Influence of Cultural Norms on Formal Service Engagement Among Survivors of Intimate Partner Violence: A Qualitative Meta-synthesis.

For victim-survivors of intimate partner violence (IPV), receiving help from formal services such as specialist family violence, health, or criminal justice services can be critical for their safety and well-being. Previous research has found cross-cultural differences in the rates of help-seeking behavior, with women from non-Anglo-Saxon communities less likely to seek formal help than Anglo-Saxon populations. This qualitative meta-synthesis has integrated qualitative evidence to examine the relationship between specific cultural norms and formal service engagement for female victim-survivors of IPV from non-Anglo-Saxon communities. A comprehensive search of seven databases was conducted for peer-reviewed articles published between 1985 to May 2021, in addition to searching gray literature. Thirty-five articles met the criteria for inclusion, representing 1,286 participants from 20 cultural groups. Based on a thematic synthesis approach, five key themes that captured specific cultural norms that influence formal service engagement were identified: (1) gender roles and social expectations, (2) community recognition and acceptance of abuse, (3) honor-based society, (4) the role of religion, and (5) cultural beliefs and attitudes toward formal services. These findings have important implications for responses to family violence, particularly concerning family violence education for non-Anglo-Saxon ethnically diverse communities and best-practice strategies to improve the cultural relevancy of formal service providers.

Retinal Dystrophy Associated With RLBP1 Retinitis Pigmentosa: A Five-Year Prospective Natural History Study.

Purpose: To assess the progression in functional and structural measures over a five-year period in patients with retinal dystrophy caused by RLBP1 gene mutation. Methods: This prospective, noninterventional study included patients with biallelic RLBP1 mutations from two clinical sites in Sweden and Canada. Key assessments included ocular examinations, visual functional measures (best-corrected visual acuity [BCVA], contrast sensitivity [CS], dark-adaptation [DA] kinetics up to six hours for two wavelengths [450 and 632 nm], Humphrey visual fields [HVF], full-field flicker electroretinograms), and structural ocular assessments. Results: Of the 45 patients enrolled, 38 completed the full five years of follow-up. At baseline, patients had BCVA ranging from -0.2 to 1.3 logMAR, poor CS, HVF defects, and prominent thinning in central foveal thickness. All patients had extremely prolonged DA rod recovery of approximately six hours at both wavelengths. The test-retest repeatability was high across all anatomic and functional endpoints. Cross-sectionally, poorer VA was associated with older age (right eye, correlation coefficient [CC]: 0.606; left eye, CC: -0.578; P < 0.001) and HVF MD values decreased with age (right eye, CC: -0.672, left eye, CC: -0.654; P < 0.001). However, no major changes in functional or structural measures were noted longitudinally over the five-year period. Conclusions: This natural history study, which is the first study to monitor patients with RLBP1 RD for five years, showed that severely delayed DA sensitivity recovery, a characteristic feature of this disease, was observed in all patients across all age groups (17-69 years), making it a potentially suitable efficacy assessment for gene therapy treatment in this patient population.

Qualitative exploration of the visual function impairments and impacts on vision-dependent activities of daily living in Retinitis Pigmentosa and Leber Congenital Amaurosis: content validation of the ViSIO-PRO and ViSIO-ObsRO measures.

BACKGROUND: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The associated visual impairments have significant impacts on patients' vision-dependent activities of daily living (ADL), mobility, and distal health-related quality of life (HRQoL). To adequately capture patient and caregiver perspectives in clinical trials, patient and observer-reported outcome instruments must demonstrate sufficient evidence of content validity in the target population. This study aimed to explore the patient experience of RP/LCA and assess the content validity of the Visual Symptom and Impact Outcomes PRO (ViSIO-PRO) and ObsRO (ViSIO-ObsRO) instruments in RP/LCA. METHODS: A total of 66 qualitative, combined concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted (33 adults, 10 adolescents, 8 children and 15 caregivers of children) in the US, France, Germany, and Canada. Patients had a clinical and genetic diagnosis of RP/LCA from a range of genotypes. CE results were used to further inform the development of a conceptual model and CD interviews assessed the relevance and understanding of the 44-item ViSIO-PRO and 26-item ViSIO-ObsRO instruments. Interviews were conducted across two iterative rounds to allow item modifications. RESULTS: Findings were consistent across RP/LCA genotypes. Night blindness, reduced peripheral vision, vision in very bright lighting and light/dark adaptation were the most frequently reported visual function symptoms impacting vision-dependent ADL and mobility. Impacts on distal HRQoL domains were also reported. The ViSIO-PRO and ObsRO items were well understood by participants and relevant across genotypes. The instructions, 7-day recall period and response scales were well understood and endorsed. Participant and expert clinician feedback supported modifications to item wording, the addition of six new ViSIO-PRO items and one new ViSIO-ObsRO item, and the removal of one ViSIO-PRO item due to lack of relevance. CONCLUSIONS: Findings support the content validity of the ViSIO-PRO and ViSIO-ObsRO instruments for use across RP/LCA genotypes. Ongoing research to evaluate the psychometric validity of the instruments will support future use of the instruments as efficacy endpoints in clinical trials and in general clinical practice to track disease severity and impact of disease on functioning.

An overview of interventions used across the life span to support transitions of those with a neurological condition: A systematic review of reviews.

OBJECTIVES: To systematically appraise published reviews on interventions used to support transitions for individuals with neurological conditions. DATA SOURCES: MEDLINE, CINAHL, The Allied and Complementary Medicine, AMED, PsycINFO, Cochrane database of systematic reviews and Web of Science were searched between 31st December 2010 and 15th September 2022. METHOD: The systematic review followed PRISMA guidelines. The quality and risk of bias were measured using A MeaSurement Tool to Assess systematic Reviews 2 and the Risk Of Bias In Systematic reviews' tool. All types of reviews which involved participants with neurological conditions were included. RESULTS: Seven reviews met the inclusion criteria. A total of 172 studies were included in the reviews. Effectiveness of transition interventions could not be calculated due to the lack of data. The findings suggested that the use of health applications may be beneficial by increasing self-management capabilities and disease knowledge. Education and clear communication between healthcare providers and recipients may also have positive impacts on quality of life. Risk of bias was found to be high in four of the reviews. Four reviews had low or critically low levels of evidence. CONCLUSIONS: There is a paucity of published evidence on interventions used to support the transitions of individuals with neurological conditions and the effect that these have on quality of life.

Development of Novel Patient-Reported Outcome (PRO) and Observer-Reported Outcome (ObsRO) Instruments in Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA): ViSIO-PRO and ViSIO-ObsRO.

INTRODUCTION: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are rare inherited retinal degenerative disorders resulting in visual impairments and impacts on patients' vision-dependent activities of daily living (ADL), mobility and distal health-related quality of life (HRQoL). This study aimed to conduct qualitative research to understand the patient experience of RP/LCA across genotypes and inform development of patient- and observer-reported outcome (PRO/ObsRO) instruments in RP/LCA. METHODS: Research activities included a qualitative literature review and review of existing visual function PRO instruments in RLBP1 RP, and concept elicitation (CE) and cognitive debriefing (CD) interviews of existing PRO instruments with patients with RLBP1 RP, expert clinicians, and payers. In wider RP/LCA, a social media listening (SML) study and a qualitative literature review was conducted, while psychometric evaluation of a PRO instrument in LCA was performed. Input from expert clinicians was sought at key stages. RESULTS: Findings from the qualitative literature reviews identified a range of visual function symptoms which had significant impacts on patients' vision-related ADL and distal HRQoL. Patient interviews identified additional visual function symptoms and impacts not previously reported in published literature. These sources informed development and refinement of a conceptual model displaying the patient experience of RP/LCA. Review of existing visual function PRO instruments, and CD interviews evaluating their content validity, confirmed that no existing instrument provides a comprehensive assessment of all concepts relevant to patients with RP/LCA. This highlighted the need for development of the Visual Symptom and Impact Outcomes PRO and ObsRO instruments to adequately assess the patient experience of RP/LCA. CONCLUSIONS: Results informed and supported development of the instruments to assess visual functioning symptoms and vision-dependent ADL, mobility and distal HRQoL in RP/LCA, in accordance with regulatory standards. Next steps to further support use in RP/LCA clinical trials/practice includes content and psychometric validation of the instruments in this population.

Combined and progestagen-only hormonal contraceptives and breast cancer risk: A UK nested case-control study and meta-analysis.

BACKGROUND: Current or recent use of combined oral contraceptives (containing oestrogen+progestagen) has been associated with a small increase in breast cancer risk. Progestagen-only contraceptive use is increasing, but information on associated risks is limited. We aimed to assess breast cancer risk associated with current or recent use of different types of hormonal contraceptives in premenopausal women, with particular emphasis on progestagen-only preparations. METHODS AND FINDINGS: Hormonal contraceptive prescriptions recorded prospectively in a UK primary care database (Clinical Practice Research Datalink [CPRD]) were compared in a nested case-control study for 9,498 women aged <50 years with incident invasive breast cancer diagnosed in 1996 to 2017, and for 18,171 closely matched controls. On average, 7.3 (standard deviation [SD] 4.6) years of clinical records were available for each case and their matched controls prior to the date of diagnosis. Conditional logistic regression yielded odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by the hormonal contraceptive type last prescribed, controlled for age, GP practice, body mass index, number of recorded births, time since last birth, and alcohol intake. MEDLINE and Embase were searched for observational studies published between 01 January 1995 and 01 November 2022 that reported on the association between current or recent progestagen-only contraceptive use and breast cancer risk in premenopausal women. Fixed effects meta-analyses combined the CPRD results with previously published results from 12 observational studies for progestagen-only preparations. Overall, 44% (4,195/9,498) of women with breast cancer and 39% (7,092/18,171) of matched controls had a hormonal contraceptive prescription an average of 3.1 (SD 3.7) years before breast cancer diagnosis (or equivalent date for controls). About half the prescriptions were for progestagen-only preparations. Breast cancer ORs were similarly and significantly raised if the last hormonal contraceptive prescription was for oral combined, oral progestagen-only, injected progestagen, or progestagen-releasing intrauterine devices (IUDs): ORs = 1.23 (95% CI [1.14 to 1.32]; p < 0.001), 1.26 (95% CI [1.16 to 1.37]; p < 0.001), 1.25 (95% CI [1.07 to 1.45]; p = 0.004), and 1.32 (95% CI [1.17 to 1.49]; p < 0.001), respectively. Our meta-analyses yielded significantly raised relative risks (RRs) for current or recent use of progestagen-only contraceptives: oral = 1.29 (95% CI [1.21 to 1.37]; heterogeneity χ25 = 6.7; p = 0.2), injected = 1.18 (95% CI [1.07 to 1.30]; heterogeneity χ28 = 22.5; p = 0.004), implanted = 1.28 (95% CI [1.08 to 1.51]; heterogeneity χ23 = 7.3; p = 0.06), and IUDs = 1.21 (95% CI [1.14 to 1.28]; heterogeneity χ24 = 7.9; p = 0.1). When the CPRD results were combined with those from previous published findings (which included women from a wider age range), the resulting 15-year absolute excess risk associated with 5 years use of oral combined or progestagen-only contraceptives in high-income countries was estimated at: 8 per 100,000 users from age 16 to 20 years and 265 per 100,000 users from age 35 to 39 years. The main limitation of the study design was that, due to the nature of the CPRD data and most other prescription databases, information on contraceptive use was recorded during a defined period only, with information before entry into the database generally being unavailable. This means that although our findings provide evidence about the short-term associations between hormonal contraceptives and breast cancer risk, they do not provide information regarding longer-term associations, or the impact of total duration of contraceptive use on breast cancer risk. CONCLUSIONS: This study provides important new evidence that current or recent use of progestagen-only contraceptives is associated with a slight increase in breast cancer risk, which does not appear to vary by mode of delivery, and is similar in magnitude to that associated with combined hormonal contraceptives. Given that the underlying risk of breast cancer increases with advancing age, the absolute excess risk associated with use of either type of oral contraceptive is estimated to be smaller in women who use it at younger rather than at older ages. Such risks need be balanced against the benefits of using contraceptives during the childbearing years.

Psychometric Validation of the ViSIO-PRO and ViSIO-ObsRO in Retinitis Pigmentosa and Leber Congenital Amaurosis.

INTRODUCTION: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The Visual Symptom and Impact Outcomes patient-reported outcome (ViSIO-PRO) and observer-reported outcome (ViSIO-ObsRO) instruments were developed in this population to assess visual function symptoms and impacts on vision-dependent activities of daily living (ADL) and distal health-related quality of life (HRQoL). This study aimed to explore the psychometric properties of the ViSIO-PRO and ViSIO-ObsRO in RP/LCA. METHODS: The 49-item ViSIO-PRO and 27-item ViSIO-ObsRO instruments were completed by 83 adult and adolescent patients and 22 caregivers of child patients aged 3-11 years with RP/LCA, respectively, at baseline and 12-16-day follow-up. Concurrent measures were also administered at baseline. Psychometric analyses assessed item (question) properties, dimensionality, scoring, reliability, validity, and score interpretation. RESULTS: Item responses were mainly evenly distributed across the response scale, and inter-item correlations were mostly moderate to strong (> 0.30) at baseline within hypothesized domains. Item deletion was informed by item properties, qualitative data, and clinical input and supported retention of 35 ViSIO-PRO items and 25 ViSIO-ObsRO items. Confirmatory factor analysis in line with pre-hypothesized domains supported a four-factor model assessing visual function symptoms, mobility, vision-dependent ADL, and distal HRQoL. A bifactor model supported calculation of total scores and four domain scores. Internal consistency was high for domain and total scores (Cronbach's alpha > 0.70) and test-retest reliability for total scores was strong between baseline and 12-16-day follow-up (intraclass correlation coefficients 0.66-0.98). Convergent validity was supported by strong correlations in a logical pattern with concurrent measures. Mean baseline scores differed significantly between severity groups. Distribution-based methods provided initial insights to guide interpretation of scores. CONCLUSIONS: Findings supported item reduction and established scoring of the instruments. Evidence of reliability and validity as outcome measures in RP/LCA was also reported. Further research is ongoing to explore responsiveness of the ViSIO-PRO and ViSIO-ObsRO instruments and interpretation of change scores.

Depression, anxiety, psychotropic drugs, and acute myocardial infarction: large prospective study of United Kingdom women.

BACKGROUND: Reported associations between depression and myocardial infarction in some studies might be explained by use of psychotropic drugs, residual confounding, and/or reverse causation (whereby heart disease precedes depression). We investigated these hypotheses in a large prospective study of UK women with no previous vascular disease. METHODS: At baseline in median year 2001 (IQR 2001-2003), Million Women Study participants reported whether or not they were currently being treated for depression or anxiety, their self-rated health, and medication use during the previous 4 weeks. Follow-up was through linkage to national hospital admission and mortality databases. Cox regression yielded adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the first myocardial infarction event in those reporting treatment for depression or anxiety (subdivided by whether or not the treatment was with psychotropic drugs) v. not, and stratified by self-reported health and length of follow-up. RESULTS: During mean follow-up of 13.9 years of 690 335 women (mean age 59.8 years) with no prior heart disease, stroke, transient ischaemic attack, or cancer, 12 819 had a first hospital admission or death from myocardial infarction. The aHRs for those reporting treatment for depression or anxiety with, and without, regular use of psychotropic drugs were 0.96 (95% CI 0.89-1.03) and 0.99 (0.89-1.11), respectively. No associations were found separately in women who reported being in good/excellent or poor/fair health or by length of follow-up. CONCLUSION: The null findings in this large prospective study are consistent with depression not being an independent risk factor for myocardial infarction.

Cancer prevention in cancer predisposition syndromes: A protocol for testing the feasibility of building a hereditary cancer research registry and nurse navigator follow up model.

Monogenic, high penetrance syndromes, conferring an increased risk of malignancies in multiple organs, are important contributors to the hereditary burden of cancer. Early detection and risk reduction strategies in patients with a cancer predisposition syndrome can save their lives. However, despite evidence supporting the benefits of early detection and risk reduction strategies, most Canadian jurisdictions have not implemented programmatic follow up of these patients. In our study site in the province of Newfoundland and Labrador (NL), Canada, there is no centralized, provincial registry of high-risk individuals. There is no continuity or coordination of care providing cancer genetics expertise and no process to ensure that patients are referred to the appropriate specialists or risk management interventions. This paper describes a study protocol to test the feasibility of obtaining and analyzing patient risk management data, specifically patients affected by hereditary breast ovarian cancer syndrome (HBOC; BRCA 1 and BRCA 2 genes) and Lynch syndrome (LS; MLH1, MSH2, MSH6, and PMS2 genes). Through a retrospective cohort study, we will describe these patients' adherence to risk management guidelines and test its relationship to health outcomes, including cancer incidence and stage. Through a qualitative interviews, we will determine the priorities and preferences of patients with any inherited cancer mutation for a follow up navigation model of risk management. Study data will inform a subsequent funding application focused on creating and evaluating a research registry and follow up nurse navigation model. It is not currently known what proportion of cancer mutation carriers are receiving care according to guidelines. Data collected in this study will provide clinical uptake and health outcome information so gaps in care can be identified. Data will also provide patient preference information to inform ongoing and planned research with cancer mutation carriers.

The Effectiveness of Culturally Specific Male Domestic Violence Offender Intervention Programs on Behavior Changes and Mental Health: A Systematic Review.

The objective of domestic violence intervention programs is to address perpetrator behavior. However, the suitability and effectiveness of these programs in confronting problematic behavior for ethnically diverse groups is unclear. Therefore, the aim of this systematic review was to cohesively examine whether such programs are effective in reducing recidivism, changing perpetrator behavior, and addressing mental health issues for culturally diverse groups. Several databases were searched for peer-reviewed articles that included culturally specific components or ethnically diverse cohorts in offender intervention programs. 10 articles met the inclusion criteria. The findings demonstrate greater effectiveness of programs with greater cultural engagement: through culturally trained facilitators, addressing the cultural and patriarchal norms relevant to the specific client group, and discussion of gender roles and attitudes to gender equality specific to the cultural context. Such programs achieved some positive outcomes including: reduced recidivism, improved mental health, and better attitudes to gender equality. However, the findings are limited to a few ethnically diverse groups, and not all studies measured all outcomes listed above. This review suggests the development and implementation of suitable offender intervention programs that address perpetrator behavior and mental health in ethnically diverse client groups. When culturally relevant and effective programs are implemented, it could lead to men's modification of perpetrating behavior and create safer family relationships.

What Matters When Examining Attitudes of Economic Abuse? Gender and Student Status as Predictors of Blaming, Minimizing, and Excusing Economic Abuse.

Extensive research has been conducted regarding attitudes toward various types and patterns of violence against intimate partners, but there is a lack of research on attitudes toward economic abuse in general. In the current study, we examined attitudes toward economic abuse by examining how participants blamed the victim, minimized the economic abuse, and excused the perpetrator in hypothetical scenarios. We also examined two characteristics of participants: binary gender differences (i.e., woman, man) and differences between students and non-students. Participants (N = 239) were recruited via the SONA system of a private university (n = 120) and via Amazon's Mechanical Turk (n = 119). Participants were randomly assigned to read one of two hypothetical scenarios to evaluate how scenario condition (i.e., victim employed, victim unemployed), participant gender, and participant student status predicted attitudes toward economic abuse involving blaming, minimizing, and excusing. Moreover, we also examined ambivalent sexism and gender role ideology as predictors. A 2 (scenario condition: job, no job) × 2 (participant gender: woman, man) × 2 (student status: college student, non-college student) MANOVA indicated main effects of both participant gender and participant student status. Follow-up ANOVAs revealed that men were more likely to blame victims, minimize the economic abuse, and excuse perpetrators compared to women. Additionally, students were less likely to minimize the economic abuse compared to non-students. Moreover, both hostile sexism and traditional gender role ideology were significant predictors. Implications of the findings and future directions for researchers are discussed.

Body size in early life and the risk of postmenopausal breast cancer.

BACKGROUND: Greater early life adiposity has been reported to reduce postmenopausal breast cancer risk but it is unclear whether this association varies by tumour characteristics. We aimed to assess associations of early life body size with postmenopausal breast cancer and its subtypes, allowing for body size at other ages. METHODS: A total of 342,079 postmenopausal UK women who reported their body size at age 10, clothes size at age 20, and body mass index (BMI) at baseline (around age 60) were followed by record linkage to national databases for cancers and deaths. Cox regression yielded adjusted relative risks (RRs) of breast cancer, overall and by tumour subtype, in relation to body size at different ages. RESULTS: During an average follow-up of 14 years, 15,506 breast cancers were diagnosed. After adjustment for 15 potential confounders, greater BMI at age 60 was associated with an increased risk of postmenopausal breast cancer (RR per 5 kg/m2=1.20, 95%CI 1.18-1.22) whereas greater adiposity in childhood and, to a lesser extent, early adulthood, was associated with a reduced risk (0.70, 0.66-0.74, and 0.92, 0.89-0.96, respectively). Additional adjustment for midlife BMI strengthened associations with BMI at both age 10 (0.63, 0.60-0.68) and at age 20 (0.78, 0.75-0.81). The association with midlife adiposity was confined to hormone sensitive subtypes but early life adiposity had a similar impact on the risk of all subtypes. CONCLUSION: Early life and midlife adiposity have opposite effects on postmenopausal breast cancer risk and the biological mechanisms underlying these associations are likely to differ.

Ovarian cancer survival by stage, histotype, and pre-diagnostic lifestyle factors, in the prospective UK Million Women Study.

BACKGROUND: Ovarian cancer is the fifth leading cause of cancer mortality in UK women. Ovarian cancer survival varies by disease stage at diagnosis, but evidence is mixed on the effect of tumour histological type (histotype) and other factors. METHODS: 1.3 million UK women completed a detailed health questionnaire in 1996-2001 and were followed for incident cancers and deaths via linkage to national databases. Using Cox regression models, we estimated adjusted relative risks (RRs) of death from ovarian cancer, by stage at diagnosis, tumour histotype, and 16 other personal characteristics of the women. RESULTS: During 17.7 years' average follow-up, 13,222 women were diagnosed with ovarian cancer, and 8697 of them died from the disease. Stage at diagnosis was a major determinant of survival (stage IV vs I, RR=10.54, 95% CI: 9.16-12.13). Histotype remained a significant predictor after adjustment for stage and other factors, but associations varied over the follow-up period. Histotype-specific survival was worse for high-grade than low-grade tumours. Survival appeared worse with older age at diagnosis (per 5 years: RR=1.19, 95% CI: 1.15-1.22), higher BMI (per 5-unit increase: RR=1.06, 95% CI: 1.02-1.11), and smoking (current vs never: RR=1.17, 95% CI: 1.07-1.27), but there was little association with 13 other pre-diagnostic reproductive, anthropometric, and lifestyle factors. CONCLUSION: Stage at diagnosis is a strong predictor of ovarian cancer survival, but tumour histotype and grade remain predictors of survival even after adjustment for stage and other factors, contributing further evidence of biological dissimilarity between the ovarian cancer histotypes. Obesity and smoking represent potentially-modifiable determinants of survival, but the stronger association with stage suggests that improving earlier diagnosis would have a greater impact on increasing ovarian cancer survival.

Social isolation and risk of heart disease and stroke: analysis of two large UK prospective studies.

BACKGROUND: Social isolation has been associated with increased risk of coronary heart disease and stroke. However, it is unclear whether the associations differ between fatal and non-fatal events or by the type of isolation (living alone or having few social contacts). We aimed to examine these associations in two large UK prospective cohorts. METHODS: Million Women Study and UK Biobank participants without previous coronary heart disease or stroke who provided data in median year 2010 (IQR 2009-2011) on social contacts were included in this prospective analysis. Participants were followed up to median year 2017 (2017-2017) by electronic linkage to national hospital and death records. Risk ratios (RRs) were calculated using Cox regression for first coronary heart disease and stroke event (overall, and separately for hospital admission as the first event and for death without an associated hospital admission as the first event) by three levels of social isolation (based on living alone, contact with family or friends, and group participation) adjusted for age, sex, study, region, deprivation, smoking, alcohol intake, body-mass index, physical activity, and self-rated health. FINDINGS: 938 558 participants were included in our analyses (mean age 63 years [SD 9]): 481 946 participants from the Million Women Study (mean age 68 years [5]) and 456 612 participants (mean age 57 years [8]) from UK Biobank. During a mean follow-up period of 7 years (2), 42 402 first coronary heart disease events (of which 1834 were fatal without an associated hospital admission) and 19 999 first stroke events (of which 529 were fatal without an associated hospital admission) occurred. Little, if any, association was found between social isolation and hospital admission for a first coronary heart disease or stroke event (combined RR for both studies 1·01 [95% CI 0·98-1·04] for coronary heart disease and 1·13 [1·08-1·18] for stroke, when comparing the most isolated group with the least isolated group). However, the risk of death without an associated hospital admission was substantially higher in the most isolated group than the least isolated group for coronary heart disease (1·86 [1·63-2·12]) and stroke (1·91 [1·48-2·46]). For coronary heart disease or stroke death as the first event, RRs were substantially higher (test for heterogeneity, p=0·002) for participants living alone versus those not living alone (1·60 [1·46-1·75]) than for those with fewer versus more contact with family, friends, or groups (1·27 [1·16-1·38]). These findings did not differ greatly between studies, or by self-rated health. INTERPRETATION: Social isolation seems to have little direct effect on the risk of developing a first coronary heart disease or stroke. By contrast, social isolation substantially increases the risk that the first such event is fatal before reaching hospital, particularly among people who live alone, perhaps because of the absence of immediate help in responding to an acute heart attack or stroke. FUNDING: UK Medical Research Council, Cancer Research UK.

Cognitive and social activities and long-term dementia risk: the prospective UK Million Women Study.

BACKGROUND: Although dementia is associated with non-participation in cognitive and social activities, this association might merely reflect the consequences of dementia, rather than any direct effect of non-participation on the subsequent incidence of dementia. Because of the slowness with which dementia can develop, unbiased assessment of any such direct effects must relate non-participation in such activities to dementia detection rates many years later. Prospective studies with long-term follow-up can help achieve this by analysing separately the first and second decade of follow-up. We report such analyses of a large, 20-year study. METHODS: The UK Million Women Study is a population-based prospective study of 1·3 million women invited for National Health Service (NHS) breast cancer screening in median year 1998 (IQR 1997-1999). In median year 2001 (IQR 2001-2003), women were asked about participation in adult education, groups for art, craft, or music, and voluntary work, and in median year 2006 (IQR 2006-2006), they were asked about reading. All participants were followed up through electronic linkage to NHS records of hospital admission with mention of dementia, the first mention of which was the main outcome. Comparing non-participation with participation in a particular activity, we used Cox regression to assess fully adjusted dementia risk ratios (RRs) during 0-4, 5-9, and 10 or more years, after information on that activity was obtained. FINDINGS: In 2001, 851 307 women with a mean age of 60 years (SD 5) provided information on participation in adult education, groups for art, craft, or music, and voluntary work. After 10 years, only 9591 (1%) had been lost to follow-up and 789 339 (93%) remained alive with no recorded dementia. Follow-up was for a mean of 16 years (SD 3), during which 31 187 (4%) had at least one hospital admission with mention of dementia, including 25 636 (3%) with a hospital admission with dementia mentioned for the first time 10 years or more after follow-up began. Non-participation in cognitive or social activities was associated with higher relative risks of dementia detection only during the first decade after participation was recorded. During the second decade, there was little association. This was true for non-participation in adult education (RR 1·04, 99% CI 0·98-1·09), in groups for art, craft, or music (RR 1·04, 0·99-1·09), in voluntary work (RR 0·96, 0·92-1·00), or in any of these three (RR 0·99, 0·95-1·03). In 2006, 655 118 women provided information on reading. For non-reading versus any reading, there were similar associations with dementia, again with strong attenuation over time since reading was recorded, but longer follow-up is needed to assess this reliably. INTERPRETATION: Life has to be lived forwards, but can be understood only backwards. Long before dementia is diagnosed, there is a progressive reduction in various mental and physical activities, but this is chiefly because its gradual onset causes inactivity and not because inactivity causes dementia. FUNDING: UK Medical Research Council, Cancer Research UK.

Low rate of subsequent surgery and serious complications following intra-articular steroid injection for base of thumb osteoarthritis: national cohort analysis.

OBJECTIVES: Intra-articular steroid injection is commonly used to treat base of thumb osteoarthritis (BTOA), despite a lack of large-scale data on safety and effectiveness. We estimate the incidence of serious complications and further procedures following BTOA injection, including the risk of post-operative serious surgical site infection for subsequent operative intervention. METHODS: Hospital Episode Statistics data linked to mortality records from 1 April 1998 to 31 March 2017 were used to identify all BTOA injections undertaken in adults in the National Health Service secondary care in England. Patients were followed up longitudinally until death or 31 March 2017. A multivariable regression with a Fine and Gray model adjusting for the competing risk of mortality in addition to age, sex and socioeconomic deprivation was used to identify factors associated with progression to further procedure. Secondary outcomes included serious complications after injection and subsequent surgical site infection. RESULTS: A total of 19 120 primary injections were performed during the 19-year period in 18 356 patients. Of these 76.5% were female; mean age 62 years (s.d. 10.6); 50.48% underwent further procedure; 22.40% underwent surgery. Median time to further intervention was 412 days (IQR 110-1945). Female sex was associated with increased risk of proceeding to surgery. Serious complication rate following injection was 0.04% (0.01-0.08) within 90 days. Of those proceeding to surgery 0.16% (0.06-0.34) presented with a wound infection within 30 days and 90 days, compared with an overall post-operative wound infection rate of 0.03% (0.02-0.05). CONCLUSIONS: Very low rates of serious complications were identified following BTOA injections performed in secondary care; only one in five patients proceeded to subsequent surgery. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, https://www.clinicaltrials.gov, NCT03573765.

Chlamydia Testing in New Zealand: Analysis of the 2014/2015 National Health Survey.

BACKGROUND: Diagnosis rates of Chlamydia trachomatis are high in New Zealand; 1.3% of men and 3.7% of women aged 15 to 29 years were diagnosed in 2016. Because testing rates are also higher in women, we sought to understand chlamydia testing by demographic and behavioral characteristics. METHODS: Chlamydia testing in the past year, sexual behavior, and demographic characteristics were reported in the population-based 2014/2015 New Zealand Health Survey. Those aged 16 to 44 years who had a sexual partner in the past year were included. Testing prevalence was calculated, and associations were modeled. RESULTS: A total of 1677 men and 2323 women participated (89% response rate). Of these, 5.6% (95% confidence interval, 4.3%-7.2%) of men and 16.6% (14.7%-18.7%) of women were tested in the past year. Likelihood of testing in men was associated with having multiple partners and any condomless sex (adjusted relative risk, 11.93; 95% confidence interval, 5.70-24.98) and multiple partners with consistent condom use (3.77, 1.40-10.15) compared with one sexual partner and consistent condom use, and with Maori ethnicity (1.87, 1.05-3.31) compared with European/other. Among women, testing was associated with multiple partners with and without condomless sex (3.61 [2.69-4.85] and 2.81 [1.95-4.05], respectively), pregnancy (1.61, 1.18-2.18), and Asian ethnicity (0.52, 0.30-0.89). CONCLUSIONS: The study confirms that New Zealand men are much less likely to be tested than women, a potential reason for ongoing high chlamydia incidence among both sexes. The high testing rate in women includes many at low risk, and this divergence from recommendations is another issue to address.

Serious postoperative complications and reoperation after carpal tunnel decompression surgery in England: a nationwide cohort analysis.

BACKGROUND: Carpal tunnel decompression surgery to treat carpal tunnel syndrome is a common procedure, yet data on safety and effectiveness of the operation in the general population remain scarce. We aimed to estimate the incidence of reoperation and serious postoperative complications (requiring admission to hospital or further surgery) following carpal tunnel decompression in routine clinical practice and to identify the patient factors associated with these adverse outcomes. METHODS: We did a nationwide cohort analysis including all carpal tunnel decompression surgeries in patients aged 18 years or older, done in the National Health Service in England between April 1, 1998, and March 31, 2017, using the Hospital Episode Statistics dataset linked to mortality records. Patients were followed-up until death or until the end of the study (March 31, 2017). Primary outcomes were the overall incidence of carpal tunnel decompression reoperation and serious postoperative complications (surgical site infection or dehiscence, or neurovascular or tendon injury, requiring admission to hospital or further surgery) within 30 days and 90 days after surgery. Multivariable Cox regression analysis was used to identify factors influencing complications and reoperation, and the Fine and Gray method was used to adjust for the competing risk of mortality. This study is registered with ClinicalTrials.gov, NCT03573765. FINDINGS: 855 832 carpal tunnel decompression surgeries were done between April 1, 1998, and March 31, 2017 (incidence rate 1·10 per 1000 person-years [95% CI 1·02-1·17]). 29 288 procedures (3·42%) led to carpal tunnel decompression reoperation (incidence rate 3·18 per 1000 person-years [95% CI 3·12-3·23]). Of the 855 832 initial surgeries, 620 procedures (0·070% [95% CI 0·067-0·078]) led to a serious complication within 30 days after surgery, and 698 procedures (0·082% [0·076-0·088]) within 90 days. Local complications within 90 days after surgery were associated with male sex (adjusted hazard ratio 2·32 [95% CI 1·74-3·09]) and age category 18-29 years (2·25 [1·10-4·62]). Male sex (adjusted subhazard ratio 1·09 [95% CI 1·06-1·13]), old age (>80 years vs 50-59 years: 1·09 [1·03-1·15]), and greater levels of comorbidity (Charlson score ≥5 vs 0: 1·25 [1·19-1·32]) and socioeconomic deprivation (most deprived 10% vs least deprived 10%: 1·18 [1·10-1·27]) were associated with increased reoperation risk. INTERPRETATION: To our knowledge, this is the largest national study on carpal tunnel decompression to date, providing strong evidence on serious postoperative complication and reoperation rates. Carpal tunnel decompression appears to be a safe operation in most patients, with an overall serious complication rate (requiring admission to hospital or further surgery) of less than 0·1%. FUNDING: Versus Arthritis; Medical Research Council; Royal College of Surgeons of England and National Joint Registry research fellowship; University of Oxford; National Institute for Health Research; and National Institute for Health Research Biomedical Research Centre, Oxford.

A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features.

Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients' hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients.

The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate.

Stargardt disease (STGD1) is a form of inherited retinal dystrophy attributed to variants affecting function of the large ABCA4 gene and is arguably the most complex monogenic disease. Therapeutic trials in patients depend on identifying causal ABCA4 variants in trans, which is complicated by extreme allelic and clinical heterogeneity. We report the genetic architecture of STGD1 in the young genetically isolated population of Newfoundland, Canada. Population-based clinical recruitment over several decades yielded 29 STGD1 and STGD1-like families (15 multiplex, 14 singleton). Family interviews and public archival records reveal the vast majority of pedigree founders to be of English extraction. Full gene sequencing and haplotype analysis yielded a high solve rate (38/41 cases; 92.7%) for STGD1 and identified 16 causative STGD1 alleles, including a novel deletion (NM_000350.3: ABCA4 c.67-1delG). Several STGD1 alleles of European origin (including NM_000350.3: ABCA4 c.5714 + 5G>A and NM_000350.3: ABCA4 c.5461-10T>C) have drifted to a relatively high population frequency due to founder effect. We report on retinal disease progression in homozygous patients, providing valuable allele-specific insights. The least involved retinal disease is seen in patients homozygous for c.5714 + 5G>A variant, a so-called "mild" variant which is sufficient to precipitate a STGD1 phenotype in the absence of other pathogenic variants in the coding region and intron/exon boundaries of ABCA4. The most severe retinal disease is observed in cases with ABCA4 c.[5461-10T>C;5603A>T] complex allele. We discuss the advantages of determining genetic architecture in genetic isolates in order to begin to meet the grand challenge of human genetics.