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 neuroplastic pathway, which includes cyclic adenosine monophosphate response element-binding protein 1 ( CREB1 ), brain-derived neurotrophic factor ( BDNF ), and its receptor ...(neurotrophic tyrosine kinase receptor, type 2 NTRK2 ), plays a crucial role in the adaptation of brain to stress, and thus variations of these genes are plausible risk factors for depression. Methods A population-based sample was recruited, subsets of which were interviewed and underwent functional magnetic resonance imaging. We investigated the association of nine polymorphisms throughout the CREB1-BDNF-NTRK2 pathway with lifetime depression, rumination, current depression severity, negative life events, and sad face emotion processing in a three-level design. Results In the population study, BDNF -rs6265 and CREB1 -rs2253206 major alleles were significantly associated with rumination and through rumination with current depression severity. However, childhood adversity increased the risk of lifetime depression in the minor allele carriers of BDNF -rs6265 and CREB1 -rs2253206 and in alleles of six other single nucleotide polymorphisms (SNPs). We validated our findings in the interviewed subjects using structural equation modeling. Finally, using functional magnetic resonance imaging, we found that viewing sad faces evoked greater activity in depression-related areas in healthy control subjects possessing the minor alleles of BDNF -rs6265 and CREB1 -rs2253206. Conclusions Genetic variation associated with reduced function in the CREB1-BDNF-NTRK2 pathway has multiple, sometimes opposing, influences on risk mechanisms of depression, but almost all the SNPs studied amplified the effect of childhood adversity. The use of cognitive and neural intermediate phenotypes together with a molecular pathway approach may be critical to understanding how genes influence risk of depression.
Background
Recent studies have reported substantial variability in response to repetitive transcranial magnetic stimulation (rTMS). We hypothesized that an individual's genetic predisposition may ...contribute to such variability in the pharyngeal motor cortex. This study aimed to investigate the response to 1 and 5 Hz rTMS paradigms on pharyngeal motor cortex in healthy participants and its relationship with genetic predisposition.
Methods
Forty‐one healthy participants (25.4 ± 4.6 years old) received either or both 1 Hz (n = 39) and 5 Hz rTMS (n = 40) over pharyngeal motor cortex. Pharyngeal and thenar motor–evoked potentials were recorded at baseline and for 1 hour post‐rTMS. The participants were then classified according to their response. The associations between rTMS response and gender, time of day of the stimulation, and eight prespecified single nucleotide polymorphisms (SNPs) were analyzed.
Key Results
There was no direction‐specific response to either paradigm (1 Hz: F3.69, 129.21 = 0.78, P = 0.56; 5 Hz: F4.08, 146.85 = 1.38, P = 0.25). Only 13% of participants showed the expected bidirectional response (inhibition for 1 Hz and excitation for 5 Hz). Significant associations were found between response and COMT (1 Hz: P = 0.03) and DRD2 (1 Hz: P = 0.02; 5 Hz: P = 0.04) polymorphisms. Carriers of minor allele G from SNP rs6269 (COMT) were more likely to show inhibitory or excitatory outcomes after 1 Hz rTMS. By contrast, carriers of minor allele A from SNP rs1800497 (DRD2) were more likely to show no response to 1 Hz rTMS and inhibition after 5 Hz rTMS.
Conclusions & Inferences
Two SNPs from COMT and DRD2 genes may partially explain the response variability to rTMS in the pharyngeal motor system. Further research should focus on stratified approaches for neurostimulatory dysphagia treatment using rTMS.
The response to 1 and 5 Hz repetitive transcranial magnetic stimulation varies substantially among individuals. We found that the response was associated with polymorphisms in the genes COMT and DRD2. Our findings suggested that genetic variation may partially explain the observed response variability.
An important role is predicted for virtual reality (VR) in the future of medical education. We performed a systematic review of the literature with a narrative synthesis, to examine the current ...evidence for VR in simulation-based emergency skills training. We broadly define emergency skills as any clinical skill used in the emergency care of patients across all clinical settings.
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. The data sources accessed during this study included: PubMed, CINAHL, EMBASE, AMED, EMCARE, HMIC, BNI, PsychINFO, Medline, CENTRAL, SCOPUS, Web of Science, BIOSIS Citation Index, ERIC, ACM Digital Library, IEEE Xplore, and ProQuest Dissertations and Thesis Global. Cochrane’s Rob 2 and ROBVIS tools were used during study quality assessment. No ethical review was required for this work.
Thirty-four articles published between 14th March 1998 and 1st March 2022 were included in this review. Studies were predominantly conducted in the USA and Europe and focussed on a variety of healthcare disciplines including medical, nursing, and allied health. VR education was delivered using head-mounted displays, Cave Automatic Virtual Environment systems, and bespoke setups. These systems delivered education in a variety of areas (emergency medicine, equipment training, obstetrics, and basic/advanced life support). Subjective potential advantages of this technology included realism, replayability, and time-effectiveness. Reports of adverse events were low in frequency across the included studies. Whilst clear educational benefit was generally noted, this was not reflected in changes to patient-based outcomes.
There may be educational benefit to using VR in the context of simulation-based emergency skills training including knowledge gain and retention, skill performance, acceptability, usability, and validity. Currently, there is insufficient evidence to demonstrate clear cost-effectiveness, or direct improvement of patient or institutional outcomes, at this stage.
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.
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.
Background & Aims Polymorphisms in brain-derived neurotrophic factor (BDNF) can affect brain and behavioral responses. However, little is known about the effects of a single nucleotide polymorphism ...(SNP) in BDNF , at codon 66 (the Val−Met substitution, detected in approximately 33% of the Caucasian population) on stimulation-induced plasticity in the cortico-bulbar system. We examined whether this SNP influenced outcomes of different forms of neurostimulation applied to the pharyngeal motor cortex. Methods Thirty-eight healthy volunteers were assessed for corticobulbar excitability after single-pulse, transcranial magnetic stimulation of induced pharyngeal electromyographic responses, recorded from a swallowed intraluminal catheter. Thereafter, volunteers were conditioned with pharyngeal electrical stimulation, or 2 forms of repetitive (1 and 5 Hz) transcranial magnetic stimulation (rTMS). Repeated measurements of pharyngeal motor-evoked potentials were assessed with transcranial magnetic stimulation for as long as 1 hour after the 3 forms of neurostimulation and correlated with SNPs at codon 66 of BDNF (encoding Val or Met). Results Pharyngeal electrical stimulation significantly increased the amplitude of motor-evoked potentials in individuals with the SNP that encoded Val66, compared to those that encoded Met66, with a strong GENOTYPE*TIME interaction ( F8,112 = 2.4; P = .018). By contrast, there was a significant reduction in latencies of subjects with the SNP that encoded Met66 after 5-Hz rTMS ( F3,60 = 4.9; P = .04). In addition, the expected inhibitory effect of 1-Hz rTMS on amplitude was not observed in subjects with the SNP that encoded Met66 in BDNF ( F7,140 = 2.23; P = .035). Conclusions An SNP in human BDNF at codon 66 affects plasticity of the pharyngeal cortex to different forms of neurostimulation. Genetic analysis might help select specific forms of neurostimulation as therapeutics for patients with disorders such as dysphagic stroke.
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.
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