The effect of acute and 14-day exogenous ketone supplementation on glycemic control in adults with type 2 diabetes: two randomized controlled trials.

Acute ingestion of the exogenous ketone monoester supplement [(R)-3-hydroxybutyl-(R)-3-hydroxybutyrate] lowers blood glucose, suggesting therapeutic potential in individuals with impaired glucose metabolism. However, it is unknown how acute or repeated ingestion of exogenous ketones affects blood glucose control in individuals with type 2 diabetes (T2D). We conducted two randomized, counterbalanced, double-blind, placebo-controlled crossover trials to determine if 1) acute exogenous ketone monoester (0.3 g/kg body mass; N = 18) or 2) 14-day thrice daily premeal exogenous ketone monoester (15 g; N = 15) supplementation could lower blood glucose in individuals living with T2D. A single dose of the ketone monoester supplement elevated blood ß-OHB to ∼2 mM. There were no differences in the primary outcomes of plasma glucose concentration (acutely) or serum fructosamine (glycemic control across 14 days) between conditions. Ketone monoester ingestion acutely increased insulin and lowered nonesterified fatty acid concentrations; plasma metabolomics confirmed a reduction in multiple free fatty acids species and select gluconeogenic amino acids. In contrast, no changes were observed in fasting metabolic outcomes following 14 days of supplementation. In the context of these randomized controlled trials, acute or repeated ketone monoester ingestion in adults with T2D did not lower blood glucose when consumed acutely in a fasted state and did not improve glycemic control following thrice daily premeal ingestion across 14 days. Future studies exploring the mechanistic basis for the (lack of) glucose-lowering effect of exogenous ketone supplementation in T2D and other populations are warranted.NEW & NOTEWORTHY Exogenous ketone supplements can acutely lower blood glucose, suggesting therapeutic potential in individuals with impaired glucose metabolism. However, the effect of exogenous ketones on glucose metabolism in adults with type 2 diabetes has not been investigated in a controlled setting. In adults with type 2 diabetes, ketone monoester ingestion did not lower blood glucose acutely in a fasted state and did not improve glycemic control across thrice daily premeal ingestion across 14 days.

Effect of the ketone beta-hydroxybutyrate on markers of inflammation and immune function in adults with type 2 diabetes.

Pre-clinical and cell culture evidence supports the role of the ketone beta-hydroxybutyrate (BHB) as an immunomodulatory molecule that may inhibit inflammatory signalling involved in several chronic diseases such as type 2 diabetes (T2D), but studies in humans are lacking. Therefore, we investigated the anti-inflammatory effect of BHB in humans across three clinical trials. To investigate if BHB suppressed pro-inflammatory cytokine secretion, we treated LPS-stimulated leukocytes from overnight-fasted adults at risk for T2D with BHB (Study 1). Next (Study 2), we investigated if exogenously raising BHB acutely in vivo by ketone monoester supplementation (KME) in adults with T2D would suppress pro-inflammatory plasma cytokines. In Study 3, we investigated the effect of BHB on inflammation via ex vivo treatment of LPS-stimulated leukocytes with BHB and in vivo thrice-daily pre-meal KME for 14 days in adults with T2D. Ex vivo treatment with BHB suppressed LPS-stimulated IL-1ß, TNF-α, and IL-6 secretion and increased IL-1RA and IL-10 (Study 1). Plasma IL-10 increased by 90 min following ingestion of a single dose of KME in T2D, which corresponded to peak blood BHB (Study 2). Finally, 14 days of thrice-daily KME ingestion did not significantly alter plasma cytokines or leukocyte subsets including monocyte and T-cell polarization (Study 3). However, direct treatment of leukocytes with BHB modulated TNF-α, IL-1ß, IFN-γ, and MCP-1 secretion in a time- and glucose-dependent manner (Study 3). Therefore, BHB appears to be anti-inflammatory in T2D, but this effect is transient and is modulated by the presence of disease, glycaemia, and exposure time.

Short-term ketone monoester supplementation improves cerebral blood flow and cognition in obesity: A randomized cross-over trial.

Adults with obesity are at increased risk of neurocognitive impairments, partly as a result of reduced cerebral blood flow and brain-derived neurotrophic factor (BDNF). Ketone supplements containing ß-hydroxybutyrate (ß-OHB) are a purported therapeutic strategy for improving brain health in at-risk populations. We tested the hypothesis that short-term ß-OHB supplementation will elevate cerebral blood flow and BDNF, as well as improve cognition in adults with obesity. In a placebo-controlled double-blind, cross-over design, 14 adults with obesity (10 females; aged 56 ± 12 years; body mass index = 33.8 ± 6.9 kg m-2 ) consumed 30 mL (12 g) of ß-OHB or placebo thrice-daily for 14 days. Blood flow (Q) and cerebrovascular conductance (CVC) were measured in the common carotid (CCA), internal carotid (ICA) and vertebral (VA) arteries by duplex ultrasound. BDNF was measured by an enzyme-linked immunosorbent assay. Cognition was assessed by the digit-symbol substitution (DSST), Stroop and task-switching tests. Following 14 days of ketone supplementation, we observed significant improvements in cerebrovascular outcomes including QCCA (+12%), QVA (+11%), VACVC (+12%) and VA shear rate (+10%). DSST performance significantly improved following ketone supplementation (+2.7 correct responses) and improved DSST performance was positively associated improvements in cerebrovascular outcomes including QCCA , CCACVC , QVA and VACVC . By contrast to one hypothesis, ß-OHB did not impact fasting serum and plasma BDNF. ß-OHB supplementation improved cognition in adults with obesity, which may be partly facilitated by improvements in cerebral blood flow. ß-OHB supplementation was well-tolerated and appears to be safe for cerebrovascular health, suggesting potential therapeutic benefits of ß-OHB in a population at risk of neurocognitive impairment. KEY POINTS: People with obesity are at increased risk of neurocognitive dysfunction, partly as a result of -induced reductions in cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF). Ketone supplements containing ß-hydroxybutyrate (ß-OHB) reduce postprandial hyperglycaemia, which may increase CBF and BDNF, thereby protecting against obesity-related cognitive dysfunction. We show for the first time that 14 days of thrice-daily ß-OHB supplementation improves aspects of cognition and increases cerebrovascular flow, conductance and shear rate in the extracranial arteries of adults with obesity. Our preliminary data indicate a significant positive relationship between elevated CBF and improved cognition following ß-OHB supplementation. This trial provides a foundation for the potential non-pharmacological therapeutic application of ß-OHB supplementation in patient groups at risk of hyperglycaemic cerebrovascular disease and cognitive dysfunction.

Clinical Data Extraction During Public Health Emergencies: A Blockchain Technology Assessment.

OBJECTIVE: We sought to explore the technical and legal readiness of healthcare institutions for novel data-sharing methods that allow clinical information to be extracted from electronic health records (EHRs) and submitted securely to the Food and Drug Administration's (FDA's) blockchain through a secure data broker (SDB). MATERIALS AND METHODS: This assessment was divided into four sections: an institutional EHR readiness assessment, legal consultation, institutional review board application submission, and a test of healthcare data transmission over a blockchain infrastructure. RESULTS: All participating institutions reported the ability to electronically extract data from EHRs for research. Formal legal agreements were deemed unnecessary to the project but would be needed in future tests of real patient data exchange. Data transmission to the FDA blockchain met the success criteria of data connection from within the four institutions' firewalls, externally to the FDA blockchain via a SDB. DISCUSSION: The readiness survey indicated advanced analytic capability in hospital institutions and highlighted inconsistency in Fast Healthcare Interoperability Resources format utilitzation across institutions, despite requirements of the 21st Century Cures Act. Further testing across more institutions and annual exercises leveraging the application of data exchange over a blockchain infrastructure are recommended actions for determining the feasibility of this approach during a public health emergency and broaden the understanding of technical requirements for multisite data extraction. CONCLUSION: The FDA's RAPID (Real-Time Application for Portable Interactive Devices) program, in collaboration with Discovery, the Critical Care Research Network's PREP (Program for Resilience and Emergency Preparedness), identified the technical and legal challenges and requirements for rapid data exchange to a government entity using the FDA blockchain infrastructure.

Changes in the Brain-Derived Neurotrophic Factor Are Associated with Improvements in Diabetes Risk Factors after Exercise Training in Adolescents with Obesity: The HEARTY Randomized Controlled Trial.

Obesity in youth increases the risk of type 2 diabetes (T2D), and both are risk factors for neurocognitive deficits. Exercise attenuates the risk of obesity and T2D while improving cognitive function. In adults, these benefits are associated with the actions of the brain-derived neurotrophic factor (BDNF), a protein critical in modulating neuroplasticity, glucose regulation, fat oxidation, and appetite regulation in adults. However, little research exists in youth. This study examined the associations between changes in diabetes risk factors and changes in BDNF levels after 6 months of exercise training in adolescents with obesity. The sample consisted of 202 postpubertal adolescents with obesity (70% females) aged 14-18 years who were randomized to 6 months of aerobic and/or resistance training or nonexercise control. All participants received a healthy eating plan designed to induce a 250/kcal deficit per day. Resting serum BDNF levels and diabetes risk factors, such as fasting glucose, insulin, homeostasis model assessment (HOMA-B-beta cell insulin secretory capacity) and (HOMA-IS-insulin sensitivity), and hemoglobin A1c (HbA1c), were measured after an overnight fast at baseline and 6 months. There were no significant intergroup differences on changes in BDNF or diabetes risk factors. In the exercise group, increases in BDNF were associated with reductions in fasting glucose (ß = -6.57, SE = 3.37, p = 0.05) and increases in HOMA-B (ß = 0.093, SE = 0.03, p = 0.004) after controlling for confounders. No associations were found between changes in diabetes risk factors and BDNF in controls. In conclusion, exercise-induced reductions in some diabetes risk factors were associated with increases in BDNF in adolescents with obesity, suggesting that exercise training may be an effective strategy to promote metabolic health and increases in BDNF, a protein favoring neuroplasticity. This trial is registered with ClinicalTrials.gov NCT00195858, September 12, 2005 (funded by the Canadian Institutes of Health Research).

Regulation of plasma agouti-related protein and its relationship with hunger in lean and obese men.

Agouti-related protein (AgRP) is an orexigenic (appetite stimulating) neuropeptide suggested to exert tonic control over long-term energy balance. While some have speculated AgRP is not involved in the episodic (i.e. meal to meal energy intake) control, acute decreases in plasma agouti-related protein (AgRP) following a meal have been observed in humans in a role consistent with episodic control for AgRP. Whether changes in plasma AgRP are associated with episodic, and/or tonic changes in appetite has yet to be directly examined. The present study examined the relationship between agouti-related protein (AgRP), leptin and the regulation of appetite following a 48-h fast and an acute meal challenge. Blood samples were obtained from young lean and obese men before and after a 48 h fast (lean n = 10; obese n = 7). Fasting resulted in an increase in AgRP and a decrease in leptin with these changes being greater in lean than obese. In addition, blood samples were obtained from lean men before and 1, 2, 3 and 4 h after a meal (n = 8). Following a meal, AgRP was reduced from 2 to 4 h, a change that was dissociated from both leptin and subjective measures of hunger and satiety. These results demonstrate that AgRP is not associated with changes in hunger or satiety, and can change without corresponding changes in leptin. This suggests that AgRP may not be involved in the episodic control of appetite and the release of AgRP may involve signals other than leptin.

Evaluation of 1D convolutional neural network in estimation of mango dry matter content.

This study empirically validates prior claims regarding the superior performance of a Convolutional Neural Network (CNN) model for estimating mango Dry Matter Content (DMC) using Near Infrared (NIR) spectroscopy. The Partial Least Squares (PLS), Artificial Neural Network (ANN), and CNN models employed in the previous publications were compared on an equal footing, i.e., employing the same training and test data, with consideration of the effect of other practices employed in those studies, i.e., outlier removal, training set partitioning, sample ordering, and spectral pretreatment and augmentation. A new benchmark RMSEP of 0.77 %FW was achieved, being statistically significant (P<0.05) different than the previously published best RMSEP for the same independent test set. This CNN model was also shown to be more robust when tested on a new season of fruit than optimised ANN and PLS models, with RMSEPs of 1.18, 2.62, and 1.87, and bias of 0.16, 2.36 and 1.56 %FW, respectively. The combination of model type and data augmentation was important, with the CNN model only slightly outperforming the ANN model when using only a second derivative pretreatment. This requirement highlights the need for chemometric input to model development. The quantification of the sensitivity of neural network model training to use of differing seeds for pseudo-random sequence generation is also recommended. The standard deviation in RMSEP of 50 ANN and CNN models trained with differing random seeds was 0.03 and 0.02 %FW, respectively.

Orienteering combines vigorous-intensity exercise with navigation to improve human cognition and increase brain-derived neurotrophic factor.

Exercise enhances aspects of human cognition, but its intensity may matter. Recent animal research suggests that vigorous exercise, which releases greater amounts of lactate, activates more brain-derived neurotrophic factor (BDNF) in the hippocampus and, thus, may be optimal for supporting cognitive function. The cognitive benefits of exercise may be further augmented when combined with cognitive training. The sport of orienteering simultaneously combines exercise with spatial navigation and, therefore, may result in greater cognitive benefits than exercising only, especially at vigorous intensities. The present study aimed to examine the effects of an acute bout of orienteering at different intensities on cognition and BDNF compared to exercising only. We hypothesized that vigorous-intensity orienteering would increase lactate and BDNF and improve cognition more than moderate-intensity orienteering or vigorous exercise alone. Sixty-three recreationally active, healthy young adults (Mage = 21.10±2.75 years) with no orienteering experience completed a 1.3 km intervention course by navigating and exercising at a vigorous (80-85% of heart rate reserve) or moderate (40-50% of heart rate reserve) intensity or exercising vigorously without navigation. Exercise intensity was monitored using peak lactate, heart rate and rating of perceived exertion. Serum BDNF was extracted immediately before and after the intervention. Memory was assessed using the Mnemonic Similarity Task (high-interference memory) and the Groton Maze Learning Test (spatial memory). Both exercising and orienteering at a vigorous intensity elicited greater peak lactate and increases in BDNF than moderate-intensity orienteering, and individuals with higher peak lactate also had greater increases in BDNF. High-interference memory improved after both vigorous-intensity interventions but did not improve after the moderate-intensity intervention. Spatial memory only increased after vigorous-intensity orienteering, suggesting that orienteering at a vigorous intensity may particularly benefit spatial cognition. Overall, the results demonstrate the benefits of vigorous exercise on human cognition and BDNF.

The BDNF Val66Met polymorphism and health-related quality of life in youth with obesity.

The brain derived-neurotrophic factor (BDNF) Val66Met polymorphism causes functional changes in BDNF, and is associated with obesity and some psychiatric disorders, but its relationship to health-related quality of life (HRQoL) remains unknown. This study examined, in youth with obesity, whether carriers of the BDNF Val66met polymorphism Met-alleles (A/A or G/A) differed from noncarriers (G/G) on HRQoL. The participants were 187 adolescents with obesity. Ninety-nine youth were carriers of the homozygous Val/Val (G/G) alleles, and 88 were carriers of the Val/Met (G/A) or Met/Met (A/A) alleles. Blood samples were drawn in the morning after an overnight fast for genotyping. HRQoL was measured using the Pediatric-Quality of Life core version. Compared to carriers of the Val66Met Val (G/G) alleles, carriers of the Met-Alleles reported significantly higher physical -HRQoL (p = 0.02), school-related HRQoL, (p = 0.05), social-related HRQoL (p = 0.05), and total HRQoL (p = 0.03), and a trend for Psychosocial-HRQoL. Research is needed to confirm our findings and determine whether carriers of the BDNF Val66Met homozygous Val (G/G) alleles may be at risk of diminished HRQoL, information that can influence interventions in a high-risk population of inactive youth with obesity.

Double Thyroglossal Duct Cyst: A Case Report.

Thyroglossal duct cysts are one of the most common cervical congenital anomalies. They occur along the thyroid migration tract, which extends from the base of the tongue through the midline of the neck to the level of the cricoid cartilage. Thyroglossal duct cysts present as a midline neck mass and are closely associated with the hyoid bone. Here, we describe a case where two cystic structures were found just inferior to the thyroid gland and inferior to the hyoid bone, suggesting a double thyroglossal duct cyst. It is important to diagnose and surgically manage thyroglossal duct cysts as they are associated with complications, such as infection and malignancy.

Palatal Supernumerary Tooth in a Pediatric Patient.

This report describes the case of a child with a congenital palatal lesion that grew rapidly in the first year of life and was found to be a supernumerary tooth. A 14-month-old male presented with a congenital midline palatal lesion visible behind his newly erupted maxillary central incisors. The lesion had been present since birth and was round, raised, firm, and covered with normal-appearing mucosa. The results from CT imaging indicated the lesion was a rudimentary tooth crown. It was excised and confirmed to be a supernumerary tooth. The patient healed without complications. Congenital palatal lesions with this appearance are most commonly hamartomas, cysts, epulides, and teratomas. Congenital midline palatal lesions are uncommon, and supernumerary teeth are not typically in the differential diagnosis. Imaging is helpful for the management of congenital palatal lesions.

Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes.

Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes.

Agreement and correlation between the self-report leeds assessment of neuropathic symptoms and signs and Douleur Neuropathique 4 Questions neuropathic pain screening tools in subjects with low back-related leg pain.

OBJECTIVE: The self-report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) and Douleur Neuropathique 4 Questions (DN4) neuropathic pain screening tools have been shown to be reliable, valid, and able to differentiate neuropathic pain from inflammatory or mixed pain syndromes. However, no studies have compared these tools to determine whether their outcomes are similar. This study evaluated agreement and correlation between the S-LANSS and DN4 in the identification of neuropathic pain in subjects with low back-related leg pain. METHODS: This observational study compared S-LANSS and DN4 scores in 45 patients with low back-related leg pain. The S-LANSS and DN4 cutoff scores of 12 and 4, respectively, were used to classify subjects as positive or negative for the presence of neuropathic pain for each screening tool. The κ statistic was used to determine whether there was agreement in classification of neuropathic pain between the 2 screening tools. Pearson correlation coefficient was used to determine correlation between scores of the 2 screening tools. RESULTS: Neuropathic pain was identified in 15 subjects (33%) using the S-LANSS and in 19 subjects (42%) using the DN4. Agreement on neuropathic pain classification was fair, with a κ value of 0.34. There was moderate to good correlation (r = 0.62; P < .001) between scores obtained from the 2 tools. CONCLUSIONS: The finding of fair agreement suggests that despite the moderate to good correlation between scores, the cutoff points for the classification of neuropathic pain of the 2 tools may not be congruent.

Acute submaximal exercise does not impact aspects of cognition and BDNF in people with spinal cord injury: A pilot study.

Objective: To investigate the effect of acute submaximal exercise, based on the spinal cord injury (SCI) Exercise Guidelines, on cognition and brain-derived neurotrophic factor (BDNF) in people with SCI. Design: Eight adults (7 males) with traumatic SCI volunteered in this pre-registered pilot study. In randomized order, participants completed submaximal intensity arm cycling (60% of measured peak-power output at 55-60 rpm) for 30 min or time-matched quiet rest (control condition) on separate days. Blood-borne BDNF was measured in serum and plasma at pre-intervention, 0 min and 90 min post-intervention. Cognition was assessed using the Stroop Test and Task-Switching Test on an electronic tablet pre- and 10 min post-intervention. Results: Submaximal exercise had no effect on plasma [F(2,12) = 1.09; P = 0.365; η² = 0.069] or serum BDNF [F(2,12) = 0.507; P = 0.614; η² = 0.024] at either 0 min or 90 min post-intervention. Similarly, there was no impact of exercise on either Stroop [F(1,7) = 2.05; P = 0.195; η² = 0.065] or Task-Switching performance [F(1,7) = 0.016; P = 0.903; η² < 0.001] compared to the control condition. Interestingly, there was a positive correlation between years since injury and resting levels of both plasma (r = 0.831; P = 0.011) and serum BDNF (r = 0.799; P = 0.023). However, there was not relationship between years since injury and the BDNF response to exercise. Conclusions: Acute guideline-based exercise did not increase BDNF or improve aspects of cognition in persons with SCI. This work establishes a foundation for continued investigations of exercise as a therapeutic approach to promoting brain health among persons with SCI.

Impact of an Acute Bout of Submaximal Aerobic Exercise on Circulating Leukocytes in Individuals with Spinal Cord Injury.

Individuals with spinal cord injury (SCI) may experience cardiovascular, musculoskeletal and organ function dysregulation. Sequelae include reduced catecholamine secretion and attenuated immune responses which may impact exercise-induced leukocytosis. The purpose of this study was to characterize major leukocyte subtypes following 30 minutes of acute, submaximal aerobic exercise, in line with updated international SCI exercise guidelines for adults. It was hypothesized that exercise would increase major leukocyte subtypes when compared to fasted baseline. Eight participants with SCI (incomplete n = 6; complete n = 2) completed a 30-minute bout of aerobic exercise on an arm cycle ergometer at 60% of their peak power output followed by 90 minutes of recovery, or a 2-hour seated control condition, in a randomized crossover design, separated by 7-14 days. Blood samples were taken at baseline, post exercise, and 90 minutes after exercise (with time matched control). Leukocyte subtypes were analyzed via flow cytometry and plasma catecholamines by ELISA. Several leukocytes increased from pre- to post-exercise (time X condition interaction; all P < 0.05; mean ± SD), including CD3+ Lymphocytes (19 ± 16%), CD4+ T helper (16 ± 13%), CD8+ T cytotoxic (24 ± 23%), CD3+/CD56+ natural killer T (31 ± 34%), and CD3-/CD56+ natural killer (63 ± 82%). CD16+/CD14dim monocytes decreased by 27 ± 38% following exercise to 90 minutes post-exercise. No changes were observed for catecholamines for either condition. Thirty minutes of acute submaximal aerobic exercise sufficiently increased most lymphocyte subsets with effector functions, while leading to decreased proinflammatory monocytes during the recovery phase. This exercise duration and intensity appear to be an appropriate option for modulating circulating immune cells in individuals with SCI.

Interindividual Differences in Trainability and Moderators of Cardiorespiratory Fitness, Waist Circumference, and Body Mass Responses: A Large-Scale Individual Participant Data Meta-analysis.

Although many studies have assumed variability reflects variance caused by exercise training, few studies have examined whether interindividual differences in trainability are present following exercise training. The present individual participant data (IPD) meta-analysis sought to: (1) investigate the presence of interindividual differences in trainability for cardiorespiratory fitness (CRF), waist circumference, and body mass; and (2) examine the influence of exercise training and potential moderators on the probability that an individual will experience clinically important differences. The IPD meta-analysis combined data from 1879 participants from eight previously published randomized controlled trials. We implemented a Bayesian framework to: (1) test the hypothesis of interindividual differences in trainability by comparing variability in change scores between exercise and control using Bayes factors; and (2) compare posterior predictions of control and exercise across a range of moderators (baseline body mass index (BMI) and exercise duration, intensity, amount, mode, and adherence) to estimate the proportions of participants expected to exceed minimum clinically important differences (MCIDs) for all three outcomes. Bayes factors demonstrated a lack of evidence supporting a high degree of variance attributable to interindividual differences in trainability across all three outcomes. These findings indicate that interindividual variability in observed changes are likely due to measurement error and external behavioural factors, not interindividual differences in trainability. Additionally, we found that a larger proportion of exercise participants were expected to exceed MCIDs compared with controls for all three outcomes. Moderator analyses identified that larger proportions were associated with a range of factors consistent with standard exercise theory and were driven by mean changes. Practitioners should prescribe exercise interventions known to elicit large mean changes to increase the probability that individuals will experience beneficial changes in CRF, waist circumference and body mass.

14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial.

CONTEXT: Postprandial hyperglycemia increases systemic inflammation and is a risk factor for cardiovascular disease. A ketone monoester (KME) drink containing ß-hydroxybutyrate (ß-OHB) rapidly lowers plasma glucose, which may be a strategy protecting against postprandial hyperglycemia. OBJECTIVE: We hypothesized that KME would attenuate 2-hour postprandial glucose, lower systemic inflammation, and improve vascular function in adults with obesity. METHODS: In a randomized crossover design, 14 participants with obesity (age = 56 ±â€…12 years; body mass index = 32.8 ±â€…7.7 kg/m2) consumed KME (12 g ß-OHB) or placebo 15 minutes prior to each meal for 14 days with all meals provided and matched between conditions. Postprandial glycemia was assessed by continuous glucose monitoring. Vascular function and inflammation were assessed before and after treatment periods. RESULTS: Postprandial glucose was 8.0% lower in KME versus placebo (g = 0.735; P = 0.011) and 24-hour average glucose reduced by 7.8% (g = 0.686; P = 0.0001). Brachial artery flow-mediated dilation increased from 6.2  ±â€… 1.5% to 8.9 ±â€…3.3% in KME (g = 1.05; P = 0.0004) with no changes in placebo (condition × time interaction, P = 0.004). There were no changes in plasma cytokines; however, lipopolysaccharide-stimulated monocyte caspase-1 activation was lower following KME supplementation versus placebo (stimulation × condition × time interaction; P = 0.004). The KME supplement was well tolerated by participants and adherence to the supplementation regimen was very high. CONCLUSIONS: In adults with obesity, 14 days of premeal KME supplementation improves glucose control, enhances vascular function, and may reduce cellular inflammation. KME supplementation may be a viable, nonpharmacological approach to improving and protecting vascular health in people with heightened cardiometabolic risk.

Perceived mental strain dissociates from perceived physical strain during relative intensity submaximal exercise on ascent from low to high altitude.

Perceived fatigability, which has perception of physical strain and of mental strain as its components, can impact exercise tolerance. Upon ascent to high altitude, low landers experience reduced exercise capacity and reduced tolerance for a given absolute submaximal work rate. It is established that perceived physical strain tracks with relative exercise intensity. However, it is not known how altitude ascent affects perceived mental strain relative to perceived physical strain. We tested the hypothesis that when exercising at the same relative exercise intensity perceived physical strain will remain unchanged whereas perceived mental strain will decrease on ascent from low to high altitude in the Everest region in Nepal. Twelve hours after arriving at each of three elevations; 1400 m, 3440 m, and 4240 m, 12 untrained participants used the task effort awareness (TEA) and physical-rating of perceived exertion (P-RPE) scales to report perceived mental and physical strain during a 20 min walking test at a self-monitored heart rate reserve (HRR) range of 40-60% (Polar HR Monitor). TEA and P-RPE were recorded twice during exercise (5-7 min and 14-16 min). Neither P-RPE (1400 m: 11.1 ± 1.8, 3440 m: 10.7 ± 1.2, 4240 m: 11.5 ± 1.5) nor %HRR (1400 m: 55.25 ± 7.34, 3440 m: 51.70 ± 6.70, 4240 m: 50.17 ± 4.02) changed as altitude increased. TEA decreased at 4240 m (2.05 ± 0.71) compared to 1400 m (3.44 ± 0.84)--this change was not correlated with any change in %HRR nor was it due to a change in core affect. These findings support our hypothesis and demonstrate the independence of perceived physical and perceived mental strain components of perceived fatigability. Implications for exercise tolerance remain to be determined.

Serum and plasma brain-derived neurotrophic factor concentration are elevated by systemic but not local passive heating.

Brain-derived neurotrophic factor (BDNF) plays a key role in neuronal adaptations. While previous studies suggest that whole-body heating can elevate circulating BDNF concentration, this is not known for local heating protocols. This study investigated the acute effects of whole-body versus local passive heating on serum and plasma BDNF concentration. Using a water-perfused suit, ten recreationally active males underwent three 90 min experimental protocols: heating of the legs with upper-body cooling (LBH), whole-body heating (WBH) and a control condition (CON). Blood samples were collected before, immediately after and 1 h post-heating for the determination of serum and plasma BDNF concentration, platelet count as well as the BDNF release per platelet. Rectal temperature, cardiac output and femoral artery shear rate were assessed at regular intervals. Serum and plasma BDNF concentration were elevated after WBH (serum: 19.1±5.0 to 25.9±11.3 ng/ml, plasma: 2.74±0.9 to 4.58±2.0; p<0.044), but not LBH (serum: 19.1±4.7 to 22.3±4.8 ng/ml, plasma: 3.25±1.13 to 3.39±0.90 ng/ml; p>0.126), when compared with CON (serum: 18.6±6.4 to 16.8±3.4 ng/ml, plasma: 2.49±0.69 to 2.82±0.89 ng/ml); accompanied by an increase in platelet count (p<0.001). However, there was no change in BDNF content per platelet after either condition (p = 0.392). All physiological measures were elevated to a larger extent after WBH compared with LBH (p<0.001), while shear rate and rectal temperature were higher during LBH than CON (p<0.038). In conclusion, WBH but not LBH acutely elevates circulating BDNF concentration. While these findings further support the use of passive heating to elevate BDNF concentration, a larger increase in shear rate, sympathetic activity and/or rectal temperature than found after LBH appears needed to induce an acute BDNF response by passive heating.

Screen time is independently associated with serum brain-derived neurotrophic factor (BDNF) in youth with obesity.

Low levels of brain derived-neurotrophic factor (BDNF) and excessive screen exposure are risk factors for neurocognitive deficits and obesity in youth, but the relationship between screen time and BDNF remains unknown. This study examined whether duration and/or type of sedentary screen time behaviour (TV viewing, video games, recreational computer use) are associated with serum BDNF levels in youth with obesity. The sample consisted of 250 inactive, postpubertal adolescents with obesity (172 females/78 males, aged 15.5 ± 1.4 years) at the baseline assessment of the Healthy Eating, Aerobic, Resistance Training in Youth Study. After controlling for self-reported age, sex, race, parental education, puberty stage, physical activity, and diet, higher total screen exposure was significantly associated with lower serum BDNF levels (ß = -0.21, p = 0.002). TV viewing was the only type of screen behaviour that was associated with BDNF levels (ß = -0.22, p = 0.001). Higher exposure to traditional forms of screen time was independently associated with lower serum BDNF levels, and this association appears to be driven primarily by TV viewing. Future intervention research is needed to determine whether limiting screen time is an effective way to increase BDNF and associated health benefits in a high-risk population of youth with obesity. Trial Registration: ClinicalTrials.Gov NCT00195858. Novelty: This study is the first to show that recreational screen time is inversely associated with serum BDNF levels. The inverse association between screen time and BDNF is driven primarily by TV viewing, indicating the type of screen might matter.