Search results
Found 31265 matches for
Bidirectional Mendelian Randomization Highlights Causal Relationships Between Circulating INHBC and Multiple Cardiometabolic Diseases and Traits.
Human genetic and transgenic mouse studies have highlighted a potential liver-adipose tissue endocrine axis, involving activin C (Act-C) and/or Act-E and ALK7, influencing fat distribution and systemic metabolism. We investigated the bidirectional effects between circulating INHBC, which homodimerizes into Act-C, and adiposity traits, insulin resistance, inflammation, and cardiometabolic disease risk. Additionally, we examined whether Act-C is an ALK7 ligand in human adipocytes. We used Mendelian randomization and in vitro studies in immortalized human abdominal and gluteal adipocytes. Circulating INHBC was causally linked to reduced lower-body fat, dyslipidemia, and increased risks of coronary artery disease (CAD) and nonalcoholic fatty liver disease (NAFLD). Conversely, upper-body fat distribution, obesity, hypertriglyceridemia, subclinical inflammation, and type 2 diabetes positively impacted plasma INHBC levels. Mechanistically, an atherogenic lipid profile may partly explain the INHBC-CAD link, while inflammation and hypertriglyceridemia may partly explain how adiposity traits affect circulating INHBC. Phenome-wide Mendelian randomization showed weak causal relationships between higher plasma INHBC and impaired kidney function and higher gout risk. In human adipocytes, recombinant Act-C activated SMAD2/3 signaling via ALK7 and suppressed lipolysis. In summary, INHBC influences systemic metabolism by activating ALK7 in adipose tissue and may serve as a drug target for atherogenic dyslipidemia, CAD, and NAFLD.
Microscale droplet assembly enables biocompatible multifunctional modular iontronics.
Hydrogel iontronic devices can emulate biological functions and communicate with living matter. But the fabrication of miniature, soft iontronic devices according to modular designs has not been achieved. In this work, we report the use of surfactant-supported assembly of freestanding microscale hydrogel droplets to construct various iontronic modules, circuits, and biointerfaces. Chemical modifications of silk fibroin produced a pair of oppositely charged hydrogels. Microscale assembly of various combinations of hydrogel droplets produced iontronic diodes, npn- and pnp-type transistors, and diverse reconfigurable logic gates. Through the incorporation of poly(amino acid)s, we have demonstrated a droplet-based synthetic synapse with ionic polymer-mediated long-term plasticity. Further, our iontronic transistor can serve as a biocompatible sensor to record electrophysiological signals from sheets of human cardiomyocytes, paving a way to the building of miniature bioiontronic systems.
Myocardial iron intake following intravenous iron therapy with ferric carboxymaltose is sustained at 1 year despite recurrence of iron deficiency.
In clinical practice, intravenous (IV) iron therapy is used for the correction of iron deficiency. Patients with chronic causes of iron deficiency, for example, women with abnormal uterine bleeding, patients with inflammatory bowel disease often require repeated dosing with IV iron therapy. After a single standard dose of IV iron therapy (1000 mg) with ferric carboxymaltose, there is a rapid intake of iron into the myocardium, resulting in a sustained increase in myocardial iron content. The increase in myocardial iron content is independent of changes in plasma ferritin levels, and the recurrence of iron deficiency is not accompanied by a normalisation of myocardial iron. The most important implication is that repeated dosing with IV iron (ferric carboxymaltose) can result in cumulative build-up of iron in the myocardium.
Incidence of diabetes mellitus following hospitalisation for COVID-19 in the United Kingdom: A prospective observational study.
BACKGROUND: People hospitalised for coronavirus disease 2019 (COVID-19) have elevated incidence of diabetes. However, it is unclear whether this is due to shared risk factors, confounding or stress hyperglycaemia in response to acute illness. METHODS: We analysed a multicentre prospective cohort study (PHOSP-COVID) of people ≥18 years discharged from NHS hospitals across the United Kingdom following COVID-19. Individuals were included if they attended at least one research visit with a HbA1c measurement within 14 months of discharge and had no history of diabetes at baseline. The primary outcome was new onset diabetes (any type), as defined by a first glycated haemoglobin (HbA1c) measurement ≥6.5% (≥48 mmol/mol). Follow-up was censored at the last HbA1c measurement. Age-standardised incidence rates and incidence rate ratios (adjusted for age, sex, ethnicity, length of hospital stay, body mass index, smoking, physical activity, deprivation, hypertension, hyperlipidaemia/hypercholesterolaemia, intensive therapy unit admission, invasive mechanical ventilation, corticosteroid use and C-reactive protein score) were calculated using Poisson regression. Incidence rates were compared with the control groups of published clinical trials in the United Kingdom by applying the same inclusion and exclusion criteria, where possible. RESULTS: Incidence of diabetes was 91.4 per 1000 person-years and was higher in South Asian (incidence rate ratios [IRR] = 3.60; 1.77, 7.32; p
Risk of major vascular events in patients without traditional risk factors after transient ischemic attack or minor ischemic stroke: An international prospective cohort.
INTRODUCTION: To investigate the clinical characteristics in patients without traditional risk factors (TRFs) after transient ischemic attack or minor ischemic stroke, who were recruited in the TIAregistry.org. PATIENTS AND METHODS: A total of 3847 patients were analyzed. TRFs included hypertension, diabetes, hypercholesterolemia, current smoking, and atrial fibrillation. Background characteristics and outcomes at 1 and 5 years in patients without TRFs were compared to those in patients with TRFs. The primary outcome was major cardiovascular event (MACE), which was non-fatal stroke, non-fatal acute coronary syndrome, or vascular death. To evaluate the causes, we applied the ASCOD (atherosclerosis, small vessel disease, cardiac pathology, other causes or dissection) grading system. RESULTS: One-year risk of MACE (5.3% vs 6.3%, hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.53-1.31) was comparable between patients without TRFs (n = 402) and those with TRFs (n = 3445). Five-year risk of MACE was significantly lower in patients without TRFs than in those with TRFs (7.9% vs 13.9%, HR 0.57, 95% CI 0.39-0.82). In patients without TRFs, causal atherosclerosis was a potent risk factor (HR 5.67, 95% CI 2.68-12.02) and ipsilateral extra- or intra-cranial arterial stenosis was only significant predictor of MACE (interaction p = 0.0046) at 5 years. CONCLUSION AND DISCUSSION: The 5-year risk of MACE was lower in patients without TRFs than those with TRFs, although a certain level of risk persisted in the absence of TRFs. The most significant predictor of MACE in patients without TRFs was arterial stenosis.
Evaluation of an integrated variable flip angle protocol to estimate coil B1 for hyperpolarized MRI.
PURPOSE: The purpose of this work is to validate a simple and versatile integrated variable flip angle (VFA) method for mapping B1 in hyperpolarized MRI, which can be used to correct signal variations due to coil inhomogeneity. THEORY AND METHODS: Simulations were run to assess performance of the VFA B1 mapping method compared to the currently used constant flip angle (CFA) approach. Simulation results were used to inform the design of VFA sequences, validated in four volunteers for hyperpolarized xenon-129 imaging of the lungs and another four volunteers for hyperpolarized carbon-13 imaging of the human brain. B1 maps obtained were used to correct transmit and receive inhomogeneity in the images. RESULTS: Simulations showed improved performance of the VFA approach over the CFA approach with reduced sensitivity to T1. For xenon-129, the B1 maps accurately reflected the variation of signal depolarization, but in some cases could not be used to correct for coil receive inhomogeneity due to a lack of transmit-receive reciprocity resulting from suboptimal coil positioning. For carbon-13, the B1 maps showed good agreement with a separately acquired B1 map of a phantom and were effectively used to correct coil-induced signal inhomogeneity. CONCLUSION: A simple, versatile, and effective VFA B1 mapping method was implemented and evaluated. Inclusion of the B1 mapping method in hyperpolarized imaging studies can enable more robust signal quantification.
Predictors of cardiovascular disease risk: findings from the National Survey of Health and Development Cohort
Abstract Background Cardiovascular disease (CVD) remains a significant cause of mortality and morbidity within the UK. CVDs and all-cause mortality can be predicted with varying levels of certainty with different models. Purpose This study aimed to explore the incremental effect of risk factors and respective biomarkers on CVD events risk estimation models. Methods The National Survey for Health and Development (NSHD) birth cohort study, including 2547 women 2815 men, was used to model relationships between conventional and emerging risk factors and cardiometabolic and vascular outcomes, including myocardial infarction and stroke between 1999 and 2009. Logistic regression or XGBoost (eXtreme Gradient Boosting) models were used to predict the outcomes (myocardial infarction and strokes). Model fit was assessed by comparing predicted and known incident events in a two-by-two error matrix for binary outcomes. Results In a model including both sex and smoking alcohol intake (β = -0.029g; p < 0.05), body mass index (BMI) (β = 0.095 kg/m2; p < 0.05), glycated haemoglobin (HbA1c) (β = 0.033 mmol/mol; p < 0.01) and total cholesterol/high density lipoprotein (TC/HDL) ratio (β = 0.459 mg/dL; p < 0.0001) waist-to-hip ratio (β = 5.632cm; p = 0.05) and waist circumference (β = 0.031cm; p < 0.01) were significant predictors of myocardial infarction. A lower risk was observed among those with higher average alcohol intake, whereas higher risk being observed among those with higher BMI, HbA1c levels, total cholesterol/HDL ratio, waist-to-hip ratio and waist circumference. For stroke, exercising 5+ times (β = -1.47; p < 0.01), systolic blood pressure (SBP) (β = 0.040mmHg; p < 0.001), diastolic blood pressure (DBP) (β = 0.027mmHg; p < 0.001), pulse pressure (β = 0.033mmHg; p < 0.01), triglycerides (β = 0.388; p < 0.05) and total cholesterol/HDL ratio (β = 0.419; p < 0.01) were all significant predictors of stroke. We found that higher values of SBP, DBP, pulse pressure, triglycerides and total cholesterol/HDL ratio were associated with higher risk of stroke, whereas higher levels of physical activity were associated with a lower risk. Additionally, by combining BMI, HbA1c and total cholesterol/HDL ratio to the baseline model it provided the greatest F1 score of all models (0.123) and the greatest precision (6.7%), with a recall of 72.4%. With XGBoost we observed a reduced F1 score from 0.123 to 0.079, although adding information on alcohol intake and waist to hip ratio to this model, as previous analysis indicated great improvements in prediction, the F1 score obtained using the XGBoost increased from to 0.079 to 0.103. Conclusion This research shows that clinical and laboratory measurements play a potentially powerful role in predicting health outcomes when using evidence-based risk calculators. Using large cohorts allows for real-life long-term associations to be explored and quantified with a higher level of certainty for replicability across other populations.
Abstract 4144972: Predictors of cardiovascular disease risk and total mortality: Findings from the UK Biobank.
Background: Cardiovascular disease (CVD) continues to remain a major health challenge with several physiological and lifestyle markers associated with its incidence, burden and mortality. Purpose: We aimed to investigate diet and other lifestyle variables in combination with CVD risk markers (clinical and laboratory measurements) to estimate the risk of CVD events, all-cause Mortality, and survival rates over an 18-year period. Methods: Data from the UK biobank was utilised. Participants recruited between 2006 and 2010. Variables included predictor (sex, age, smoking history, and Townsend deprivation), Clinical (BMI, SBP, DBP, HBA1C, triglycerides, TC/HDL ratio, and total cholesterol (TC)) and behavioural (diet, physical activity). Deaths were coded using the ICD, 10th revision. COX proportional hazard models used to analyse each outcome for every predictor variable and models adjusted for confounders. Survival analysis was done with logistic regression models. Outcomes included all-cause mortality and incidence of fatal cardiovascular disease. Results: Over 502,621participants aged between 40-69 years with 54.4% males. 4.6% developed CVDs. High (>8) and low (<7) sleep hours, High BMI, HBA1C, SBP, triglycerides and TC/HDL had a higher CVD incidence risk. Age, Sex, smoking, and Townsend deprivation were independent predictors of mortality with sex and smoking carrying the highest risk. Vegetarians and participants on combined special diets had a lower total mortality. Physical activity of 2-4 hrs and 4-6 hrs weekly had lower mortality compared to no physical activity. However, light or vigorous physical activity had no significant effect on total mortality. Similarly, individuals with no metabolic equivalent task (MET) had an increased mortality compared to those with 12-14 hrs, 14-16hrs, and 16-84hrs MET. High BMI, triglycerides, HBA1C and TC/HDL ratio were associated with significantly decreased survival rates while High HDL and high TC was associated with increased survival rates. Conclusion: Lifestyle factors including physical activity, sleep, and diets were identified as important predictors of all-cause mortality and CVD risk events. The findings further strengthen the evidence on the role of other known modifiable and non-modifiable factors in predicting CVD incidence risk and total mortality. The identified predictors would be useful in the development of risk scoring systems which incorporate lifestyle factors not factored into most CVD risk prediction models.
Younger-onset compared with later-onset type 2 diabetes: an analysis of the UK Prospective Diabetes Study (UKPDS) with up to 30 years of follow-up (UKPDS 92).
BACKGROUND: Younger-onset type 2 diabetes is associated with accelerated complications. We assessed whether complications and mortality rates differed for younger age compared with older age at diagnosis over 30 years of follow-up. METHODS: In this study, we used data from the UKPDS, collected between 1977 and 2007, of participants aged 25-65 years with newly diagnosed type 2 diabetes with younger-onset (younger than 40 years) or later-onset (40 years or older), and without diabetes autoantibodies. We analysed standardised mortality ratios (SMR) using UK general population data, and incidence rates of prespecified outcomes by 10-year age intervals at diagnosis. FINDINGS: Of 4550 participants testing negative to all measured autoantibodies, 429 (9·4%) had younger-onset type 2 diabetes. 2704 (59·4%) were male, and mean HbA1c was 76 mmol/mol (SD 24·6). The median follow-up was 17·5 years (IQR 12·7-20·8). SMR for younger-onset type 2 diabetes was higher (3·72 [95% CI 2·98-4·64]) compared with later-onset type 2 diabetes (1·54 [1·47-1·61]). The incidence rate was higher for all outcomes in later-onset type 2 diabetes, except for microvascular disease (younger-onset 14·5 (11·9-17·7) vs later-onset 12·1 (11·3-13·0) per 1000 person-years). However, at any given age, the 5-year incidence of any diabetes-related endpoint, all-cause mortality, microvascular disease, and myocardial infarction was higher with younger age at diagnosis. Annual mean HbA1c was higher in the first 20 years in younger-onset compared with later-onset type 2 diabetes. Among participants randomised to intensive versus conventional glycaemic control, we observed no interactions by subgroup of younger-onset versus later-onset type 2 diabetes for any outcome. INTERPRETATION: The risk of dying relative to the general population is even greater for people diagnosed with type 2 diabetes at younger ages. The increased risk of complications and poorer glycaemic control in younger-onset type 2 diabetes calls for the development of services to identify and manage these individuals. FUNDING: National Institute of Health and Care Research's Biomedical Research Centre.
Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis.
We report on 2 patients of East African ancestry with the same novel homozygous variant in the parathyroid hormone receptor type 1 (PTH1R). Both patients shared skeletal features, including brachydactyly, extensive metacarpal pseudo-epiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, and deficient sacral ossification, suggestive of Eiken syndrome. Strikingly, both patients exhibited clinically manifest parathyroid hormone (PTH) resistance with hypocalcemia and elevated serum phosphate levels. These laboratory and clinical abnormalities initially suggested pseudohypoparathyroidism, which is typically associated with GNAS abnormalities. In both patients, however, a homozygous novel PTH1R variant was identified (c.710 T > A; p.IIe237Asn, p.I237N) that is located in the second transmembrane helical domain. Previously, others have reported a patient with a nearby PTH1R mutation (D241E) who presented with similar clinical features (eg, delayed bone mineralization as well as clinical PTH resistance). Functional analysis of the effects of both novel PTH1R variants (I237N- and D241E-PTH1R) in HEK293 reporter cells transfected with plasmid DNA encoding the wild-type or mutant PTH1Rs demonstrated increased basal cAMP signaling for both variants, with relative blunting of responses to both PTH and PTH-related peptide (PTHrP) ligands. The clinical presentation of PTH resistance and delayed bone mineralization combined with the functional properties of the mutant PTH1Rs suggest that this form of Eiken syndrome results from alterations in PTH1R-mediated signaling in response to both canonical ligands, PTH and PTHrP.
Feasibility of Transfer Learning from Finger PPG to In-Ear PPG.
The success of deep learning methods has enabled many modern wearable health applications, but has also highlighted the critical caveat of their extremely data hungry nature. While the widely explored wrist and finger photoplethysmography (PPG) sites are less affected, given the large available databases, this issue is prohibitive to exploring the full potential of novel recording locations such as in-ear wearables. To this end, we assess the feasibility of transfer learning from finger PPG to in-ear PPG in the context of deep learning for respiratory monitoring. This is achieved by introducing an encoder-decoder framework which is set up to extract respiratory waveforms from PPG, whereby simultaneously recorded gold standard respiratory waveforms (capnography, impedance pneumography and air flow) are used as a training reference. Next, the data augmentation and training pipeline is examined for both training on finger PPG and the subsequent fine tuning on in-ear PPG. The results indicate that, through training on two large finger PPG data sets (95 subjects) and then retraining on our own small in-ear PPG data set (6 subjects), the model achieves lower and more consistent test error for the prediction of the respiratory waveforms, compared to training on the small in-ear data set alone. This conclusively demonstrates the feasibility of transfer learning from finger PPG to in-ear PPG, leading to better generalisation across a wide range of respiratory rates.