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The recent mpox outbreak (in 2022–2023) has different clinical and epidemiological features compared with previous outbreaks of the disease. During this outbreak, sexual contact was believed to be the primary transmission route of the disease. In addition, the community of men having sex with men (MSM) was disproportionately affected by the outbreak. This population is also disproportionately affected by HIV infection. Given that both diseases can be transmitted sexually, the endemicity of HIV, and the high sexual behavior associated with the MSM community, it is essential to understand the effect of the two diseases spreading simultaneously in an MSM population. Particularly, we aim to understand the potential effects of HIV on an mpox outbreak in the MSM population. We develop a mechanistic mathematical model of HIV and mpox co-infection. Our model incorporates the dynamics of both diseases and considers HIV treatment with anti-retroviral therapy (ART). In addition, we consider a potential scenario where HIV infection increases susceptibility to mpox, and investigate the potential impact of this mechanism on mpox dynamics. Our analysis shows that HIV can facilitate the spread of mpox in an MSM population, and that HIV treatment with ART may not be sufficient to control the spread of mpox in the population. However, we showed that a moderate use of condoms or reduction in sexual contact in the population combined with ART is beneficial in controlling mpox transmission. Based on our analysis, it is evident that effective control of HIV, specifically through substantial ART use, moderate condom compliance, and reduction in sexual contact, is imperative for curtailing the transmission of mpox in an MSM population and mitigating the compounding impact of these intertwined epidemics.

Abstract Breast cancer is the most frequently diagnosed cancer in females globally. However, we know relatively little about trends in males. This study describes United Kingdom (UK) secular trends in breast cancer from 2000 to 2021 for both sexes. We describe a population-based cohort study using UK primary care Clinical Practice Research Datalink (CPRD) GOLD and Aurum databases. There were 5,848,436 eligible females and 5,539,681 males aged 18+ years, with ≥ one year of prior data availability in the study period. We estimated crude breast cancer incidence rates (IR), prevalence and survival probability at one-, five- and 10-years after diagnosis using the Kaplan–Meier method. Analyses were further stratified by age. Crude IR of breast cancer from 2000 to 2021 was 194.4 per 100,000 person-years for females and 1.16 for males. Crude prevalence in 2021 was 2.1% for females and 0.009% for males. Both sexes have seen around a 2.5-fold increase in prevalence across time. Incidence increased with age for both sexes, peaking in females aged 60–69 years and males 90+ . There was a drop in incidence for females aged 70–79 years. From 2003–2019, incidence increased > twofold in younger females (aged 18–29: IR 2.12 in 2003 vs. 4.58 in 2018); decreased in females aged 50–69 years; and further declined from 2015 onwards in females aged 70–89 years. Survival probability for females after one-, five-, and ten-years after diagnosis was 95.1%, 80.2%, and 68.4%, and for males 92.9%, 69.0%, and 51.3%. Survival probability at one-year increased by 2.08% points, and survival at five years increased by 5.39% from 2000–2004 to 2015–2019 for females, particularly those aged 50–70 years. For males, there were no clear time-trends for short-term and long-term survival probability. Changes in incidence of breast cancer in females largely reflect the success of screening programmes, as rates rise and fall in synchronicity with ages of eligibility for such programmes. Overall survival from breast cancer for females has improved from 2000 to 2021, again reflecting the success of screening programmes, early diagnosis, and improvements in treatments. Male breast cancer patients have worse survival outcomes compared to females, highlighting the need to develop male-specific diagnosis and treatment strategies to improve long-term survival in line with females.

Francesco Pesce,1 Giacomo Matteo Bruno,2 Giorgio Lorenzo Colombo,2 Sergio Di Matteo,3 Anna Rita Maurizi,4 Valentina Mongelli,4 Silvia Mele,5 Lavinia Narici,5 Stefano Bianchi,6 Mario Bonomini,7 Giuseppe Castellano,8 Luca De Nicola,9 Giovanni Gambaro,10 Giuseppe Grandaliano,11 Gaetano La Manna,12 Antonello Pani,13 Andrea Ranghino,14 Loreto Gesualdo15 1Division of Renal Medicine, “Fatebenefratelli Isola Tiberina—Gemelli Isola”, Rome, 00186, Italy; 2Department of Drug Sciences, University of Pavia, Pavia, Italy; 3S.A.V.E. Studi Analisi Valutazioni Economiche, Milan, Italy; 4Cardiovascular, Renal and Metabolism Medical Affairs, AstraZeneca, Milan, Italy; 5Value & Access, AstraZeneca, Milan, Italy; 6Nephrology and Dialysis Unit, Department of Internal Medicine, ASL Toscana Nordovest, Regione Toscana, Livorno, Italy; 7Department of Medicine, Section of Nephrology and Dialysis, G. D’Annunzio University, Chieti, 66013, Italy; 8UOC of Nephrology, Dialysis, and Kidney Transplant, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 9Department of Advanced Medical and Surgical Sciences, Nephrology and Dialysis Unit, University Vanvitelli, Naples, Italy; 10Division of Nephrology and Dialysis, Department of Medicine, University of Verona, Verona, Italy; 11Department of Translational Medicine and Surgery, Università Cattolica Sacro Cuore, Rome, Italy; 12Nephrology Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy; 13Department of Nephrology and Dialysis, G. Brotzu Hospital, Cagliari, Italy; 14Nephrology, Dialysis and Kidney Transplant Unit, Ospedali Riuniti Ancona, Ancona, Italy; 15Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (Dimepre-J), University of Bari “aldo Moro”, Bari, ItalyCorrespondence: Giorgio Lorenzo Colombo, Email colombog@unipv.itIntroduction: The underdiagnosis of chronic kidney disease (CKD) remains a significant public health concern. The Early chroNic kiDney disease pOint of caRe Screening (ENDORSE) project aimed to evaluate the clinical and economic implications of a targeted training intervention for general practitioners (GPs) to enhance CKD awareness and early diagnosis.Methods: Data on estimated Glomerular Filtration Rate (eGFR) and Urinary Albumin-Creatinine Ratio (uACR) were collected by 53 Italian GPs from 112,178 patients at baseline and after six months. The intervention involved six months of hybrid training provided by 11 nephrologists, which included formal lectures, instant messaging support, and joint visits for complex cases.Results: The results demonstrated a substantial increase in the use of eGFR (+44.7%) and uACR (+95.2%) tests. This led to a 128.9% rise in the number of individuals screened for CKD using the KDIGO classification, resulting in a 62% increase in CKD diagnoses. The intervention’s impact was particularly notable in high-risk groups, including patients with type 2 diabetes, hypertension, and heart failure.Discussion: A budget impact analysis projected cumulative five-year savings of € 1.7 million for the study cohort. When these findings were extrapolated to the entire Italian CKD population, potential savings were estimated at € 106.6 million, highlighting significant cost savings for the national health service. The clinical simulation assumed that early diagnosed CKD patients would be treated according to current indications for dapagliflozin, which slows disease progression.Conclusion: The ENDORSE model demonstrated that targeted training for GPs can significantly improve early CKD detection, leading to better patient outcomes and considerable economic benefits. This approach shows promise for broader implementation to address the underdiagnosis of CKD on a national and potentially international scale. Keywords: eGFR, uACR, awareness, chronic kidney disease, general practice, economic impact, training intervention, early diagnosis

Abstract Effective prevention strategies for post-COVID complications are crucial for patients, clinicians, and policy makers to mitigate their cumulative burden. This study evaluated the association of modifiable lifestyle factors (smoking, alcohol intake, BMI, physical activity, sedentary time, sleep duration, and dietary habits) with COVID-19 multisystem sequelae, death, and hospitalization in the UK Biobank cohort (n = 68,896). A favorable lifestyle (6-10 healthy factors; 46.4%) was associated with a 36% lower risk of multisystem sequelae (HR, 0.64; 95% CI, 0.58-0.69; ARR at 210 days, 7.08%; 95% CI, 5.98-8.09) compared to an unfavorable lifestyle (0-4 factors; 12.3%). Risk reductions spanned all 10 organ systems, including cardiovascular, coagulation, metabolic, gastrointestinal, kidney, mental health, musculoskeletal, respiratory disorders, and fatigue. This beneficial effect was largely attributable to direct lifestyle impacts independent of corresponding pre-infection comorbidities (71% for any sequelae). A favorable lifestyle was also related to the risk of post-COVID death (HR 0.59, 0.52-0.66) and hospitalization (HR 0.78, 0.73-0.84). These associations persisted across acute and post-acute infection phases, irrespective of hospitalization status, vaccination, or SARS-CoV-2 variant. These findings underscore the clinical and public health importance of adhering to a healthy lifestyle in mitigating long-term COVID-19 adverse impacts and enhancing future pandemic preparedness.

Abstract Background The aim of this study was to investigate the relationship between Problematic Internet Use (PIU), emotional states of stress, anxiety and depression, and the practice of physical activity among Tunisian students. Methods Cross-sectional data were collected from 976 university students aged 20.76 ± 1.63 years (46.8% female). They filled out an online survey comprised of a socio-demographic questionnaire, the depression, anxiety and stress scale– 21 items (DASS-21), the international physical activity questionnaire (IPAQ) and the compulsive internet use scale (CIUS). Students were divided, based on their economic levels, into three groups: low (n = 256, 26.23%), medium (n = 523, 53.59%) and high (n = 197, 20.18%). Results Mediation analysis: Indirect effects of IPAQ and gender on DASS-21 were highlighted: β= -0.18 (p

Summary: Background: CVN424 is a GPR6 inverse agonist that provides selective pharmacological control of the indirect striatopallidal pathway. We assessed the safety and efficacy of CVN424 as an adjunctive treatment to levodopa for reducing OFF-time in individuals with Parkinson's disease (PD) experiencing motor-fluctuations. Methods: This was a randomised, double-blind, placebo-controlled study conducted at 21 sites across the United States to evaluate two doses of CVN424 (NCT04191577). Patients with PD (Hoehn and Yahr stages 2–4) who were on a stable dose of levodopa and experiencing ≥2 h of daily OFF-time were randomised (1:1:1) to receive either once-daily CVN424 (50 mg or 150 mg) or placebo for a 28-day treatment period. The primary endpoints were safety and tolerability. The key secondary endpoint was the change from baseline to Day 27 in OFF-time. Findings: The study was conducted from December 23, 2019, to October 14, 2021. Out of 198 participants screened, 141 eligible participants were randomised to one of the three treatment groups (n = 47 per group), and 127 participants completed the 28-day treatment period. The most common treatment emergent adverse events (TEAEs) were headache (2% with CVN424 50 mg, 9% with CVN424 150 mg, and 2% with placebo) and nausea (4% with CVN424 50 mg, 6% with CVN424 150 mg and 2% with placebo). No serious treatment-related adverse events were reported. On Day 27, the mean ± standard deviation (SD) change from baseline in daily OFF-time was −1.3 ± 3.0 h in the CVN424 50 mg group, −1.6 ± 2.5 h in the CVN424 150 mg group, and −0.5 ± 2.9 h in the placebo group. The placebo-adjusted LS mean ± standard error (SE) treatment difference was significant for the CVN424 150 mg dose (1.3 ± 0.56 h, [95 CI% −2.41 to −0.19], nominal p = 0.02). Interpretation: Treatment with CVN424 was safe and well-tolerated. Despite the short study duration and small sample size, the 150 mg CVN424 dose provided a clinically meaningful reduction in daily OFF-time. This study supports the development of CVN424 for the treatment of PD. Funding: Cerevance.

Abstract Worldwide, over 2 billion children under the age of 5 experience stunting, wasting, or are underweight. Malnutrition contributes to 45% of all deaths in this age group (approximately 3.1 million deaths) [1]. Poverty, food insecurity, suboptimal feeding practices, climate change, and conflict are all contributing factors. Malnutrition causes significant respiratory problems, including increased risk of respiratory infections, impaired lung function, and increased risk of subsequent adult respiratory disease, including asthma, COPD, and lung cancer. Childhood malnutrition not only has serious consequences for children's health but it also has numerous consequences on wellbeing and educational attainment. Childhood malnutrition is a complex and multifaceted problem. However, by understanding and addressing the underlying causes, and investing in prevention and treatment programs, it is possible to maximize children's health and wellbeing on a global scale. This narrative review will focus on the impact of childhood malnutrition on lung development, the consequent respiratory disease, and what actions can be taken to reduce the burden of malnutrition on lung health.

Abstract Background Videos to support learning of clinical skills are effective; however, little is known about the scope and educational quality of the content of freely available online videos demonstrating task-specific training (TST). This review aimed to determine the extent, characteristics of freely available online videos, and whether the content is suitable to guide skill acquisition of task-specific training for neurological physiotherapists and students. Methods A scoping review was conducted. Google video and YouTube were searched in December 2022. Videos that met our eligibility criteria and were explicitly designed for (TST) skill acquisition were included in the report. Results Ten videos met the inclusion criteria and were difficult to find amongst the range of videos available. Most were presented by physiotherapists or occupational therapists, originated from the USA, featured stroke as the condition of the person being treated, and involved a range of interventions (upper limb, constraint induced movement therapy, balance, bicycling). Most videos were created by universities or private practices and only two used people with a neurological condition as the participant. When the content of videos and their presentation (instruction and/or demonstration), was assessed against each key component of TST (practice structure, specificity, repetition, modification, progression, feedback), five of the videos were rated very suitable and five moderately suitable to guide skill acquisition. Most videos failed to demonstrate and provide instruction on each key component of TST and were missing at least one component, with feedback most frequently omitted. Conclusions There are many freely available online videos which could be described as demonstrating TST; very few are suitable to guide skill acquisition. The development of a standardised and validated assessment tool, that is easy to use and assesses the content of TST videos is required to support learners to critically evaluate the educational quality of video content. Guidelines based on sound teaching theory and practice are required to assist creators of online videos to provide suitable resources that meet the learning needs of neurological physiotherapists and students.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Intestinal helminth infection triggers a type 2 immune response that promotes a 'weep-and sweep' response characterised by increased mucus secretion and intestinal hypermotility, which function to dislodge the worm from its intestinal habitat. Recent studies have discovered that several other pathogens cause intestinal dysmotility through major alterations to the immune and enteric nervous systems (ENS), and their interactions, within the gastrointestinal tract. However, the involvement of these systems has not been investigated for helminth infections. Eosinophils represent a key cell type recruited by the type 2 immune response and alter intestinal motility under steady-state conditions. Our study aimed to investigate whether altered intestinal motility driven by the murine hookworm, Nippostrongylus brasiliensis, infection involves eosinophils and how the ENS and smooth muscles of the gut are impacted. Eosinophil deficiency did not influence helminth-induced intestinal hypermotility and hypermotility did not involve gross structural or functional changes to the ENS. Hypermotility was instead associated with a dramatic increase in smooth muscle thickness and contractility, an observation that extended to another rodent nematode, Heligmosomoides polygyrus. In summary our data indicate that, in contrast to other pathogens, helminth-induced intestinal hypermotility is driven by largely by myogenic, rather than neurogenic, alterations with such changes occurring independently of eosinophils. (

Summary: Eosinophils are involved in host protection against multicellular organisms. However, their recruitment to the mesenteric lymph node (mLN) during type 2 immunity is understudied. Our results demonstrate that eosinophil association with lymphoid stromal niches constructed by fibroblastic reticular cells (FRCs) and lymphatic endothelial cells is diminished in mice selectively lacking interleukin (IL)-4Rα or lymphotoxin-β (LTβ) expression on B cells. Furthermore, eosinophil survival, activation, and enhanced Il1rl1 receptor expression are driven by stromal cell and B cell dialogue. The ligation of lymphotoxin-β receptor (LTβR) on FRCs improves eosinophil survival and significantly augments IL-33 expression and eosinophil homing to the mLN, thus confirming the significance of lymphotoxin signaling for granulocyte recruitment. Eosinophil-deficient ΔdblGATA-1 mice show diminished mLN expansion, reduced interfollicular region (IFR) alarmin expression, and delayed helminth clearance, elucidating their importance in type 2 immunity. These findings provide insight into dialogue between stromal cells and B cells, which govern mLN eosinophilia, and the relevance of these mechanisms during type 2 immunity.

Abstract Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K+ efflux as a key signaling event, suggesting that K+-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K+ channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K+ conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K+ efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K+ conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K+-independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation. Graphical Abstract

Background: The prevalence of obesity-related cardiometabolic disease in Samoa is among the highest globally. While physical activity is a modifiable risk factor for obesity-related disease, little is known about physical activity levels among adult Samoans. Using wrist-worn accelerometer-based devices, this study aimed to characterize physical activity among Samoan adults. Methods: Samoan adults (n = 385; 55% female, mean [SD] age 52 [10] y) wore Actigraph GT3X+ devices for 7 to 10 days. General linear models were used to examine mean daily minutes of sedentary time, light physical activity, and moderate to vigorous physical activity by various participant characteristics. Results: Time spent in moderate to vigorous physical activity did not differ statistically between men (88 [5] min; 95% confidence interval [CI], 80–97) and women (78 [4] min; 95% CI, 70–86; P =.08). Women, however, spent more time than men in light physical activity: 380 (7) minutes (95% CI, 367–393) versus 344 (7) minutes (95% CI, 329–358; P <.001). While there were no differences in physical activity by census region, education, or occupation among women, men in urban areas spent significantly less time in moderate to vigorous physical activity than those in peri-urban and rural areas (P =.015). Women with class II/III obesity spent more time in sedentary activities than those with healthy weight or overweight/class I obesity (P =.048). Conclusions: This study characterizes physical activity among Samoan adults and highlights variation by sex, urbanicity, and weight status. In providing initial device-measured estimates of physical activity in Samoa, this analysis establishes a baseline from which the success of future attempts to intervene on physical activity may be assessed. [ABSTRACT FROM AUTHOR]

BackgroundThe availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.MethodsWe conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.ResultsTwo blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P

Background: The COVID-19 pandemic affected cancer screening, diagnosis and treatments. Many surgeries were substituted with bridging therapies during the initial lockdown, yet consideration of treatment side effects and their management was not a priority. Objectives: To examine how the changing social restrictions imposed by the pandemic affected incidence and trends of endocrine treatment prescriptions in newly diagnosed (incident) breast and prostate cancer patients and, secondarily, endocrine treatment-related outcomes (including bisphosphonate prescriptions, osteopenia and osteoporosis), in UK clinical practice from March 2020 to June 2022. Design: Population-based cohort study using UK primary care Clinical Practice Research Datalink GOLD database. Methods: There were 13,701 newly diagnosed breast cancer patients and 12,221 prostate cancer patients with ⩾1-year data availability since diagnosis between January 2017 and June 2022. Incidence rates (IR) and incidence rate ratios (IRR) were calculated across multiple time periods before and after lockdown to examine the impact of changing social restrictions on endocrine treatments and treatment-related outcomes, including osteopenia, osteoporosis and bisphosphonate prescriptions. Results: In breast cancer patients, aromatase inhibitor (AI) prescriptions increased during lockdown versus pre-pandemic [IRR: 1.22 (95% confidence interval (CI): 1.11–1.34)], followed by a decrease post-first lockdown [IRR: 0.79 (95% CI: 0.69–0.89)]. In prostate cancer patients, first-generation antiandrogen prescriptions increased versus pre-pandemic [IRR: 1.23 (95% CI: 1.08–1.4)]. For breast cancer patients on AIs, diagnoses of osteopenia, osteoporosis and bisphosphonate prescriptions were reduced across all lockdown periods versus pre-pandemic (IRR range: 0.31–0.62). Conclusion: During the first 2 years of the pandemic, newly diagnosed breast and prostate cancer patients were prescribed more endocrine treatments compared to pre-pandemic due to restrictions on hospital procedures replacing surgeries with bridging therapies. But breast cancer patients had fewer diagnoses of osteopenia and osteoporosis and bisphosphonate prescriptions. These patients should be followed up in the coming years for signs of bone thinning. Evidence of poorer management of treatment-related side effects will help assess resource allocation for patients at high risk for bone-related complications.

Neuroinflammation is one of the hallmarks contributing to Parkinson's Disease (PD) pathology, where microglial activation occurs as one of the earliest events, triggered by extracellular alpha synuclein (aSYN) binding to the CD36 receptor. Here, CD36-binding nanoparticles (NPs) containing synthetic tartaric acid-based amphiphilic polymers (AMs) were rationally designed to inhibit this aSYN-CD36 binding. In silico docking revealed that four AMs with varying alkyl side chain lengths presented differential levels of CD36 binding affinity and that an optimal alkyl chain length would promote the strongest inhibitory activity towards aSYN-CD36 interactions. In vitro competitive binding assays indicated that the inhibitory activity of AM-based NPs plateaued at intermediate side chain lengths of 12- and 18-carbons, supporting the in silico docking predictions. These 12- and 18-carbon length AM NPs also had significantly stronger effects on reducing aSYN internalization and inhibiting the production of the proinflammatory molecules TNF-α and nitric oxide from aSYN-challenged microglia. All four NPs modulated the gene expression of aSYN-challenged microglia, downregulating the expression of the proinflammatory genes TNF, IL-6, and IL-1β, and upregulating the expression of the anti-inflammatory genes TGF-β and Arg1. Overall, this work represents a novel polymeric nanotechnology platform that can be used to modulate aSYN-induced microglial activation in PD.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Abstract The involvement of patients and the public in research is now an expectation in research with funders requesting a clear plan of involvement and engagement. In the United Kingdom involvement typically focuses on research prioritisation, design and delivery, in contrast activities that share the results of research or research methods more generally are considered to be engagement. Clinical trials tend to concentrate on involvement activities with less emphasis on engagement. To promote engagement activities in the context of clinical trials we asked people attending the 2022 International Clinical Trials Methodology Conference to share ideas on how we can best engage with patients and the public. Responses were reviewed and 22 themes identified. One suggestion was to create an advent calendar and so these 22 themes plus two from the authors were used as a daily tweet from the 1st to the 24th December 2022. Here we share these ideas and draw comparisons between engagement activities in research and traditions of the Christmas period. The ideas shared are not intended as a definitive list but instead a novel way to start discussions between experts by experience, researchers, health professionals and communities to facilitate co-production of meaningful engagement strategies.

Abstract As global temperatures continue to rise, shallow coral reef bleaching has become more intense and widespread. Mesophotic coral ecosystems reside in deeper (30–150 m), cooler water and were thought to offer a refuge to shallow-water reefs. Studies now show that mesophotic coral ecosystems instead have limited connectivity with shallow corals but host diverse endemic communities. Given their extensive distribution and high biodiversity, understanding their susceptibility to warming oceans is imperative. In this multidisciplinary study of an atoll in the Chagos Archipelago in the central Indian Ocean, we show evidence of coral bleaching at 90 m, despite the absence of shallow-water bleaching. We also show that the bleaching was associated with sustained thermocline deepening driven by the Indian Ocean Dipole, which might be further enhanced by internal waves whose influence varied at a sub-atoll scale. Our results demonstrate the potential vulnerability of mesophotic coral ecosystems to thermal stress and highlight the need for oceanographic knowledge to predict bleaching susceptibility and heterogeneity.