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Narcolepsy type I (NT1) is a life-long debilitating autoimmune neurological condition characterised by excessive daytime sleepiness (EDS); the only symptom universal to all patients. Issues regarding sleep efficiency is also prevalent in individuals with NT1, however it remains relatively understudied due to the difficulty in measuring the effect. Genetic traits have shown to predispose an individual to NT1 and while HLA-DQB1 * 06:02 remains the most impactful genetic risk factor additional genes that contribute to immune cell processing have also been identified. In this retrospective study we impute 13 non-MHC narcolepsy associated single nucleotide polymorphisms (SNPs) from 1,558 non-pathological elderly volunteers who have been followed for up to a 24-year period to determine the association with sleep efficiency. Utilising a healthy cohort allows us to independently assess the potential contribution of each SNP on the impact of the sleep cycle disruption. We observed significant associations between SNPs and various elements of the sleep process; however, the main findings were the associations with disturbed night sleep (DNS). We observed an association with rs10915020 and rs1551570 with an increased number of wake episodes during the night, conversely rs2859998 and rs2834168 showed a protective effect—reducing the frequency of nighttime disturbances. While the association with NT1 and DNS has long been established, this is the first investigation that attributes elements of DNS to the genetic profile of the patient. This suggests that the issues with sleep efficiency reported by patients may be due to genetic predispositions and supports the variation seen in the co-morbidities associated with the condition.

ObjectivesExposures in utero and during infancy may impact the development of diseases later in life. They may be linked with development of frailty, although the mechanism is unclear. This study aims to determine the associations between early life risk factors and development of frailty among middle-aged and older adults as well as potential pathways via education, for any observed association.DesignA cross-sectional study.SettingsThis study used data from UK Biobank, a large population-based cohort.Participants502 489 individuals aged 37–73 years were included in the analysis.Primary and secondary outcome measuresEarly life factors in this study included being breast fed as a baby, maternal smoking, birth weight, the presence of perinatal diseases, birth month and birth place (in or outside the UK). We developed a frailty index comprising 49 deficits. We used generalised structural equation modelling to examine the associations between early life factors and development of frailty and whether any observed association was mediated via educational attainment.ResultsA history of breast feeding and normal birth weight were associated with a lower frailty index while maternal smoking, the occurrence of perinatal diseases and birth month with a longer day length were associated with a higher frailty index. Educational level mediated the relationship between these early life factors and frailty index.ConclusionsThis study highlights that biological and social risk occurring at different stages of life are related to the variations in frailty index in later life and suggests opportunities for prevention across the life course.

Human leukocyte antigens (HLA) have been associated with renal function, but previous studies report contradictory findings with little consensus on the exact nature or impact of this observation. This study included 401,307 white British subjects aged 39–73 when they were recruited by UK Biobank. Subjects’ HLA types were imputed using HLA*IMP:02 software. Regression analysis was used to compare 362 imputed HLA types with estimated glomerular filtration rate (eGFR) as a primary outcome and clinical indications as secondary outcome measures. 22 imputed HLA types were associated with increased eGFR (and therefore increased renal function). Decreased eGFR (decreased renal function) was associated with 11 imputed HLA types, seven of which were also associated with increased risk of end-stage renal disease and/or chronic kidney disease. Many of these HLA types are commonly inherited together in established haplotypes, for example: HLA-A*01:01, B*08:01, C*07:01, DRB1*03:01, DQB1*02:01. This haplotype has a population frequency of 9.5% in England and each allele was associated with decreased renal function. 33 imputed HLA types were associated with kidney function in white British subjects. Linkage disequilibrium in HLA heritance suggests that this is not random and particularly affects carriers of established haplotypes. This could have important applications for the diagnosis and treatment of renal disease and global population health.

Background The insertion of a tracheostomy is an established technique used to wean patients off ventilatory support, manage secretions in complex conditions, and as a potentially life-saving procedure to bypass upper airway obstruction. Life-threatening complications during aftercare are not uncommon and may be influenced by a lack of education of carers or healthcare providers of children and young people living with a tracheostomy. Education programmes designed and supported by the National Tracheostomy Safety Project are effective, but resources are not available to educate the workforce at scale. With the overarching aim of widening access to paediatric tracheostomy skills training, we present the protocol for the development and evaluation of a novel virtual reality (VR) training tool designed to simulate the emergency management of paediatric tracheostomy complications. Methods and discussion A multi-centre, non-inferiority educational interventional study with historical controls will be used to evaluate the novel VR training package. A group of 69 healthcare staff and students will have one week to use the educational intervention as often as necessary to learn paediatric emergency tracheostomy skills. The primary outcome measure is skill performance in simulation in a pre- and post-intervention structure within subjects. Participant performance will also be assessed using non-inferiority metrics against historical traditional educational control data. Secondary outcomes include knowledge gain, knowledge retention, usability, side effects, and participant satisfaction. To minimise the risk of cybersickness, teleportation was the preferred locomotion method for the user navigation within the VR environment. Trial registration Full registration of this study was completed at ClinicalTrials.gov. The registration number is NCT06350708 and was accepted on the 4th April 2024.

Background Older adults are vulnerable to mistimed food intake due to health and environmental changes; characterizing meal timing may inform strategies to promote healthy aging. We investigated longitudinal trajectories of self-reported meal timing in older adults and their associations with morbidity, genetic profiles, and all-cause mortality. Methods We analyzed data from 2945 community-dwelling older adults from the University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, with up to five repeated assessments of meal timing and health behaviors conducted between 1983 and 2017. Linear mixed-effects models, latent class analysis, and Cox regression were used to examine relationships between meal timing with illness and behavioral factors, genetic scores for chronotype and obesity, and mortality. Results Here we show older age is associated with later breakfast and dinner times, a later eating midpoint, and a shorter daily eating window. Physical and psychological illnesses, including fatigue, oral health problems, depression, anxiety, and multimorbidity, are primarily associated with later breakfast. Genetic profiles related to an evening chronotype, but not obesity, are linked to later meals. Later breakfast timing is also associated with increased mortality. Latent class analysis of meal timing trajectories identify early and late eating groups, with 10-year survival rates of 86.7% in the late eating group compared to 89.5% in the early eating group. Conclusions Meal timing, particularly later breakfast, shifts with age and may reflect broader health changes in older adults, with implications for morbidity and longevity. Plain language summary As people get older, changes in health and daily routines can affect when they eat their meals. This study followed nearly 3000 older adults in the UK over several decades to understand how meal timing changes with age and how it relates to health and longevity. Participants reported the times they ate meals and completed health and lifestyle surveys across multiple years. We found that as people aged, they tended to eat breakfast and dinner later, and those with more health problems or a genetic tendency to stay up late also tended to eat later. Importantly, eating breakfast later with aging was linked to a higher risk of death. Our findings suggest that later meal timing, especially breakfast, could serve as a simple marker of health in older adults and may guide future strategies for healthy aging. Dashti et al. characterize whether meal timing changes with age in older adults using longitudinal data from nearly 3000 individuals. They link later breakfast timing with increased multimorbidity and higher mortality risk and reveal behavioral and genetic factors that influence meal timing during aging.

The term “Primary age-related tauopathy” (PART) was coined in 2014 to describe the common neuropathological observation of neurofibrillary tangles without associated beta-amyloid (Aβ) pathology. It is possible for PART pathology to be present in both cognitively normal and cognitively impaired individuals. Genetically, Apolipoprotein E ( APOE ) ε4 has been shown to occur less commonly in PART than in Alzheimer’s disease (AD). Here, we investigate the relationships between PART, AD and those pathologically normal for age, with an emphasis on APOE and cognition, using 152 selected participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and the Manchester arm of the Brains for Dementia Research cohort. APOE genotype differed between PART and AD with APOE ε2 more common in the former and APOE ε4 more common in the latter. Individuals with definite PART were less likely to be cognitively impaired than those with AD and those with pathology considered pathologically normal for age. We postulate that the lack of Aβ in definite PART cases may be due either to an increased frequency of APOE ε2 or decreased frequency of APOE ε4 as their resulting protein isoforms have differing binding properties in relation to Aβ. Similarly, an increased frequency of APOE ε2 or decreased frequency of APOE ε4 may lead to decreased levels of cognitive impairment, which raises questions regarding the impact of Aβ pathology on overall cognition in elderly subjects. We suggest that it may be possible to use the increased frequency of APOE ε2 in definite PART to assist neuropathological diagnosis.

Perinatal light exposure predisposes towards health and behaviour in adulthood. Season of birth is associated with psychiatric, allergic, cardiovascular and metabolic problems. It has been proposed that early-life environmental light disrupts the development of biological rhythms which, in turn, influence later-life health. However, the mechanisms linking perinatal seasonal light to later-life biological rhythm and health in humans are unknown. In this study, we investigated the association between season of birth and epigenome-wide DNA methylation of two postmortem human brain regions (16 hypothalamus, 14 temporal cortex). We did not find statistically significant differences at the whole epigenome level, either because we lacked statistical power or that no association exists. However, when we examined 24 CpG sites that had the highest significance or differential methylation, we identified regions which may be associated with circadian rhythm entrainment, cholinergic neurotransmission and neural development. Amongst methylation of the core clock genes, we identified that hypothalamus Neuronal PAS Domain Protein 2 (NPAS2) gene has hypermethylated regions in long photoperiod-born individuals. In addition, we found nominal associations between season of birth and genes linked to chronotype and narcolepsy. Season of birth-related brain DNA methylation profile was different than a previously reported blood methylation profile, suggesting a tissue-specific mechanism of perinatal light programming. Overall, we are the first to analyse the relationship between season of birth and human brain DNA methylation. Further studies with larger sample sizes are required to confirm an imprinting effect of perinatal light on the circadian clock.

Identifying the risk factors for individual differences in age-related cognitive ability and decline is amongst the greatest challenges facing the healthcare of older people. Cognitive impairment caused by “normal ageing” is a major contributor towards overall cognitive deficit in the elderly and a process that exhibits substantial inter- and intra-individual differences. Both cognitive ability and its decline with age are influenced by genetic variation that may act independently or via epistasis/gene-environment interaction. Over the past fourteen years genetic research has aimed to identify the polymorphisms responsible for high cognitive functioning and successful cognitive ageing. Unfortunately, during this period a bewildering array of contrasting reports have appeared in the literature that have implicated over 50 genes with effect sizes ranging from 0.1 to 21%. This review will provide a comprehensive account of the studies performed on cognitively healthy individuals, from the first study conducted in 1995 to present. Based on current knowledge the strong and weak methodologies will be identified and suggestions for future study design will be presented.

We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. We observe antibodies recognizing a wider repertoire of microbial antigens in dermatomyositis. Antibodies recognizing viruses and Poxviridae family species are significantly enriched. The identified autoantibodies recognise a large portion of the human proteome, including interferon regulated proteins; these proteins cluster in specific biological processes. In addition to TRIM33, we identify autoantibodies against eleven further TRIM proteins, including TRIM21. Some of these TRIM proteins share epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis.Megremis, Walker at al. identify immunogenic epitopes in dermatomyositis patients. They identify antibodies recognizing a wider diversity of microbial antigens including poxviruses, and autoantibodies recognizing a large portion of the human proteome. Shared epitope homology between viral and human proteins suggests that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis.

Differences in genomic structure between individuals are ubiquitous features of human genetic variation. Specific copy number variants (CNVs) have been associated with susceptibility to numerous complex psychiatric disorders, including attention-deficit-hyperactivity disorder, autism-spectrum disorders and schizophrenia. These disorders often display co-morbidity with low intelligence. Rare chromosomal deletions and duplications are associated with these disorders, so it has been suggested that these deletions or duplications may be associated with differences in intelligence. Here we investigate associations between large (≥500kb), rare (<1% population frequency) CNVs and both fluid and crystallized intelligence in community-dwelling older people. We observe no significant associations between intelligence and total CNV load. Examining individual CNV regions previously implicated in neuropsychological disorders, we find suggestive evidence that CNV regions around SHANK3 are associated with fluid intelligence as derived from a battery of cognitive tests. This is the first study to examine the effects of rare CNVs as called by multiple algorithms on cognition in a large non-clinical sample, and finds no effects of such variants on general cognitive ability.