Randomized Crossover Trial Research Articles

Impact of Operative Room Noise on Laparoscopic Performance—A Prospective, Randomized Crossover Trial

IntroductionSurgeons are often exposed to different types of operative room (OR) noise, for instance machine alarms, phone calls, and interacting objects. The aim of this study was to evaluate the effect of OR noise on the surgeons’ laparoscopic performance. MethodsA total of 30 laparoscopic novices participated in this single-center, prospective, randomized cross-over trial after completing a standardized laparoscopic training until reaching proficiency. Afterward, all participants performed four different laparoscopic tasks (peg transfer, circle cutting, balloon resection, suture, and knot) twice, once under noise exposure (intervention group), and once without any noise (control group). Primary endpoints were the force exertion and motion analyses. To assess the psychological workload the NASA task load index score was used. ResultsThe error rates varied and were significantly different between the noise and the control group. More complex tasks like the circle cutting and suture and knot task revealed higher error rates concerning precision (circle cutting: P < 0.01; suture and knot: P < 0.01). In line with increased error rates in the circle cutting task, increased NASA task load index scores were observed in this task (P = 0.03). However, no significant differences were found in force parameters, such as the maximal force exertion (peg transfer: P = 0.43; circle cutting: P = 0.54; balloon resection: P = 0.64; suture and knot: P = 0.63) and the mean force exertion (peg transfer: P = 0.43; circle cutting: P = 0.54; balloon resection: P = 0.64; suture and knot: P = 0.63) between the groups. ConclusionsExposure to normal OR noise led to higher error rates in two of four tasks. This effect could be linked to an increased psychological workload that was present under normal OR noise exposure. However, normal OR noise does not appear to impact surgical novices' laparoscopic task performance regarding applied forces and instrument motion.

Chronic Cannabidiol Administration Mitigates Excessive Daytime Sleepiness and Fatigue in Patients with Primary Hypertension: Insights from a Randomized Crossover Trial.

Background: The chronic effects of cannabidiol (CBD) supplementation on factors that could impact the quality of life (anxiety, sleeping quality, memory, etc.) are poorly explored. Hence, the aim of this study was to establish whether chronic CBD supplementation will improve self-reported outcomes related to quality of life. Methods: In this randomized crossover trial, 64 patients with primary hypertension were assigned to receive CBD (225-450 mg) for 5 weeks followed by 5 weeks of placebo or vice versa, with a 2-week washout in-between the two. Self-reported outcomes were assessed using short form-36 (SF-36), Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), memory complaint questionnaire (MAC-Q), and state-trait anxiety inventory (STAI). Results: Five-week administration of CBD, but not of placebo, resulted in improvement of ESS score (F = 6.738, p = 0.011), as well as fatigue/vitality (ΔCBD = 5.0, p < 0.001) and psychological well-being dimensions of SF-36 (ΔCBD = 7.4, p = 0.039). No overall benefit of CBD on quality of life was noted (p = 0.674). No changes were seen in total scores of MAC-Q, PSQI, or STAI (p = 0.151, p = 0.862, p = 0.702, respectively). No significant correlations were found between plasma CBD concentrations and any of the scores. Conclusions: Chronic CBD administration reduced excessive daytime sleepiness, despite the fact that no change was observed in self-reported quality of sleep. Furthermore, self-reported fatigue and psychological well-being dimensions of quality of life also improved following chronic CBD use.

The effect of Dynamic tape’s directional support on shoulder fatigue and pitching performance in amateur baseball players: a randomized crossover trial

BackgroundTo evaluate whether the application of Dynamic tape to the pitching shoulder could result in reduced shoulder fatigue, reduced delayed onset muscle soreness, or improved performance.MethodsThis is a randomized crossover study, in which participants and investigators were blinded, included 20 amateur adult baseball players without shoulder pain. Sham taping and Dynamic taping were randomized, using an internal rotation support taping method in both groups. Bilateral shoulder strength and range of motion were measured with a handheld dynamometer and clinical goniometer before and after each test. The percentage of strength decrease, range of motion, pitch velocity, spin rate, and shoulder pain were recorded. The post-pitching decrease in strength and percentage of strength decrease were calculated by paired t-test and the pitching speed and spin rates in the innings for both the sham and Dynamic taping groups were analyzed using two-way ANOVA.ResultsCompared with the sham group, the Dynamic tape group showed a significant loss in the percentage of strength decrease in internal rotation compared to the sham group (-1.4% vs. 7.0%, p = 0.03). However, no significant differences were observed in other strength declines, shoulder range of motion, pain, pitching velocity, or spin rate.ConclusionsDynamic tape reduced direction-specific shoulder fatigue but did not significantly enhance pitching performance or prevent delayed onset muscle soreness.Trial registrationClinicalTrials: N201912094.

Physiological effects of high-flow nasal cannula during sustained high-intensity exercise in healthy volunteers: a randomised crossover trial

IntroductionHigh-flow nasal cannula (HFNC) has increased exercise capacity in patients with chronic respiratory diseases. However, it remains unknown whether HFNC impacts respiratory physiological variables during exercise. This study aimed to evaluate the effect of HFNC on respiratory physiological variables during sustained high-intensity exercise in healthy volunteers.MethodsWe performed a single-center, open-label, and randomised crossover trial to compare HFNC (60 L·min−1) and Sham-HFNC (2 L·min−1) interventions during a constant work-rate exercise (CWRET) through randomised order. The primary outcome was ΔPes, and the secondary outcomes were other variables of inspiratory effort, ventilation distribution, ventilatory variables, and clinical assessment. We evaluated volunteers at seven-time points (Baseline= T0; CWRET= T1-T2-T3 (minutes: 1′, 4′ and 6′); Cooldown-period= T4-T5-T6 (minutes: 1′; 6′;10′)) in both interventions.ResultsFourteen healthy volunteers (50% women; age: 22 [21–27] years) were enrolled. Mean differences in ΔPes decreased to favor the HFNC intervention compared to Sham-HFNC at T2 (−2.8 cmH2O; 95%CI −5.3 to −0.3), as well as the sPTPmin at T2 (−86.1 cmH2O×s·min−1;95%CI −146.2 to −26.1), and T3 (−79.9 cmH2O×s·min−1;95%CI −142.3 to −17.6). The standard deviation of the regional ventilation delay index was also lower with HFNC compared to Sham-HFNC (T1: −1.38; 95%CI −1.93 to −0.83; T2: −0.71; 95%CI −1.27 to −0.16). There was decreased dyspnea to favor the HFNC, but sPTP-per-breath, spatial distribution ventilation indexes, ventilatory variables, and clinical assessments were nonsignificant between interventions.ConclusionHFNC intervention reduces respiratory effort, dyspnea and improves temporal ventilation distribution in healthy volunteers during CWRET.

Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2DM with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2DM and HFpEF remain unknown. A total of 24 patients with T2DM and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. In patients with T2DM and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2DM and HFpEF. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.

Acute salivary antimicrobial peptide secretion response to different exercise intensities and durations.

Antimicrobial peptides, key players of innate mucosal immunity in the oral cavity, exert antibacterial and bacteriolytic effects. This study aimed to clarify the effects of acute exercise at different intensities and durations on salivary antimicrobial peptide levels. In a randomized crossover trial, 14 young healthy untrained men performed intensity trials (cycling at 35%, 55%, and 75% of maximal oxygen uptake [VO2max] for 30 min) and duration trials (cycling at 55% VO2max for 30, 60, and 90 min). Saliva samples were collected at baseline and 0 and 60 min after exercise. In intensity trials, the change in salivary Lactoferrin levels from baseline to 0 min after 30-min exercise was greater at 75% VO2max exercise intensity compared to that at 35% VO2max. Furthermore, the change in salivary human beta defensin-2 (HBD-2) levels was greater at 75% VO2max compared to that at 35% and 55% VO2max. Salivary Lysozyme levels increased after exercise, independent of exercise intensity. However, salivary LL-37 levels did not change after exercise at any intensity. Additionally, in duration trials, the change in salivary levels of LL-37 and HBD-2 from baseline to 0 min after exercise at 55% VO2max was greater after 60 min and 90 min of exercise compared to that after 30 min of exercise. However, salivary Lactoferrin and Lysozyme levels increased after exercise, independent of exercise duration. Our findings suggest that secretory responses to acute exercise with exercise intensity and duration differ among salivary antimicrobial peptides.

Reaction to at-home air purifiers installed to reduce traffic-related air pollution in near-highway residences

Background and aimTraffic-related ultrafine particle pollution near highways is associated with adverse health. Reducing exposure by use of portable air purifiers in homes is one approach to reducing this risk. However, the reaction of residents to having air purifiers in homes is not well studied.MethodsWithin the framework of our randomized crossover trial of air purifiers in homes near a major highway, we collected data about participants’ use and reactions to air purifiers using questionnaires at their 30-day and 90-day home visits, recorded electricity consumption using HOBO monitors, and conducted structured interviews with participants.ResultsNearly all 150 participants reported running the air purifiers virtually 24 h every day in both their living room and their bedroom in the prior month. The units’ HOBO electricity use, from a subset of 45 participants, supported the participants’ responses from the questionnaire. Approximately 80% of participants reported setting their air purifier on the medium setting. Tolerance to air purifier noise increased significantly between the 30-day and 90-day home visits, with approximately two thirds reporting not being bothered at all by the noise. The qualitative interviews in a subset of 26 participants yielded consistent responses to those from the questionnaires. Size of unit, airflow, and energy consumption were additional concerns that emerged during the interviews.ConclusionsResults from the questionnaires, HOBO data, and structured interviews all suggest participants had positive reactions towards the presence of in-home APs, and therefore may be receptive to using air purifiers in their homes on a regular basis.Trial registrationClinicalTrials.gov, NCT04279249. Registered 09 October 2019.

Exploring immediate cardiorespiratory responses: low-intensity blood flow restricted cycling vs. moderate-intensity traditional exercise in a randomized crossover trial

PurposeBlood-flow restriction (BFR) endurance training may increase endurance performance and muscle strength similar to traditional endurance training while requiring a lower training intensity. We aimed to compare acute cardiorespiratory responses to low-intensity interval exercise under BFR with moderate-intensity traditional interval exercise (TRA).MethodsWe conducted a randomized crossover study. The protocol involved three cycling intervals interspersed with 1 min resting periods. With a 48-h washout period, individuals performed the protocol twice in random order: once as BFR-50 (i.e., 50% incremental peak power output [IPPO] and 50% limb occlusion pressure [LOP]) and once as TRA-65 (65% IPPO without occlusion). TRA-65 intervals lasted 2 min, and time-matched BFR-50 lasted 2 min and 18 s. Respiratory parameters were collected by breath-by-breath analysis. The ratings of perceived breathing and leg exertion (RPE, 0 to 10) were assessed. Linear mixed models were used for analysis.ResultsOut of the 28 participants initially enrolled in the study, 24 healthy individuals (18 males and 6 females) completed both measurements. Compared with TRA-65, BFR-50 elicited lower minute ventilation (VE, primary outcome) (-3.1 l/min [-4.4 to -1.7]), oxygen consumption (-0.22 l/min [-0.28 to -0.16]), carbon dioxide production (-0.25 l/min [-0.29 to -0.20]) and RPE breathing (-0.9 [-1.2 to -0.6]). RPE leg was significantly greater in the BFR-50 group (1.3 [1.0 to 1.7]).ConclusionBFR endurance exercise at 50% IPPO and 50% LOP resulted in lower cardiorespiratory work and perceived breathing effort compared to TRA at 65% IPPO. BFR-50 could be an attractive alternative for TRA-65, eliciting less respiratory work and perceived breathing effort while augmenting perceived leg muscle effort.Trial registrationNCT05163600; December 20, 2021.

Changes in appetite during acute passive intermittent and continuous hypoxemia in postprandial and fasting states: A combined analysis of four laboratory-based randomized crossover trials

Hypoxemia occurs during exposure to high altitude (continuous hypoxemia) or in the context of breathing disorders such as obstructive sleep apnea (OSA; intermittent hypoxemia). Growing evidence demonstrates that hypoxemia induces an anorexigenic effect on appetite; however, few studies have assessed hypoxemia-related reductions in appetite during acute passive exposures and during intermittent hypoxemia. This study thus pooled together four same-single-site randomized crossover trials using simulated models of high altitude (fraction of inspired oxygen = 0.1200, ∼5000 m) and moderate OSA (∼15 hypoxemic cycles per hour, ∼85 oxyhemoglobin saturation). Changes in appetite were evaluated during 6 h of passive normoxia and intermittent or continuous hypoxemia in postprandial or fasting states among healthy young adults (n = 40) and middle-aged individuals living with OSA (n = 7). Our results demonstrate that (1) acute passive intermittent hypoxemia leads to statistically significant, but likely not clinically significant reductions in appetite in the postprandial state, (2) the anorexigenic effect of acute passive hypoxemia on appetite is not consistent across hypoxemic methods and nutritional states, and (3) variations in individual factors may influence appetite responses during normoxia and hypoxemia. These findings indicate that the effect of acute passive hypoxemia on appetite is heterogeneous, particularly across different hypoxemic methods and nutritional states.

Post-activation performance enhancement (PAPE) protocols do not further increase jumping performance beyond warm-up effects: findings from three acute randomized crossover trials.

Introduction: Post-activation performance enhancement (PAPE) cannot be clearly distinguished from and may be explained in large by warm-up effects. To disentangle PAPE from a systemic warm-up effect, we conducted three randomized crossover trials (RCT). Methods: Each RCT consisted of a familiarization/one-repetition-maximum (1RM) assessment session followed by two interventional sessions (random order). In Study I, 18 participants (age: 26 ± 4years; height: 1.84 ± 0.06m; mass: 83.7 ± 8.7kg; Squat-1RM: 146 ± 19kg) performed either a 3-s isometric squat at 130%1RM or a 6-s isometric squat at 65%1RM. In Study II, 28 participants (11 female; age: 23 ± 3 years; height: 1.77 ± 0.08m; mass: 76.5 ± 10.4kg; Squat-1RM: 109 ± 38kg) completed either Squat (3 × 3 repetitions, 85%1RM) or local electromyostimulation of the quadriceps muscle (85% of individual pain threshold). In Study III, 20 participants (6 female, age: 25.0 ± 3.5 years, mass: 78.5 ± 15.8kg, height: 1.75 ± 0.08m; SQ-1RM: 114 ± 33kg, chest-press-1RM: 74 ± 29kg) performed either squats or chest press (4 repetitions, 80%1RM). Counter-Movement-Jump height (CMJ) was assessed after a general (PRE) and/or muscle-specific warm-up (POST_WU) and for up to 11min after the PAPE protocols. To identify possible differences in CMJ between the experimental conditions, mixed-design ANOVA models were used for each study individually, with condition and time modelled as fixed effects, while participants were included as a random effect blocking factor. The level of statistical significance was set at α = 5%. Results: In studies I and II, significant effects for time (p < 0.05, ωp 2 = 0.06 and p < 0.001, ωp 2 = 0.43) were found with the highest CMJ compared to all other time points at PRE (≤8.2 ± 4.6%, standardized mean difference: ≤0.39), regardless of condition. In study III, no significant effects were observed. Discussion: Thus, PAPE protocols do not further improve jumping performance compared to a general and muscle-specific traditional warm-up. Prior to tasks requiring explosive strength, general and sport-specific warm-up strategies should be used.

The effect of foot immersion and neck cooling on cardiac autonomic function in older adults exposed to indoor overheating: a randomized crossover trial.

Foot immersion and neck cooling are recommended cooling strategies for protecting heat-vulnerable persons during heat waves. While we recently showed that these strategies do not limit core temperature increases in older adults during prolonged heat exposure, we did observe small reductions in heart rate. Expanding on these findings, we examined the effects of foot immersion with and without neck cooling on cardiac autonomic function. Seventeen adults (9 females; 65-81 years) underwent 3 randomized, 6 h exposures to 38 °C and 35% relative humidity with: no cooling (control), foot immersion (20°C water), or foot immersion with a wet towel (20°C) around the neck. Cardiac autonomic responses were measured at baseline and end-exposure. These included heart rate variability, cardiac and systolic blood pressure responses to standing, indexed via the 30:15 ratio and supine-to-standing systolic pressure change, respectively, and baroreflex sensitivity during repeated sit-to-stand maneuvers. The 30:15 ratio was 0.04 [95% CI: 0.01, 0.07] greater with foot immersion and neck cooling (1.08 (SD: 0.04)) relative to control (1.04 (0.06); P=0.018). Similarly, standing systolic blood pressure was elevated 9 [0, 17] mmHg with foot immersion and neck cooling (P=0.043). That said, neither difference remained statistically significant after adjusting for multiplicity (Padjusted≥0.054). No differences in 30:15 ratio or standing systolic blood pressure were observed with foot immersion alone, while heart rate variability and baroreflex sensitivity were unaffected by either cooling intervention. While foot immersion with neck cooling potentially improved cardiac autonomic responses in older adults exposed to simulated indoor overheating, these effects were small and of questionable clinical importance.

Efficacy of an internet-delivered cognitive enhancement intervention for subjective residual cognitive deficits in remitted major depressive disorder: A randomized crossover trial

BackgroundCognitive deficits such as difficulties with attention, memory, and executive functions are frequently reported during remission from depression and relates to adverse functioning in daily life and risk of relapse. There is therefore a need for interventions targeting cognitive deficits after depression. However, few randomized controlled trials have investigated the efficacy of interventions targeting subjective residual cognitive deficits in adults remitted from depression. MethodsThis randomized crossover trial aimed to investigate the efficacy of an internet-delivered cognitive enhancement intervention on subjective residual cognitive deficits. Forty-four formerly depressed adults (89 % female;mean age = 39 years) were included. Twenty-three participants received the intervention, and 21 participants were assigned to a waitlist control group. The waitlist control group received the intervention after seven weeks. Analyses of follow-up assessment after six months were conducted for the combined sample. ResultsSignificant differences were found between the intervention and waitlist control group in subjective cognitive functioning (d = 1.83) and rumination (d = 1.65). There was a difference in symptoms of depression between the groups (d = 1.22), whereas symptoms of depression increased in the waitlist control, but not in the intervention group. Fewer participants in the waitlist control group (43 %), compared to the intervention group (78 %) showed reliable improvement in self-reported cognitive deficits after receiving the intervention. LimitationsFindings should be interpreted with caution due to the small sample, and lack of an active control group. ConclusionsInternet-delivered cognitive enhancement interventions may improve subjective cognitive deficits. Waiting time to receive cognitive enhancement interventions may worsen symptoms and treatment response.

Impact of a drug allergy education course for non-specialists: Findings from ADAPT-A randomized crossover trial.

The consequences of drug allergy remain a global health concern. Drug allergy is often a neglected topic and many non-specialists lack sufficient knowledge or confidence in evaluating or managing this common condition. Evidence-based interventions to better equip non-specialists to tackle drug allergy are needed. The aim of the study is to evaluate the effectiveness of an intensive educational course on drug allergy knowledge and practice of non-specialists. A randomized crossover trial (NCT06399601) was conducted among practicing physicians and nurses participating in an intensive drug allergy course-Advances in Drug Allergy & Penicillin Testing (ADAPT). Participants' baseline knowledge and self-reported practices were assessed with standardized questionnaires (scored from 0 to 100, with "satisfactory" defined as ≥60/100). Participants were randomized into two cohorts and attended ADAPT at different time points. Serial responses before and after the course were compared within and between cohorts. Seventy participants (25 physicians, 45 nurses) randomized into two groups completed the course. Baseline drug allergy knowledge (58.0 ± 19.9) and self-reported practice (36.9 ± 24.3) were unsatisfactory among non-specialists, with significantly lower scores from nurses than physicians in both domains (knowledge: 49.0 ± 17.4 vs. 74.0 ± 12.7; practice: 32.1 ± 21.3 vs. 53.3 ± 23.1; all p < 0.001). Following completion of ADAPT, participants demonstrated significant improvements in knowledge (58.0 ± 19.9 vs. 77.7 ± 15.9, p < 0.001) and self-reported practice (36.9 ± 24.3 vs. 71.0 ± 20.2, p < 0.001). All participants (100%) and 99% of participants agreed that the course improved their clinical knowledge and practice, respectively. ADAPT, an intensive drug allergy educational course was effective in improving drug allergy knowledge and practice for non-specialists. Further longitudinal studies are required to evaluate long-term impact.

Short, frequent physical activity breaks improve working memory while preserving cerebral blood flow in adolescents during prolonged sitting - AbbaH teen, a randomized crossover trial

PurposePhysical activity (PA) breaks during school lessons have been suggested as a promising strategy to improve working memory performance in children and adolescents. There is a lack of studies investigating the underlying physiological mechanisms of PA on cognition, especially among adolescents. This study aimed to investigate the effects of different types of short frequent PA on adolescents’ cognitive task-related changes in cerebral blood flow in the prefrontal cortex (PFC) and working memory performance compared to prolonged sitting.MethodsIn this randomized crossover study, adolescents visited the laboratory on three different occasions for 80-minute sessions of prolonged sitting interrupted by four breaks for three minutes of simple resistance training (SRA), step-up at a pre-determined pace (STEP), or remaining seated (SOCIAL). Before and after each session, cognitive task-related changes in cerebral blood flow (oxygenated-hemoglobin, Oxy-Hb) during working memory tasks (1-, 2-, 3-back tests) were measured using functional near-infrared spectroscopy in the PFC. Accuracy and reaction time were derived from the working memory tasks. Linear mixed-effect models were used to analyze the data.ResultsA total of 17 students participated (mean age 13.6 years, 11 girls). Significant time x condition interactions were noted for Oxy-Hb in the most demanding working memory task (3-back), with a decrease following prolonged sitting in the SOCIAL condition compared to both the SRA (β 0.18, 95% CI 0.12, 0.24) and the STEP (β 0.11, 95% CI 0.05, 0.17). This was observed in parallel with improvements in reaction time following SRA (β -30.11, 95% CI -59.08, -1.13) and STEP (β -34.29, 95% CI -69.22, 0.63) although this was only significant for the SRA and no improvements in the SOCIAL condition.ConclusionWe found that short frequent PA breaks during prolonged sitting among adolescents can prevent the decrease in cognitive task-related changes in cerebral blood flow that occur following prolonged sitting. This was observed simultaneously with improvements in working memory, indicating that changes in cerebral blood flow could be one factor explaining the effects on working memory. Future studies should investigate the efficacy of implementing these PA breaks in schools.Trial registrationRetrospectively registered on 21/09/2020, ClinicalTrial (NCT04552626).

Camu-camu decreases hepatic steatosis and liver injury markers in overweight, hypertriglyceridemic individuals: A randomized crossover trial

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the adult population with no effective drug treatments available. Previous animal studies reported that a polyphenol-rich extract from the Amazonian berry camu-camu (CC) prevented hepatic steatosis in a mouse model of diet-induced obesity. This study aims to determine the impact of CC on hepatic steatosis (primary outcome) and evaluate changes in metabolic and gut microbiota profiles (exploratory outcomes). A randomized, double-blind, placebo-controlled crossover trial is conducted on 30 adults with overweight and hypertriglyceridemia, who consume 1.5g of CC capsules or placebo daily for 12weeks. CC treatment decreases liver fat by 7.43%, while it increases by 8.42% during the placebo intervention, showing a significant difference of 15.85%. CC decreases plasma aspartate and alanine aminotransferases levels and promotes changes in gut microbiota composition. These findings support that polyphenol-rich prebiotic may reduce liver fat in adults with overweight, reducing the risk of developing NAFLD.

Thermal and Cardiovascular Responses during Exertional Heat Stress after Diphenhydramine Use: A Randomized Crossover Trial.

Despite sparse systematic evidence, current exercise heat safety recommendations suggest that antihistamines blunt sweating and increase the risk for heat-related injury during exertional heat stress. The primary purpose of the present study was to examine whether diphenhydramine hydrochloride (DPH), a first-generation antihistamine, effects the sweating, core temperature, and heart rate response during exertional heat stress using a double-blind randomized crossover design. On two occasions separated by >48 h, 20 healthy adults (10 females, 23 ± 3 y, BSA: 1.9 ± 0.2 m2, BMI: 23.7 ± 2.2 kg·m-2) orally consumed either 50 mg of DPH or placebo (PLA), and then rested for 2 h in a climate-controlled room maintained at 30 °C and 35%RH (Heat Index of ~29 °C), followed by a 60-minute fixed-heat production treadmill walk (6.3 ± 1.0 W·kg-1). Whole-body sweat loss (WBSL), local sweat rate (LSR), rectal temperature (Trec), and heart rate (HR) were measured. WBSL was not different between conditions (PLA: 406 ± 78 g; DPH: 396 ± 75 g, P = 0.26, treatment effect: -10 g 95%CI [-28, 8]). No differences were observed for the onset for sweating (PLA: 13.5 ± 2.4 min; DPH: 13.3 ± 2.7 mins, P = 0.79), and steady-state LSR (PLA: 0.83 ± 0.26 mg·cm-2·min-1; DPH: 0.82 ± 0.27 mg·cm-2·min-1, P = 0.99). No difference in baseline Trec was observed (PLA: 37.09 ± 0.35 °C, DPH: 37.13 ± 0.33 °C, P = 0.68), and the 60-min ΔTrec was not different (P = 0.99) between PLA (0.83 ± 0.29 °C) and DPH (0.81 ± 0.30 °C). HR was similar at baseline (PLA: 86 ± 13 BPM, DPH: 84 ± 11 BPM, P = 0.30) and end-exercise (PLA: 134 ± 28 BPM, DPH: 132 ± 26BPM, P = 0.90). 50 mg of DPH does not modify the sweating, core temperature, and heart rate response during exertional heat stress in young healthy adults.

Optimal designs using generalized estimating equations in cluster randomized crossover and stepped wedge trials.

Cluster randomized crossover and stepped wedge cluster randomized trials are two types of longitudinal cluster randomized trials that leverage both the within- and between-cluster comparisons to estimate the treatment effect and are increasingly used in healthcare delivery and implementation science research. While the variance expressions of estimated treatment effect have been previously developed from the method of generalized estimating equations for analyzing cluster randomized crossover trials and stepped wedge cluster randomized trials, little guidance has been provided for optimal designs to ensure maximum efficiency. Here, an optimal design refers to the combination of optimal cluster-period size and optimal number of clusters that provide the smallest variance of the treatment effect estimator or maximum efficiency under a fixed total budget. In this work, we develop optimal designs for multiple-period cluster randomized crossover trials and stepped wedge cluster randomized trials with continuous outcomes, including both closed-cohort and repeated cross-sectional sampling schemes. Local optimal design algorithms are proposed when the correlation parameters in the working correlation structure are known. MaxiMin optimal design algorithms are proposed when the exact values are unavailable, but investigators may specify a range of correlation values. The closed-form formulae of local optimal design and MaxiMin optimal design are derived for multiple-period cluster randomized crossover trials, where the cluster-period size and number of clusters are decimal. The decimal estimates from closed-form formulae can then be used to investigate the performances of integer estimates from local optimal design and MaxiMin optimal design algorithms. One unique contribution from this work, compared to the previous optimal design research, is that we adopt constrained optimization techniques to obtain integer estimates under the MaxiMin optimal design. To assist practical implementation, we also develop four SAS macros to find local optimal designs and MaxiMin optimal designs.

Noninvasive targeted modulation of pain circuits with focused ultrasonic waves.

Direct interventions into deep brain circuits constitute promising treatment modalities for chronic pain. Cingulotomy and deep brain stimulation targeting the anterior cingulate cortex have shown notable improvements in the unpleasantness of pain, but these interventions require brain surgeries. In this study, we have developed an approach that can modulate this deep brain affective hub entirely noninvasively, using low-intensity transcranial-focused ultrasound. Twenty patients with chronic pain received two 40-minute active or sham stimulation protocols and were monitored for one week in a randomized crossover trial. Sixty percent of subjects experienced a clinically meaningful reduction of pain on day 1 and on day 7 following the active stimulation, while sham stimulation provided such benefits only to 15% and 20% of subjects, respectively. On average, active stimulation reduced pain by 60.0% immediately following the intervention and by 43.0% and 33.0% on days 1 and 7 following the intervention. The corresponding sham levels were 14.4%, 12.3%, and 6.6%. The stimulation was well tolerated, and no adverse events were detected. Side effects were generally mild and resolved within 24 hours. Together, the direct, ultrasonic stimulation of the anterior cingulate cortex offers rapid, clinically meaningful, and durable improvements in pain severity.

The role of glucagon-like peptide 1 in the postprandial effects of metformin in type 2 diabetes: a randomized crossover trial.

Although metformin is widely used for treatment of type 2 diabetes (T2D), its glucose-lowering mechanism remains unclear. Using the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) antagonist exendin(9-39)NH2, we tested the hypothesis that postprandial GLP-1-mediated effects contribute to the glucose-lowering potential of metformin in T2D. In a randomized, placebo-controlled, double-blind, crossover study, 15 individuals with T2D (median HbA1c 50 mmol/mol [6.7%], body mass index 30.1 kg/m2, age 71 years) underwent, in randomized order, 14 days of metformin and placebo treatment, respectively. Each treatment period was preceded by 14 days without any glucose-lowering medicine and concluded by two 4 h mixed meal tests performed in randomized order and separated by >24 h with either continuous intravenous exendin(9-39)NH2 or saline infusion. Compared to placebo, metformin treatment lowered fasting plasma glucose (mean of differences [MD] 1.4 mmol/L × min [95% CI 0.8-2.0]) as well as postprandial plasma glucose excursions during both saline infusion (MD 186 mmol/L × min [95% CI 64-307]) and exendin(9-39)NH2 infusion (MD 268 mmol/L × min [95% CI 108-427]). The metformin-induced improvement in postprandial glucose tolerance was unaffected by GLP-1R antagonization (MD 82 mmol/L × min [95% CI -6564-170]). Metformin treatment increased fasting plasma GLP-1 (MD 1.7 pmol/L × min [95% CI 0.39-2.9]) but did not affect postprandial GLP-1 responses (MD 820 pmol/L × min [95% CI -1750-111]). Using GLP-1R antagonization, we could not detect GLP-1-mediated postprandial glucose-lowering effect of metformin in individuals with T2D. We show that 2 weeks of metformin treatment increases fasting plasma GLP-1, which may contribute to metformin's beneficial effect on fasting plasma glucose in T2D. Trial registration: Clinicaltrials.gov NCT03246451.

Recipe for Heart Health: A Randomized Crossover Trial on Cardiometabolic Effects of Extra Virgin Olive Oil Within a Whole-Food Plant-Based Vegan Diet.

Whole-food, plant-based vegan diets, low in oils, and Mediterranean diets, rich in extra virgin olive oil (EVOO), reduce cardiovascular disease risk factors. Optimal quantity of dietary fat, particularly EVOO, is unclear. In a randomized crossover trial with weekly cooking classes, adults with ≥5% cardiovascular disease risk followed a high (4 tablespoons/day) to low (<1 teaspoon/day) or low to high EVOO whole-food, plant-based diet for 4 weeks each, separated by a 1-week washout. The primary outcome was difference in low-density lipoprotein cholesterol (LDL-C) from baseline. Secondary measures were changes in additional cardiometabolic markers. Linear mixed models assessed changes from baseline between phases, with age, sex, and body weight change as covariates. In 40 participants, fat intake comprised 48% and 32% of energy during high and low EVOO phases, respectively. Both diets resulted in comparable reductions in LDL-C, total cholesterol, apolipoprotein B, high-density lipoprotein cholesterol, glucose, and high-sensitivity C-reactive protein (all P<0.05). With diet-sequence interactions for LDL-C, differences were detected between diets by diet order (mean±SEM high to low: Δ-12.7[5.9] mg/dL, P=0.04 versus low to high: Δ+15.8[6.8] mg/dL, P=0.02). Similarly, low to high order led to increased glucose, total cholesterol, and high-density lipoprotein cholesterol (all P<0.05). Over period 1, LDL-C reductions were -25.5(5.1) post-low versus -16.7(4.2) mg/dL post-high EVOO, P=0.162, which diminished over period 2. Both plant-based diet patterns improved cardiometabolic risk profiles compared with baseline diets, with more pronounced decreases in LDL-C after the low EVOO diet. Addition of EVOO after following a low intake pattern may impede further lipid reductions. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04828447.