participants had been recruited. We gathered information from recruiting sites on strategies which led to the successful recruitment in SCIMITAR+ and in this article present our approach to trial management along with the strategies employed by the recruiting sites. RESULTS: Alongside having a dedicated trial manager and trial management team, we identified three main themes that led to successful recruitment. These were: clinicians with a positive attitude to research; researchers and clinicians working together; and the use of NHS targets. The overriding theme was the importance of relationships between both the researchers and the recruiting clinicians and the recruiting clinicians and the participants. CONCLUSIONS: This study makes a significant contribution to the limited evidence base of real-world cases of successful recruitment to RCTs and offers practical guidance to those planning and conducting trials. Building positive relationships between clinicians, researchers and participants is crucial to successful recruitment

Sex and gender in infection and immunity: addressing the bottlenecks from basic science to public health and clinical applications

Although sex and gender are recognized as major determinants of health and immunity, their role is rarely considered in clinical practice and public health. We identified six bottlenecks preventing the inclusion of sex and gender considerations from basic science to clinical practice, precision medicine and public health policies. (i) A terminology-related bottleneck, linked to the definitions of sex and gender themselves, and the lack of consensus on how to evaluate gender. (ii) A data-related bottleneck, due to gaps in sex-disaggregated data, data on trans/non-binary people and gender identity. (iii) A translational bottleneck, limited by animal models and the underrepresentation of gender minorities in biomedical studies. (iv) A statistical bottleneck, with inappropriate statistical analyses and results interpretation. (v) An ethical bottleneck posed by the underrepresentation of pregnant people and gender minorities in clinical studies. (vi) A structural bottleneck, as systemic bias and discriminations affect not only academic research but also decision makers. We specify guidelines for researchers, scientific journals, funding agencies and academic institutions to address these bottlenecks. Following such guidelines will support the development of more efficient and equitable care strategies for all

Sex and gender in infection and immunity: addressing the bottlenecks from basic science to public health and clinical applications.

Although sex and gender are recognized as major determinants of health and immunity, their role is rarely considered in clinical practice and public health. We identified six bottlenecks preventing the inclusion of sex and gender considerations from basic science to clinical practice, precision medicine and public health policies. (i) A terminology-related bottleneck, linked to the definitions of sex and gender themselves, and the lack of consensus on how to evaluate gender. (ii) A data-related bottleneck, due to gaps in sex-disaggregated data, data on trans/non-binary people and gender identity. (iii) A translational bottleneck, limited by animal models and the underrepresentation of gender minorities in biomedical studies. (iv) A statistical bottleneck, with inappropriate statistical analyses and results interpretation. (v) An ethical bottleneck posed by the underrepresentation of pregnant people and gender minorities in clinical studies. (vi) A structural bottleneck, as systemic bias and discriminations affect not only academic research but also decision makers. We specify guidelines for researchers, scientific journals, funding agencies and academic institutions to address these bottlenecks. Following such guidelines will support the development of more efficient and equitable care strategies for all