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NEW FINDINGS What is the central question of this study? Is the estrous cycle affected during disuse atrophies and if so, how do estrous cycle changes relate to musculoskeletal outcomes? What is the main finding and its importance? Rodent estrous cycles are altered during disuse atrophy, which corresponds to musculoskeletal outcomes. However, the estrous cycle does not appear changed in Lewis Lung Carcinoma, which corresponded to no differences in muscle size compared to healthy controls. These findings suggest a relationship between estrous cycle and muscle size during atrophic pathologies. ABSTRACT Hyperglycemia can cause disruptions in vascular function, whereas exercise has been shown to restore vascular function. The primary aim of this study is to investigate the effect of performing whole-body resistance exercise, 30-min before, immediately following, or 30- or 60-min after a high carbohydrate meal, on endothelial function, measured by flow-mediated dilation (FMD). Healthy adults will be recruited to this randomized crossover trial to compare the postprandial glycaemic and vascular responses to four different exercise timing conditions and a control: i) C- control, high carbohydrate meal/no exercise, ii) 30Pre- 30 min of resistance exercises (~30% of 1RM [Repetition Maximum]), 30 min before a high carbohydrate meal, iii) IP- 30 min of resistance exercises (~30% of 1RM), immediately following a high carbohydrate meal, iv) 30Post- 30 min of resistance exercises, 30 min after a high carbohydrate meal and v) 60Post- 30 min of resistance exercises, 60 min after a high carbohydrate meal. Measures of metabolic and vascular function will be assessed at baseline and for two hours following the carbohydrate-based breakfast meal.

BACKGROUND LDL particle size and number (LDL-P) are emerging lipid risk factors. Nonsystematic reviews have suggested that diets lower in carbohydrates and higher in fats may result in increased LDL particle size when compared with higher-carbohydrate diets. OBJECTIVES This study aimed to systematically review available evidence and conduct meta-analyses of studies addressing the association of carbohydrate restriction with LDL particle size and LDL-P. METHODS We searched 6 electronic databases on 4 January, 2021 for randomized trials of any length that reported on dietary carbohydrate restriction (intervention) compared with higher carbohydrate intake (control). We calculated standardized mean differences (SMDs) in LDL particle size and LDL-P between the intervention and control groups of eligible studies, and pooled effect sizes using random-effects models. We performed prespecified subgroup analyses and examined the effect of potential explanatory factors. Internal validity and publication bias were assessed using Cochrane's risk-of-bias tool and funnel plots, respectively. Studies that could not be meta-analyzed were summarized qualitatively. RESULTS This review summarizes findings from 38 randomized trials including a total of 1785 participants. Carbohydrate-restricted dietary interventions were associated with an increase in LDL peak particle size (SMD = 0.50; 95% CI: 0.15, 0.86; P

Clinical practice guidelines on physical activity and diabetes currently stipulate physical activity can be accumulated in bouts of ≥10 minutes to meet recommendations for health benefits. Individuals are also encouraged to interrupt prolonged sitting with brief activity breaks of ∼1 to 5 minutes in duration. Growing research highlights accumulating activity in shorter bouts across the day as a potential strategy to improve glycemic control and to help those who are largely sedentary meet physical activity guidelines. Research has shown favourable glycemic benefits for postprandial glucose and glycated hemoglobin with either 3 short (10 to 15 minutes) or frequent brief (1 to 5 minutes) bouts of activity spread around meals or throughout the day. To date, most studies examining accumulated activity were done with people with type 2 diabetes compared with sedentary conditions, were short term and measured various indices of glycemic control using continuous glucose monitoring. The 7 trials comparing accumulating 3 short bouts to a single bout showed comparable benefits for glycemic control (i.e. fasting glucose, 24 h mean glucose and postprandial hyperglycemia). Furthermore, timing short bouts around meals may improve postprandial glucose and hyperglycemia more than a single bout. It is unknown whether a threshold for the duration of accumulated bouts exists---that is, "how much is enough?" In this narrative review, we focus on the glycemic effects of physical activity accumulated in short or brief bouts for people with prediabetes and diabetes as compared with a single continuous bout. Given that poor adherence to physical activity recommendations and that fewer opportunities exist in modern societies for incidental (nonexercise) physical activity, accumulating activity may be a choice strategy for improving glycemic control in those with and at risk of diabetes.

Summary In type 2 diabetes, liver insulin resistance and excess hepatic glucose production results in elevated fasting glucose. A bedtime snack has been recommended to improve fasting glucose, yet there is little evidence supporting this recommendation. Moreover, the optimal composition of a bedtime snack is unknown. Purpose To determine whether a low-carbohydrate protein-rich bedtime snack (Egg) could reduce fasting plasma glucose levels in people with type 2 diabetes when compared to a high-carbohydrate protein-rich bedtime snack (Yogurt) or a No Bedtime Snack condition. Secondary outcomes included glucose control assessed by continuous glucose monitoring (CGM) and fasting insulin sensitivity markers. Methods Using a randomized crossover design, participants with type 2 diabetes (N = 15) completed three separate isocaloric conditions: i) Egg, ii) Yogurt, and iii) No Bedtime Snack, each lasting three days. CGM was collected throughout and duplicate fasting blood samples were obtained on the morning of day 4 in each condition. Results Fasting plasma glucose (P = 0.04, d = 0.68), insulin (P = 0.04, d = 0.45), and nocturnal glucose (P = 0.02, d = 0.94) were significantly lower, and quantitative insulin sensitivity check index (QUICKI; P = 0.003) was improved, in the Egg compared to the Yogurt bedtime snack. There were no significant differences between either bedtime snack and No Bedtime Snack. Conclusion In the short-term, a low-carbohydrate bedtime snack (Egg) lowered fasting glucose and improved markers of insulin sensitivity when compared to a high-carbohydrate protein-matched bedtime snack (Yogurt). However, consuming a low- or high-carbohydrate bedtime snack did not appear to lower fasting glucose compared to consuming an isocaloric diet with no bedtime snack. Clinical trial registry clinicaltrials.gov ( NCT03207269 ).

Gestational diabetes mellitus (GDM) is the most common complication of pregnancy and a significant clinical and public health problem with lifelong and intergenerational adverse health consequences for mothers and their offspring. The preconception, early pregnancy, and interconception periods represent opportune windows to engage women in preventive and health promotion interventions. This review provides an overview of findings from observational and intervention studies on the role of diet, physical activity, and weight (change) during these periods in the primary prevention of GDM. Current evidence suggests that supporting women to increase physical activity and achieve appropriate weight gain during early pregnancy and enabling women to optimize their weight and health behaviors prior to and between pregnancies have the potential to reduce rates of GDM. Translation of current evidence into practice requires further development and evaluation of co-designed interventions across community, health service, and policy levels to determine how women can be reached and supported to optimize their health behaviors before, during, and between pregnancies to reduce GDM risk.

The objective of this study was to test if a low-calorie diet plus interval exercise (LCD+INT) improves adiposopathy, an endocrine dysfunction, when compared with an energy-deficit–matched LCD in obese women. Subjects (age: 48.2 ± 2.4 years, body mass index: 37.8 ± 1.3 kg/m2) were randomized to a 13-day LCD (n = 12; mixed meals of ∼1200 kcal/day) or LCD+INT (n = 12; 12 sessions of 60 min/day alternating 3 min at 50% and 90% peak heart rate). Exercise was estimated to expend 350 kcal per oxygen uptake–heart rate regression analysis and individuals were refed calories expended to match energy availability between groups. Absolute (post – pre caloric intake) and relative (total daily and exercise energy expenditure relative to calorie intake) energy deficits were calculated. Fitness (peak oxygen uptake) and body composition (BodPod; Cosmed USA Inc.) were measured and a 120-min, 75g oral glucose tolerance test was performed at pre- and post-intervention to assess adiposopathy (i.e., ratio of high molecular weight–adiponectin to leptin) and estimate insulin sensitivity. LCD and LCD+INT had similar absolute (P = 0.55) and relative (P = 0.76) energy deficits. LCD and LCD+INT had similar reductions in fat mass (both P < 0.001), despite LCD inducing greater weight loss (P = 0.02) than LCD+INT. Both treatments improved adiposopathy (P = 0.003) and peripheral insulin sensitivity (P = 0.02). Absolute energy deficit correlated to improved adiposopathy (r = –0.41, P = 0.05), and absolute and relative energy deficits were associated with increased insulin sensitivity (r = –0.47, P = 0.02; and r = –0.40, P = 0.05, respectively), independent of body composition changes and increased peak oxygen uptake. Taken together, LCD, with or without INT, improves adiposopathy in relation to insulin sensitivity in obese women, suggesting that a short-term energy deficit is key for reducing risk of type 2 diabetes.

BACKGROUND: The breakfast meal often results in the largest postprandial hyperglycemic excursion in people with type 2 diabetes. OBJECTIVE: Our purpose was to investigate whether restricting carbohydrates at breakfast would be a simple and feasible strategy to reduce daily exposure to postprandial hyperglycemia. DESIGN: Adults with physician-diagnosed type 2 diabetes [n = 23; mean ± SD age: 59 ± 11 y; glycated hemoglobin: 6.7% ± 0.6%; body mass index (kg/m(2)): 31 ± 7] completed two 24-h isocaloric intervention periods in a random order. Participants consumed one of the following breakfasts: 1) a very-low-carbohydrate high-fat breakfast (LCBF

Background Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr). Objective To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes. Methods Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial. Results Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation. Conclusion This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal.

Background Low cardiorespiratory fitness (V̇O2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O2peak, there is considerable inter-individual variability in the V̇O2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O2peak response following exercise training. Methods Participant change in objectively measured V̇O2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P –5) with the magnitude of V̇O2peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research. Results No variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇O2peak, individual study, principal components which were significantly associated with the trait). A Quantile–Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇O2peak response that reached suggestive significance (P –5). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10–7). A PPS created from the 12 lead SNPs was unable to predict V̇O2peak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P –4) and the validation study (P –6), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent. Conclusions Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇O2peak response variance, and whether genomic predictors for V̇O2peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true.

Summary Background & aims Postprandial metabolic imbalances are important indicators of later developing cardiovascular disease (CVD). This study investigated the effects of food anthocyanins on vascular and microvascular function, and CVD associated biomarkers following a high fat high energy (HFHE) meal challenge in overweight older adults. Methods Sixteen subjects (13 female, 3 male, mean age 65.9 SD 6.0 and body mass index 30.6 kg/m2 SD 3.9) participated in a crossover, randomized, controlled, double-blind clinical trial (registered under Australian New Zealand Clinical Trials Registry, identifier no. ACTRN12620000437965). Participants consumed a HFHE meal with a 250 mL dose of either intervention (anthocyanins-rich Queen Garnet Plum) or control (apricot) juice. Blood samples and blood pressure measures were collected at baseline, 2 h and 4 h following the HFHE meal. Vascular and microvascular function were evaluated at baseline and 2 h after the HFHE meal. Results Participants had a higher 2 h postprandial flow-mediated dilatation (+1.14%) and a higher microvascular post-occlusive reactive hyperaemia (+0.10 perfusion units per mmHg) when allocated to the anthocyanin compared to the control arm (P = 0.019 and P = 0.049, respectively). C-reactive protein was lower 4 h postprandially in the anthocyanins (1.80 mg/L, IQR 0.90) vs control arm (2.30 mg/L, IQR 1.95) (P = 0.026), accompanied by a trend for lower concentrations of interleukin-6 (P = 0.075). No significant postprandial differences were observed between treatments for blood pressure, triacylglycerol, total cholesterol, serum derivatives of reactive oxidative metabolites, tumor necrosis factor alpha, interleukin-1 beta, or maximum microvascular perfusion following iontophoresis of acetylcholine. Conclusion Fruit-based anthocyanins attenuated the potential postprandial detrimental effects of a HFHE challenge on parameters of vascular and microvascular function, and inflammatory biomarkers in overweight older adults. Anthocyanins may reduce cardiovascular risk associated with endothelial dysfunction and inflammatory responses to a typical high fat ‘Western’ meal. Further studies are required to better elucidate the clinical implications of postprandial biomarkers of CVD.

Arachidonic acid (AA) and docosahexaenoic acid (DHA) are important for neurological development. The aim was to determine the distribution and relative enrichment of AA and DHA among lipoprotein fractions prior to pregnancy, throughout gestation and in the post-partum period. Our hypothesis was that in pregnancy, in contrast to the non-pregnant state, AA and DHA are carried in highest concentration in the very low density lipoprotein (VLDL) fraction secondary to increased gestational liver triglyceride secretion. Two independent prospective, observational cohort studies carried out in Glasgow were combined; one early in pregnancy and one later in pregnancy with post-partum follow up. Across the pregnancy timeline plasma lipoproteins were isolated using sequential ultracentrifugation and lipoprotein fatty acids were extracted and analysed by gas chromatography. High density lipoprotein (HDL) had the highest concentration of AA and DHA compared to other lipoproteins. HDL became progressively enriched in the proportion of triglycerides at 16 weeks of gestation, which peaked at 35 weeks and returned to baseline at 13 weeks postpartum. HDL DHA per HDL-cholesterol and HDL DHA per apoA-I became progressively enriched at 16 weeks of gestation, peaked at 25 weeks and returned to baseline at 13 weeks postpartum, whereas HDL AA (per HDL-C or HDL-apoA-I) did not differ. DHA is carried primarily in HDL rather than VLDL. HDL has anti-oxidant properties that might afford DHA protection against oxidation.

OBJECTIVE Aneurysmal subarachnoid hemorrhage (aSAH) is associated with significant morbidity and mortality. The presence of thick, diffuse subarachnoid blood may portend a worse clinical course and outcome, independently of other known prognostic factors such as age, aneurysm size, and initial clinical grade. METHODS In this post hoc analysis, patients with aSAH undergoing surgical clipping (n = 383) or endovascular coiling (n = 189) were pooled from the placebo arms of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS)–2 and CONSCIOUS-3 randomized, double-blind, placebo-controlled phase 3 studies, respectively. Patients without and with thick, diffuse SAH (≥ 4 mm thick and involving ≥ 3 basal cisterns) on admission CT scans were compared. Clot size was centrally adjudicated. All-cause mortality and vasospasm-related morbidity at 6 weeks and Glasgow Outcome Scale–Extended (GOSE) scores at 12 weeks after aSAH were assessed. The effect of the thick and diffuse cisternal aSAH on vasospasm-related morbidity and mortality, and on poor clinical outcome at 12 weeks, was evaluated using logistic regression models. RESULTS Overall, 294 patients (51.4%) had thick and diffuse aSAH. Compared to patients with less hemorrhage burden, these patients were older (median age 55 vs 50 years) and more often had World Federation of Neurosurgical Societies (WFNS) grade III–V SAH at admission (24.1% vs 16.5%). At 6 weeks, all-cause mortality and vasospasm-related morbidity occurred in 36.1% (95% CI 30.6%–41.8%) of patients with thick, diffuse SAH and in 14.7% (95% CI 10.8%–19.5%) of those without thick, diffuse SAH. Individual event rates were 7.5% versus 2.5% for all-cause death, 19.4% versus 6.8% for new cerebral infarct, 28.2% versus 9.4% for delayed ischemic neurological deficit, and 24.8% versus 10.8% for rescue therapy due to cerebral vasospasm, respectively. Poor clinical outcome (GOSE score ≥ 4) was observed in 32.7% (95% CI 27.3%–38.3%) and 16.2% (95% CI 12.1%–21.1%) of patients with and without thick, diffuse SAH, respectively. CONCLUSIONS In a large, centrally adjudicated population of patients with aSAH, WFNS grade at admission and thick, diffuse SAH independently predicted vasospasm-related morbidity and poor 12-week clinical outcome. Patients with thick, diffuse cisternal SAH may be an important cohort to target in future clinical trials of treatment for vasospasm.

The purpose of this study was to examine whether the combination of high-intensity interval training (HIIT) and post-exercise protein supplementation would improve cardiovascular outcomes in individuals with T2D.In a double-blind controlled trial, fifty-three adults with T2D (free of CVD and not on exogenous insulin) were randomized to 12weeks of cardio and resistance-based HIIT (4-10×1min at 90% maximal heart rate) with post-exercise milk, milk-protein, or placebo supplementation, thrice weekly. Before and after, carotid and femoral artery intima media thickness (IMT) and femoral flow profiles were assessed using high-resolution ultrasound. Central and peripheral arterial stiffness were assessed by pulse wave velocity (PWV), and resting and maximal heart rate rates were measured.After 12weeks of HIIT femoral IMT (Pre: 0.84±0.21mm vs. Post: 0.81±0.16mm, p=0.03), carotid-femoral PWV (Pre: 10.1±3.2m/s vs. Post: 8.6±1.8m/s, p0.01) and resting heart rate (Pre: 70.4±10.8bpm vs. Post: 67.8±8.6 bpm, p=0.01) were all significantly lower. There were no differences between nutrition groups (all significant main effects of time) for all outcomes.HIIT reduces femoral IMT, arterial stiffness and resting heart rate in individuals with T2D. The addition of post-exercise milk or protein to HIIT did not have additive effects for improving cardiovascular outcomes in the present study. Taken together, HIIT alone may be an effective means to reduce the burden of cardiovascular complications in T2D.

Background: The COVID-19 pandemic rapidly spread in Europe and France Cancer patients were identified at higher risk of infection and evolution to severe forms, especially those undergoing active treatment Academic and experts’ recommendations proposed to protect cancer units and prioritize cancer treatment In the same time, French authorities implemented a national lockdown from march 16, 2020 Most anti-cancer institutions have modified their organization, trying to combine cancer units COVID-free sanctuarization, continuity in priority care and precautionary principle The impact of COVID-19 outbreak on global cancer care has not been formally evaluated Methods: Data of oncological practice at the Antoine Lacassagne Center (mild-COVID-19 incidence rate area) were recorded (per week) for 3 periods, based on the timing of french lockdown: before (Jan-1 to Mar-15), during (Mar-16 to May-10) and after the end of lockdown (May-11 to Jul-12) We collected the number of chemotherapy and radiotherapy sessions, surgery procedures (senology and gynecology), blood products transfusions, on-site / telemedicine visits and inclusions in clinical trials Results: Preliminary results compare period 1 (Jan-1 to Mar-15) to interim period 2 (Mar-16 to Apr-19, available data at the time of submission) Variation of practice is detailed in the table Activities were negatively impacted by the lockdown, mostly reconstructive surgery (-90%), on-site oncology visits (-73%) and clinical research (-69%) In parallel, telemedicine visits were multiplied by 100 [Formula presented] Conclusions: The evaluation of practice variation for cancer care is essential to understand the real impact of COVID-19 outbreak on global cancer management, so as to get prepared to further epidemic waves (for ex implementation of telehealth innovations) or long-term consequences on cancer outcome Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: D Borchiellini: Advisory/Consultancy, Research grant/Funding (institution): Astellas;Astra Zeneca;MSD;Novartis;Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS;Janssen;Pfizer;Roche;Research grant/Funding (institution): Calithera;Exelixis;Infinity;Merck KGaA;Advisory/Consultancy: Ipsen;Sanofi J-M Hannoun-Levi: Advisory/Consultancy: Eckert & Ziegler BEBIG E Francois: Honoraria (self): Amgen;MSD;Novartis;Honoraria (self), Travel/Accommodation/Expenses: Servier;Advisory/Consultancy, Travel/Accommodation/Expenses: Roche All other authors have declared no conflicts of interest

Background and Purpose— Clazosentan, an endothelin receptor antagonist, has been shown to reduce angiographic vasospasm and vasospasm-related morbidity after aneurysmal subarachnoid hemorrhage (SAH), although no effect on long-term functional outcome has been demonstrated. Thick clot on initial computed tomography is associated with an increased risk of vasospasm and delayed cerebral ischemia. In this post hoc analysis, we hypothesized that use of clazosentan in this subpopulation would provide stronger benefit. Methods— We analyzed SAH patients enrolled in the CONSCIOUS-2 and CONSCIOUS-3 studies (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage) and compared the effects of clazosentan 5 mg/h, 15 mg/h, and placebo starting the day after aneurysm repair. The analysis was performed separately based on the presence or absence of thick (≥4 mm) and diffuse (≥3 cisterns) SAH on admission computed tomography. The primary composite end point was all-cause mortality and vasospasm-related morbidity at 6 weeks, and the main secondary end point was the extended Glasgow Outcome Scale at 3 months, adjusted for admission clinical grade. Results— Of 1718 randomized patients, 919 (53%) had thick and diffuse SAH. The primary composite end point in this group occurred in 36% of placebo-treated patients (n=294), 30% patients treated with clazosentan 5 mg/h (n=514; relative risk, 0.82; 95% CI, 0.67–0.99), and 19% patients treated with clazosentan 15 mg/h (n=111; relative risk, 0.54; 95% CI, 0.36–0.80). Despite this, death or poor functional outcome (Glasgow Outcome Scale ≤4) occurred in 33% of placebo-treated patients, 34% of patients treated with clazosentan 5 mg/h (relative risk 1.02; 95% CI, 0.84–1.23), and 35% of patients treated with clazosentan 15 mg/h (relative risk 1.14; 95% CI, 0.88–1.48). Conclusions— In an enriched population with thick and diffuse SAH, clazosentan at a dose of 5 and 15 mg/h was able to significantly reduce vasospasm-related morbidity in a dose-dependent manner. The absence of an effect on long-term functional status likely reflects the complexity and multiplicity of factors that contribute to poor outcome after SAH. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00558311; NCT00940095.

Background Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). It has been hypothesized that clazosentan can also reverse established angiographic vasospasm. Methods The REVERSE (resynchronization reverses remodeling in systolic left ventricular dysfunction) study was a prospective, multicenter, open-label, 2-stage pilot study of adult patients with aSAH who had received intravenous clazosentan (15 mg/hour) after developing moderate-to-severe angiographic vasospasm. The primary efficacy endpoint was the reversal of global cerebral vasospasm in large cerebral artery segments 3 hours after clazosentan initiation. The secondary endpoints included large artery vasospasm reversal at 24 hours and the maximum change in the angiographic cerebral circulation time. The change in vasospasm severity in the proximal and distal segments was investigated in an exploratory analysis. Results The primary efficacy endpoint was met in 3 of 11 evaluable patients (27.3%; 95% confidence interval, 6.0–61.0). However, recruitment was stopped after stage 1 in accordance with the predefined interim analysis criteria. In the exploratory analysis, 50.0% and 77.8% of the patients showed a significant reversal of vasospasm or improvement to the admission state in ≥2 distal segments at 3 and 24 hours and 28.6% and 77.8% in ≥2 proximal segments, respectively. Conclusions Although the main analysis showed a reversal of large vessel vasospasm 3 hours after clazosentan initiation in a few patients, the exploratory analysis indicated a clear pharmacodynamic dilating effect on vasospastic cerebral vessels at 24 hours in most patients, in particular, in the distal arterial beds. This observation supported the inclusion of patients with established vasospasm in the ongoing REACT (prevention and treatment of vasospasm with clazosentan) trial.

Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. National Institute of Neurological Disorders and Stroke and Genentech. [Abstract copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.]

There is heterogeneity in the observed VO2peak response to similar exercise training, and different exercise approaches produce variable degrees of exercise response (trainability). The aim of this study was to combine data from different laboratories to compare VO2peak trainability between various volumes of interval training and Moderate Intensity Continuous Training (MICT). For interval training, volumes were classified by the duration of total interval time. High-volume High Intensity Interval Training (HIIT) included studies that had participants complete more than 15 min of high intensity efforts per session. Low-volume HIIT/Sprint Interval Training (SIT) included studies using less than 15 min of high intensity efforts per session. In total, 677 participants across 18 aerobic exercise training interventions from eight different universities in five countries were included in the analysis. Participants had completed 3 weeks or more of either high-volume HIIT (n = 299), low-volume HIIT/SIT (n = 116), or MICT (n = 262) and were predominately men (n = 495) with a mix of healthy, elderly and clinical populations. Each training intervention improved mean VO2peak at the group level (P < 0.001). After adjusting for covariates, high-volume HIIT had a significantly greater (P < 0.05) absolute VO2peak increase (0.29 L/min) compared to MICT (0.20 L/min) and low-volume HIIT/SIT (0.18 L/min). Adjusted relative VO2peak increase was also significantly greater (P < 0.01) in high-volume HIIT (3.3 ml/kg/min) than MICT (2.4 ml/kg/min) and insignificantly greater (P = 0.09) than low-volume HIIT/SIT (2.5 mL/kg/min). Based on a high threshold for a likely response (technical error of measurement plus the minimal clinically important difference), high-volume HIIT had significantly more (P < 0.01) likely responders (31%) compared to low-volume HIIT/SIT (16%) and MICT (21%). Covariates such as age, sex, the individual study, population group, sessions per week, study duration and the average between pre and post VO2peak explained only 17.3% of the variance in VO2peak trainability. In conclusion, high-volume HIIT had more likely responders to improvements in VO2peak compared to low-volume HIIT/SIT and MICT. © 2019 Williams, Gurd, Bonafiglia, Voisin, Li, Harvey, Croci, Taylor, Gajanand, Ramos, Fassett, Little, Francois, Hearon, Sarma, Janssen, Van Craenenbroeck, Beckers, Cornelissen, Pattyn, Howden, Keating, Bye, Stensvold, Wisloff, Papadimitriou, Yan, Bishop, Eynon and Coombes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Summary Background Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage. Methods MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18–80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, number NCT00224770. Findings Between Feb 2, 2006, and April 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7–22.6] vs eight [14·8%, 6·6–27·1], p=0·542), 7 day mortality (zero [0%, 0–8·4] vs one [1·9%, 0·1–9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1–12·6] vs five [9·3%, 3·1–20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1–12·6] vs zero [0%, 0–6·6], p=0·438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22·2%; 95% CI 12·0–35·6] vs three [7·1%; 1·5–19·5]; p=0·051). Interpretation MIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage. Funding National Institute of Neurological Disorders and Stroke, Genentech, and Codman.

Resume Objectif de l’etude Cette etude retrospective a evalue les modalites de prise en charge et le pronostic des cancers du rectum chez le sujet âge en comparaison avec ceux des sujets plus jeunes. Patients et methodes Les donnees de 160 patients de plus 80 ans, ayant recu un traitement pour un cancer du rectum diagnostique entre 2006 et 2008, en region Provence-Alpes-Cote-d’Azur, independamment du stade et du traitement de la maladie ont ete analysees retrospectivement. Les taux de survie globale et sans rechute ont ete correles avec les caracteristiques de la tumeur et les traitements administres. Le traitement administre a ensuite ete compare aux standards therapeutiques recommandes pour les patients plus jeunes. Resultats Avec 36 mois de suivi median, les taux de survie globale et sans rechute a 3 ans etaient respectivement de 59,2 % et 76,6 % pour les 117 patients ayant recu un traitement a visee curative. En analyse multifactorielle, la survie globale etait independamment influencee par le statut N et l’exerese chirurgicale, alors que la survie sans rechute etait influencee par l’âge, le statut N, et le sexe. Les tumeurs de stade T0–T2 ont ete traitees conformement aux recommandations pour les patients plus jeunes, avec respectivement des taux a 3 ans de 83,6 % et 95,2 % de survie globale et de survie sans rechute. Pour les patients atteints de tumeur de stade T3–T4, le taux de survie sans rechute a 3 ans etait de 65 %, malgre une strategie moins agressive. Conclusion Sous reserve d’une bonne evaluation oncogeriatrique, la chirurgie reste le standard de traitement des tumeurs localisees (de stade T0–T2) des patients âges. Pour les tumeurs localement evoluees (de stade T3–T4), les resultats obtenus dans cette etude suggerent qu’une approche conservatrice pourrait etre envisagee.

The effect of work-matched exercise intensity on β-cell function is unknown in people with prediabetes before clinical weight loss. We determined if short-term moderate continuous (CONT) vs. high-intensity interval (INT) exercise increased β-cell function. Thirty-one subjects (age: 61.4 ± 2.5 yr; body mass index: 32.1 ± 1.0 kg/m2) with prediabetes [American Diabetes Association criteria, 75-g oral glucose tolerance test (OGTT)] were randomized to work-matched CONT (70% HRpeak) or INT (3 min 90% HRpeak and 3 min 50% HRpeak) exercise for 60 min/day over 2 wk. A 75-g 2-h OGTT was conducted after an overnight fast, and plasma glucose, insulin, C-peptide, and free fatty acids were determined for calculations of skeletal muscle [oral minimal model (OMM)], hepatic (homeostatic model of insulin resistance), and adipose (Adipose-IR) insulin sensitivity. β-Cell function was defined from glucose-stimulated insulin secretion (GSIS, deconvolution modeling) and the disposition index (DI). Glucagon-like polypeptide-1 [GLP-1(active)] and glucose-dependent insulinotropic polypeptide (GIP) were also measured during the OGTT, along with peak oxygen consumption and body composition. CONT and INT increased skeletal muscle- but not hepatic- or adipose-derived DI ( P < 0.05). Although both treatments tended to reduce fasting GLP-1(active) ( P = 0.08), early phase GLP-1(active) increased post-CONT and INT training ( P < 0.001). Interestingly, CONT exercise increased fasting GIP compared with decreases in INT ( P = 0.02). Early and total-phase skeletal muscle DI correlated with decreased total glucose area under the curve ( r = −0.52, P = 0.002 and r = −0.50, P = 0.003, respectively). Independent of intensity, short-term training increased pancreatic function adjusted to skeletal muscle in relation to improved glucose tolerance in adults with prediabetes. Exercise also uniquely affected GIP and GLP-1(active). Further work is needed to elucidate the dose-dependent mechanism(s) by which exercise impacts glycemia. NEW & NOTEWORTHY Exercise is cornerstone for reducing blood glucose, but whether high-intensity interval training is better than moderate continuous exercise is unclear in people with prediabetes before weight loss. We show that 2 wk of exercise training, independent of intensity, increased pancreatic function in relation to elevated glucagon-like polypeptide-1 secretion. Furthermore, β-cell function, but not insulin sensitivity, was also correlated with improved glucose tolerance. These data suggest that β-cell function is a strong predictor of glycemia regardless of exercise intensity.

Exercise improves pancreatic function in an energy dose-dependent manner. We previously showed that when calories are matched, an acute exercise bout changes glucose-stimulated insulin secretion (GSIS) relative to multi-organ insulin resistance (IR) in an intensity-based manner during the immediate post-exercise period in people with prediabetes. However, the impact of short-term training intensity on ß-cell function is unknown. Thus, we examined the impact of high-intensity interval and moderate-continuous training on GSIS relative to multi-organ IR in adults with prediabetes. Thirty-one adults (Age: 61±8y; BMI: 33±6 kg/m2) with prediabetes according to ADA 75g OGTT and/or HbA1c criteria were randomized to energy-matched interval (INT: 60-min/d alternating 3-min at 90 and 50% HRpeak) or continuous training (CONT: 60-min/d 70% HRpeak) for 2 weeks. Fitness (VO2peak) and body mass were measured before and after, and a 120-min 75g OGTT with blood samples for glucose, insulin, C-peptide and FFA were determined every 30-min. GSIS (C-pep/Glc tAUC0-120min) and ß-cell function (Disposition Index [DI: GSIS/IR]) relative to skeletal muscle (InsulintAUC x GlctAUC), hepatic (HOMA-IR) and adipose (Adipose-IRfasting) IR were calculated. Training increased VO2peak (+1.1±2.1 mL/kg/min), and reduced body mass (-0.6±1.1 kg) and IR (-11±31%), independent of intensity (P Disclosure M.E. Francois: None. N. Eichner: None. N.M. Gilbertson: None. E.M. Heiston: None. E. Barrett: None. S.K. Malin: None.

Although low-calorie diets (LCD) improve glucose regulation, it is unclear if interval exercise (INT) is additive. We examined the impact of an LCD versus LCD + INT training on &szlig, cell function in relation to glucose tolerance in obese adults. Twenty-six adults (Age: 46 &plusmn, 12 year, BMI 38 &plusmn, 6 kg/m2) were randomized to 2-week of LCD (~1200 kcal/day) or energy-matched LCD + INT (60 min/day alternating 3 min at 90 and 50% HRpeak). A 2 h 75 g oral glucose tolerance test (OGTT) was performed. Insulin secretion rates (ISR) were determined by deconvolution modeling to assess glucose-stimulated insulin secretion ([GSIS: ISR/glucose total area under the curve (tAUC)]) and &szlig, cell function (Disposition Index [DI: GSIS/IR]) relative to skeletal muscle (Matsuda Index), hepatic (HOMA-IR) and adipose (Adipose-IRfasting) insulin resistance (IR). LCD + INT, but not LCD alone, reduced glucose and total-phase ISR tAUC (Interactions: p = 0.04 and p = 0.05, respectively). Both interventions improved skeletal muscle IR by 16% (p = 0.04) and skeletal muscle and hepatic DI (Time: p &lt, 0.05). Improved skeletal muscle DI was associated with lower glucose tAUC (r = &minus, 0.57, p &lt, 0.01). Thus, LCD + INT improved glucose tolerance more than LCD in obese adults, and these findings relate to &szlig, cell function. These data support LCD + INT for preserving pancreatic function for type 2 diabetes prevention.

Purpose Conflicting results are reported for maintenance treatment with bevacizumab during chemotherapy-free intervals (CFI) in metastatic colorectal cancer after induction chemotherapy. Patients and Methods In this open-label, phase III, randomized controlled trial, we compared the tumor control duration (TCD) observed with bevacizumab maintenance and with no treatment (observation) during CFI subsequent to induction chemotherapy with 12 cycles of fluorouracil, leucovorin, and irinotecan plus bevacizumab. After disease progression, the induction regimen was repeated for eight cycles, followed by a new CFI. Results From March 2010 to July 2013, 491 patients were randomly assigned. Disease progression or death occurred during induction chemotherapy in 85 patients (17%); 261 patients (53%) had at least one reinduction, 107 (22%) had two reinductions, and 56 (11%) had three or more reinductions. The median TCD was 15 months in both groups; the median progression-free survival (PFS) from randomization was 9.2 and 8.9 months in the maintenance group and observation groups, respectively. The TCD observed in both groups was higher compared with the TCD hypotheses of the trial. The median overall survival (OS) was 21.7 and 22.0 months in the maintenance and observation groups, respectively. In the per-protocol population, defined as patients with at least one reinduction after the first progression, the median duration of the first CFI was 4.3 months in both arms; the median TCD was 17.8 and 23.3 months ( P = .339), the median PFS was 9.9 and 9.5 months, and the median OS was 27.6 and 28.5 months in the maintenance and observation groups, respectively. Multivariable analysis revealed that female gender, WHO performance status ≥ 2, and unresected primary tumors were associated with a shorter TCD. Conclusion Bevacizumab maintenance monotherapy did not improve TCD, CFI duration, PFS, or OS.

IF 11.855; International audience; Background :Metastatic colorectal cancer frequently occurs in elderly patients. Bevacizumab in combination with front line chemotherapy (CT) is a standard treatment but some concern raised about tolerance of bevacizumab for these patients. The purpose of PRODIGE 20 was to evaluate tolerance and efficacy of bevacizumab according to specific end points in this population.Patients and methods :Patients aged 75 years and over were randomly assigned to bevacizumab + CT (BEV) versus CT. LV5FU2, FOLFOX and FOLFIRI regimen were prescribed according to investigator’s choice. The composite co-primary end point, assessed 4 months after randomization, was based on efficacy (tumor control and absence of decrease of the Spitzer QoL index) and safety (absence of severe cardiovascular toxicities and unexpected hospitalization). For each arm, the treatment will be consider as inefficient if 20% or less of the patients met the efficacy criteria and not safe if 40% or less met the safety criteria.Results :About 102 patients were randomized (51 BEV and 51 CT), median age was 80 years (range 75–91). Primary end point was met for efficacy in 50% and 58% and for safety in 61% and 71% of patients in BEV and CT, respectively. Median progression-free survival was 9.7 months in BEV and 7.8 months in CT. Median overall survival was 21.7 months in BEV and 19.8 months in CT. The 36-month overall survival rate was 27% in BEV and 10.1% in CT. Severe toxicities grade 3/4 were mainly non-hematologic toxicities (80.4% in BEV, 63.3% in CT).Conclusion :Bevacizumab combined with CT was safe and efficient. Both arms met the primary safety and efficacy criteria.

Background KEYNOTE-181 (NCT02564263) was an open-label, randomized, phase 3 trial of pembrolizumab (pembro) vs investigator choice of single-agent paclitaxel/docetaxel/irinotecan (chemo) in advanced/metastatic esophageal AC or SCC. Pts were enrolled in partially overlapping periods, initially globally and then in China with an extension period. We present results from the global and China cohorts. Methods Pts were randomized 1:1 to receive pembro or chemo. Randomization was stratified by histology (SCC vs AC) and region (Asia vs rest of world). Primary end points were OS in the ITT, SCC, and PD-L1 CPS ≥10 populations. Results There were 628 and 123 pts in the global and China cohorts, respectively. In the global cohort, 314 pts were randomized to receive pembro (199 [63%] had SCC; 107 [34%] had CPS ≥10 tumors); 314 pts to chemo (204 [65%] had SCC; 115 [37%] had CPS ≥10 tumors). Median follow-up was 7.1 mo (pembro) vs 6.9 mo (chemo). Median OS with pembro vs chemo was similar in the ITT group (7.1 vs 7.1 mo) and longer in the SCC (8.2 vs 7.1 mo) and CPS ≥10 groups (9.3 vs 6.7 mo). 12-month OS rates were higher with pembro in all groups (ITT 32% vs 24%; SCC 39% vs 25%; CPS ≥10 42% vs 20%). In the China cohort, 62 pts were randomized to pembro (60 had SCC; 25 had CPS ≥10 tumors); and 61 pts to chemo (59 had SCC; 29 had CPS ≥10 tumors). Median follow-up was 8.3 mo (pembro) vs 5.6 mo (chemo). Median OS was higher with pembro in the ITT (8.4 vs 5.6 mo; HR 0.55; 95% CI 0.36-0.82), SCC (8.4 vs 5.6 mo; HR 0.55; 95% CI 0.37-0.83), and CPS ≥10 groups (12.0 vs 5.3 mo; HR 0.34; 95% CI 0.17-0.69). 12-month OS rates were higher with pembro in all groups (ITT 36% vs 17%; SCC 36% vs 16%; CPS ≥10 53% vs 16%). Fewer pts had TRAEs with pembro than chemo (global 64% vs 86%; China 76% vs 83%). TRAE rates resulting in discontinuation with pembro vs chemo were comparable in the global cohort (6% each) and lower with pembro in the China cohort (6% vs 12%). Conclusions Pembro and chemo showed comparable OS as 2L therapy for esophageal AC/SCC in the global ITT cohort. Pembro showed favorable OS in SCC and CPS ≥10 groups in the global cohort and in all groups in the China cohort, in which most patients had SCC. Pembro showed favorable safety in both cohorts. Clinical trial identification NCT02564263. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Traci Stuve, MA, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure S-B. Kim: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi-Aventis; Research grant / Funding (institution): Kyowa-Kirin; Research grant / Funding (institution): DongKook Pharmaceutical. T. Doi: Advisory / Consultancy: Kyowa Hakko Kirin, MSD, Daiichi Sankyo, Amgen, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, AbbVie, Novartis, Bayer; Research grant / Funding (institution): Taiho Pharmaceutical, Novartis, Merck Serono, MSD, Boehringer Ingelheim, Pfizer, Lilly Japan, Sumitomo Group, Kyowa Hakko Kirin, Daiichi Sankyo, Bristol-Myers Squibb, AbbVie, Quintiles, Eisai. K. Kato: Research grant / Funding (institution): MSD, ONO Pharmaceutical, Shionogi, Merck Serono. M. Shah: Research grant / Funding (institution): Merck, Roche, Boston Biomedical. A. Adenis: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier. T. Kojima: Non-remunerated activity/ies, Other- Patents, Royalties, other Intellectual Property: Ono Pharmaceutical, MSD, Shionogi Pharma, Oncolys BioPharma, Astellas Amgen BioPharama; Honoraria (self): Oncolys BioPharma. J-P. Metges: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck; Honoraria (self): Bayer-Health; Honoraria (self): Lilly; Advisory / Consultancy: ERYTECH Pharma; Advisory / Consultancy: Sanofi. E. Francois: Research grant / Funding (institution): MSD; Non-remunerated activity/ies, +Personal Fees: Roche; Non-remunerated activity/ies, +Personal Fees: Servier; Non-remunerated activity/ies, +Personal Fees: Merck; Non-remunerated activity/ies, +Personal Fees: Amgen; Non-remunerated activity/ies, +Personal Fees: Sanofi; Non-remunerated activity/ies, +Personal Fees: Novartis; Non-remunerated activity/ies, +Personal Fees: Bayer. K. Muro: Honoraria (self): Takeda, Chugai Pharma, Yakult Honsha, Merck Serono, Taiho Pharmaceutical, Lilly, Ono Pharmaceutical, Bayer; Research grant / Funding (institution): Ono Pharmaceutical, MSD, Daiichi Sankyo, Shionogi, Kyowa Hakko Kirin, Gilead Sciences, Merck Serono, Pfizer, Sanofi. R. Wang: Full / Part-time employment: Merck & Co., Inc. Y. Cui: Full / Part-time employment: MSD China. P. Bhagia: Full / Part-time employment: Merck & Co., Inc. All other authors have declared no conflicts of interest.

Background Anal squamous cell carcinoma (SCCA) is associated with E6 and E7 oncoproteins encoded by human papillomavirus (HPV) 16. Addition of Docetaxel to 5-Fluorouracil plus Cisplatin (DCF) induces favorable disease control and complete remission rate in recent clinical trials. Taking this observation into account, we decided to analyze the impact of DCF chemotherapy on adaptive immunity and immunosuppressive cells in SCCA. Methods Peripheral blood mononuclear cells from healthy donors and SCCA patients included in Epitopes-HPV01 and 02 studies were analyzed. The presence of T-cell responses after short term T-cell stimulation against HPV16-E6/E7 and TERT-antigens was measured by IFNγ-ELISpot. Immune checkpoint expression and immunosuppressive cells were monitored by flow cytometry. Results We first observed an enhanced HPV-specific T-cell response following DCF chemotherapy. Our investigations also suggest that TERT might be a relevant antigen in HPV-driven cancers. TERT-restricted CD4 Th1 were correlated to E6 responses and also enhanced following DCF treatment of SCCA patients. The distribution of T-cell exhaustion markers on peripheral T lymphocytes unraveled a drop of CD226 expression and the emergence of CD226-TIGIT+ T-cell subset. Monocytic-myeloid-derived-suppressor cells (M-MDSC) and regulatory T-cell (Treg) rates were increased. Treg levels and T-cell exhaustion markers did not influence clinical outcomes and frequencies of specific immune responses. M-MDSC levels monitored after DCF chemotherapy were correlated with progression free survival and antigen-specific T-cell response intensity and diversity. Conclusions DCF chemotherapy did not impair antigen-specific T-cell responses, supporting the potential interest to combine DCF chemotherapy with immunotherapies. Moreover, our study identifies post-therapy M-MDSC as a prognostic factor in SCCA patients. Clinical trial identification Epitopes-HPV01: NCT01845779 Epitopes-HPV02: NCT02402842. Legal entity responsible for the study University Hospital of Besancon. Funding Besancon University Hospital, Ligue Contre le cancer Grand-Est and Association Nationale de la Recherche et de la Technologie. Disclosure All authors have declared no conflicts of interest.

Postprandial hyperglycemia has deleterious effects on endothelial function. Restricting carbohydrate intake and postmeal walking have each been shown to reduce postprandial hyperglycemia, but their combination and subsequent effects on endothelial function have not been investigated. Here, we sought to examine the effect of blunting postprandial hyperglycemia by following a low-carbohydrate diet, with or without postmeal walking exercise, on markers of vascular health in type 2 diabetes (T2D). In a randomized crossover design, individuals with T2D ( n = 11) completed three 4-day controlled diet interventions consisting of 1) low-carbohydrate diet alone (LC), 2) low-carbohydrate diet with 15-min postmeal walks (LC + Ex), and 3) low-fat control diet (CON). Fasting blood samples and brachial artery flow-mediated dilation (%FMD) were measured before and after each intervention. Total circulating microparticles (MPs), endothelial MPs, platelet MPs, monocyte-platelet aggregates, and adhesion molecules were assessed as biomarkers of vascular health. There was a significant condition × time interaction for %FMD ( P = 0.01), with post hoc tests revealing improved %FMD after LC + Ex (+0.8 ± 1.0%, P = 0.02), with no change after LC or CON. Endothelial MPs were significantly reduced with the LC diet by ~45% (from 99 ± 60 to 44 ± 31 MPs/μl, P = 0.02), with no change after LC + Ex or CON (interaction: P = 0.04). Total MPs were lower (main effect time: P = 0.02), whereas monocyte-platelet aggregates were higher (main effect time: P < 0.01) after all interventions. Plasma adhesion molecules and C-reactive protein were unaltered. Attenuating postprandial hyperglycemic excursions using a low-carbohydrate diet combined with postmeal walking appears to be an effective strategy to improve endothelial function in individuals with T2D.NEW & NOTEWORTHY Carbohydrate restriction and postmeal walking lower postprandial hyperglycemia in individuals with type 2 diabetes. Here, we show that the combination significantly improved endothelial function and that carbohydrate restriction alone reduced circulating endothelial microparticles in individuals with type 2 diabetes.Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/low-carb-diet-and-exercise-improve-endothelial-health/ .

Lifestyle interventions incorporating both diet and exercise strategies remain cornerstone therapies for treating metabolic disease. Carbohydrate-restriction and high-intensity interval training (HIIT) have independently been shown to improve cardiovascular and metabolic health. Carbohydrate-restriction reduces postprandial hyperglycemia, thereby limiting potential deleterious metabolic and cardiovascular consequences of excessive glucose excursions. Additionally, carbohydrate-restriction has been shown to improve body composition and blood lipids. The benefits of exercise for improving insulin sensitivity are well known. In this regard, HIIT has been shown to rapidly improve glucose control, endothelial function, and cardiorespiratory fitness. Here, we report the available evidence for each strategy and speculate that the combination of carbohydrate-restriction and HIIT will synergistically maximize the benefits of both approaches. We hypothesize that this lifestyle strategy represents an optimal intervention to treat metabolic disease; however, further research is warranted in order to harness the potential benefits of carbohydrate-restriction and HIIT for improving cardiometabolic health.

IF 11.855; International audience

IF 11.855; International audience

Type 2 diabetes (T2D) is characterized by chronic low-grade inflammation that contributes to disease pathophysiology. Exercise has anti-inflammatory effects, but the impact of high-intensity interval training (HIIT) is not known. The purpose of this study was to determine the impact of a single session of HIIT on cellular, molecular, and circulating markers of inflammation in individuals with T2D. Participants with T2D ( n = 10) and healthy age-matched controls (HC; n = 9) completed an acute bout of HIIT (7 × 1 min at ~85% maximal aerobic power output, separated by 1 min of recovery) on a cycle ergometer with blood samples obtained before (Pre), immediately after (Post), and at 1 h of recovery (1-h Post). Inflammatory markers on leukocytes were measured by flow cytometry, and TNF-α was assessed in both LPS-stimulated whole blood cultures and plasma. A single session of HIIT had an overall anti-inflammatory effect, as evidenced by 1) significantly lower levels of Toll-like receptor (TLR) 2 surface protein expression on both classical and CD16+ monocytes assessed at Post and 1-h Post compared with Pre ( P < 0.05 for all); 2) significantly lower LPS-stimulated TNF-α release in whole blood cultures at 1-h Post ( P < 0.05 vs. Pre); and 3) significantly lower levels of plasma TNF-α at 1-h Post ( P < 0.05 vs. Pre). There were no differences between T2D and HC, except for a larger decrease in plasma TNF-α in HC vs. T2D (group × time interaction, P < 0.05). One session of low-volume HIIT has immunomodulatory effects and provides potential anti-inflammatory benefits to people with, and without, T2D.

Summary Background Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. Funding National Institute of Neurological Disorders and Stroke.

Purpose To compare energy use and substrate partitioning arising from repeated lower- versus upper-body sprints, or endurance exercise, across a 24-h period. Methods Twelve untrained males (24 ± 4 y) completed three trials in randomized order: (1) repeated sprints (five 30-s Wingate, 4.5-min recovery) on a cycle ergometer (SITLegs); (2) 50-min continuous cycling at 65% VO2max (END); (3) repeated sprints on an arm-crank ergometer (SITArms). Respiratory gas exchange was assessed before and during exercise, and at eight points across 22 h of recovery. Results Metabolic rate was elevated to greater extent in the first 8 h after SITLegs than SITArms (by 0.8 ± 1.1 kJ/min, p = 0.03), and tended to be greater than END (by 0.7 ± 1.3 kJ/min, p = 0.08). Total 24-h energy use (exercise + recovery) was equivalent between SITLegs and END (p = 0.55), and SITLegs and SITArms (p = 0.13), but 24-h fat use was higher with SITLegs than END (by 26 ± 38 g, p = 0.04) and SITArms (by 27 ± 43 g, p = 0.05), whereas carbohydrate use was higher with SITArms than SITLegs (by 32 ± 51 g, p = 0.05). Plasma volume-corrected post-exercise and fasting glucose and lipid concentrations were unchanged. Conclusion Despite much lower energy use during five sprints than 50-min continuous exercise, 24-h energy use was not reliably different. However, (i) fat metabolism was greater after sprints, and (ii) carbohydrate metabolism was greater in the hours after sprints with arms than legs, while 24-h energy usage was comparable. Thus, sprints using arms or legs may be an important adjunct exercise mode for metabolic health.

IMPACT: 5.922; International audience; BACKGROUND: This trial evaluated the feasibility and efficacy of combined sorafenib and irinotecan (NEXIRI) as second- or later-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), who had progressed after irinotecan-based chemotherapy. METHODS: In Phase I, in a 3+3 dose escalation schedule, patients received irinotecan (125, 150 or 180 mg m(-2) every 2 weeks), in combination with 400 mg sorafenib b.d. The primary end point was the maximum-tolerated dose of irinotecan. In Phase II, the primary end point was disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Phase I included 10 patients (median age 63 (49-73)); no dose-limiting toxicity was seen. In Phase II, 54 patients (median age 60 (43-80) years) received irinotecan 180 mg m(-)(2) every 2 weeks with sorafenib 400 mg b.d. Nine patients (17%) remained on full-dose sorafenib. The DCR was 64.9% (95% CI, 51-77). Median PFS and OS were 3.7 (95% CI, 3.2-4.7) and 8.0 (95% CI, 4.8-9.7) months, respectively. Toxicities included Grade 3 diarrhoea (37%), neutropenia (18%), hand-foot syndrome (13%) and Grade 4 neutropenia (17%). CONCLUSION: The NEXIRI regimen showed promising activity as second- or later-line treatment in this heavily pretreated mCRC population (ClinicalTrials.gov NCT00989469).

High-intensity interval training (HIIT) interventions improve cardiovascular health, yet the acute effects on circulating and functional biomarkers of cardiovascular function are unclear in individuals with type 2 diabetes (T2D). To explore this, we conducted two investigations to examine the acute response to HIIT in individuals with T2D. Study 1 measured blood pressure, endothelial-dependent dilation, circulating measures of endothelial activation, and troponin T, 30 min and 2 h after HIIT (7 × 1-min intervals) in T2D (n = 8) and age-matched normoglycemic controls (CTL; n = 8). Study 2 assessed circulating measures of endothelial activation and troponin T, 30 min, and 24 h after HIIT (10 × 1-min intervals) in ten previously trained T2D men. In study 1, markers of endothelial function and activation within the first 2 h after HIIT did not differ from baseline between T2D and CTL participants, except at 30 min after HIIT for glucose, which was reduced more in T2D than CTL (by −0.8 ± 1.2 mmol/L, p = 0.04), and VCAM-1, which was reduced more 30 min after HIIT in CTL compared to T2D (by −187 ± 221 ng/mL, p = 0.05). Study 2 saw no significant difference in any circulating markers of endothelial activation and troponin T, 30 min, and 24 h after HIIT in trained T2D males. Exploratory findings from these two studies suggest that acute HIIT does not substantially alter circulating and functional markers of cardio(vascular) health in individuals with T2D who are unaccustomed (study 1) and accustomed to HIIT (study 2).

Background Standard treatment for T2-3 M0 rectal adenocarcinoma is rectal resection (TME) often combined with neoadjuvant CRT. If a clinical complete response (cCR) is achieved a “watch and wait” (or local excision) is a possible option to improve quality of life. The Lyon R96-02 phase III trial has demonstrated that adding a CXB boost to CRT was able to increase safely the chance of cCR (1). Since the manufacture in 2010 of the PapillonTM CXB machine, this strategy has seen a renaissance. Methods Between 2003 and 2016, 74 patients M0 have been treated in 3 French centres (Lyon, Mâcon, Nice). Median age was 74 years. Classification was done using MRI and/or Endorectal ultrasound. T2: 45, T3: 29. CRT was: CAP 50 (capecitabine: 800 mg/m2 BID + RT: 50 Gy/ 25 fr/5 weeks). CXB delivered a local boost of 90-110 Gy in3-4 fractions over 4-6 weeks either before or after CRT. The boost was given first if T Results Out of 74 patients with a median follow-up time of 40 months, the cCR rate at 6 months (after treatment initiation) was 95%. The 3-year local recurrence rate and specific cancer survival were respectively 10% and 88%. Organ preservation was seen in 95% with a good bowel function in 90% of cases. Among 6 patients with local recurrence none was seen for polypoid T2T3a Conclusions A possible option for T2 T3 a-b References: 1- Gerard JP et al. J Clin Oncol. 2004 Jun 15;22(12):2404-9. 2- Gerard JP et al. Eur J Cancer. 2019 Feb; 108:1-16. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure J. Gerard: Advisory / Consultancy, None: Ariane Medical Systems. All other authors have declared no conflicts of interest.

Background The addition of docetaxel to cisplatin and 5FU (DCF) has shown a promising efficacy in Epitopes-HPV01 study with 4 of first 8 consecutive patients presenting a long-lasting complete response. Then, the prospective, multicenter, Epitopes-HPV02 trial, settled the modified DCF regimen as a new standard of care in metastatic or non-resectable locally advanced recurrent anal squamous cell carcinoma (ASCC). Here we present updated results of Epitopes-HPV02 study, as well as final results of Epitopes-HPV01 study. Methods Epitopes-HPV02 was a phase 2 study supported by the GERCOR and FFCD collaborative oncological groups, performed in 25 academic and community hospitals in France. Epitopes-HPV01 was a real-life based cohort study performed by the regional cancer network of Franche-Comte, France, and including one university hospital, 5 community hospitals, and 1 private center. Both studies included patients with histologically confirmed ASCC, with metastatic disease, or with unresectable local recurrence after chemoradiotherapy, and treated with DCF regimen. Results In Epitopes-HPV02, 69 patients were enrolled between Sept 2014-Dec 2016, and 66 patients were included for analysis; while 51 patients were included between Sept 2012- January 2019 in Epitopes-HPV01, and 49 patients for analysis. Pooled analysis of 115 patients showed a median PFS of 12 months (95% CI 10.6-16.0) [11.0 months (9.3-16.0) in -HPV02, and 12.7 months (11.2-34.5) in -HPV01, (p = 0.14)]. The median OS was 50.2 months (26.0-120.0) [not reached in -HPV02, and 50.2 months (21.4-120.0) in -HPV01 (p = 0.73)]. ORR was 87.7% (89% in -HPV02 and 85.1% in -HPV01) with 40.7% of CR (45% in -HPV02 and 34% in -HPV01). No difference was observed between standard DCF (n = 54) and modified DCF (n = 58) in OS (p = 0.93) and PFS (p = 0.52).No treatment-related death was observed in both studies. The median PFS in second-line was 5.9 months (3.3-7.1). Conclusions Pooled analysis of Epitopes-HPV01 and 2 results, confirm mDCF as the regimen of choice in fit patients with metastatic or locally advanced recurrent ASCC. Clinical trial identification NCT01845779, NCT02402842. Legal entity responsible for the study CHU Jean Minjoz, Besancon. Funding Besancon University Hospital and Ligue Contre le Cancer Grand-Est. Disclosure All authors have declared no conflicts of interest.

Object Aneurysmal subarachnoid hemorrhage (aSAH) predisposes to delayed neurological deficits, including stroke and cognitive and neuropsychological abnormalities. Heparin is a pleiotropic drug that antagonizes many of the pathophysiological mechanisms implicated in secondary brain injury after aSAH. Methods The authors performed a retrospective analysis in 86 consecutive patients with Fisher Grade 3 aSAH due to rupture of a supratentorial aneurysm who presented within 36 hours and were treated by surgical clipping within 48 hours of their ictus. Forty-three patients were managed postoperatively with a low-dose intravenous heparin infusion (Maryland low-dose intravenous heparin infusion protocol: 8 U/kg/hr progressing over 36 hours to 10 U/kg/hr) beginning 12 hours after surgery and continuing until Day 14 after the ictus. Forty-three control patients received conventional subcutaneous heparin twice daily as deep vein thrombosis prophylaxis. Results Patients in the 2 groups were balanced in terms of baseline characteristics. In the heparin group, activated partial thromboplastin times were normal to mildly elevated; no clinically significant hemorrhages or instances of heparin-induced thrombocytopenia or deep vein thrombosis were encountered. In the control group, the incidence of clinical vasospasm requiring rescue therapy (induced hypertension, selective intraarterial verapamil, and angioplasty) was 20 (47%) of 43 patients, and 9 (21%) of 43 patients experienced a delayed infarct on CT scanning. In the heparin group, the incidence of clinical vasospasm requiring rescue therapy was 9% (4 of 43, p = 0.0002), and no patient suffered a delayed infarct (p = 0.003). Conclusions In patients with Fisher Grade 3 aSAH whose aneurysm is secured, postprocedure use of a low-dose intravenous heparin infusion may be safe and beneficial.

Object The object of this study was to assess outcomes in patients with arteriovenous malformations (AVMs) treated by Gamma Knife stereotactic radiosurgery (SRS); lesions were stratified by size, symptomatology, and Spetzler-Martin (S-M) grade. Methods The authors performed a retrospective analysis of 102 patients treated for an AVM with single-dose or staged-dose SRS between 1993 and 2004. Lesions were grouped by S-M grade, as hemorrhagic or nonhemorrhagic, and as small (< 3 cm) or large (≥ 3 cm). Outcomes included death, morbidity (new neurological deficit, new-onset seizure, or hemorrhage/rehemorrhage), nidus obliteration, and Karnofsky Performance Scale score. Results The mean follow-up was 8.5 years (range 5–16 years). Overall nidus obliteration (achieved in 75% of patients) and morbidity (19%) correlated with lesion size and S-M grade. For S-M Grade I–III AVMs, nonhemorrhagic and hemorrhagic combined, treatment yielded obliteration rates of 100%, 89%, and 86%, respectively; high functional status (Karnofsky Performance Scale Score ≥ 80); and 1% mortality. For S-M Grade IV and V AVMs, outcomes were less favorable, with obliteration rates of 54% and 0%, respectively. The AVMs that were not obliterated had a mean reduction in nidus volume of 69% (range 35%–96%). On long-term follow-up, 10% of patients experienced hemorrhage/rehemorrhage (6% mortality rate), which correlated with lesion size and S-M grade; the mean interval to hemorrhage was 81 months. Conclusions For patients with S-M Grade I–III AVMs, SRS offers outcomes that are favorable and that, except for the timing of obliteration, appear to be comparable to surgical outcomes reported for the same S-M grades. Staged-dose SRS results in lesion obliteration in half of patients with S-M Grade IV lesions.

International audience

Different modes of exercise, disease, and training status can modify endothelial shear stress and result in distinct effects on endothelial function. To date, no study has examined the influence of type 2 diabetes (T2D) and training status on the acute endothelial response to different modes of interval exercise (INT). We examined the effect of a single session of resistance- and cardio-based INT compared with a time-matched control on endothelial function in 12 age-matched T2D participants, 12 untrained, and 11 trained adults (aged 56 ± 7 yr). Flow-mediated dilation (%FMD) of the brachial artery was assessed at baseline and immediately, 1, and 2 h after an acute bout of cardio interval (C-INT), resistance interval (R-INT), and seated control (CTL); these interventions were randomized and separated by >2 days. C-INT involved seven 1-min cycling intervals at 85% of peak power with 1-min recovery between. R-INT involved the same pattern of seven 1-min intervals using leg resistance exercises. Endothelial function (%FMD) was improved after R-INT in all groups (Condition × Time interaction, P < 0.01), an effect that was most robust in T2D where %FMD was higher immediately (+4.0 ± 2.8%), 1 h (+2.5 ± 2.5%), and 2 h (+1.9 ± 1.9%) after R-INT compared with CTL ( P < 0.01 for all). C-INT improved %FMD in T2D at 1-h postexercise (+1.6 ± 2.2%, P = 0.03) compared with CTL. In conclusion, R-INT acutely improves endothelial function throughout the 2-h postexercise period in T2D patients. The long-term impact of resistance exercise performed in an interval pattern is warranted.