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Caristo Diagnostics, an Oxford University spinout company, has been launched to commercialise a new coronary CT image analysis technology that can flag patients at risk of deadly heart attacks years before they occur.
Early Atrial Remodeling Drives Arrhythmia in Fabry Disease.
BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by α-Gal A (α-galactosidase A) deficiency, resulting in multiorgan accumulation of sphingolipid, namely globotriaosylceramide. This triggers ventricular myocardial hypertrophy, fibrosis, and inflammation, driving arrhythmia and sudden death. Atrial fibrillation is common, yet the cellular mechanisms accounting for this are unknown. METHODS: To address this, we conducted ECG analysis from a large cohort of 115 adults with FD at varying cardiomyopathy stages. ECG P-wave characteristics were compared with non-FD controls. Cellular contractile and electrophysiological function were examined in a novel atrial cellular FD model developed and imputed into in silico atrial models to provide insight into mechanisms of arrhythmia. Induced pluripotent stem cells were genome-edited using Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 to introduce the GLA p.N215S variant and differentiated into induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-CMs). Contraction, calcium handling, and electrophysiology experiments were conducted. Bi-atrial in silico models were developed with cellular changes as in GLA p.N215S iPSC-CMs. RESULTS: ECG analysis demonstrated P-wave duration and PQ interval shortening in FD adults before the onset of cardiomyopathy. Patients with FD exhibited a higher incidence of premature atrial contractions and increased risk of atrial fibrillation compared with healthy controls. GLA p.N215S iPSC-CMs were deficient in α-Gal A and exhibited globotriaosylceramide accumulation. Atrial GLA p.N215S iPSC-CMs demonstrated a more positive diastolic membrane potential, faster action potential upstroke velocity, greater incidence of delayed afterdepolarizations, greater contraction force, and alterations in calcium handling compared with wild-type iPSC-CMs. Simulations with these changes in the in silico models resulted in similar P-wave morphology changes to those seen in early FD cardiomyopathy and increased atrial fibrillation vulnerability. CONCLUSIONS: These findings provide novel insights into underpinning mechanisms for atrial arrhythmia and a rationale for early P-wave changes in FD. These may be targeted to develop therapeutic strategies to reduce the arrhythmic burden in FD.
Effect of supplementation with vitamin D on biochemical markers of iron status and erythropoiesis in older people: BEST-D trial.
Previous observational studies suggested that vitamin D may control absorption of iron by inhibition of hepcidin, but the causal relevance of these associations is uncertain. Using placebo-controlled randomization, we assessed the effects of supplementation with vitamin D on biochemical markers of iron status and erythropoiesis in community-dwelling older people living in the United Kingdom (UK). The BEST-D trial, designed to establish the optimum dose of vitamin D3 for future trials, had 305 participants, aged 65 years or older, randomly allocated to 4000 IU vitamin D3 (n=102), 2000 IU vitamin D3 (n=102), or matching placebo (n=101). We estimated the effect of vitamin D allocation on plasma levels of hepcidin, soluble transferrin receptor (sTfR), ferritin, iron, transferrin, saturated transferrin (TSAT%), and the sTfR-ferritin index. Despite increases in 25-hydroxy-vitamin D, neither dose had significant effects on biochemical markers of iron status or erythropoiesis. Geometric mean concentrations were similar in vitamin D3 arms vs placebo for hepcidin (20.7 [SE 0.90] vs 20.5 [1.21] ng/mL), sTfR (0.69 [0.010] vs 0.70 [0.015] µg/mL), ferritin (97.1 [2.81] vs 97.8 [4.10] µg/L) and sTfR-ferritin ratio (0.36 [0.006] vs 0.36 [0.009]), respectively, while arithmetic mean levels were similar for iron (16.7 [0.38] vs 17.3 [0.54] µmol/L), transferrin (2.56 [0.014] vs 2.60 [0.021] g/dL), and TSAT% (26.5 [0.60] vs 27.5 [0.85]). The proportions of participants with ferritin <15 µg/L and TSAT<16% were unaltered by vitamin D3 suggesting that 12 months of daily supplementation with moderately high doses of vitamin D3 are unlikely to alter the iron status of older adults.
Alcohol consumption and cancer risk in South Korea and the UK: prospective cohort studies.
BACKGROUND: This study aimed to compare cancer incidence rates between South Korea and the UK, and assess the associated cancer risks due to alcohol consumption. METHODS: Data were pooled from the Korean Cancer Prevention Study-II and the Korean Genome Epidemiology Study Biobank for South Korea, and from UK Biobank (UKB) for the UK, with follow-up until 2020. Age-standardized incidence rates were calculated by using the World Health Organization standard population. Hazard ratios (HRs) for cancer incidence were analysed in relation to alcohol consumption levels. RESULTS: The overall cancer incidence rates were similar between South Korea and the UK. However, the incidence of liver, stomach, and thyroid cancers was more than five times higher in the Korean cohort. Compared with never drinkers, consuming ≥50 g of alcohol daily increased the overall cancer risk by 24% in the Korean data and by 11% in the UKB data. In Korea, heavy drinking (≥50 g/day) was associated with higher risks of esophageal cancer (HR = 12.59), liver cancer (HR = 1.65), head and neck cancer (HR = 2.06), alcohol-related cancers (HR = 1.60), and stomach cancer (HR = 1.43). In the UKB cohort, it was linked to increased risks of head and neck cancer (HR = 1.95), breast cancer (HR = 1.12), and alcohol-related cancers (HR = 1.18). Both cohorts showed a lower risk of thyroid cancer with increased alcohol consumption. CONCLUSION: Alcohol consumption is associated with an increased risk of alcohol-related cancers in both South Korean and UK populations.
Stent-Retriever Thrombectomy in STEMI With Large Thrombus Burden: The RETRIEVE AMI Randomized Trial.
BACKGROUND: Percutaneous coronary intervention (PCI) restores epicardial flow in ST-segment elevation myocardial infarction (STEMI), but large thrombus burden (LTB) can impair myocardial perfusion due to embolization. While manual aspiration (MA) devices have limited efficacy in STEMI, the success of stent-retriever thrombectomy (SRT) in stroke suggests it as a promising option for STEMI. OBJECTIVES: The RETRIEVE AMI (stent-retriever thrombectomy for thrombus burden reduction in patients with acute myocardial infarction) trial assessed the safety and efficacy of Solitaire X SRT vs Export MA in STEMI patients with LTB. METHODS: This single-center study enrolled 81 STEMI patients with LTB (TIMI thrombus grade ≥4) and randomized them to PCI, MA-assisted, or SRT-assisted PCI. The primary endpoint was difference in prestent thrombus volume by optical coherence tomography between SRT and either comparator; coprimary endpoints included device-related target vessel complications and major adverse cardiac and cerebrovascular events through 6 months. RESULTS: SRT was performed in 26 cases (one crossover), and MA in 27. No device-related arterial complications or cerebrovascular events occurred in the SRT arm. Baseline thrombus volume was significantly higher in the SRT group (18.3 mm3) compared to MA (7.7 mm3) and no modification (9.8 mm3; P = 0.04). Prestent thrombus volume was not significantly different between SRT (7.7; IQR: 2.3-18.6) and either MA (4.8; IQR: 1.8-8.4; P = 0.17) or no thrombus modification (9.8; IQR: 4.5-18.1; P = 1.00). Both techniques significantly reduced prestent thrombus burden (SRT: 12.8%; IQR: 4.4%-21.5%; P = 0.016 and MA: 13.0%; IQR: 3.8%-19.4%; P = 0.003) compared to no modification (22.8%; IQR: 10.4%-27.7%). No device-related clinically relevant arterial injury was detected and in-hospital and 6-month major adverse cardiac and cerebrovascular events did not differ between arms. CONCLUSIONS: RETRIEVE AMI demonstrates the feasibility of Solitaire X SRT in STEMI with LTB. Prestent thrombus volume was not different between SRT, MA, or no thrombus modification, although SRT extracted larger thrombus volume than MA. Larger multicenter studies using optical coherence tomography-based criteria are needed to minimize variability and enhance comparative assessments.
[Prevalence and influencing factors of preserved ratio impaired spirometry in adults aged 40 years and above in 10 areas in China].
Objective: To describe the prevalence of preserved ratio impaired spirometry (PRISm) in participants from the China Kadoorie Biobank (CKB) and explore the influencing factors. Methods: The CKB project conducted the baseline survey, the first and the second resurvey in 2004-2008, 2008, and 2013-2014, respectively. Based on the lung function tests, the participants were categorized into three groups: regular, PRISm, and airflow obstruction. The prevalence of PRISm was reported by gender, age, and region at the baseline survey. The secular trend in the prevalence of PRISm was described during the three surveys. Finally, we used the multiple logistic regression model to examine the factors related to PRISm in the baseline survey. Results: After standardization for gender, age, and region according to the sixth national census data in 2010, the overall prevalence of PRISm and airflow obstruction among the 434 760 participants at baseline was 24.8% and 6.1%, respectively. The prevalence of PRISm was higher in rural (25.4%) than that in urban areas (24.3%). Of the 10 study regions, Gansu had the highest prevalence of PRISm (56.0%), while Henan had the lowest (15.4%). After standardization for gender, age, and region according to the baseline population, the prevalence of PRISm decreased from 24.9% at baseline to 15.7% in the second resurvey, and the prevalence of airflow obstruction increased from 5.9% to 21.4%. Unmarried status, current smoking, using solid fuels for cooking, low body weight, being overweight, obesity, and central obesity were associated with an increased risk of PRISm. In contrast, higher education attainments, increased household income, and maintaining a specific degree of physical activity were associated with a reduced risk of PRISm. Conclusions: The prevalence of PRISm was high in adults aged 40 years and above in China, and it varied by sociodemographic and lifestyle factors.
All-cause and cause-specific mortality in individuals with COPD in China: a 16-year follow-up cohort study.
The prevalence of chronic obstructive pulmonary disease (COPD) is rising in China, yet population-based evidence on COPD-related mortality risk remains limited. This study examined the association between prevalent COPD and all-cause and cause-specific mortality in a large Chinese cohort. 484,301 adults aged 30 to 79 years who received spirometry at the baseline of the China Kadoorie Biobank Study (2004-2008) were included. COPD was defined as FEV1/ FVC
Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.
Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P
Neuroticism, omega-3 fatty acids, and risk of incident dementia.
BACKGROUND: High levels of neuroticism are associated with an increased risk of dementia, yet the underlying biological mechanisms remain poorly understood. Investigating the role of metabolites, the downstream products of metabolic processes, may offer valuable insights into this association. METHODS: In 215,624 dementia-free UK Biobank participants aged 40-69 years, we assessed neuroticism's associations with 249 nuclear magnetic resonance-measured metabolites using linear regression. Metabolites reaching Bonferroni-corrected significance were further tested for associations with incident all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VaD) using Cox proportional-hazards regression, and with white matter hyperintensities volume using linear regression. Causality in significant observational relationships was evaluated through two-sample Mendelian randomization. RESULTS: Neuroticism was significantly associated with 119 out of 249 metabolites (Bonferroni-adjusted p
GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy.
Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicated the association of CSF biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci included BIN1 for Aβ42 and GNA12, MS4A6A, SLCO1A2 with both t-tau and p-tau181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrated that these variants were not only associated with CSF level of the three biomarkers but also showed significant association with AD risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent APOE , as well as autophagy and brain volume regulation driven by t-tau and p-tau181 dysregulation.
Associations Between Trust in Healthcare Professionals and Perceptions of Modifiability of Dementia and Stroke Risks Through Maintaining or Changing Lifestyle Habits
Purpose: To investigate the trust levels in health information sources from a United States (U.S.) sample, and to examine the relationships between trust in healthcare professionals (HCPs) and perceptions of modifiability of dementia and stroke risks through maintaining or changing lifestyle habits. Design: Cross-sectional. Setting: A survey distributed via the vendor platform Prolific to a sample of the U.S. population. Participants: Data included on U.S. adults (n = 1478) in 2023. Measures: Outcome variables were perceiving that dementia and stroke risk can be modified through maintaining or changing lifestyle habits. Independent variables were trust levels in HCPs. Analysis: Descriptive analysis was performed to assess levels of trust in information sources. Subsequently, we performed multivariable regression analyses between trust in HCPs and perceptions of risk modifiability in dementia and stroke. A hierarchal cluster analysis was conducted to characterize trust patterns in this cohort. Results: Participants with high trust in HCPs compared to those with low trust in HCPs were more likely to perceive that maintaining (adjusted odds ratio [aOR] = 1.57, 95% confidence interval [CI]:1.15-2.12) and changing lifestyle habits (aOR = 1.72, 95% CI: 1.26-2.33) could reduce risk of dementia. Similar associations were found for perceptions of stroke risk reduction through maintaining (aOR = 1.49, 95% CI: 1.07-2.04) and changing (aOR = 2.68, 95% CI: 1.72-4.12) lifestyle habits. Cluster analyses identified three trust patterns amongst the participants: (i) a generally trusting cluster, (ii) a trusting of “official” health sources only cluster, and (iii) a generally not trusting cluster. Conclusion: This study found statistically significant associations between trusting HCPs and the perceptions that maintaining or changing lifestyle habits can modify risks of dementia and stroke, highlighting the importance of trust when developing preventive strategies.
Association of Daily Steps with Incident Non-Alcoholic Fatty Liver Disease: Evidence from the UK Biobank Cohort.
PURPOSE: Low physical activity has been shown to be associated with higher risk of non-alcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported physical activity measures. This report aims to investigate the relationship of median daily step count with NAFLD using accelerometer-derived step count from a large prospective cohort study. METHODS: The wrist-worn accelerometer sub-study of the UK Biobank (N = ~100,000) was used to characterise median daily step count over a seven-day period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted. RESULTS: Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000-step increase (representing 10 minutes of walking) was associated with a 12% (95% CI: 10%-14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1,000-step increase was associated with a 6% (95% CI: 6%-7%) lower risk. There was evidence for mediation by adiposity, accounting for 39% of the observed association. CONCLUSIONS: Daily step count, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.
Consensus recommendations for hyperpolarized [1-13C]pyruvate MRI multi-center human studies.
MRI of hyperpolarized (HP) [1-13C]pyruvate allows in vivo assessment of metabolism and has translated into human studies across diseases at 15 centers worldwide. To determine consensus on best practice for multi-center studies for development of clinical applications. This paper presents the results of a two-round formal consensus building exercise carried out by experts with HP [1-13C]pyruvate human study experience. Twenty-nine participants from 13 sites brought together expertise in pharmacy methods, MR physics, translational imaging, and data analysis with the goal of providing recommendations and best practice statements on conduct of multi-center human studies of HP [1-13C]pyruvate MRI. Overall, the group reached consensus on approximately two-thirds of 246 statements in the questionnaire, covering HP 13C-pyruvate preparation; MRI system setup, calibration, and phantoms; acquisition and reconstruction; and data analysis and quantification. Consensus was present across categories. Examples include: (i) Different HP pyruvate preparation methods could be used in human studies, but the same release criteria have to be followed; (ii) site qualification and quality assurance must be performed with phantoms and the same field strength must be used, but the rest of the system setup and calibration methods could be determined by individual sites; (iii) the same pulse sequence and reconstruction methods were preferable, but the exact choice should be governed by the anatomical target; (iv) normalized metabolite area-under-curve values and metabolite area under curve were the preferred metabolism metrics. The consensus proces revealed that HP[1-13C] pyruvate MRI as a technology has progressed sufficiently to plan multi-center studies. The work confirmed areas of consensus for multi-center study conduct and identified where further research is required to ascertain best practice.
Genetics of monozygotic twins reveals the impact of environmental sensitivity on psychiatric and neurodevelopmental phenotypes
Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes, but these variants have proven challenging to detect. Genome-wide association studies of monozygotic twin differences are conducted through family-based variance analyses, which are more robust to the systemic biases that impact population-based methods. We combined data from 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct one of the largest genome-wide association study meta-analyses of monozygotic phenotypic differences, in children, adolescents and adults separately, for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism and wellbeing. The proportions of phenotypic variance explained by single-nucleotide polymorphisms in these phenotypes were estimated (h2 = 0–18%), but were imprecise. We identified 13 genome-wide significant associations (single-nucleotide polymorphisms, genes and gene sets), including genes related to stress reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. This is the largest genetic study of monozygotic twins to date by an order of magnitude, evidencing an alternative method to study the genetic architecture of environmental sensitivity. The statistical power was limited for some analyses, calling for better-powered future studies.
The impact of estrogen deficiency on liver metabolism; implications for hormone replacement therapy
Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD, previously NAFLD) is the most common chronic liver condition globally. It affects 1-in-3 individuals and is associated with increased liver and cardiovascular mortality. MASLD is a sexually dimorphic condition and in women the prevalence and severity of MASLD rises significantly following menopause. Preclinical data shows that lack of estrogen promotes multisystem metabolic dysfunction that is characteristic of MASLD. This not only includes hepatic lipid accumulation, insulin resistance and fibrosis, but also extra-hepatic metabolic processes in adipose and skeletal muscle. There are currently no available MASLD treatments tailored to women. The uptake of estrogen-based menopausal hormone replacement therapy (HRT) has seen a dramatic increase in recent years. Despite the changing attitudes to HRT and the strong evidence base implicating estrogen deficiency in the development of MASLD, the impact of HRT on MASLD in postmenopausal women is poorly studied. In this review, we discuss the burden of MASLD in women, the effect of estrogen deficiency on the processes that drive MASLD development and progression, and explore potential sex-specific therapeutic strategies that may prevent or limit MASLD development after menopause.