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NEW FINDINGS: What is the central question of this study? Are biomarkers of endothelial function, oxidative stress and inflammation altered by non-freezing cold injury (NFCI)? What is the main finding and its importance? Baseline plasma [interleukin-10] and [syndecan-1] were elevated in individuals with NFCI and cold-exposed control participants. Increased [endothelin-1] following thermal challenges might explain, in part, the increased pain/discomfort experienced with NFCI. Mild to moderate chronic NFCI does not appear to be associated with either oxidative stress or a pro-inflammatory state. Baseline [interleukin-10] and [syndecan-1] and post-heating [endothelin-1] are the most promising candidates for diagnosis of NFCI. ABSTRACT: Plasma biomarkers of inflammation, oxidative stress, endothelial function and damage were examined in 16 individuals with chronic NFCI (NFCI) and matched control participants with (COLD, n = 17) or without (CON, n = 14) previous cold exposure. Venous blood samples were collected at baseline to assess plasma biomarkers of endothelial function (nitrate, nitrite and endothelin-1), inflammation [interleukin-6 (IL-6), interleukin-10 (IL-10), tumour necrosis factor alpha and E-selectin], oxidative stress [protein carbonyl, 4-hydroxy-2-nonenal (4-HNE), superoxide dismutase and nitrotyrosine) and endothelial damage [von Willebrand factor, syndecan-1 and tissue type plasminogen activator (TTPA)]. Immediately after whole-body heating and separately, foot cooling, blood samples were taken for measurement of plasma [nitrate], [nitrite], [endothelin-1], [IL-6], [4-HNE] and [TTPA]. At baseline, [IL-10] and [syndecan-1] were increased in NFCI (P < 0.001 and P = 0.015, respectively) and COLD (P = 0.033 and P = 0.030, respectively) compared with CON participants. The [4-HNE] was elevated in CON compared with both NFCI (P = 0.002) and COLD (P < 0.001). [Endothelin-1] was elevated in NFCI compared with COLD (P < 0.001) post-heating. The [4-HNE] was lower in NFCI compared with CON post-heating (P = 0.032) and lower than both COLD (P = 0.02) and CON (P = 0.015) post-cooling. No between-group differences were seen for the other biomarkers. Mild to moderate chronic NFCI does not appear to be associated with a pro-inflammatory state or oxidative stress. Baseline [IL-10] and [syndecan-1] and post-heating [endothelin-1] are the most promising candidates for diagnosing NFCI, but it is likely that a combination of tests will be required.

Elexacaftor/Tezacaftor/Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator with the potential to improve exercise capacity. This case series of three adolescents with CF aimed to investigate whether 6 weeks treatment with Elexacaftor/Tezacaftor/Ivacaftor could improve exercise capacity in CFTR modulator naive adolescents with CF.Three adolescents (14.0 ± 1.4 years) with CF (FEVClinically meaningful improvements inmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:movermml:miV/mml:mimml:mȯ/mml:mo/mml:mover/mml:mrowmml:annotation$\dot{{\rm{V}}}$/mml:annotation/mml:semantics/mml:mathOIn this case series, we have observed, for the first time, improvements in exercise capacity following 6 weeks of treatment with Elexacaftor/Tezacaftor/Ivacaftor. Improvements were greatest in the presence of more severe CF lung disease and lower aerobic fitness at baseline. The mechanism(s) responsible for these changes warrant further investigation in larger trials.

Background Treatment of end-stage renal disease (ESRD) is necessary to maintain life. However, it can cause physiological, psychosocial, and cognitive impairments, which may impact physical activity (PA) and sleep, although there is insufficient device-based data to elucidate such impacts. Methods PA, sedentary time (SED), and sleep were measured over 7 consecutive days in 12 adults with ESRD (9 dialyzing at home, 3 dialyzing in center) using wrist-worn accelerometers. Validated raw acceleration thresholds were used to quantify time spent in each PA intensity domain and SED, and sleep duration and efficiency. Results Adults with ESRD engaged in little moderate-to-vigorous PA (MVPA; 6.9 ± 9.7 min·d−1) and spent 770.0 ± 68.6 min·d−1 SED. People dialyzing at home engaged in more light-intensity PA than those attending in center (131.2 ± 28.1 versus 106.9 ± 5.4 min·d−1, respectively; P = 0.05); however, neither group met the recommended guidelines for daily MVPA. Individuals with ESRD slept for an average of 286.8 ± 79.3 min·night−1 with an efficiency of 68.4 ± 18.5%, although people dialyzing at home slept for longer and more efficiently (74.5% versus 50.0%, P = 0.07) than those attending in center. Conclusion In this study, we suggest that adults with ESRD engage in less total PA than recommended guidelines and are characterized by poor sleep duration and efficiency. Moreover, results indicate that dialysis mode may influence PA, SED, and sleep, with those dialyzing at home engaging in greater leisure time PA and achieving a greater sleep duration and efficiency.

When people with chronic kidney disease reach kidney failure, renal replacement therapy is usually required to improve symptoms and maintain life. Although in-centre haemodialysis is most commonly used for this purpose, other forms of dialysis are available, including home haemodialysis and peritoneal dialysis.We aimed to explore the experiences of adults living with chronic kidney disease who were either approaching the need for dialysis or had reached kidney failure and were receiving a form of dialysis. In particular, we explored how different forms of dialysis affect their quality of life, wellbeing, and physical activity.Individual semistructured interviews were conducted with 40 adults with kidney failure, comprising four groups (n = 10 each): those receiving in-centre haemodialysis, home haemodialysis or peritoneal dialysis, or predialysis. Interviews were transcribed verbatim, thematically analysed, and then composite vignettes were subsequently developed to present a rich narrative of the collective experiences of each group.Compared with adults who were predialysis, quality of life and wellbeing improved upon initiation of their home haemodialysis or peritoneal dialysis. Conversely, minimal improvement was perceived by those receiving in-centre haemodialysis. Low physical activity was reported across all four groups, although those receiving home haemodialysis and peritoneal dialysis reported a greater desire and ability to be physically active than those in-centre.These findings highlight that dialysis modalities not requiring regular hospital attendance (i.e., home haemodialysis and peritoneal dialysis) improve independence, quality of life, wellbeing, and can facilitate a more physically active lifestyle.

Although kidney transplantation is the best treatment for kidney failure, scarce research has examined its effects on physical activity, physical function and quality of life.To investigate the experiences of a group of adults living with advanced kidney disease focusing on quality of life, physical activity and function and to see how findings differ in a group of kidney transplant recipients.Individual semi-structured interviews were conducted with adults with advanced kidney disease (n = 10; 70.5 ± 8.9 years) and adults who had received a kidney transplant (n = 10; 50.7 ± 11.5 years; transplant age: 42.7 ± 20.9 months). Interviews were transcribed verbatim, thematically analysed and composite vignettes developed.Individuals with advanced kidney disease described a sense of loss and alteration to their life plans. Kidney transplant recipients reported increased freedom, independence and a return to near normality, with improved quality of life, physical activity and function compared with their pre-transplant lives. However, transplant recipients also described living with anxiety about the health of their transplant and fear it may fail.Whilst adults living with advanced kidney disease often experience a reduced quality of life, physical activity and function, kidney transplantation can help facilitate a return to pre-disease levels of physical activity, physical function and quality of life. However, transplant recipients also reported living with anxiety around their new kidney failing. This study demonstrates the variability in the lived experiences of adults living with advanced kidney disease or a kidney transplant and highlights the need for patient-centred care.

Background: The development of cystic fibrosis (CF)-related diabetes (CFRD) in paediatric groups is associated with a reduced aerobic fitness. However, this has yet to be investigated in adults with more severe lung disease.Methods: Cardiopulmonary exercise and glycaemic control tests were retrospectively analysed in 46 adults with CF (age: 26.9 y [range: 16.3–66.5 y]; forced expiratory volume in 1s: 65.3% [range: 26.8–105.7%]; 26 males), diagnosed with CFRD (n = 19), impaired glucose tolerance (IGT; n = 8) or normal glucose tolerance (NGT; n = 19). Results: Maximal oxygen uptake (V ̇O2max) was reduced in adults with IGT and CFRD compared to their age- and gender-matched counterparts with NGT (p < 0.05); however, there was no difference when lung function was included as a covariate (all p > 0.05). V ̇O2max was greater in adults who experienced post-reactive hypoglycaemia vs. NGT without hypoglycaemia (p < 0.05). The frequency of ventilatory limitation (84%, 63% and 37%, respectively; p < 0.05) but not ventilation-perfusion mismatch (42%, 38% and 16%, respectively; p > 0.05), was greater with CFRD and IGT vs. NGT. There was also no difference in arterial oxygen saturation changes between groups (p > 0.05). Gender and body mass index were significant predictors of V ̇O2max (adjusted R2 = 0.37, p < 0.01), but glycaemic control did not explain additional variance (p > 0.05).Conclusions: Adults with CF-related dysglycaemia had a reduced V ̇O2max compared to age- and gender-matched counterparts, due to a greater degree of CF lung disease in these populations.

Micro‐ and macrovascular endothelial dysfunction in response to shear stress has been observed in cystic fibrosis (CF), and has been associated with inflammation and oxidative stress. We tested the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) regulates endothelial actin cytoskeleton dynamics and cellular alignment in response to flow. Human lung microvascular endothelial cells (HLMVEC) were cultured with either the CFTR inhibitor GlyH‐101 (20 µM) or CFTRinh‐172 (20 µM), tumor necrosis factor (TNF)‐α (10 ng/ml) or a vehicle control (0.1% dimethyl sulfoxide) during 24 and 48 h of exposure to shear stress (11.1 dynes/cm2) or under static control conditions. Cellular morphology and filamentous actin (F‐actin) were assessed using immunocytochemistry. [Nitrite] and endothelin‐1 ([ET‐1]) were determined in cell culture supernatant by ozone‐based chemiluminescence and ELISA, respectively. Treatment of HLMVECs with both CFTR inhibitors prevented alignment of HLMVEC in the direction of flow after 24 and 48 h of shear stress, compared to vehicle control (both p 0.05). CFTR appears to limit cytosolic actin polymerization, while maintaining a cortical rim actin distribution that is important for maintaining barrier integrity and promoting alignment with flow, without effects on endothelial nitrite or ET‐1 production., Cystic fibrosis transmembrane conductance regulator (CFTR) in human lung microvascular endothelial cells (HLMVEC) appears to limit cytosolic actin polymerization while maintaining a cortical rim filamentous actin (F‐actin) distribution, as demonstrated by staining F‐actin with rhodamine phalloidin (red) under static conditions in the absence and presence of the CFTR inhibitor GlyH‐101. The CFTR inhibitor induced loss of the cortical rim F‐actin leading to loss of cell‐cell contacts and reduced alignment with flow, without effects on endothelial nitrite or endothelin‐1 production.

Purpose Hemiparesis and physical deconditioning following stroke lead to an increase in falls, which many individuals cannot get up from. Teaching stroke survivors to independently get off the floor (IGO) might mitigate long-lie complications. IGO was taught as part of a community-based, functional rehabilitation training programme (ReTrain). We explore the feasibility of teaching IGO and assess participant's level of mastery, adherence, and injury risk. Materials and methods Videos of participants (n = 17) performing IGO at early, middle, and late stages of the ReTrain programme were compared to a manualised standard. A visual, qualitative analysis was used to assess technique mastery, adherence, and injury risk. Results Most participants (64%) achieved independent, safe practice of IGO. A good (73%) level of adherence to IGO and low incidence of risk of injury (6.8%) were observed. Deviations were made to accommodate for non-stroke related comorbidities. Conclusions IGO was successfully and safely practised by stroke survivors including those with hemiparesis. Trainers should be aware of comorbidities that may impede completion of IGO and modify teaching to accommodate individual need. Further research should assess if IGO can be utilised by individuals who have other disabilities with unilateral impairments and whether IGO has physical, functional and economic benefit.Implications for rehabilitationFalls are common in stroke survivors, and many are unable to get up despite being uninjured, leading to long-lie complications or ambulance call-outs but non-conveyance to hospital.Teaching the independently getting up off the floor (IGO) technique to stroke survivors was possible for those with or without hemiparesis, and remained safe despite modifications to accommodate an individual's needs.Individual assessment is needed to check if a stroke survivor is suitable for learning IGO including, but not limited to, their ability to safely get to the floor and to temporarily stand (without support) at the end of the technique.

Background Pelvic surgery has the potential to leave behind a large raw surface, which can bleed and ooze postoperatively. The adoption of precision surgical approach for rectal cancers has led to reduction in blood loss. We aimed to assess 1) the feasibility and 2) the safety of using a self-assembling peptide (SAP) haemostatic agent (PuraStat®) after rectal cancer surgery to reduce the incidence of pelvic collections. Materials and methods This prospective cohort pilot study compared the results of 25 consecutive cases of total mesorectal excision (TME) with use of 5–10 ml of SAP, and 25 consecutive cases without PuraStat® application (CON, control group). The groups were compared for complications (Clavien-Dindo grade III and IV classification), postoperative drain output and length of hospital stay (LOS). Statistical analysis was carried out using paired samples T test and Fisher's exact test Results Fifty patients (SAP = 25, CON = 25) were enrolled into this study. Mean drain outputs (ml) on day 1, day 2 and day 3 were 60 ± 18, 89 ± 42 and 64 ± 45 in SAP group, and 102 ± 31, 95 ± 52, 66 ± 37 in CON group. This was significantly better for SAP group in day one after surgery. The mean LOS was shorter in SAP group (5.7 versus 7.4 days in CON, p 0.04). Clavien-Dindo III & IV complications were seen in two and five cases respectively (p 0.18). R0 resection rate (p 0.32) and lymph node harvest (p 0.13) were similar in both groups. There were no complications seen in relation to the application of the SAP. Conclusions These initial data suggest that SAP is a safe product, and feasible to apply in the pelvis after TME surgery. It appears to shorten the LOS and reduce the postoperative drain output and may reduce the incidence of Clavien-Dindo grade III & IV complications., Highlights • This is a first study to evaluate role of haemostatic agents in robotic colorectal surgery to reduce postoperative bleeding. • We have demonstrated the use of this novel gel is associated with significantly reduced pelvic drain output after surgery. • It has also highlighted a reduction in the length of stay, and possibly in the rate of postoperative complications. • Further studies are necessary to establish the efficacy of prophylactic application of this gel after TME surgery for cancer.

Background Dietary inorganic nitrate (NO3−) is a polyatomic ion, which is present in large quantities in green leafy vegetables and beetroot, and has attracted considerable attention in recent years as a potential health-promoting dietary compound. Numerous small, well-controlled laboratory studies have reported beneficial health effects of inorganic NO3− consumption on blood pressure, endothelial function, cerebrovascular blood flow, cognitive function, and exercise performance. Translating the findings from small laboratory studies into ‘real-world’ applications requires careful consideration. Main body This article provides a brief overview of the existing empirical evidence basis for the purported health-promoting effects of dietary NO3− consumption. Key areas for future research are then proposed to evaluate whether promising findings observed in small animal and human laboratory studies can effectively translate into clinically relevant improvements in population health. These proposals include: 1) conducting large-scale, longer duration trials with hard clinical endpoints (e.g. cardiovascular disease incidence); 2) exploring the feasibility and acceptability of different strategies to facilitate a prolonged increase in dietary NO3− intake; 3) exploitation of existing cohort studies to explore associations between NO3− intake and health outcomes, a research approach allowing larger samples sizes and longer duration follow up than is feasible in randomised controlled trials; 4) identifying factors which might account for individual differences in the response to inorganic NO3− (e.g. sex, genetics, habitual diet) and could assist with targeted/personalised nutritional interventions; 5) exploring the influence of oral health and medication on the therapeutic potential of NO3− supplementation; and 6) examining potential risk of adverse events with long term high- NO3− diets. Conclusion The salutary effects of dietary NO3− are well established in small, well-controlled laboratory studies. Much less is known about the feasibility and efficacy of long-term dietary NO3− enrichment for promoting health, and the factors which might explain the variable responsiveness to dietary NO3− supplementation between individuals. Future research focussing on the translation of laboratory data will provide valuable insight into the potential applications of dietary NO3− supplementation to improve population health.

Early in the coronavirus-2019 (COVID-19) containment strategy, people with end-stage renal disease (ESRD) were identified as extremely clinically vulnerable and subsequently asked to ‘shield’ at home where possible. The aim of this study was to investigate how these restrictions and the transition to an increased reliance on telemedicine within clinical care of people living with kidney disease impacted the physical activity (PA), wellbeing and quality of life (QoL) of adults dialysing at home (HHD) or receiving in-centre haemodialysis (ICHD) in the UK. Individual semistructured telephone interviews were conducted with adults receiving HHD (n = 10) or ICHD (n = 10), were transcribed verbatim and, subsequently, thematically analysed. As result of the COVID-19 restrictions, PA, wellbeing and QoL of people with ESRD were found to have been hindered. However, widespread support for the continued use of telemedicine was strongly advocated and promoted independence and satisfaction in patient care. These findings highlight the need for more proactive care of people with ESRD if asked to shield again, as well as increased awareness of safe and appropriate PA resources to help with home-based PA and emotional wellbeing.

This is the first study to investigate the timing of acute passive heating on glucose tolerance and extracellular heat shock protein 70 concentration ([eHSP70]) in people with type 2 diabetes. The principal novel findings from this study were that both passive heating conditions: 1) did not reduce the area under the curve or peak blood glucose concentration, 2) elevated heart rate, and 3) increased [eHSP70], which was blunted by glucose ingestion, while passive heating following glucose ingestion, 4) increased total energy expenditure, and 5) reduced diastolic blood pressure.

Background: Perturbation of endothelial function in people with cystic fibrosis (CF) has been reported, which may be associated with endothelial cell expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Previous reports indicate that CFTR activity upregulates endothelial barrier function, endothelial nitric oxide synthase (eNOS) expression and NO release, while limiting interleukin-8 (IL-8) release, in human umbilical vein endothelial cells (HUVECs) in cell culture. In view of reported microvascular dysfunction in people with CF we investigated the role of CFTR expression and activity in the regulation of oxidative stress, cell signaling and inflammation in human lung microvascular endothelial cells (HLMVECs) in cell culture.Methods: HLMVECs were cultured in the absence and presence of the CFTR inhibitor GlyH-101 and CFTR siRNA. CFTR expression was analyzed using qRT-PCR, immunocytochemistry (IHC) and western blot, and function by membrane potential assay. IL-8 expression was analyzed using qRT-PCR and ELISA. Nrf2 expression, and NF-κB and AP-1 activation were determined using IHC and western blot. The role of the epidermal growth factor receptor (EGFR) in CFTR signaling was investigated using the EGFR tyrosine kinase inhibitor AG1478. Oxidative stress was measured as intracellular ROS and hydrogen peroxide (H2O2) concentration. VEGF and SOD-2 were measured in culture supernatants by ELISA.Results: HLMVECs express low levels of CFTR that increase following inhibition of CFTR activity. Inhibition of CFTR, significantly increased intracellular ROS and H2O2 levels over 30 min and significantly decreased Nrf2 expression by 70% while increasing SOD-2 expression over 24 h. CFTR siRNA significantly increased constitutive expression of IL-8 by HLMVECs. CFTR inhibition activated the AP-1 pathway and increased IL-8 expression, without effect on NF-κB activity. Conversely, TNF-α activated the NF-κB pathway and increased IL-8 expression. The effects of TNF-α and GlyH-101 on IL-8 expression were additive and inhibited by AG1478. Inhibition of both CFTR and EGFR in HLMVECs significantly increased VEGF expression. The antioxidant N-acetyl cysteine significantly reduced ROS production and the increase in IL-8 and VEGF expression following CFTR inhibition.Conclusion: Functional endothelial CFTR limits oxidative stress and contributes to the normal anti-inflammatory state of HLMVECs. Therapeutic strategies to restore endothelial CFTR function in CF are warranted.

The validity and safety of using supramaximal verification (Smax) to confirm a maximal effort during cardiopulmonary exercise testing (CPET) in people with cystic fibrosis (CF) and/or those with severe disease has been questioned. Therefore, this study aimed to investigate these concerns in children, adolescents, and adults with mild-to-severe CF lung disease. Retrospective analysis of 17 pediatric and 28 adult participants with CF [age range: 9.2–62.9 y; forced expiratory volume in 1 s: 66.7% (range: 29.9%–102.3%); 30 men] who completed a routine ramp-incremental cycling test to determine peak oxygen uptake (V̇o2peak) was studied. Maximal oxygen uptake (V̇o2max) was subsequently confirmed by Smax at 110% of peak power output. All participants satisfied the criteria to verify a maximal effort during CPET. However, Smax-V̇o2peak exceeded ramp-V̇o2peak in 3/14 (21.4%) of pediatric and 6/28 (21.4%) adult exercise tests. A valid measurement of V̇o2max was attained in 85.7% of pediatric and 96.4% of adult exercise tests, as Smax-V̇o2peak did not exceed ramp-V̇o2peak by >9%. Adults ( n = 9) experienced a ≥5% reduction in arterial O2 saturation during CPET, 4 during both the ramp and Smax, 3 during only the ramp, and 2 during only Smax. Smax did not significantly worsen perceived breathing effort, chest tightness, throat narrowing, or exertion compared with ramp-incremental testing. Given the clinical importance of aerobic fitness in people with CF, incorporating Smax is recommended to provide a safe and valid measure of V̇o2max in children, adolescents, and adults who span the spectrum of CF disease severity. NEW & NOTEWORTHY Incorporating supramaximal verification into cardiopulmonary exercise testing protocols did not increase the frequency of adverse events or perceived discomfort versus a single-phase incremental exercise test in people with mild-to-severe cystic fibrosis. Furthermore, a valid measure of maximal oxygen uptake (V̇o2max) was obtained from 85.7% of pediatric and 96.4% of adult exercise tests, whereas peak oxygen uptake underestimated aerobic fitness in comparison with V̇o2max in 21.4% of cases (by up to 24.4%).

Raynaud’s phenomenon (RP) is characterized by recurrent transient peripheral vasospasm and lower nitric oxide (NO) bioavailability in the cold. We investigated the effect of nitrate-rich beetroot juice (BJ) supplementation on 1) NO-mediated vasodilation, 2) cutaneous vascular conductance (CVC) and skin temperature (Tsk) following local cooling, and 3) systemic anti-inflammatory status. Following baseline testing, 23 individuals with RP attended four times, in a double-blind, randomized crossover design, following acute and chronic (14 days) BJ and nitrate-depleted beetroot juice (NDBJ) supplementation. Peripheral Tskand CVC were measured during and after mild hand and foot cooling, and during transdermal delivery of acetylcholine and sodium nitroprusside. Markers of anti-inflammatory status were also measured. Plasma nitrite concentration ([nitrite]) was increased in the BJ conditions ( P < 0.001). Compared with the baseline visit, thumb CVC was greater following chronic-BJ (Δ2.0 flux/mmHg, P = 0.02) and chronic-NDBJ (Δ1.45 flux/mmHg, P = 0.01) supplementation; however, no changes in Tskwere observed ( P > 0.05). Plasma [interleukin-10] was greater, pan endothelin and systolic and diastolic blood pressure (BP) were reduced, and forearm endothelial function was improved, by both BJ and NDBJ supplementation ( P < 0.05). Acute and chronic BJ and NDBJ supplementation improved anti-inflammatory status, endothelial function and blood pressure (BP). CVC following cooling increased post chronic-BJ and chronic-NDBJ supplementation, but no effect on Tskwas observed. The key findings are that beetroot supplementation improves thumb blood flow, improves endothelial function and anti-inflammatory status, and reduces BP in people with Raynaud’s.NEW & NOTEWORTHY This is the first study to examine the effect of dietary nitrate supplementation in individuals with Raynaud’s phenomenon. The principal novel findings from this study were that both beetroot juice and nitrate-depleted beetroot juice 1) increased blood flow in the thumb following a cold challenge; 2) enhanced endothelium-dependent and -independent vasodilation in the forearm; 3) reduced systolic and diastolic blood pressure, and pan-endothelin concentration; and 4) improved inflammatory status in comparison to baseline.

The validity and safety of using supramaximal verification (S

Rehabilitation Training (ReTrain) is a group-based approach to functional training post stroke. ReTrain has recently been evaluated through a pilot randomised controlled trial.ObjectiveThis article reports on the acceptability of the intervention as described by trial participants.DesignA qualitative approach was undertaken. Of the 45 participants recruited into the trial, 23 were randomised to receive ReTrain. Following a sampling strategy, 10 participants undertook 1:1 semistructured audio-recorded interviews. Transcripts were analysed following a modified Framework Approach.ResultsSix themes were developed including exploration of: the physical and psychological impacts of training,the perceived mechanisms of change, the interaction of the group and approach of the trainer. A further theme considered the reported longer term impact of participation. Overall, the results indicated the acceptability of the intervention, but also key areas for potential modification in the definitive trial. These include a need to consider potential impact on both physical and psychological function, careful consideration of dosing and fatigue and the interpersonal factors that facilitate appropriate level of delivery, the trainer to participant ratio, and enhancing features that support continuation of activity postintervention.ConclusionOverall, this study supports the acceptability of ReTrain and the development of a definitive trial evaluation of this intervention to full.Trial registration numberNCT02429180.

Stroke can lead to physiological and psychological impairments and impact individuals’ physical activity (PA), fatigue and sleep patterns. We analysed wrist-worn accelerometry data and the Fatigue Assessment Scale from 41 stroke survivors following a physical rehabilitation programme, to examine relationships between PA levels, fatigue and sleep. Validated acceleration thresholds were used to quantify time spent in each PA intensity/sleep category. Stroke survivors performed less moderate to vigorous PA (MVPA) in 10 minute bouts than the National Stroke guidelines recommend. Regression analysis revealed associations at baseline between light PA and fatigue (p = 0.02) and MVPA and sleep efficiency (p = 0.04). Light PA was positively associated with fatigue at 6 months (p = 0.03), whilst sleep efficiency and fatigue were associated at 9 months (p = 0.02). No other effects were shown at baseline, 6 or 9 months. The magnitude of these associations were small and are unlikely to be clinically meaningful. Larger trials need to examine the efficacy and utility of accelerometry to assess PA and sleep in stroke survivors Stroke Association for funding this research (TSA – 2014-03) and the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula at the Royal Devon and Exeter NHS Foundation Trust

ObjectivesTo assess acceptability and feasibility of trial processes and the Rehabilitation Training (ReTrain) intervention including an assessment of intervention fidelity.DesignA two-group, assessor-blinded, randomised controlled trial with parallel mixed methods process and economic evaluations.SettingCommunity settings across two sites in Devon.ParticipantsEligible participants were: 18 years old or over, with a diagnosis of stroke and with self-reported mobility issues, no contraindications to physical activity, discharged from National Health Service or any other formal rehabilitation programme at least 1 month before, willing to be randomised to either control or ReTrain and attend the training venue, possessing cognitive capacity and communication ability sufficient to participate. Participants were individually randomised (1:1) via a computer-generated randomisation sequence minimised for time since stroke and level of functional disability. Only outcome assessors independent of the research team were blinded to group allocation.InterventionsReTrain comprised (1) an introductory one-to-one session; (2) ten, twice-weekly group classes with up to two trainers and eight clients; (3) a closing one-to-one session, followed by three drop-in sessions over the subsequent 3 months. Participants received a bespoke home-based training programme. All participants received treatment as usual. The control group received an exercise after stroke advice booklet.Outcome measuresCandidate primary outcomes included functional mobility and physical activity.ResultsForty-five participants were randomised (ReTrain=23; Control=22); data were available from 40 participants at 6 months of follow-up (ReTrain=21; Control=19) and 41 at 9 months of follow-up (ReTrain=21; Control=20). We demonstrated ability to recruit and retain participants. Participants were not burdened by the requirements of the study. We were able to calculate sample estimates for candidate primary outcomes and test procedures for process and health economic evaluations.ConclusionsAll objectives were fulfilled and indicated that a definitive trial of ReTrain is feasible and acceptable.Trial registration numberNCT02429180; Results.

Background - Chronic obstructive pulmonary disease (COPD) results in exercise intolerance. Dietary nitrate supplementation has been shown to lower blood pressure (BP), reduce the oxygen cost of exercise, and enhance exercise tolerance in healthy volunteers. This study assessed the effects of dietary nitrate on the oxygen cost of cycling, walking performance and BP in individuals with mild–moderate COPD.Methods - Thirteen patients with mild–moderate COPD were recruited. Participants consumed 70 ml of either nitrate-rich (6.77 mmol nitrate; beetroot juice) or nitrate-depleted beetroot juice (0.002 mmol nitrate; placebo) twice a day for 2.5 days, with the final supplement ~3 hours before testing. BP was measured before completing two bouts of moderate-intensity cycling, where pulmonary gas exchange was measured throughout. The six-minute walk test (6MWT) was completed 30 minutes subsequent to the second cycling bout.Results - Plasma nitrate concentration was significantly elevated following beetroot juice vs. placebo (placebo; 48 ± 86 vs. beetroot juice; 215 ± 84 µM, P = 0.002). No significant differences were observed between placebo vs. beetroot juice for oxygen cost of exercise (933 ± 323 vs. 939 ± 302 ml: min−1; P = 0.88), distance covered in the 6MWT (456 ± 86 vs. 449 ± 79 m; P = 0.37), systolic BP (123 ± 14 vs. 123 ± 14 mmHg; P = 0.91), or diastolic BP (77 ± 9 vs. 79 ± 9 mmHg; P = 0.27).Conclusion - Despite a large rise in plasma nitrate concentration, two days of nitrate supplementation did not reduce the oxygen cost of moderate intensity cycling, increase distance covered in the 6MWT, or lower BP.

Individuals with cold sensitivity have low peripheral skin blood flow and skin temperature possibly due to reduced nitric oxide (NO•) bioavailability. Beetroot has a high concentration of inorganic nitrate and may increase NO-mediated vasodilation. Using a placebo-controlled, double blind, randomised, crossover design, this study tested the hypotheses that acute beetroot supplementation would increase the rate of cutaneous rewarming following a local cold challenge and augment endothelium-dependent vasodilation in cold sensitive individuals.Thirteen cold sensitive participants completed foot and hand cooling (separately, in 15 °C water for 2 min) with spontaneous rewarming in 30 °C air whilst skin temperature and cutaneous vascular conductance (CVC) were measured (Baseline). On two further separate visits, participants consumed 140 ml of either concentrated beetroot juice (nitrate supplementation) or nitrate-depleted beetroot juice (Placebo) 90 min before resting seated blood pressure was measured. Endothelial function was assessed by measuring CVC at the forearm, finger and foot during iontophoresis of 1% w/v acetylcholine followed by foot and hand cooling as for Baseline.Plasma nitrite concentrations significantly increased in nitrate supplementation compared to Placebo and Baseline (502 ± 246 nmol L−1; 73 ± 45 nmol L−1; 74 ± 49 nmol L−1 respectively; n = 11; P < 0.001). Resting blood pressure and the response to foot and hand cooling did not differ between conditions (all P > 0.05). Nitrate supplementation did not alter endothelial function in the forearm, finger or foot (all P > 0.05) compared to Placebo.Despite a physiologically meaningful rise in plasma nitrite concentrations, acute nitrate supplementation does not alter extremity rewarming, endothelial function or blood pressure in individuals with cold sensitivity.

Nitric oxide alters gastric blood flow, improves vascular function and mediates glucose uptake within the intestines and skeletal muscle. Dietary nitrate, acting as a source of nitric oxide, appears to be a potential low cost therapy that may help maintain glucose homeostasis. In a randomised, double-blind, placebo-controlled crossover study, 31 young and older adult participants had a standardised breakfast, supplemented with either nitrate rich beetroot juice (11.91 mmol nitrate) or nitrate depleted beetroot juice as placebo (0.01 mmol nitrate). MRI was used to assess apparent diffusion coefficient (ADC), portal vein flux and velocity. Plasma glucose, incretin and C-peptide concentrations and BP were assessed. Outcome variables were measured at baseline and hourly for 3 hours. Compared with a placebo, beetroot juice resulted in a significant elevation in plasma nitrate and plasma nitrite concentration. No differences were seen for the young or older adult cohorts between placebo and beetroot juice for ADC, or portal vein flux. There was an interaction effect in the young adults, which was absent in the older adults between visits for portal vein velocity. Nitrate supplementation did not reduce plasma glucose active GLP-1, total GLP-1 or plasma C-peptide concentrations for the young or older adult cohorts. Despite a significant elevation in plasma nitrite concentration following an acute dose of 11.91 mmol of nitrate, there was no effect on hepatic blood flow, plasma glucose, C-peptide, or incretin concentration in healthy adults.

Dietary nitrate supplementation has been shown to reduce the oxygen (O2) cost of exercise and enhance exercise tolerance in healthy individuals. This study assessed whether similar effects could be observed in individuals with type 2 diabetes (T2DM). In a randomized, double-blind, placebo-controlled crossover study, 48 participants with T2DM supplemented their diet for 4 days with either nitrate-rich beetroot juice (70 ml/day, 6.43 mmol nitrate/day) or nitrate-depleted beetroot juice as placebo (70 ml/day, 0.07 mmol nitrate/day). After each intervention period, resting plasma nitrate and nitrite concentrations were measured subsequent to participants completing moderate-paced walking. Pulmonary gas exchange was measured to assess the O2 cost of walking. After a rest period, participants performed the 6-min walk test (6MWT). Relative to placebo, beetroot juice resulted in a significant increase in plasma nitrate (placebo, 57±66 vs beetroot, 319±110 µM; P < 0.001) and plasma nitrite concentration (placebo, 680±256 vs beetroot, 1065±607 nM; P < 0.001). There were no differences between placebo juice and beetroot juice for the O2 cost of walking (946±221 vs 939±223 ml/min, respectively; P = 0.59) and distance covered in the 6MWT (550±83 vs 554±90 m, respectively; P = 0.17). Nitrate supplementation did not affect the O2 cost of moderate-paced walking or improve performance in the 6MWT. These findings indicate that dietary nitrate supplementation does not modulate the response to exercise in individuals with T2DM.

Chronic sugar-sweetened beverage (SSB) consumption is associated with obesity and type 2 diabetes mellitus (T2DM). Hyperglycaemia contributes to metabolic alterations observed in T2DM, such as reduced oxidative capacity and elevated glycolytic and lipogenic enzyme expressions in skeletal muscle tissue. We aimed to investigate the metabolic alterations induced by SSB supplementation in healthy individuals and to compare these with the effects of chronic hyperglycaemia on primary muscle cell cultures.Lightly active, healthy, lean subjects (n = 11) with sporadic soft drink consumption underwent a 4-week SSB supplementation (140 ± 15 g/day, ~2 g glucose/kg body weight/day, glucose syrup). Before and after the intervention, body composition, respiratory exchange ratio (RER), insulin sensitivity, muscle metabolic gene and protein expression were assessed. Adaptive responses to hyperglycaemia (7 days, 15 mM) were tested in primary human myotubes.SSB supplementation increased fat mass (+1.0 kg, P0.05), fasting RER (+0.12, P0.05), fasting glucose (+0.3 mmol/L, P0.05) and muscle GAPDH mRNA expressions (+0.94 AU, P0.05). PGC1α mRNA was reduced (-0.20 AU, P0.05). Trends were found for insulin resistance (+0.16 mU/L, P = 0.09), and MondoA protein levels (+1.58 AU, P = 0.08). Primary myotubes showed elevations in GAPDH, ACC, MondoA and TXNIP protein expressions (P0.05).Four weeks of SSB supplementation in healthy individuals shifted substrate metabolism towards carbohydrates, increasing glycolytic and lipogenic gene expression and reducing mitochondrial markers. Glucose-sensing protein MondoA might contribute to this shift, although further in vivo evidence is needed to corroborate this.