Critical reasoning on the co-expression module QTL in the dorsolateral prefrontal cortex.

Expression quantitative trait locus (eQTL) analysis is a popular method of gaining insight into the function of regulatory variation. While cis-eQTL resources have been instrumental in linking GWAS variants to gene function, complex trait heritability may be additionally mediated by other forms of gene regulation. Towards this end, novel eQTL methods leverage gene co-expression (module-QTL) to investigate joint regulation of gene modules by single genetic variants. Here we broadly define a "module-QTL" as the association of a genetic variant with a summary measure of gene co-expression. This approach aims to reduce the multiple testing burden of a trans-eQTL search through the consolidation of gene-based testing, and provide biological context to eQTLs shared between genes. In this article we provide an in-depth examination of the co-expression module eQTL (module-QTL) through literature review, theoretical investigation, and real-data application of the module-QTL to three large prefrontal cortex genotype-RNA seq datasets. We find module-QTLs in our study that are disease-associated and reproducible are not additionally informative beyond cis- or trans-eQTLs for module genes. Through comparison to prior studies, we highlight promises and limitations of the module-QTL across study designs, and provide recommendations for further investigation of the module-QTL framework.

The development and internal pilot trial of a digital physical activity and emotional well-being intervention (Kidney BEAM) for people with chronic kidney disease.

This trial assessed the feasibility and acceptability of Kidney BEAM, a physical activity and emotional well-being self-management digital health intervention (DHI) for people with chronic kidney disease (CKD), which offers live and on-demand physical activity sessions, educational blogs and videos, and peer support. In this mixed-methods, multicentre randomised waitlist-controlled internal pilot, adults with established CKD were recruited from five NHS hospitals and randomised 1:1 to Kidney BEAM or waitlist control. Feasibility outcomes were based upon a priori progression criteria. Acceptability was primarily explored via individual semi-structured interviews (n = 15). Of 763 individuals screened, n = 519 (68%, 95% CI 65 to 71%) were eligible. Of those eligible, n = 303 (58%, 95% CI 54-63%) did not respond to an invitation to participate by the end of the pilot period. Of the 216 responders, 50 (23%, 95% CI 18-29%) consented. Of the 42 randomised, n = 22 (10 (45%) male; 49 ± 16 years; 14 (64%) White British) were allocated to Kidney BEAM and n = 20 (12 (55%) male; 56 ± 11 years; 15 (68%) White British) to the waitlist control group. Overall, n = 15 (30%, 95% CI 18-45%) withdrew during the pilot phase. Participants completed a median of 14 (IQR 5-21) sessions. At baseline, 90-100% of outcome data (patient reported outcome measures and a remotely conducted physical function test) were completed and 62-83% completed at 12 weeks follow-up. Interview data revealed that remote trial procedures were acceptable. Participants' reported that Kidney BEAM increased their opportunity and motivation to be physically active, however, lack of time remained an ongoing barrier to engagement with the DHI. An randomised controlled trial of Kidney BEAM is feasible and acceptable, with adaptations to increase recruitment, retention and engagement.Trial registration NCT04872933. Date of first registration 05/05/2021.

Evaluating the effect of a digital health intervention to enhance physical activity in people with chronic kidney disease (Kidney BEAM): a multicentre, randomised controlled trial in the UK.

BACKGROUND: Remote digital health interventions to enhance physical activity provide a potential solution to improve the sedentary behaviour, physical inactivity, and poor health-related quality of life that are typical of chronic conditions, particularly for people with chronic kidney disease. However, there is a need for high-quality evidence to support implementation in clinical practice. The Kidney BEAM trial evaluated the clinical effect of a 12-week physical activity digital health intervention on health-related quality of life. METHODS: In a single-blind, randomised controlled trial conducted at 11 centres in the UK, adult participants (aged ≥18 years) with chronic kidney disease were recruited and randomly assigned (1:1) to the Kidney BEAM physical activity digital health intervention or a waiting list control group. Randomisation was performed with a web-based system, in randomly permuted blocks of six. Outcome assessors were masked to treatment allocation. The primary outcome was the difference in the Kidney Disease Quality of Life Short Form version 1.3 Mental Component Summary (KDQoL-SF1.3 MCS) between baseline and 12 weeks. The trial was powered to detect a clinically meaningful difference of 3 arbitrary units (AU) in KDQoL-SF1.3 MCS. Outcomes were analysed by an intention-to-treat approach using an analysis of covariance model, with baseline measures and age as covariates. The trial was registered with ClinicalTrials.gov, NCT04872933. FINDINGS: Between May 6, 2021, and Oct 30, 2022, 1102 individuals were assessed for eligibility, of whom 340 participants were enrolled and randomly assigned to the Kidney BEAM intervention group (n=173) or the waiting list control group (n=167). 268 participants completed the trial (112 in the Kidney BEAM group and 156 in the waiting list control group). All 340 randomly assigned participants were included in the intention-to treat population. At 12 weeks, there was a significant improvement in KDQoL-SF.13 MCS score in the Kidney BEAM group (from mean 44·6 AU [SD 10·8] at baseline to 47·0 AU [10·6] at 12 weeks) compared with the waiting list control group (from 46·1 AU [10·5] to 45·0 AU [10·1]; between-group difference of 3·1 AU [95% CI 1·8-4·4]; p<0·0001). INTERPRETATION: The Kidney BEAM physical activity platform is an efficacious digital health intervention to improve mental health-related quality of life in patients with chronic kidney disease. These findings could facilitate the incorporation of remote digital health interventions into clinical practice and offer a potential intervention worthy of investigation in other chronic conditions. FUNDING: Kidney Research UK.

The Womb Cancer Awareness Measure (WCAM): development of an instrument to assess public awareness of endometrial cancer.

OBJECTIVE: To develop and test a novel instrument to assess public awareness of endometrial cancer symptoms and risk factors in a UK population. METHODS: A 36-item questionnaire was developed through literature review and extraction from cancer awareness materials. The Womb Cancer Awareness Measure (WCAM) was tested for content validity in 65 self-identified female research participants and 10 endometrial cancer experts prior to UK-wide field testing using social media. Test-retest reliability was assessed over 2 weeks, construct validity was assessed by comparing womb cancer experts and non-medical academics, and sensitivity to change was assessed by comparing scores of participants who read an endometrial cancer leaflet with those given a control leaflet. RESULTS: Fifty-two percent of the items in the test-retest reliability showed >80% agreement. Construct validity was demonstrated; endometrial cancer experts achieved higher scores (median 79 (IQR 18)) than non-medical academics (median 50 (IQR 18)) (p<0.001). The WCAM was sensitive to change; volunteers who read an endometrial cancer leaflet showed greater awareness (median 73 (IQR 9)) than those who read the control leaflet (median 59 (IQR 9)) (p<0.001). Knowledge of endometrial cancer red flag symptoms and risk factors was poor in the 847 UK-based participants. CONCLUSIONS: Our findings support the validity and reliability of the Womb Cancer Awareness Measure in assessing public awareness of endometrial cancer. In a UK population sample, knowledge of warning symptoms and risk factors was low, highlighting the need for public awareness campaigns.

Achieving consensus on psychosocial and physical rehabilitation management for people living with kidney disease.

Background: People living with chronic kidney disease (CKD) need to be able to live well with their condition. The provision of psychosocial interventions (psychological, psychiatric and social care) and physical rehabilitation management is variable across England, as well as the rest of the UK. There is a need for clear recommendations for standards of psychosocial and physical rehabilitation care for people living with CKD, and guidance for the commissioning and measurement of these services. The National Health Service (NHS) England Renal Services Transformation Programme (RSTP) supported a programme of work and modified Delphi process to address the management of psychosocial and physical rehabilitation care as part of a larger body of work to formulate a comprehensive commissioning toolkit for renal care services across England. We sought to achieve expert consensus regarding the psychosocial and physical rehabilitation management of people living with CKD in England and the rest of the UK. Methods: A Delphi consensus method was used to gather and refine expert opinions of senior members of the kidney multi-disciplinary team (MDT) and other key stakeholders in the UK. An agreement was sought on 16 statements reflecting aspects of psychosocial and physical rehabilitation management for people living with CKD. Results: Twenty-six expert practitioners and other key stakeholders, including lived experience representatives, participated in the process. The consensus (>80% affirmative votes) amongst the respondents for all 16 statements was high. Nine recommendation statements were discussed and refined further to be included in the final iteration of the 'Systems' section of the NHS England RSTP commissioning toolkit. These priority recommendations reflect pragmatic solutions that can be implemented in renal care and include recommendations for a holistic wellbeing assessment for all people living with CKD who are approaching dialysis, or who are at listing for kidney transplantation, which includes the use of validated measurement tools to assess the need for further intervention in psychosocial and physical rehabilitation management. It is recommended that the scores from these measurement tools be included in the NHS England Renal Data Dashboard. There was also a recommendation for referral as appropriate to NHS Talking Therapies, psychology, counselling or psychotherapy, social work or liaison psychiatry for those with identified psychosocial needs. The use of digital resources was recommended to be used in addition to face-to-face care to provide physical rehabilitation, and all healthcare professionals should be educated to recognize psychosocial and physical rehabilitation needs and refer/sign-post people with CKD to appropriate services. Conclusion: There was high consensus amongst senior members of the kidney MDT and other key stakeholders, including those with lived experience, in the UK on all aspects of the psychosocial and physical rehabilitation management of people living with CKD. The results of this process will be used by NHS England to inform the 'Systems' section of the commissioning toolkit and data dashboard and to inform the National Standards of Care for people living with CKD.

Rapid Evolution of Glycan Recognition Receptors Reveals an Axis of Host-Microbe Arms Races beyond Canonical Protein-Protein Interfaces.

Detection of microbial pathogens is a primary function of many mammalian immune proteins. This is accomplished through the recognition of diverse microbial-produced macromolecules including proteins, nucleic acids, and carbohydrates. Pathogens subvert host defenses by rapidly changing these structures to avoid detection, placing strong selective pressures on host immune proteins that repeatedly adapt to remain effective. Signatures of rapid evolution have been identified in numerous immunity proteins involved in the detection of pathogenic protein substrates, but whether similar signals can be observed in host proteins engaged in interactions with other types of pathogen-derived molecules has received less attention. This focus on protein-protein interfaces has largely obscured the study of fungi as contributors to host-pathogen conflicts, despite their importance as a formidable class of vertebrate pathogens. Here, we provide evidence that mammalian immune receptors involved in the detection of microbial glycans have been subject to recurrent positive selection. We find that rapidly evolving sites in these genes cluster in key functional domains involved in carbohydrate recognition. Further, we identify convergent patterns of substitution and evidence for balancing selection in one particular gene, MelLec, which plays a critical role in controlling invasive fungal disease. Our results also highlight the power of evolutionary analyses to reveal uncharacterized interfaces of host-pathogen conflict by identifying genes, like CLEC12A, with strong signals of positive selection across mammalian lineages. These results suggest that the realm of interfaces shaped by host-microbe conflicts extends beyond the world of host-viral protein-protein interactions and into the world of microbial glycans and fungi.

The effect of a novel, digital physical activity and emotional well-being intervention on health-related quality of life in people with chronic kidney disease: trial design and baseline data from a multicentre prospective, wait-list randomised controlled trial (kidney BEAM).

BACKGROUND: Physical activity and emotional self-management has the potential to enhance health-related quality of life (HRQoL), but few people with chronic kidney disease (CKD) have access to resources and support. The Kidney BEAM trial aims to evaluate whether an evidence-based physical activity and emotional wellbeing self-management programme (Kidney BEAM) leads to improvements in HRQoL in people with CKD. METHODS: This was a prospective, multicentre, randomised waitlist-controlled trial, with health economic analysis and nested qualitative studies. In total, three hundred and four adults with established CKD were recruited from 11 UK kidney units. Participants were randomly assigned to the intervention (Kidney BEAM) or a wait list control group (1:1). The primary outcome was the between-group difference in Kidney Disease Quality of Life (KDQoL) mental component summary score (MCS) at 12 weeks. Secondary outcomes included the KDQoL physical component summary score, kidney-specific scores, fatigue, life participation, depression and anxiety, physical function, clinical chemistry, healthcare utilisation and harms. All outcomes were measured at baseline and 12 weeks, with long-term HRQoL and adherence also collected at six months follow-up. A nested qualitative study explored experience and impact of using Kidney BEAM. RESULTS: 340 participants were randomised to Kidney BEAM (n = 173) and waiting list (n = 167) groups. There were 96 (55%) and 89 (53%) males in the intervention and waiting list groups respectively, and the mean (SD) age was 53 (14) years in both groups. Ethnicity, body mass, CKD stage, and history of diabetes and hypertension were comparable across groups. The mean (SD) of the MCS was similar in both groups, 44.7 (10.8) and 45.9 (10.6) in the intervention and waiting list groups respectively. CONCLUSION: Results from this trial will establish whether the Kidney BEAM self management programme is a cost-effective method of enhancing mental and physical wellbeing of people with CKD. TRIAL REGISTRATION: NCT04872933. Registered 5th May 2021.

The measurement of college athletes' knowledge and behavior on pre- and post-workout nutrition utilizing a text message intervention.

Objective: The purpose of this study was to measure college student athletes' nutrition knowledge and behavior before and after a text message-based educational intervention. Participants: Athletes (n = 35) participated by completing a pre- and post-intervention survey. Methods: This survey gathered information on ability to identify carbohydrate and protein food sources, pre-and post-workout intake, and behavior. Text messages were sent during the 4-week intervention and included information regarding the importance of carbohydrate consumption before training, and a carbohydrate-protein mixture for recovery. Results: Dependent t-tests revealed a lack of statistically significant increases in total knowledge (p = 0.156) or behavior (p = 0.177), but an increase in the behavior questions regarding efficacy of carbohydrate before training (p = 0.026) and carbohydrate and protein after training (p = 0.016). Conclusion: This suggests the text message educational intervention did influence behavioral outcomes. Future research should focus on the effectiveness, length, and frequency of the text message intervention, and investigate the athletes' willingness to change dietary behaviors.

Individual frailty phenotype components and mortality in adults with type 2 diabetes: A UK Biobank study.

AIMS: This study aimed to explore associations between frailty components and mortality and rank prognostic relevance of each frailty component in predicting mortality in adults with and without type 2 diabetes (T2D). METHODS: We used data from the UK Biobank. Associations and prognostic discrimination of individual Fried's frailty components and the overall frailty status with all-cause and cardiovascular (CVD) mortality were investigated using Cox proportional-hazard models and C-index in adults with and without T2D. RESULTS: In both populations the strongest association with all-cause mortality across all frailty components and overall frailty status was observed for slow walking pace (without T2D Hazard Ratio [HR] 2.25, 95 %CI: 2.12-2.38 and with T2D HR 1.95, 95 %CI: 1.67-2.28). Similarly, slow walking pace was associated with a greater risk of CVD mortality. The combination of T2D and slow walking pace had the strongest association with all-cause and CVD mortality, compared to the combination of T2D and other frailty components or overall frailty status. Slow walking pace also provided the greatest prognostic discrimination. CONCLUSION: Slow walking pace has a stronger predictive factor for all-cause and CVD mortality compared to other frailty components and overall frailty status, especially when simultaneously present with T2D.

Common genetic variation impacts stress response in the brain.

To explain why individuals exposed to identical stressors experience divergent clinical outcomes, we determine how molecular encoding of stress modifies genetic risk for brain disorders. Analysis of post-mortem brain (n=304) revealed 8557 stress-interactive expression quantitative trait loci (eQTLs) that dysregulate expression of 915 eGenes in response to stress, and lie in stress-related transcription factor binding sites. Response to stress is robust across experimental paradigms: up to 50% of stress-interactive eGenes validate in glucocorticoid treated hiPSC-derived neurons (n=39 donors). Stress-interactive eGenes show brain region- and cell type-specificity, and, in post-mortem brain, implicate glial and endothelial mechanisms. Stress dysregulates long-term expression of disorder risk genes in a genotype-dependent manner; stress-interactive transcriptomic imputation uncovered 139 novel genes conferring brain disorder risk only in the context of traumatic stress. Molecular stress-encoding explains individualized responses to traumatic stress; incorporating trauma into genomic studies of brain disorders is likely to improve diagnosis, prognosis, and drug discovery.

Outcomes and care priorities for older people living with frailty and advanced chronic kidney disease: a multi-professional scoping review.

The growing older population with advanced chronic kidney disease (ACKD stages 4-5) poses a challenge for healthcare worldwide. The high prevalence of frailty and associated adverse health outcomes highlights concerns for management and interventions specific to this population. The aim was to objectively review the evidence relating to older people (≥65 years) living with frailty and ACKD. More specifically how frailty is identified, what interventions have been studied and what outcomes have been reported including outcomes important to patients, families and carers. A scoping review was undertaken following the PRISMA-Scr guidelines. Nine databases were searched and a review team of five people followed a process using defined inclusion and exclusion criteria. Data were then analysed to answer the specific questions of the review. The World Health Organization's International Classification of Functioning Disability and Health was used to map outcomes across the domains. A total of 90 studies were included. The most reported frailty measure was the frailty phenotype. The most reported outcomes were mortality, hospitalisation and healthcare utilisation. Health-related quality of life was the most common patient-reported outcome measure. There were few intervention studies and limited evidence of patient and carer perspectives. This scoping review highlights important areas for further research in older people living with frailty and ACKD. This includes a 'gold standard' measure for identifying frailty, interventions and improvements in outcome measures that matter to patients (including studies that focus on carers and carer burden) and priority setting for future research.

The Codevelopment of "My Kidneys & Me": A Digital Self-management Program for People With Chronic Kidney Disease.

BACKGROUND: Health care self-management is important for people living with nondialysis chronic kidney disease (CKD). However, the few available resources are of variable quality. OBJECTIVE: This work describes the systematic codevelopment of "My Kidneys & Me" (MK&M), a theory-driven and evidence-based digital self-management resource for people with nondialysis CKD, guided by an established process used for the successful development of the diabetes education program MyDESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed, DESMOND). METHODS: A multidisciplinary steering group comprising kidney health care professionals and researchers and specialists in the development of complex interventions and digital health provided expertise in the clinical and psychosocial aspects of CKD, self-management, digital health, and behavior change. A patient and public involvement group helped identify the needs and priorities of MK&M and co-design the resource. MK&M was developed in 2 sequential phases. Phase 1 involved the codevelopment process of the MK&M resource (content and materials), using Intervention Mapping (IM) as a framework. The first 4 IM steps guided the development process: needs assessment was conducted to describe the context of the intervention; intervention outcomes, performance objectives, and behavioral determinants were identified; theory- and evidence-based change methods and practical strategies to deliver change methods were selected; and program components were developed and refined. Phase 2 involved the adoption and adaptation of the existing MyDESMOND digital platform to suit the MK&M resource. RESULTS: The needs assessment identified that individuals with CKD have multiple differing needs and that delivering a self-management program digitally would enable accessible, tailored, and interactive information and support. The intended outcomes of MK&M were to improve and maintain effective self-management behaviors, including physical activity and lifestyle, improve knowledge, promote self-care skills, increase self-efficacy, and enhance well-being. This was achieved through the provision of content and materials designed to increase CKD knowledge and patient activation, reduce health risks, manage symptoms, and improve physical function. Theories and behavior change techniques selected include Self-Management Framework, Capability, Opportunity, Motivation Behavior model components of Behaviour Change Wheel and taxonomy of behavior change techniques, Health Action Process Approach Model, Common Sense Model, and Social Cognitive Theory. The program components developed comprised educational and behavior change sessions, health trackers (eg, monitoring blood pressure, symptoms, and exercise), goal-setting features, and forums for social support. The MyDESMOND digital platform represented an ideal existing platform to host MK&M; thus, the MyDESMOND interface and features were adopted and adapted for MK&M. CONCLUSIONS: Applying the IM framework enabled the systematic application of theory, empirical evidence, and practical perspectives in the codevelopment of MK&M content and materials. Adopting and adapting a preexisting platform provided a cost- and time-efficient approach for developing our digital intervention. In the next stage of work, the efficacy of MK&M in increasing patient activation will be tested in a randomized controlled trial.

Primary care provider-led cancer survivorship care in the first 5 years following initial cancer treatment: a scoping review of the barriers and solutions to implementation.

PURPOSE: To synthesize the barriers to primary care provider (PCP)-led cancer survivorship care (≤ 5 years after initial cancer treatment) experienced by healthcare systems around the world, and to explore potential solutions that would succeed within a developed country. METHODS: A scoping review of peer-reviewed articles and grey literature was conducted. Four electronic databases (Medline, Embase, Web of Science Core Collection, and Google Scholar) were searched for articles prior to April 2021. RESULTS: Ninety-seven articles published across the globe (USA, Canada, Australia, European Union, and UK) met the review inclusion/exclusion criteria. The four most frequently discussed barriers to PCP-led survivorship care in healthcare systems were as follows: (1) insufficient communication between PCPs and cancer specialists, (2) limited PCP knowledge, (3) time restrictions for PCPs to provide comprehensive survivorship care, and (4) a lack of resources (e.g., survivorship care guidelines). Potential solutions to combat these barriers were as follows: (1) improving interdisciplinary communication, (2) bolstering PCP education, and (3) providing survivorship resources. CONCLUSIONS: This scoping review identified and summarized key barriers and solutions to the provision of PCP-led cancer survivorship care. Importantly, the findings from this review provide insight and direction to guide optimization of cancer care practice within BC's healthcare system. IMPLICATIONS FOR CANCER SURVIVORS: Optimizing the PCP-led survivorship care model will be a valuable contribution to the field of cancer survivorship care and will hopefully lead to more widespread use of this model, ultimately lessening the growing demand for cancer-specific care by cancer specialists.

Living with frailty and haemodialysis: a qualitative study.

BACKGROUND: Frailty is highly prevalent in people receiving haemodialysis (HD) and is associated with poor outcomes. Understanding the lived experiences of this group is essential to inform holistic care delivery. METHODS: Semi-structured interviews with N = 25 prevalent adults receiving HD from 3 HD units in the UK. Eligibility criteria included a Clinical Frailty Scale (CFS) score of 4-7 and a history of at least one fall in the last 6 months. Sampling began guided by maximum variation sampling to ensure diversity in frailty status; subsequently theoretical sampling enabled exploration of preliminary themes. Analysis was informed by constructivist grounded theory; later we drew upon the socioecological model. RESULTS: Participants had a mean age of 69 ± 10 years, 13 were female, and 13 were White British. 14 participants were vulnerable or mildly frail (CFS 4-5), and 11 moderately or severely frail (CFS 6-7). Participants characterised frailty as weight loss, weakness, exhaustion, pain and sleep disturbance arising from multiple long-term conditions. Participants' accounts revealed: the consequences of frailty (variable function and psychological ill-health at the individual level; increasing reliance upon family at the interpersonal level; burdensome health and social care interactions at the organisational level; reduced participation at the community level; challenges with financial support at the societal level); coping strategies (avoidance, vigilance, and resignation); and unmet needs (overprotection from family and healthcare professionals, transactional health and social care exchanges). CONCLUSIONS: The implementation of a holistic needs assessment, person-centred health and social care systems, greater family support and enhancing opportunities for community participation may all improve outcomes and experience. An approach which encompasses all these strategies, together with wider public health interventions, may have a greater sustained impact. TRIAL REGISTRATION: ISRCTN12840463 .

Associations between frailty trajectories and cardiovascular, renal, and mortality outcomes in chronic kidney disease.

BACKGROUND: Frailty is characterized by the loss of biological reserves and vulnerability to adverse outcomes. In individuals with chronic kidney disease (CKD), numerous pathophysiological factors may be responsible for frailty development including inflammation, physical inactivity, reduced energy intake, and metabolic acidosis. Given that both CKD and frailty incur a significant healthcare burden, it is important to understand the relationship of CKD and frailty in real-world routine clinical practice, and how simple frailty assessment methods (e.g. frailty indexes) may be useful. We investigated the risk of frailty development in CKD and the impact of frailty status on mortality and end-stage kidney disease (ESKD). METHODS: A retrospective cohort study using primary care records from the Clinical Practice Research Datalink linked to Hospital Episode Statistics and the UK Office for National Statistics was undertaken in 819 893 participants aged ≥40 years, of which 140 674 had CKD. Frailty was defined using an electronic frailty index, generated electronically from primary care records. Cox proportional hazard and flexible parametric survival models were used to investigate the risk of developing frailty and the effect of frailty on risk of all-cause and cardiovascular mortality, and ESKD. RESULTS: The mean age of those with CKD was 77.5 (SD 9.7) years [61.0 (SD 12.1) years in no-CKD group]; 62.0% of the CKD group were female (compared with 53.3% in no-CKD group). The mean estimated glomerular filtration rate of those with CKD was 46.1 (SD 9.9) mL/min/1.73 m2 . The majority of those with CKD (75.3%) were frail [vs. 45.4% in those without CKD (no-CKD)]. Over 3 years (median), 69.5% of those with CKD developed frailty. Compared with no-CKD, those with CKD had increased rates of developing mild (hazard ratio: 1.02; 95% confidence interval: 1.01-1.04), moderate (1.30; 1.26-1.34), and severe (1.50; 1.37-1.65) frailty. Mild (1.22; 1.19-1.24), moderate (1.60; 1.56-1.63), and severe (2.16; 2.11-2.22) frailty was associated with increased rates of all-cause and cardiovascular-related mortality (mild 1.35; 1.31-1.39; moderate 1.96; 1.90-2.02; and severe 2.91; 2.81-3.02). All stages of frailty significantly increased ESKD rates. CONCLUSIONS: Frailty is highly prevalent and associated with adverse outcomes in people with CKD, including mortality and risk of ESKD. Preventative interventions should be initiated to mitigate the development of frailty. The use of a simple frailty index, generated electronically from health records, can predict outcomes and may aid prioritization for management of people with frailty.

Risk of deaths due to injuries in travellers: a systematic review.

BACKGROUND: Annual global travel reached an all-time high of 1.4 billion international tourist visits in 2019. It is estimated that injury accounts for close to 25% of deaths in travellers, most of which are theoretically preventable. However, there are limited data available on injury occurrence and outcomes in travellers. Our objective was to better understand the relative risk of dying from injury that arises from the novel environments and behavioural changes associated with foreign travel. METHODS: A systematic literature review was conducted (PubMed, Embase and Scopus) according to PRISMA guidelines that included studies published in English since 1990 that reported injury deaths in tourists per 100 000-person years or as a proportion of total tourist deaths in comparison to a non-traveller population. We also included studies that reported data allowing calculation of these rates. Relative rates or proportions of overall injury mortality, mortality due to traffic accidents, drowning and homicide were summarized. RESULTS: In total, 1847 articles were identified, 105 underwent full-text review, and 10 articles were suitable for data extraction. There was great variability of relative risk reported, but overall, travellers appear to have a higher risk of injury mortality than domestic populations, with relative rates of injury death ranging from 1.04 to 16.7 and proportionate mortality ratios ranging from 1.43 to 3. CONCLUSIONS: Tourists should be aware of the increased risk of dying from road traffic hazards, drowning and homicide while traveling abroad. Specific geographies and activities associated with higher risk should be emphasized. Travel medicine practitioners and organizations that send people abroad should counsel travellers regarding these risks and seek ways to reduce them, including encouraging potential risk-mitigating behaviours. There is a need to improve systems of data collection and reporting on injury deaths in travellers and to study the impact of pre-travel and institutional interventions aimed at reducing this risk.

Measuring quality of life in trials including patients on haemodialysis: methodological issues surrounding the use of the Kidney Disease Quality of Life Questionnaire.

BACKGROUND: Haemodialysis (HD) treatment causes a significant decrease in quality of life (QoL). When enrolled in a clinical trial, some patients are lost prior to follow-up because they die or they receive a kidney transplant. It is unclear how these patients are dealt with in the analysis of QoL data. There are questions surrounding the consistency of how QoL measures are used, reported and analysed. METHODS: A systematic search of electronic databases for trials measuring QoL in HD patients using any variation of the Kidney Disease Quality of Life (KDQoL) Questionnaire was conducted. The review was conducted in Covidence version 2. Quantitative analysis was conducted in Stata version 16. RESULTS: We included 61 trials in the review, of which 82% reported dropouts. The methods to account for missing data due to dropouts include imputation (7%) and complete case analysis (72%). Few trials (7%) conducted a sensitivity analysis to assess the impact of missing data on the study results. Single imputation techniques were used, but are only valid under strong assumptions regarding the type and pattern of missingness. There was inconsistency in the reporting of the KDQoL, with many articles (70%) amending the validated questionnaires or reporting only statistically significant results. CONCLUSIONS: Missing data are not dealt with according to the missing data mechanism, which may lead to biased results. Inconsistency in the use of patient-reported outcome measures raises questions about the validity of these trials. Methodological issues in nephrology trials could be a contributing factor to why there are limited effective interventions to improve QoL in this patient group. PROSPERO REGISTRATION: CRD42020223869.

Physical activity and sedentary behaviour interventions for people living with both frailty and multiple long-term conditions: a scoping review protocol.

INTRODUCTION: The number of people living with multiple long-term conditions (MLTCs) is predicted to rise. Within this population, those also living with frailty are particularly vulnerable to poor outcomes, including decreased function. Increased physical activity, including exercise, has the potential to improve function in those living with both MLTCs and frailty but, to date, the focus has remained on older people and may not reflect outcomes for the growing number of younger people living with MLTCs and frailty. For those with higher burdens of frailty and MLTCs, physical activity may be challenging. Tailoring physical activity in response to symptoms and periods of ill-health, involving family and reducing sedentary behaviour may be important in this population. How the tailoring of interventions has been approached within existing studies is currently unclear. This scoping review aims to map the available evidence regarding these interventions in people living with both frailty and MLTCs. METHODS AND ANALYSIS: We will use a six-stage process: (1) identifying the research questions; (2) identifying relevant studies (via database searches); (3) selecting studies; (4) charting the data; (5) collating and summarising and (6) stakeholder consultation. Studies will be critically appraised using the Mixed Methods Appraisal Tool. ETHICS AND DISSEMINATION: All data in this project will be gathered through database searches. Stakeholder consultation will be undertaken with an established patient and public involvement group. We will disseminate our findings via social media, publication and engagement meetings.

The Impact of Falls: A Qualitative Study of the Experiences of People Receiving Haemodialysis.

The prevalence of falls is high in people receiving haemodialysis (HD). This study aimed to explore the experiences of people receiving HD who had fallen in the last six months. A qualitative study, informed by constructivist grounded theory, used semi-structured interviews in combination with falls diaries. Twenty-five adults (mean age of 69 ± 10 years, 13 female, 13 White British) receiving HD with a history of at least one fall in the last six months (median 3, IQR 2-4) participated. Data were organised within three themes: (a) participants' perceptions of the cause of their fall(s): poor balance, weakness, and dizziness, exacerbated by environmental causes, (b) the consequences of the fall: injuries were disproportionate to the severity of the fall leading to loss of confidence, function and disruptions to HD, (c) reporting and coping with falls: most did not receive any specific care regarding falls. Those who attended falls services reported access barriers. In response, personal coping strategies included avoidance, vigilance, and resignation. These findings indicate that a greater focus on proactively identifying falls, comprehensive assessment, and timely access to appropriate falls prevention programmes is required to improve care and outcomes.

Characterization of interactions within the Igα/Igß transmembrane domains of the human B-cell receptor provides insights into receptor assembly.

The B-cell receptor (BCR), a complex comprised of a membrane-associated immunoglobulin and the Igα/ß heterodimer, is one of the most important immune receptors in humans and controls B-cell development, activity, selection, and death. BCR signaling plays key roles in autoimmune diseases and lymphoproliferative disorders, yet, despite the clinical significance of this protein complex, key regions (i.e., the transmembrane domains) have yet to be structurally characterized. The mechanism for BCR signaling also remains unclear and has been variously described by the mutually exclusive cross-linking and dissociation activation models. Common to these models is the significance of local plasma membrane composition, which implies that interactions between BCR transmembrane domains (TMDs) play a role in receptor functionality. Here we used an in vivo assay of TMD oligomerization called GALLEX alongside spectroscopic and computational methods to characterize the structures and interactions of human Igα and Igß TMDs in detergent micelles and natural membranes. We observed weak self-association of the Igß TMD and strong self-association of the Igα TMD, which scanning mutagenesis revealed was entirely stabilized by an E-X10-P motif. We also demonstrated strong heterotypic interactions between the Igα and Igß TMDs both in vitro and in vivo, which scanning mutagenesis and computational models suggest is multiconfigurational but can accommodate distinct interaction sites for self-interactions and heterotypic interactions of the Igα TMD. Taken together, these results demonstrate that the TMDs of the human BCR are sites of strong protein-protein interactions that may direct BCR assembly, endoplasmic reticulum retention, and immune signaling.