Increased Salt Intake Decreases Diet-Induced Thermogenesis in Healthy Volunteers: A Randomized Placebo-Controlled Study.

High salt intake ranks among the most important risk factors for noncommunicable diseases. Western diets, which are typically high in salt, are associated with a high prevalence of obesity. High salt is thought to be a potential risk factor for obesity independent of energy intake, although the underlying mechanisms are insufficiently understood. A high salt diet could influence energy expenditure (EE), specifically diet-induced thermogenesis (DIT), which accounts for about 10% of total EE. We aimed to investigate the influence of high salt on DIT. In a randomized, double-blind, placebo-controlled, parallel-group study, 40 healthy subjects received either 6 g/d salt (NaCl) or placebo in capsules over 2 weeks. Before and after the intervention, resting EE, DIT, body composition, food intake, 24 h urine analysis, and blood pressure were obtained. EE was measured by indirect calorimetry after a 12 h overnight fast and a standardized 440 kcal meal. Thirty-eight subjects completed the study. Salt intake from foods was 6 g/d in both groups, resulting in a total salt intake of 12 g/d in the salt group and 6 g/d in the placebo group. Urine sodium increased by 2.29 g/d (p < 0.0001) in the salt group, indicating overall compliance. The change in DIT differed significantly between groups (placebo vs. salt, p = 0.023). DIT decreased by 1.3% in the salt group (p = 0.048), but increased by 0.6% in the placebo group (NS). Substrate oxidation indicated by respiratory exchange ratio, body composition, resting blood pressure, fluid intake, hydration, and urine volume did not change significantly in either group. A moderate short-term increase in salt intake decreased DIT after a standardized meal. This effect could at least partially contribute to the observed weight gain in populations consuming a Western diet high in salt.

Association of Single-blind Placebo Run-in Periods With the Placebo Response in Randomized Clinical Trials of Antidepressants: A Systematic Review and Meta-analysis.

Importance: Single-blind placebo run-in (PRI) periods are common in randomized clinical trials (RCTs) of treatment for depression. They aim to increase sensitivity to detect drug effects; however, the association of PRI periods with study outcomes remains unclear. This is concerning given the costs of PRI periods to patients and investigators. Objective: To examine the association of the use of PRI periods with the placebo response, drug response, and drug-placebo difference among RCTs of antidepressants. Data Sources: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO, as well as repositories of unpublished studies, were systematically searched up to July 2021. Study Selection: Included studies were double-blind, placebo-controlled RCTs of antidepressant medication among adults with depressive disorders. Data Extraction and Synthesis: Data were extracted into a coding sheet, including the characteristics of studies, the characteristics of PRI periods, and the outcomes of studies. Main Outcomes and Measures: Study outcomes were the primary depression symptom measure reported by the RCT. These outcomes were used to calculate effect sizes (Hedges g) of the within-group drug response and placebo response as well as the drug-placebo difference. Random-effects meta-analysis was used to calculate effect sizes, and subgroup analyses were used to compare outcomes depending on use of PRI periods. Results: A total of 347 trials (representing 89 183 participants) were included; 174 studies (50%) reported using a single-blind PRI period. Response outcome data were available for 189 studies. Studies using PRI periods reported a smaller placebo response (g = 1.05 [95% CI, 0.98-1.11]; I2 = 82%) than studies that did not use a PRI period (g = 1.15 [95% CI, 1.09-1.21]; I2 = 81%; P = .02). Subgroup analysis showed a larger drug response size among studies that did not use a PRI period (g = 1.55 [95% CI, 1.49-1.61]; I2 = 85%) than those that did use a PRI period (g = 1.42 [95% CI, 1.36-1.48]; I2 = 81%; P = .001). The drug-placebo difference did not differ by use of PRI periods (g = 0.33 [95% CI, 0.29-0.38]; I2 = 47% for use of a PRI period vs g = 0.34 [95% CI, 0.30-0.38]; I2 = 54% for no use of PRI periods; P = .92). The likelihood of response to drug vs placebo also did not differ between studies that used a PRI period (odds ratio, 1.89 [95% CI, 1.76-2.03]) and those that did not use a PRI period (odds ratio, 1.77 [95% CI, 1.65-1.89]; P = .18). Conclusions and Relevance: This study suggests that RCTs using PRI periods yield smaller within-group changes across both placebo and drug groups compared with RCTs without PRI periods. The reduction in effect size across groups was equivalent in magnitude. Consequently, PRI studies do not observe larger drug-placebo differences, suggesting that they do not increase trial sensitivity. As such, given the resources and probable deception required and risk to external validity, the practice of using PRI periods in RCTs of antidepressants should be ended.

Brainstem Mechanisms of Pain Modulation: A within-Subjects 7T fMRI Study of Placebo Analgesic and Nocebo Hyperalgesic Responses.

Pain perception can be powerfully influenced by an individual's expectations and beliefs. Although the cortical circuitry responsible for pain modulation has been thoroughly investigated, the brainstem pathways involved in the modulatory phenomena of placebo analgesia and nocebo hyperalgesia remain to be directly addressed. This study used ultra-high-field 7 tesla functional MRI (fMRI) to accurately resolve differences in brainstem circuitry present during the generation of placebo analgesia and nocebo hyperalgesia in healthy human participants (N = 25, 12 male). Over 2 successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled lidocaine (placebo) and capsaicin (nocebo) were acting to modulate their pain relative to a third Vaseline (control) cream. In a subsequent test phase, fMRI image sets were collected while participants were given identical noxious stimuli to all three cream sites. Pain intensity ratings were collected and placebo and nocebo responses determined. Brainstem-specific fMRI analysis revealed altered activity in key pain modulatory nuclei, including a disparate recruitment of the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway when both greater placebo and nocebo effects were observed. Additionally, we found that placebo and nocebo responses differentially activated the parabrachial nucleus but overlapped in engagement of the substantia nigra and locus coeruleus. These data reveal that placebo and nocebo effects are generated through differential engagement of the PAG-RVM pathway, which in concert with other brainstem sites likely influences the experience of pain by modulating activity at the level of the dorsal horn.SIGNIFICANCE STATEMENT Understanding endogenous pain modulatory mechanisms would support development of effective clinical treatment strategies for both acute and chronic pain. Specific brainstem nuclei have long been known to play a central role in nociceptive modulation; however, because of the small size and complex organization of the nuclei, previous neuroimaging efforts have been limited in directly identifying how these subcortical networks interact during the development of antinociceptive and pro-nociceptive effects. We used ultra-high-field fMRI to resolve brainstem structures and measure signal change during placebo analgesia and nocebo hyperalgesia. We define overlapping and disparate brainstem circuitry responsible for altering pain perception. These findings extend our understanding of the detailed organization and function of discrete brainstem nuclei involved in pain processing and modulation.

Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial.

Importance: Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes. Objective: To determine whether the combination of vasopressin and methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021. Intervention: Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses. Main Outcomes and Measures: The primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2). Results: Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean [SD] age, 71 [13] years; 322 men [64%]). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 [95% CI, 1.03-1.63]; risk difference, 9.6% [95% CI, 1.1%-18.0%]; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 [95% CI, 0.50-1.37]; risk difference: -2.0% [95% CI, -7.5% to 3.5%]; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 [95% CI, 0.55-1.83]; risk difference, 0.0% [95% CI, -4.7% to 4.9%]; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively. Conclusions and Relevance: Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03640949.

Mitochondria-targeted antioxidant supplementation improves 8 km time trial performance in middle-aged trained male cyclists.

BACKGROUND: Exercise increases skeletal muscle reactive oxygen species (ROS) production, which may contribute to the onset of muscular fatigue and impair athletic performance. Mitochondria-targeted antioxidants such as MitoQ, which contains a ubiquinone moiety and is targeted to mitochondria through the addition of a lipophilic triphenylphosphonium cation, are becoming popular amongst active individuals as they are designed to accumulate within mitochondria and may provide targeted protection against exercise-induced oxidative stress. However, the effect of MitoQ supplementation on cycling performance is currently unknown. Here, we investigate whether MitoQ supplementation can improve cycling performance measured as time to complete an 8 km time trial. METHOD: In a randomized, double-blind, placebo-controlled crossover study, 19 middle-aged (age: 44 ± 4 years) recreationally trained (VO2peak: 58.5 ± 6.2 ml·kg- 1·min- 1, distance cycled per week during 6 months prior to study enrollment: 158.3 ± 58.4 km) male cyclists completed 45 min cycling at 70% VO2peak followed by an 8 km time trial after 28 days of supplementation with MitoQ (20 mg·day- 1) and a placebo. Free F2-isoprostanes were measured in plasma samples collected at rest, after 45 min cycling at 70% VO2peak and after completion of the time trial. Respiratory gases and measures of rating of perceived exertion (RPE) were also collected. RESULTS: Mean completion time for the time trial was 1.3% faster with MitoQ (12.91 ± 0.94 min) compared to placebo (13.09 ± 0.95 min, p = 0.04, 95% CI [0.05, 2.64], d = 0.2). There was no difference in RPE during the time trial between conditions (p = 0.82) despite there being a 4.4% increase in average power output during the time trial following MitoQ supplementation compared to placebo (placebo; 270 ± 51 W, MitoQ; 280 ± 53 W, p = 0.04, 95% CI [0.49, 8.22], d = 0.2). Plasma F2-isoprostanes were lower on completion of the time trial following MitoQ supplementation (35.89 ± 13.6 pg·ml- 1) compared to placebo (44.7 ± 16.9 pg·ml- 1 p = 0.03). CONCLUSION: These data suggest that MitoQ supplementation may be an effective nutritional strategy to attenuate exercise-induced increases in oxidative damage to lipids and improve cycling performance.

Habitual Caffeine Consumption Does Not Interfere With the Acute Caffeine Supplementation Effects on Strength Endurance and Jumping Performance in Trained Individuals.

The long-standing caffeine habituation paradigm was never investigated in strength endurance and jumping exercise performance through a straightforward methodology. The authors examined if habitual caffeine consumption would influence the caffeine ergogenic effects on strength endurance and jumping performance as well as perceptual responses. Thirty-six strength-trained individuals were mathematically allocated into tertiles according to their habitual caffeine consumption: low (20 ± 11 mg/day), moderate (88 ± 33 mg/day), and high consumers (281 ± 167 mg/day). Then, in a double-blind, crossover, counterbalanced fashion, they performed a countermovement vertical jump test and a strength endurance test either after caffeine (6 mg/kg) and placebo supplementation or after no supplementation (control). Perceptual responses such as ratings of perceived exertion and pain were measured at the termination of the exercises. Acute caffeine supplementation improved countermovement vertical jump performance (p = .001) and total repetitions (p = .004), regardless of caffeine habituation. Accordingly, analysis of absolute change from the control session showed that caffeine promoted a significantly greater improvement in both countermovement vertical jump performance (p = .004) and total repetitions (p = .0001) compared with placebo. Caffeine did not affect the rating of perceived exertion and pain in any exercise tests, irrespective of tertiles (for all comparisons, p > .05 for both measures). Caffeine side effects were similar in low, moderate, and high caffeine consumers. These results show that habitual caffeine consumption does not influence the potential of caffeine as an ergogenic aid in strength endurance and jumping exercise performance, thus challenging recommendations to withdraw from the habitual caffeine consumption before supplementing with caffeine.

The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysis.

BACKGROUND: Clinical trials in irritable bowel syndrome are associated with high placebo response rates. We aimed to identify the magnitude of the placebo response and the contributing factors to this occurrence. METHODS: We did a systematic review and meta-analysis with a search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials between April 1, 1959, and April 30, 2020. We included all randomised controlled trials that compared an active pharmacotherapeutic agent with placebo and had a dichotomous outcome of response to therapy (in terms of global improvement or improvement in abdominal pain) in adults (aged ≥18 years) with irritable bowel syndrome. Exclusion criteria were trials reporting on treatment satisfaction as a dichotomous outcome of response to therapy or clinician-reported outcomes and a treatment duration of less than 4 weeks. Our main outcome was identification of the magnitude of the pooled placebo response rate for the following endpoints: global improvement, abdominal pain, and US Food and Drug Administration (FDA) endpoints. We extracted information from published reports and pooled proportions through meta-analysis with random effects. The study was registered with PROSPERO, CRD42020170908. FINDINGS: Of the 6863 publications identified, 70 articles describing 73 randomised controlled trials were included in our analysis. The pooled placebo response rate was 27·3% (95% CI 24·3-30·9) using the global improvement endpoint, 34·4% (31·2-37·8) using the abdominal pain endpoint, and 17·9% (15·2-21·0) using the composite FDA endpoint responder definition, all with substantial heterogeneity between the trials. Studies published before 2006, and those done in Europe, with a parallel design, a run-in period of 2 weeks or less, a dose schedule of three times a day or more, or a smaller sample size of the control group were significantly associated with an increased pooled placebo response rate. INTERPRETATION: More than a quarter of patients with irritable bowel syndrome had a placebo response in terms of global improvement, with multiple associated moderators. We recommend future trials apply a run-in period of at least 2 weeks and dose once or twice a day to minimise the placebo response rate. FUNDING: None.

4-week eicosapentaenoic acid-rich fish oil supplementation partially protects muscular damage following eccentric contractions.

BACKGROUND: We previously showed 8-week of fish oil supplementation attenuated muscle damage. However, the effect of a shorter period of fish oil supplementation is unclear. The present study investigated the effect of fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for 4 weeks on muscular damage caused by eccentric contractions (ECCs) of the elbow flexors. METHODS: Twenty-two untrained men were recruited in this double-blind, placebo-controlled, parallel design study and the subjects were randomly assigned to the EPA and DHA group (EPA and DHA, n = 11) and placebo group (PL, n = 11). They consumed either EPA 600 mg and DHA 260 mg per day or placebo supplement for 4 weeks prior to exercise. Subjects performed 60 ECCs at 100 % maximal voluntary contraction (MVC) using a dumbbell. Changes in MVC torque, range of motion (ROM), upper arm circumference, muscle soreness, echo intensity, muscle thickness, serum creatine kinase (CK), and interleukin-6 (IL-6) were assessed before exercise; immediately after exercise; and 1, 2, 3, and 5 days after exercise. RESULTS: ROM was significantly higher in the EPA and DHA group than in the PL group immediately after performing ECCs (p < 0.05). No differences between groups were observed in terms of MVC torque, upper arm circumference, muscle soreness, echo intensity, and thickness. A significant difference was observed in serum CK 3 days after ECCs (p < 0.05). CONCLUSIONS: We concluded that shorter period EPA and DHA supplementation benefits joint flexibility and protection of muscle fiber following ECCs.

The effects of 14-week betaine supplementation on endocrine markers, body composition and anthropometrics in professional youth soccer players: a double blind, randomized, placebo-controlled trial.

OBJECTIVE: Betaine supplementation may enhance body composition outcomes when supplemented chronically during an exercise program. The purpose of this study was to evaluate the effect of betaine supplementation on development-related hormones, body composition, and anthropometrics in professional youth soccer players during a competitive season. METHODS: Twenty-nine players (age, 15.45 ± 0.25 years) were matched based upon position and then randomly assigned to a betaine group (2 g/day; n = 14, BG) or placebo group (PG, n = 15). All subjects participated in team practices, conditioning, and games. If a subject did not participate in a game, a conditioning protocol was used to ensure workload was standardized throughout the 14-week season. Growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, cortisol, height, weight, and body composition were assessed at pre-season (P1), mid-season (P2) and post-season (P3). Anthropometric variables were also measured following a one-year follow-up (F). RESULTS: Significant (p < 0.05) group x time interactions were found for testosterone and testosterone to cortisol ratio (T/C). Both variables were greater in BG at P2 and P3 compared to P1, however, the testosterone was less in the PG at P3 compared to P2. There was no significant group by time interactions for GH, IGF-1, lean body mass, or body fat. There was a significant (p < 0.05) group x time interaction in height and weight at F, with the greater increases in BG compared to PG. CONCLUSION: Betaine supplementation increased testosterone levels and T/C ratio in youth professional soccer players during a competitive season. Betaine supplementation had no negative effects on growth (height and weight) and may attenuate reductions in testosterone due to intense training during puberty.

Nicotine supplementation enhances simulated game performance of archery athletes.

BACKGROUND: Nicotine is beneficial to mood, arousal and cognition in humans. Due to the importance of cognitive functioning for archery athletes, we investigated the effects of nicotine supplementation on the cognitive abilities, heart rate variability (HRV), and sport performance of professional archers. METHODS: Eleven college archers were recruited and given 2 mg of nicotine supplementation (NIC group) and placebo (PLA group) in a crossover design. RESULTS: The results showed that at 30 min after the intake of nicotine gum, the "correct rejection" time in the NIC group was significantly lower than that of the PLA group (7.29 ± 0.87 vs. 8.23 ± 0.98 msec, p < 0.05). In addition, the NIC group completed the grooved pegboard test in a shorter time than the PLA group (48.76 ± 3.18 vs. 53.41 ± 4.05 s, p < 0.05), whereas motor reaction times were not different between the two groups. Saliva α-amylase activity was significantly lower after nicotine supplementation (p < 0.01) but increased immediately after the archery test in the NIC group (p < 0.05). In addition, nicotine supplementation significantly decreased HRV and increased the archery score (290.58 ± 10.09 vs. 298.05 ± 8.56, p < 0.01). CONCLUSIONS: Nicotine enhances the performance of archery athletes by increasing cognitive function and stimulating the sympathetic adrenergic system.

Effect of atorvastatin on testosterone levels.

BACKGROUND: Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolaemia and dyslipidaemia. By reducing the level of cholesterol, which is the precursor of the steroidogenesis pathway, atorvastatin may cause a reduction in levels of testosterone and other androgens. Testosterone and other androgens play important roles in biological functions. A potential reduction in androgen levels, caused by atorvastatin might cause negative effects in most settings. In contrast, in the setting of polycystic ovary syndrome (PCOS), reducing excessive levels of androgens with atorvastatin could be beneficial. OBJECTIVES: Primary objective To quantify the magnitude of the effect of atorvastatin on total testosterone in both males and females, compared to placebo or no treatment. Secondary objectives To quantify the magnitude of the effects of atorvastatin on free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulphate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs) in both males and females, compared to placebo or no treatment. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to 9 November 2020: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; ;two international trials registries, and the websites of the US Food and Drug Administration, the European Patent Office and the Pfizer pharmaceutical corporation. These searches had no language restrictions. We also contacted authors of relevant articles regarding further published and unpublished work. SELECTION CRITERIA: RCTs of daily atorvastatin for at least three weeks, compared with placebo or no treatment, and assessing change in testosterone levels in males or females. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the citations, extracted the data and assessed the risk of bias of the included studies. We used the mean difference (MD) with associated 95% confidence intervals (CI) to report the effect size of continuous outcomes,and the risk ratio (RR) to report effect sizes of the sole dichotomous outcome (WDAEs). We used a fixed-effect meta-analytic model to combine effect estimates across studies, and risk ratio to report effect size of the dichotomous outcomes. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included six RCTs involving 265 participants who completed the study and their data was reported. Participants in two of the studies were male with normal lipid profile or mild dyslipidaemia (N = 140); the mean age of participants was 68 years. Participants in four of the studies were female with PCOS (N = 125); the mean age of participants was 32 years. We found no significant difference in testosterone levels in males between atorvastatin and placebo, MD -0.20 nmol/L (95% CI -0.77 to 0.37). In females, atorvastatin may reduce total testosterone by -0.27 nmol/L (95% CI -0.50 to -0.04), FAI by -2.59 nmol/L (95% CI -3.62 to -1.57), androstenedione by -1.37 nmol/L (95% CI -2.26 to -0.49), and DHEAS by -0.63 µmol/l (95% CI -1.12 to -0.15). Furthermore, compared to placebo, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L (95% CI 0.23 to 5.99). We identified no studies in healthy females (i.e. females with normal testosterone levels) or children (under age 18). Importantly, no study reported on free testosterone levels. AUTHORS' CONCLUSIONS: We found no significant difference between atorvastatin and placebo on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed.

Caffeine increases maximal fat oxidation during a graded exercise test: is there a diurnal variation?

BACKGROUND: There is evidence that caffeine increases the maximal fat oxidation rate (MFO) and aerobic capacity, which are known to be lower in the morning than in the afternoon. This paper examines the effect of caffeine intake on the diurnal variation of MFO during a graded exercise test in active men. METHODS: Using a triple-blind, placebo-controlled, crossover experimental design, 15 active caffeine-naïve men (age: 32 ± 7 years) completed a graded exercise test four times at seven-day intervals. The subjects ingested 3 mg/kg of caffeine or a placebo at 8 am in the morning and 5 pm in the afternoon (each subject completed tests under all four conditions in a random order). A graded cycling test was performed. MFO and maximum oxygen uptake (VO2max) were measured by indirect calorimetry, and the intensity of exercise that elicited MFO (Fatmax) calculated. RESULTS: MFO, Fatmax and VO2max were significantly higher in the afternoon than in the morning (all P < 0.05). Compared to the placebo, caffeine increased mean MFO by 10.7% (0.28 ± 0.10 vs. 0.31 ± 0.09 g/min respectively, P < 0.001) in the morning, and by a mean 29.0% (0.31 ± 0.09 vs. 0.40 ± 0.10 g/min, P < 0.001) in the afternoon. Caffeine also increased mean Fatmax by 11.1% (36.9 ± 14.4 [placebo] vs. 41.0 ± 13.1%, P = 0.005) in the morning, and by 13.1% (42.0 ± 11.6 vs. 47.5 ± 10.8%, P = 0.008) in the afternoon. CONCLUSION: These findings confirm the previously reported diurnal variation in the whole-body fat oxidation rate during graded exercise in active caffeine-naïve men, and indicate that the acute ingestion of 3 mg/kg of caffeine increases MFO, Fatmax and VO2max independent of the time of day. TRIAL REGISTRATION: NCT04320446 . Registered 25 March 2020 - Retrospectively registered.

The effects of alpha lipoic acid on muscle strength recovery after a single and a short-term chronic supplementation - a study in healthy well-trained individuals after intensive resistance and endurance training.

BACKGROUND: Alpha lipoic acid (ALA) has been demonstrated to have anti-inflammatory activity and was tested as a drug for the treatment of various diseases. ALA is also frequently used as a nutrition supplement, in healthy individuals or in competitive athletes. However, information from intervention studies investigating physiological effects of an ALA in athletes after exercise is limited. Therefore, the aim of this study was to investigate the effects of single and short-term chronic ALA supplementation on the muscle strength recovery and performance of athletes after intensive exercise. METHODS: In a double-blind, randomised, controlled trial in cross-over design, 17 male resistance and endurance-experienced athletes successfully participated. The subjects were divided into two groups (ALA and Placebo) and underwent a standardized single training session and a high intense training week. At certain time points (T0, T1a (+ 3 h), T1b (+ 24 h) and T2 (+7d)) blood samples were taken and markers for muscle damage, inflammation and oxidative stress were investigated. In addition, the maximum performance in the back squat was measured at all time points. RESULTS: In the chronic training experiment, a moderate inhibition of muscle damage and inflammation could be observed in the ALA-group. Performance in the back squat was significantly reduced in the placebo-group, but not in the ALA-group. No anti-oxidative effects could be observed. CONCLUSIONS: Our data indicate possible effects of ALA supplementation, during intensive training periods result in a reduction of muscle damage, inflammation and an increase of recovery. Whether ALA supplementation in general may enhance performance and the exact training / supplementation scenarios needs to be investigated in future studies.

Understanding the effects of beetroot juice intake on CrossFit performance by assessing hormonal, metabolic and mechanical response: a randomized, double-blind, crossover design.

BACKGROUND: Acute beetroot juice (BJ) intake has shown to enhance aerobic and anaerobic performance. However, no studies have evaluated the effects of BJ intake on CrossFit (CF) performance by linking hormonal, metabolic, and mechanical responses. The purpose of this study was to determine the causal physiological association between hormonal, metabolic and mechanical responses, and CF workouts performance after acute BJ intake. METHODS: Twelve well-trained male practitioners undertook a CF workout after drinking 140 mL of BJ (~ 12.8 mmol NO3-) or placebo. The two experimental conditions (BJ or placebo) were administered using a randomized, double-blind, crossover design. The CF workout consisted of repeating the same exercise routine twice: Wall ball (WB) shots plus full back squat (FBS) with 3-min rest (1st routine) or without rest (2nd routine) between the two exercises. A 3-min rest was established between the two exercise routines. RESULTS: An interaction effect was observed in the number of repetitions performed (p = 0.04). The Bonferroni test determined a higher number of repetitions after BJ than placebo intake when a 3-min rest between WB and FBS (1st routine) was established (p = 0.007). An interaction effect was detected in cortisol response (p = 0.04). Cortisol showed a higher increase after BJ compared to placebo intake (76% vs. 36%, respectively). No interaction effect was observed in the testosterone and testosterone/cortisol ratio (p > 0.05). A significant interaction effect was found in oxygen saturation (p = 0.01). A greater oxygen saturation drop was observed in BJ compared to placebo (p <  0.05). An interaction effect was verified in muscular fatigue (p = 0.03) with a higher muscular fatigue being observed with BJ than placebo (p = 0.02). CONCLUSIONS: BJ intake improved anaerobic performance only after the recovery time between exercises. This increase in performance in the first routine probably generated greater hypoxia in the muscle mass involved, possibly conditioning post-exercise performance. This was observed with a fall in oxygen saturation and in muscle fatigue measured at the end of the CF workout. The greatest perceived changes in cortisol levels after BJ intake could be attributed to the nitrate-nitrite-nitric oxide pathway.

Placebo use and outcome quality: A protocol for systematic review and meta-analysis.

BACKGROUND: The Pharmaceutical industry sponsorship, research outcome and quality has been already evaluated for clinical trials in order to analyze if this kind of sponsorship affects the results of clinical trials. In this sense, this study has the aim to investigate whether placebo use allows positive outcomes regarding efficacy and safety compared to synthetic medicines. METHODS: We designed and registered a study protocol for a systematic review for methodology data. We will only randomized clinical trials that use placebo as comparator. The main outcome will be the evaluation of placebo use regarding the tendency for positive results (efficacy and security) when comparing to synthetic medicines. PubMed, Cochrane, LILACS (BVS), Web of Science, Scopus, and Excerpta Medica dataBASE (EMBASE) databases will be searched. Gray literature will be identified through the databases Proquest (Dissertation and Theses), OpenGrey and Google Scholar. Two review authors will independently assess trial quality and will extract data in accordance with standard Cochrane methodology. If necessary, we will also contact authors for additional information. The Cochrane Collaboration's risk of bias tool will be used. If feasible, it means homogenous data, we will conduct random effects meta-analysis. Subgroup analyses will be conducted for different justifications for placebo use and for studies sponsored/not sponsored by the pharmaceutical industry. RESULTS: Our present findings will indicate the effects of placebo use as comparator regarding efficacy and safety of the oral synthetic medicines. DISCUSSION: This systematic review will identify, summarize, and analyze if there is a trend for positive efficacy and safety results for synthetic medicines in clinical trials when compared with placebo and if the justification for placebo use is considered ethically acceptable. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018110829.

TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls.

BACKGROUND: Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions. METHODS AND FINDINGS: We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator. CONCLUSIONS: We encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.

Caffeine improves various aspects of athletic performance in adolescents independent of their 163 C > A CYP1A2 genotypes.

PURPOSE: The purpose of this study was to investigate whether variations in 163 C > A CYP1A2 genotypes (rs 762 551) (AA, AC, and CC) modify the ergogenic effects of caffeine (CAF) on strength, power, muscular endurance, agility, and endurance in adolescent athletes. METHODS: One hundred adolescents (age = 15 ± 2 years) were recruited. Participants ingested CAF (6 mg.kg-1 ) or placebo (PLA, 300 mg of cellulose) 1 hour before performing a sequence of physical tests: handgrip strength, vertical jumps, agility test, sit-ups, push-ups, and the Yo-Yo intermittent recovery test level 1 (Yo-Yo IR1). RESULTS: Compared to PLA, CAF enhanced (P < .05) sit-up (CAF = 37 ± 9; PLA = 35 ± 8 repetitions) and push-up repetitions (CAF = 26 ± 11; PLA = 24 ± 11 repetitions), and increased distance covered in Yo-Yo IR1 test (CAF = 1010.4 ± 378.9; PLA = 903.2 ± 325.7 m). There was no influence of CAF on handgrip strength (CAF = 35.1 ± 8.9; PLA = 33.7 ± 8.7 kgf), countermovement jump height (CAF = 49.3 ± 12.6; PLA = 47.9 ± 13.8 cm), spike jump height (CAF = 54.2 ± 13.6; PLA = 52.9 ± 14.5 cm), and time in agility test (CAF = 15.8 ± 1.1; PLA = 15.9 ± 1.3 s, P > .05). When present, the ergogenic effect of CAF was not dependent of genotype. CONCLUSION: CAF improves muscular endurance and aerobic performance in adolescent athletes, regardless of their 163 C > A CYP1A2 genotype.

Merely Possessing a Placebo Analgesic Improves Analgesia Similar to Using the Placebo Analgesic.

BACKGROUND: Placebo analgesia studies generally reported that the actual use of a placebo analgesic reduces pain. Yeung, Geers, and Kam found that the mere possession (without use) of a placebo analgesic also reduces pain. PURPOSE: We investigated the relative effectiveness of using versus possessing a placebo analgesic on pain outcomes. METHODS: In Study 1a, 120 healthy adults were randomized to either the experimental (EXP) conditions (EXP1: used a placebo analgesic cream, EXP2: possessed a placebo analgesic cream) or control (CO) conditions (CO1: possessed a sham cream, CO2: no cream). All participants underwent a cold pressor test (CPT). Study 1b further delineated the effect of possession from the effect of use. Sixty healthy adults were randomized to either the placebo-possession condition (merely possessed a placebo analgesic cream) or the placebo-possession-use condition (possessed and used a placebo analgesic cream). All participants did a CPT. RESULTS: In Study 1a, as expected, a placebo effect was found-participants who used a placebo analgesic cream showed better pain outcomes than the two CO groups. Surprisingly, participants who merely possessed a placebo analgesic cream performed equally well as those who actually used it. In Study 1b, participants in the two conditions did not differ in most pain outcomes. Participants who possessed and used a placebo analgesic cream only showed slightly more reduction in pain intensity compared to participants who merely possessed the placebo analgesic cream. CONCLUSIONS: Our results suggest that merely possessing a placebo analgesic could enhance pain outcomes similar to that of applying the placebo analgesic.