Transancestral mapping and genetic load in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (B50% of these regions have multiple independent associations); these include 24 novel SLE regions (Po5 10 8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SL

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

Exploring the development of an appropriate women's health service for Mt Isa City: report to the Queensland Nursing Council Research Committee

This project explored the appropriateness of women's health services in Mt Isa city. The intention was to assess the current provision of health services to women and identify any areas in which these could be strengthened. For this purpose, information was gathered from general practitioners, nurses, health workers, community agencies and women consumers from ethnic and indigenous backgrounds. Where gaps in service provision were identified, the project team involved both health providers and women within the community to collaboratively develop recommendations for women's health care services that would be more appropriate to the community's diverse needs. Health professionals from Townsville, Cairns and Mt Isa formed the project team. Several novice researchers in the team benefited from mentoring during this research experience. Using a participatory action approach, data were collected using both interviews and focus groups. Findings were disseminated to participants and recommendations developed collaboratively. The population of this remote mining centre includes a large Aboriginal community along with migrants from 32 countries. Women in rural and remote areas have been identified as having a poorer health status than those in metropolitan districts. Well documented contributing factors include geographic and social isolation, distance from specialised health services, lower socio-economic status, lack of continuity of care and concerns about confidentiality. In addition, Mt Isa city has a significant number of women for whom language barriers and cultural beliefs require special consideration. Anecdotal evidence from local women had suggested that the well women's services in Mt Isa were not meeting their gender and cultural requirements. Health providers within the community supported the need for a woman-centred health service, suggesting that this would increase the number of women accessing screening and well women's services. However, while these assumptions were not well supported in the findings of this study, a number of issues about the appropriateness of services that were of concern to women in Mt Isa did emerge. The study revealed that Mt Isa had a range of services available where women from different socio-economic and cultural backgrounds could access Pap smears, breast examination, sexual health and contraceptive services. The main health concerns facing women in Mt Isa city were related to the following areas: • Lack of adequate information. Many women were not aware of the extent and diversity of services available and neither were the health providers and community agencies. Readily accessible information on available services that was timely and in a language minority groups could understand was required. Hard copy and oral information dissemination through informal networks were identified as being most effective. • Mental health issues were a major concern for women. Specific mental health issues identified by women include the need for relationship counselling, management of alcohol and substance abuse, depression, gambling, suicide, and domestic violence. These problems exist in a community already challenged by issues of social and cultural diversity, lack of social support, geographic isolation and unemployment. Because of their pivotal role within the family, women highlighted how any problems affecting their families created an emotional burden that impacted on their well being. In addition, concerns were raised about the appropriateness of available mental health services in the city. • Continuity of care. The transience of health providers led to gaps in services by general practitioners, obstetricians, nurses and health workers. Attempts were made to remediate this through role sharing, however recruitment and retention of appropriately qualified staff was an ongoing problem. This resulted in significant changes in health services between initial data collection and final consultation within the community with both the number of doctors, nurses and, in particular, female health practitioners notably decreasing. • Particular areas of need identified were related to breast cancer screening and support, access to appropriate services for young teens and migrant women, and the need for transport to and from clinics. It is evident from this study that further research can be undertaken into strategies to improve information dissemination, explore ways to improve access to appropriate health services for young teens and migrant women from non-English speaking backgrounds. Further investigation into participants' perceptions of gaps in the available mental health services is also required

Exploring the development of an appropriate women's health service for Mt Isa City: report to the Queensland Nursing Council Research Committee

This project explored the appropriateness of women's health services in Mt Isa city. The intention was to assess the current provision of health services to women and identify any areas in which these could be strengthened. For this purpose, information was gathered from general practitioners, nurses, health workers, community agencies and women consumers from ethnic and indigenous backgrounds. Where gaps in service provision were identified, the project team involved both health providers and women within the community to collaboratively develop recommendations for women's health care services that would be more appropriate to the community's diverse needs. Health professionals from Townsville, Cairns and Mt Isa formed the project team. Several novice researchers in the team benefited from mentoring during this research experience. Using a participatory action approach, data were collected using both interviews and focus groups. Findings were disseminated to participants and recommendations developed collaboratively. The population of this remote mining centre includes a large Aboriginal community along with migrants from 32 countries. Women in rural and remote areas have been identified as having a poorer health status than those in metropolitan districts. Well documented contributing factors include geographic and social isolation, distance from specialised health services, lower socio-economic status, lack of continuity of care and concerns about confidentiality. In addition, Mt Isa city has a significant number of women for whom language barriers and cultural beliefs require special consideration. Anecdotal evidence from local women had suggested that the well women's services in Mt Isa were not meeting their gender and cultural requirements. Health providers within the community supported the need for a woman-centred health service, suggesting that this would increase the number of women accessing screening and well women's services. However, while these assumptions were not well supported in the findings of this study, a number of issues about the appropriateness of services that were of concern to women in Mt Isa did emerge. The study revealed that Mt Isa had a range of services available where women from different socio-economic and cultural backgrounds could access Pap smears, breast examination, sexual health and contraceptive services. The main health concerns facing women in Mt Isa city were related to the following areas: • Lack of adequate information. Many women were not aware of the extent and diversity of services available and neither were the health providers and community agencies. Readily accessible information on available services that was timely and in a language minority groups could understand was required. Hard copy and oral information dissemination through informal networks were identified as being most effective. • Mental health issues were a major concern for women. Specific mental health issues identified by women include the need for relationship counselling, management of alcohol and substance abuse, depression, gambling, suicide, and domestic violence. These problems exist in a community already challenged by issues of social and cultural diversity, lack of social support, geographic isolation and unemployment. Because of their pivotal role within the family, women highlighted how any problems affecting their families created an emotional burden that impacted on their well being. In addition, concerns were raised about the appropriateness of available mental health services in the city. • Continuity of care. The transience of health providers led to gaps in services by general practitioners, obstetricians, nurses and health workers. Attempts were made to remediate this through role sharing, however recruitment and retention of appropriately qualified staff was an ongoing problem. This resulted in significant changes in health services between initial data collection and final consultation within the community with both the number of doctors, nurses and, in particular, female health practitioners notably decreasing. • Particular areas of need identified were related to breast cancer screening and support, access to appropriate services for young teens and migrant women, and the need for transport to and from clinics. It is evident from this study that further research can be undertaken into strategies to improve information dissemination, explore ways to improve access to appropriate health services for young teens and migrant women from non-English speaking backgrounds. Further investigation into participants' perceptions of gaps in the available mental health services is also required

OpenSAFELY: The impact of COVID-19 on azathioprine, leflunomide and methotrexate monitoring, and factors associated with change in monitoring rate.

AIMS: The COVID-19 pandemic created unprecedented pressure on healthcare services. This study investigates whether disease-modifying antirheumatic drug (DMARD) safety monitoring was affected during the COVID-19 pandemic. METHODS: A population-based cohort study was conducted using the OpenSAFELY platform to access electronic health record data from 24.2 million patients registered at general practices using TPP's SystmOne software. Patients were included for further analysis if prescribed azathioprine, leflunomide or methotrexate between November 2019 and July 2022. Outcomes were assessed as monthly trends and variation between various sociodemographic and clinical groups for adherence with standard safety monitoring recommendations. RESULTS: An acute increase in the rate of missed monitoring occurred across the study population (+12.4 percentage points) when lockdown measures were implemented in March 2020. This increase was more pronounced for some patient groups (70-79 year-olds: +13.7 percentage points; females: +12.8 percentage points), regions (North West: +17.0 percentage points), medications (leflunomide: +20.7 percentage points) and monitoring tests (blood pressure: +24.5 percentage points). Missed monitoring rates decreased substantially for all groups by July 2022. Consistent differences were observed in overall missed monitoring rates between several groups throughout the study. CONCLUSION: DMARD monitoring rates temporarily deteriorated during the COVID-19 pandemic. Deterioration coincided with the onset of lockdown measures, with monitoring rates recovering rapidly as lockdown measures were eased. Differences observed in monitoring rates between medications, tests, regions and patient groups highlight opportunities to tackle potential inequalities in the provision or uptake of monitoring services. Further research should evaluate the causes of the differences identified between groups

Enhanced activation of interleukin-10, heme oxygenase-1, and AKT in C5aR2-deficient mice is associated with protection from ischemia reperfusion injury–induced inflammation and fibrosis

Nephrolog