Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease.

Genetic hypertrophic cardiomyopathy (HCM) is classically caused by pathogenic/likely pathogenic variants in sarcomere genes (G+). Currently, HCM is diagnosed if there is unexplained left ventricular (LV) hypertrophy with LV wall thickness ≥15 mm in probands or ≥13 mm in at-risk relatives. Although LV hypertrophy is a key feature, this binary metric does not encompass the full constellation of phenotypic features, particularly in the subclinical stage of the disease. Subtle phenotypic manifestations can be identified in sarcomere variant carriers with normal LV wall thickness, before diagnosis with HCM (G+/LV hypertrophy-; subclinical HCM). We conducted a systematic review to summarize current knowledge about the phenotypic spectrum of subclinical HCM and factors influencing penetrance and expressivity. Although the mechanisms driving the development of LV hypertrophy are yet to be elucidated, activation of profibrotic pathways, impaired relaxation, abnormal Ca2+ signaling, altered myocardial energetics, and microvascular dysfunction have all been identified in subclinical HCM. Progression from subclinical to clinically overt HCM may be more likely if early phenotypic manifestations are present, including ECG abnormalities, longer mitral valve leaflets, lower global E' velocities on Doppler echocardiography, and higher serum N-terminal propeptide of B-type natriuretic peptide. Longitudinal studies of variant carriers are critically needed to improve our understanding of penetrance, characterize the transition to disease, identify risk predictors of phenotypic evolution, and guide the development of novel treatment strategies aimed at influencing disease trajectory.

APOE ε4 carriage associates with improved myocardial performance from adolescence to older age.

BACKGROUND: Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy). METHODS: Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR). RESULTS: Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e', posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1-7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0-1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged < 24 years had a 2% higher MCF (95% CI 0-5%, p = 0.059). CONCLUSIONS: By triangulating results in four independent cohorts, across imaging modalities (echocardiography and CMR), and in ~ 37,000 individuals, our results point towards an association between ε4 carriage and improved cardiac performance in terms of LV MCF. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to the pleiotropic effects APOE ε4 carriage that might collectively explain its persistence in human populations.

Validity of European-centric cardiometabolic polygenic scores in multi-ancestry populations.

Polygenic scores (PGSs) provide an individual level estimate of genetic risk for any given disease. Since most PGSs have been derived from genome wide association studies (GWASs) conducted in populations of White European ancestry, their validity in other ancestry groups remains unconfirmed. This is especially relevant for cardiometabolic diseases which are known to disproportionately affect people of non-European ancestry. Thus, we aimed to evaluate the performance of PGSs for glycaemic traits (glycated haemoglobin, and type 1 and type 2 diabetes mellitus), cardiometabolic risk factors (body mass index, hypertension, high- and low-density lipoproteins, and total cholesterol and triglycerides) and cardiovascular diseases (including stroke and coronary artery disease) in people of White European, South Asian, and African Caribbean ethnicity in the UK Biobank. Whilst PGSs incorporated some GWAS data from multi-ethnic populations, the vast majority originated from White Europeans. For most outcomes, PGSs derived mostly from European populations had an overall better performance in White Europeans compared to South Asians and African Caribbeans. Thus, multi-ancestry GWAS data are needed to derive ancestry stratified PGSs to tackle health inequalities.

Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted. METHODS: A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. RESULTS: In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7. CONCLUSIONS: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.

The atrial and ventricular myocardial proteome of end-stage lamin heart disease.

Lamins A/C (encoded by LMNA gene) can lead to dilated cardiomyopathy (DCM). This pilot study sought to explore the postgenomic phenotype of end-stage lamin heart disease. Consecutive patients with end-stage lamin heart disease (LMNA-group, n = 7) and ischaemic DCM (ICM-group, n = 7) undergoing heart transplantation were prospectively enrolled. Samples were obtained from left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV) and interventricular septum (IVS), avoiding the infarcted myocardial segments in the ICM-group. Samples were analysed using a discovery 'shotgun' proteomics approach. We found that 990 proteins were differentially abundant between LMNA and ICM samples with the LA being most perturbed (16-fold more than the LV). Abundance of lamin A/C protein was reduced, but lamin B increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Carbonic anhydrase 3 (CA3) was over-abundant across all LMNA tissue samples (LA, LV, RA, RV, and IVS) when compared to ICM. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM, while sarcomeric proteins such as titin and cardiac alpha-cardiac myosin heavy chain were generally less abundant in RA/LA of LMNA. Protein expression profiling and enrichment analysis pointed towards sarcopenia, extracellular matrix remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Compared to ICM, end-stage lamin heart disease is a biventricular but especially a biatrial disease appearing to have an abundance of lamin B, CA3 and transthyretin, potentially hinting to compensatory responses.

Accelerated DNA methylation age plays a role in the impact of cardiovascular risk factors on the human heart.

BACKGROUND: DNA methylation (DNAm) age acceleration (AgeAccel) and cardiac age by 12-lead advanced electrocardiography (A-ECG) are promising biomarkers of biological and cardiac aging, respectively. We aimed to explore the relationships between DNAm age and A-ECG heart age and to understand the extent to which DNAm AgeAccel relates to cardiovascular (CV) risk factors in a British birth cohort from 1946. RESULTS: We studied four DNAm ages (AgeHannum, AgeHorvath, PhenoAge, and GrimAge) and their corresponding AgeAccel. Outcomes were the results from two publicly available ECG-based cardiac age scores: the Bayesian A-ECG-based heart age score of Lindow et al. 2022 and the deep neural network (DNN) ECG-based heart age score of Ribeiro et al. 2020. DNAm AgeAccel was also studied relative to results from two logistic regression-based A-ECG disease scores, one for left ventricular (LV) systolic dysfunction (LVSD), and one for LV electrical remodeling (LVER). Generalized linear models were used to explore the extent to which any associations between biological cardiometabolic risk factors (body mass index, hypertension, diabetes, high cholesterol, previous cardiovascular disease [CVD], and any CV risk factor) and the ECG-based outcomes are mediated by DNAm AgeAccel. We derived the total effects, average causal mediation effects (ACMEs), average direct effects (ADEs), and the proportion mediated [PM] with their 95% confidence intervals [CIs]. 498 participants (all 60-64 years) were included, with the youngest ECG heart age being 27 and the oldest 90. When exploring the associations between cardiometabolic risk factors and Bayesian A-ECG cardiac age, AgeAccelPheno appears to be a partial mediator, as ACME was 0.23 years [0.01, 0.52] p = 0.028 (i.e., PM≈18%) for diabetes, 0.34 [0.03, 0.74] p = 0.024 (i.e., PM≈15%) for high cholesterol, and 0.34 [0.03, 0.74] p = 0.024 (PM≈15%) for any CV risk factor. Similarly, AgeAccelGrim mediates ≈30% of the relationship between diabetes or high cholesterol and the DNN ECG-based heart age. When exploring the link between cardiometabolic risk factors and the A-ECG-based LVSD and LVER scores, it appears that AgeAccelPheno or AgeAccelGrim mediate 10-40% of these associations. CONCLUSION: By the age of 60, participants with accelerated DNA methylation appear to have older, weaker, and more electrically impaired hearts. We show that the harmful effects of CV risk factors on cardiac age and health, appear to be partially mediated by DNAm AgeAccelPheno and AgeAccelGrim. This highlights the need to further investigate the potential cardioprotective effects of selective DNA methyltransferases modulators.

The role of DSC MR perfusion in predicting IDH mutation and 1p19q codeletion status in gliomas: meta-analysis and technical considerations.

PURPOSE: Isocitrate dehydrogenase (IDH) mutation and 1p19q codeletion status are important for managing glioma patients. However, current practice dictates invasive tissue sampling for histomolecular classification. We investigated the current value of dynamic susceptibility contrast (DSC) MR perfusion imaging as a tool for the non-invasive identification of these biomarkers. METHODS: A systematic search of PubMed, Medline, and Embase up to 2023 was performed, and meta-analyses were conducted. We removed studies employing machine learning models or using multiparametric imaging. We used random-effects standardized mean difference (SMD) and bivariate sensitivity-specificity meta-analyses, calculated the area under the hierarchical summary receiver operating characteristic curve (AUC) and performed meta-regressions using technical acquisition parameters (e.g., time to echo [TE], repetition time [TR]) as moderators to explore sources of heterogeneity. For all estimates, 95% confidence intervals (CIs) are provided. RESULTS: Sixteen eligible manuscripts comprising 1819 patients were included in the quantitative analyses. IDH mutant (IDHm) gliomas had lower rCBV values compared to their wild-type (IDHwt) counterparts. The highest SMD was observed for rCBVmean, rCBVmax, and rCBV 75th percentile (SMD≈ - 0.8, 95% CI ≈ [- 1.2, - 0.5]). In meta-regression, shorter TEs, shorter TRs, and smaller slice thicknesses were linked to higher absolute SMDs. When discriminating IDHm from IDHwt, the highest pooled specificity was observed for rCBVmean (82% [72, 89]), and the highest pooled sensitivity (i.e., 92% [86, 93]) and AUC (i.e., 0.91) for rCBV 10th percentile. In the bivariate meta-regression, shorter TEs and smaller slice gaps were linked to higher pooled sensitivities. In IDHm, 1p19q codeletion was associated with higher rCBVmean (SMD = 0.9 [0.2, 1.5]) and rCBV 90th percentile (SMD = 0.9 [0.1, 1.7]) values. CONCLUSIONS: Identification of vascular signatures predictive of IDH and 1p19q status is a novel promising application of DSC perfusion. Standardization of acquisition protocols and post-processing of DSC perfusion maps are warranted before widespread use in clinical practice.

Developing a medical device-grade T2 phantom optimized for myocardial T2 mapping by cardiovascular magnetic resonance.

INTRODUCTION: A long T2 relaxation time can reflect oedema, and myocardial inflammation when combined with increased plasma troponin levels. Cardiovascular magnetic resonance (CMR) T2 mapping therefore has potential to provide a key diagnostic and prognostic biomarkers. However, T2 varies by scanner, software, and sequence, highlighting the need for standardization and for a quality assurance system for T2 mapping in CMR. AIM: To fabricate and assess a phantom dedicated to the quality assurance of T2 mapping in CMR. METHOD: A T2 mapping phantom was manufactured to contain 9 T1 and T2 (T1|T2) tubes to mimic clinically relevant native and post-contrast T2 in myocardium across the health to inflammation spectrum (i.e., 43-74 ms) and across both field strengths (1.5 and 3 T). We evaluated the phantom's structural integrity, B0 and B1 uniformity using field maps, and temperature dependence. Baseline reference T1|T2 were measured using inversion recovery gradient echo and single-echo spin echo (SE) sequences respectively, both with long repetition times (10 s). Long-term reproducibility of T1|T2 was determined by repeated T1|T2 mapping of the phantom at baseline and at 12 months. RESULTS: The phantom embodies 9 internal agarose-containing T1|T2 tubes doped with nickel di-chloride (NiCl2) as the paramagnetic relaxation modifier to cover the clinically relevant spectrum of myocardial T2. The tubes are surrounded by an agarose-gel matrix which is doped with NiCl2 and packed with high-density polyethylene (HDPE) beads. All tubes at both field strengths, showed measurement errors up to ≤ 7.2 ms [< 14.7%] for estimated T2 by balanced steady-state free precession T2 mapping compared to reference SE T2 with the exception of the post-contrast tube of ultra-low T1 where the deviance was up to 16 ms [40.0%]. At 12 months, the phantom remained free of air bubbles, susceptibility, and off-resonance artifacts. The inclusion of HDPE beads effectively flattened the B0 and B1 magnetic fields in the imaged slice. Independent temperature dependency experiments over the 13-38 °C range confirmed the greater stability of shorter vs longer T1|T2 tubes. Excellent long-term (12-month) reproducibility of measured T1|T2 was demonstrated across both field strengths (all coefficients of variation < 1.38%). CONCLUSION: The T2 mapping phantom demonstrates excellent structural integrity, B0 and B1 uniformity, and reproducibility of its internal tube T1|T2 out to 1 year. This device may now be mass-produced to support the quality assurance of T2 mapping in CMR.

Disopyramide is a safe and effective treatment for children with obstructive hypertrophic cardiomyopathy.

BACKGROUND: Left ventricular outflow tract obstruction (LVOTO) is present in 1/3 of children with Hypertrophic Cardiomyopathy (HCM). Disopyramide improves symptoms associated with LVOTO and delays surgical intervention in adults, but it is not licensed in children. AIM: To describe a single-centre thirty-year experience of using disopyramide to treat LVOTO-related symptoms in a paediatric HCM cohort. METHODS: Clinical data were collected for all patients meeting diagnostic criteria for HCM (<18 years) at the time of initiation, 6 months after, and last follow-up or end of disopyramide treatment. It included demographics, clinical history, 12­lead electrocardiography, and echocardiography. Comparisons between baseline and 6 month follow up, and end of follow up respectively were performed. RESULTS: Fifty-one patients with HCM were started on disopyramide at a mean age 10.2±5.3 years. At 6 months, of those previously symptomatic, 33(86.8%) reported an improvement of symptoms and 12(31.6%) were asymptomatic. PR interval, corrected QT interval and maximal LVOT gradient had not significantly changed, but fewer participants were noted to have systolic anterior motion of the mitral valve 31 (72.1%) vs. 26 (57.80%). Patients were followed up for a median of 1.9 years (IQR 0.83-4.5). Nine patients (17.6%) reported side effects, and eleven patients (33.3%) with initial improvement in symptoms reported a return or worsening of symptoms requiring a change in medication (n = 4, 12.1%) or left ventricular septal myomectomy (n = 7, 21.2%) during follow up. CONCLUSION: Disopyramide is a safe and effective treatment for LVOTO-related symptoms in childhood obstructive HCM. Any delay in the need for invasive intervention, particularly during childhood, is of clear clinical benefit.

The use of attention-deficit hyperactivity disorder medications in cardiac disease.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with onset usually in childhood characterized by inattention, impulsivity, and hyperactivity causing a functional impairment. Untreated ADHD, or treatment delay is associated with adverse outcomes and poor quality of life. Although conservative management strategies such as behavioral and psychological interventions are important, pharmacological treatment has a strong evidence base with improved outcomes. ADHD medications are broadly divided into stimulant and non-stimulant medications. Stimulant medications are generally more effective than non-stimulants. Cardiovascular safety of ADHD medication has been a matter of debate for decades. Treatment guidelines advise the careful consideration of risks and benefits in people with cardiovascular diseases such as congenital heart disease or cardiomyopathy. Although stimulants can increase systemic blood pressure and heart rate, no significant associations were found between their use and serious cardiovascular events. Concerns regarding QT effects and attendant sudden cardiac death risks deter clinicians from initiating much-needed ADHD medications in patients with heart disease. This overly cautious approach is potentially depriving low-risk individuals from significant benefits associated with timely ADHD drug treatment. This review discusses the cardiovascular risks reportedly associated with ADHD medications, the evidence base for their safe usage in persons with established cardiovascular disease, and highlights future research directions.

Plasma proteomic signature predicts who will get persistent symptoms following SARS-CoV-2 infection.

BACKGROUND: The majority of those infected by ancestral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the UK first wave (starting March 2020) did not require hospitalisation. Most had a short-lived mild or asymptomatic infection, while others had symptoms that persisted for weeks or months. We hypothesized that the plasma proteome at the time of first infection would reflect differences in the inflammatory response that linked to symptom severity and duration. METHODS: We performed a nested longitudinal case-control study and targeted analysis of the plasma proteome of 156 healthcare workers (HCW) with and without lab confirmed SARS-CoV-2 infection. Targeted proteomic multiple-reaction monitoring analysis of 91 pre-selected proteins was undertaken in uninfected healthcare workers at baseline, and in infected healthcare workers serially, from 1 week prior to 6 weeks after their first confirmed SARS-CoV-2 infection. Symptom severity and antibody responses were also tracked. Questionnaires at 6 and 12 months collected data on persistent symptoms. FINDINGS: Within this cohort (median age 39 years, interquartile range 30-47 years), 54 healthcare workers (44% male) had PCR or antibody confirmed infection, with the remaining 102 (38% male) serving as uninfected controls. Following the first confirmed SARS-CoV-2 infection, perturbation of the plasma proteome persisted for up to 6 weeks, tracking symptom severity and antibody responses. Differentially abundant proteins were mostly coordinated around lipid, atherosclerosis and cholesterol metabolism pathways, complement and coagulation cascades, autophagy, and lysosomal function. The proteomic profile at the time of seroconversion associated with persistent symptoms out to 12 months. Data are available via ProteomeXchange with identifier PXD036590. INTERPRETATION: Our findings show that non-severe SARS-CoV-2 infection perturbs the plasma proteome for at least 6 weeks. The plasma proteomic signature at the time of seroconversion has the potential to identify which individuals are more likely to suffer from persistent symptoms related to SARS-CoV-2 infection. FUNDING INFORMATION: The COVIDsortium is supported by funding donated by individuals, charitable Trusts, and corporations including Goldman Sachs, Citadel and Citadel Securities, The Guy Foundation, GW Pharmaceuticals, Kusuma Trust, and Jagclif Charitable Trust, and enabled by Barts Charity with support from University College London Hospitals (UCLH) Charity. This work was additionally supported by the Translational Mass Spectrometry Research Group and the Biomedical Research Center (BRC) at Great Ormond Street Hospital.

T2 and T2⁎ mapping and weighted imaging in cardiac MRI.

Cardiac imaging is progressing from simple imaging of heart structure and function to techniques visualizing and measuring underlying tissue biological changes that can potentially define disease and therapeutic options. These techniques exploit underlying tissue magnetic relaxation times: T1, T2 and T2*. Initial weighting methods showed myocardial heterogeneity, detecting regional disease. Current methods are now fully quantitative generating intuitive color maps that do not only expose regionality, but also diffuse changes - meaning that between-scan comparisons can be made to define disease (compared to normal) and to monitor interval change (compared to old scans). T1 is now familiar and used clinically in multiple scenarios, yet some technical challenges remain. T2 is elevated with increased tissue water - edema. Should there also be blood troponin elevation, this edema likely reflects inflammation, a key biological process. T2* falls in the presence of magnetic/paramagnetic materials - practically, this means it measures tissue iron, either after myocardial hemorrhage or in myocardial iron overload. This review discusses how T2 and T2⁎ imaging work (underlying physics, innovations, dependencies, performance), current and emerging use cases, quality assurance processes for global delivery and future research directions.

Childhood Bradycardia Associates With Atrioventricular Conduction Defects in Older Age: A Longitudinal Birth Cohort Study.

Background This study explored the association between childhood bradycardia and later-life cardiac phenotype using longitudinal data from the 1946 National Survey of Health and Development (NSHD) birth cohort. Methods and Results Resting heart rate was recorded at 6 and 7 years of age to provide the bradycardia exposure defined as a childhood resting heart rate <75 bpm. Three outcomes were studied: (1) echocardiographic data at 60 to 64 years of age, consisting of ejection fraction, left ventricular mass index, myocardial contraction fraction index, and E/e'; (2) electrocardiographic evidence of atrioventricular or ventricular conduction defects by 60 to 64 years of age; and (3) all-cause and cardiovascular mortality. Generalized linear models or Cox regression models were used, and adjustment was made for relevant demographic and health-related covariates, and for multiple testing. Mixed generalized linear models and fractional polynomials were used as sensitivity analyses. One in 3 older adults with atrioventricular conduction defects had been bradycardic in childhood, with defects being serious (Mobitz type II second-degree atrioventricular block or higher) in 12%. In fully adjusted models, childhood bradycardia was associated with 2.91 higher odds of atrioventricular conduction defects (95% CI, 1.59-5.31; P=0.0005). Associations persisted in random coefficients mixed generalized linear models (odds ratio, 2.50; 95% CI, 1.01-4.31). Fractional polynomials confirmed a linear association between the log odds of atrioventricular conduction defects at 60 to 64 years of age and resting heart rate at 7 years of age. There was no association between bradycardia in childhood and mortality outcomes or with echocardiographic parameters and ventricular conduction defects in older age. Conclusions Longitudinal birth cohort data indicate that childhood bradycardia trebles the odds of having atrioventricular conduction defects in older age, 88% of which are benign. In addition, it does not influence mortality or heart size and function. Future research should concentrate on identifying children at risk.

Machine learning with neuroimaging data to identify autism spectrum disorder: a systematic review and meta-analysis.

PURPOSE: Autism Spectrum Disorder (ASD) is diagnosed through observation or interview assessments, which is time-consuming, subjective, and with questionable validity and reliability. Thus, we aimed to evaluate the role of machine learning (ML) with neuroimaging data to provide a reliable classification of ASD. METHODS: A systematic search of PubMed, Scopus, and Embase was conducted to identify relevant publications. Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used to assess the studies' quality. A bivariate random-effects model meta-analysis was employed to evaluate the pooled sensitivity, the pooled specificity, and the diagnostic performance through the hierarchical summary receiver operating characteristic (HSROC) curve of ML with neuroimaging data in classifying ASD. Meta-regression was also performed. RESULTS: Forty-four studies (5697 ASD and 6013 typically developing individuals [TD] in total) were included in the quantitative analysis. The pooled sensitivity for differentiating ASD from TD individuals was 86.25 95% confidence interval [CI] (81.24, 90.08), while the pooled specificity was 83.31 95% CI (78.12, 87.48) with a combined area under the HSROC (AUC) of 0.889. Higgins I2 (> 90%) and Cochran's Q (p < 0.0001) suggest a high degree of heterogeneity. In the bivariate model meta-regression, a higher pooled specificity was observed in studies not using a brain atlas (90.91 95% CI [80.67, 96.00], p = 0.032). In addition, a greater pooled sensitivity was seen in studies recruiting both males and females (89.04 95% CI [83.84, 92.72], p = 0.021), and combining imaging modalities (94.12 95% [85.43, 97.76], p = 0.036). CONCLUSION: ML with neuroimaging data is an exciting prospect in detecting individuals with ASD but further studies are required to improve its reliability for usage in clinical practice.

Impact of lockdown on key workers: findings from the COVID-19 survey in four UK national longitudinal studies.

BACKGROUND: Key workers played a pivotal role during the national lockdown in the UK's response to the COVID-19 pandemic. Although protective measures have been taken, the impact of the pandemic on key workers is yet to be fully elucidated. METHODS: Participants were from four longitudinal age-homogeneous British cohorts (born in 2001, 1990, 1970 and 1958). A web-based survey provided outcome data during the first UK national lockdown (May 2020) on COVID-19 infection status, changes in financial situation, trust in government, conflict with people around, household composition, psychological distress, alcohol consumption, smoking and sleep duration. Generalised linear models with logit link assessed the association between being a key worker and the above outcomes. Adjustment was made for cohort design, non-response, sex, ethnicity, adult socioeconomic position (SEP), childhood SEP, the presence of a chronic illness and receipt of a shielding letter. Meta-analyses were performed across the cohorts. FINDINGS: 13 736 participants were included. During lockdown, being a key worker was associated with increased chances of being infected with COVID-19 (OR 1.43, 95% CI 1.22 to 1.68) and experiencing conflict with people around (OR 1.19, 95% CI 1.03 to 1.37). However, key workers were less likely to be worse off financially (OR 0.32, 95% CI 0.24 to 0.65), to consume more alcohol (OR 0.88, 95% CI 0.79 to 0.98) or to smoke more (OR 0.60, 95% CI 0.44 to 0.80) during lockdown. Interestingly, being a key worker was not associated with psychological distress (OR 0.95, 95% CI 0.85 to 1.05). INTERPRETATION: Being a key worker during the first UK COVID-19 lockdown was a double-edged sword, with both benefits and downsides. The UK government had the basic duty to protect its key workers from SARS-CoV-2 infection, but it may have failed to do so, and there is an urgent need to rectify this in light of the ongoing third wave.

Evaluating access to health and care services during lockdown by the COVID-19 survey in five UK national longitudinal studies.

OBJECTIVE: Access to health services and adequate care is influenced by sex, ethnicity, socioeconomic position (SEP) and the burden of comorbidities. Our study aimed to assess whether the COVID-19 pandemic further deepened these already existing health inequalities. DESIGN: Cross-sectional study. SETTING: Data were collected from five longitudinal age-homogenous British cohorts (born in 2000-2002, 1989-1990, 1970, 1958 and 1946). PARTICIPANTS: A web survey was sent to the cohorts. Anybody who responded to the survey was included, resulting in 14 891 eligible participants. MAIN OUTCOMES MEASURED: The survey provided data on cancelled surgical or medical appointments, and the number of care hours received in a week during the first UK COVID-19 national lockdown. INTERVENTIONS: Using binary or ordered logistic regression, we evaluated whether these outcomes differed by sex, ethnicity, SEP and having a chronic illness. Adjustment was made for study design, non-response weights, psychological distress, presence of children or adolescents in the household, COVID-19 infection, key worker status, and whether participants had received a shielding letter. Meta-analyses were performed across the cohorts, and meta-regression was used to evaluate the effect of age as a moderator. RESULTS: Women (OR 1.40, 95% CI 1.27 to 1.55) and those with a chronic illness (OR 1.84, 95% CI 1.65 to 2.05) experienced significantly more cancellations during lockdown (all p<0.0001). Ethnic minorities and those with a chronic illness required a higher number of care hours during the lockdown (both OR≈2.00, all p<0.002). SEP was not associated with cancellation or care hours. Age was not independently associated with either outcome in the meta-regression. CONCLUSION: The UK government's lockdown approach during the COVID-19 pandemic appears to have deepened existing health inequalities, impacting predominantly women, ethnic minorities and those with chronic illnesses. Public health authorities need to implement urgent policies to ensure equitable access to health and care for all in preparation for a fourthwave.

Longitudinal birth cohort study finds that life-course frailty associates with later-life heart size and function.

A frailty index (FI) counts health deficit accumulation. Besides traditional risk factors, it is unknown whether the health deficit burden is related to the appearance of cardiovascular disease. In order to answer this question, the same multidimensional FI looking at 45-health deficits was serially calculated per participant at 4 time periods (0-16, 19-44, 45-54 and 60-64 years) using data from the 1946 Medical Research Council (MRC) British National Survey of Health and Development (NSHD)-the world's longest running longitudinal birth cohort with continuous follow-up. From these the mean and total FI for the life-course, and the step change in deficit accumulation from one time period to another was derived. Echocardiographic data at 60-64 years provided: ejection fraction (EF), left ventricular mass indexed to body surface area (LVmassi, BSA), myocardial contraction fraction indexed to BSA (MCFi) and E/e'. Generalized linear models assessed the association between FIs and echocardiographic parameters after adjustment for relevant covariates. 1375 participants were included. For each single new deficit accumulated at any one of the 4 time periods, LVmassi increased by 0.91-1.44% (p < 0.013), while MCFi decreased by 0.6-1.02% (p < 0.05). A unit increase in FI at age 45-54 and 60-64, decreased EF by 11-12% (p < 0.013). A single health deficit step change occurring between 60 and 64 years and one of the earlier time periods, translated into higher odds (2.1-78.5, p < 0.020) of elevated LV filling pressure. Thus, the accumulation of health deficits at any time period of the life-course associates with a maladaptive cardiac phenotype in older age, dominated by myocardial hypertrophy and poorer function.

Artificial Intelligence in Medicine: A Multinational Multi-Center Survey on the Medical and Dental Students' Perception.

Background: The emerging field of artificial intelligence (AI) will probably affect the practice for the next generation of doctors. However, the students' views on AI have not been largely investigated. Methods: An anonymous electronic survey on AI was designed for medical and dental students to explore: (1) sources of information about AI, (2) AI applications and concerns, (3) AI status as a topic in medicine, and (4) students' feelings and attitudes. The questionnaire was advertised on social media platforms in 2020. Security measures were employed to prevent fraudulent responses. Mann-Whitney U-test was employed for all comparisons. A sensitivity analysis was also performed by binarizing responses to express disagreement and agreement using the Chi-squared test. Results: Three thousand one hundred thirty-three respondents from 63 countries from all continents were included. Most respondents reported having at least a moderate understanding of the technologies underpinning AI and of their current application, with higher agreement associated with being male (p < 0.0001), tech-savvy (p < 0.0001), pre-clinical student (p < 0.006), and from a developed country (p < 0.04). Students perceive AI as a partner rather than a competitor (72.2%) with a higher agreement for medical students (p = 0.002). The belief that AI will revolutionize medicine and dentistry (83.9%) with greater agreement for students from a developed country (p = 0.0004) was noted. Most students agree that the AI developments will make medicine and dentistry more exciting (69.9%), that AI shall be part of the medical training (85.6%) and they are eager to incorporate AI in their future practice (99%). Conclusion: Currently, AI is a hot topic in medicine and dentistry. Students have a basic understanding of AI principles, a positive attitude toward AI and would like to have it incorporated into their training.

The association between plasma metabolites and sleep quality in the Southall and Brent Revisited (SABRE) Study: A cross-sectional analysis.

We examined the association between plasma metabolites and abnormal sleep patterns using data from the Southall and Brent REvisited (SABRE) cohort. Nuclear magnetic resonance spectroscopy provided 146 circulating plasma metabolites. Sleep questionnaires identified the presence or absence of: difficulty falling asleep, early morning waking, waking up tired, and snoring. Metabolites were compared between the sleep quality categories using the t test, and then filtered using a false discovery rate of 0.05. Generalised linear models with logit-link assessed the associations between filtered metabolites and sleep phenotypes. Adjustment was made for important demographic and health-related covariates. In all, 2,718 participants were included in the analysis. After correcting for multiple testing, three metabolites remained for difficulty falling asleep, 59 for snoring, and none for early morning waking and waking up tired. After adjusting for sex, age, ethnicity and years of education, 1 standard deviation increase in serum histidine and valine associated with lower odds of difficulty falling asleep by 0.89-0.90 (95% confidence intervals [CIs] 0.80-0.99). Branched-chain and aromatic amino acids (odds ratios [ORs] 1.19-1.25, 95% CIs 1.09-1.36) were positively associated with snoring. Total cholesterol in low-density lipoprotein (OR 0.90, 95% CI 0.83-0.97) and high-density lipoprotein (OR 0.88, 95% CI 0.81-0.95) associated with lower odds of snoring. In the fully adjusted model, most associations persisted. To conclude, histidine and valine associated with lower odds of difficulty falling asleep, while docosahexaenoic acid and cholesterol in low-density lipoprotein and high-density lipoprotein subfractions associated with lower odds of snoring. Identified metabolites could provide guidance on the metabolic pathways associated with adverse sleep quality.