Crossover Design Research Articles

The relationship of pain intensity and opioid craving with delayed methadone dose: A preliminary study of individuals with opioid use disorder.

Despite a strong theoretical link between opioid craving and pain, little is known about the temporal relationship between pain and craving and the acute experience of pain in the context of methadone treatment. Using a cross-over design, the current study evaluated the time course of pain and craving and objective experience of pain as a function of the last methadone dose. Participants (n = 20) presented for the study in the morning and either received methadone dose as scheduled or delayed dose until the afternoon. During the 4-h study visit, participants completed a series of tasks, including repeated assessment of pain and craving at 0, +40, +70, +130, +160 and +240 min and a cold pressor test (CPT) at +15 and +220 min. Separate mixed model results demonstrated no effect of dosing condition on craving; however, there was a significant dosing condition by time interaction (F(5,209) = 3.38, P = .006) such that pain increased over time in the delayed methadone condition but decreased in time in the scheduled methadone condition. A mixed model predicting self-reported pain revealed a three-way interaction between dosing condition, craving and time (F(5,197) = 2.39, P = .039) explained by a positive association between craving and pain at each time point (except 240 min) in delayed condition (P-range = .004-.0001). A separate mixed model on CPT data indicated a significant condition by time interaction such that pain threshold decreased in the delayed, but not scheduled, condition (F(1,57) = 4.01, P = .050). These preliminary findings highlight the potential for increased risks after even a short delay in receiving a methadone dose.

Acute Treatment with the Nootropic CILTEP® Does Not Improve Cognitive Performance in Healthy Middle-Aged Participants

This study investigated the acute effects of the dietary nootropic stack CILTEP®. It contains a combination of ingredients that have been individually reported to improve cognitive performance. Especially, the ingredients luteolin, which is considered a phosphodiesterase type 4 (PDE4) inhibitor, and forskolin, an adenylate cyclase stimulator, were of interest since they can increase the second messenger cAMP and thus also intracellular signaling. Numerous studies have shown that inhibition of PDE4 can improve memory in animals and humans. We examined whether acute dosing of 3 capsules of CILTEP® would improve cognitive function in healthy participants aged 30 to 40 (n = 33). We used a randomized, double-blind, placebo-controlled, two-way cross-over design. Our test battery was aimed at measuring memory performance, attention, and sensorimotor speed. The primary outcome measures were the performance on the verbal learning task and the spatial pattern separation task. Secondary outcomes included other cognitive tests, event-related potentials (ERPs), and assessment of the activity of the enzyme beta-glucuronidase and its effect on the bioavailability of luteolin, heart rate, and blood pressure. No relevant effects of acute CILTEP® treatment were found on any measure of the test battery or ERPs. Blood plasma concentrations of luteolin increased, yet about 2000 times too low to likely exert any PDE4 inhibition. CILTEP® treatment did neither affect heart rate nor blood pressure. In summary, there is no evidence that a single standardized dose of 3 capsules of CILTEP® can improve cognitive function in healthy middle-aged participants.

Demonstrating Bioequivalence for Two Dose Strengths of Niraparib andAbiraterone AcetateDual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.

The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs. This open-label randomized BA/BE study (NCT04577833) was conducted at 14 sites in the USA and Europe. The study had a sequential design, including a 21-day screening phase, a pharmacokinetic (PK) assessment phase comprising three periods [namely (1) single-dose with up to 1-week run-in, (2) daily doseon days 1-11, and (3) daily dose ondays 12-22], an extension where both niraparib and AA as single-agent combination (SAC; reference) or AA alone was continued from day 23 until discontinuation, and a 30-day follow-up phase. Patients were randomly assigned in a parallel-group design (four-sequence randomization) to receive a single oral dose of niraparib 100 mg/AA 1000 mg as a LS-DAT or SAC in period 1, and patients continued as randomized into a two-way crossover design during periods 2 and 3 where they received niraparib 200 mg/AA 1000 mg once daily as a RS-DAT or SAC. The design was powered on the basis of crossover assessment of RS-DAT versus SAC. During repeated dosing (periods 2 and 3, and extension phase), all patients also received prednisone/prednisolone 5 mg twice daily. Plasma samples were collected for measurement of niraparib and abiraterone plasma concentrations. Statistical assessment of the RS-DAT and LS-DAT versus SAC was performed on log-transformed pharmacokinetic parameters data from periods 2 and 3 (crossover) and from period 1 (parallel), respectively. Additional paired analyses and model-based bioequivalence assessments were conducted to evaluate the similarity between the LS-DAT and SAC. For the RS-DAT versus SAC, the 90% confidence intervals (CI) of geometric mean ratios (GMR) for maximum concentration at a steady state (Cmax,ss) and area under the plasma concentration-time curve from 0-24 h at a steady state (AUC 0-24h,ss) were respectively 99.18-106.12% and 97.91-104.31% for niraparib and 87.59-106.69 and 86.91-100.23% for abiraterone. For the LS-DAT vs SAC, the 90% CI of GMR for AUC0-72h of niraparib was 80.31-101.12% in primary analysis, the 90% CI of GMR for Cmax,ss and AUC 0-24h,ss of abiraterone was 85.41-118.34% and 86.51-121.64% respectively, and 96.4% of simulated LS-DAT versus SAC BE trials met the BE criteria for both niraparib and abiraterone. The RS-DAT met BE criteria (range 80%-125%) versus SAC based on 90% CI of GMR for Cmax,ss and AUC 0-24h,ss. The LS-DAT was considered BE to SAC on the basis of the niraparib component meeting the BE criteria in the primary analysis for AUC 0-72h; abiraterone meeting the BE criteria in additional paired analyses based on Cmax,ss and AUC 0-24h,ss; and the percentage of simulated LS-DAT versus SAC BE trials meeting the BE criteria for both. NCT04577833.

Carbohydrate ingestion does not suppress increases in fatty acid-binding protein 4 concentrations post-acute aerobic exercise in healthy men: a randomized crossover study

BackgroundFatty acid-binding protein 4 (FABP4) has been associated with cardiovascular disease and diabetes. Acute aerobic exercise increases circulating FABP4 concentrations, but the underlying mechanisms remain unclear. The purpose of this study was to investigate the effects of inhibition of lipolysis by carbohydrate ingestion on circulating FABP4 concentrations during and after acute aerobic exercise in healthy men.MethodsMen aged between 20 and 40, with no exercise habits and no metabolic diseases, were recruited. In a randomized crossover design, the participants underwent a carbohydrate-ingestion exercise (CE) and a fasted exercise (FE) trial. The CE trial consisted of 40-min acute aerobic exercise with ingestion of carbohydrates and 60-min bed rest. The FE trial followed the same protocol as the CE trial but without carbohydrate ingestion. Venous blood samples were collected to measure hormones (adrenaline, noradrenaline, and insulin) metabolites (glycerol, free fatty acids, and glucose), and FABP4 concentrations. Ventilation and gas exchange were also collected to measure substrate oxidation.ResultsThirteen healthy men participated in and completed both the CE and FE trials. The insulin concentration was more than 4 times higher in the CE trial than in the FE trial (p < 0.004, effect size [ES] > 2.00). Free fatty acid concentrations were more than 4 times lower in the CE trial than in the FE trial (p < 0.02, ES > 2.04). However, there was no significant difference in the changes in circulating FABP4 concentrations between the CE and FE trials (p = 0.108), which did not change during aerobic exercise and significantly increased post-aerobic exercise in both trials (p < 0.002, ES > 1.212). Changes in FABP4 concentrations following aerobic exercise were not significantly correlated with changes in glycerol or free fatty acid concentrations during aerobic exercise.ConclusionsThe results suggest that suppression of lipolysis and elevation of insulin are not strongly involved in increases in FABP4 secretion following acute aerobic exercise.

High oleic soybean oil maintains milk fat and increases apparent total-tract fat digestibility and fat deposition in lactating dairy cows

Due to the bioactive properties of oleic acid, the objective of this study was to feed high oleic soybean oil (HOSO) to lactating cows and evaluate milk production, body composition, and apparent total-tract digestibility variables. Thirty Holstein cows (n = 16 primiparous, n = 14 multiparous at 87 ± 26 DIM at the start of the trial) were used in a crossover design with periods lasting 21 d. The treatments were a control (CON) diet with no added soybean oil and a HOSO diet with 1.5% diet DM of high oleic soybean oil. Dry matter and milk production data were collected the last 7 d of each period, and milk composition was collected the last 3 d of each period. Fecal samples were collected 6 times during the last 3 d of each period. Body weights were collected on the last 3 d of each period after the morning milking and ultrasound scans of the longissimus dorsi on the last day of each period. Compared with CON, HOSO did not affect DMI, milk production, and milk component yields. However, a parity effect was observed with multiparous cows having increased DMI (5.9 kg/d), milk production (11.2 kg/d), and component yields, with no treatment by parity interactions. Milk fat concentration tended to be greater for HOSO cows. Body weight data tended to have an interaction between treatment and parity, with multiparous HOSO cows having increased BW compared with CON and no effect on primiparous cows. Similar treatment by parity effects were observed for BCS. Compared with CON, HOSO increased fat depth by 0.44 mm and apparent total-tract fat digestibility by 12 percentage units. The results of this study indicated no detrimental effects of HOSO on milk production parameters with an increase in milk fat concentration, fat digestibility, and deposition compared with a control diet.

Pairwise fitting of piecewise mixed models for the joint modeling of multivariate longitudinal outcomes, in a randomized crossover trial.

Many statistical models have been proposed in the literature for the analysis of longitudinal data. One may propose to model two or more correlated longitudinal processes simultaneously, with a goal of understanding their association over time. Joint modeling is then required to carefully study the association structure among the outcomes as well as drawing joint inferences about the different outcomes. In this study, we sought to model the associations among six nutrition outcomes while circumventing the computational challenge posed by their clustered and high-dimensional nature. We analyzed data from a 2 2 randomized crossover trial conducted in Kenya, to compare the effect of high-dose and low-dose iodine in household salt on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in women of reproductive age and their household matching pair of school-aged children. Two additional outcomes, namely, urinary iodine concentration (UIC) in women and children were measured repeatedly to monitor the amount of iodine excreted through urine. We extended the model proposed by Mwangi etal. (2021, Communications in Statistics: Case Studies, Data Analysis and Applications, 7(3), 413-431) allowing flexible piecewise joint models for six outcomes to depend on separate random effects, which are themselves correlated. This entailed fitting 15 bivariate general linear mixed models and deriving inference for the joint model using pseudo-likelihood theory. We analyzed the outcomes separately and jointly using piecewise linear mixed-effects (PLME) model and further validated the results using current state-of-the-art Jones and Kenward methodology (JKME model) used for analyzing randomized crossover trials. The results indicate that high-dose iodine in salt significantly reduced blood pressure (BP) compared to low-dose iodine in salt. Estimates for the random effects and residual error components showed that SBP and DBP had strong positive correlation, with effect of the random slope indicating that significantly related outcomes are strongly associated in their evolution. There was a moderately strong inverse relationship between evolutions of UIC and BP both in women and children. These findings confirmed the original hypothesis that high-dose iodine salt has significant lowering effect on BP. We further sought to evaluate the performance of our proposed PLME model against the widely used JKME model, within the multivariate joint modeling framework through a simulation study mimicking a crossover design. From our findings, the multivariate joint PLME model performed exceptionally well both in estimation of random-effects matrix (G) and Hessian matrix (H), allowing satisfactory model convergence during estimation. It allowed a more complex fit to the data with both random intercepts and slopes effects compared to the multivariate joint JKME model that allowed for random intercepts only. When a hierarchical viewpoint is adopted, in the sense that outcomes are specified conditionally upon random effects, the variance-covariance matrix of the random effects must be positive definite. In some cases, additional random effects could explain much variability in the data, thus improving precision in estimation of the estimands (effect size) parameters. The key highlight in this evaluation shows that multivariate joint JKME model is a powerful tool especially while fitting mixed models with random intercepts only, in crossover design settings. Addition of random slopes may lead to model complexities in most cases, resulting in unsatisfactory model convergence during estimation. To circumvent convergence pitfalls, extention of JKME model to PLME model allows a more flexible fit to the data (generated from crossover design settings), especially in the multivariate joint modelingframework.

The effect of a single cycle of ischemia on bar velocity during bench press exercise

Introduction: The main goal of this study was to investigate the effects of a single cycle of ischemia applied before the bench press exercise on acute bar velocity changes. Materials and Methods: Twelve physically active males participated in the study. The experiment followed a randomized, cross-over design under two testing conditions. The experimental condition involved the application of a single cycle of ischemia (5 minutes; 80% arterial occlusion pressure [AOP]) before the first set of bench press exercise (2 sets at 60% 1RM). The control condition did not use ischemia. The peak and mean bar velocities were measured using a linear position transducer. Results: Two-way repeated measures ANOVA revealed no statistically significant differences in the peak or mean bar velocity between the ischemia and control conditions both during the first and the second set of the bench press exercise. Conclusions: The results of this study indicate that a single cycle of ischemia applied before the bench press exercise did not influence changes in peak or mean bar velocity.

Impact of immersive virtual reality games or traditional physical exercise on cardiovascular and autonomic responses, enjoyment and sleep quality: a randomized crossover study

Objectives: To assess the potential of immersive virtual reality (IVR) in achieving moderate exercise intensity, and 2) to examine the acute effects of two IVR exergame sessions (BOXVR and Beat Saber), comparing them with the impact of traditional exercise on heart rate variability (HRV), perceived effort, delayed onset muscle soreness, motivation, and sleep. Materials and methods: A crossover design was used. The participants (n = 22) randomly performed two sessions of IVR and one session of moderate intensity physical activity, each session lasting 30 min. Heart Rate (HR) and HRV, Perceived Exertion Scale, Intrinsic Motivation Inventory, sleep quality, and perceived pain, were evaluated. Results: The cardiac response to the activities was significantly higher when participants performed traditional physical activity as compared to the BOXVR and Beat Saber games. Traditional training provided a different HRV response as compared to Beat Saber (LnRMSSD, p = 0.025; SDNN, p = 0.031). Although the sessions were planned for moderate intensity, BOXVR generated a moderate intensity (49.3% HRreserve), Beat Saber (29.6% HRreserve) a light one, and the Circuit session, a vigorous one (62.9% HRreserve). In addition, traditional training reported higher perceived exertion and pain with less enjoyment. Differences were observed between the exergames. BOXVR resulted in a lower cardiac response (HRmax and HRmean), and a higher perception of exertion and pain at 72 h. The sleep variables analyzed were not altered by any of the sessions. Conclusions: BOXVR and traditional training can lead to moderate intensity physical activity. However, traditional training could result in lower adherence to physical exercise programs, as it was perceived as more intense and less enjoyable.

Effects of different sonication parameters of theta burst transcranial ultrasound stimulation on human motor cortex

BackgroundTheta burst TUS (tbTUS) can induce increased cortical excitability in human, but how different sonication parameters influence the effects are still unknown. ObjectiveTo examine how a range of sonication parameters, including acoustic intensity, pulse repetition frequency, duty cycle and sonication duration, influence the effects of tbTUS on human motor cortical excitability. Methods14 right-handed healthy subjects underwent 8 sessions with different tbTUS parameters in a randomized, cross-over design on separate days. The original tbTUS protocol was studied in one session and one parameter was changed in each of the seven sessions. To examine changes in cortical excitability induced by tbTUS, we measured the motor-evoked potential (MEP) amplitude, resting motor threshold, short-interval intracortical inhibition and intracortical facilitation, as well as short-interval intracortical facilitation before and up to 90 min after tbTUS. ResultsAll conditions increased MEP amplitudes except the condition with low acoustic intensity of 10 W/cm2. Pulse repetition frequency of 5 Hz produced higher MEP amplitudes compared to pulse repetition frequencies of 2 and 10 Hz. In addition, higher duty cycles (5%, 10%, and 15%) and longer sonication durations (40, 80, and 120 s) were associated with longer duration of increased MEP amplitudes. Resting motor threshold remained stable in all conditions. For paired-pulse TMS measures, tbTUS reduced short-interval intracortical inhibition and enhanced short-interval intracortical facilitation, but had no effect on intracortical facilitation. ConclusionsUltrasound bursts repeated at theta (∼5 Hz) frequency is optimal to produce increased cortical excitability with the range of 2–10 Hz. Furthermore, there was a dose-response effect regarding duty cycle and sonication duration in tbTUS for plasticity induction. The aftereffects of tbTUS were associated with a shift of the inhibition/excitation balance toward less inhibition and more excitation in the motor cortex. These findings can be used to determine the optimal tbTUS parameters in neuroscience research and treatment of neurological and psychiatric disorders.

Neural signatures of shared subjective affective engagement and disengagement during movie viewing.

When watching a negative emotional movie, we differ from person to person in the ease with which we engage and the difficulty with which we disengage throughout a temporally evolving narrative. We investigated neural responses of emotional processing, by considering inter-individual synchronization in subjective emotional engagement and disengagement. The neural underpinnings of these shared responses are ideally studied in naturalistic scenarios like movie viewing, wherein individuals emotionally engage and disengage at their own time and pace throughout the course of a narrative. Despite the rich data that naturalistic designs can bring to the study, there is a challenge in determining time-resolved behavioral markers of subjective engagement and disengagement and their underlying neural responses. We used a within-subject cross-over design instructing 22 subjects to watch clips of either neutral or sad content while undergoing functional magnetic resonance imaging (fMRI). Participants watched the same movies a second time while continuously annotating the perceived emotional intensity, thus enabling the mapping of brain activity and emotional experience. Our analyses revealed that between-participant similarity in waxing (engagement) and waning (disengagement) of emotional intensity was directly related to the between-participant similarity in spatiotemporal patterns of brain activation during the movie(s). Similar patterns of engagement reflected common activation in the bilateral ventromedial prefrontal cortex, regions often involved in self-referenced evaluation and generation of negative emotions. Similar patterns of disengagement reflected common activation in central executive and default mode network regions often involved in top-down emotion regulation. Together this work helps to better understand cognitive and neural mechanisms underpinning engagement and disengagement from emotionally evocative narratives.

Crushing tablets or sprinkling capsules: Implications for clinical strategy and study performance based on BE studies of rivaroxaban and deferasirox.

Administration of oral medicinal products as crushed tablets or open capsules is an important delivery option for patients suffering from dysphagia. To obtain full interchangeability of generics with the original products, demonstration of bioequivalence (BE) between both products administered as crushed tablets/open capsules was required for poorly soluble product by European Medicines Agency (EMA) at the time of development of our rivaroxaban and deferasirox generic products. We present the results of two BE studies with modified administration of these products, which compared relative bioavailability between generic and reference products. In the rivaroxaban study, the test product was administered as a capsule sprinkled on and mixed with applesauce, whereas the reference tablet was crushed and administered with applesauce under fed conditions. In the deferasirox study, both treatments were administered as crushed tablets under fasting conditions. Both studies applied a two-way crossover design and were conducted after a single-dose in healthy volunteers. The 90% confidence interval of the geometric mean ratio area under the analyte concentration versus time curve, from time zero to the time of the last measurable analyte concentration and maximum measured analyte concentration over the sampling period of the test to reference ratio were 103.36-110.37% and 97.98-108.45% for rivaroxaban, respectively, and 96.69-107.29% and 94.19-109.45% for deferasirox, respectively. Thus, the BE criteria (80.00-125.00%) were met in both studies which demonstrated that bioavailability was not affected when the test and reference products were administered in the form of crushed tablet/open capsule. These results support the argument of redundancy of crushed product studies for poorly soluble drugs, which is in line with the currently revised position of the EMA on this topic.

Milk or Kefir, in Comparison to Water, Do Not Enhance Running Time-Trial Performance in Endurance Master Athletes.

This study compared flavored kefir (KFR) and flavored milk (MLK) as a recovery drink in endurance master athletes. Using a randomized, placebo-controlled, non-blinded crossover design, 11 males and females completed three testing visits whilst acutely ingesting either KFR, MLK, or water as a placebo (PLA). KFR supplementation occurred for 14 days before the KFR-testing day, followed by a 3-week washout period. Testing visits consisted of an exhausting-exercise (EE) bout, a 4-h rest period where additional carbohydrate feeding was provided, and a treadmill 5 km time trial (TT). The Gastrointestinal Symptom Rating Scale (GSRS) survey was assessed at four timepoints. Blood was collected at baseline and after the TT and was analyzed for I-FABP levels. No significant difference (PLA: 33:39.1 ± 6:29.0 min, KFR: 33:41.1 ± 5:44.4 min, and MLK: 33:36.2 ± 6:40.5 min, p = 0.99) was found between the groups in TT performance. The KFR GSRS total score was significantly lower than the PLA after EE (p = 0.005). No differences in I-FABP were observed between conditions. In conclusion, acute KFR supplementation did not impact TT performance or I-FABP levels but may have reduced subjective GI symptoms surrounding exercise when compared to MLK or PLA.

Postprandial plasma amino acid and appetite responses with ingestion of a novel salmon-derived protein peptide in healthy young adults.

This study assessed postprandial plasma aminoacidemia, glycemia, insulinemia and appetite responses to ingestion of a novel salmon-derived protein peptide (Salmon PP) compared with milk protein isolate (Milk PI). In a randomised, participant-blind crossover design, eleven healthy adults (M = 5, F = 6; mean ± sd age: 22 ± 3 years; BMI: 24 ± 3 kg/m2) ingested 0·3 g/kg/body mass of Salmon PP or Milk PI. Arterialised blood samples were collected whilst fasted and over a 240-min postprandial period. Appetite sensations were measured via visual analogue scales. An ad libitum buffet-style test meal was administered after each trial. The incremental AUC (iAUC) plasma essential amino acid (EAA) response was similar between Salmon PP and Milk PI. The iAUC plasma leucine response was significantly greater following Milk PI ingestion (P < 0·001), whereas temporal and iAUC plasma total amino acid (P = 0·001), non-essential amino acid (P = 0·002), glycine (P = 0·0025) and hydroxyproline (P < 0·001) responses were greater following Salmon PP ingestion. Plasma insulin increased similarly above post-absorptive values following Salmon PP and Milk PI ingestion, whilst plasma glucose was largely unaltered. Indices of appetite were similarly altered following Salmon PP and Milk PI ingestion, and total energy and macronutrient intake during the ad libitum meal was similar between Salmon PP and Milk PI. The postprandial plasma EAA, glycine, proline and hydroxyproline response to Salmon PP ingestion suggest this novel protein source could support muscle and possibly connective tissue adaptive remodelling, which warrants further investigation, particularly as the plasma leucine response to Salmon PP ingestion was inferior to Milk PI.

The impact of restricting sleep duration on physical activity: Secondary analysis of a randomized crossover study.

This study investigated the causal impact of sleep durations on participants' physical activity (PA) in real-world conditions. We performed a secondary analysis of PA data from 146 young adults using a randomized crossover design: both restricted (5-6 hr/night) and well-rested (8-9 hr/night) sleep weeks were assessed, with a washout week in between. Sleep and activity were tracked via research-grade actigraphy. Data analysis of PA involved repeated-measures analysis of variance (ANOVA) and regression techniques. Analysis plans and hypothesis were preregistered before data analysis. The exogenously assigned sleep restriction (SR) treatment reduced nightly sleep an average of 92.65 min (± 40.44 min) compared to one's well-rested sleep treatment. The impact of SR on PA was substantial, leading to a 7% reduction in average hourly PA: 18,081.2 (well-rested) versus 16,818.2 (restricted sleep). Significant findings were revealed in daily, F(1, 6) = 84.37, p < .001, ηp² = 0.934, and hourly comparisons, F(1, 166) = 30.47, p < .001, ηp² = 0.155. Further, sensitivity analysis using a variety of regression specifications also found that exogenously assigned SR decreased average wake-hour activity counts by approximately 4.4%-4.7% (p < .01 in all cases) when controlling for other factors. Exploratory analysis showed the PA effects of SR manifested via reductions in PA intensity with concurrent increases in the proportion of time considered as sedentary. SR significantly lowered PA by around 7%, characterized by reduced intensity and elevated sedentary behavior in a naturalistic setting. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Investigation of the Effects of Short-Term Body Weight Loss on Elite Wrestlers on Anaerobic Performance and Reaction Time in Tournament Conditions

Athletes, who engage in wrestling, perform weight adjustment before the competitions like all weight loss category sports. For this reason, weight management is a very important factor prior to matches. When the studies on weight loss are examined, it is seen that athletes lose weight in a short time close to the competition. This study aimed to investigate the effects of short-term body weight loss in elite wrestlers on anaerobic performance and reaction time during tournament conditions. Ten experienced international level male wrestlers participated as a volunteer in this study. Participants lost 5% of their body weight within 48 hours, in 72 hours; 1 kg tolerance was given over 5% of body weight. During this process, body composition measurement, Wingate anaerobic performance test (WAnT), Countermovement Jump (CMJ), and visual and auditory reaction tests were conducted. In this study, a randomized crossover design was used and applications lasted four days. Two-way ANOVA with repeated measures was used for statistical analysis. Due to short-term body weight loss in body composition, total body water (TBW) and fat-free mass (FFM) were significantly reduced. In contrast, there was no statistically significant difference in body fat percentage (BF %), visual and auditory reaction time, CMJ and average power (AP). However, there was a significant increase was seen in Peak power (PP) and fatigue index (FI). The results indicate that 5% loss of body weight within 48 hours caused significant changes in body composition and negatively affected the fatigue index. For this reason, athletes who lose weight should avoid rapid weight-loss practices that will cause sudden changes in body composition in order to maintain their athletic performance.

Tonic and phasic transcutaneous auricular vagus nerve stimulation (taVNS) both evoke rapid and transient pupil dilation

BackgroundTranscutaneous auricular vagus nerve stimulation (tVNS or taVNS) is a non-invasive method of electrical stimulation of the afferent pathway of the vagus nerve, suggested to drive changes in putative physiological markers of noradrenergic activity, including pupil dilation. ObjectiveHowever, it is unknown whether different taVNS modes can map onto the phasic and tonic modes of noradrenergic activity. The effects of taVNS on pupil dilation in humans are inconsistent, largely due to differences in stimulation protocols. Here, we attempted to address these issues. MethodsWe investigated pupil dilation under phasic (1 s) and tonic (30 s) taVNS, in a pre-registered, single-blind, sham-controlled, within-subject cross-over design, in the absence of a behavioural task. ResultsPhasic taVNS induced a rapid increase in pupil size over baseline, significantly greater than under sham stimulation, which rapidly declined after stimulation offset. Tonic taVNS induced a similarly rapid (and larger than sham) increase in pupil size over baseline, returning to baseline within 5 s, despite the ongoing stimulation. Thus, both active and sham tonic modes closely resembled the phasic effect. There were no differences in tonic baseline pupil size, and no sustained effects of stimulation on tonic baseline pupil size. ConclusionsThese results suggest that both phasic- and tonic-like taVNS under the standard stimulation parameters may modulate primarily the phasic mode of noradrenergic activity, as indexed by evoked pupil dilation, over and above somatosensory effects. This result sheds light on the temporal profile of phasic and tonic stimulation, with implications for their applicability in further research.

Anti-Anginal Efficacy of Zibotentan in the Coronary Slow-Flow Phenomenon.

Patients with coronary microvascular disorders often experience recurrent angina for which there are limited evidence-based therapies. These patients have been found to exhibit increased plasma levels of endothelin; thus, selective endothelin-A (Et-A) receptor blockers such as zibotentan may be an effective anti-anginal therapy in these patients. The study evaluated the impact of a 10 mg daily dose of zibotentan on spontaneous angina episodes in patients with the coronary slow-flow phenomenon who had refractory angina (i.e., experiencing angina at least three times/week despite current anti-anginal therapy). Using a randomized, double-blind, placebo-controlled, crossover trial design with 4-week treatment periods, 18 patients (63.2 ± 9.9 years, 33% females) were recruited. The primary endpoint was angina frequency as measured by an angina diary, with secondary endpoints including nitrate consumption, angina duration/severity and the Seattle Angina Questionnaire (SAQ) domains. During the 4 weeks of therapy, angina frequency significantly improved with zibotentan therapy (placebo 41.4 (58.5) vs. zibotentan 29.2 (31.6), p < 0.05), and sublingual nitrate consumption significantly reduced (placebo 11.8 (15.2) vs. zibotentan 8.8 (12.9), p < 0.05. Zibotentan improved the frequency of spontaneous angina episodes and reduced sublingual nitrate consumption in patients unresponsive to standard anti-anginal therapy.

Effects of periodic breathing on sleep at high altitude: a randomized, placebo-controlled, crossover study using inspiratory CO2.

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo-controlled approach to prevent nPB by increasing inspiratory CO2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single-blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4weeks) in hypobaric hypoxia corresponding to 4000m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO2 , and CO2 concentration in the canopy (i.e. inspiratory CO2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%-2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%-80.8%) and 45.0% (24.5%-56.5%) during the first and the third night, respectively (P=0.042). Increased inspiratory CO2 reduced TST with nPB by an absolute 38.1% (28.1%-48.1%), the apnoea-hypopnoea index by 58.1/h (40.1-76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1-73.2/h) (all P<0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%-3.5%, P=0.035). Increased inspiratory CO2 slightly increased the percentage of N3sleep during the third night (P=0.045), without other effects on sleep architecture. Increasing inspiratory CO2 effectively prevented hypoxia-induced nPB without affecting sleep macro-architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. KEY POINTS: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture. We developed a placebo-controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia. Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO2 fraction in a blinded manner. Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia. We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude.

No effect of a commercial carbohydrate‐menthol drink on thermal perceptual measures or 15‐min time trial performance compared to commercial carbohydrate drink in hot humid conditions

AbstractThis study assessed the effect of a commercial carbohydrate menthol drink on cycling time trial (TT) performance in hot and humid conditions compared with a carbohydrate only drink. Ten participants (5 women; V̇O2max: 52.3 ± 8.6 mL kg−1 min−1, Peak Power Output: 286 ± 56 W) completed a 40‐min cycling preload (50% V̇O2max) followed by a 15‐min self‐paced TT in hot (∼35°C) and humid (∼54%) conditions on two occasions (double blind, crossover design). Every 10‐min, 85 mL of carbohydrate (CHO; SIS GO Energy, 60 g h−1) or carbohydrate and menthol (CHO + MEN; SIS Turbo+ 60 g h−1, 0.01% menthol) was swilled (∼10‐s) and ingested. Rectal temperature (Trec) and heart rate (HR) were recorded throughout. Thermal sensation (TS), thermal comfort (TC) and rating of perceived exertion (RPE) were recorded every 5‐min. Taste and aftertaste were rated from very pleasant (+5) to very unpleasant (−5). TT performance (total work; kJ) was similar between CHO (153 kJ [95% CI: 129–177 kJ]) and CHO + MEN (151 kJ [128–178 kJ]). During preload exercise, Trec increased by ∼0.9°C and was similar at the end of the TT (∼38.20°C). Mean preload HR was ∼140 b min−1 in each condition and reached ∼177 b min−1 at the end of the TT. TC was rated as ‘much too warm’ and TS rated as ‘very hot’ in both conditions. Both conditions were ‘extremely hard’ (end point RPE ∼19). All participants preferred the taste and aftertaste of the CHO drink. The commercial carbohydrate menthol drink offered no additional ergogenic benefit compared to a carbohydrate only drink during cycling exercise performed in hot and humid conditions.

Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes.

Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [18F]FDG positron emission tomography/computed tomography (PET/CT) and [11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, μmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, μmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, μmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10-9min-1, p < 0.01) and glucose effectiveness (2.6 × 10-2 ± 0.3 × 10-2 vs. 2.4 × 10-2 ± 0.3 × 10-2, dL/kg/min, p = 0.02). Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.