Molecular mechanisms underpinning favourable physiological adaptations to exercise prehabilitation for urological cancer surgery.

BACKGROUND: Surgery for urological cancers is associated with high complication rates and survivors commonly experience fatigue, reduced physical ability and quality of life. High-intensity interval training (HIIT) as surgical prehabilitation has been proven effective for improving the cardiorespiratory fitness (CRF) of urological cancer patients, however the mechanistic basis of this favourable adaptation is undefined. Thus, we aimed to assess the mechanisms of physiological responses to HIIT as surgical prehabilitation for urological cancer. METHODS: Nineteen male patients scheduled for major urological surgery were randomised to complete 4-weeks HIIT prehabilitation (71.6 ± 0.75 years, BMI: 27.7 ± 0.9 kg·m2) or a no-intervention control (71.8 ± 1.1 years, BMI: 26.9 ± 1.3 kg·m2). Before and after the intervention period, patients underwent m. vastus lateralis biopsies to quantify the impact of HIIT on mitochondrial oxidative phosphorylation (OXPHOS) capacity, cumulative myofibrillar muscle protein synthesis (MPS) and anabolic, catabolic and insulin-related signalling. RESULTS: OXPHOS capacity increased with HIIT, with increased expression of electron transport chain protein complexes (C)-II (p = 0.010) and III (p = 0.045); and a significant correlation between changes in C-I (r = 0.80, p = 0.003), C-IV (r = 0.75, p = 0.008) and C-V (r = 0.61, p = 0.046) and changes in CRF. Neither MPS (1.81 ± 0.12 to 2.04 ± 0.14%·day-1, p = 0.39) nor anabolic or catabolic proteins were upregulated by HIIT (p > 0.05). There was, however, an increase in phosphorylation of AS160Thr642 (p = 0.046) post-HIIT. CONCLUSIONS: A HIIT surgical prehabilitation regime, which improved the CRF of urological cancer patients, enhanced capacity for skeletal muscle OXPHOS; offering potential mechanistic explanation for this favourable adaptation. HIIT did not stimulate MPS, synonymous with the observed lack of hypertrophy. Larger trials pairing patient-centred and clinical endpoints with mechanistic investigations are required to determine the broader impacts of HIIT prehabilitation in this cohort, and to inform on future optimisation (i.e., to increase muscle mass).

Post-operative electrical muscle stimulation attenuates loss of muscle mass and function following major abdominal surgery in older adults: a split body randomised control trial.

INTRODUCTION: Significant losses of muscle mass and function occur after major abdominal surgery. Neuromuscular electrical stimulation (NMES) has been shown to reduce muscle atrophy in some patient groups, but evidence in post-operative patients is limited. This study assesses the efficacy of NMES for attenuating muscle atrophy and functional declines following major abdominal surgery in older adults. METHODS: Fifteen patients undergoing open colorectal resection completed a split body randomised control trial. Patients' lower limbs were randomised to control (CON) or NMES (STIM). The STIM limb underwent 15 minutes of quadriceps NMES twice daily on post-operative days (PODs) 1-4. Ultrasound measurements of Vastus Lateralis cross-sectional area (CSA) and muscle thickness (MT) were made preoperatively and on POD 5, as was dynamometry to determine knee extensor strength (KES). Change in CSA was the primary outcome. All outcomes were statistically analysed using linear mixed models. RESULTS: NMES significantly reduced the loss of CSA (-2.52 versus -9.16%, P < 0.001), MT (-2.76 versus -8.145, P = 0.001) and KES (-10.35 versus -19.69%, P = 0.03) compared to CON. No adverse events occurred, and patients reported that NMES caused minimal or no discomfort and felt that ~90-minutes of NMES daily would be tolerable. DISCUSSION: NMES reduces losses of muscle mass and function following major abdominal surgery, and as such, may be the promising tool for post-operative recovery. This is important in preventing long-term post-operative dependency, especially in the increasingly frail older patients undergoing major abdominal surgery. Further studies should establish the efficacy of bilateral NMES for improving patient-centred outcomes.

The time course of disuse muscle atrophy of the lower limb in health and disease.

Short, intermittent episodes of disuse muscle atrophy (DMA) may have negative impact on age related muscle loss. There is evidence of variability in rate of DMA between muscles and over the duration of immobilization. As yet, this is poorly characterized. This review aims to establish and compare the time-course of DMA in immobilized human lower limb muscles in both healthy and critically ill individuals, exploring evidence for an acute phase of DMA and differential rates of atrophy between and muscle groups. MEDLINE, Embase, CINHAL and CENTRAL databases were searched from inception to April 2021 for any study of human lower limb immobilization reporting muscle volume, cross-sectional area (CSA), architecture or lean leg mass over multiple post-immobilization timepoints. Risk of bias was assessed using ROBINS-I. Where possible meta-analysis was performed using a DerSimonian and Laird random effects model with effect sizes reported as mean differences (MD) with 95% confidence intervals (95% CI) at various time-points and a narrative review when meta-analysis was not possible. Twenty-nine studies were included, 12 in healthy volunteers (total n = 140), 18 in patients on an Intensive Therapy Unit (ITU) (total n = 516) and 3 in patients with ankle fracture (total n = 39). The majority of included studies are at moderate risk of bias. Rate of quadriceps atrophy over the first 14 days was significantly greater in the ITU patients (MD -1.01 95% CI -1.32, -0.69), than healthy cohorts (MD -0.12 95% CI -0.49, 0.24) (P < 0.001). Rates of atrophy appeared to vary between muscle groups (greatest in triceps surae (-11.2% day 28), followed by quadriceps (-9.2% day 28), then hamstrings (-6.5% day 28), then foot dorsiflexors (-3.2% day 28)). Rates of atrophy appear to decrease over time in healthy quadriceps (-6.5% day 14 vs. -9.1% day 28) and triceps surae (-7.8% day 14 vs. -11.2% day 28), and ITU quadriceps (-13.2% day 7 vs. -28.2% day 14). There appears to be variability in the rate of DMA between muscle groups, and more rapid atrophy during the earliest period of immobilization, indicating different mechanisms being dominant at different timepoints. Rates of atrophy are greater amongst critically unwell patients. Overall evidence is limited, and existing data has wide variability in the measures reported. Further work is required to fully characterize the time course of DMA in both health and disease.

The role of resistance exercise training for improving cardiorespiratory fitness in healthy older adults: a systematic review and meta-analysis.

BACKGROUND: Declines in cardiorespiratory fitness (CRF) and muscle mass are both associated with advancing age and each of these declines is associated with worse health outcomes. Resistance exercise training (RET) has previously been shown to improve muscle mass and function in the older population. If RET is also able to improve CRF, as it has been shown to do in younger populations, it has the potential to improve multiple health outcomes in the expanding older population. METHODS: This systematic review aimed to identify the role of RET for improving CRF in healthy older adults. A search across CINAHL, MEDLINE, EMBASE and EMCARE databases was conducted with meta-analysis performed on eligible papers to identify improvements in established CRF parameters (VO2 peak, aerobic threshold (AT), 6-minute walking distance test (6MWT) following RET intervention. Main eligibility criteria included older adults (aged over 60), healthy cohorts (disease-specific cohorts were excluded) and RET intervention. RESULTS: Thirty-seven eligible studies were identified. Meta-analysis revealed a significant improvement in VO2 peak (MD 1.89 ml/kg/min; 95% confidence interval (CI) 1.21-2.57 ml/kg/min), AT (MD 1.27 ml/kg/min; 95% CI 0.44-2.09 ml/kg/min) and 6MWT (MD 30.89; 95% CI 26.7-35.08) in RET interventions less than 24 weeks. There was no difference in VO2 peak or 6MWT in interventions longer than 24 weeks. DISCUSSION: This systematic review adds to a growing body of evidence supporting the implementation of RET in the older population for improving whole-body health, particularly in time-limited timeframes.

Equipment-free, unsupervised high intensity interval training elicits significant improvements in the physiological resilience of older adults.

BACKGROUND: Reduced cardiorespiratory fitness (CRF) is an independent risk factor for dependency, cognitive impairment and premature mortality. High-intensity interval training (HIIT) is a proven time-efficient stimulus for improving both CRF and other facets of cardiometabolic health also known to decline with advancing age. However, the efficacy of equipment-free, unsupervised HIIT to improve the physiological resilience of older adults is not known. METHODS: Thirty independent, community-dwelling older adults (71(SD: 5) years) were randomised to 4 weeks (12 sessions) equipment-free, supervised (in the laboratory (L-HIIT)) or unsupervised (at home (H-HIIT)) HIIT, or a no-intervention control (CON). HIIT involved 5, 1-minute intervals of a bodyweight exercise each interspersed with 90-seconds recovery. CRF, exercise tolerance, blood pressure (BP), body composition, muscle architecture, circulating lipids and glucose tolerance were assessed at baseline and after the intervention period. RESULTS: When compared to the control group, both HIIT protocols improved the primary outcome of CRF ((via anaerobic threshold) mean difference, L-HIIT: +2.27, H-HIIT: +2.29, both p < 0.01) in addition to exercise tolerance, systolic BP, total cholesterol, non-HDL cholesterol and m. vastus lateralis pennation angle, to the same extent. There was no improvement in these parameters in CON. There was no change in diastolic BP, glucose tolerance, whole-body composition or HDL cholesterol in any of the groups. CONCLUSIONS: This is the first study to show that short-term, time-efficient, equipment-free, HIIT is able to elicit improvements in the CRF of older adults irrespective of supervision status. Unsupervised HIIT may offer a novel approach to improve the physiological resilience of older adults, combating age-associated physiological decline, the rise of inactivity and the additional challenges currently posed by the COVID-19 pandemic. TRIAL REGISTRATION: This study was registered at clinicaltrials.gov and coded: NCT03473990 .

Curcumin Enhances Fed-State Muscle Microvascular Perfusion but Not Leg Glucose Uptake in Older Adults.

Therapeutic interventions aimed at enhancing blood flow may combat the postprandial vascular and metabolic dysfunction that manifests with chronological ageing. We compared the effects of acute curcumin (1000 mg) coupled with an oral nutritional supplement (ONS, 7.5 g protein, 24 g carbohydrate and 6 g fat) versus a placebo and ONS (control) on cerebral and leg macrovascular blood flow, leg muscle microvascular blood flow, brachial artery endothelial function, and leg insulin and glucose responses in healthy older adults (n = 12, 50% male, 73 ± 1 year). Curcumin enhanced m. tibialis anterior microvascular blood volume (MBV) at 180 and 240 min following the ONS (baseline: 1.0 vs. 180 min: 1.08 ± 0.02, p = 0.01 vs. 240 min: 1.08 ± 0.03, p = 0.01), and MBV was significantly higher compared with the control at both time points (p < 0.05). MBV increased from baseline in the m. vastus lateralis at 240 min after the ONS in both groups (p < 0.05), and there were no significant differences between groups. Following the ONS, leg blood flow and leg vascular conductance increased, and leg vascular resistance decreased similarly in both conditions (p < 0.05). Brachial artery flow-mediated dilation and middle cerebral artery blood flow were unchanged in both conditions (p > 0.05). Similarly, the curcumin and control groups demonstrated comparable increases in glucose uptake and insulin in response to the ONS. Thus, acute curcumin supplementation enhanced ONS-induced increases in m. tibialis anterior MBV without potentiating m. vastus lateralis MBV, muscle glucose uptake, or systemic endothelial or macrovascular function in healthy older adults.

Green Tea Extract Concurrent with an Oral Nutritional Supplement Acutely Enhances Muscle Microvascular Blood Flow without Altering Leg Glucose Uptake in Healthy Older Adults.

Postprandial macro- and microvascular blood flow and metabolic dysfunction manifest with advancing age, so vascular transmuting interventions are desirable. In this randomised, single-blind, placebo-controlled, crossover trial, we investigated the impact of the acute administration of green tea extract (GTE; containing ~500 mg epigallocatechin-3-gallate) versus placebo (CON), alongside an oral nutritional supplement (ONS), on muscle macro- and microvascular, cerebral macrovascular (via ultrasound) and leg glucose/insulin metabolic responses (via arterialised/venous blood samples) in twelve healthy older adults (42% male, 74 ± 1 y). GTE increased m. vastus lateralis microvascular blood volume (MBV) at 180 and 240 min after ONS (baseline: 1.0 vs. 180 min: 1.11 ± 0.02 vs. 240 min: 1.08 ± 0.04, both p < 0.005), with MBV significantly higher than CON at 180 min (p < 0.05). Neither the ONS nor the GTE impacted m. tibialis anterior perfusion (p > 0.05). Leg blood flow and vascular conductance increased, and vascular resistance decreased similarly in both conditions (p < 0.05). Small non-significant increases in brachial artery flow-mediated dilation were observed in the GTE only and middle cerebral artery blood flow did not change in response to GTE or CON (p > 0.05). Glucose uptake increased with the GTE only (0 min: 0.03 ± 0.01 vs. 35 min: 0.11 ± 0.02 mmol/min/leg, p = 0.007); however, glucose area under the curve and insulin kinetics were similar between conditions (p > 0.05). Acute GTE supplementation enhances MBV beyond the effects of an oral mixed meal, but this improved perfusion does not translate to increased leg muscle glucose uptake in healthy older adults.

Six weeks of high-intensity interval training enhances contractile activity induced vascular reactivity and skeletal muscle perfusion in older adults.

Impairments in muscle microvascular function are associated with the pathogenesis of sarcopenia and cardiovascular disease. High-intensity interval training (HIIT) is an intervention by which a myriad of beneficial skeletal muscle/cardiovascular adaptations have been reported across age, including capillarisation and improved endothelial function. Herein, we hypothesised that HIIT would enhance muscle microvascular blood flow and vascular reactivity to acute contractile activity in older adults, reflecting HIIT-induced vascular remodelling. In a randomised controlled-trial, twenty-five healthy older adults aged 65-85 years (mean BMI 27.0) were randomised to 6-week HIIT or a no-intervention control period of an equal duration. Measures of microvascular responses to a single bout of muscle contractions (i.e. knee extensions) were made in the m. vastus lateralis using contrast-enhanced ultrasound during a continuous intravenous infusion of Sonovue™ contrast agent, before and after the intervention period, with concomitant assessments of cardiorespiratory fitness and resting blood pressure. HIIT led to improvements in anaerobic threshold (13.2 ± 3.4 vs. 15.3 ± 3.8 ml/kg/min, P < 0.001), dynamic exercise capacity (145 ± 60 vs. 159 ± 59 W, P < 0.001) and resting (systolic) blood pressure (142 ± 15 vs. 133 ± 11 mmHg, P < 0.01). Notably, HIIT elicited significant increases in microvascular blood flow responses to acute contractile activity (1.8 ± 0.63 vs. 2.3 ± 0.8 (arbitrary contrast units (AU), P < 0.01)), with no change in any of these parameters observed in the control group. Six weeks HIIT improves skeletal muscle microvascular responsiveness to acute contractile activity in the form of active hyperaemia-induced by a single bout of resistance exercise. These findings likely reflect reports of enhanced large vessel distensibility, improved endothelial function, and muscle capillarisation following HIIT. Moreover, our findings illustrate that HIIT may be effective in mitigating deleterious alterations in muscle microvascular mediated aspects of sarcopenia.

A systematic review of the applications of Expert Systems (ES) and machine learning (ML) in clinical urology.

BACKGROUND: Testing a hypothesis for 'factors-outcome effect' is a common quest, but standard statistical regression analysis tools are rendered ineffective by data contaminated with too many noisy variables. Expert Systems (ES) can provide an alternative methodology in analysing data to identify variables with the highest correlation to the outcome. By applying their effective machine learning (ML) abilities, significant research time and costs can be saved. The study aims to systematically review the applications of ES in urological research and their methodological models for effective multi-variate analysis. Their domains, development and validity will be identified. METHODS: The PRISMA methodology was applied to formulate an effective method for data gathering and analysis. This study search included seven most relevant information sources: WEB OF SCIENCE, EMBASE, BIOSIS CITATION INDEX, SCOPUS, PUBMED, Google Scholar and MEDLINE. Eligible articles were included if they applied one of the known ML models for a clear urological research question involving multivariate analysis. Only articles with pertinent research methods in ES models were included. The analysed data included the system model, applications, input/output variables, target user, validation, and outcomes. Both ML models and the variable analysis were comparatively reported for each system. RESULTS: The search identified n = 1087 articles from all databases and n = 712 were eligible for examination against inclusion criteria. A total of 168 systems were finally included and systematically analysed demonstrating a recent increase in uptake of ES in academic urology in particular artificial neural networks with 31 systems. Most of the systems were applied in urological oncology (prostate cancer = 15, bladder cancer = 13) where diagnostic, prognostic and survival predictor markers were investigated. Due to the heterogeneity of models and their statistical tests, a meta-analysis was not feasible. CONCLUSION: ES utility offers an effective ML potential and their applications in research have demonstrated a valid model for multi-variate analysis. The complexity of their development can challenge their uptake in urological clinics whilst the limitation of the statistical tools in this domain has created a gap for further research studies. Integration of computer scientists in academic units has promoted the use of ES in clinical urological research.

Cocoa Flavanols Adjuvant to an Oral Nutritional Supplement Acutely Enhances Nutritive Flow in Skeletal Muscle without Altering Leg Glucose Uptake Kinetics in Older Adults.

Ageing is associated with postprandial muscle vascular and metabolic dysfunction, suggesting vascular modifying interventions may be of benefit. Reflecting this, we investigated the impact of acute cocoa flavanol (450-500 mg) intake (versus placebo control) on vascular (via ultrasound) and glucose/insulin metabolic responses (via arterialised/venous blood samples and ELISA) to an oral nutritional supplement (ONS) in twelve healthy older adults (50% male, 72 ± 4 years), in a crossover design study. The cocoa condition displayed significant increases in m. vastus lateralis microvascular blood volume (MBV) in response to feeding at 180 and 240-min after ONS consumption (baseline: 1.00 vs. 180 min: 1.09 ± 0.03, p = 0.05; 240 min: 1.13 ± 0.04, p = 0.002), with MBV at these timepoints significantly higher than in the control condition (p < 0.05). In addition, there was a trend (p = 0.058) for MBV in m. tibialis anterior to increase in response to ONS in the cocoa condition only. Leg blood flow and vascular conductance increased, and vascular resistance decreased in response to ONS (p < 0.05), but these responses were not different between conditions (p > 0.05). Similarly, glucose uptake and insulin increased in response to ONS (p < 0.05) comparably between conditions (p > 0.05). Thus, acute cocoa flavanol supplementation can potentiate oral feeding-induced increases in MBV in older adults, but this improvement does not relay to muscle glucose uptake.

The physiological impact of high-intensity interval training in octogenarians with comorbidities.

BACKGROUND: Declines in cardiorespiratory fitness (CRF) and fat-free mass (FFM) with age are linked to mortality, morbidity and poor quality of life. High-intensity interval training (HIIT) has been shown to improve CRF and FFM in many groups, but its efficacy in the very old, in whom comorbidities are present is undefined. We aimed to assess the efficacy of and physiological/metabolic responses to HIIT, in a cohort of octogenarians with comorbidities (e.g. hypertension and osteoarthritis). METHODS: Twenty-eight volunteers (18 men, 10 women, 81.2 ± 0.6 years, 27.1 ± 0.6 kg·m-2 ) with American Society of Anaesthesiology (ASA) Grade 2-3 status each completed 4 weeks (12 sessions) HIIT after a control period of equal duration. Before and after each 4 week period, subjects underwent body composition assessments and cardiopulmonary exercise testing. Quadriceps muscle biopsies (m. vastus lateralis) were taken to quantify anabolic signalling, mitochondrial oxidative phosphorylation, and cumulative muscle protein synthesis (MPS) over 4-weeks. RESULTS: In comorbid octogenarians, HIIT elicited improvements in CRF (anaerobic threshold: +1.2 ± 0.4 ml·kg-1 ·min-1 , P = 0.001). HIIT also augmented total FFM (47.2 ± 1.4 to 47.6 ± 1.3 kg, P = 0.04), while decreasing total fat mass (24.8 ± 1.3 to 24 ± 1.2 kg, P = 0.0002) and body fat percentage (33.1 ± 1.5 to 32.1 ± 1.4%, P = 0.0008). Mechanistically, mitochondrial oxidative phosphorylation capacity increased after HIIT (i.e. citrate synthase activity: 52.4 ± 4 to 67.9 ± 5.1 nmol·min-1 ·mg-1 , P = 0.005; membrane protein complexes (C): C-II, 1.4-fold increase, P = 0.002; C-III, 1.2-fold increase, P = 0.03), as did rates of MPS (1.3 ± 0.1 to 1.5 ± 0.1%·day-1 , P = 0.03). The increase in MPS was supported by up-regulated phosphorylation of anabolic signalling proteins (e.g. AKT, p70S6K, and 4E-BP1; all P < 0.05). There were no changes in any of these parameters during the control period. No adverse events were reported throughout the study. CONCLUSIONS: The HIIT enhances skeletal muscle mass and CRF in octogenarians with disease, with up-regulation of MPS and mitochondrial capacity likely underlying these improvements. HIIT can be safely delivered to octogenarians with disease and is an effective, time-efficient intervention to improve muscle mass and physical function in a short time frame.

Contrast-enhanced ultrasound assessed renal microvascular perfusion may predict postoperative renal complications following colorectal surgery.

Colorectal surgery is associated with an above-average mortality rate of approximately 15%. During surgery, maintenance of vital organ perfusion is essential in order to reduce postoperative mortality and morbidity, with renal perfusion of particular importance. Oesophageal Doppler monitors (ODM) are commonly used to try and provide accurate measures of fluid depletion during surgery; however, it is unclear to what extent they reflect organ perfusion. In addition, it is not known whether macro- and/ or microvascular perfusion indices are associated with renal complications following colorectal surgery. Thirty-two participants scheduled for colorectal surgery had three measures of macro- and microvascular renal blood flow via contrast enhanced ultrasound (CEUS), and simultaneous measures of cardiac output indices via ODM: (i) pre-operatively; (ii) intra-operatively at the mid-point of operation, and (iii) after the conclusion of surgery. The Postoperative Morbidity Survey (POMS) was used to assess postoperative complications. Intra-operatively, there was a significant correlation between renal microvascular flow (RT) and renal macrovascular flow (TTI) (ρ = 0.52; p = 0.003). Intra-operative TTI, but not RT, was associated with cardiac index (ρ = -0.50; p=0.0003). Intra-operative RT predicted increases in renal complications (OR 1.46; 95% CI 1.03-2.09) with good discrimination (C-statistic, 0.85). Complications were not predicted by TTI or ODM-derived indices. There was no relationship between RT and TTI before or after surgery. ODM measures of haemodynamic status do not correlate with renal microvascular blood flow, and as such are likely not suitable to determine vital organ perfusion. Only CEUS-derived measures of microvascular perfusion were predictive of postoperative renal complications.

Methodologies for systematic reviews with meta-analysis of randomised clinical trials in pain, anaesthesia, and perioperative medicine.

Systematic reviews and meta-analyses (SRMAs) are increasing in popularity, but should they be used to inform clinical decision-making in anaesthesia? We present evidence that the certainty of evidence from SRMAs in anaesthesia (and in general) may be unacceptably low because of risks of bias exaggerating treatment effects, unexplained heterogeneity reducing certainty in estimates, random errors, and widespread prevalence of publication bias. We also present the latest methodological advances to help improve the certainty of evidence from SRMAs. The target audience includes both review authors and practising clinicians to help with SRMA appraisal. Issues discussed include minimising risks of bias from included trials, trial sequential analysis to reduce random error, updated methods for presenting effect estimates, and novel publication bias tests for commonly used outcome measures. These methods can help to reduce spurious conclusions on clinical significance, explain statistical heterogeneity, and reduce false positives when evaluating small-study effects. By reducing concerns in these domains of Grading of Recommendations, Assessment, Development and Evaluation, it should help improve the certainty of evidence from SRMAs used for decision-making in anaesthesia, pain, and perioperative medicine.

Time-efficient physical activity interventions to reduce blood pressure in older adults: a randomised controlled trial.

BACKGROUND: Hypertension is a risk factor for both cardiovascular and cerebrovascular disease, with an increasing incidence with advancing patient age. Exercise interventions have the potential to reduce blood pressure in older adults, however, rates of exercise uptake and adherence are low, with 'lack of time' a commonly cited reason. As such, there remains the need for time-efficient physical activity interventions to reduce blood pressure in older adults. OBJECTIVE: To compare the effect of three, novel time-efficient physical activity interventions on resting blood pressure in older adults. METHODS: Forty-eight, healthy, community-dwelling older adults (mean age: 71 years) were recruited to a 6-week randomised control trial. Resting blood pressure was measured before and after one of three supervised, time-efficient interventions: high-intensity interval training (HIIT) on a cycle ergometer; isometric handgrip training (IHG); unilateral, upper limb remote ischaemic preconditioning (RIPC) or non-intervention control. RESULTS: Both HIIT and IHG led to a statistically significant reduction in resting systolic blood pressure (SBP) of 9 mmHg, with no significant change in the RIPC or control groups. There was no change in diastolic blood pressure or pulse pressure in any group. CONCLUSIONS: Supervised HIIT or IHG using the protocols described in this study can lead to statistically significant and clinically relevant reductions in resting SBP in healthy older adults in just 6 weeks.

Funnel plots may show asymmetry in the absence of publication bias with continuous outcomes dependent on baseline risk: presentation of a new publication bias test.

This study aimed to determine for continuous outcomes dependent on baseline risk, whether funnel plot asymmetry may be due to statistical artefact rather than publication bias and evaluate a novel test to resolve this. Firstly, we conducted assessment for publication bias in nine meta-analyses of postoperative analgesics (344 trials with 25 348 participants). Secondly, we attempted to resolve the observed asymmetry by considering meta-regression residuals as outcome (rather than mean difference) and (inverse) sample size as the exploratory variable (rather than SE). Since the approach resolved the asymmetry, we evaluated it, and related approaches, using a simulation study considering four scenarios comprised of every combination of baseline interactions and absolute selective publication bias being present or not (10 000 simulated meta-analyses per scenario with no residual between-study heterogeneity). The test based on meta-regression residuals and inverse sample size performed as well as conventional tests (Egger's test) when no baseline risk was present and reduced type I errors when baseline risk was present. It also had modest power to detect publication bias in the presence of baseline risk. We demonstrated that correlation between effect estimates and SEs produces funnel plot asymmetry in the presence of no publication bias for continuous outcomes dependent on baseline risk. Our novel approach of assessing funnel plot asymmetry using a modified funnel plot and test based on residuals and inverse sample size may have improved performance when carrying out publication bias assessments for unstandardized mean differences where treatment effects are dependent on baseline risk.

Network analysis of human muscle adaptation to aging and contraction.

Resistance exercise (RE) remains a primary approach for minimising aging muscle decline. Understanding muscle adaptation to individual contractile components of RE (eccentric, concentric) might optimise RE-based intervention strategies. Herein, we employed a network-driven pipeline to identify putative molecular drivers of muscle aging and contraction mode responses. RNA-sequencing data was generated from young (21±1 y) and older (70±1 y) human skeletal muscle before and following acute unilateral concentric and contralateral eccentric contractions. Application of weighted gene co-expression network analysis identified 33 distinct gene clusters ('modules') with an expression profile regulated by aging, contraction and/or linked to muscle strength. These included two contraction 'responsive' modules (related to 'cell adhesion' and 'transcription factor' processes) that also correlated with the magnitude of post-exercise muscle strength decline. Module searches for 'hub' genes and enriched transcription factor binding sites established a refined set of candidate module-regulatory molecules (536 hub genes and 60 transcription factors) as possible contributors to muscle aging and/or contraction responses. Thus, network-driven analysis can identify new molecular candidates of functional relevance to muscle aging and contraction mode adaptations.

The time course of physiological adaptations to high-intensity interval training in older adults.

OBJECTIVE: High-intensity interval training (HIIT) has been shown to be more effective than moderate continuous aerobic exercise for improving cardiorespiratory fitness (CRF) in a limited time frame. However, the length of time required for HIIT to elicit clinically significant improvements in the CRF of older adults is currently unknown. The aim of this study was to compare changes in the CRF of older adults completing identical HIIT protocols of varying durations. METHODS: Forty healthy, community-dwelling older adults completed a cardiopulmonary exercise test (CPET) before and after 2, 4, or 6 weeks of fully supervised HIIT on a cycle ergometer, or a no-intervention control period. RESULTS: Anaerobic threshold (AT) was increased only after 4 (+1.9 [SD 1.1] mL/kg/min) and 6 weeks (+1.9 [SD 1.8] mL/kg/min) of HIIT (both P < 0.001), with 6-week HIIT required to elicit improvements in VO2 peak (+3.0 [SD 6] mL/kg/min; P = 0.04). Exercise tolerance increased after 2 (+15 [SD 15] W), 4 (+17 [SD 11] W), and 6 weeks (+16 [SD 11] W) of HIIT (all P < 0.001), with no difference in increase between the groups. There were no changes in any parameter in the control group. CONCLUSION: Improvements in exercise tolerance from HIIT precede changes in CRF. Just 4 weeks of a well-tolerated, reduced-exertion HIIT protocol are required to produce significant changes in AT, with a further 2 weeks of training also eliciting improvements in VO2 peak.

A double-blind randomized controlled trial of the effects of eicosapentaenoic acid supplementation on muscle inflammation and physical function in patients undergoing colorectal cancer resection.

BACKGROUND: Resection of colorectal cancer (CRC) initiates inflammation, mediated at least partly by NFĸB (nuclear factor kappa-light-chain-enhancer of activated B-cells), leading to muscle catabolism and reduced physical performance. Eicosapentaenoic acid (EPA) has been shown to modulate NFĸB, but evidence for its benefit around the time of surgery is limited. OBJECTIVE: To assess the effect of EPA supplementation on muscle inflammation and physical function around the time of major surgery. DESIGN: In a double-blind randomized control trial, 61 patients (age: 68.3 ± 0.95 y; 42 male) scheduled for CRC resection, received 3 g per day of EPA (n = 32) or placebo (n = 29) for 5-days before and 21-days after operation. Lean muscle mass (LMM) (via dual energy X-ray absorptiometry (DXA)), anaerobic threshold (AT) (via cardiopulmonary exercise testing (CPET)) and hand-grip strength (HG) were assessed before and 4-weeks after surgery, with muscle biopsies (m. vastus lateralis) obtained for the assessment of NF-ĸB protein expression. RESULTS: There were no differences in muscle NFĸB between EPA and placebo groups (mean difference (MD) -0.002; 95% confidence interval (CI) -0.19 to 0.19); p = 0.98). There was no difference in LMM (MD 704.77 g; 95% CI -1045.6 g-2455.13 g; p = 0.42) or AT (MD 1.11 mls/kg/min; 95% CI -0.52 mls/kg/min to 2.74 mls/kg/min; p = 0.18) between the groups. Similarly, there was no difference between the groups in HG at follow up (MD 0.1; 95% CI -1.88 to 2.08; p = 0.81). Results were similar when missing data was imputed. CONCLUSION: EPA supplementation confers no benefit in terms of inflammatory status, as judged by NFĸB, or preservation of LMM, aerobic capacity or physical function following major colorectal surgery. CLINICAL TRIALS REFERENCE: NCT01320319.