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Background: Identifying clusters of multiple long-term conditions (MLTCs), also known as multimorbidity, and their associated burden may facilitate the development of effective and cost-effective targeted healthcare strategies. This study aimed to identify clusters of MLTCs and their associations with long-term health-related quality of life (HRQoL) in two UK population-based cohorts., Methods: Age-stratified clusters of MLTCs were identified at baseline in UK Biobank (n = 502,363, 54.6% female) and UKHLS (n = 49,186, 54.8% female) using latent class analysis (LCA). LCA was applied to people who self-reported ≥ 2 LTCs (from n = 43 LTCs [UK Biobank], n = 13 LTCs [UKHLS]) at baseline, across four age-strata: 18-36, 37-54, 55-73, and 74 + years. Associations between MLTC clusters and HRQoL were investigated using tobit regression and compared to associations between MLTC counts and HRQoL. For HRQoL, we extracted EQ-5D index data from UK Biobank. In UKHLS, SF-12 data were extracted and mapped to EQ-5D index scores using a standard preference-based algorithm. HRQoL data were collected at median 5 (UKHLS) and 10 (UK Biobank) years follow-up. Analyses were adjusted for available sociodemographic and lifestyle covariates., Results: LCA identified 9 MLTC clusters in UK Biobank and 15 MLTC clusters in UKHLS. Clusters centred around pulmonary and cardiometabolic LTCs were common across all age groups. Hypertension was prominent across clusters in all ages, while depression featured in younger groups and painful conditions/arthritis were common in clusters from middle-age onwards. MLTC clusters showed different associations with HRQoL. In UK Biobank, clusters with high prevalence of painful conditions were consistently associated with the largest deficits in HRQoL. In UKHLS, clusters of cardiometabolic disease had the lowest HRQoL. Notably, negative associations between MLTC clusters containing painful conditions and HRQoL remained significant even after adjusting for number of LTCs., Conclusions: While higher LTC counts remain important, we have shown that MLTC cluster types also have an impact on HRQoL. Health service delivery planning and future intervention design and risk assessment of people with MLTCs should consider both LTC counts and MLTC clusters to better meet the needs of specific populations., Competing Interests: Declarations. Ethics approval and consent to participate: All participants gave informed consent to data provision. UK Biobank has full ethical approval from the NHS National Research Ethics Service (16/NW/0274). The University of Essex Ethics Committee has approved all data collection on UKHLS main study and innovation panel waves. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Cryptosporidiosis is a diarrheal disease that commonly affects calves under 6 weeks old. The causative agent, Cryptosporidium parvum, has been associated with the abundance of specific taxa in the faecal microbiome during active infection. However, the long-term impact of these microbiome shifts, and potential effects on calf growth and health have not yet been explored in depth., Methods: Three hundred and forty-six (346) calves from three dairy farms had one faecal swab collected during the first week of life (W1). Thereafter, sampled calves were monitored for diarrhoeal disease and those that suffered a diarrhoea event were tested for C. parvum by lateral flow testing (LFT). Calves that experienced diarrhoea and tested positive for C. parvum by LFT were assigned to the Cryptosporidium-positive (Cp+) group (n = 32). Matched healthy (H) controls with no history of diarrhoea were selected from the remaining cohort (n = 33). The selected subset of calves (n = 65) was observed until weaning, collecting a faecal swab, at approximately Week 5 (W5) and Week 10 (W10) after birth, resulting in a total of 191 samples (W1; n = 65, W5; n = 64, W10; n = 62). 16S rRNA gene amplicon sequencing was performed on all extracted samples., Results: Analysis of the longitudinal microbiome showed significant changes in the microbial diversity and composition across all three time-points. Whilst Firmicutes were elevated in the Cp+ group at W5 compared to the H group, no other significant differences were detected between H and Cp+ groups. Whilst the core microbiota showed some taxa were exclusive to each group, the role of these taxa in health and disease has yet to be determined. Antibiotics were also found to have an impact on the relative abundance of some taxa. Though healthy calves received a significantly higher body condition score than Cp+ calves at W5, the difference did not reach significance at W10, suggesting that Cp+ calves may catch up to their healthy counterparts once the infection has resolved., Conclusions: The findings of this study illustrated the changes in the microbial diversity and composition during the preweaning period in dairy calves. The results also indicated that the faecal microbiome is not predictive of cryptosporidiosis and implied that cryptosporidiosis doesn't cause long-term gut dysbiosis. This study furthered our understanding of the parasite-microbiome relationship and its impact on the bovine host., Competing Interests: Declarations. Ethical approval: The study was conducted following ethical approval by the University of Liverpool Research Ethics Committee (VREC927), and procedures regulated by the Animals (Scientific Procedures) Act were conducted under a United Kingdom (UK) Home Office Licence (P191F589B). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: We aimed to identify specific multimorbidity latent classes among multi-ethnic community-dwelling adults aged ≥ 18 years in Malaysia. We further explored the risk factors associated with these patterns and examined the relationships between the multimorbidity patterns and 11-year all-cause mortality risk, as well as health-related quality of life (HRQoL)., Methods: Using data from 18,101 individuals (aged 18-97 years) from the baseline Census 2012, Health Round 2013, and Verbal Autopsies 2012-2023 of the South East Asia Community Observatory (SEACO) health and demographic surveillance system, latent class analysis was performed on 13 chronic health conditions to identify statistically and clinically meaningful groups. Multinomial logistic regression and Cox proportional hazards regression models were conducted to investigate the adjusted association of multimorbidity patterns with the risk factors and mortality, respectively. HRQoL was analyzed by linear contrasts in conjunction with ANCOVA adjusted for baseline confounders., Results: Four distinct multimorbidity latent classes were identified: (1) relatively healthy (n = 10,640); (2) cardiometabolic diseases (n = 2428); (3) musculoskeletal, mobility and sensory disorders (n = 2391); and (4) complex multimorbidity (a group with more severe multimorbidity with combined profiles of classes 2 and 3) (n = 699). Significant variations in associations between socio-demographic characteristics and multimorbidity patterns were discovered, including age, sex, ethnicity, education level, marital status, household monthly income and employment status. The complex multimorbidity group had the lowest HRQoL across all domains compared to other groups (p < 0.001), including physical health, psychological, social relationships and environment. This group also exhibited the highest mortality risk over 11 years even after adjustment of confounders (age, sex, ethnicity, education and employment status), with a hazard of death of 1.83 (95% CI 1.44-2.33), followed by the cardiometabolic group (HR 1.42, 95% CI 1.18-1.70) and the musculoskeletal, mobility and sensory disorders group (HR 1.29, 95% CI 1.04-1.59)., Conclusions: Our study advances the understanding of the complexity of multimorbidity and its implications for health outcomes and healthcare delivery. The findings suggest the need for integrated healthcare approaches that account for the clusters of multiple conditions and prioritize the complex multimorbidity cohort. Further longitudinal studies are warranted to explore the underlying mechanisms and evolution of multimorbidity patterns., Competing Interests: Declarations. Ethics approval and consent to participate: Ethics approvals were obtained from the Monash University Human Research Ethics Committee (MUHREC); Census 2012 (CF11/3663–2011001930), Health Round 2013 (2013–3837-3646) and Verbal Autopsies (2014–4731-4540, 2019–19407-33428). All participants had provided written consent before data collection. Consent for publication: Not applicable. For the purpose of open access, the authors have applied a Creative Commons Attribution 4.0 (CC BY 4.0) licence to any Accepted Author Manuscript version arising from this submission. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Autistic people commonly have physical and mental health conditions. They also frequently experience barriers to accessing healthcare, contributing to problems identifying and treating health conditions. These factors may lead to increased and earlier morbidity and lower average life expectancy for autistic people. Health checks specifically designed for autistic people, incorporating adjustments to healthcare, may help to overcome these barriers and reduce health inequalities. This trial aims to investigate the clinical and cost-effectiveness of a primary care health check for autistic adults and explore factors related to implementation such as acceptability and feasibility of delivery. The trial is co-designed and delivered by health professionals, autistic people, carers and supporters, and researchers., Methods: This is a clinical and cost-effectiveness, cluster randomised controlled trial of a primary care health check for autistic adults. Primary care practices will be randomised into one of two groups (intervention or control). Two hundred autistic adults (aged 18 years and over) who provide baseline data will be recruited via participating practices. Data will be collected through quantitative and qualitative methods. The primary outcome will be the incidence of new health needs/conditions detected and met at 9 months (data gathered from participant's GP records). Secondary outcomes will include the following: cost-effectiveness, measured as incremental cost per quality-adjusted life year gained over 9 months; the extent of health monitoring and health promotion needs met at 9 months; the incidence of social care needs identified at 9 months; changes in participant or carer general health; changes in quality of life; primary and secondary health and social care resource usage and costs. A qualitative study will explore views about the acceptability of the health check, its utility and future use., Discussion: This study will examine the effectiveness and cost-effectiveness of a primary care health check for autistic adults in identifying new health conditions and needs. If the intervention is effective, it would provide strong evidence for implementation into routine healthcare, therefore enabling earlier health condition diagnosis and opportunities for treatment, reducing the health inequalities experienced by autistic people., Trial Registration: ISRCTN, retrospectively registered on 20 July 2023. https://www.isrctn.com/ISRCTN30156776 (ISRCTN registration number: 30156776)., Competing Interests: Declarations. Ethics approval and consent to participate: This study received ethical approval from the North Wales Research Ethics Committee (Wales REC 5) and the NHS Health Research Authority (ref: 21/WA/0196; IRAS Project ID: 272808). Informed consent will be obtained from all study participants. Important protocol modifications will be reported in writing to relevant parties. A list of all protocol modifications will be provided during study reporting. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests. Primary care practices are receiving funding for research activities at sites. To the best of our knowledge, primary care sites have no competing or financial interests., (© 2024. The Author(s).)

Background: Despite an urgent need for multi-domain lifestyle interventions to reduce dementia risk, there is a lack of interventions which are informed by theory- and evidence-based behaviour change strategies, and no interventions in this domain have investigated the feasibility or effectiveness of behaviour change maintenance. We tested the feasibility, acceptability and cognitive effects of a personalised theory-based 24-week intervention to improve Mediterranean diet (MD) adherence alone, or in combination with physical activity (PA), in older-adults at risk of dementia, defined using a cardiovascular risk score., Methods: Participants (n = 104, 74% female, 57-76 years) were randomised to three parallel intervention arms: (1) control, (2) MD, or (3) MD + PA for 24 weeks and invited to an optional 24-week follow-up period with no active intervention. Behaviour change was supported using personalised targets, a web-based intervention, group sessions and food provision. The primary outcome was behaviour change (MD adherence and PA levels), and the secondary outcomes included feasibility and acceptability, cognitive function, cardiometabolic health (BMI and 24-h ambulatory blood pressure) and process measures., Results: The intervention was feasible and acceptable with the intended number of participants completing the study. Participant engagement with group sessions and food provision components was high. There was improved MD adherence in the two MD groups compared with control at 24 weeks (3.7 points on a 14-point scale (95% CI 2.9, 4.5) and 48 weeks (2.7 points (95% CI 1.6, 3.7)). The intervention did not significantly change objectively measured PA. Improvements in general cognition (0.22 (95% CI 0.05, 0.35), memory (0.31 (95% CI 0.10, 0.51) and select cardiovascular outcomes captured as underpinning physiological mechanisms were observed in the MD groups at 24 weeks., Conclusions: The intervention was successful in initiating and maintaining dietary behaviour change for up to 12 months which resulted in cognitive benefits. It provides a framework for future complex behaviour change interventions with a range of health and well-being endpoints., Trial Registration: ClinicalTrials.gov NCT03673722., Competing Interests: Declarations. Ethics approval and consent to participate: Ethical approval for the study was given by the National Research Ethics Committee Northern Ireland (18/NI/0191). Participants provided initial consent for the 24-week study intervention during the online screening and written consent during the in-person screening. During the initial 24-week intervention, participants were invited to take part in the 24- to 48-week behaviour maintenance phase, and further written consent was obtained. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Necrotising enterocolitis (NEC) is a devastating bowel disease that primarily occurs in infants born prematurely and is associated with abnormal gut microbiome development. While gut microbiome compositions associated with NEC have been well studied, there is a lack of experimental work investigating microbiota functions and their associations with disease onset. The aim of this pilot study was to characterise the metabolic functionality of the preterm gut microbiome prior to the onset of NEC compared with healthy controls., Results: Eight NEC infants were selected of median gestation 26.5 weeks and median day of life (DOL) of NEC onset 20, with one sample used per infant, collected within one to eight days (median four) before NEC onset. Each NEC case was matched to a control infant based on gestation and sample DOL, the main driver of microbiome composition in this population, giving a total cohort of 16 infants for this study. Dietary exposures were well matched. The microbiota of NEC and control infants showed similar wide-ranging metabolic functionalities. All 94 carbon sources were utilised to varying extents but NEC and control samples clustered separately by supervised ordination based on carbon source utilisation profiles. For a subset of eight samples (four NEC, four control) for which pre-existing metagenome data was available, microbiome composition was found to correlate significantly with metabolic activity measured on Biolog plates (p = 0.035). Comparisons across all 16 samples showed the NEC microbiota to have greater utilisation of carbon sources that are the products of proteolytic fermentation, specifically amino acids. In pairwise comparisons, L-methionine was highly utilised in NEC samples, but poorly utilised in controls (p = 0.043). Carbon sources identified as discriminatory for NEC also showed a greater enrichment for established markers of inflammatory disease, such as inflammatory bowel disease, irritable bowel syndrome and diverticular disease., Conclusions: Before NEC onset, the preterm gut microbiota showed greater metabolic utilisation of amino acids, potentially indicating a shift from predominantly saccharolytic to proteolytic fermentation. Products of amino acid breakdown could therefore act as biomarkers for NEC development. A larger study is warranted, ideally with infants from multiple sites., Competing Interests: Declarations. Ethics approval and consent to participate: Infants contributing samples were all participating in the REC approved Supporting Enhanced Research in Vulnerable Infants (SERVIS) study at the Royal Victoria Infirmary, as approved by the National Research Ethics Service Committee North East and North Tyneside 2 10/H0908/39, of Newcastle Hospitals NHS Foundation Trust, after signed parental informed consent. Consent for publication: Not applicable. Competing interests: JEB & NDE report grants to their institutions from Prolacta Biosciences US and Danone Early Life Nutrition. CJS declares lecture honoraria from Nestlé Nutrition Institute. NDE declares lecture honoraria from Nestlé Nutrition Institute donated to charity. The other authors have no relevant conflicts of interest to disclose., (© 2024. The Author(s).)

Context: The COVID-19 pandemic led to an increase in numbers of patients dying at home in the UK, meaning that general practitioners (GPs) were exposed to more patient death than would be pre-COVID. This project aimed to gain insight into GP trainees' experiences of patient death between March and July 2020. This insight can inform support for GPs, leading to improved wellbeing, workforce retention and ultimately, better patient-centred care., Methods: Interpretative Phenomenological Analysis (IPA) of semi-structured interviews was used to explore GP trainees' experiences of patient death in one region of England., Results: Seven trainees, two male and five female, participated. They were working in both rural and urban community settings and were at different stages of GP training. Group experiential themes related to heightened emotional responses to patient death, managing uncertainty and the increased salience of relationships. Most appreciated positive teamworking and solidarity, though some had felt isolated within their surgery and wider community. There were some unforeseen positive experiences of individual and organisational healthcare changes, including a perceived new appreciation for the NHS workforce equality, diversity and inclusion (EDI) by actions to identify and reduce occupational hazards to at-risk healthcare staff. There were potential effects on career choice with participants feeling that changes during COVID-19 offered new flexibility in working arrangements and opportunity to sub-specialise within GP., Conclusion: More support to help navigate the amplified emotional responses to managing dying and death in the community is needed. Some experiences, particularly around managing uncertainty, can cause moral injury if not managed in a safe and supportive environment., Competing Interests: Declarations. Ethics approval and consent to participate: Ethical approval was granted from Newcastle University Ethics committee (3734/2020) and the Health Education England North East team. Participants understood that participation was voluntary and informed consent was gained. Consent for publication: Consent to publish was obtained from all participants as part of the written consent process. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Intervening to modify frailty trajectories may be critical to maintain health and independence in later life. The Active Ageing Programme (AAP) is a 16-week community-based intervention for older people with mild frailty that combines physical activity and social interaction. The programme aims to positively impact resilience and wellbeing, changing the physical, mental and social factors that impact on frailty trajectories. We conducted a rapid qualitative study with the first cohort to understand the acceptability and feasibility of the AAP., Methods: Purposive sampling was used to identify and recruit staff and participants involved in the AAP for semi-structured interviews. The topic guides covered experiences and perceptions of training and referral, delivery and participation in activities, and benefits and challenges. Data from 20 interviews were analysed using a reflexive thematic approach with inductive coding. The Theoretical Domains Framework prompted consideration of potential individual, social and environmental factors influencing changes in behaviour and practice., Results: Sixteen AAP staff (10) and participants (6) completed interviews. Two themes were developed: combining motivating components; addressing what matters. The AAP brought together a number of components that supported its acceptability and successful implementation by motivating older people and staff and sustaining their engagement. These included the convenient and familiar location, the opportunity to improve physical health (participants) and to gain experience of an activity intervention, training and confidence (staff), and the variety of activities on offer. The programme was perceived to have potential to improve physical and mental health and increase the personal resources (e.g. knowledge, confidence, motivation) of those taking part. Areas identified as important for the AAP's future sustainability and success were: tailoring recruitment practices; enhancing organisational communication; and strengthening support for participants to achieve long-term increased physical and social activity and resilience., Conclusions: Our findings suggest that community-based physical and social activity interventions targeting frailty may be acceptable, feasible and useful. Further work is needed to investigate the impact of such programmes on health and service utilisation. Efforts should be targeted at improving the potential for long-term sustainability of programmes and their impacts., Competing Interests: Declarations. Ethics approval and consent to participate: This rapid qualitative study was conducted in July – November 2022. The study received ethical approval from Newcastle University Research Ethics Committee (REC) (Ref. 21499 − 2022). Health Research Authority (HRA) approvals and NHS REC review were not required because the project was defined as a service evaluation according to the UK Policy Framework for Health and Social Care Research. Written informed consent was obtained from all participants. Participants were informed that they were able to withdraw from the study at any stage up until the findings were produced. To ensure confidentiality, data was anonymised and securely stored. All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication: Consent for publication was confirmed with all participants at the same time as consent to participate was obtained. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Cancer-related fatigue (CRF) is the most prevalent, distressing, and quality of life disturbing symptom during and after cancer treatment for many cancer types including breast cancer. The experience and burden of this symptom can induce a cognitive bias towards fatigue or a fatigue-related self-image, which can further increase the fatigue symptoms and related behaviour. For this, a Cognitive Bias Modification (CBM) eHealth app (IVY) has been developed. The app aims to counter the fatigue-related self-image and to modify it towards vitality, which might translate to less experienced fatigue and more experienced vitality. This study aims to evaluate the feasibility of the IVY CBM training and the research design of a wait-list control trial. If feasibility is judged sufficient, the effectiveness of the CBM app will also be analyzed on (1) underlying mechanisms (cognitive fatigue bias), (2) symptom fatigue (self-reported fatigue and vitality), and (3) related behaviours (avoidance and all-or-nothing behaviour)., Methods: This feasibility study addresses individuals being treated for breast cancer receiving (neo)adjuvant treatment or metastatic care. The number of target participants is 120 (60 (neo)adjuvant, and 60 metastatic) patients. Both groups will be randomized with 30 people in the IVY treatment group and 30 people in the delayed treatment control group. All participants will receive the training via the IVY app, in which participants categorize words related to vitality with words related to 'I' and words related to fatigue with words related to 'other'. If feasibility is judged sufficient, the effects of the training will be explored on 3 levels: (1) self-identity bias, which will be measured with a short computer task based on the Implicit Association Test (IAT), (2) avoidance and all-or-nothing behaviour, and (3) fatigue and vitality levels, which will all be measured with questionnaires., Discussion: This study aims to evaluate the feasibility of a larger-scale multi-centre Randomized Controlled Trial (RCT) to investigate a novel eHealth application and, if possible, to give indications on the effectiveness of this intervention to counter fatigue in individuals with breast cancer. Using the IVY CBM app requires very little effort, both in time and cognitive load, which could be especially beneficial for fatigue symptoms., Trial Registration: Registered at the Open Science Framework (OSF; https://osf.io/e85g7/ ) on October 20, 2023., Competing Interests: Declarations. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Vascular dementia (VaD) is the second most common cause of dementia globally and is associated with a significant economic and social burden. Diet could represent an important tractable risk factor for VaD. We synthesised current evidence on associations between consumption of specific foods or dietary patterns and VaD risk., Methods: Five databases were searched from inception to January 2024 for prospective cohort studies exploring associations between individual foods or dietary patterns and incident VaD., Results: Sixteen studies were included. Compared with low intake reference groups, higher fruit and vegetable intake, moderate alcoholic drink intake (1-3 drinks/day), higher tea and coffee intake, and following a plant-based dietary pattern were associated with lower VaD risk. Conversely, moderate fried fish intake (0.25-2 servings/week), higher ultra-processed food intake (especially intake of sweetened beverages) and higher processed meat intake (≥ 2 servings/week) were associated with increased VaD risk. Inconsistent findings were observed for other dietary exposures., Discussion: A healthy diet could lower VaD risk. However, evidence is characterised by a limited number of studies for specific dietary exposures. Further research is needed to inform personalised and population-based approaches to lower VaD risk., Competing Interests: Declarations. Competing interests: ET’s salary is supported by an NIHR Clinical Lectureship. SG has received research funding to her institution from the Royal Society of Edinburgh, Scottish Neurological Research Fund and Alzheimer’s Association, alongside an ISTAART Travel Fellowship. SG has also received consulting fees from Scottish Brain Sciences and is a part time employee of Scottish Brain Sciences. SG is vice chair of an NHS research ethics committee, and her salary was funded during part of this project by a grant from the UK Medical Research Council. OMS has received research funding to his institution from the Fruit Juice Science Centre. All other authors declare no conflict of interest., (© 2024. The Author(s).)

Background: MUC1 and UMOD pathogenic variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD). MUC1 is expressed in kidney, nasal mucosa and respiratory tract, while UMOD is expressed only in kidney. Due to haplo-insufficiency ADTKD-MUC1 patients produce approximately 50% of normal mucin-1., Methods: To determine whether decreased mucin-1 production was associated with an increased COVID-19 risk, we sent a survey to members of an ADTKD registry in September 2021, after the initial, severe wave of COVID-19. We linked results to previously obtained ADTKD genotype and plasma CA15-3 (mucin-1) levels and created a longitudinal registry of COVID-19 related deaths., Results: Surveys were emailed to 637 individuals, with responses from 89 ADTKD-MUC1 and 132 ADTKD-UMOD individuals. 19/83 (23%) ADTKD-MUC1 survey respondents reported a prior COVID-19 infection vs. 14/125 (11%) ADTKD-UMOD respondents (odds ratio (OR) 2.35 (95%CI 1.60-3.11, P = 0.0260). Including additional familial cases reported from survey respondents, 10/41 (24%) ADTKD-MUC1 individuals died of COVID-19 vs. 1/30 (3%) with ADTKD-UMOD, with OR 9.21 (95%CI 1.22-69.32), P = 0.03. The mean plasma mucin-1 level prior to infection in 14 infected and 27 uninfected ADTKD-MUC1 individuals was 7.06 ± 4.12 vs. 10.21 ± 4.02 U/mL (P = 0.035). Over three years duration, our longitudinal registry identified 19 COVID-19 deaths in 360 ADTKD-MUC1 individuals (5%) vs. 3 deaths in 478 ADTKD-UMOD individuals (0.6%) (P = 0.0007). Multivariate logistic regression revealed the following odds ratios (95% confidence interval) for COVID-19 deaths: ADTKD-MUC1 8.4 (2.9-29.5), kidney transplant 5.5 (1.6-9.1), body mass index (kg/m 2 ) 1.1 (1.0-1.2), age (y) 1.04 (1.0-1.1)., Conclusions: Individuals with ADTKD-MUC1 are at an eight-fold increased risk of COVID-19 mortality vs. ADTKD-UMOD individuals. Haplo-insufficient production of mucin-1 may be responsible., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Wake Forest University Health Sciences Institutional Review Board, Winston-Salem, NC, United States, in accordance with the Declaration of Helsinki. All individuals presented in the study provided voluntary, autonomous consent to participate. Consent for publication: Not applicable. Competing interests: AJB has also received funding from the Black Brogan Foundation, The Slim Health Foundation, Soli Deo Gloria. He has received compensation as follows: advisory board, Horizon Pharma; speaker, Natera; author, UpToDate; advisor, First Faculty of Medicine, Charles University; royalty; patent for UMOD genetic diagnosis. PJC has received funding from Astra Zeneca, Bohringher, Hansa, and medical advisory board fees. KOK, AHW, AT, AK, LM, VR, APR-C, JAS, EO, HRM, GP, CD, CS, REH, EE, DS, CI, AV, LP, TZ, MP, MR, PV, KH, MZ, and SK have nothing to disclose., (© 2024. The Author(s).)

Background: Poor social connectedness has been identified as a risk factor for poor mental health but there is a lack of standardisation in how it is measured. This systematic review aimed to identify suitable measures of social connectedness for use in UK adult general populations., Methods: Searches were undertaken in two stages to identify: (1) measures of social connectedness from review articles and grey literature and (2) studies reporting on the psychometric properties of the identified measures. Grey literature and five databases were searched: MEDLINE, Embase and PsycINFO; CINAHL and Web of Science. Studies based on UK adult general populations (16-65 years) or other English language speaking countries with similar cultures (US, Canada, Ireland, Australia and New Zealand) were included. Psychometric evidence was extracted relating to six general domains: conceptual model, content validity, reliability, construct validity, scoring and interpretability, and respondent burden and presentation. A narrative synthesis summarised these psychometric properties., Results: Stage (1) 2,396 studies were retrieved and, 24 possible measures of social connectedness were identified; stage (2) 6,218 studies were identified reporting on psychometrics of identified measures and 22 studies were included. These studies provided psychometric evidence for 10 measures, and we did not find psychometric studies for the other identified measures. Six measures (6/10, 60%) reported assessing loneliness and four (4/10, 40%) reported assessing social support but there was a degree of overlap between the assessments of each concept. There was good evidence of reliability across measures, 90% (9/10) had adequate internal consistency, but evidence of content validity was only available for one scale. Five measures (5/10, 50%) reported on at least half of the psychometric criteria, and these were: UCLA-3 (for loneliness), and MSPSS, F-SozU K-6, SPS-10 and SPS-5 (for social support)., Conclusions: This review identified ten social connectedness measures, and identified UCLA-3, MSPSS, F-SozUK-6, SPS-10, and SPS-5 as having the most robust psychometric properties for the UK adult population. Further testing is required to establish content validity, and to clarify the definition and conceptualisation of social connectedness, to enable standardisation in the approach to measuring social connectedness., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The use of surveillance technologies is becoming increasingly common in inpatient mental health settings, commonly justified as efforts to improve safety and cost-effectiveness. However, their use has been questioned in light of limited research conducted and the sensitivities, ethical concerns and potential harms of surveillance. This systematic review aims to (1) map how surveillance technologies have been employed in inpatient mental health settings, (2) explore how they are experienced by patients, staff and carers and (3) examine evidence regarding their impact., Methods: We searched five academic databases (Embase, MEDLINE, PsycInfo, PubMed and Scopus), one grey literature database (HMIC) and two pre-print servers (medRxiv and PsyArXiv) to identify relevant papers published up to 19/09/2024. We also conducted backwards and forwards citation tracking and contacted experts to identify relevant literature. The Mixed Methods Appraisal Tool assessed quality. Data were synthesised narratively., Results: Thirty-two studies met the inclusion criteria. They reported on CCTV/video monitoring (n = 13), Vision-Based Patient Monitoring and Management (n = 9), body-worn cameras (n = 6), GPS electronic monitoring (n = 2) and wearable sensors (n = 2). Sixteen papers (50.0%) were low quality, five (15.6%) medium quality and eleven (34.4%) high quality. Nine studies (28.1%) declared a conflict of interest. Qualitative findings indicate patient, staff and carer views of surveillance technologies are mixed and complex. Quantitative findings regarding the impact of surveillance on outcomes such as self-harm, violence, aggression, care quality and cost-effectiveness were inconsistent or weak., Conclusions: There is currently insufficient evidence to suggest that surveillance technologies in inpatient mental health settings are achieving their intended outcomes, such as improving safety and reducing costs. The studies were generally of low methodological quality, lacked lived experience involvement, and a substantial proportion (28.1%) declared conflicts of interest. Further independent coproduced research is needed to more comprehensively evaluate the impact of surveillance technologies in inpatient settings. If they are to be implemented, all key stakeholders should be engaged in the development of policies, procedures and best practice guidance to regulate their use, prioritising patients' perspectives., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: AS, UF and ET have undertaken and published research on BWCs. We have received no financial support from BWC companies or any other surveillance technology companies. All other authors declare no competing interests., (© 2024. The Author(s).)

Background: Making Every Contact Count (MECC) is a public health strategy which strives to enable brief interventions to be implemented through opportunistic healthy lifestyle conversations. In a mental health inpatient setting a bespoke MECC training package has been developed to encourage cascade training through a train the trainer model and to incorporate an additional regional health strategy A Weight Off Your Mind into Core MECC training to provide a focus on healthy weight management. This study evaluated the fidelity of design of MECC in the mental health inpatient setting and fidelity of the training package currently being cascaded across the region., Methods: Initially a documentary analysis of six documents shared through the mental health inpatient setting including MECC implementation guide, logic model, checklist and evaluation framework. Documents were analysed using the Template for Intervention Description and Replication (TIDieR) checklist and coded using the Behaviour Change Technique (BCT) Taxonomy version one (BCTTv1) and the Expert Recommendations for Implementing Change (ERIC) Taxonomy. Coding was compared against MECC guidance documents to complete the fidelity assessment. A training delivery guide, training slides and two recordings of both train the trainer and Core MECC + A Weight Off Your Mind training were analysed for behaviour change techniques (BCTs) and compared to conduct a fidelity training assessment., Results: Overall the implementation of MECC in the mental health inpatient setting had moderate fidelity to the MECC guidance, with a total of 31 BCTs identified across guidance and provider documents and a 77% adherence of provider documents to guidance. The highest level of fidelity applied to the MECC implementation guide where 86% of identified BCTs were also present. The training package showed high fidelity that both training programmes were being delivered as intended with 100% of BCT matched from training materials to training transcripts. Potential loss of fidelity through additional BCTs was present across provider documents and training transcripts., Conclusion: The implementation of MECC across the mental health inpatient setting and the training package appear to be delivered as intended therefore demonstrating good fidelity and potential benefits to public health. Future research would benefit from assessing cascade training sessions from those who have completed train the trainer to evaluate ongoing fidelity of training across the trust., Competing Interests: Declarations. Ethics approval and consent to participate: This project was approved by Northumbria University Ethics Approval Committee (ref: 2064). All participants provided verbal consent to enable recording of training sessions. Informed consent was obtained from all human participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Neovascular age-related macular degeneration (nAMD) is one of the largest single-disease contributors to hospital outpatient appointments. Challenges in finding the clinical capacity to meet this demand can lead to sight-threatening delays in the macular services that provide treatment. Clinical artificial intelligence (AI) technologies pose one opportunity to rebalance demand and capacity in macular services. However, there is a lack of evidence to guide early-adopters seeking to use AI as a solution to demand-capacity imbalance. This study aims to provide guidance for these early adopters on how AI-enabled macular services may best be implemented by exploring what will influence the outcome of AI implementation and why., Methods: Thirty-six semi-structured interviews were conducted with participants. Data were analysed with the Nonadoption, Abandonment, Scale-up, Spread and Sustainability (NASSS) framework to identify factors likely to influence implementation outcomes. These factors and the primary data then underwent a secondary analysis using the Fit between Individuals, Technology and Task (FITT) framework to propose an actionable intervention., Results: nAMD treatment should be initiated at face-to-face appointments with clinicians who recommend year-long periods of AI-enabled scheduling of treatments. This aims to maintain or enhance the quality of patient communication, whilst reducing consultation frequency. Appropriately trained photographers should take on the additional roles of inputting retinal imaging into the AI device and overseeing its communication to clinical colleagues, while ophthalmologists assume clinical oversight and consultation roles. Interoperability to facilitate this intervention would best be served by imaging equipment that can send images to the cloud securely for analysis by AI tools. Picture Archiving and Communication Software (PACS) should have the capability to output directly into electronic medical records (EMR) familiar to clinical and administrative staff., Conclusion: There are many enablers to implementation and few of the remaining barriers relate directly to the AI technology itself. The proposed intervention requires local tailoring and prospective evaluation but can support early adopters in optimising the chances of success from initial efforts to implement AI-enabled macular services., Protocol Registration: Hogg HDJ, Brittain K, Teare D, Talks J, Balaskas K, Keane P, Maniatopoulos G. Safety and efficacy of an artificial intelligence-enabled decision tool for treatment decisions in neovascular age-related macular degeneration and an exploration of clinical pathway integration and implementation: protocol for a multi-methods validation study. BMJ Open. 2023 Feb 1;13(2):e069443. https://doi.org/10.1136/bmjopen-2022-069443 . PMID: 36725098; PMCID: PMC9896175., Competing Interests: Declarations. Ethics approval and consent to participate: Ethical approval was granted for this work by the Greater Manchester South Research Ethics Committee, reference 21/NW/0138. All interview participants were consented with study-specific ink or digitally signed consent forms. Consent for publication: Participant consent included pseudonymised publication of interview extracts. All authors have reviewed the manuscript and give their consent for publication. Competing interests: No authors have competing interests., (© 2024. The Author(s).)

Background: Learning analytics (LA) is a tool for gathering, analysing, and interpreting data related to student's learning behaviour, engagement, and performance. As the student data collected by the institutions are used to construct LA, it is essential to understand the acceptance and readiness of the students regarding the implementation of LA., Methods: A sequential mixed method research design was used in this study. A validated questionnaire was distributed to undergraduate students of Medicine, Dentistry and Pharmacy programmes to collect their general views on LA. Focus group interviews with a total of 18 students were conducted to explore their perceptions in depth, followed by thematic analysis of the transcribed data., Results: Generally, the students were aware of their demographic data, utilisation of learning management system and academic performance data being collected by the university. They were agreeable for collection of those data which had direct association with their learning to be used for LA. However, they expressed concerns about the privacy, confidentiality, and security of the collected data. Three themes emerged from the interviews, i.e., self-regulated learning, evidence-based decision making and data management. The students perceived that LA could help them to monitor achievement of learning outcomes and provide support for individualised learning paths through recommendations of learning resources and learning motivation. They also opined that LA could help educators and institutions by providing feedback on teaching and learning methods, resource allocation and interventions to create conducive learning environment., Conclusions: LA is a useful tool to support self-regulated learning, however, precautions should be exercised during implementation to ensure data privacy and security., Competing Interests: Declarations. Ethics approval and consent to participate: The study was reviewed and approved by the International Medical University Joint Committee on Research and Ethics. All participants provided their informed consent to participate in the study. The study was conducted in accordance with relevant guidelines and regulations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Deaths related to suicide, drug misuse, and alcohol-specific causes, known collectively as "deaths of despair" are of growing interest to researchers in England. Rates of death from these causes are highest in deprived northern communities and are closely tied to the social determinants of health and the policy decisions that have shaped them. The aim of this paper is to explore how stakeholders and community members living in Middlesbrough and South Tyneside, two Northern towns with above average rates of deaths of despair, understood the relationship between austerity policies and rates of deaths from these causes in their areas., Methods: I conducted interviews and one focus group with a total of 54 stakeholders and community members in Middlesbrough and South Tyneside. Data were analysed using the iterative categorisation technique and the findings were interpreted through thematic analysis., Results: The findings highlight four primary ways through which austerity exacerbated rates of deaths of despair in Middlesbrough and South Tyneside: reduced access to mental health services, diminished substance abuse treatment capacity, loss of youth services, and the closure of community institutions. Participants linked these cuts to rising social isolation, declining mental health, and increased substance misuse, which collectively deepened geographic inequalities in deaths of despair., Conclusions: This study underscores the urgent need for reinvestment in local services to reduce inequalities and prevent further unnecessary deaths due to drug, suicide, and alcohol-specific causes. Prioritising the restoration and enhancement of services lost to austerity is critical. Such reinvestment will not only help to alleviate some of the most immediate need but also form a foundation for addressing the wider structural inequalities that perpetuate deaths of despair., Competing Interests: Declarations Ethics approval and consent to participate This research was carried out in accordance with the Declaration of Helsinki. Stakeholder interviews were granted ethical approval by the Newcastle University Faculty of Medical Science (FMS) Research Ethics Committee (REC) on 01/05/2022 (REF:22812/2022). Ethical approval for community members was received from FMS REC on 23/02/2023 (Ref: 2443/26851). Each participant provided informed consent prior to the interview or participation in the focus group. Consent for publication All participants provided informed consent for using their anonymised data in scientific publications. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: People experiencing homelessness often face obstacles accessing health and social care support. Challenges are further exacerbated when support provision for multiple unmet needs are not integrated or coordinated. To overcome these challenges, there has been growing attention on integrating and co-locating health and wellbeing services for people experiencing homelessness. In an urban area of North East England, a long-standing Hub or 'drop-in centre' offers a range of health and wellbeing support by bringing together the different health and care system agencies in one space. However, little is known about the perspectives of providers on what works well and less well in how the different services are coordinated., Methods: Using a participatory action research approach, a qualitative service evaluation was undertaken between June and September 2023. Fourteen interviews were conducted with providers who work in a paid or voluntary capacity operating some of their service offerings or support in the Hub. Interview transcripts were analysed using inductive reflexive thematic analysis., Results: Three themes were evident from the evaluation: 1) location and space matter, 2) co-location and relationships make a difference, and 3) service consistency and flexibility are paramount., Conclusion: Co-locating support to cover the breadth of health and care needs has the potential to increase engagement and access for people experiencing homelessness, and to enhance trust with service users and between agencies. This model provides a unique example of co-location and integration of support, particularly with it being operated by a community housing organisation., Competing Interests: Declarations Ethics approval and consent to participate All data collection was performed in accordance with the Declaration of Helsinki. The study was reviewed and approved by the Newcastle University Ethics Committee in May 2023 (Ref: 33139/2023). Informed consent was obtained from all participants. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The benefits of randomised trials are not shared equally, and people from ethnic minority groups are a key constituency under-served by clinical research and clinical care. The STRIDE project aimed to give trialists practical information about how to decide which ethnic groups should be in their trials, and at what proportion., Methods: We considered trials in six clinical areas: cancer, cardiovascular, diabetes, maternal health, mental health, and smoking cessation. We created a summary for each, including participants-intervention-comparators-outcomes, and data on disease prevalence by ethnicity. These were discussed with panels with clinical expertise, trial and methodology expertise, lived experience, funding, and experience of working with and on behalf of ethnic communities. For each trial, we asked panel members to decide which ethnic groups should have been involved and at what proportion., Results: We discussed 23 trials with 40 individual panel members. Panels found our questions difficult to answer. The lack of publicly available data on prevalence by ethnicity was central to this. Where data were available, decision-making was easier but not simple. The discussions led to eight STRIDE recommendations. We recommend that discussions involve diverse teams and that discussions need time, with access to the best available data. In the absence of data or consensus, we recommend the adoption of 'default' minimum rates of inclusion, with oversampling considered. These discussions should inform site selection, and the practical challenges of recruitment and retention should not determine which groups are to be included. We also suggest five policy initiatives to support implementation of the recommendations. Broadly, these are (1) funders need to signal that ethnic diversity is expected, (2) trial teams need access to better data, (3) funders and others need to signal that ethnic diversity means better science, (4) more funding is needed for evaluation, and (5) Good Clinical Practice training should cover ethnic diversity., Conclusions: Agreeing targets for which ethnic groups to involve in a trial is essential but difficult. Our eight recommendations could help to make trials more ethnically diverse if followed, and we suggest five policy initiatives that would create a supportive environment for their implementation., Competing Interests: Declarations Ethics approval and consent to participate Ethics approval was not required for this work. Members of the public who took part did so as patient and public partners helping to drive and shape the work, not as research participants. Consent for publication Not applicable for this article. Competing interests KK is Director for Centre for Ethnic Health Research, University of Leicester, UK. ST is an Editor-in-Chief of Trials. All other authors declare no competing interests., (© 2024. The Author(s).)

Introduction: The Irish Prostate Cancer Outcomes Research (IPCOR) Study collected longitudinal data on men newly diagnosed with Prostate Cancer (PC). Understanding the nuances of disease presentation is essential, considering the high incidence of PC in Ireland. This study aims to characterise disease presentation features, identify factors related to socio demographic disparities in presentation following opportunistic screening, and shed light on potential inequality challenges within Ireland's healthcare structure., Methods: Data were collected on demographics, diagnosis, and treatment of 6,816 men newly diagnosed with PC across 16 hospitals in the Republic of Ireland from February 2016 to January 2020. A complete case analysis was carried out, complemented by a sensitivity analysis for addressing sites with high rates of missing values. Multivariable logistic regression was conducted to examine the association between various predictor variables and the initial presentation to the urology clinic subsequent to opportunistic screening., Results: A multivariable logistic regression model revealed that the type of hospital was a key determinant in post-opportunistic screening presentation, with patients in public hospitals 45.7% more likely to be presented following screening compared to those in private hospitals. Urban residents were 34% more likely to present following screening than rural ones. Age negatively influenced presentation following screening likelihood, decreasing by 3.4% yearly., Discussion: Our research has highlighted the key features of PC presentation in Ireland, revealing potential inequalities affecting mainly urban populations, middle socioeconomic groups, and individuals with inadequate healthcare coverage. While the differences we observed in various groups may appear subtle and may indicate the success of the Rapid Access Prostate Clinics, they are still significant in pinpointing specific populations that require special attention., Conclusions: By addressing these nuanced differences in access to healthcare, socioeconomic status, and urban versus rural residence and implementing tailored strategies, we can work towards closing disparity gaps in PC, ultimately leading to improved health outcomes and equity across all population segments., Competing Interests: Declarations Ethics approval and consent to participate Ethics approval was obtained from each of the individual hospitals participating in the IPCOR project. An ethical waiver was issued by University College Dublin LS-E-22-131-GALVIN to allow the use of the IPCOR dataset in University College Dublin. Patient consent was not required for the patient data, as this was carried out under the auspices of the National Cancer Registry Ireland (NCRI). The NCRI has permission under the Health (Provision of Information) Act 1997 to collect and hold data on all persons diagnosed with cancer in Ireland. The use of these data for research is covered by the Statutory Instrument, which established the Registry Board in 1991. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The value of patient and public involvement (PPI) during the earliest stages of clinical trial development, and prior to the award of substantive funding, is widely recognised. However, it is often under-resourced and PPI processes during this phase are rarely reported in detail. Having benefitted from seed funding to develop an international clinical trial proposal, we sought to describe and appraise PPI activities and processes that support pre-award co-development., Methods: A 12-month "accelerator" award facilitated development of a substantive funding application to deliver the Rheumatoid Arthritis Prevention PlatfORm Trial (RAPPORT), conceived to prioritise preventative interventions for people at risk of RA. PPI partners, including individuals at risk of rheumatoid arthritis (RA), RA patients, relatives and members of the public, provided feedback on key trial design issues through online meetings, a feedback form and emails. PPI processes employed during the one-year accelerator project were thereafter evaluated by PPI partners using an anonymous online feedback form with reference to National Institute of Health and Care Research (NIHR) UK standards for public involvement in research., Results: Sixteen out of the 25-strong PPI partner panel completed an online feedback form (64%). Respondents perceived PPI processes positively in relation to all NIHR standard domains. Several key facilitators and challenges were identified, including the need for adequate PPI funding during pre-award phases of research, strategies for creating an inclusive environment, flexibility around levels of involvement, and challenges in achieving representatively diverse participation, and the importance of communicating transparent processes for role-assignment and time-reimbursement., Conclusions: In general, RAPPORT was considered an example of PPI well done, and in line with UK standards for public involvement in research. Facilitators and challenges of relevance for the development of future translational and clinical trial funding applications are highlighted., (© 2024. The Author(s).)

Introduction: The Medication Home Delivery (MHD) service from community pharmacies involves the safe and efficient delivery of pharmaceuticals (prescription and non-prescription medications), and health products directly to the patient's/consumer's home. There are several issues encountered by the users of the MHD service that have an impact on their satisfaction with the service. The study aimed to assess the public's perceptions of the MHD service in the United Arab Emirates (UAE), their willingness to utilize it, and the practical use of the service., Method: A cross-sectional exploratory study was conducted in the UAE using a validated online survey. The inclusion criteria were adults residing in the UAE. Statistical analysis was performed to identify the association between the variables, the service use, and the level of service efficiency., Results: A total of 556 participants filled out the survey, with 69.4% of them using the service. The majority of participants were females (75.9%) and aged less than 40 years old (71.6%). Three variables showed a statistically significant association with the use of the MHD service (P < 0.05): the participant's educational level, their medical/health background, and the frequency of visits to community pharmacies. The most common issues raised were receiving the wrong order, delay in delivery, and paying delivery fees. Most participants agreed that the MHD service reduces the risk of exposure during pandemics, serves the elderly, serves disabled people, makes it more comfortable for parents with children at home, and reduces overcrowding in health facilities, as well as the MHD service making pharmacy services more efficient., Conclusion: The study indicated positive perceptions among the public in the UAE towards the MHD service. However, there was a concern that this service may diminish the communication between pharmacists and patients, which potentially minimizes the amount of information received by patients regarding their treatments., (© 2024. The Author(s).)

Amphibians represent a diverse group of tetrapods, marked by deep divergence times between their three systematic orders and families. Studying amphibian biology through the genomics lens increases our understanding of the features of this animal class and that of other terrestrial vertebrates. The need for amphibian genomic resources is more urgent than ever due to the increasing threats to this group. Amphibians are one of the most imperiled taxonomic groups, with approximately 41% of species threatened with extinction due to habitat loss, changes in land use patterns, disease, climate change, and their synergistic effects. Amphibian genomic resources have provided a better understanding of ontogenetic diversity, tissue regeneration, diverse life history and reproductive modes, anti-predator strategies, and resilience and adaptive responses. They also serve as essential models for studying broad genomic traits, such as evolutionary genome expansions and contractions, as they exhibit the widest range of genome sizes among all animal taxa and possess multiple mechanisms of genetic sex determination. Despite these features, genome sequencing of amphibians has significantly lagged behind that of other vertebrates, primarily due to the challenges of assembling their large, repeat-rich genomes and the relative lack of societal support. The emergence of long-read sequencing technologies, combined with advanced molecular and computational techniques that improve scaffolding and reduce computational workloads, is now making it possible to address some of these challenges. To promote and accelerate the production and use of amphibian genomics research through international coordination and collaboration, we launched the Amphibian Genomics Consortium (AGC, https://mvs.unimelb.edu.au/amphibian-genomics-consortium ) in early 2023. This burgeoning community already has more than 282 members from 41 countries. The AGC aims to leverage the diverse capabilities of its members to advance genomic resources for amphibians and bridge the implementation gap between biologists, bioinformaticians, and conservation practitioners. Here we evaluate the state of the field of amphibian genomics, highlight previous studies, present challenges to overcome, and call on the research and conservation communities to unite as part of the AGC to enable amphibian genomics research to "leap" to the next level., (© 2024. The Author(s).)

Background: We aimed to develop risk tools for dementia, stroke, myocardial infarction (MI), and diabetes, for adults aged ≥ 65 years using shared risk factors., Methods: Data were obtained from 10 population-based cohorts (N = 41,755) with median follow-up time (years) for dementia, stroke, MI, and diabetes of 6.2, 7.0, 6.8, and 7.4, respectively. Disease-free participants at baseline were included, and 22 risk factors (sociodemographic, medical, lifestyle, laboratory biomarkers) were evaluated. Two risk tools (DemNCD and DemNCD-LR based on Fine and Gray sub-distribution and logistic regression [LR], respectively) were developed and validated. Predictive accuracies of these risk tools were assessed using Harrel's C-statistics and area under the curve (AUC) and 95% confidence interval (CI). Model calibration was conducted using Hosmer-Lemeshow goodness of fit test along calibration plots., Results: Both the DemNCD and DemNCD-LR resulted in similar predictive accuracy for each outcome. The overall AUC (95% CI) for dementia, stroke, MI, and diabetes risk tool were 0·68 (0·65, 0·70), 0·58 (0·54, 0·61), 0·65 (0·61, 0·68), and 0·68 (0·64, 0·72), respectively, for males. For females, these figures were 0·65 (0·63, 0·67), 0·55 (0·52, 0·57), 0·65 (0·62, 0·68), and 0·61 (0·57, 0·65)., Conclusions: The DemNCD is the first tool to predict both dementia and multiple cardio-metabolic diseases using comprehensive risk factors and provided similar predictive accuracy to existing risk tools. It has similar predictive accuracy as tools designed for single outcomes in this age-group. DemNCD has the potential to be used in community and clinical settings as it includes self-reported and routinely available clinical measures., (© 2024. The Author(s).)

Background: Management of type 1 diabetes (T1D) requires the use of insulin, which can cause hypoglycaemia (low blood glucose levels). While most hypoglycaemic episodes can be self-treated, all episodes can be sudden, inconvenient, challenging to prevent or manage, unpleasant and/or cause unwanted attention or embarrassment. Severe hypoglycaemic episodes, requiring assistance from others for recovery, are rare but potentially dangerous. Repeated exposure to hypoglycaemia can reduce classic warning symptoms ('awareness'), thereby increasing risk of severe episodes. Thus, fear of hypoglycaemia is common among adults with T1D and can have a negative impact on how they manage their diabetes, as well as on daily functioning, well-being and quality of life. While advances in glycaemic technologies and group-based psycho-educational programmes can reduce fear, frequency and impact of hypoglycaemia, they are not universally or freely available, nor do they fully resolve problematic hypoglycaemia or associated worries. This study aims to determine the effectiveness of a fully online, self-directed, scalable, psycho-educational intervention for reducing fear of hypoglycaemia: the Hypoglycaemia Prevention, Awareness of Symptoms, and Treatment (HypoPAST) programme., Methods: A 24-week, two-arm, parallel-group, hybrid type 1 randomised controlled trial, conducted remotely (online and telephone). Australian adults (≥ 18 years) with self-reported T1D and fear of hypoglycaemia will be recruited, and allocated at random (1:1) to HypoPAST or control (usual care). The primary outcome is the between-group difference in fear of hypoglycaemia (assessed using HFS-II Worry score) at 24 weeks. A sample size of N = 196 is required to detect a 9-point difference, with 90% power and allowing for 30% attrition. Multiple secondary outcomes include self-reported psychological, behavioural, biomedical, health economic, and process evaluation data. Data will be collected at baseline, 12 and 24 weeks using online surveys, 2-week ecological momentary assessments, website analytics and semi-structured interviews., Discussion: This study will provide evidence regarding the effectiveness, cost-effectiveness and acceptability of a novel, online psycho-educational programme: HypoPAST. Due to the fully online format, HypoPAST is expected to provide an inexpensive, convenient, accessible and scalable solution for reducing fear of hypoglycaemia among adults with T1D., Trial Registration: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12623000894695 (21 August 2023)., (© 2024. The Author(s).)

Background: Many countries have introduced school food standards to improve the dietary intakes of school-aged children. England has school food standards (SFS) legislation in place but little is known about how well secondary schools comply with this. We aimed to assess compliance with the SFS legislation in English secondary schools and explore the impact of the SFS on pupils' nutritional intake., Methods: We conducted a cross-sectional study with English secondary schools from 2019 to 2022. We compared SFS compliance and pupil nutritional intake in schools mandated or not mandated to comply with the SFS legislation, and explored the association between school compliance and pupil nutritional intake. We assessed the percentage of SFS (%SFS) complied with by reviewing school food menus and observing food served in school canteens. We assessed pupil nutritional intake using a 24-hour dietary recall measure (Intake24) and estimated intakes of free sugar (primary outcome) and other nutrients/foods. We used adjusted multilevel models to compare pupil intakes in the SFS-mandated and SFS-non-mandated schools, and to explore the association between school SFS compliance and pupil intakes., Results: 36 schools (23 not mandated and 13 mandated to comply with the SFS) and 2,273 pupils participated. The median %SFS complied with was 63.9% (interquartile range 60.0-70.0%). This was similar for SFS-non-mandated (64.5%) and SFS-mandated schools (63.3%). Compliance was highest for standards applying to lunchtime (median = 81.3%) and lowest for those applying across the whole school day (median = 41.7%). It was also lower for standards restricting high fat, sugar and energy-dense items (median = 26.1%) than for standards aiming to increase dietary variety (median = 92.3%). Pupils from SFS-mandated schools had a lower mean lunchtime intake of free sugar (g) (adjusted mean difference: -2.78g; 95% CI: -4.66g to -0.90g). There were few significant associations between %SFS complied with and pupil nutritional intake., Conclusions: English secondary schools do not fully comply with SFS legislation regardless of whether they are mandated to comply. Schools and caterers may require monitoring and support to fully comply. There is little evidence that SFS compliance is associated with better pupil nutritional intake. Food environments outside of school also need to be considered., Study Registration: ISRCTN68757496 (17-10-2019)., (© 2024. The Author(s).)

Background: GP registrars (specialist vocational trainees in general practice) are interested in teaching, and there are considerable benefits to teaching during training. There are, however, significant barriers for registrars as teachers, including inadequate funding, time pressures, and limited teacher training. Current evidence does not include medical educator (ME) perspectives or compare teaching settings (e.g. university vs. in-practice). Further evidence is needed to inform programs supporting registrar teaching roles. This project aimed to explore the experiences of Australian GP registrars as teachers in different contexts and from multiple stakeholder perspectives., Methods: A qualitative study with GP registrars, GP supervisors, MEs, and medical students was conducted. Participants were registrars and new (within 12 months) Fellows with teaching experience during training, supervisors who supervised a registrar in the preceding 12 months, Royal Australian College of General Practitioner MEs, and medical students with experiences of being taught by registrars. Recruitment was open to participants nationwide and sampling was purposive, aiming for a maximum variation sample. Data collection was performed via videoconference and analysed using reflexive thematic analysis., Findings: Interviews were conducted with 15 registrars, 10 supervisors, and one ME. Two focus groups involved four MEs and five medical students respectively. Registrar participants taught in a variety of settings, including in-practice, universities, hospitals, and at educational workshop days. Three had experience in GP academic posts and one as a registrar ME. There were four major themes. 1) Near-peer teaching by registrars is valuable - both for medical students and registrars. 2) Teaching makes you a better GP - participants noted the transferability of teaching skills to clinical practice. 3) The importance of the teaching context - this was identified as an important determinant for registrars in teaching roles. 4) Registrar teaching strengthens the GP workforce - participants noted that teaching could elevate general practice as a specialty and increase interest in GP training., Conclusions: Study participants saw teaching as a core skill for GPs, with transferability to their clinical practice. Registrar participants wanted greater promotion and support for teaching opportunities that counted towards attainment of Fellowship. These findings have implications for teaching practices, MEs, universities, and training providers., (© 2024. The Author(s).)

Background: Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation., Methods: Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations., Results: The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues (n=5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression (n=2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation., Conclusion: This study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy., (© 2024. The Author(s).)

Background: Facioscapulohumeral dystrophy (FSHD) is a myopathy characterized by the loss of repressive epigenetic features affecting the D4Z4 locus (4q35). The assessment of DNA methylation at two regions (DUX4-PAS and DR1) of D4Z4 locus proved to be an effective method to detect epigenetic signatures compatible with FSHD. The present study aims at validating the employment of this method into clinical practice and improving the protocol by refining the classification thresholds of 4qA/4qA patients. To this purpose, 218 subjects with clinical suspicion of FSHD collected in 2022-2023 were analyzed. Each participant underwent in parallel the traditional FSHD molecular testing (D4Z4 sizing) and the proposed methylation assay. The results provided by both analyses were compared to evaluate the concordance and calculate the performance metrics of the methylation test., Results: Among the 218 subjects, the 4q variant type distribution was 54% 4qA/4qA, 43% 4qA/4qB and 3% 4qB/4qB. The methylation analysis was performed only on carriers of at least one 4qA allele. After refining the classification threshold, the test reached the following performance metrics: sensitivity = 0.90, specificity = 1.00 and accuracy = 0.93. These results confirmed the effectiveness of the methylation assay in identifying patients with genetic signature compatible with FSHD1 and FSHD2 based on their DUX4-PAS and DR1 profile, respectively. The methylation data were also evaluated with respect to the clinical information., Conclusions: The study confirmed the ability of the method to accurately identify methylation profiles compatible with FSHD genetic signatures considering the 4q genotype. Moreover, the test allows the detection of hypomethylated profiles in asymptomatic patients, suggesting its potential application in identifying preclinical conditions in patients with positive family history and FSHD genetic signatures. Furthermore, the present work emphasizes the importance of interpreting methylation profiles considering the patients' clinical data., (© 2024. The Author(s).)

Background: Osteoporotic vertebral compression fractures (OVCF) severely affect the quality of life in the aged population. Percutaneous vertebroplasty (PVP) alleviates pain and stabilizes vertebrae, but suboptimal bone cement distribution can cause complications. Hence, this study aimed to clarify whether a new technique for PVP, using a curved guide wire, enhances the distribution of bone cement and improves clinical outcomes in patients with OVCF., Methods: Patients with single-segment OVCF underwent PVP or curved guide wire percutaneous vertebroplasty (C-PVP). Propensity score matching (PSM) was employed to balanced the baseline characteristics. The primary outcomes were the visual analog scale (VAS) and Oswestry disability index (ODI) scores. The secondary outcomes included assessments of bone cement distribution, bone cement injection volume, radiological parameters, and general clinical results. Additionally, Complications and adverse events were documented., Results: After PSM analysis, each group comprised 54 patients, which significantly reduced baseline differences. The C-PVP group showed better clinical outcomes compared to the traditional PVP group. One month after surgery, the C-PVP group had significantly lower VAS and ODI scores (p < 0.001). These improvements persisted at six months and the final follow-up. Additionally, bone cement distribution scores were better (p < 0.001), injection volume was higher (p = 0.03), leakage was less frequent (p = 0.02), and adjacent vertebral fractures occurred less frequently (p = 0.04) in the C-PVP group. Radiological parameters and overall clinical outcomes revealed no significant differences between the two groups., Conclusion: The use of curved guide wire in PVP significantly improves bone cement distribution and injection volume, resulting in better clinical efficacy in patients with OVCF., (© 2024. The Author(s).)

Background: Gestational diabetes mellitus occurs in approximately 15-17% of pregnant women worldwide and causes high mortality and morbidity for mothers and infants. Pregnant women who are newly diagnosed with gestational diabetes mellitus experience higher levels of stress and anxiety than pregnant women without this condition. Thus, it is important to identify effective interventions to help pregnant women cope with the additional stress and anxiety associated with pregnancy-related complications., Aim: This integrative review aimed to synthesise evidence on the effects of educational interventions for pregnant women with gestational diabetes mellitus regarding knowledge, self-efficacy, self-care behaviour, anxiety, depression, and birth outcomes., Methods: An integrative review of articles published between 2009 and 2024, written in English and Arabic. The review followed the Whittemore and Knafl's 5-stage process framework., Results: From the 922 abstracts identified using search terms, 16 articles were eligible for this review. Psychoeducational interventions were provided for (1) informational support: information about gestational diabetes mellitus, diabetes mellitus, blood glucose monitoring, exercise management, diet management, and stress; (2) motivational support: setting individual goals, enhancing health behaviours, and motivational messages; (3) emotional support: expression of feelings, enforcement of self-management, and sharing of experiences; and (4) relaxation techniques: breathing exercises, meditation, and mindfulness. In this review, only two studies entirely focused on reducing stress and anxiety through cognitive-behavioural stress management training and mindfulness training. The effects of the interventions on self-efficacy, knowledge, depression, anxiety, and birthing outcomes were inconsistent due to variations in intervention designs and duration. However, consistent positive outcomes were found in self-care behaviours., Conclusion: This integrative review found informational and motivational support were frequently used by pregnant women. In contrast, emotional support and relaxation techniques were rarely used. Psychoeducational interventions may enhance self-care behaviours, improve self-efficacy, and reduce stress and depression for women with gestational diabetes mellitus. Nurses and midwives play an essential role in providing holistic care through comprehensive psychoeducational interventions for pregnant women., (© 2024. The Author(s).)

Background: Focal epilepsy is common in children and adults with mitochondrial disease. Seizures are often refractory to pharmacological treatment and, in this patient group, frequently evolve to refractory focal status epilepticus (also known as epilepsia partialis continua). Where this occurs, the long-term prognosis is poor. Transcranial DC stimulation (tDCS) is a promising, non-invasive, adjunctive treatment alternative to common surgical procedures. Limited recruitment of study participants with this rare disease and the ethical challenges of administering a treatment to one group and not another, while maintaining strict methodological rigour can pose challenges to the design of a clinical study., Method: We designed the first delayed start, double-blinded, sham-controlled study to evaluate the efficacy of tDCS as an adjunctive treatment for focal epilepsy. We will include participants with a genetically confirmed diagnosis of mitochondrial disease with drug-resistant focal epilepsy aged ≥ 2 years, aiming to collect 30 episodes of focal status epilepticus, each treated for a maximum period of 14 days. The early start intervention arm will receive tDCS from day 1. The delayed start intervention arm will receive sham stimulation until crossover on day 3. Our primary endpoint is a greater than 50% reduction from baseline (on day 0) in seizure frequency assessed by 3x daily reporting, accelerometery, and video monitoring. Changes in the underlying epileptogenic focus within the brain related to the tDCS intervention will be assessed by magnetic resonance imaging (MRI) and/or electroencephalography (EEG)., Discussion: Study results in favour of treatment efficacy would support development of tDCS into a mainstream treatment option for focal epileptic seizures related to mitochondrial disease., Trials Registration: ISRCTN: 18,241,112; registered on 16/11/2021., (© 2024. The Author(s).)

Background: Though artificial intelligence holds great value for healthcare, it may also amplify health inequalities through risks of bias. In this paper, we explore bias risks in targeted medicines manufacturing. Targeted medicines manufacturing refers to the act of making medicines targeted to individual patients or to subpopulations of patients within a general group, which can be achieved, for example, by means of cell and gene therapies. These manufacturing processes are increasingly reliant on digitalised systems which can be controlled by artificial intelligence algorithms. Whether and how bias might turn up in the process, however, is uncertain due to the novelty of the development., Methods: Examining stakeholder views across bioethics, precision medicine, and artificial intelligence, we document a range of opinions from eleven semi-structured interviews about the possibility of bias in AI-driven targeted therapies manufacturing., Result: Findings show that bias can emerge in upstream (research and development) and downstream (medicine production) processes when manufacturing targeted medicines. However, interviewees emphasized that downstream processes, particularly those not relying on patient or population data, may have lower bias risks. The study also identified a spectrum of bias meanings ranging from negative and ambivalent to positive and productive. Notably, some participants highlighted the potential for certain biases to have productive moral value in correcting health inequalities. This idea of "corrective bias" problematizes the conventional understanding of bias as primarily a negative concept defined by systematic error or unfair outcomes and suggests potential value in capitalizing on biases to help address health inequalities. Our analysis also indicates, however, that the concept of "corrective bias" requires further critical reflection before they can be used to this end., (© 2024. The Author(s).)

Background: The process of identifying and discontinuing medicines in instances in which harms outweigh benefits (deprescribing) can mitigate the negative consequences of problematic polypharmacy. This process should be conducted with a focus on the patient and involve collaborative decision-making. Evidence is needed regarding patients' views on how deprescribing should be safely and routinely implemented in English primary care to improve its application. This study aimed to identify optimal methods of introducing and actioning deprescribing from the patient's perspective., Methods: Participants in England aged 65 and above who were taking five or more medicines and residing in their own homes were recruited through social media and service user groups. An interview guide was created from deprescribing literature and input from patients and the public, guided by the Normalisation Process Theory (NPT). The interviews were held online using Microsoft Teams ® or via phone, recorded, and then transcribed. The data was analysed using the Framework analysis., Results: Twenty patients (mean age of 74.5, SD = 6.93), with 75% being female, were enrolled in the study. Three main themes emerged: (1) 'Why deprescribe now?' emphasised the significance of explaining the reasons behind deprescribing; (2) 'Monitoring and follow-up' underscored the necessity of safety measures during deprescribing and patients' willingness to self-monitor post-intervention; (3) 'Roles and relationships' explored patient perceptions of various healthcare professionals involved in deprescribing and the essential interpersonal skills for fostering therapeutic relationships., Conclusion: Optimal methods of introducing deprescribing included communicating a convincing rationale for stopping medicines and preparing patients for deprescribing conversations. Patients required support from a range of healthcare professionals with whom they had an existing therapeutic relationship. Whilst patients were motivated to self-monitor unwanted/unexpected effects post-deprescribing, timely support was required. The nature of such bolstered collective action and cognitive participation within NPT enhances the normalisation potential of deprescribing. These findings highlight the significance of considering the content and process of deprescribing consultations to enhance normalisation and tackle problematic polypharmacy. This provides a deeper understanding of patients' needs for implementing safe and routine deprescribing in primary care, which should be considered when designing medication review and deprescribing services., (© 2024. The Author(s).)

Background: Older adults living with multiple long-term conditions (MLTC, also known as multimorbidity) and frailty are more likely to experience a deterioration in their health requiring specialist referral or hospital admission than individuals without these syndromes. However, this group of older people are underserved by research meaning that there is a limited evidence base for their care. This study therefore aimed (1) to determine if it is feasible to recruit and collect quantitative data to describe the health and lifestyle of older adults living with MLTC, frailty and a recent deterioration in health and (2) to assess if taking part in research is acceptable to this group of older adults., Methods: Participants were approached and recruited for this study via an Older People's Medicine Day Unit in Newcastle upon Tyne, UK. The study took a mixed methods approach, involving quantitative and qualitative data collection. To determine the feasibility of carrying out research in this group, we quantified recruitment rate and collected data on the health and lifestyle, including diet and physical activity, of the participants. Qualitative semi-structured interviews were undertaken to assess acceptability. Two separate interviews were carried out focusing on involving older adults in research and the participants' experiences of taking part in the research. Interviews were analysed using thematic analysis., Results: Fifty patients were approached to participate in the study with twenty-nine (58%) successfully recruited. It was feasible to collect information to describe the health and lifestyle of these older adults who demonstrated very low levels of physical activity. Participants reported that taking part in the research was acceptable to them with interview analysis generating three themes (1) developing a meaningful partnership, (2) enabling factors to participation: research at home with flexible delivery and (3) social and psychological benefits of research participation., Conclusions: It is feasible and acceptable to recruit and carry out research with this underserved group of older adults. Participants found taking part in this research to be acceptable and reported overall positive experiences of their involvement in the study and indicated that they would be willing to contribute to further research in the future., (© 2024. The Author(s).)

Background: Pangolins are the only mammals that have overlapping scales covering most of their bodies, and they play a crucial role in the ecosystem, biological research, and human health and disease. Previous studies indicated pangolin scale might provide an important mechanical defense to themselves. The origin and exact functions of this unique trait remain a mystery. Using a multi-omics analysis approach, we report a novel functional explanation for how mammalian scales can provide host-pathogen defense., Results: Our data suggest that pangolin scales have a sophisticated structure that could potentially trap pathogens. We identified numerous proteins and metabolites exhibiting antimicrobial activity, which could suggest a role for scales in pathogen defense. Notably, we found evidence suggesting the presence of exosomes derived from diverse cellular origins, including mesenchymal stem cells, immune cells, and keratinocytes. This observation suggests a complex interplay where various cell types may contribute to the release of exosomes and antimicrobial compounds at the interface between scales and viable tissue. These findings indicate that pangolin scales may serve as a multifaceted defense system, potentially contributing to innate immunity. Comparisons with human nail and hair revealed pangolin-specific proteins that were enriched in functions relating to sensing, immune responses, neutrophil degranulation, and stress responses. We demonstrated the antimicrobial activity of key pangolin scale components on pathogenic bacteria by antimicrobial assays., Conclusions: This study identifies a potential role of pangolin scales and implicates scales, as possible determinants of pathogen defense due to their structure and contents. We indicate for the first time the presence of exosomes in pangolin scales and propose the new functions of scales and their mechanisms. This new mechanism could have implications for multiple fields, including providing interesting new research directions and important insights that can be useful for synthesizing and implementing new biomimetic antimicrobial approaches., (© 2024. The Author(s).)

Background: The delivery of high-quality services in chronically underfunded social or long-term care systems is a major challenge internationally. National guidelines, developed by the National Institute for Health and Care Excellence, set out how local authorities in England and Wales should fund and provide care based on best available evidence. Theoretical and participatory approaches can usefully inform the design and evaluation of implementation strategies for guidelines. The aim of the study is to develop a Theory-of-Change for how the implementation of these guidelines is expected to lead to impacts from a local authority perspective., Methods: As part of a comparative case study (The 'Valuing Care Guidelines' study; February 2022 to April 2024) with three local authority sites in England and Wales, we involved altogether 17 participants in two Theory-of-Change online workshops per site, each of 2 hours. Additional data gathered from the same participants as part of the overall study were used to conceptualise and enrich information from the workshops., Results: Participants described the Theory-of-Change map as follows: A wide range of activities (categorised in stages of 'pre-implementation', 'implementation', 'sustainment and scaling') and skills were required to implement guidelines, and achieve long-term organisational sustainability and service delivery outcomes, leading to final impacts for service users and carers. Participants described a co-creation implementation model, led by 'Implementation Support Practitioners', who utilised relational skills to achieve motivation, trust, and confidence at different organisational levels, addressing contextual barriers such as inadequate staffing, lack of resources and of organisational support systems. Consistent use of guidelines by frontline staff could only be achieved if the value of guideline implementation was promoted widely, and if consideration was given to the roles of stakeholders, such as the inspection body, local health care providers, users and carers., Conclusions: Our study is the first to investigate the implementation of national social care guidelines by local authorities in England and Wales. It generates insights that can guide implementation practice as well as inform the evaluation of future implementation strategies., (© 2024. The Author(s).)

Background: Cell therapy can protect cardiomyocytes from hypoxia, primarily via paracrine secretions, including extracellular vesicles (EVs). Since EVs fulfil specific biological functions based on their cellular origin, we hypothesised that EVs from human cardiac stromal cells (CMSCLCs) obtained from coronary artery bypass surgery may have cardioprotective properties., Objectives: This study characterises CMSCLC EVs (C&#95;EVs), miRNA cargo, cardioprotective efficacy and transcriptomic modulation of hypoxic human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). C&#95;EVs are compared to bone marrow mesenchymal stromal cell EVs (B&#95;EVs) which are a known therapeutic EV type., Methods: Cells were characterised for surface markers, gene expression and differentiation potential. EVs were compared for yield, phenotype, and ability to protect hiPSC-CMs from hypoxia/reoxygenation injury. EV dose was normalised by both protein concentration and particle count, allowing direct comparison. C&#95;EV and B&#95;EV miRNA cargo was profiled and RNA-seq was performed on EV-treated hypoxic hiPSC-CMs, then data were integrated by multi-omics. Confirmatory experiments were carried out using miRNA mimics., Results: At the same dose, C&#95;EVs were more effective than B&#95;EVs at protecting CM integrity, reducing apoptotic markers, and cell death during hypoxia. While C&#95;EVs and B&#95;EVs shared 70-77% similarity in miRNA content, C&#95;EVs contained unique miRNAs, including miR-202-5p, miR-451a and miR-142-3p. Delivering miRNA mimics confirmed that miR-1260a and miR-202/451a/142 were cardioprotective, and the latter upregulated protective pathways similar to whole C&#95;EVs., Conclusions: This study demonstrates the potential of cardiac tissues, routinely discarded following surgery, as a valuable source of EVs for myocardial infarction therapy. We also identify miR-1260a as protective of CM hypoxia., (© 2024. The Author(s).)

Background: Sarcopenia is a leading cause of functional decline, loss of independence, premature mortality, and frailty in older adults. Reducing and breaking up sedentary behaviour is associated with positive sarcopenia and frailty outcomes. This study aimed to explore the acceptability, engagement and experiences of a remotely delivered sedentary behaviour intervention to improve sarcopenia and independent living in older adults with frailty., Methods: This was a mixed-methods study. In-depth qualitative semi-structed interviews were conducted with a subset (N = 15) of participants with frailty (aged 74 ± 6 years) who had participated in the Frail-LESS (LEss Sitting and Sarcopenia in Frail older adults) intervention aimed at reducing sedentary behaviour. The interviews explored acceptability of the intervention overall and its individual components (a psychoeducation workbook, wrist-worn activity tracker, health coaching, online peer support and tailored feedback on sitting, standing and stepping). Process evaluation questionnaires with closed and scaled questions explored intervention engagement, fidelity and experiences., Results: Overall acceptability of the intervention was good with most participants perceiving the intervention to have supported them in reducing and/or breaking up their sedentary behaviour. The wrist-worn activity tracker and health coaching appeared to be the most acceptable and useful components, with high levels of engagement. There was attendance at 104 of 150 health coaching sessions offered and 92% of participants reported using the wrist-worn activity tracker. There was a mixed response regarding acceptability of, and engagement with, the psychoeducation workbook, tailored feedback, and online peer support., Conclusions: The Frail-LESS intervention had good levels of acceptability and engagement for some components. The findings of the study can inform modifications to the intervention to optimise acceptability and engagement in a future definitive randomised controlled trial., Trial Registration: The trial was registered with ISRCTN (number ISRCTN17158017)., (© 2024. The Author(s).)

Background: Antibiotic resistant infections cause over 700,000 deaths worldwide annually. As antimicrobial stewardship (AMS) helps minimise the emergence of antibiotic resistance resulting from inappropriate use of antibiotics in healthcare, we developed ePAMS+ (ePrescribing-based Anti-Microbial Stewardship), an ePrescribing and Medicines Administration (EPMA) system decision-support tool complemented by educational, behavioural and organisational elements., Methods: We conducted a non-randomised before-and-after feasibility trial, implementing ePAMS+ in two English hospitals using the Cerner Millennium EPMA system. Wards of several specialties were included. Patient participants were blinded to whether ePAMS+ was in use; prescribers were not. A mixed-methods evaluation aimed to establish: acceptability and usability of ePAMS+ and trial processes; feasibility of ePAMS+ implementation and quantitative outcome recording; and a Fidelity Index measuring the extent to which ePAMS+ was delivered as intended. Longitudinal semi-structured interviews of doctors, nurses and pharmacists, alongside non-participant observations, gathered qualitative data; we extracted quantitative prescribing data from the EPMA system. Normal linear modelling of the defined daily dose (DDD) of antibiotic per admission quantified its variability, to inform sample size calculations for a future trial of ePAMS+ effectiveness., Results: The research took place during the SARS-CoV-2 pandemic, from April 2021 to November 2022. 60 qualitative interviews were conducted (33 before ePAMS+ implementation, 27 after). 1,958 admissions (1,358 before ePAMS+ implementation; 600 after) included 24,884 antibiotic orders. Qualitative interviews confirmed that some aspects of ePAMS+ , its implementation and training were acceptable, while other features (e.g. enabling combinations of antibiotics to be prescribed) required further development. ePAMS+ uptake was low (28 antibiotic review records from 600 admissions; 0.047 records per admission), preventing full development of a Fidelity Index. Normal linear modelling of antibiotic DDD per admission showed a residual variance of 1.086 (log-transformed scale). Unavailability of indication data prevented measurement of some outcomes (e.g. number of antibiotic courses per indication)., Conclusions: This feasibility trial encountered unforeseen circumstances due to contextual factors and a global pandemic, highlighting the need for careful adaptation of complex intervention implementations to the local setting. We identified key refinements to ePAMS+ to support its wider adoption in clinical practice, requiring further piloting before a confirmatory effectiveness trial., Trial Registration: ISRCTN Registry ISRCTN13429325, 24 March 2022., (© 2024. The Author(s).)

Background: Internationally, there has been a move towards fostering diverse healthcare workforces that are representative of the patient populations they serve. Selection criteria for academic-clinicians often aim to capture skills and attributes that demonstrate both clinical and academic excellence. Currently, it is not known whether the selection criteria for early academic-clinical careers advantage or disadvantage certain ethnic or socioeconomic groups. The UK has a structured route of integrated clinical academic training with entry level training for newly qualified doctors administered through the 'Specialised Foundation Programme' which provides protected time for research within the first two years of postgraduate clinical training. In this study, we aim to identify what selection criteria are used within the UK Specialised Foundation Programme, and how these relate to demographic factors., Methods: We will perform a mixed methods study consisting of a document analysis of person specifications and selection criteria used in the 2024 UK Specialised Foundation Programme, and a national cross-sectional survey of current medical students in the UK. We will obtain the person specifications, selection criteria, white space (open ended questions used during shortlisting) and interview questions and mark schemes from each Specialised Unit of Applications via information available on their websites or through Freedom of Information requests. Our survey will collect information relating to demographic data, selection criteria, and perceptions of specialised foundation programme selection., Discussion: International literature has demonstrated inequity in academic markers used in selection of post-graduate clinicians and that disadvantages caused by selection can compound over time. As such it is important to understand what inequity exists within the selection of early academic-clinicians, as this can help inform more equitable selection practices and help nurture a more diverse academic-clinical workforce., (© 2024. The Author(s).)

Background: The path of a complaint and patient satisfaction with complaint resolution is often dependent on the responses of healthcare professionals (HCPs). It is therefore important to understand the influences shaping HCP behaviour. This systematic review aimed to (1) identify the key actors, behaviours and factors influencing HCPs' responses to complaints, and (2) apply behavioural science frameworks to classify these influences and provide recommendations for more effective complaints handling behaviours., Methods: A systematic literature review of UK published and unpublished (so-called grey literature) studies was conducted (PROSPERO registration: CRD42022301980). Five electronic databases [Scopus, MEDLINE/Ovid, Embase, Cumulated Index to Nursing and Allied Health Literature (CINAHL) and Health Management Information Consortium (HMIC)] were searched up to September 2021. Eligibility criteria included studies reporting primary data, conducted in secondary and tertiary care, written in English and published between 2001 and 2021 (studies from primary care, mental health, forensic, paediatric or dental care services were excluded). Extracted data included study characteristics, participant quotations from qualitative studies, results from questionnaire and survey studies, case studies reported in commentaries and descriptions, and summaries of results from reports. Data were synthesized narratively using inductive thematic analysis, followed by deductive mapping to the Theoretical Domains Framework (TDF)., Results: In all, 22 articles and three reports met the inclusion criteria. A total of 8 actors, 22 behaviours and 24 influences on behaviour were found. Key factors influencing effective handling of complaints included HCPs' knowledge of procedures, communication skills and training, available time and resources, inherent contradictions within the role, role authority, HCPs' beliefs about their ability to handle complaints, beliefs about the value of complaints, managerial and peer support and organizational culture and emotions. Themes mapped onto nine TDF domains: knowledge, skills, environmental context and resources, social/professional role and identity, social influences, beliefs about capability, intentions and beliefs about consequences and emotions. Recommendations were generated using the Behaviour Change Wheel approach., Conclusions: Through the application of behavioural science, we identified a wide range of individual, social/organizational and environmental influences on complaints handling. Our behavioural analysis informed recommendations for future intervention strategies, with particular emphasis on reframing and building on the positive aspects of complaints as an underutilized source of feedback at an individual and organizational level., (© 2024. The Author(s).)

Background: Enhancing long-term support for post-stroke cognitive impairment is a top research priority. Addressing current gaps in UK post-stroke cognitive care provision requires a pragmatic and scalable intervention that can be integrated within the existing stroke care pathway. This study aimed to develop consensus on an initial set of core features for a UK-based monitoring and psychoeducational intervention for cognitive changes after stroke., Methods: An expert panel of UK healthcare professionals and researchers participated in an online modified Delphi survey. Candidate intervention features were identified from clinical guidelines, existing literature, research team/collaborator expertise, and PPI group lived experience. Survey participants indicated whether they agreed/disagreed/had no opinion about including each candidate feature in the intervention and free-text responses were invited. We analysed responses for consensus (≥ 75% agreement) using descriptive statistics, with items not reaching consensus carried into subsequent rounds. Template analysis was used to identify similarities/differences in viewpoints for items that did not reach consensus., Results: Three survey rounds were completed by 36, 29 and 26 participants, respectively. Participants agreed reviews should include a stroke-specific cognitive screen (97% agree) and assessment of other psychological changes (low mood, anxiety, fatigue: 94%, 90%, 89% agree, respectively). They agreed stroke survivors should be offered at least one review, regardless of their cognitive profile in hospital. They agreed on the importance of various cognition-focused psychoeducation topics, and formal (100% agree) and informal (79% agree) training for those conducting reviews. Consensus was not reached on the review mode (in person/remote options: 67% agree), offering reviews one-year post-discharge to patients without acute cognitive impairments (68% disagree), or including a dementia screen (63% disagree) and/or neuropsychological assessment battery (58% disagree). However, there were similarities in participant viewpoints. For example, participants emphasised the importance of onwards referral where clinically indicated.   CONCLUSIONS: The UK-based post-stroke monitoring and psychoeducation intervention was originally conceptualised as a cognitive care pathway, but expert participants agreed on the importance of simultaneously addressing related psychological changes (e.g. low mood, anxiety). There was clear consensus on a minimum set of intervention features. Recommendations outlined here may usefully inform local service improvements., (© 2024. The Author(s).)

Background: Patients undergo regular clinical follow-up after laminoplasty for cervical myelopathy. However, those whose symptoms significantly improve and remain stable do not need to conform to a regular follow-up schedule. Based on the 1-year postoperative outcomes, we aimed to use a machine-learning (ML) algorithm to predict 2-year postoperative outcomes., Methods: We enrolled 80 patients who underwent cervical laminoplasty for cervical myelopathy. The patients' Japanese Orthopedic Association (JOA) scores (range: 0-17) were analyzed at the 1-, 3-, 6-, and 12-month postoperative timepoints to evaluate their ability to predict the 2-year postoperative outcomes. The patient acceptable symptom state (PASS) was defined as a JOA score ≥ 14.25 at 24 months postoperatively and, based on clinical outcomes recorded up to the 1-year postoperative timepoint, eight ML algorithms were developed to predict PASS status at the 24-month postoperative timepoint. The performance of each of these algorithms was evaluated, and its generalizability was assessed using a prospective internal test set., Results: The long short-term memory (LSTM)-based algorithm demonstrated the best performance (area under the receiver operating characteristic curve, 0.90 ± 0.13)., Conclusions: The LSTM-based algorithm accurately predicted which group was likely to achieve PASS at the 24-month postoperative timepoint. Although this study included a small number of patients with limited available clinical data, the concept of using past outcomes to predict further outcomes presented herein may provide insights for optimizing clinical schedules and efficient medical resource utilization., Trial Registration: This study was registered as a clinical trial (Clinical Trial No. NCT02487901), and the study protocol was approved by the Seoul National University Hospital Institutional Review Board (IRB No. 1505-037-670)., (© 2024. The Author(s).)

Background: The karyotype is a major determinant of prognosis in myelodysplastic syndrome (MDS). Details of the cytogenetic profile of MDS in South Asia are limited because cytogenetic services are not widely available., Methods: We performed a retrospective analysis of the cytogenetic and clinicopathologic profile of adult primary MDS seen consecutively at a tertiary-care centre in South India between 2003 and 2017. Patients were re-categorised according to the 2022 World Health Organisation (WHO) and the International Consensus classifications (ICC)., Results: There were 936 patients aged 18-86 years (median age 53, 65% males), with MDS with del 5q, low blasts and increased blasts in 7.5%, 58.4% and 34.1% respectively. Clonal abnormalities were seen in 55% of patients, with solitary abnormalities in 29.8% and complex karyotypes (CK, ≥ 3 abnormalities) in 15%. The most frequent abnormalities were monosomy 7/deletion 7q (16.1%), deletion 5q (14.5%), trisomy 8 (11.5%), and deletion 20q (5.1%). Cytogenetic prognosis groups were distributed as follows: very good, 2%; good, 55.6%; intermediate, 16.2%; poor, 15%; very poor, 11.2%. Clinical (IPSS-R) risk stratification (842 patients) showed: very low-risk, 3.9%; low-risk, 30.9%; intermediate-risk, 24.2%; high-risk, 21%; very high-risk, 20%. Age-adjustment (IPSS-RA) raised the very low-risk group to 12.4%; the other groups decreased by 1-3% each., Conclusion: The most significant finding of this cytogenetic analysis of MDS in India is that abnormal karyotypes with poor prognosis markers including monosomy 7 and CK were more frequent than in most other reports, among patients who were overall younger. Trisomy 8, deletion 20q, the IPSS-R intermediate-risk and both high-risk groups were more common than in the West. Trisomy 8 was less common than in South-East Asia while CK and deletion 20q were comparable. Evaluation of such large cohorts highlights the unique features of MDS in different parts of the world. These findings suggest that there could be differences in predisposing factors, environmental or genetic, and emphasise the need for further exploration to better understand the varied nature of MDS., (© 2024. The Author(s).)

The Illumina Methylation array platform has facilitated countless epigenetic studies on DNA methylation (DNAme) in health and disease, yet relatively few studies have so studied its reliability, i.e., the consistency of repeated measures. Here we investigate the reliability of both type I and type II Infinium probes. We propose a method for excluding unreliable probes based on dynamic thresholds for mean intensity (MI) and 'unreliability', estimated by probe-level simulation of the influence of technical noise on methylation β values using the background intensities of negative control probes. We validate our method in several datasets, including newly generated Illumina MethylationEPIC BeadChip v1.0 data from paired whole blood samples taken six weeks apart and technical replicates spanning multiple sample types. Our analysis revealed that specifically probes with low MI exhibit higher β value variability between repeated samples. MI was associated with the number of C-bases in the respective probe sequence and correlated negatively with unreliability scores. The unreliability scores were substantiated through validation in a new EPIC v1.0 (blood and cervix) and a publicly available 450k (blood) dataset, as they effectively captured the variability observed in β values between technical replicates. Finally, despite promising higher robustness, the newer version v2.0 of the MethylationEPIC BeadChip retained a substantial number of probes with poor unreliability scores. To enhance current pre-processing pipelines, we developed an R package to calculate MI and unreliability scores and provide guidance on establishing optimal dynamic score thresholds for a given dataset., (© 2024. The Author(s).)

Background: In Ethiopia, 79 million people live in soil transmitted helminths endemic areas. The Ethiopia established a National goal to eradicate STH transmission by 2025. To meet that goal, it is imperative that data is acquired on community helminth infection risk. This study examined the prevalence of STH and risk factors for infection in vegetable farmers working on Akaki River Bank, Addis Ababa, Ethiopia., Methods: A cross-sectional study was conducted between November 7, 2022, and June 2023. A stratified random sampling was used to select farming households. Two hundred and sixteen farmers were enrolled in the study. Data on socio-demographic, WASH, wastewater irrigation related factors were collected by trained data collectors using a structured questionnaire. Kato-Katz concentration was utilized to detect STH. The data were entered using EpiData 3.1 and analyzed with Stata 14.0, using p-values less than 0.05 to identify significant factors. Logistic regression was used to identify independent risk factors for infection., Results: The prevalence of STH was 22.2% (95% CI = 13.6-27.9%), with Ascaris lumbricoides being the most common (11.1%), followed by hookworm (7.4%), and Trichuris trichiura (3.7%). Low income levels (AOR = 1.85, 95% CI = 1.25-5.99), lack of handwashing before eating (AOR = 2.25, 95% CI = 1.58 - 11.3), absence of fingernails cleanliness (AOR = 1.97, 95% CI = 1.74-39.5), not wearing shoes at work (AOR = 3.4, 95% CI = 2.98-82.2), touching the face with dirty hands (AOR = 2.9, 95% CI = 0.68-28.2), washing vegetables with irrigation wastewater (AOR = 2.1, 95% CI = 1.95-45.2), and not wearing protective clothing during farming activities (AOR = 2.99, 95% CI = 1.58 - 22.4) were the significant risk factors for infection with STH., Conclusion: Of the farming communities examined in this study, one of the five was found to be infected with soil transmitted helminth. This research has shown clear risk factors for STH infection including: lack of personal hygiene practices, insufficient sanitation access, and limited use of protective equipment. To achieve the national goal, there is a need for farming communities to understand preventative risks of infection, improve WASH (Water access, sanitation and hygine) practices, WASH access, protective equipment, and health education., (© 2024. The Author(s).)