Damned if they do, damned if they don't: negotiating the tricky context of anti-social behaviour and keeping safe in disadvantaged urban neighbourhoods

Young people's relationship with anti-social behaviour (ASB) is complicated. While their behaviours are often stereotyped as anti-social (e.g. ‘hanging about’), they also experience ASB in their neighbourhood. In this study, we explore young people's own perspectives on ASB, comparing results from ‘go-along’ interviews and focus groups conducted in disadvantaged neighbourhoods in Glasgow, Scotland. This article discusses how young people's everyday experience of ASB was contextualised by social factors such as cultural stereotyping of marginalised groups, poor social connectivity and spatial marginalisation within their neighbourhood. Furthermore, we found that these social factors were mutually reinforcing and interacted in a way that appeared to leave young people in a ‘no-win’ situation regarding their association with ASB. Participation in ASB and attempts to avoid such involvement were seen to involve negative consequences: participation could entail violence and spatial restrictions linked to territoriality, but avoidance could lead to being ostracised from their peer group. Regardless of involvement, young people felt that adults stereotyped them as anti-social. Our findings therefore provide support for policies and interventions aimed at reducing ASB (perpetrated by residents of all ages); in part by better ensuring that young people have a clear incentive for avoiding such behaviours

LIMPRINT in Australia

Background and study objective: Australia was one of nine participating countries in the epidemiology Phase II LIMPRINT project to determine the number of people with chronic oedema in local health services. Methods and results: Data collection occurred through questionnaire-based interviews and clinical assessment with provided LIMPRINT tools. Four different types of services across three states in Australia participated. A total of 222 adults participated with an age range from 22 to 102 years, and 60% were female. Site 1 included three residential care facilities (54% of participants had swelling), site 2 was community delivered aged care services (24% of participants had swelling), site 3 was a hospital setting (facility-based prevalence study) (28% of participants had swelling) and site 4 was a wound treatment centre (specific patient population) (100% of participants had swelling). Of those with chronic oedema or secondary lymphoedema 93% were not related to cancer, the lower limbs were affected in 51% of cases and 18% of participants with swelling reported one or more episodes of cellulitis in the previous year. Wounds were identified in 47% (n=105) of all participants with more than half of those with wounds coming from the dedicated wound clinic. Leg/foot ulcer was the most common type of wound (65% n=68). Conclusion: Distances between services, lack of specialised services and various state funding models contribute to inequities in CO treatment. Understanding the high number of non-cancer related chronic oedema presentations will assist health services to provide timely, effective care and improve referral pathways

The possibility of critical realist randomised controlled trials.

BACKGROUND: Some realists have criticised randomised controlled trials for their inability to explain the causal relations that they identify; to take into account the influence of the social context of the interventions they evaluate; and to account for individual difference. However, among realists, there is controversy over whether it is possible to improve trials by making them realist, or whether realism and the philosophical assumptions underlying trials are incompatible. This paper contributes to the debate in Trials on this issue. The debate thus far has concentrated on the possibility of combining trial methodology with that of realist evaluation. MAIN BODY: We concur with the contention that it is not feasible to combine randomised controlled trial design with the realist evaluation approach. However, we argue that a different variant of realism, critical realism, provides a more appropriate theoretical grounding for realist trials. In contrast to realist evaluation, which regards social mechanisms as an amalgam of social resources and people's reasoning, critical realism insists on their distinction. It does so on the basis of its assertion of the need to distinguish between social structures (in which resources lie) and human agency (which is at least partly guided by reasoning). From this perspective, conceiving of social mechanisms as external to participants can be seen as a valid methodological strategy for supplementing the exclusive concentration of trials on outcomes. While accepting realist evaluation's insistence that causality in open systems involves a configuration of multiple generative mechanisms, we adopt the critical realist interpretation of the experimental method, which sees it as creating artificial closure in order to identify the effects of specific causal mechanisms. If randomised controlled trials can be regarded as epidemiological proxies that substitute probabilistic controls over extraneous factors for closed experiments, their examination of the powers of discrete mechanisms through observation of the variation of outcomes is appropriate. CONCLUSION: While there are still issues to be resolved, critical realist randomised controlled trials are possible and have the potential to overcome some of the difficulties faced by traditional trial designs in accounting for the influence of social context and individual interpretation

Silk garments plus standard care compared with standard care for treating eczema in children: a randomised controlled, observer blind, pragmatic trial (CLOTHES Trial)

Background The role of clothing in the management of eczema (syn. atopic dermatitis, atopic eczema) is poorly understood. This trial evaluated the effectiveness and cost-effectiveness of silk garments (in addition to standard care) for the management of eczema in children with moderate to severe disease. Methods and findings This was a parallel group randomised controlled, observer-blind trial. Children aged 1 to 15 years with moderate to severe eczema were recruited from secondary care and the community in five UK centres. Participants were allocated using on-line randomisation (1:1) to standard care, or standard care plus silk garments; stratified by age and recruiting centre. Silk garments were worn for 6 months. Primary outcome (eczema severity) was assessed at baseline, 2, 4 and 6 months, by nurses blinded to treatment allocation using the Eczema Area and Severity Index (EASI), which was log-transformed for analysis (intention-to-treat analysis). Safety outcome: number of skin infections. Three hundred children were randomised (26th Nov 2013 to 5th May 2015): 42% girls, 79% white, mean age 5 years. Primary analysis included 282/300 (94%) children (n = 141 in each group). The garments were worn more often at night than in the day (median of 81% of nights (25th to 75th centile 57% to 96%) and 34% of days (25th to 75th centile 10% to 76%)). Geometric mean EASI scores at baseline, 2, 4 and 6 months were 9·2, 6·4, 5·8, 5·4 for silk clothing and 8·4, 6·6, 6·0, 5·4 for standard care. There was no evidence of any difference between the groups in EASI score averaged over all follow up visits adjusted for baseline EASI score, age and centre (adjusted ratio of geometric means: 0·95, 95% CI 0·85 to 1·07). This confidence interval is equivalent to a difference of -1·5 to 0·5 in the original EASI scale units which is not clinically important. Skin infections occurred in 36/142 (25%) and 39/141 (28%) for silk clothing and standard care respectively. Even if the small observed treatment effect was genuine, the incremental cost per QALY was £56,881 in the base case analysis from an NHS perspective, suggesting that silk garments are unlikely to be cost-effective within currently accepted thresholds. Main limitations: whilst minimising detection bias, use of an objective primary outcome may have underestimated treatment effects. Conclusions Silk clothing is unlikely to provide additional benefit over standard care in children with moderate to severe eczema

Regulation of early steps of GPVI signal transduction by phosphatases: a systems biology approach

We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population