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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.
CRAC channels and patho-physiology of peripheral organ systems.
A rise in cytosolic Ca2+ is used as a key signalling messenger in eukaryotic cells. The Ca2+ signal drives life and death and controls myriad responses in between. Inherent in the use of such a multifarious signal is the danger of disease, arising from dysregulated Ca2+ signalling. One ancient, highly conserved and widespread Ca2+ entry pathway is the store-operated Ca2+ release-activated Ca2+ (CRAC) channel. Mutations in STIM1 and ORAI1, the genes that encode the functional channel, are tightly linked to a CRAC channelopathy in humans, which encompasses severe combined immune deficiency, myopathy and anhidrotic ectodermal dysplasia. Moreover, sustained Ca2+ entry through the channels leads to a range of systemic disorders, including acute pancreatitis, asthma and inflammatory bowel disease. In this review, we describe how aberrant CRAC channel activity causes a range of diseases, highlighting commonalities between these diverse pathologies.
Sex-specific cardiometabolic multimorbidity, metabolic syndrome and left ventricular function in heart failure with preserved ejection fraction in the UK Biobank.
BACKGROUND: Cardiometabolic disturbances play a central role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Due to its complexity, HFpEF is a challenging condition to treat, making phenotype-specific disease management a promising approach. However, HFpEF phenotypes are heterogenous and there is a lack of detailed evidence on the different, sex-specific profiles of cardiometabolic multimorbidity and metabolic syndrome present in HFpEF. METHODS: We performed a retrospective, modified cross-sectional study examining a subset of participants in the UK Biobank, an ongoing multi-centre prospective cohort study in the United Kingdom. We defined HFpEF as a record of a heart failure diagnosis using ICD-10 code I50, coupled with a left ventricular ejection fraction (LVEF) ≥ 50% derived from cardiac magnetic resonance (CMR) imaging. We examined sex-specific differences in cardiometabolic comorbidity burden and metabolic syndrome, performed latent class analysis (LCA) to identify distinct clusters of patients based on their cardiometabolic profile, and compared CMR imaging-derived parameters of left ventricular function at rest in the different clusters identified to reflect possible differences in adverse cardiac remodelling. RESULTS: We ascertained HFpEF in 445 participants, of which 299 (67%) were men and 146 (33%) women. The median age was 70 years old (interquartile range: [66.0-74.0]). A combination of hypertension and obesity was the most prevalent cardiometabolic pattern both in men and women with HFpEF. Most men had 2-3 clinical cardiometabolic comorbidities while most women had 1-2, despite a similar metabolic syndrome profile (p = 0.05). LCA revealed three distinct, clinically relevant phenogroups, namely (1) a most male and multimorbid group (n = 117); (2) a group with a high prevalence of severe obesity, abnormal waist circumference and with the highest relative proportion of females (n = 116); and finally (3) a group with an apparently lower comorbidity burden aside from hypertension (n = 212). There were significant differences in clinical measurements and medication across the three phenogroups identified. Cardiac output at rest was significantly higher in group 2 vs. group 3 (males: median 5.6 L/min vs. 5.2 L/min, p
Population Biobank Studies: A Practical Guide
This book describes some of the key epidemiological principles, scientific approaches and quality assurance frameworks required to design and conduct biobank studies in various settings. Using examples from contemporary biobanks, the book addresses the design features and practical procedures needed in order to launch and manage biobank studies, including consent and regulatory approval, the organisation of field work, management of data and biological samples, follow-up and verification of disease outcomes, development of IT systems for data collection, quality assurance and study management. Over the last two decades, several large biobank studies have been initiated in different populations, intended to greatly enhance the development of precision medicine. Contemporary biobank studies are extremely large and complex, and involve several decades of follow-up. Such studies pose major challenges in terms of ensuring rapid recruitment, obtaining high-quality data, minimisingloss to follow-up, reliably classifying disease outcomes, and optimising the use of the biological samples collected. In this regard, the key to success lies not in planning the perfect study, but in planning the most appropriate, reliable, sustainable and future-proof study given the practical constraints of available resources, time and capacity. The authors of this handbook are epidemiologists, clinicians, software engineers, and laboratory and data scientists with extensive experience in conducting large biobank studies. The eight chapters can be read separately or together, and provide readers with essential information on how to design, implement and manage these studies. The state-of-the-art, innovative and scalable approaches and methodologies presented here are intended to stimulate the development of further population-based and hospital-based biobank studies in diverse populations.
Handheld Spatially Offset Raman Spectroscopy for Rapid Non-invasive Detection of Ethylene Glycol and Diethylene Glycol in Medicinal Syrups
We investigate the potential of Spatially Offset Raman Spectroscopy (SORS) as a rapid, non-invasive screening tool deployable in the field to detect diethylene glycol (DEG) and ethylene glycol (EG) in medicinal syrups within closed containers. Measurements were performed on neat propylene glycol (PG) and glycerol, key components of many medicinal syrups, as well as marketed medicinal syrup formulations spiked with DEG and EG at various concentration levels to assess the technique’s limit of detection in real-life samples. SORS was able to detect these down to ~0.5% concentration level in neat PG for both DEG and EG compounds and ~1% concentration level for DEG and EG in neat glycerol. The DEG and EG detection thresholds for the marketed formulations measured through original bottles was ~1%, for Benylin (active ingredient: Glycerol) and Piriteze (active ingredient: Cetirizine Hydrochloride). For Calpol (active ingredient: Paracetamol) the detection limit was higher, ~2% for EG and ~5% for DEG. Although not reaching the International Pharmacopeial 0.1% detection threshold currently required for purity checks for human consumption, the method can still be used to detect products where DEG or EG has been wrongly used instead of PG or glycerol or if present in large quantities. The technique could also be used for raw material identification testing to ensure no mislabelling has occurred in pre-production stages and as a screening device in distribution chains to detect major deviations from permitted content in non-diffusely scattering, clear formulations, to help prevent serious adverse outcomes, such as acute renal failure and deaths.
Planning, Organisation, and Management of Fieldwork in Biobank Studies
The importance of fieldwork in population health research has not diminished in the era of big data. Contemporary prospective biobank studies tend to collect large amounts of exposure and health outcome data from a large number of participants. Although disease outcome data are often obtained through linkages with registries and hospital records, the exposure data are generally collected directly from the participants, through questionnaire surveys (e.g., in-person, telephone, postal, or online), physical measurements, and collection and assays of biological samples (e.g., blood, urine, and saliva) at baseline recruitment and at other time points. There are many legal, logistic, and practical challenges in establishing large biobank studies, many of which are related to the fieldwork. Careful planning and organisation, efficient coordination and management, and effective implementation and monitoring are critical to ensure a successful launch and smooth operation of fieldwork. This chapter delineates key considerations and procedures involved in planning and organising fieldwork in biobank studies. Moreover, it describes certain novel methodological approaches relevant for the smooth operation of assessment centres and acquisition of high quality data. The general approaches described should also be applicable to other population-based studies (e.g., cross-sectional surveys and case–control studies).
Collection, Processing, and Management of Biological Samples in Biobank Studies
Prospective biobanks provide opportunities for investigating the contributions of a wide range of lifestyle, environmental, and genetic factors to risk, aetiology, and prediction of many different diseases. A growing array of high throughput technologies, capable of measuring of hundreds, thousands, or millions of biochemical and genetic factors, can support investigation of the relationship of such factors to disease risk or risk factors, inform on aspects of behaviour or lifestyle that are otherwise difficult to measure reliably (e.g., diet), and enable the generation and testing of hypotheses concerning the causes of disease. Thus, integral to any biobank study is the collection, processing, and storage of biological samples for use in such technologies. This chapter describes the main steps involved in these processes. There will be an emphasis on study design and developing procedures to ensure that the types of samples collected will be suitable for the intended analyses, and that they are processed, transported, and stored under conditions that will preserve their integrity and allow them to be used for a range of future research purposes. Requirements for sample linkage and security will also be considered. These considerations are not limited to prospective studies, but are relevant to any study (e.g., retrospectively recruited case-control cohorts) that involves the collection and storage of biological samples from large numbers of individuals.
Population-Based Health Studies: An Overview of Principles and Methods
Chronic non-communicable diseases (NCDs) are the major causes of premature death and disability in both high-income and low- and middle-income countries (LMICs). However, there is substantial variation in the age and sex-specific rates of major NCDs that are not fully explained by differences in the distributions of established risk factors, suggesting that other important causes remain to be discovered. Population-based epidemiological studies are needed for reliable assessment of lifestyle, biochemical and genetic determinants for NCDs, and for assessing prognosis and clustering of NCDs. Moreover, analysis of genetic variants for particular traits can be used to elucidate the causal relevance of particular exposures with disease and to anticipate the likely effects of treatments. Epidemiological studies conducted in diverse populations with prolonged follow-up for both fatal and non-fatal disease outcomes can provide important evidence about the causes of NCDs that may inform disease prevention strategies globally. The aim of this chapter is to provide readers with an overview of basic concepts and the epidemiological principles that underlie the design and conduct of epidemiological studies, including the chief strengths and limitations of different study designs. Moreover, it will highlight the importance of large prospective biobank studies, which involve assessment of a sufficiently large number of participants, together with strict control of bias and confounding to be able to detect moderate relative risks of major disease outcomes reliably.
Clinically relevant niclosamide concentrations modulate TMEM16A and CaV1.2 channels to control artery tone and capillary diameter
AbstractBackground and PurposeTMEM16A Ca2+‐gated Cl− channels mediate depolarisation of contractile vascular cells. The anthelmintic niclosamide was reported to modulate the TMEM16A channel, suggesting possible repurposing for vascular pharmacology. Here, we investigate the mechanism of TMEM16A modulation by niclosamide and explore its effect on the function of a range of vessel types.Experimental ApproachPatch‐clamp electrophysiology, alongside genetically encoded systems to modulate plasmalemmal PIP2 content, was used to define the mechanism of action of niclosamide on the TMEM16A channel. Vascular contractility was investigated using isometric tension recordings of isolated rat arteries and differential interference contrast imaging of capillary diameter in rat brain slices.Key ResultsIn low intracellular free Ca2+ concentrations ([Ca2+]i), clinically relevant niclosamide concentrations inhibited or enhanced heterologous TMEM16A currents at positive or negative membrane potentials (Vm), respectively. In saturating [Ca2+]i, niclosamide inhibited the channel at each Vm tested, independent of plasmalemmal PIP2 levels. Niclosamide caused a transient contraction of isolated aortae and mesenteric and pulmonary arteries but dampened responses to phenylephrine, a Gq protein‐coupled receptor (GqPCR) agonist. Niclosamide reduced brain cortical pericyte constriction evoked by endothelin‐1. Unlike Ani9, a selective TMEM16A inhibitor, niclosamide reduced arterial response to elevated extracellular K+. Niclosamide also inhibited heterologous and native voltage‐gated Ca2+ (CaV) currents in smooth muscle cells.Conclusion and ImplicationsNiclosamide dampened vascular responses to GqPCR stimulation due to concomitant modulation of TMEM16A and CaV channels. Elucidating the molecular pharmacology of niclosamide supports its potential use in disorders of altered vessel tone including stroke, hypertension and vascular dementia.
Targeting glucose metabolism with dichloroacetate (DCA) reduces zika virus replication in brain cortical progenitors at different stages of maturation.
The underlying threat of new Zika virus (ZIKV) outbreaks remains, as no vaccines or therapies have yet been developed. In vitro research has shown that glycolysis is a key factor to enable sustained ZIKV replication in neuroprogenitors. However, neither in vivo nor clinical investigation of glycolytic modulators as potential therapeutics for ZIKV-related fetal abnormalities has been conducted. Accordingly, we tested the therapeutic potential of metabolic modulators in relevant in vitro systems comprising two pools of neuroprogenitors (NPCs), which resemble early and late stages of pregnancy. Effective doses of metabolic modulators [3.0 μM] dimethyl fumarate (DMF), [3.2 mM] dichloroacetate (DCA), and [6.3 μM] VER-246608 were determined for these cells by their effect on lactate release, pyruvate dehydrogenase (PDH) activity and cell survival. The drugs were used in a 24h pre-treatment and kept throughout ZIKV infection of NPCs. Drug effects and ZIKV replication were assessed at 24- and 56-h post-infection. In early NPCs treated with DMF, DCA and VER-246608, there was a significant reduction in the extracellular release of ZIKV potentially by PDH-mediated increased mitochondrial oxidation of glucose. Out of the three drugs, only DCA was observed to reduce viral replication in late NPCs treated with DCA. Altogether, our findings suggest that reduction of anaerobic glycolysis could be of therapeutic potential against ZIKV-related fetal abnormalities and that clinical translation should consider the use of specific glycolytic modulators over different trimesters.
Lung development genes, adult lung function and cardiovascular comorbidities.
BACKGROUND: The association between lower adult lung function and increased cardiovascular comorbidity has not been adequately explained. We investigated whether shared developmental signalling pathways, critical to lung development and repair, could partly explain it. METHODS: In UK Biobank (UKB), we performed pairwise colocalisation analysis of variants in 55 lung development genes associated with adult forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1)/FVC, to see if these are also associated with coronary heart disease (CHD), blood pressure (systolic, diastolic, hypertension), pulse pressure, Arterial Stiffness index and carotid intima-media thickness. For CHD, we meta-analysed data from UKB and the CARDIoGRAM consortium. RESULTS: We found that 12 of the 55 genes shared the same variant between one (or more) lung function trait and one (or more) cardiovascular trait (H4colocalisation). The direction of effects was always in keeping with our hypothesis (lower lung function-higher cardiovascular risk) for FVC, but not always for FEV1/FVC. The seven signals for hypertension and CHD all replicated nominally in the FinnGen study, while replication was poor in the China Kadoorie Biobank (CKB) study. In addition, we found a further 10 genes where genetic associations with lung function and cardiovascular traits were within the same gene but involved different variants (H3 colocalisation). Interestingly, six of all 22 genes (H4 and H3 colocalisation) were novel for cardiovascular traits; four replicated in FinnGen, three in CKB. CONCLUSION: Lung function and cardiovascular traits have shared developmental pathways that may partly explain why lower lung function, especially FVC, is associated with increased cardiovascular risk.
AICAR confers prophylactic cardioprotection in doxorubicin-induced heart failure in rats.
Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to heart failure (HF). Impaired mitochondrial function is thought to be key factor driving progression into HF. We have previously shown in a rat model of DOX-HF that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and energy metabolism, including fatty acid oxidation. We hypothesised that AMPK activation could restore mitochondrial function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this chronic intravenous rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number, and in the absence of observable AMPK-activation. In addition, we found that AICAR prevented loss of myocardial mass. RNAseq analysis showed that this may be driven by normalisation of pathways associated with ribosome function and protein synthesis, which are impaired in DOX-treated rat hearts. AICAR furthermore prevented dyslipidemia and excessive body-weight loss in DOX-treated rats, which may contribute to preservation of myocardial mass. Though it is unclear whether AICAR exerted its cardioprotective effect through cardiac or extra-cardiac AMPK-activation or via an AMPK-independent effect, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.
SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides.
SARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleotides (ASOs) targeting human SARM1, demonstrating robust neuroprotection against morphological, metabolic, and mitochondrial impairment in human iPSC-derived dopamine neurons induced by the lethal neurotoxin vacor, a potent SARM1 activator. Furthermore, our findings reveal that axon fragmentation can be prevented, and mitochondrial dysfunction reversed using the NAD precursor nicotinamide, a form of vitamin B3, even after SARM1 activation has occurred, when neurons are already unhealthy. This research identifies ASOs as a promising therapeutic strategy to block SARM1, and provides an extensive characterisation and further mechanistic insights that demonstrate the reversibility of SARM1 toxicity in human neurons. It also identifies the SARM1 activator vacor as a specific and reversible neuroablative agent in human neurons.
Dissecting metabolic dysfunction- and alcohol-associated liver disease (MetALD) using proteomic and metabolomic profiles.
BACKGROUND: & Aim, Metabolic dysfunction associated and alcohol associated liver disease (MetALD) is a poorly understood condition that bridges cardiometabolic and alcohol-related pathological characteristics. We aim to distinguish MetALD patients who share similar molecular signatures with alcohol-related liver disease (ALD) and those share signatures with metabolic dysfunction-associated steatotic liver disease (MASLD), and assess their prognostic risk for complications and mortality. METHODS: Our analysis involved 443,453 European participants from UK Biobank, including 34,147 with MetALD, 11,220 with ALD, and 124,034 with MASLD. We employed Elastic Net Regression to classify ALD and MASLD involving 249 plasma metabolites and/or 2,941 plasma proteins with various sensitivity analyses. We then used the selected concise model in MetALD patients to identify alcohol-predominant group (classified to ALD) and cardiometabolic-predominant group (classified to MASLD). Finally, we explored their 15-year risk of major outcomes (i.e., heart failure, myocardial infarction, stroke, cirrhosis, hepatocellular carcinoma and mortality) using Cox regression. RESULTS: The metabolome alone discriminated ALD from MASLD with an Area under the Curve (AUC) of 0.86, while the proteome alone achieved an AUC of 0.96. Adding age, sex, BMI, liver enzymes, or metabolome information did not enhance the AUC of the proteome model. A ten-protein model differentiated ALD and MASLD with an AUC of 0.93. This model identified that alcohol-predominant MetALD patients had significantly higher risks of mortality, and cirrhosis, along with elevated fibrosis scores and higher fibrosis stages, compared to cardiometabolic-predominant patients. CONCLUSIONS: This study emphasizes the importance of subtyping differentiation using proteome data for personalized treatment and improved prognostic outcomes in MetALD patients.