An evidence-based guide to the efficacy and safety of isometric resistance training in hypertension and clinical implications.

More than 30 randomized controlled trials, supported by individual patient-level and group-level meta-analyses and a Delphi analysis of expert opinion, unequivocally show isometric resistance training (IRT) elicits antihypertensive benefits in healthy people and those with chronic illness. We aim to provide efficacy and safety evidence, and a guide for IRT prescription and delivery. Recommendations are made for the use of IRT in specific patient populations and appropriate methods for IRT delivery. Published data suggest IRT consistently elicits mean blood pressure reductions of 7.4/3.3 mmHg systolic blood pressure/diastolic blood pressure, equivalent to antihypertensive medication monotherapy. Blood pressure reductions of this size are associated with an approximate 13% to 22% reduction in major cardiovascular events. Moreover, IRT is safe in a range of patient populations. We suggest that IRT has the greatest potential benefit when used as an antihypertensive therapy in individuals unwilling and/or unable to complete aerobic exercise, or who have had limited adherence or success with it; individuals with resistant or uncontrolled hypertension, already taking at least two pharmacological antihypertensive agents; and healthy or clinical populations, as an adjunct to aerobic exercise and dietary intervention in those who have not yet attained control of their hypertension. IRT is efficacious and produces clinically meaningful blood pressure reductions (systolic blood pressure, 7 mmHg; diastolic blood pressure, 3 mmHg). IRT is safe and typical program delivery requires only about 17 min weekly. IRT should be used as an adjunct to other exercise modalities, in people unable to complete other types of exercise, or in resistant hypertension. [Abstract copyright: © 2023. The Author(s).

Exercise therapy and cardiac, autonomic and systemic function in patients with chronic heart failure

Background Exercise training is now accepted as a safe, adjunct therapy in stable heart failure patients. Acceptance of exercise training or therapy within this population is due to the benefits that have been demonstrated over the past three decades in trials and data syntheses presented in systematic reviews and meta-analyses. As new concepts emerge and with an increase in the number of trials comes the challenge of keeping up-to date with all the information, deciphering what's relevant, deciding how to interpret and apply the findings and what should happen next. Fortunately, the research methodologies of systematic review and meta-analysis provide a suitable platform for collecting, analysing and critically appraising studies. Methods An initial evidence mapping exercise identified the current level of research activity in regard to the synthesis of evidence focusing on the broad question of the benefits and/or effects of exercise training in heart failure patients. The objective of the exercise was to identify gaps in research synthesis and areas in which research synthesis would be valuable. A series of research syntheses were then conducted based on the identified gaps, using systematic reviews as the research methodology, and applying the statistical technique of meta-analysis where possible. Results While some of the effects of exercise training are now well established, e.g., improved functional capacity and quality of life, new trials and new concepts continue to emerge. Evidencing mapping highlighted a number of areas in which research synthesis was limited or out dated. The identified areas addressed the effect of exercise training on specific areas of cardiac, autonomic and systemic inflammatory markers in chronic heart failure patients; all associated with the pathogenesis and progression of heart failure. Evidence from systematic reviews and meta-analyses demonstrated that exercise training/therapy resulted in statistically significant improvements in: 1) endothelial function (FMD and EPCs), 2) direct (MSNA) and indirect (HRR, HRV) measures of autonomic function, 3) cardiac biomarkers (BNP, NT-proBNP) and 4) diastolic function, measured as E/E’. However, the evidence for improvements in a number of inflammatory markers was inconclusive, and limited evidence is currently available to allow for any conclusion to be drawn on the effect of exercise on emerging heart failure biomarkers. Conclusion This thesis utilised systematic reviews and meta-analyses as the research methodology to answer questions in relation to exercise training in heart failure patients. This work adds to the current evidence base by providing a robust synthesis of data in regard to effects of exercise training and therapy on endothelial function, autonomic function, inflammatory markers, biomarkers and diastolic function in heart failure patients

Novel DNA methylation profiles associated with key gene regulation and transcription pathways in blood and placenta of growth-restricted neonates

BB/H012494/1/ Biotechnology and Biological Sciences Research Counci

Exercise-based cardiac rehabilitation improves exercise capacity and health-related quality of life in people with atrial fibrillation: a systematic review and meta-analysis of randomised and non-randomised trials

Objective: The aim of this study was to undertake a contemporary review of the impact of exercise-based cardiac rehabilitation (CR) targeted at patients with atrial fibrillation (AF). Methods: We conducted searches of PubMED, EMBASE and the Cochrane Library of Controlled Trials (up until 30 November 2017) using key terms related to exercise-based CR and AF. Randomised and non-randomised controlled trials were included if they compared the effects of an exercise-based CR intervention to a no exercise or usual care control group. Meta-analyses of outcomes were conducted where appropriate. Results: The nine randomised trials included 959 (483 exercise-based CR vs 476 controls) patients with various types of AF. Compared with control, pooled analysis showed no difference in all-cause mortality (risk ratio (RR) 1.08, 95% CI 0.77 to 1.53, p=0.64) following exercise-based CR. However, there were improvements in health-related quality of life (mean SF-36 mental component score (MCS): 4.00, 95% CI 0.26 to 7.74; p=0.04 and mean SF-36 physical component score: 1.82, 95% CI 0.06 to 3.59; p=0.04) and exercise capacity (mean peak VO2: 1.59 ml/kg/min, 95% CI 0.11 to 3.08; p=0.04; mean 6 min walk test: 46.9 m, 95% CI 26.4 to 67.4; p<0.001) with exercise-based CR. Improvements were also seen in AF symptom burden and markers of cardiac function. Conclusions: Exercise capacity, cardiac function, symptom burden and health-related quality of life were improved with exercise-based CR in the short term (up to 6 months) targeted at patients with AF. However, high-quality multicentre randomised trials are needed to clarify the impact of exercise-based CR on key patient and health system outcomes (including health-related quality of life, mortality, hospitalisation and costs) and how these effects may vary across AF subtypes

Leveraging DNA-Methylation Quantitative-Trait Loci to Characterize the Relationship between Methylomic Variation, Gene Expression, and Complex Traits

Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation has the potential to increase understanding about the mechanisms underpinning health and disease phenotypes. We undertook a comprehensive analysis of common genetic variation on DNA methylation (DNAm) by using the Illumina EPIC array to profile samples from the UK Household Longitudinal study. We identified 12,689,548 significant DNA methylation quantitative trait loci (mQTL) associations (p 60 human traits by using summary-data-based Mendelian randomization (SMR) to identify 1,662 pleiotropic associations between 36 complex traits and 1,246 DNAm sites. We also use SMR to characterize the relationship between DNAm and gene expression and thereby identify 6,798 pleiotropic associations between 5,420 DNAm sites and the transcription of 1,702 genes. Our mQTL database and SMR results are available via a searchable online database as a resource to the research community

Bigmelon:Tools for analysing large DNA methylation datasets

Motivation The datasets generated by DNA methylation analyses are getting bigger. With the release of the HumanMethylationEPIC micro-array and datasets containing thousands of samples, analyses of these large datasets using R are becoming impractical due to large memory requirements. As a result there is an increasing need for computationally efficient methodologies to perform meaningful analysis on high dimensional data. Results Here we introduce the bigmelon R package, which provides a memory efficient workflow that enables users to perform the complex, large scale analyses required in epigenome wide association studies (EWAS) without the need for large RAM. Building on top of the CoreArray Genomic Data Structure file format and libraries packaged in the gdsfmt package, we provide a practical workflow that facilitates the reading-in, preprocessing, quality control and statistical analysis of DNA methylation data. We demonstrate the capabilities of the bigmelon package using a large dataset consisting of 1193 human blood samples from the Understanding Society: UK Household Longitudinal Study, assayed on the EPIC micro-array platform. copy; 2018 The Author(s). Published by Oxford University Press.</p

Systematic under-estimation of the epigenetic clock and age acceleration in older subjects

Background: The Horvath epigenetic clock is widely used. It predicts age quite well from 353 CpG sites in the DNA methylation profile in unknown samples and has been used to calculate 'age acceleration’ in various tissues and environments. Results: The model systematically underestimates age in tissues from older people. This is seen in all examined tissues but most strongly in the cerebellum and is consistently observed in multiple datasets. Age acceleration is thus age-dependent, and this can lead to spurious associations. The current literature includes examples of association tests with age acceleration calculated in a wide variety of ways. Conclusions: The concept of an epigenetic clock is compelling, but caution should be taken in interpreting associations with age acceleration. Association tests of age acceleration should include age as a covariate

An evidence-based guide to the efficacy and safety of isometric resistance training in hypertension and clinical implications

More than 30 randomized controlled trials, supported by individual patient-level and group-level meta-analyses and a Delphi analysis of expert opinion, unequivocally show isometric resistance training (IRT) elicits antihypertensive benefits in healthy people and those with chronic illness. We aim to provide efficacy and safety evidence, and a guide for IRT prescription and delivery. Recommendations are made for the use of IRT in specific patient populations and appropriate methods for IRT delivery. Published data suggest IRT consistently elicits mean blood pressure reductions of 7.4/3.3 mmHg systolic blood pressure/diastolic blood pressure, equivalent to antihypertensive medication monotherapy. Blood pressure reductions of this size are associated with an approximate 13% to 22% reduction in major cardiovascular events. Moreover, IRT is safe in a range of patient populations. We suggest that IRT has the greatest potential benefit when used as an antihypertensive therapy in individuals unwilling and/or unable to complete aerobic exercise, or who have had limited adherence or success with it; individuals with resistant or uncontrolled hypertension, already taking at least two pharmacological antihypertensive agents; and healthy or clinical populations, as an adjunct to aerobic exercise and dietary intervention in those who have not yet attained control of their hypertension. IRT is efficacious and produces clinically meaningful blood pressure reductions (systolic blood pressure, 7 mmHg; diastolic blood pressure, 3 mmHg). IRT is safe and typical program delivery requires only about 17 min weekly. IRT should be used as an adjunct to other exercise modalities, in people unable to complete other types of exercise, or in resistant hypertension

Hypocoagulability and Platelet Dysfunction Are Exacerbated by Synthetic Colloids in a Canine Hemorrhagic Shock Model

Background: Hemorrhagic shock and volume replacement can alter coagulation. Synthetic colloids, hydroxyethyl starch (HES), and gelatin, may enhance hypocoagulability. Our primary objective was to describe the effect of four fluid products on coagulation in canine hemorrhagic shock. Our secondary objective was to compare measurements of coagulation during shock to baseline in all dogs.Methods: Anesthetized greyhounds subjected to atraumatic hemorrhage for 60 min were administered 20 mL kg−1 of either fresh whole blood (FWB), 6% HES 130/0.4, 4% succinylated gelatin (GELO), or 80 mL kg−1 of isotonic crystalloid over 20 min (n = 6 per group). Platelet closure time (PCT), rotational thromboelastometry (ROTEM) and plasma coagulation assays were measured at baseline, end of hemorrhage (shock), and 40 (T60), and 160 (T180) min after study fluid. ROTEM parameters included clotting time (CT), clot formation time (CFT), alpha angle, maximum clot firmness (MCF), lysis index at 60 min (LI60), and thrombodynamic potential index (TPI) for INTEM, EXTEM, FIBTEM (MCF only), and APTEM (LI60 only) profiles. Plasma coagulation assays included prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen concentration and activities of factor VII (FVII), factor VIII (FVIII), and von Willebrand Factor antigen (vWF). Between-group differences were tested using linear mixed models with post-hoc between-group comparisons (Bonferroni-Holm corrected). Differences between baseline and shock were tested using paired t-tests. Significance was set at P &lt; 0.05.Results: GELO showed longer PCT at T60, compared with FWB and CRYST, and at T180, compared with all other groups. HES showed longer EXTEM CT at T60, compared with all other groups. HES showed lower INTEM and EXTEM MCF at T60 and lower INTEM MCF at T180, compared with FWB. Some plasma coagulation assays showed greater hypocoagulability with HES. Comparing shock to baseline, EXTEM CT, INTEM CFT, EXTEM CFT, PT, and FVIII significantly increased and PCT, INTEM CT, INTEM MCF, EXTEM MCF, EXTEM LI60, EXTEM TPI, FIBTEM MCF, APTT, fibrinogen, FVII, and vWF significantly decreased.Conclusions: In dogs with hemorrhagic shock, volume replacement with GELO caused mild platelet dysfunction and HES was associated with coagulation changes consistent with hypocoagulability, beyond effects of hemodilution. Shock alone produced some evidence of hypocoagulability

Effect of modified vaccinia Ankara–5T4 and low-dose cyclophosphamide on antitumor immunity in metastatic colorectal cancer: A randomized clinical trial

Importance The success of immunotherapy with checkpoint inhibitors is not replicated in most cases of colorectal cancer; therefore, different strategies are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of cases of metastatic colorectal cancer (mCRC). Preliminary data using modified vaccinia Ankara–5T4 (MVA-5T4) in mCRC demonstrated that it safely induced serologic and T-cell responses. Objective To determine whether antitumor immunity in mCRC could be increased using MVA-5T4, metronomic low-dose cyclophosphamide, or a combination of both treatments. Design, Setting, and Participants In this randomized clinical trial, 55 patients with inoperable mCRC and prior stable disease after standard chemotherapy were enrolled at a single center and randomized to watch and wait (n = 9), cyclophosphamide treatment only (n = 9), MVA-5T4 only (n = 19), and a combination of MVA-5T4 and cyclophosphamide (n = 18). Patients were enrolled and treated from July 9, 2012, through February 8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed based on intention to treat. Interventions Patients randomized to a cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15 to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection at a dose of 1 × 109 50% tissue culture infectious dose on treatment days 22, 36, 50, 64, 78, and 106. Main Outcomes and Measures The predefined primary end point was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody levels) generated at treatment week 7. Secondary end points included analysis of the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall survival (OS). Results Fifty-two patients (38 men and 14 women; mean [SD] age, 64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody immune responses were significantly increased in the MVA-5T4 (83.41 [36.09] relative units [RU]; P = .02) and combination treatment (65.81 [16.68] RU; P = .002) groups compared with no treatment (20.09 [7.20] RU). Cyclophosphamide depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients, resulting in significantly prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI, 0.09-0.47; P < .001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P = .008). No grade 3 or 4 adverse events were observed. Conclusions and Relevance This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects. Larger clinical trials are planned to further validate these data