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University of Oxford, Dr P.Hales/BBSRC.
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.
Immunotherapy for atherosclerosis.
Cardiovascular disease is the global #1 cause of mortality and morbidity. The majority of cardiovascular diseases is caused by atherosclerosis, a lipid-driven, inflammatory disease of the middle- and large-sized arteries. The disease is characterized by the formation of atherosclerotic plaques throughout the arterial tree. Over the years, insights into the pathogenesis of atherosclerosis have shifted from a 'lipid-driven' model to a 'response-to-injury' perspective, and more recently to a 'lipid-driven inflammatory disease' viewpoint. We are now aware that a network of multiple immune cell-types and -subsets of the innate and adaptive immune system inhabit our arteries. Intricate interactions between these immune cellsubsets, non-immune cells, and local environmental substances such as lipids, cell debris and calcium cause a fluidic balance of pro-inflammatory and regulatory responses. A dysregulation of this balance towards a pro-inflammatory milieu drives atherosclerotic disease progression. Although we have acknowledged that atherosclerosis is an inflammatory disease, state-of-theart treatments are still based on lipid lowering, anti-hypertensive and lifestyle-changing strategies. In the past decade, clinical phase I, II and III trials targeting the immune system revealed that patients tolerate immunotherapy, show decreased inflammation and/or had a reduction in cardiovascular endpoints. However, the search for novel immunotherapeutic targets and treatment regimens as well as stratification of patients who would benefit from such treatments to combat atherosclerotic cardiovascular disease is only just beginning. In this review article, we will highlight the newest insights on the different cell subsets and components of the immune system in atherosclerosis and elaborate on current and future immunotherapeutics to treat atherosclerotic cardiovascular disease.
Clinical Implications of Slope of GFR in Clinical Trials of CKD Progression
BackgroundSlope of the GFR is considered a validated surrogate endpoint for CKD trials. However, differing short-term and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before 3 months) and chronic (after 3 months) slopes for treatment effects on clinical endpoints (CEs).MethodsWe estimated treatment effects on the acute and chronic GFR slopes and on the established CE of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes.ResultsTreatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R2 (95% credible interval) of 0.95 (0.79 to 1.00). For a fixed treatment effect on the chronic slope, each 1 ml/min per 1.73 m2 greater acute GFR decline for the treatment versus control increased the hazard ratio for the established CE by 11.4% (7.9%-15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the 3-year total slope defined as the average slope extending from baseline to 3 years.ConclusionsTreatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects affect the CE independently of treatment effects on the chronic slope and support the 3-year total slope as the primary slope-based outcome in randomized trials.
Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches.
Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.
The effects of fasting on acute ischemic infarcts in the rat.
Inflammation is largely detrimental early in the acute phase of stroke but beneficial at more chronic stages. Fasting has been shown to reduce inflammation acutely. This preliminary study aimed to determine whether post-ischemic fasting improves stroke outcomes through attenuated inflammation. After an endothelin-1 lesion was created in the striatum, Wistar rats were subjected to either regular feeding or water-only fasting for 24 hours. Brain damage and central inflammation were measured histologically, while systemic inflammation was assessed through blood analysis. After 24 hours, fasting was found to reduce infarct volume and BBB breakdown, and lower both circulating and brain neutrophils. These findings suggest that fasting may be a beneficial non-pharmacological additive therapeutic option for cerebral ischemia, potentially by reducing inflammation in the acute stage of the disease.
Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke.
The contraction and subsequent death of brain pericytes may play a role in microvascular no-reflow following the reopening of an occluded artery during ischemic stroke. Mammalian target of rapamycin (mTOR) inhibition has been shown to reduce motility/contractility of various cancer cell lines and reduce neuronal cell death in stroke. However, the effects of mTOR inhibition on brain pericyte contraction and death during ischemia have not yet been investigated. Cultured pericytes exposed to simulated ischemia for 12 h in vitro contracted after less than 1 h, which was about 7 h prior to cell death. Rapamycin significantly reduced the rate of pericyte contraction during ischemia; however, it did not have a significant effect on pericyte viability at any time point. Rapamycin appeared to reduce pericyte contraction through a mechanism that is independent of changes in intracellular calcium. Using a mouse model of middle cerebral artery occlusion, we showed that rapamycin significantly increased the diameter of capillaries underneath pericytes and increased the number of open capillaries 30 min following recanalisation. Our findings suggest that rapamycin may be a useful adjuvant therapeutic to reduce pericyte contraction and improve cerebral reperfusion post-stroke.
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.
Sotrovimab versus usual care in patients admitted to hospital with COVID-19: a randomised, controlled, open-label, platform trial (RECOVERY)
Background: Sotrovimab is a neutralising monoclonal antibody targeting the SARS-COV-2 spike protein that was evaluated in the RECOVERY trial, a randomised, controlled, open-label, platform trial testing treatments for COVID-19. Methods: Patients hospitalised with COVID-19 pneumonia from 107 UK hospitals were randomly allocated to either usual care alone or usual care plus a single 1g infusion of sotrovimab, using web-based unstratified randomisation. Participants were retrospectively categorised as ‘high-antigen’ (the prespecified primary analysis population) if baseline serum SARS-CoV-2 nucleocapsid antigen was above the median concentration, and otherwise as ‘low-antigen’. The primary outcome was 28-day mortality assessed by intention to treat. Recruitment closed on 31 March 2024 when funding ended. ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings: From 4 January 2022 to 19 March 2024, 1723 patients were recruited, 828 allocated sotrovimab and 895 allocated usual care. 720 (42%) were classified as high-antigen, 717 (42%) as low-antigen, and 286 (17%) had unknown antigen status. 1389 (81%) patients were vaccinated, 1179/1438 with known serostatus (82%) had anti-spike antibodies at randomisation, and almost all were infected with Omicron variants. Among high-antigen patients, 82/355 (23%) allocated sotrovimab versus 106/365 (29%) allocated usual care died within 28 days (rate ratio 0.75; 95% CI 0.56-0.99; p=0.046). In an analysis of all randomised patients (regardless of antigen status), 177/828 (21%) allocated sotrovimab versus 201/895 (22%) allocated usual care died within 28 days (rate ratio 0.95; 95% CI 0.77-1.16; p=0.60). Interpretation: In patients hospitalised with COVID-19, sotrovimab was associated with reduced mortality in the primary analysis population who had a high serum SARS-CoV-2 antigen concentration at baseline, but not in the overall population. Treatment options for hospitalised patients are limited, and mortality in those receiving current standard care was high. The emergence of high-level resistance to sotrovimab among subsequent SARS-CoV-2 variants limits its current usefulness, but these results indicate that targeted neutralising antibody therapy could potentially still benefit high-risk hospitalised patients in an era of widespread vaccination and Omicron infection.
Contrast-Free Myocardial Scar Segmentation in Cine MRI using Motion and Texture Fusion
Late gadolinium enhancement MRI (LGE MRI) is the gold standard for the detection of myocardial scars post myocardial infarction (MI). LGE MRI requires the injection of a contrast agent, which carries potential side effects and increases scanning time and patient discomfort. To address these issues, we propose a novel framework that combines cardiac motion observed in cine MRI with image texture information to segment the myocardium and scar tissue in the left ventricle. Cardiac motion tracking can be formulated as a full cardiac image cycle registration problem, which can be solved via deep neural networks. Experimental results prove that the proposed method can achieve scar segmentation based on non-contrast cine images with comparable accuracy to LGE MRI. This demonstrates its potential as an alternative to contrast-enhanced techniques for scar detection.