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Background: Web-based experimentation, accelerated by the COVID-19 pandemic, has enabled large-scale participant recruitment and data collection. Auditory testing on the web has shown promise but faces challenges such as uncontrolled environments and verifying headphone use. Prior studies have successfully replicated auditory experiments but often involved younger participants, limiting the generalizability to older adults with varying hearing abilities. This study explores the feasibility of conducting reliable auditory cognitive testing using a web-based platform, especially among older adults., Objective: This study aims to determine whether demographic factors such as age and hearing status influence participation in web-based auditory cognitive experiments and to assess the reproducibility of auditory cognitive measures-specifically speech-in-noise perception and auditory memory (AuM)-between in-person and web-based settings. Additionally, this study aims to examine the relationship between musical sophistication, measured by the Goldsmiths Musical Sophistication Index (GMSI), and auditory cognitive measures across different testing environments., Methods: A total of 153 participants aged 50 to 86 years were recruited from local registries and memory clinics; 58 of these returned for web-based, follow-up assessments. An additional 89 participants from the PREVENT cohort were included in the web-based study, forming a combined sample. Participants completed speech-in-noise perception tasks (Digits-in-Noise and Speech-in-Babble), AuM tests for frequency and amplitude modulation rate, and the GMSI questionnaire. In-person testing was conducted in a soundproof room with standardized equipment, while web-based tests required participants to use headphones in a quiet room via a web-based app. The reproducibility of auditory measures was evaluated using Pearson and intraclass correlation coefficients, and statistical analyses assessed relationships between variables across settings., Results: Older participants and those with severe hearing loss were underrepresented in the web-based follow-up. The GMSI questionnaire demonstrated the highest reproducibility (r=0.82), while auditory cognitive tasks showed moderate reproducibility (Digits-in-Noise and Speech-in-Babble r=0.55 AuM tests for frequency r=0.75 and amplitude modulation rate r=0.44). There were no significant differences in the correlation between age and auditory measures across in-person and web-based settings (all P>.05). The study replicated previously reported associations between AuM and GMSI scores, as well as sentence-in-noise perception, indicating consistency across testing environments., Conclusions: Web-based auditory cognitive testing is feasible and yields results comparable to in-person testing, especially for questionnaire-based measures like the GMSI. While auditory tasks demonstrated moderate reproducibility, the consistent replication of key associations suggests that web-based testing is a viable alternative for auditory cognition research. However, the underrepresentation of older adults and those with severe hearing loss highlights a need to address barriers to web-based participation. Future work should explore methods to enhance inclusivity, such as remote guided testing, and address factors like digital literacy and equipment standards to improve the representativeness and quality of web-based auditory research., (©Meher Lad, John-Paul Taylor, Timothy David Griffiths. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 09.12.2024.)

Introduction: The increasing prevalence of cardiometabolic diseases highlights the urgent need for practical interventions to mitigate their associated public health burden. Whey protein supplementation has emerged as a potential intervention for improving markers of cardiometabolic health. The aim of this systematic review and meta-analysis was to examine the effect of whey protein ingestion on cardiometabolic profile in adults., Methods: A systematic search was conducted in PubMed, Web of Science, Scopus, and Cochrane Library from inception until June 2024. Eligible RCTs compared the effect of whey protein supplementation compared to placebo or a carbohydrate-based control on markers of cardiometabolic health. Using the random effects inverse-variance model, we estimated the mean difference (MD) in blood pressure, high- and low-density lipoproteins (HDL-cholesterol, LDL-cholesterol), total cholesterol, triglycerides, and homeostatic model assessment for insulin resistance (HOMA-IR) index., Results: This meta-analysis included 21 RCTs. Whey protein supplementation had no effect on HDL-cholesterol concentration but did elicit a reduction in LDL-cholesterol in individuals aged <50 years (P < 0.01) and when combined with exercise (MD: -5.38, 95 % confidence interval (95 % CI): -8.87 to -1.88, I 2  = 0 %, P < 0.01). Total cholesterol was reduced with interventions that combined whey protein supplementation and exercise (MD: -8.58, -14.32 to -2.83, I 2  = 55 %, P < 0.01), irrespective of age, protein dose, and body mass index ≥25 kg/m 2 (MD: -6.71, 95 % CI: -11.60 to -1.83, I 2  = 74 %, P < 0.01). Whey protein supplementation of ≥12 weeks was associated with reduced triglyceride levels (MD: -6.61, 95 % CI: -11.06 to -2.17, I 2  = 70 %, P < 0.01). There was no clinically relevant effect of whey protein supplementation on blood pressure and HOMA-IR, however, changes pertinent to HDL-cholesterol, total cholesterol, and triglyceride reduction were primarily displayed in healthy adults., Conclusions: Whey protein supplementation may be an effective intervention for reducing LDL and total cholesterol levels, particularly in healthy, overweight/obese adults aged <50 years, with the greatest benefits observed when combined with exercise. Healthy adults also showed a benefit regarding triglyceride levels., Competing Interests: Conflict of interest Authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We investigated associations between 'healthy dietary pattern' scores, at ages 36, 43, 53 and 60-64 years, and body composition at age 60-64 among participants from the MRC National Survey of Health and Development (NSHD). Principal component analyses of dietary data (food diaries) at age 60-64 were used to calculate diet scores (healthy dietary pattern scores) at each age. Higher scores indicated healthier diets (higher consumption of fruit, vegetables and wholegrain bread). Linear regression was used to investigate associations between diet scores at each age and height-adjusted dual-energy x-ray absorptiometry-measured fat and lean mass measures at age 60-64. Analyses, adjusting for sex and other potential confounders (age, smoking history, physical activity and occupational class), were implemented among 692 men and women. At age 43, 53 and 60-64, higher diet scores were associated with lower fat mass index (FMI) and android: gynoid fat mass ratio; for example, in fully-adjusted analyses, a standard deviation (SD) increase in diet score at age 60-64 was associated with a difference in mean FMI of -0.18 SD (95% CI: -0.25, -0.10). In conditional analyses, higher diet scores at ages 43, 53 and 60-64 (than expected from diet scores at younger ages) were associated with lower FMI and android: gynoid fat mass ratio in fully-adjusted analyses. Diet scores at age 36 had weaker associations with the outcomes considered. No associations regarding appendicular lean mass index were robust after full adjustment. This suggests that improvements in diet through adulthood are linked to beneficial effects on adiposity in older age.

Understanding the dominant direction of association between cardiorespiratory fitness (CRF) and grip strength could help refine physical activity recommendations. We performed a Mendelian Randomization (MR) analysis to elucidate the bidirectional relationship between CRF and grip strength (GS). Using an inverse-variance weighted (IVW) MR framework, we estimated the strength of the GS (exposure)-CRF (outcome) association using genome-wide association summary data. When examining the CRF (exposure)-GS (outcome) association, the CRF genetic instrument was related to individual-level GS phenotypic data in 367 693 UK Biobank participants. Several sensitivity analyses were performed (e.g., MR-Egger, MR-weighted median estimator and MR-PRESSO) and both measures were scaled by body weight (w). In the direction GS-to-CRF, a 1-unit increase in GSw (i.e., GS/weight) was associated with 1.70 mL/kg/min (95% confidence interval (CI): 1.14,2.27) higher CRFw (IVW model). This finding persisted across most sensitivity analyses. In the reverse direction, there was no evidence supporting an effect of CRFw on GSw, e.g., a 1-unit increase in CRFw led to a 0.00 kg/kg (95% CI: -0.01,0.02) higher GSw (IVW model). Our finding of a dominant direction of association from greater GS to higher CRF is relevant when considering how to promote physical activity guidelines. For example, placing too much emphasis on improving/maintaining CRF is unlikely to result in maximum benefits for other fundamental components of physical fitness, particularly muscle strength., (© 2024 The Author(s). Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Purpose: Sarcopenia is diagnosed on the basis of low muscle strength, with low muscle mass used to confirm diagnosis. The added value of measuring muscle mass is unclear. We undertook a systematic review to assess whether muscle mass measurement in patients with hip fracture was acceptable, feasible and independently associated with adverse outcomes., Methods: Electronic databases (MEDLINE, EMBASE, CENTRAL, CINAHL, Clinicaltrials.gov) were searched for studies of patients with hip fracture aged ≥ 60 with perioperative muscle mass or strength assessments. Associations with postoperative outcomes including death, length of stay and activities of daily living were extracted. Risk-of-bias was assessed using the AXIS and ROBINS-I tools. Due to the degree of study heterogeneity, data were analysed by narrative synthesis., Results: The search strategy identified 3317 records. 36 studies were included with 7860 participants. Acceptability of muscle mass measurement was not assessed, but measurement appeared feasible using biompedance, dual energy x-ray absorptiometry and computed tomography. Univariate analyses indicated that lower muscle mass was associated with higher death rates at 30 days, worse mobility, worse activity of daily living metrics and worse physical performance but there was no significant association with length of stay or postoperative complications. Four studies included both muscle mass and strength in multivariable analyses; muscle mass was a significant independent predictor of only one adverse outcome in a single study after adjustment for muscle strength and other predictor variables., Conclusion: Current data suggest that muscle mass assessment offers no additional prognostic information to muscle strength measures in patients with hip fracture., Competing Interests: Declarations. Conflict of interest: On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent: For this type of study formal consent is not required., (© 2024. The Author(s).)

Cutaneous T cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides, can be difficult to diagnose, resulting in treatment delay. We performed single-cell and spatial transcriptomics analysis of skin from patients with mycosis fungoides-type CTCL and an integrated comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. We revealed the co-optation of T helper 2 (T H 2) cell-immune gene programs by malignant CTCL cells and modeling of the tumor microenvironment to support their survival. We identified MHC-II + fibroblasts and dendritic cells that can maintain T H 2 cell-like tumor cells. CTCL tumor cells are spatially associated with B cells, forming tertiary lymphoid structure-like aggregates. Finally, we validated the enrichment of B cells in CTCL and its association with disease progression across three independent patient cohorts. Our findings provide diagnostic aids, potential biomarkers for disease staging and therapeutic strategies for CTCL., Competing Interests: Competing interests: In the past 3 years, S.A.T. has received remuneration for scientific advisory board membership from Sanofi, GlaxoSmithKline, Foresite Labs and Qiagen. She is a co-founder of and holds equity in Transition Bio and Ensocell. From 8 January 2024, she has been a part-time employee of GlaxoSmithKline. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Magnetic resonance imaging (MRI) is routinely used in the musculoskeletal system to measure skeletal muscle structure and pathology in health and disease. Recently, it has been shown that MRI also has promise for detecting the functional changes, which occur in muscles, commonly associated with a range of neuromuscular disorders. This review focuses on novel adaptations of MRI, which can detect the activity of the functional sub-units of skeletal muscle, the motor units, referred to as "motor unit MRI (MUMRI)." MUMRI utilizes pulsed gradient spin echo, pulsed gradient stimulated echo and phase contrast MRI sequences and has, so far, been used to investigate spontaneous motor unit activity (fasciculation) and used in combination with electrical nerve stimulation to study motor unit morphology and muscle twitch dynamics. Through detection of disease driven changes in motor unit activity, MUMRI shows promise as a tool to aid in both earlier diagnosis of neuromuscular disorders and to help in furthering our understanding of the underlying mechanisms, which proceed gross structural and anatomical changes within diseased muscle. Here, we summarize evidence for the use of MUMRI in neuromuscular disorders and discuss what future research is required to translate MUMRI toward clinical practice. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To investigate associations between glycaemic measures (HbA1c, random glucose), and grip strength (GS) in adults without prevalent diabetes., Methods: We included 381,715 UK Biobank participants aged 38-73 years without diabetes (any type) with complete baseline measures for GS and HbA1c (main analyses), and glucose (supplementary analyses). Cross-sectional sex- and age-stratified associations between each glycaemic measure, GS, and probable sarcopenia (low GS) were examined with regression analyses. Changes in GS over 8.9 years were classified into four groups (decline, stable low, stable high, or reference (increase or maintained within the normal range)) in 36,228 participants and associations with baseline glycaemic measures explored using multinomial regression., Results: Higher HbA1c (mmol/mol) was associated with weaker mean GS (kg) (regression coefficient and 95% confidence intervals (CI): - 0.08 (- 0.09, - 0.07)), and increased odds of probable sarcopenia (odds ratio (OR) and 95% CIs: 1.02 (95% CI: 1.01, 1.02)) in males and across the age groups. In females, higher HbA1c was associated with weaker mean GS only in mid-life (e.g., 50-59 years: - 0.06 (- 0.07, - 0.05)). In males, but not in females with repeated GS, higher HbA1c was associated with decreased odds of stable high (0.97 (0.96, 0.99) and increased odds of stable low (1.03 (1.01, 1.04)) GS pattern (0.98 (0.97, 0.980)) over the follow-up. The results for glucose in supplementary analyses were mixed, especially in females., Conclusions: The associations between HbA1c and GS in people without diabetes warrant replication and consideration of the effect on muscle strength when interventions to promote normoglycaemia are trialled., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest. Ethical approval: Ethical approval for the UK Biobank cohort study was obtained from the North West Multi‐Centre Research Ethics Committee, United Kingdom (ref: 11/NW/0382 on 17/06/2011; renewal ref: 21/NW/0157 on 29/06/2021). The ethical approvals also cover secondary data analyses. This research has been conducted using the UK Biobank Resource under Application Number 27567 (14/12/2016). Informed consent: All participants in the UK Biobank study gave written informed consent in accordance with the principals of the Declaration of Helsinki., (© 2024. The Author(s).)

Introduction: The aging population is a growing challenge for healthcare services and as such multi-morbidity and associated aging are the focus of research programs. Chronic limb threatening ischaemia (CLTI) in the older patient is perceived to be associated with high morbidity and mortality but a potentially contentious area with limited evidence., Methods: Retrospective review of all consecutive CLTI admissions to a UK tertiary vascular during 2020. Analysis included descriptive statistics and comparisons by age. The primary outcome was survival (by Kaplan-Meier with secondary outcomes being major adverse limb (MALE) and cardiovascular events (MACE)., Results: 183 patients, with a median age of 72 of which 55(30%) were octogenarians. Fewer octogenarians were diabetic (38.2% vs 58.6% , p=0.015), but comorbidities such as previous stroke (25.5% vs 10.9% , p=0.015) and atrial fibrillation (36.4% vs 16.4%, p=0.004) were increasingly common. 87.3% of octogenarians had moderate or severe frailty compared to 57.8% in those <80 (p=0.001)(by electronic frailty index). Median survival time was 30 months with no significant difference between groups (p=0.406). MACE (10.9% vs 7.81%, p=0.504) and MALE (34.5% vs 24.2% p=0.261) were comparable between groups. Octogenarians were less likely to have open surgery (10.9% vs 25.8%, p=0.024)., Conclusions: Octogenarians have similar cardiovascular, limb and survival outcomes following intervention despite being increasingly frail and comorbid. Holistic assessment, perioperative optimisation and risk stratification are important in this group., (Copyright © 2024. Published by Elsevier Inc.)

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: This scoping review mapped evidence on physical activity (including structured exercise) and sedentary behaviour interventions (interventions to reduce sedentary behaviour) in people living with both frailty and multiple long-term conditions (MLTCs) and their informal carers., Methods: Ten databases and grey literature were searched from 2000 to October 2023. Two reviewers screened studies and one extracted data. Results were shared with three stakeholder groups (n = 21) in a consultation phase., Results: After screening, 155 papers from 144 studies (1 ongoing) were retained. The majority were randomised controlled trials (86, 55%). Participants' mean age was 73 ± 12 years, and 73% were of White ethnicity. MLTC and frailty measurement varied widely. Most participants were pre-to-moderately frail. Physical health conditions predominated over mental health conditions.Interventions focused on structured exercise (83 studies, 60%) or combined interventions (55 studies, 39%). Two (1%) and one (0.7%) focused solely on habitual physical activity or sedentary behaviour. Adherence was 81% (interquartile range 62%-89%) with goal setting, monitoring and support important to adherence. Carers were only involved in 15 (11%) studies. Most interventions reported positive outcomes, primarily focusing on body functions and structures., Conclusions: A modest volume of evidence exists on multicomponent structured exercise interventions, with less focus on habitual physical activity and sedentary behaviour. Interventions report largely positive effects, but an updated systematic review is required. The field could be advanced by more rigorous characterisation of MLTCs, socioeconomic status and ethnicity, increased informal carer involvement and further evaluation of habitual physical activity and sedentary behaviour interventions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: Frailty is of increasing interest in trials, either as a target of intervention, as an outcome or as a potential treatment modifier. However, frailty measurement is often highly variable. This scoping review assessed how frailty is quantified in randomised controlled trials (RCTs), in what context and for what purposes., Methods: We searched five electronic databases for RCTs in which frailty was measured among trial participants. We extracted data on intervention type, the frailty measure used and the purpose for which frailty was assessed. We then compared these data according to reasons for frailty assessment., Results: We identified 415 RCTs assessing frailty across a range of interventions. Frailty was used to define the target population (166 trials), as an outcome (156 trials), as an effect modifier examining interaction of frailty on treatment effect (61 trials), as a purely descriptive characteristic (42 trials) or as a prognostic marker examining the impact of frailty on future health outcome (78 trials). The trials used 28 different measures of frailty (plus 29 additional trial-specific measures). The frailty phenotype model was the most common overall (164 trials), for defining the target population (90/166 trials) and as an outcome (81/156 trials). The cumulative deficit model frailty index was also frequently used (102 trials) and was most common among trials assessing treatment effect modification (21/61 trials)., Conclusion: Frailty measurement in RCTs is highly variable. Understanding the properties of respective frailty measures and how these relate to frailty as encountered in clinical practice is a priority to ensure that trial findings can inform healthcare delivery for people living with frailty., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

T cells develop from circulating precursor cells, which enter the thymus and migrate through specialized subcompartments that support their maturation and selection 1 . In humans, this process starts in early fetal development and is highly active until thymic involution in adolescence. To map the microanatomical underpinnings of this process in pre- and early postnatal stages, we established a quantitative morphological framework for the thymus-the Cortico-Medullary Axis-and used it to perform a spatially resolved analysis. Here, by applying this framework to a curated multimodal single-cell atlas, spatial transcriptomics and high-resolution multiplex imaging data, we demonstrate establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions by the beginning of the the second trimester of fetal development. We pinpoint tissue niches of thymic epithelial cell progenitors and distinct subtypes associated with Hassall's corpuscles and identify divergence in the timing of medullary entry between CD4 and CD8 T cell lineages. These findings provide a basis for a detailed understanding of T lymphocyte development and are complemented with a holistic toolkit for cross-platform imaging data analysis, annotation and OrganAxis construction (TissueTag), which can be applied to any tissue., Competing Interests: Competing interests: J.C.M. has been an employee of Genentech since September 2022. S.A.T. is a scientific advisory board member of ForeSite Labs, OMass Therapeutics, Qiagen, a co-founder and equity holder of TransitionBio and EnsoCell Therapeutics, a non-executive director of 10x Genomics and a part-time employee of GlaxoSmithKline. The other authors declare no competing interests., (© 2024. The Author(s).)

The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases 1,2 has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease 3 . Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states. We anchor 12 gastrointestinal disease datasets spanning gastrointestinal cancers, coeliac disease, ulcerative colitis and Crohn's disease to this reference. Utilizing this 1.6 million cell resource (gutcellatlas.org), we discover epithelial cell metaplasia originating from stem cells in intestinal inflammatory diseases with transcriptional similarity to cells found in pyloric and Brunner's glands. Although previously linked to mucosal healing 4 , we now implicate pyloric gland metaplastic cells in inflammation through recruitment of immune cells including T cells and neutrophils. Overall, we describe inflammation-induced changes in stem cells that alter mucosal tissue architecture and promote further inflammation, a concept applicable to other tissues and diseases., Competing Interests: Competing interests: S.A.T. is a scientific advisory board member of ForeSite Labs, OMass Therapeutics, a co-founder and equity holder of TransitionBio and EnsoCell Therapeutics, a non-executive director of 10x Genomics and a part-time employee of GlaxoSmithKline. R.E. is an equity holder in EnsoCell. P.K. has consulted for AstraZeneca, UCB, Biomunex and Infinitopes. N.M.P reports consulting fees from Infinitopes. J.S.-R. reports funding from GSK, Pfizer and Sanofi and fees/honoraria from Travere Therapeutics, Stadapharm, Astex, Owkin, Pfizer, Moderna and Grunenthal. A.S. is the recipient of research grants from Roche-Genentech, Abbvie, GSK, Scipher Medicine, Pfizer, Alimentiv, Boehringer Ingelheim and Agomab and has received consulting fees from Genentech, GSK, Pfizer, HotSpot Therapeutics, Alimentiv, Agomab, Goodgut and Orikine. R.E. and S.A.T are inventors on the patent GB2412853.0 filed in the UK, some components of which are related to this work. All other authors declare no competing interests., (© 2024. The Author(s).)

Human embryonic bone and joint formation is determined by coordinated differentiation of progenitors in the nascent skeleton. The cell states, epigenetic processes and key regulatory factors that underlie lineage commitment of these cells remain elusive. Here we applied paired transcriptional and epigenetic profiling of approximately 336,000 nucleus droplets and spatial transcriptomics to establish a multi-omic atlas of human embryonic joint and cranium development between 5 and 11 weeks after conception. Using combined modelling of transcriptional and epigenetic data, we characterized regionally distinct limb and cranial osteoprogenitor trajectories across the embryonic skeleton and further described regulatory networks that govern intramembranous and endochondral ossification. Spatial localization of cell clusters in our in situ sequencing data using a new tool, ISS-Patcher, revealed mechanisms of progenitor zonation during bone and joint formation. Through trajectory analysis, we predicted potential non-canonical cellular origins for human chondrocytes from Schwann cells. We also introduce SNP2Cell, a tool to link cell-type-specific regulatory networks to polygenic traits such as osteoarthritis. Using osteolineage trajectories characterized here, we simulated in silico perturbations of genes that cause monogenic craniosynostosis and implicate potential cell states and disease mechanisms. This work forms a detailed and dynamic regulatory atlas of bone and cartilage maturation and advances our fundamental understanding of cell-fate determination in human skeletal development., Competing Interests: Competing interests: C.D.B. is a founder of Mestag Therapeutics. S.A.T. is a scientific advisory board member of ForeSite Labs, OMass Therapeutics, Qiagen, a co-founder and equity holder of TransitionBio and EnsoCell Therapeutics, a non-executive director of 10x Genomics and a part-time employee of GlaxoSmithKline. Sarah also holds equity in TransitionBio and options for equity in Element Biosciences, where she is a former SAB member.  All other authors declare no competing interests., (© 2024. The Author(s).)

Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7-17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin 1 . The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells., Competing Interests: Competing interests: J.L. and K.R.K., with the Indiana University Research and Technology Corporation, have a patent relating to the methodology and composition of SkOs (PCT/US2016/058174). K.R.K. is a consultant for StemCell Technologies. All other authors declare no competing interests., (© 2024. The Author(s).)

Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling leading to various complications, such as bone deformity, deafness, secondary osteoarthritis, and pathological fracture. Pain is the most common presenting symptom of PDB, but it is unclear to what extent this is due to increased metabolic activity of the disease, complications, or unrelated causes. We conducted a cross-sectional study of 168 people with PDB attending secondary care referral centres in the UK. We documented the presence of musculoskeletal pain and sought to determine its underlying causes. Musculoskeletal pain was reported by 122/168 (72.6%) individuals. The most common cause was osteoarthritis of joints distant from an affected PDB site in 54 (44.3%), followed by metabolically active PDB in 18 (14.7%); bone deformity in 14 (11.4%); osteoarthritis of a joint neighbouring an affected site in 11 (9.0%), neuropathic pain in 10 (8.2%), and various other causes in the remainder. Pain was more common in women (p<0.019) and in older individuals (p<0.001). Circulating concentrations of macrophage colony-stimulating factor (M-CSF) were significantly higher in those with pain (p = 0.008), but there was no difference between groups of patients with and without pain in concentrations of interleukin-6 (IL-6) or biochemical markers of bone turnover. Pain is a common symptom in PDB but is most often due to osteoarthritis at an unaffected site. The study illustrates the importance of fully evaluating people with PDB to determine the underlying cause of pain so that management can be tailored appropriately., (© 2024. The Author(s).)

Background: Nephronophthisis (NPHP) is an autosomal recessive genetic disorder that can cause early-onset kidney failure. ANKS6 plays an important role in early kidney development and encodes a protein that interacts with other proteins within the primary cilium. ANKS6 mutations are known to cause nephronophthisis 16 (NPHP-16). Little is known regarding fetal ultrasound imaging and the antenatal diagnosis of fetuses with ANKS6 -associated kidney disease. Here, we report the detection of ANKS6 variants in consanguineous families with polycystic kidney antenatally and in the early stages of life., Methods: Three unrelated Saudi Arabian patients (two prenatal patients and one neonate) were investigated. These cases were referred to the hospital due to the presence of echogenic kidneys on antenatal scanning. After clinical and phenotypic evaluation, whole-exome sequencing (WES) was performed on the cord and peripheral blood to identify the molecular genetic causes associated with the echogenic kidney phenotypes., Results: Two homozygous sequence variants were detected in ANKS6 . The homozygous missense novel variant ANKS6 : c.1159A>C was detected in Families 1 and 2. In the third family, the known homozygous loss-of-function variant ANKS6 : c.907+2T>A was detected., Conclusions: We identified homozygous ANKS6 variants in three families presenting with antenatal polycystic kidney disease. The findings provide an expanded clinical presentation of ANKS6 and emphasize the utility of WES in the diagnosis of echogenic kidneys in prenatal settings.

Background: Psoriasis is associated with poor mental health and reduced quality of life. Although the high risk for depression in patients with psoriasis is well-established, their suicidality risk is uncertain. Previous studies provide contrasting results and have not included patients with clinically-confirmed severe disease., Objectives: Our aim was to determine risk of suicide among patients with moderate to severe psoriasis compared with the general population, and investigate if psychiatric comorbidity or history of suicidality increases future suicidality risk in psoriasis. We further estimated the incidence of suicidal and self-injurious behaviours in patients., Methods: Analysis was performed using the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR). As controls, general population mortality and suicide data were used., Results: There were 9 suicides in BADBIR. The incidence rate of suicide was 12.5 per 100,000 person-years (95% CI 6.53, 24.11) in BADBIR versus 11.0 per 100,000 person-years (95% CI 10.7, 11.3) in the general population in England and Wales. Among patients, psychiatric comorbidity or past suicidality was associated with higher risk for suicidal ideation, suicide attempts and self-injurious behaviours., Conclusions: Suicide rates among patients with moderate to severe psoriasis were not significantly higher compared with the general population. Suicide is a rare event and our results are limited by the uncertainty in the estimate reliability. However, considering the high depression prevalence in psoriasis, our findings support the need for prompt assessment of patients for psychiatric comorbidities and suicidality history. Further research is required on suicidal behaviours and the role of psoriasis severity., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Loss of skeletal muscle strength and mass (sarcopenia) is common in older adults and associated with an increased risk of disability, frailty and premature death. Finding cost-effective prevention and treatment strategies for sarcopenia for the growing ageing population is therefore of great public health interest. Although nutrition is considered an important factor in the aetiology of sarcopenia, its potential for sarcopenia prevention and/or treatment is still being evaluated. Nutrition research for sarcopenia utilises three main approaches to understand muscle-nutrition relationships, evaluating: single nutrients, whole foods and whole diet effects - both alone or combined with exercise. Applying these approaches, we summarise recent evidence from qualitative and quantitative syntheses of findings from observational and intervention studies of healthy older adults, and those with sarcopenia. We consider protein supplements, whole foods (fruits and vegetables) and the Mediterranean diet as exemplars. There is some evidence of beneficial effects of protein supplementation ≥ 0·8 g/kg body weight/d on muscle mass when combined with exercise training in intervention studies of healthy and sarcopenic older adults. In contrast, evidence for effects on muscle function (strength and physical performance) is inconclusive. There is reasonably consistent epidemiological evidence suggesting benefits of higher fruits and vegetables consumption for better physical performance. Similarly, higher adherence to the Mediterranean diet is associated with beneficial effects on muscle function in observational studies. However, intervention studies are lacking. This review discusses how current evidence may inform the development of preventive and intervention strategies for optimal muscle ageing and nutritional public policy aimed at combatting sarcopenia.

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy. However, there is a lack of reliable predictors of VNS response in clinical use. The identification of factors predictive of VNS response is important for patient selection and stratification as well as tailored stimulation programming. We conducted a narrative review of the existing literature on prognostic markers for VNS response using clinical, demographic, biochemical, and modality-specific information such as from electroencephalography (EEG), magnetoencephalography, and magnetic resonance imaging (MRI). No individual marker demonstrated sufficient predictive power for individual patients, although several have been suggested, with some promising initial findings. Combining markers from underresearched modalities such as T1-weighted MRI morphometrics and EEG may provide better strategies for treatment optimization., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Hearing impairment is a frequent clinical feature in patients with mitochondrial disease harbouring the pathogenic variant, m.3243A>G. However, auditory neural dysfunction, its perceptual consequences and implications for patient management are not established. Similarly, the association with vestibular impairment has not yet been explored. This case-control study investigated in 12 adults with genetically confirmed m.3243A>G adults [9 females; 45.5 ± 16.3 years (range 18-66); 47.1 ± 21.5 hearing level, dB] compared with 12 age, sex and hearing level-matched controls with sensory (cochlear level) hearing loss [9 females; 46.6 ± 11.8 years (range 23-59); 47.7 ± 25.4 hearing level, dB]. Participants underwent a battery of electroacoustic, electrophysiologic and perceptual tests, which included pure tone audiometry, otoacoustic emissions, auditory brainstem responses, auditory temporal processing measures, monaural/binaural speech perception, balance and vestibular testing and self-reported questionnaires (dizziness and hearing disability). Our findings showed evidence of auditory neural abnormality and perceptual deficits greater than expected for cochlear pathology. Compared with matched controls with sensory hearing loss, adults with mitochondrial disease harbouring m.3243A>G had abnormal electrophysiologic responses from the VIII nerve and auditory brainstem ( P = 0.005), an impaired capacity to encode rapidly occurring acoustic signal changes ( P = 0.005), a reduced ability to localize sound sources ( P = 0.028) and impaired speech perception in background noise ( P = 0.008). Additionally, vestibular dysfunction ( P = 0.011), greater perceived dizziness ( P = 0.001) and reduced stance time (balance, P = 0.009) were also seen in participants with m.3243A>G mitochondrial disease when compared with matched counterparts. This pilot study revealed that auditory evaluation including evoked potential responses from the auditory nerve/brainstem and speech perception in noise tests should form an important part of the management for individuals with m.3243A>G-related mitochondrial disease. Those presenting with hearing impairment and symptoms concerning balance and dizziness should undergo vestibular testing and appropriate management., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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).)

The 30th Olympiad took place in July 2024. At first glance, sports science and training of elite athletes may appear to be of little relevance to geriatric medicine. However, there are important parallels between the practice of geriatric medicine and elite sports and lessons that we can learn from our sports science colleagues. Elite athletes and older people are operating at the margins of physiological capacity. Both benefit from tailored, scientifically informed training programmes delivered and monitored by a multidisciplinary team. There are parallels between the comprehensive geriatric assessment and the philosophy of marginal gains pioneered by British Cycling. Insights into the biology of skeletal muscle function are beginning to translate into the development of clinical interventions and substances that offer an unfair advantage in sport by improving muscle strength and physical performance may be of therapeutic benefit in sarcopenia. The 2024 Olympics provide an opportunity for us to learn lessons for excellence in our research and provide an opportunity to promote exercise across the life course-important for healthy ageing., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: White blood cell count (WBC) is a widely used marker for the prediction of serious bacterial infection (SBI); however, previous research has shown poor performance. This study aims to assess the value of WBC in the prediction of SBI in children at the emergency department (ED) and compare its value with C reactive protein (CRP) and absolute neutrophil count (ANC)., Methods: This study is an observational multicentre study including febrile children aged 0-18 years attending 1 of 12 EDs in 8 European countries. The association between WBC and SBI was assessed by multivariable logistic regression, adjusting for age, CRP and duration of fever. Additionally, diagnostic performance was assessed by sensitivity and specificity. Results were compared with CRP and ANC., Results: We included 17 082 children with WBC measurements, of which 1854 (10.9%) had an SBI. WBC >15 had an adjusted OR of 1.9 (95% CI 1.7 to 2.1) for prediction of SBI, after adjusting for confounders. Sensitivity and specificity were 0.56 (95% CI 0.54 to 0.58) and 0.74 (0.73 to 0.75) for WBC >15, and 0.32 (0.30 to 0.34) and 0.91 (0.91 to 0.91) for WBC >20, respectively. In comparison, CRP >20 mg/L had a sensitivity of 0.87 (95% CI 0.85 to 0.88) and a specificity of 0.59 (0.58 to 059). For CRP >80 mg/L, the sensitivity was 0.55 (95% CI 0.52 to 057) and the specificity was 0.91 (0.90 to 0.91). Additionally, for ANC >10, the sensitivity was 0.55 (95% CI 0.53 to 0.58) and the specificity was 0.75 (0.75 to 0.76). The combination of WBC and CRP did not improve performance compared with CRP alone., Conclusion: WBC does not have diagnostic benefit in identifying children with an SBI compared with CRP and should only be measured for specific indications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Sarcopenia is the accelerated loss of skeletal muscle mass and function commonly, but not exclusively, associated with advancing age. It is observed across many species including humans in whom it can lead to decline in physical function and mobility as well as to increased risk of adverse outcomes including falls, fractures and premature mortality. Although prevalence estimates vary because sarcopenia has been defined in different ways, even using a conservative approach, the prevalence is between 5% and 10% in the general population. A life course framework has been proposed for understanding not only the occurrence of sarcopenia in later life but also influences operating at earlier life stages with potentially important implications for preventive strategies. Harnessing progress in understanding the hallmarks of ageing has been key to understanding sarcopenia pathophysiology. Considerable convergence in approaches to diagnosis of sarcopenia has occurred over the last 10 years, with a growing emphasis on the central importance of muscle strength. Resistance exercise is currently the mainstay of treatment; however, it is not suitable for all. Hence, adjunctive and alternative treatments to improve quality of life are needed. An internationally agreed approach to definition and diagnosis will enable a step change in the field and is likely to be available in the near future through the Global Leadership Initiative in Sarcopenia., (© 2024. Springer Nature Limited.)

Maximising the potential benefit of resistance exercise (RE) programs by ensuring optimal recovery is an important aim of exercise prescription. Despite this, research surrounding recovery from RE in older adults is limited and inconsistent. The following randomised controlled trial was designed to investigate the efficacy of milk consumption for improving recovery from RE in older adults. However, the study encountered various challenges that may be applicable to similar studies. These include recruitment issues, a lack of measurable perturbations in muscle function following RE, and potential learning effects amongst participants. Various considerations for exercise research have arisen from the data which could inform the design of future studies in this area. These include (i) recruitment-consider ways in which the study design could be altered to aid recruitment or allow a longer recruitment period; (ii) learning effects and familiarisation-consider potential learning effects of outcome measures and adjust familiarisation accordingly; (iii) identify, validate and optimise protocols for outcome measures that are applicable for the specific population; (iv) adjust the exercise protocol according to the specific aims of the study (e.g., are you replicating a usual exercise bout or is the intent to cause large amounts of muscle damage?).

Progressive gait impairment is common among aging adults. Remote phenotyping of gait during daily living has the potential to quantify gait alterations and evaluate the effects of interventions that may prevent disability in the aging population. Here, we developed ElderNet, a self-supervised learning model for gait detection from wrist-worn accelerometer data. Validation involved two diverse cohorts, including over 1000 participants without gait labels, as well as 83 participants with labeled data: older adults with Parkinson's disease, proximal femoral fracture, chronic obstructive pulmonary disease, congestive heart failure, and healthy adults. ElderNet presented high accuracy (96.43 ± 2.27), specificity (98.87 ± 2.15), recall (82.32 ± 11.37), precision (86.69 ± 17.61), and F1 score (82.92 ± 13.39). The suggested method yielded superior performance compared to two state-of-the-art gait detection algorithms, with improved accuracy and F1 score (p < 0.05). In an initial evaluation of construct validity, ElderNet identified differences in estimated daily walking durations across cohorts with different clinical characteristics, such as mobility disability (p < 0.001) and parkinsonism (p < 0.001). The proposed self-supervised method has the potential to serve as a valuable tool for remote phenotyping of gait function during daily living in aging adults, even among those with gait impairments., (© 2024. The Author(s).)

Objectives: This study aims to determine whether machine learning can identify specific combinations of long-term conditions (LTC) associated with increased sarcopenia risk and hence address an important evidence gap-people with multiple LTC (MLTC) have increased risk of sarcopenia but it has not yet been established whether this is driven by specific combinations of LTC., Design: Decision trees were used to identify combinations of LTC associated with increased sarcopenia risk. Participants were classified as being at risk of sarcopenia based on maximum grip strength of <32 kg for men and <19 kg for women. The combinations identified were triangulated with logistic regression., Setting: UK Biobank., Participants: UK Biobank participants with MLTC (two or more LTC) at baseline., Results: Of 140 001 participants with MLTC (55.3% women, median age 61 years), 21.0% were at risk of sarcopenia. Decision trees identified several LTC combinations associated with an increased risk of sarcopenia. These included drug/alcohol misuse and osteoarthritis, and connective tissue disease and osteoporosis in men, which showed the relative excess risk of interaction of 3.91 (95% CI 1.71 to 7.51) and 2.27 (95% CI 0.02 to 5.91), respectively, in age-adjusted models., Conclusion: Knowledge of LTC combinations associated with increased sarcopenia risk could aid the identification of individuals for targeted interventions, recruitment of participants to sarcopenia studies and contribute to the understanding of the aetiology of sarcopenia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objectives: The Benchmarking Exercise Programme for Older People (BEPOP) service improvement project seeks to determine and promote the exercise training characteristics associated with positive outcomes for resistance exercise for older people living with, or at risk of, sarcopenia or physical frailty., Methods: Mixed-methods service improvement project. Ten UK National Health Service physiotherapist-led therapy services delivering exercise interventions for older people submitted anonymized data for up to 20 consecutive patients. A multidisciplinary expert panel generated a report and recommendations with site-specific benchmarking data and feedback. In parallel, participating physiotherapy team members were interviewed to elicit feedback on BEPOP rationale, processes and perceived value., Results: Data from 188 patients were included, mean age 80 years (range 60-101). 115 (61%) received objective assessment of strength-based physical performance. Bodyweight exercises (173 [92%]) and resistance bands (49 [26%]) were the commonest exercise modalities. Exercises progressed predominantly through increased repetitions (163 [87%]) rather than increased load. 50 (30%) had no reassessment of outcomes; only 68 (41%) were signposted to follow-on exercise services. Staff interviews identified themes around knowledge, diagnosis, data collection and practice reflection., Conclusion: BEPOP was feasible to deliver and generated actionable insights for service improvement via improved diagnosis, measurement and progression of resistance exercise., (Copyright: © 2024 Hylonome Publications.)

Background: Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies have shown a high heritability of nephrolithiasis, but data on the prevalence and characteristics of genetic disease in unselected adults with nephrolithiasis are lacking. This study was conducted to fill this important knowledge gap., Methods: We performed whole exome sequencing in 787 participants in the Bern Kidney Stone Registry, an unselected cohort of adults with one or more past kidney stone episodes [kidney stone formers (KSFs)] and 114 non-kidney stone formers (NKSFs). An exome-based panel of 34 established nephrolithiasis genes was analysed and variants assessed according to American College of Medical Genetics and Genomics criteria. Pathogenic (P) or likely pathogenic (LP) variants were considered diagnostic., Results: The mean age of KSFs was 47 ± 15 years and 18% were first-time KSFs. A Mendelian kidney stone disease was present in 2.9% (23/787) of KSFs. The most common genetic diagnoses were cystinuria (SLC3A1, SLC7A9; n = 13), vitamin D-24 hydroxylase deficiency (CYP24A1; n = 5) and primary hyperoxaluria (AGXT, GRHPR, HOGA1; n = 3). Of the KSFs, 8.1% (64/787) were monoallelic for LP/P variants predisposing to nephrolithiasis, most frequently in SLC34A1/A3 or SLC9A3R1 (n = 37), CLDN16 (n = 8) and CYP24A1 (n = 8). KSFs with Mendelian disease had a lower age at the first stone event (30 ± 14 versus 36 ± 14 years; P = .003), were more likely to have cystine stones (23.4% versus 1.4%) and less likely to have calcium oxalate monohydrates stones (31.9% versus 52.5%) compared with KSFs without a genetic diagnosis. The phenotype of KSFs with variants predisposing to nephrolithiasis was subtle and showed significant overlap with KSFs without diagnostic variants. In NKSFs, no Mendelian disease was detected and LP/P variants were significantly less prevalent compared with KSFs (1.8% versus 8.1%)., Conclusion: Mendelian disease is uncommon in unselected adult KSFs, yet variants predisposing to nephrolithiasis are significantly enriched in adult KSFs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Chronic kidney disease is common, affecting up to 13 % of the global population, and is predicted to become the fifth leading cause of 'life years lost' by 2040. Individuals with end-stage kidney disease commonly develop complications such as protein-energy wasting and cachexia which further worsens their prognosis. The syndrome of 'renal cachexia' is poorly understood, under-diagnosed and even if recognised has limited treatment options., Objective: To explore the lived experience of renal cachexia for individuals with end-stage kidney disease and the interrelated experiences of their carers., Design: This interpretive phenomenological study was designed to facilitate an in-depth exploration of how patients and carers experience of renal cachexia. To improve and document the quality, transparency, and consistency of patient and public involvement in this study the Guidance for Reporting Involvement of Patients and the Public-Short Format was followed., Setting: The study was conducted across two nephrology directorates, within two healthcare trusts in the United Kingdom., Participants: Seven participants who met the inclusion criteria were recruited for this study, four patients (three female, one male) and three carers (two male, one female)., Methods: We employed a purposive sampling strategy. Data collection was conducted between July 2022 and December 2023. Interviews were semi-structured, audio-recorded, transcribed verbatim and analysed in six steps by two researchers using interpretive phenomenological analysis. Ethical approval was approved by the Office for Research Ethics Committees Northern Ireland (Reference: 22/NI/0107)., Results: Analysis generated six group experiential themes: the lived experience of appetite loss, functional decline and temporal coping, weight loss a visual metaphor of concern, social withdrawal and vulnerability, the emotional toll of eating challenges and psychological strain amidst a lack of information about cachexia., Conclusion: This is the first qualitative study exploring the lived experience of renal cachexia for patients and carers. Our study highlights that psycho-social and educational support is urgently needed. Additionally, healthcare professionals need better information provision to help them to recognise and respond to the needs of this population. Further research is required to develop models of holistic support which could help patients and carers cope with the impact of renal cachexia and optimally manage this syndrome within the family unit., Registration: N/A., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

MySkinSelfie is a mobile phone application for skin self-monitoring, enabling secure sharing of patient-captured images with healthcare providers. This retrospective study assessed MySkinSelfie's role in remote skin cancer assessment at two centres for urgent (melanoma and squamous cell carcinoma) and nonurgent skin cancer referrals, investigating the feasibility of using patient-captured images without dermoscopy for remote diagnosis. The total number of lesions using MySkinSelfie was 814, with a mean patient age of 63 years. Remote consultations reduced face-to-face appointments by 90% for basal cell carcinoma and by 63% for referrals on a 2-week waiting list. Diagnostic concordance (consultant vs. histological diagnosis) rates of 72% and 83% were observed for basal cell carcinoma (n = 107) and urgent skin cancers (n = 704), respectively. Challenges included image quality, workflow integration and lack of dermoscopy. Higher sensitivities were observed in recent artificial intelligence algorithms employing dermoscopy. While patient-captured images proved useful during the COVID-19 pandemic, further research is needed to explore the feasibility of widespread patient-led dermoscopy to enable direct patient-to-artificial intelligence diagnostic assessment., Competing Interests: Conflicts of interest P.H. collaborated in designing MySkinSelfie, the mobile application (app) discussed in this report. However, his involvement in the design of the app had no influence on the design, methodology, data analysis or reporting of this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722-9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia., Methods: We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants' blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures., Results: Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9-1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019)., Conclusion: In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Shrestha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes., (© 2023. The Author(s).)

The development and deployment of single-cell genomic technologies have driven a resolution revolution in our understanding of the immune system, providing unprecedented insight into the diversity of immune cells present throughout the body and their function in health and disease. Waldeyer's ring is the collective name for the lymphoid tissue aggregations of the upper aerodigestive tract, comprising the palatine, pharyngeal (adenoids), lingual, and tubal tonsils. These tonsils are the first immune sentinels encountered by ingested and inhaled antigens and are responsible for mounting the first wave of adaptive immune response. An effective mucosal immune response is critical to neutralizing infection in the upper airway and preventing systemic spread, and dysfunctional immune responses can result in ear, nose, and throat pathologies. This review uses Waldeyer's ring to demonstrate how single-cell technologies are being applied to advance our understanding of the immune system and highlight directions for future research.

Common to all inflammatory arthritides, namely rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and juvenile idiopathic arthritis, is a potential for reduced mobility that manifests through joint pain, swelling, stiffness, and ultimately joint damage. Across these conditions, consensus has been reached on the need to capture outcomes related to mobility, such as functional capacity and physical activity, as core domains in randomised controlled trials. Existing endpoints within these core domains rely wholly on self-reported questionnaires that capture patients' perceptions of their symptoms and activities. These questionnaires are subjective, inherently vulnerable to recall bias, and do not capture the granularity of fluctuations over time. Several early adopters have integrated sensor-based digital health technology (DHT)-derived endpoints to measure physical function and activity in randomised controlled trials for conditions including Parkinson's disease, Duchenne's muscular dystrophy, chronic obstructive pulmonary disease, and heart failure. Despite these applications, there have been no sensor-based DHT-derived endpoints in clinical trials recruiting patients with inflammatory arthritis. Borrowing from case studies across medicine, we outline the opportunities and challenges in developing novel sensor-based DHT-derived endpoints that capture the symptoms and disease manifestations most relevant to patients with inflammatory arthritis., Competing Interests: Declaration of interests HY reports receiving a personal payment via the University of Oxford for developed software licenses. APC reports being employed by the University of Oxford at the time of submission and was partially funded by GSK, at the time of publication they are employed by Sanome and no company mentioned is involved or affiliated with this Review. JG reports being an unpaid volunteer member on the Board of Directors for the Digital Medicine Society and Coalition for Health AI. WGD reports receiving consultancy fees from Google unrelated to this work. AD is supported by the Wellcome Trust [223100/Z/21/Z], Novo Nordisk, Swiss Re, the British Heart Foundation Centre of Research Excellence (grant number RE/18/3/34214), and Health Data Research UK; AD's research group reports receiving funding from GSK; reports receiving personal payments via the University of Oxford for consulting services provided to Harvard University and the University of Wisconsin; reports receiving a personal payment via the University of Oxford for developed software licenses. LCC reports receiving research grants from AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; reports receiving consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Moonlake, Novartis, Pfizer, and UCB; reports receiving payment for lectures and presentations from AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Medac, Novartis, Pfizer, and UCB. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: There are established risk factors for liver fibrosis (LF), but data on the impact of methotrexate on LF in patients with psoriasis are lacking., Objectives: This cross-sectional study aimed to determine the prevalence of LF in patients with psoriasis and to evaluate the relationship between LF, cumulative methotrexate dose and other LF risk factors., Methods: Adults with a history of moderate-to-severe chronic plaque psoriasis were recruited between June 2020 and March 2021. Patients underwent transient elastography to evaluate LF. Three values for liver stiffness measurement (LSM) were assessed, indicating mild or worse LF (≥ 7 kPa), moderate or worse LF (≥ 7.9 kPa) and advanced LF (≥ 9.5kPa). Cumulative methotrexate dose and other potential risk factors for LF were assessed., Results: Overall, 240 patients were recruited and 204 participants with valid LSM values were included in the analysis [median age 48 years [interquartile range (IQR) 37-57]; 51% female sex; 56% body mass index (BMI) ≥ 30 (kg m-2) and a median Alcohol Use Disorders Identification Test (AUDIT) score of 4 (IQR 1-7, 23% score ≥ 8)]. In total, 91% had received methotrexate [median duration 36 months (IQR 14-78)]. Prevalence of LF was 36%, 25% and 17% using LSM ≥ 7 kPa, ≥ 7.9 kPa and ≥ 9.5 kPa, respectively. There was no association between cumulative methotrexate dose [median 2.16 (IQR 0.93-5.2)] and continuous LSM values [unstandardized coefficient 0.16, 95% confidence interval (CI) -0.49 to 0.82, P = 0.626] or using the categorical LSM cutoff values: ≥ 7 kPa [unadjusted odds ratio 1.06 (95% CI 0.97-1.15), P = 0.192], ≥ 7.9 kPa [unadjusted odds ratio 1.03 (95% CI 0.94-1.12), P = 0.577] and ≥ 9.5 kPa (unadjusted odds ratio 1.01, 95% CI 0.91-1.12; P = 0.843). The following risk factors were associated with higher LSM values: BMI (P ≤ 0.001), waist circumference (P ≤ 0.001), metabolic syndrome (P ≤ 0.001), AUDIT score (P = 0.020) and FIB-4 score (P = 0.03). BMI ≥ 28, diabetes and metabolic syndrome were shown to be better predictors of LF compared with FIB-4 score., Conclusions: This study confirms a high prevalence of significant LF in patients with psoriasis. Cumulative methotrexate dose was not associated with LF. Patients with BMI ≥ 28, metabolic syndrome and diabetes are at higher risk for LF. These risk factors may help to identify when a more detailed liver health assessment is needed., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Socioeconomic differences in movement behaviours may contribute to health inequalities. The aim of this descriptive study was to investigate socioeconomic patterns in device-measured 24-hour movement and assess whether patterns differ between weekdays and weekends., Methods: 4894 individuals aged 46 years from the 1970 British Cohort Study were included. Participants wore thigh-worn accelerometers for 7 days. Movement behaviours were classified in two 24-hour compositions based on intensity and posture, respectively: (1) sleep, sedentary behaviour, light-intensity activity and moderate-vigorous activity; and (2) sleep, lying, sitting, standing, light movement, walking and combined exercise-like activity. Four socioeconomic measures were explored: education, occupation, income and deprivation index. Movement behaviours were considered compositional means on a 24-hour scale; isometric log ratios expressed per cent differences in daily time in each activity compared with the sample mean., Results: Associations were consistent across all socioeconomic measures. For example, those with a degree spent more time in exercise-like activities across weekdays (10.8%, 95% CI 7.3 to 14.7; ref: sample mean) and weekends (21.9%, 95% CI 17.2 to 26.9). Other patterns differed markedly by the day of the week. Those with no formal qualifications spent more time standing (5.1%, 95% CI 2.3 to 7.1), moving (10.8%, 95% CI 8.6 to 13.1) and walking(4.0%, 95% CI 2.2 to 6.1) during weekdays, with no differences on weekends. Conversely, those with no formal qualifications spent less time sitting during weekdays (-6.6%, 95% CI -7.8 to -4.8), yet more time lying on both weekends (8.8%, 95% CI 4.9 to 12.2) and weekdays (7.5%, 95% CI 4.0 to 11.5)., Conclusions: There were strong socioeconomic gradients in 24-hour movement behaviours, with notable differences between weekdays/weekends and behaviour type/posture. These findings emphasise the need to consider socioeconomic position, behaviour type/posture and the day of the week when researching or designing interventions targeting working-age adults., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Recording and coding of ageing syndromes in hospital records is known to be suboptimal. Natural Language Processing algorithms may be useful to identify diagnoses in electronic healthcare records to improve the recording and coding of these ageing syndromes, but the feasibility and diagnostic accuracy of such algorithms are unclear., Methods: We conducted a systematic review according to a predefined protocol and in line with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Searches were run from the inception of each database to the end of September 2023 in PubMed, Medline, Embase, CINAHL, ACM digital library, IEEE Xplore and Scopus. Eligible studies were identified via independent review of search results by two coauthors and data extracted from each study to identify the computational method, source of text, testing strategy and performance metrics. Data were synthesised narratively by ageing syndrome and computational method in line with the Studies Without Meta-analysis guidelines., Results: From 1030 titles screened, 22 studies were eligible for inclusion. One study focussed on identifying sarcopenia, one frailty, twelve falls, five delirium, five dementia and four incontinence. Sensitivity (57.1%-100%) of algorithms compared with a reference standard was reported in 20 studies, and specificity (84.0%-100%) was reported in only 12 studies. Study design quality was variable with results relevant to diagnostic accuracy not always reported, and few studies undertaking external validation of algorithms., Conclusions: Current evidence suggests that Natural Language Processing algorithms can identify ageing syndromes in electronic health records. However, algorithms require testing in rigorously designed diagnostic accuracy studies with appropriate metrics reported., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Introduction: Delirium and multiple long-term conditions (MLTC) share numerous risk factors and have been shown individually to be associated with adverse outcomes following hospitalisation. However, the extent to which these common ageing syndromes have been studied together is unknown. This scoping review aims to summarise our knowledge to date on the interrelationship between MLTC and delirium., Methods: Searches including terms for delirium and MLTC in adult human participants were performed in PubMed, EMBASE, Medline, Psycinfo and CINAHL. Descriptive analysis was used to summarise findings, structured according to Synthesis Without Meta-analysis reporting guidelines., Results: After removing duplicates, 5256 abstracts were screened for eligibility, with 313 full-texts sought along with 17 additional full-texts from references in review articles. In total, 140 met inclusion criteria and were included in the final review. Much of the literature explored MLTC as a risk factor for delirium (n = 125). Fewer studies explored the impact of MLTC on delirium presentation (n = 5), duration (n = 3) or outcomes (n = 6) and no studies explored how MLTC impacts the treatment of delirium or whether having delirium increases risk of developing MLTC. The most frequently used measures of MLTC and delirium were the Charlson Comorbidity Index (n = 98/140) and Confusion Assessment Method (n = 81/140), respectively., Conclusion: Existing literature largely evaluates MLTC as a risk factor for delirium. Major knowledge gaps identified include the impact of MLTC on delirium treatment and the effect of delirium on MLTC trajectories. Current research in this field is limited by significant heterogeneity in defining both MLTC and delirium., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: Little is known about ageing and frailty progression in low-income settings. We aimed to describe frailty changes over time in individuals living in rural Burkina Faso and to assess which sociodemographic, disability, and multimorbidity factors are associated with frailty progression and mortality., Methods: This longitudinal, population-based study was conducted at the Nouna Health and Demographic Surveillance Systems (HDSS) site in northwestern Burkina Faso. Eligible participants were aged 40 years or older and had been primarily resident in a household within the HDSS area for at least the past 6 months before the baseline survey and were selected from the 2015 HDSS household census using a stratified random sample of adults living in unique households within the area. Participants were interviewed in their homes in 2018 (baseline), 2021 (follow-up), or both. We derived the Fried frailty score for each participant at each timepoint using data on grip strength, gait speed, self-reported weight loss, self-reported exhaustion, and physical activity, and described changes in frailty status (no frailty, pre-frailty, or frailty) between 2018 and 2021. We used multivariate regression models to assess factors (ie, sex, age, marital status, educational attainment, wealth quintile, WHO Disability Assessment Schedule (WHODAS) score, and multimorbidity) associated with frailty progression (either worsening frailty status or dying, compared with frailty status remaining the same or improving) and with mortality, and developed sequential models: unadjusted, adjusting for sociodemographic factors (sex, age, marital status, educational attainment, and wealth quintile), and adjusting for sociodemographic factors, disability, and multimorbidity., Findings: Between May 25 and July 19, 2018, and between July 1 and Aug 22, 2021, 5952 individuals were invited to participate: 1709 (28·7%) did not consent, 1054 (17·8%) participated in 2018 only and were lost to follow-up, 1214 (20·4%) participated in 2021 only, and 1975 (33·2%) were included in both years or died between years. Of 1967 participants followed up with complete demographic data, 190 (9·7%) were frail or unable to complete the frailty assessment in 2018, compared with 77 (3·9%) in 2021. Between 2018 and 2021, frailty status improved in 567 (28·8%) participants and worsened in 327 (16·6%), and 101 (5·1%) participants died. The relative risk of frailty status worsening or of dying (compared with frailty impRoving or no change) increased with age and WHODAS score, whereas female sex appeared protective. After controlling for all sociodemographic factors, multimorbidity, and WHODAS score, odds of mortality were 1·07 (odds ratio 2·07, 95% CI 1·05-4·09) times higher among pre-frail individuals and 1·1 (2·21, 0·90-5·41) times higher among frail individuals than among non-frail individuals., Interpretation: Frailty status was highly dynamic in this low-income setting and appears to be modifiable. Given the rapid increase in the numbers of older adults in low-income or middle-income countries, understanding the behaviour of frailty in these settings is of high importance for the development of policies and health systems to ensure the maintenance of health and wellbeing in ageing populations. Future work should focus on designing context-appropriate interventions to improve frailty status., Funding: Alexander Von Humboldt Foundation, Institute for Global Innovation, University of Birmingham, and Wellcome Trust., Competing Interests: Declaration of interests DG-P provides scientific consultations through Epidemiologic Research & Methods, none of which are related to the topic of the current study. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The routine use of targeted systemic immunomodulatory therapies has transformed outcomes for people with severe psoriasis, with skin clearance (clinical remission) rates up to 60% at 1 year of biologic treatment. However, psoriasis may recur following drug withdrawal, and as a result, patients tend to continue receiving costly treatment indefinitely. Here, we review research into the "inflammatory memory" in resolved psoriasis skin and the potential mechanisms leading to psoriasis recurrence following drug withdrawal. Research has implicated immune cells such as tissue resident memory T cells, Langerhans cells, and dermal dendritic cells, and there is growing interest in keratinocytes and fibroblasts. A better understanding of the interactions between these cell populations, enabled by single cell technologies, will help to elucidate the events underpinning the shift from remission to recurrence. This may inform the development of personalized strategies for sustaining remission while reducing long-term drug burden., Competing Interests: Disclosure statement Supported by the Psoriasis Association (PhD studentship ST2/21 [to L.F.] and grant BSTOP50/5 [to C.H.S.]), the National Institute for Health and Care Research (NIHR Advanced Fellowship NIHR302258 [to S.K.M.] and NIHR Senior Investigator Award [to C.H.S.]), and the Wellcome Trust (senior research fellowship [to M.H.]). Disclosure of potential conflict of interest: C. H. Smith reports departmental research funding as an investigator in the European Union’s Innovative Medicines Initiative consortia involving multiple industry partners (see biomap-imi.eu and hippocrates-imi.eu for details). F. Capon has received grant support and consultancy fees from Boehringer Ingelheim. S. K. Mahil reports departmental income from AbbVie, Almirall, Eli Lilly, Janssen, Leo, Novartis, Pfizer, Sanofi, and UCB, outside the submitted work. The rest of the authors declare no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)