Impact of nocturnal hypoxia on glycaemic control, appetite, gut microbiota and inflammation in adults with type 2 diabetes mellitus: A single-blind cross-over trial.

High altitude residents have a lower incidence of type 2 diabetes mellitus (T2DM). Therefore, we examined the effect of repeated overnight normobaric hypoxic exposure on glycaemic control, appetite, gut microbiota and inflammation in adults with T2DM. Thirteen adults with T2DM [glycated haemoglobin (HbA1c): 61.1 ± 14.1 mmol mol-1; aged 64.2 ± 9.4 years; four female] completed a single-blind, randomised, sham-controlled, cross-over study for 10 nights, sleeping when exposed to hypoxia (fractional inspired O2 [ F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ] = 0.155; ∼2500 m simulated altitude) or normoxic conditions ( F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$  = 0.209) in a randomised order. Outcome measures included: fasted plasma [glucose]; [hypoxia inducible factor-1α]; [interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]; [heat shock protein 70]; [butyric acid]; peak plasma [glucose] and insulin sensitivity following a 2 h oral glucose tolerance test; body composition; appetite indices ([leptin], [acyl ghrelin], [peptide YY], [glucagon-like peptide-1]); and gut microbiota diversity and abundance [16S rRNA amplicon sequencing]. During intervention periods, accelerometers measured physical activity, sleep duration and efficiency, whereas continuous glucose monitors were used to assess estimated HbA1c and glucose management indicator and time in target range. Overnight hypoxia was not associated with changes in any outcome measure (P > 0.05 with small effect sizes) except fasting insulin sensitivity and gut microbiota alpha diversity, which exhibited trends (P = 0.10; P = 0.08 respectively) for a medium beneficial effect (d = 0.49; d = 0.59 respectively). Ten nights of overnight moderate hypoxic exposure did not significantly affect glycaemic control, gut microbiome, appetite, or inflammation in adults with T2DM. However, the intervention was well tolerated and a medium effect-size for improved insulin sensitivity and reduced alpha diversity warrants further investigation. KEY POINTS: Living at altitude lowers the incidence of type 2 diabetes mellitus (T2DM). Animal studies suggest that exposure to hypoxia may lead to weight loss and suppressed appetite. In a single-blind, randomised sham-controlled, cross-over trial, we assessed the effects of 10 nights of hypoxia (fractional inspired O2 ∼0.155) on glucose homeostasis, appetite, gut microbiota, inflammatory stress ([interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]) and hypoxic stress ([hypoxia inducible factor 1α]; heat shock protein 70]) in 13 adults with T2DM. Appetite and inflammatory markers were unchanged following hypoxic exposure, but an increased insulin sensitivity and reduced gut microbiota alpha diversity were associated with a medium effect-size and statistical trends, which warrant further investigation using a definitive large randomised controlled trial. Hypoxic exposure may represent a viable therapeutic intervention in people with T2DM and particularly those unable or unwilling to exercise because barriers to uptake and adherence may be lower than for other lifestyle interventions (e.g. diet and exercise).

The effect of repeated hot water immersion on insulin sensitivity, heat shock protein 70, and inflammation in individuals with type 2 diabetes mellitus.

Repeated hot water immersion (HWI) can improve glycemic control in healthy individuals but data are limited for individuals with type 2 diabetes mellitus (T2DM). The present study investigated whether repeated HWI improves insulin sensitivity and inflammatory status and reduces plasma ([extracellular heat shock protein 70]) [eHSP70] and resting metabolic rate (RMR). Fourteen individuals with T2DM participated in this pre- versus postintervention study, with outcome measures assessed in fasted (≥12 h) and postprandial (2-h post-75 g glucose ingestion) states. HWI consisted of 1 h in 40°C water (target rectal temperature 38.5°C-39°C) repeated 8-10 times within a 14-day period. Outcome measures included insulin sensitivity, plasma [glucose], [insulin], [eHSP70], inflammatory markers, RMR, and substrate utilization. The HWI intervention increased fasted insulin sensitivity (QUICKI; P = 0.03) and lowered fasted plasma [insulin] (P = 0.04), but fasting plasma [glucose] (P = 0.83), [eHSP70] (P = 0.08), [IL-6] (P = 0.55), [IL-10] (P = 0.59), postprandial insulin sensitivity (P = 0.19), plasma [glucose] (P = 0.40), and [insulin] (P = 0.47) were not different. RMR was reduced by 6.63% (P < 0.05), although carbohydrate (P = 0.43) and fat oxidation (P = 0.99) rates were unchanged. This study shows that 8-10 HWIs within a 14-day period improved fasting insulin sensitivity and plasma [insulin] in individuals with T2DM, but not when glucose tolerance is challenged. HWI also improves metabolic efficiency (i.e., reduced RMR). Together these results could be clinically important and have implications for metabolic health outcomes and well-being in individuals with T2DM.NEW & NOTEWORTHY This is the first study to investigate repeated HWI to raise deep body temperature on insulin sensitivity, inflammation, eHSP70, and substrate utilization in individuals with T2DM. The principal novel findings were improvements in fasting insulin sensitivity and fasting plasma [insulin] but no change in fasting plasma [glucose], postprandial insulin sensitivity, plasma [insulin], or [glucose]. There was also no change in eHSP70, inflammatory status, or substrate utilization but there were reductions in RMR and oxygen consumption.

Plasma biomarkers of endothelial function, inflammation and oxidative stress in individuals with non-freezing cold injury.

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.

The physiological and clinical importance of cardiorespiratory fitness in people with abdominal aortic aneurysm.

NEW FINDINGS: What is the topic of this review? This review focuses on the physiological impact of abdominal aortic aneurysm (AAA) on cardiorespiratory fitness and the negative consequences of low fitness on clinical outcomes in AAA. We also discuss the efficacy of exercise training for improving cardiorespiratory fitness in AAA. What advances does it highlight? We demonstrate the negative impact of low fitness on disease progression and clinical outcomes in AAA. We highlight potential mechanistic determinants of low fitness in AAA and present evidence that exercise training can be an effective treatment strategy for improving cardiorespiratory fitness, postoperative mortality and disease progression. ABSTRACT: An abdominal aortic aneurysm (AAA) is an abnormal enlargement of the aorta, below the level of the renal arteries, where the aorta diameter increases by >50%. As an aneurysm increases in size, there is a progressive increase in the risk of rupture, which ranges from 25 to 40% for aneurysms >5.5 cm in diameter. People with AAA are also at a heightened risk of cardiovascular events and associated mortality. Cardiorespiratory fitness is impaired in people with AAA and is associated with poor (postoperative) clinical outcomes, including increased length of hospital stay and postoperative mortality after open surgical or endovascular AAA repair. Although cardiorespiratory fitness is a well-recognized prognostic marker of cardiovascular health and mortality, it is not assessed routinely, nor is it included in current clinical practice guidelines for the management of people with AAA. In this review, we discuss the physiological impact of AAA on cardiorespiratory fitness, in addition to the consequences of low cardiorespiratory fitness on clinical outcomes in people with AAA. Finally, we summarize current evidence for the effect of exercise training interventions on cardiorespiratory fitness in people with AAA, including the associated improvements in postoperative mortality, AAA growth and cardiovascular risk. Based on this review, we propose that cardiorespiratory fitness should be considered as part of the routine risk assessment and monitoring of people with AAA and that targeting improvements in cardiorespiratory fitness with exercise training might represent a viable adjunct treatment strategy for reducing postoperative mortality and disease progression.

Effects of dietary nitrate supplementation on the response to extremity cooling and endothelial function in individuals with cold sensitivity. A double blind, placebo controlled, crossover, randomised control trial.

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.

Effect of nitrate supplementation on hepatic blood flow and glucose homeostasis: a double-blind, placebo-controlled, randomized control trial.

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 randomized, double-blind, placebo-controlled crossover study, 31 young and older adult participants had a standardized 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 blood pressure were assessed. Outcome variables were measured at baseline and hourly for 3 h. 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 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) nitrate, there was no effect on hepatic blood flow, plasma glucose, C-peptide, or incretin concentration in healthy adults.

The effect of dietary nitrate supplementation on the oxygen cost of cycling, walking performance and resting blood pressure in individuals with chronic obstructive pulmonary disease: A double blind placebo controlled, randomised control trial.

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 (6 MWT) 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 6 MWT (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 6 MWT, or lower BP.

Understanding the factors that influence stroke survivors to begin or resume exercise: a qualitative exploration.

BACKGROUND: Exercise after stroke has the potential to increase survivors' physical function and decrease disability. However, despite health professional reporting they recommend exercise to stroke survivors, the majority are physically inactive. Stroke survivors have previously expressed a lack of adequate knowledge and skills to engage in exercise. OBJECTIVES: The aim of this study was to understand why active stroke survivors chose to (re)engage in exercise and how they went about doing so. A secondary aim was to understand if health professionals had a role in facilitating exercise engagement. METHODS: Semi-structured interviews were conducted with stroke survivors who regularly engaged with exercise. Seven people aged between 60 and 71 years participated in the study. Time since stroke varied from 1 to 13 years. A reflexive thematic analysis approach was used to analyze interviews. RESULTS: Exercise was spoken about in a positive light. For some, exercise had always been important, for others it became important after their stroke. The themes of Changing Support Over Time, Old and New Identity and Proactively Impacting the Future were developed. The participants felt that health professionals often facilitated engagement in exercise, although the type of support that was most valued differed at different points in the post-stroke journey. CONCLUSIONS: Authoritative support from health professionals and family members helped participants to engage in exercise in the early stages after stroke. Collaboration and being part of a team was appreciated for ongoing exercise engagement. Exercise provided hope as participants developed their identity after stroke.

Cardiac dysfunction in dialysing adults with end-stage kidney disease is associated with exercise intolerance: A pilot observational study.

People with end-stage kidney disease (ESKD) often exhibit impaired cardiac structure and function, which may contribute to poor exercise capacity. This study used multimodal exercise testing to investigate the central and peripheral mechanisms of exercise limitation in adults with ESKD, also comparing in-centre hemodialysis (ICHD) to home hemodialysis (HHD). Seventeen adults (55.5 ± 14.5 years; n = 14 male; n = 12 HHD) participated. Resting cardiac examinations, followed by submaximal cycling cardiopulmonary exercise testing (CPET) and functional exercise testing, revealed cardiac structural abnormalities (increased left ventricular mass) and cardiac injury. Aerobic fitness in adults with ESKD was low, with pulmonary oxygen uptake (V̇O2) at the gas exchange threshold (GET) occuring at 39 ± 8% predicted V̇O2peak. O2 pulse, an estimate of stroke volume (SV), was higher in HHD at rest (p = 0.05, ES = 0.58) and during unloaded cycling (p = 0.05, ES = 0.58) compared to ICHD. However, thoracic bioreactance derived SV at the GET was significantly higher in adults receiving ICHD versus HHD (p = 0.01, ES = 0.74). In adults with ESKD, cardiac output was positively associated with V̇O2 at the GET (r = 0.61, p = 0.04). This study highlights prevalent exercise dysfunction in adults with ESKD undergoing dialysis, with potential distinct differences between in-centre and home hemodialysis, mechanistically linked to underlying cardiac abnormalities.

Nitrate ingestion blunts the increase in blood pressure during cool air exposure: a double-blind, placebo-controlled, randomized, crossover trial.

Cold exposure increases blood pressure (BP) and salivary flow rate (SFR). Increased cold-induced SFR would be hypothesized to enhance oral nitrate delivery for reduction to nitrite by oral anaerobes and to subsequently elevate plasma [nitrite] and nitric oxide bioavailability. We tested the hypothesis that dietary nitrate supplementation would increase plasma [nitrite] and lower BP to a greater extent in cool compared with normothermic conditions. Twelve males attended the laboratory on four occasions. Baseline measurements were completed at 28°C. Subsequently, participants ingested 140 mL of concentrated nitrate-rich (BR; ∼13 mmol nitrate) or nitrate-depleted (PL) beetroot juice. Measurements were repeated over 3 h at either 28°C (Norm) or 20°C (Cool). Mean skin temperature was lowered compared with baseline in PL-Cool and BR-Cool. SFR was greater in BR-Norm, PL-Cool, and BR-Cool than PL-Norm. Plasma [nitrite] at 3 h was higher in BR-Cool (592 ± 239 nM) versus BR-Norm (410 ± 195 nM). Systolic BP (SBP) at 3 h was not different between PL-Norm (117 ± 6 mmHg) and BR-Norm (113 ± 9 mmHg). SBP increased above baseline at 1, 2, and 3 h in PL-Cool but not BR-Cool. These results suggest that BR consumption is more effective at increasing plasma [nitrite] in cool compared with normothermic conditions and blunts the rise in BP following acute cool air exposure, which might have implications for attenuating the increased cardiovascular strain in the cold.NEW & NOTEWORTHY Compared with normothermic conditions, acute nitrate ingestion increased plasma [nitrite], a substrate for oxygen-independent nitric oxide generation, to a greater extent during cool air exposure. Systolic blood pressure was increased during cool air exposure in the placebo condition with this cool-induced blood pressure increase attenuated after acute nitrate ingestion. These findings improve our understanding of environmental factors that influence nitrate metabolism and the efficacy of nitrate supplementation to lower blood pressure.

Adaptive metabolic response to 4 weeks of sugar-sweetened beverage consumption in healthy, lightly active individuals and chronic high glucose availability in primary human myotubes.

PURPOSE: 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. METHODS: 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. RESULTS: SSB supplementation increased fat mass (+1.0 kg, P < 0.05), fasting RER (+0.12, P < 0.05), fasting glucose (+0.3 mmol/L, P < 0.05) and muscle GAPDH mRNA expressions (+0.94 AU, P < 0.05). PGC1α mRNA was reduced (-0.20 AU, P < 0.05). 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 (P < 0.05). CONCLUSION: 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.

Exploring patients' experiences of the impact of dialysis therapies on quality of life and wellbeing.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. FINDINGS: 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. CONCLUSION: 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.

Experiences of adults living with a kidney transplant-Effects on physical activity, physical function, and quality of life: A descriptive phenomenological study.

BACKGROUND: 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. OBJECTIVES: 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. APPROACH: 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. FINDINGS: 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. CONCLUSION: 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.

Effect of different levels of acute hypoxia on subsequent oral glucose tolerance in males with overweight: A balanced cross-over pilot feasibility study.

Previous research has shown that ≤60 min hypoxic exposure improves subsequent glycaemic control, but the optimal level of hypoxia is unknown and data are lacking from individuals with overweight. We undertook a cross-over pilot feasibility study investigating the effect of 60-min prior resting exposure to different inspired oxygen fractions (CON FI O2  = 0.209; HIGH FI O2  = 0.155; VHIGH FI O2  = 0.125) on glycaemic control, insulin sensitivity, and oxidative stress during a subsequent oral glucose tolerance test (OGTT) in males with overweight (mean (SD) BMI = 27.6 (1.3) kg/m2 ; n = 12). Feasibility was defined by exceeding predefined withdrawal criteria for peripheral blood oxygen saturation (SpO2 ), partial pressure of end-tidal oxygen or carbon dioxide and acute mountain sickness (AMS), and dyspnoea symptomology. Hypoxia reduced SpO2 in a stepwise manner (CON = 97(1)%; HIGH = 91(1)%; VHIGH = 81(3)%, p < 0.001), but did not affect peak plasma glucose concentration (CON = 7.5(1.8) mmol∙L-1 ; HIGH = 7.7(1.1) mmol∙L-1 ; VHIGH = 7.7(1.1) mmol∙L-1 ; p = 0.777; η2  = 0.013), plasma glucose area under the curve, insulin sensitivity, or metabolic clearance rate of glucose (p > 0.05). We observed no between-conditions differences in oxidative stress (p > 0.05), but dyspnoea and AMS symptoms increased in VHIGH (p < 0.05), with one participant meeting the withdrawal criteria. Acute HIGH or VHIGH exposure prior to an OGTT does not influence glucose homeostasis in males with overweight, but VHIGH is associated with adverse symptomology and reduced feasibility.

Assessing the fidelity of the independently getting up off the floor (IGO) technique as part of the ReTrain pilot feasibility randomised controlled trial for stroke survivors.

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.

Elexacaftor-Tezacaftor-Ivacaftor improves exercise capacity in adolescents with cystic fibrosis.

OBJECTIVE: 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. METHODS: Three adolescents (14.0 ± 1.4 years) with CF (FEV1 % predicted: 62.5 ± 17.1; F508del/F508del genotype) completed an exhaustive maximal cardiopulmonary exercise test on a cycle ergometer to determine peak oxygen uptake ( V ̇ $\dot{{\rm{V}}}$ O2peak ) and measure changes in gas exchange and ventilation during exercise at 6 weeks. We also analyzed wrist-worn device-based physical activity (PA) data in two of the three cases. Validated acceleration thresholds were used to quantify time spent in each PA intensity category. RESULTS: Clinically meaningful improvements in V ̇ $\dot{{\rm{V}}}$ O2peak were observed in all three cases (+17.6%, +52.4%, and +32.9%, respectively), with improvements greatest in those with more severe lung disease and lower fitness at baseline. Although lung function increased in all cases, inconsistent changes in markers of ventilatory and peripheral muscle efficiency likely suggest different mechanisms of improvement in this case group of adolescents with CF. Device-based analysis of PA was variable, with one case increasing and one case decreasing. CONCLUSION: In 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.

Self-assembling peptide haemostatic gel reduces incidence of pelvic collection after total mesorectal excision: Prospective cohort study.

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.

Dietary nitrate and population health: a narrative review of the translational potential of existing laboratory studies.

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.

CFTR limits F-actin formation and promotes morphological alignment with flow in human lung microvascular endothelial cells.

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). Treatment with TNF-α significantly increased total F-actin after 24 h versus control (p < 0.05), an effect that was independent of shear stress. GlyH-101 significantly increased F-actin after 24 h of shear stress versus control (p < 0.05), with a significant (p < 0.05) reduction in cortical F-actin under both static and flow conditions. Shear stress decreased [ET-1] after 24 h (p < 0.05) and increased [nitrite] after 48 h (p < 0.05), but neither [nitrite] nor [ET-1] was affected by GlyH-101 (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.

Timing of acute passive heating on glucose tolerance and blood pressure in people with type 2 diabetes: a randomized, balanced crossover, control trial.

Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia and progressive insulin resistance, leading to macro and microvascular dysfunction. Passive heating has potential to improve glucose homeostasis and act as an exercise mimetic. We assessed the effect of acute passive heating before or during an oral glucose tolerance test (OGTT) in people with T2DM. Twelve people with T2DM were randomly assigned to the following three conditions: 1) 3-h OGTT (control), 2) 1-h passive heating (40°C water) 30 min before an OGTT (HOT-OGTT), and 3) 1-h passive heating (40°C water) 30 min after commencing an OGTT (OGTT-HOT). Blood glucose concentration, insulin sensitivity, extracellular heat shock protein 70 (eHSP70), total energy expenditure (TEE), heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded. Passive heating did not alter blood glucose concentration [control: 1,677 (386) arbitrary units (AU), HOT-OGTT: 1,797 (340) AU, and OGTT-HOT: 1,662 (364) AU, P = 0.28], insulin sensitivity (P = 0.15), or SBP (P = 0.18) but did increase eHSP70 concentration in both heating conditions [control: 203.48 (110.81) pg·mL-1; HOT-OGTT: 402.47 (79.02) pg·mL-1; and OGTT-HOT: 310.00 (60.53) pg·mL-1, P < 0.001], increased TEE (via fat oxidation) in the OGTT-HOT condition [control: 263 (33) kcal, HOT-OGTT: 278 (40) kcal, and OGTT-HOT: 304 (38) kcal, P = 0.001], increased HR in both heating conditions (P < 0.001), and reduced DBP in the OGTT-HOT condition (P < 0.01). Passive heating in close proximity to a glucose challenge does not alter glucose tolerance but does increase eHSP70 concentration and TEE and reduce blood pressure in people with T2DM.NEW & NOTEWORTHY 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.