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1.
Mixed plaque on coronary CT angiography predicts atherosclerotic events in asymptomatic intermediate-risk individuals.
Warren, J, Ellims, A, Bloom, J, Sutherland, N, Lew, P, Kavnoudias, H, Paleri, S, Stub, D, Taylor, A
Open heart. 2024;(1)
Abstract
OBJECTIVE Coronary CT angiography (CCTA) permits both qualitative and quantitative analysis of atherosclerotic plaque and may be a suitable risk modifier in assessing patients at intermediate risk of atherosclerotic cardiovascular disease. We sought to determine the association of plaque components with long-term major adverse cardiovascular events (MACEs) in asymptomatic intermediate-risk patients, compared with conventional coronary artery calcium (CAC) score. METHODS 100 intermediate-risk patients underwent double-blinded CCTA. Follow-up was conducted at 10 years and data were cross-referenced with the National Death Index. The primary outcome was MACE, which was a composite of death, acute coronary syndrome (ACS), revascularisation and stroke. RESULTS The median time from CCTA to follow-up was 9.5 years. 83 patients completed follow-up interview and mortality data were available on all 100 patients. MACE occurred in 17 (20.5%) patients, which included 2 (2%) deaths, 8 (10%) ACS, 3 (4%) strokes and 5 (6%) revascularisation procedures. 47 (57%) patients had mixed plaque, which was predictive of MACE (OR 4.68 (95% CI 1.19 to 18.5) p=0.028). The burden of non-calcified and mixed plaque, defined by non-calcified plaque segment stenosis score, was also a predictor of long-term MACE (OR 1.59 (95% CI 1.18 to 2.13) p=0.002). Neither calcified plaque (OR 3.92 (95% CI 0.80 to 19.3)) nor CAC score (OR 1.01 (95% CI 0.999 to 1.02)) was associated with long-term MACE. CONCLUSION The presence and burden of mixed plaque on CCTA is associated with an increased risk of long-term MACE among asymptomatic intermediate-risk patients and is a superior predictor to CAC score.
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2.
Mechanistic implications of the ternary complex structural models for the photoenzyme protochlorophyllide oxidoreductase.
Taylor, A, Zhang, S, Johannissen, LO, Sakuma, M, Phillips, RS, Green, AP, Hay, S, Heyes, DJ, Scrutton, NS
The FEBS journal. 2024;(7):1404-1421
Abstract
The photoenzyme protochlorophyllide oxidoreductase (POR) is an important enzyme for understanding biological H-transfer mechanisms. It uses light to catalyse the reduction of protochlorophyllide to chlorophyllide, a key step in chlorophyll biosynthesis. Although a wealth of spectroscopic data have provided crucial mechanistic insight, a structural rationale for POR photocatalysis has proved challenging and remains hotly debated. Recent structural models of the ternary enzyme-substrate complex, derived from crystal and electron microscopy data, show differences in the orientation of the protochlorophyllide substrate and the architecture of the POR active site, with significant implications for the catalytic mechanism. Here, we use a combination of computational and experimental approaches to investigate the compatibility of each structural model with the hypothesised reaction mechanisms and propose an alternative structural model for the cyanobacterial POR ternary complex. We show that a strictly conserved tyrosine, previously proposed to act as the proton donor in POR photocatalysis, is unlikely to be involved in this step of the reaction but is crucial for Pchlide binding. Instead, an active site cysteine is important for both hydride and proton transfer reactions in POR and is proposed to act as the proton donor, either directly or through a water-mediated network. Moreover, a conserved glutamine is important for Pchlide binding and ensuring efficient photochemistry by tuning its electronic properties, likely by interacting with the central Mg atom of the substrate. This optimal 'binding pose' for the POR ternary enzyme-substrate complex illustrates how light energy can be harnessed to facilitate enzyme catalysis by this unique enzyme.
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3.
Progressive exercise training improves cardiovascular psychophysiological outcomes in young adult women with a history of adverse childhood experiences.
Rogers, EM, Banks, NF, Tomko, PM, Sciarrillo, CM, Emerson, SR, Thomas, EBK, Taylor, A, Teague, TK, Jenkins, NDM
Journal of applied physiology (Bethesda, Md. : 1985). 2023;(3):742-752
Abstract
Adverse childhood experiences (ACEs) are early-life psychosocial stressors that are associated with poorer mental health and increased cardiovascular disease (CVD) risk in a dose-dependent manner. We examined the feasibility of an 8-wk combined aerobic and resistance exercise training program to improve systolic (SBP) and diastolic blood pressure (DBP), serum endothelin-1 (ET-1), resilience, hope agency, and hope pathways in young women with ACEs. Forty-two healthy women (21 ± 3 yr) with ≥4 (ACE+; n = 28) or 0 ACEs (ACE-; n = 14) participated in this study. Women with ACEs were randomly assigned to an exercise (ACE+EXT; n = 14) or nonexercise control (ACE+CON; n = 14) group, whereas all ACE- participants were assigned to a nonexercise control (n = 14) group. Hope agency and DBP did not change in any group (P ≥ 0.43), but hope pathways improved only in ACE+EXT (means ± SE change; +1.6 ± 0.74 au, P = 0.032, Hedges' g = 0.53). ET-1 decreased in ACE+EXT only (-0.31 ± 0.15 pg/mL, P = 0.043, g = 0.46). Although the interactions for resilience and SBP did not reach significance (P = 0.05-0.06), forced post hoc analyses indicated that resilience improved (+4.9 ± 1.9 au, P = 0.012, g = 0.64) and SBP tended to improve (-4.0 ± 2.0 mmHg, P = 0.053, g = 0.51) in ACE+EXT only. There were significant associations between changes in hope pathways and SBP (ρ = -0.43, P = 0.023) and ET-1 (ρ = -0.53, P = 0.005), and between changes in SBP and ET-1 (ρ = 0.49; P = 0.012) in the ACE+ group. In summary, structured exercise training reduces serum ET-1 levels, improves positive psychological coping, and may improve SBP in young women with ACEs. The relationships among the changes in hope pathways, SBP, and ET-1 suggest a cardiovascular psychophysiological relationship in young women with ACEs.NEW & NOTEWORTHY This randomized controlled pilot trial shows, for the first time, that 8 wk of structured, progressive exercise training lowers serum endothelin-1 (ET-1) and improves positive psychological coping in young women with significant early-life psychosocial stress. Furthermore, the observed associations among changes in psychological attributes, ET-1, and systolic blood pressure signify a potential interplay between positive psychology and cardiovascular disease risk among women with adverse childhood experiences.
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4.
An Updated Review on the Role of Non-dihydropyridine Calcium Channel Blockers and Beta-blockers in Atrial Fibrillation and Acute Decompensated Heart Failure: Evidence and Gaps.
Triska, J, Tamargo, J, Bozkurt, B, Elkayam, U, Taylor, A, Birnbaum, Y
Cardiovascular drugs and therapy. 2023;(6):1205-1223
Abstract
PURPOSE The 2021 European Society of Cardiology guidelines on acute and chronic heart failure (HF) recommend that non-dihydropyridine calcium channel blockers (NDCC) should be avoided in patients with HF with reduced ejection fraction. It also emphasizes that beta-blockers only be initiated in clinically stable, euvolemic patients. Despite these recommendations, NDCC and beta-blockers are often still employed in patients with AF with rapid ventricular response and acute decompensated HF. The relative safety and efficacy of these therapies in this setting is unclear. METHODS To address the question of the safety and efficacy of NDCC and beta-blockers for acute rate control in decompensated HF, we provide a perspective on the literature of NDCC and beta-blockers in chronic HF with reduced and preserved ejection fraction and AF, including trials on the management of AF with rapid ventricular response with and without HF. RESULTS Robust data demonstrates mortality benefits when beta-blockers are used in patients with chronic HF with reduced ejection fraction. The data that inform the contraindication of NDCC in HF with reduced ejection fraction are outdated and were not primarily designed to address the efficacy and safety of rate control of AF in patients with HF. Several studies indicate that for acute rate control, NDCC and beta-blockers are both efficacious therapies, especially in the setting of tachycardia-induced cardiomyopathy. CONCLUSION Future studies are needed to assess the safety and efficacy of beta-blockers and NDCC in both acute and chronic AF with HF with reduced and preserved ejection fraction.
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5.
CARE: Protocol of a randomised trial evaluating the feasibility of preoperative intentional weight loss to support postoperative recovery in patients with excess weight and colorectal cancer.
Koutoukidis, DA, Jebb, SA, Foster, C, Wheatstone, P, Horne, A, Hill, TM, Taylor, A, Realpe, A, Achana, F, Buczacki, SJA
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2023;(9):1910-1920
Abstract
AIM: Excess weight increases the risk of morbidity following colorectal cancer surgery. Weight loss may improve morbidity, but it is uncertain whether patients can follow an intensive weight loss intervention while waiting for surgery and there are concerns about muscle mass loss. The aim of this trial is to assess the feasibility of intentional weight loss in this setting and determine progression to a definitive trial. METHODS CARE is a prospectively registered, multicentre, feasibility, parallel, randomised controlled trial with embedded evaluation and optimisation of the recruitment process. Participants with excess weight awaiting curative colorectal resection for cancer are randomised 1:1 to care as usual or a low-energy nutritionally-replete total diet replacement programme with weekly remote behavioural support by a dietitian. Progression criteria will be based on the recruitment, engagement, adherence, and retention rates. Data will be collected on the 30-day postoperative morbidity, the typical primary outcome of prehabilitation trials. Secondary outcomes will include, among others, length of hospital stay, health-related quality of life, and body composition. Qualitative interviews will be used to understand patients' experiences of and attitudes towards trial participation and intervention engagement and adherence. CONCLUSION CARE will evaluate the feasibility of intensive intentional weight loss as prehabilitation before colorectal cancer surgery. The results will determine the planning of a definitive trial.
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6.
Associations between meeting 24-hour movement guidelines and quality of life among children and adolescents with autism spectrum disorder.
Kong, C, Chen, A, Ludyga, S, Herold, F, Healy, S, Zhao, M, Taylor, A, Müller, NG, Kramer, AF, Chen, S, et al
Journal of sport and health science. 2023;(1):73-86
Abstract
BACKGROUND The Canadian 24-hour movement behavior (24-HMB) guidelines suggest that a limited amount of screen time use, an adequate level of physical activity (PA), and sufficient sleep duration are beneficial for ensuring and optimizing the health and quality of life (QoL) of children and adolescents. However, this topic has yet to be examined for children and adolescents with autism spectrum disorder (ASD) specifically. The aim of this cross-sectional observational study was to examine the associations between meeting 24-HMB guidelines and several QoL-related indicators among a national sample of American children and adolescents with ASD. METHODS Data were taken from the 2020 U.S. National Survey of Children's Health dataset. Participants (n = 956) aged 6-17 years and currently diagnosed with ASD were included. The exposure of interest was adherence to the 24-HMB guidelines. Outcomes were QoL indicators, including learning interest/curiosity, repeating grades, adaptive ability, victimization by bullying, and behavioral problems. Categorical variables were described with unweighted sample counts and weighted percentages. Age, sex, race, preterm birth status, medication, behavioral treatment, household poverty level, and the educational level of the primary caregivers were included as covariates. Odds ratio (OR) and 95% confidence interval (95%CI) were used to present the strength of association between adherence to 24-HMB guidelines and QoL-related indicators. RESULTS Overall, 452 participants (45.34%) met 1 of the 3 recommendations, 216 (22.65%) met 2 recommendations, whereas only 39 participants (5.04%) met all 3 recommendations. Compared with meeting none of the recommendations, meeting both sleep duration and PA recommendations (OR = 3.92, 95%CI: 1.63-9.48, p < 0.001) or all 3 recommendations (OR = 2.11, 95%CI: 1.03-4.35, p = 0.04) was associated with higher odds of showing learning interest/curiosity. Meeting both screen time and PA recommendations (OR = 0.15, 95%CI: 0.04-0.61, p < 0.05) or both sleep duration and PA recommendations (OR = 0.24, 95%CI: 0.07-0.87, p < 0.05) was associated with lower odds of repeating any grades. With respect to adaptive ability, participants who met only the PA recommendation of the 24-HMB were less likely to have difficulties dressing or bathing (OR = 0.11, 95%CI: 0.02-0.66, p < 0.05) than those who did not. For participants who met all 3 recommendations (OR = 0.38, 95%CI: 0.15-0.99, p = 0.05), the odds of being victimized by bullying was lower. Participants who adhered to both sleep duration and PA recommendations were less likely to present with severe behavioral problems (OR = 0.17, 95%CI: 0.04-0.71, p < 0.05) than those who did not meet those guidelines. CONCLUSION Significant associations were found between adhering to 24-HMB guidelines and selected QoL indicators. These findings highlight the importance of maintaining a healthy lifestyle as a key factor in promoting and preserving the QoL of children with ASD.
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7.
A Randomized, Controlled Trial of Efficacy and Safety of Cannabidiol in Idiopathic and Diabetic Gastroparesis.
Zheng, T, BouSaba, J, Taylor, A, Dilmaghani, S, Busciglio, I, Carlson, P, Torres, M, Ryks, M, Burton, D, Harmsen, WS, et al
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2023;(13):3405-3414.e4
Abstract
BACKGROUND & AIMS Cannabis (delta-9-tetrahydrocannabinol), a nonselective cannabinoid-receptor agonist, relieves nausea and pain. Cannabidiol (CBD), a cannabinoid receptor 2 inverse agonist with central effects, also reduces gut sensation and inflammation. We compared the effects of 4 weeks of treatment with pharmaceutical CBD vs placebo in patients with idiopathic or diabetic (diabetes mellitus) gastroparesis. METHODS We performed a randomized, double-blinded, placebo-controlled study of CBD twice daily (Epidiolex escalated to 20 mg/kg/d; Jazz Pharmaceuticals, Dublin, Ireland) in patients with nonsurgical gastroparesis with delayed gastric emptying of solids (GES). Symptoms were assessed by the Gastroparesis Cardinal Symptom Index Daily Diary. After 4 weeks of treatment, we measured GES, gastric volumes, and Ensure (Abbott Laboratories, Abbott Park, IL) satiation test (1 kcal/mL, 30 mL/min) to assess volume to comfortable fullness and maximum tolerance. Patients underwent specific FAAH and CNR1 genotyping. Statistical analysis compared 2 treatments using analysis of variance including baseline measurements and body mass index as covariates. RESULTS Among 44 patients (32 idiopathic, 6 diabetes mellitus type 1, and 6 diabetes mellitus type 2), 5 patients did not tolerate full-dose escalation; 3 withdrew before completing 4 weeks of treatment (2 placebo, 1 CBD); 95% completed 4 weeks of treatment and diaries. Compared with placebo, CBD reduced the total Gastroparesis Cardinal Symptom Index score (P = .008), inability to finish a normal-sized meal (P = .029), number of vomiting episodes/24 hours (P = .006), and overall symptom severity (P = .034). Patients treated with CBD had a higher volume to comfortable fullness and maximum tolerance and slower GES. FAAH rs34420 genotype significantly impacted nutrient drink ingestion. The most common adverse events reported were diarrhea (14 patients), fatigue (8 patients), headache (8 patients), and nausea (7 patients). CONCLUSIONS CBD provides symptom relief in patients with gastroparesis and improves the tolerance of liquid nutrient intake, despite slowing of GES. CLINICALTRIALS gov NCT #03941288.
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8.
Author Correction: PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing.
Cikes, D, Elsayad, K, Sezgin, E, Koitai, E, Torma, F, Orthofer, M, Yarwood, R, Heinz, LX, Sedlyarov, V, Miranda, ND, et al
Nature metabolism. 2023;(4):711
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9.
Proteostasis in aging-associated ocular disease.
Weinberg, J, Gaur, M, Swaroop, A, Taylor, A
Molecular aspects of medicine. 2022;:101157
Abstract
Vision impairment has devastating consequences for the quality of human life. The cells and tissues associated with the visual process must function throughout one's life span and maintain homeostasis despite exposure to a variety of insults. Maintenance of the proteome is termed proteostasis, and is vital for normal cellular functions, especially at an advanced age. Here we describe basic aspects of proteostasis, from protein synthesis and folding to degradation, and discuss the current status of the field with a particular focus on major age-related eye diseases: age-related macular degeneration, cataract, and glaucoma. Our intent is to allow vision scientists to determine where and how to harness the proteostatic machinery for extending functional homeostasis in the aging retina, lens, and trabecular meshwork. Several common themes have emerged despite these tissues having vastly different metabolisms. Continued exposure to insults, including chronic stress with advancing age, increases proteostatic burden and reduces the fidelity of the degradation machineries including the ubiquitin-proteasome and the autophagy-lysosome systems that recognize and remove damaged proteins. This "double jeopardy" results in an exponential accumulation of cytotoxic proteins with advancing age. We conclude with a discussion of the challenges in maintaining an appropriate balance of protein synthesis and degradation pathways, and suggest that harnessing proteostatic capacities should provide new opportunities to design interventions for attenuating age-related eye diseases before they limit sight.
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10.
Randomised single centre double-blind placebo controlled phase II trial of Tocovid SupraBio in combination with pentoxifylline in patients suffering long-term gastrointestinal adverse effects of radiotherapy for pelvic cancer: The PPALM study.
Andreyev, HJN, Matthews, J, Adams, C, Gothard, L, Lucy, C, Tovey, H, Boyle, S, Anbalagan, S, Musallam, A, Yarnold, J, et al
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2022;:130-137
Abstract
BACKGROUND Preclinical data suggest that combined gamma-tocotrienol with pentoxifylline ameliorates radiotherapy-induced gastrointestinal damage. AIM: To test whether gastrointestinal symptoms arising after radiotherapy, and persisting after maximal medical therapy, can be improved using Tocovid SupraBio 200 mg and pentoxifylline 400 mg orally twice daily for one year. Patients stratified by severity of symptoms, and randomised to active treatment or matched placebo were assessed after 12 months. The primary end point was improvement in gastrointestinal symptoms measured using the Inflammatory Bowel Disease Questionnaire, bowel subset score. Changes in bio-markers of fibrosis were assessed. RESULTS 62 patients, median age 66, 34(55%) treated for prostate, 21(34%) gynaecological, 6(10%) anal and one(1%) rectal cancer were recruited; 40(65%) randomised to treatment, 22(35%) to placebo, 39 months (median) after radiotherapy completion. Gamma tocotrienol was not detected in serum in 41% of treated patients, despite good compliance with study medication. Treatment was completed in 28(70%) and 17(77%) patients in the treatment and placebo groups respectively. No improvement in symptom scores nor in quality of life was identified. Thirteen serious adverse events occurred. A transient ischaemic attack, was possibly related to pentoxifylline, others were assessed as unlikely to be related to treatment. Levels of EGF, PDGF and FGF were significantly reduced and consistent trends in reduced inflammation were seen during treatment but were not sustained once treatment ended. SUMMARY This single centre study closed prematurely and therefore data interpretation is of necessity limited. No clinical benefit was demonstrated. However, biochemical data suggest that this intervention does have anti-inflammatory and anti-fibrotic effects.