Caffeine gum improves 5 km running performance in recreational runners completing parkrun events.

PURPOSE: The purpose of this study was to determine whether caffeine gum improves the performance of recreational runners completing parkruns (weekly, 5 km, mass participant running events). METHODS: Thirty-six recreational runners (M = 31, F = 5; age 33.7 ± 10.7 y; BMI 23.1 ± 2.4 kg/m2) capable of running 5 km in < 25 min were recruited to a study at the Sheffield Hallam parkrun, UK. Runners were block randomized into one of three double-blind, placebo-controlled, cross-over intervention trials with caffeine gum as the treatment (n = 6 per intervention trial) or into one of three non-intervention trials that ran concurrently with the intervention trials (n = 6 per non-intervention trial). Changes in conditions across different parkruns were adjusted for using data from the non-intervention trials. Runners in the randomized cross-over intervention trials chewed gum supplying 300 mg of caffeine or a placebo gum for 5 min, starting 30 min before each parkrun. RESULTS: Caffeine gum improved 5 km parkrun performance by a mean of 17.28 s (95% CI 4.19, 30.37; P = 0.01). Adjustment for environmental conditions using data from the non-intervention trials attenuated the statistical significance (P = 0.04). Caffeine gum also decreased RPE by 1.21 (95% CI 0.30, 2.13; P = 0·01) units relative to placebo. CONCLUSIONS: A 300 mg dose of caffeine supplied in chewing gum improved the performance of recreational runners completing 5 km parkruns by an average of 17 s. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov: NCT02473575 before recruitment commenced.

Circulating total 25(OH)D and calculated free 25(OH)D in professional academy footballers at a northerly latitude in the UK.

There is limited data on the vitamin D status of UK-based professional academy footballers. Therefore, the objective of this study was to report total 25(OH)D, free 25(OH)D and free 1, 25(OH)2D at the end of the winter (March) and summer periods (October) in a cohort (n = 27) of professional academy footballers in northern England. Blood samples were collected to measure total 25(OH)D, parathyroid hormone, vitamin D binding protein, albumin and calcium. Free 25(OH)D and 1, 25(OH)2D were calculated. Dietary vitamin D intake and retrospective summer sunlight exposure were also collected. At the end of winter, 2/27 (7.4%) players were vitamin D deficient (25(OH)D < 30 nmol/l) and 11/27 (40.7%) were insufficient (25(OH)D > 30 nmol/l < 50 nmol/l). By the end of summer, none were deficient but 3/14 (21.4%) were still insufficient. Median total 25(OH)D (82.2 nmol/l [IQR: 50.3-90.2] vs. 54.2 nmol/l [IQR: 36.8-71.9]; P = .02), free 25(OH)D (25.8 pmol/l [IQR: 15.1-33.1] vs. 13.2 pmol/l [IQR: 9.0-14.9]; P = .005) and free 1, 25(OH)2D (389 fmol/l [IQR: 209-594] vs. 212 fmol/l [IQR: 108-278]; P = .034) were significantly higher at the end of summer than the end of winter. At the end of winter, free 25(OH)D was lower (P = .003) in those vitamin D insufficient (8.8 pmol/l [IQR: 5.5-11.8]) vs. sufficient (13.7 pmol/l [IQR: 12.0-17.0]). There was a high prevalence of vitamin D insufficiency at the end of the winter. Free 25(OH)D was also lower at the winter timepoint and in players that were insufficient vs. sufficient.

Assessing the effectiveness of MRI, 18F-fluciclovine PET, SUVmax, and PSA in detecting local recurrence of prostate cancer after prostatectomy.

Purpose: The primary objective of this study was to evaluate the discriminatory utility of magnetic resonance imaging (MRI), 18F-fluciclovine positron emission tomography (PET), maximum standardized uptake value (SUVmax), prostate-specific antigen (PSA), and combinations of these diagnostic modalities for detecting local prostate cancer recurrence in the setting of rising PSA after radical prostatectomy. Material and methods: Patients were characterised for clinical features such as Gleason score, PSA at surgery, PSA at follow-up, follow-up MRI result, follow-up PET result, follow-up SUVmax, and follow-up disease status. The utility of diagnostic parameters for detecting disease recurrence at the prostatectomy bed was assessed using receiver operating characteristics (ROC) analysis to determine the area under the curve (AUC) for each model. Sensitivity, specificity, and positive/negative predictive values were also calculated. Optimal cut-off points for continuous variables were determined based on maximum Youden's J statistics. Results: The study found that MRI had the highest concordance (96%), sensitivity (100%), specificity (91%), positive predictive value (93%), and negative predictive value (100%) among the diagnostic modalities. The AUC for MRI was 0.9545, indicating a high discriminatory ability for detecting prostate cancer local recurrence. When combined, PET and SUVmax (cut-off value of 2.85) showed an improved performance compared to using them individually, with an AUC of 0.8925. Conclusions: The analysis suggests that MRI is the most effective imaging modality for detecting local prostate cancer recurrence, with 18F-fluciclovine PET and SUVmax also showing promising combined results. PSA has moderate discriminatory utility at follow-up but can still provide valuable information in detecting prostate cancer recurrence. Further research and recent references are needed to support these findings.

A Physiologically-Based Pharmacokinetic Model for Cannabidiol in Healthy Adults, Hepatically-Impaired Adults, and Children.

Cannabidiol (CBD) is available as a prescription oral drug that is indicated for the treatment of some types of epilepsy in children and adults. CBD is also available over-the-counter and is used to self-treat a variety of other ailments, including pain, anxiety, and insomnia. Accordingly, CBD may be consumed with other medications, resulting in possible CBD-drug interactions. Such interactions can be predicted in healthy and hepatically-impaired (HI) adults and in children through physiologically based pharmacokinetic (PBPK) modeling and simulation. These PBPK models must be populated with CBD-specific parameters, including the enzymes that metabolize CBD in adults. In vitro reaction phenotyping experiments showed that UDP-glucuronosyltransferases (UGTs, 80%), particularly UGT2B7 (64%), were the major contributors to CBD metabolism in adult human liver microsomes. Among the cytochrome P450s (CYPs) tested, CYP2C19 (5.7%) and CYP3A (6.5%) were the major CYPs responsible for CBD metabolism. Using these and other physicochemical parameters, a CBD PBPK model was developed and validated for healthy adults. This model was then extended to predict CBD systemic exposure in HI adults and children. Our PBPK model successfully predicted CBD systemic exposure in both populations within 0.5- to 2-fold of the observed values. In conclusion, we developed and validated a PBPK model to predict CBD systemic exposure in healthy and HI adults and children. This model can be used to predict CBD-drug or CBD-drug-disease interactions in these populations. SIGNIFICANCE STATEMENT: Our PBPK model successfully predicted CBD systemic exposure in healthy and hepatically-impaired adults, as well as children with epilepsy. This model could be used in the future to predict CBD-drug or CBD-drug-disease interactions in these special populations.

Diagnostic Approaches to Neuroendocrine Neoplasms of Unknown Primary Site.

ABSTRACT: Neuroendocrine tumors (NETs) are relatively uncommon heterogeneous neoplasms arising from endocrine and neuronal origin cells showing highly variable clinical behavior. By the time these tumors are discovered, up to 14% of patients with histologically proven NETs have metastasis, with the liver as the most frequently affected organ. Sometimes, no known primary site can be identified via routine imaging. Neuroendocrine tumors of unknown origin carry a poorer prognosis (compared with metastatic NETs with a known primary site) because of a lack of tailored surgical intervention and appropriate medical therapy (eg, chemotherapy or targeted therapy). A multimethod approach is frequently used in the trial to accurately determine the primary site for NETs of unknown primary sites and may include clinical, laboratory, radiological, histopathological, and surgical data. New molecular techniques using the genomic approach to identify the molecular signature have shown promising results. Various imaging modalities include ultrasound, computed tomography (CT), dual-energy CT, magnetic resonance imaging, and functional and hybrid imaging (positron emission tomography/CT, positron emission tomography/magnetic resonance imaging); somatostatin receptor imaging with new tracers is frequently used in an attempt for localization of the primary site.

Appendiceal Neuroendocrine Neoplasms: A Comprehensive Review.

ABSTRACT: Appendiceal neuroendocrine neoplasm (NEN) is the most common adult appendiceal malignant tumor, constituting 16% of gastrointestinal NENs. They are versatile tumors with varying morphology, immunohistochemistry, secretory properties, and cancer genomics. They are slow growing and clinically silent, to begin with, or present with features of nonspecific vague abdominal pain. Most acute presentations are attributed clinically to appendicitis, with most cases detected incidentally on pathology after an appendectomy. Approximately 40% of them present clinically with features of hormonal excess, which is likened to the functional secretory nature of their parent cell of origin. The symptoms of carcinoid syndrome render their presence clinically evident. However, slow growing and symptomatically silent in its initial stages, high-grade neuroendocrine tumors and neuroendocrine carcinomas of the appendix are aggressive and usually have hepatic and lymph node metastasis at presentation. This review article focuses on imaging characteristics, World Health Organization histopathological classification and grading, American Joint Committee on Cancer/Union or International Cancer Control, European Neuroendocrine Tumor Society staging, European Neuroendocrine Tumor Society standardized guidelines for reporting, data interpretation, early-stage management protocols, and advanced-stage appendiceal NENs. Guidelines are also set for the follow-up and reassessment. The role of targeted radiotherapy, chemotherapy, and high-dose somatostatin analogs in treating advanced disease are discussed, along with types of ablative therapies and liver transplantation for tumor recurrence. The search for newer location-specific biomarkers in NEN is also summarized. Regarding the varying aggressiveness of the tumor, there is a scope for research in the field, with plenty of data yet to be discovered.

Efficacy of skin-to-skin vs. cloth-to-cloth contact for thermoregulation in low birth weight newborns: a randomized crossover trial.

OBJECTIVE: Skin-to-skin contact (SSC) is effective to maintain normal temperature in low birth weight (LBW) newborns. However, there are several barriers related to privacy and space availability for its optimum utilization. We used cloth-to-cloth contact (CCC), i.e. placing the newborn in Kangaroo position without removing cloths as an innovative alternative to SSC to test its efficacy for thermoregulation and feasibility as compared to SSC in LBW newborns. METHODS: The newborns eligible for Kangaroo Mother Care (KMC) in step-down nursery were included in this randomized crossover trial. Newborns received SSC or CCC as per randomization on the first day and then crossed over to other group on the next day and so on. A feasibility questionnaire was asked to the mothers and the nurses. Axillary temperature was measured at various time intervals. Group comparisons were made by either using independent sample t-test or Chi-square test. RESULTS: A total of 23 newborns received KMC for total 152 occasions in the SSC group and 149 times in the CCC group. There was no significant temperature difference between the groups at any time-point. Mean (standard deviation) gain of temperature at 120 min in the CCC group [0.43 (0.34)°C] was comparable to the SSC group [0.49 (0.36)°C] (p = 0.13). We did not observe any adverse effect of CCC. Most mothers and nurses perceived CCC feasible in hospital settings and felt that it could be feasible in-home settings too. CONCLUSION: CCC was safe, more feasible and not inferior to SSC for maintaining thermoregulation in LBW newborns.

Skin-to-skin contact (SSC) helps in maintaining optimum temperature of low birth weight (LBW) newborns. It is an important component of Kangaroo Mother Care (KMC), which is standard of care and reduces several neonatal morbidities and mortality. However, there are several barriers for the optimum utilization of KMC. One of the major barriers is privacy issues while putting newborn in SSC. To overcome this barrier for increasing KMC uptake, we innovatively thought of keeping the newborn on mother's chest without removing the cloths of both the mother and the newborn. We called it cloth-to-cloth contact (CCC). We compared SSC and CCC for temperature regulation in the newborns weighing between 1500 and 2499 g at the time of enrollment using a crossover design. We observed that mean temperature steadily increased in newborns while receiving SSC or CCC for 2 h. There were no significant differences in mean temperature readings between these two groups at various time points. Thus, CCC was not inferior to SSC in maintaining temperature. We did not observe any adverse effect of CCC. CCC may overcome the barrier of privacy issues of SSC. Thus, CCC was equally efficacious, safe and more feasible for maintaining thermoregulation in LBW newborns.

Significant Changes in Resting Metabolic Rate Over a Competitive Match Week Are Accompanied by an Absence of Nutritional Periodization in Male Professional Soccer Players.

Resting metabolic rate (RMR) is an important component of total daily energy expenditure; however, it is currently not understood how it varies across a typical competitive match week in professional soccer players. For the first time, we aimed to assess RMR throughout an in-season competitive week in professional soccer players. Additionally, we aimed to assess energy and carbohydrate intake across the same week. Twenty-four professional soccer players from an English Premier League club (age: 18 ± 1.6 years) completed the study. RMR was assessed each morning of a typical competitive match week (match day [MD] -3, -2, -1, +1, +2, and + 3), and dietary intake (including MD) was assessed daily via the remote food photography method and 24-hr recall. Daily training load was quantified using Global Positioning System, daily muscle soreness ratings were recorded, and body composition was assessed via dual-energy X-ray absorptiometry. There was a significant (p = .0004) increase in mean RMR of ∼261 kcal/day on MD + 1, compared with MD - 1. Additionally, volume of oxygen consumed significantly increased at MD + 1 (p = .0002) versus MD - 1. There were no significant differences in daily energy or carbohydrate intake across the competitive week (p > .05), with inadequate carbohydrate intakes on MD - 1 (∼3.9 g/kg body mass), MD (∼4.2 g/kg body mass), and MD + 1 (∼3.6 g/kg body mass) in relation to current recommendations. We report, for the first time, that RMR is significantly increased following a competitive match in professional soccer players. In addition, we confirm previous findings to reinforce that players exhibit inadequate nutrition periodization practices, which may impair physical performance and recovery.

Estimation of Fetal-to-Maternal Unbound Steady-State Plasma Concentration Ratio of P-Glycoprotein and/or Breast Cancer Resistance Protein Substrate Drugs Using a Maternal-Fetal Physiologically Based Pharmacokinetic Model.

Pregnant women are frequently prescribed drugs to treat chronic diseases such as human immunodeficiency virus infection, but little is known about the benefits and risks of these drugs to the fetus that are driven by fetal drug exposure. The latter can be estimated by fetal-to-maternal unbound plasma concentration at steady state (Kp,uu,fetal). For drugs that are substrates of placental efflux transporters [i.e., P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP)], Kp,uu,fetal is expected to be <1. Here, we estimated the in vivo Kp,uu,fetal of selective P-gp and BCRP substrate drugs by maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) modeling of umbilical vein (UV) plasma and maternal plasma (MP) concentrations obtained simultaneously at term from multiple maternal-fetal dyads. To do so, three drugs were selected: nelfinavir (P-gp substrate), efavirenz (BCRP substrate), and imatinib (P-gp/BCRP substrate). An m-f-PBPK model for each drug was developed and validated for the nonpregnant population and pregnant women using the Simcyp simulator (v20). Then, after incorporating placental passive diffusion clearance, the in vivo Kp,uu,fetal of the drug was estimated by adjusting the placental efflux clearance until the predicted UV/MP values best matched the observed data (Kp,uu,fetal) of nelfinavir = 0.41, efavirenz = 0.39, and imatinib = 0.35. Furthermore, Kp,uu,fetal of nelfinavir and efavirenz at gestational weeks (GWs) 25 and 15 were predicted to be 0.34 and 0.23 (GW25) and 0.33 and 0.27 (GW15). These Kp,uu,fetal values can be used to adjust dosing regimens of these drugs to optimize maternal-fetal drug therapy throughout pregnancy, to assess fetal benefits and risks of these dosing regimens, and to determine if these estimated in vivo Kp,uu,fetal values can be predicted from in vitro studies. SIGNIFICANCE STATEMENT: The in vivo fetal-to-maternal unbound steady-state plasma concentration ratio (Kp,uu,fetal) of nelfinavir [P-glycoprotein (P-gp) substrate], efavirenz [breast cancer resistance protein (BCRP) substrate], and imatinib (P-gp and BCRP substrate) was successfully estimated using maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) modeling. These Kp,uu,fetal values can be used to adjust dosing regimens of these drugs to optimize maternal-fetal drug therapy throughout pregnancy, to assess fetal benefits and risks of these dosing regimens, and to determine if these estimated in vivo Kp,uu,fetal values can be predicted from in vitro studies.

Predicting Regional Respiratory Tissue and Systemic Concentrations of Orally Inhaled Drugs through a Novel PBPK Model.

Oral inhalation (OI) of drugs is the route of choice to treat respiratory diseases or for recreational drug use (e.g., cannabis). After OI, the drug is deposited in and systemically absorbed from various regions of the respiratory tract. Measuring regional respiratory tissue drug concentrations at the site of action is important for evaluating the efficacy and safety of orally inhaled drugs (OIDs). Because such a measurement is routinely not possible in humans, the only alternative is to predict these concentrations, for example by physiologically based pharmacokinetic (PBPK) modeling. Therefore, we developed an OI-PBPK model to integrate the interplay between regional respiratory drug deposition and systemic absorption to predict regional respiratory tissue and systemic drug concentrations. We validated our OI-PBPK model by comparing the simulated and observed plasma concentration-time profiles of two OIDs, morphine and nicotine. Furthermore, we performed sensitivity analyses to quantitatively demonstrate the impact of key parameters on the extent and pattern of regional respiratory drug deposition, absorption, and the resulting regional respiratory tissue and systemic plasma concentrations. Our OI-PBPK model can be applied to predict regional respiratory tissue and systemic drug concentrations to optimize OID formulations, delivery systems, and dosing regimens. Furthermore, our model could be used to establish the bioequivalence of generic OIDs for which systemic plasma concentrations are not measurable or are not a good surrogate of the respiratory tissue drug concentrations. SIGNIFICANCE STATEMENT: Our OI-PBPK model is the first comprehensive model to predict regional respiratory deposition, as well as systemic and regional tissue concentrations of OIDs, especially at the drug's site of action, which is difficult to measure in humans. This model will help optimize OID formulations, delivery systems, dosing regimens, and bioequivalence assessment of generic OID. Furthermore, this model can be linked with organs-on-chips, pharmacodynamic and quantitative systems pharmacology models to predict and evaluate the safety and efficacy of OID.

Exploration of the Plausible Mechanism of Ethambutol Induced Ocular Toxicity by Using Proteomics Informed Physiologically Based Pharmacokinetic (PBPK) Modeling.

PURPOSE: Ethambutol (EMB) is a first-line anti-tubercular drug that is known to cause optic neuropathy. The exact mechanism of its eye toxicity is unknown; however, proposition is metal chelating effect of both EMB and its metabolite 2,2'-(ethylenediamino)-dibutyric acid (EDBA). The latter is formed by sequential metabolism of EMB by alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). The purpose of this study was to predict the levels of drug and EDBA in the eye using physiologically based pharmacokinetic (PBPK) modeling. METHODS: The PBPK model of EMB was developed using GastroPlus. The intrinsic hepatic clearance of ALDH, calculated by the model, was scaled down using proteomics data to estimate the rate of formation of EDBA in the eye. Additionally, the comparative permeability of EMB and EDBA was assessed by employing in silico and in vitro approaches. The rate of formation of EDBA in the eye and permeability data were then incorporated in a compartmental model to predict the ocular levels of EMB and EDBA. RESULTS: The simulation results of compartmental model highlighted that there was an on-site formation of EDBA upon metabolism of EMB. Furthermore, in silico and in vitro studies revealed that EDBA possessed much lower permeability than EMB. These observations meant that once EDBA was formed in the eye, it was not permeated out and hence achieved higher ocular concentration. CONCLUSION: The on-site formation of EDBA in the eye, its higher local concentration due to lower ocular clearance and its pre-known characteristic to chelate metal species better explains the ocular toxicity shown by EMB.

Efficacy of Skin-to-Skin Care versus Swaddling for Pain Control Associated with Vitamin K Administration in Full-Term Neonates: A Randomized Controlled Trial.

OBJECTIVE: The objective of the study was to assess the efficacy of immediate skin-to-skin care (SSC) versus swaddling in pain response to intramuscular injection of vitamin K at 30 min of birth in neonates. METHODS: Healthy full-term newborns were enrolled immediately after normal vaginal delivery and randomized in two groups, SSC and swaddling. Neonatal Infant Pain Scale (NIPS) was measured before, immediately after and at 2 min after the injection. RESULTS: Total 100 newborns were enrolled in the study (50 in each group). The mean (SD) birth weight of newborns in the SSC and swaddling group was 2668 (256) and 2730 (348) g, respectively. NIPS was comparable between the SSC and swaddling at before [1.78 (0.58) vs. 1.96 (0.83), p = 0.21], and immediately after the injection [4.82 (0.72) vs. 5.08 (0.75), p = 0.08]. NIPS at 2 min after the injection was significantly low in the SSC group compared to the swaddling group [1.38 (0.70) vs. 2.88 (1.00), p < 0.001]. At 2 min after injection, the NIPS score was significantly lower than baseline in the SSC group (p = 0.002), while it was significantly higher in the swaddling group (p < 0.001). A significantly higher proportion of newborns had a NIPS score of more than three at 2 min after injection in the swaddling group as compared to the SSC group (22% vs. 2%, p < 0.001). CONCLUSION: Immediate SSC was more efficacious as compared to swaddling as a pain control intervention while giving vitamin K injection. CLINICAL TRIAL REGISTRATION: The trial is registered with the Clinical Trial Registry of India with Registration number: CTRI/2020/01/022984.

Skin-to-skin care and swaddling are commonly used non-pharmacological measures to reduce pain perception in neonates for invasive procedures like heel prick, venipuncture and vaccination. We did this randomized control trial to compare the efficacy of immediate skin-to-skin care after birth vs. swaddling for reducing neonatal pain associated with intramuscular injection of vitamin K at 30 min after birth. We observed that the immediate skin-to-skin care, a standard of care, is more efficacious in controlling pain compared to swaddling for giving routine intramuscular vitamin K injection within one hour of birth.

Prediction of Pregnancy-Induced Changes in Secretory and Total Renal Clearance of Drugs Transported by Organic Anion Transporters.

Pregnancy can significantly change the pharmacokinetics of drugs, including those renally secreted by organic anion transporters (OATs). Quantifying these changes in pregnant women is logistically and ethically challenging. Hence, predicting the in vivo plasma renal secretory clearance (CLsec) and renal CL (CLrenal) of OAT drugs in pregnancy is important to design correct dosing regimens of OAT drugs. Here, we first quantified the fold-change in renal OAT activity in pregnant versus nonpregnant individual using available selective OAT probe drug CLrenal data (training dataset; OAT1: tenofovir, OAT2: acyclovir, OAT3: oseltamivir carboxylate). The fold-change in OAT1 activity during the 2nd and 3rd trimester was 2.9 and 1.0 compared with nonpregnant individual, respectively. OAT2 activity increased 3.1-fold during the 3rd trimester. OAT3 activity increased 2.2, 1.7 and 1.3-fold during the 1st, 2nd, and 3rd trimester, respectively. Based on these data, we predicted the CLsec, CLrenal and total clearance ((CLtotal) of drugs in pregnancy, which are secreted by multiple OATs (verification dataset; amoxicillin, pravastatin, cefazolin and ketorolac, R-ketorolac, S-ketorolac). Then, the predicted clearances (CLs) were compared with the observed values. The predicted/observed CLsec, CLrenal, and CLtotal of drugs in pregnancy of all verification drugs were within 0.80-1.25 fold except for CLsec of amoxicillin in the 3rd trimester (0.76-fold) and cefazolin in the 2nd trimester (1.27-fold). Overall, we successfully predicted the CLsec, CLrenal, and CLtotal of drugs in pregnancy that are renally secreted by multiple OATs. This approach could be used in the future to adjust dosing regimens of renally secreted OAT drugs which are administered to pregnant women. SIGNIFICANCE STATEMENT: To the authors' knowledge, this is the first report to successfully predict renal secretory clearance and renal clearance of multiple OAT substrate drugs during pregnancy. The data presented here could be used in the future to adjust dosing regimens of renally secreted OAT drugs in pregnancy. In addition, the mechanistic approach used here could be extended to drugs transported by other renal transporters.

Antioxidants for preventing and reducing muscle soreness after exercise: a Cochrane systematic review.

OBJECTIVE: To determine whether antioxidant supplements and antioxidant-enriched foods can prevent or reduce delayed-onset muscle soreness after exercise. METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, SPORTDiscus, trial registers, reference lists of articles and conference proceedings up to February 2017. RESULTS: In total, 50 studies were included in this review which included a total of 1089 participants (961 were male and 128 were female) with an age range of 16-55 years. All studies used an antioxidant dosage higher than the recommended daily amount. The majority of trials (47) had design features that carried a high risk of bias due to selective reporting and poorly described allocation concealment, potentially limiting the reliability of their findings. We rescaled to a 0-10 cm scale in order to quantify the actual difference between groups and we found that the 95% CIs for all five follow-up times were all well below the minimal important difference of 1.4 cm: up to 6 hours (MD -0.52, 95% CI -0.95 to -0.08); at 24 hours (MD -0.17, 95% CI -0.42 to 0.07); at 48 hours (mean difference (MD) -0.41, 95% CI -0.69 to -0.12); at 72 hours (MD -0.29, 95% CI -0.59 to 0.02); and at 96 hours (MD -0.03, 95% CI -0.43 to 0.37). Thus, the effect sizes suggesting less muscle soreness with antioxidant supplementation were very unlikely to equate to meaningful or important differences in practice. CONCLUSIONS: There is moderate to low-quality evidence that high-dose antioxidant supplementation does not result in a clinically relevant reduction of muscle soreness after exercise of up to 6 hours or at 24, 48, 72 and 96 hours after exercise. There is no evidence available on subjective recovery and only limited evidence on the adverse effects of taking antioxidant supplements.

Dilution-Induced Physico-Chemical Changes of Metal Oxide Nanoparticles Due to Homeopathic Preparation Steps of Trituration and Succussion.

BACKGROUND: Although the presence of starting materials in extreme dilutions of homeopathic medicines has been established, the physico-chemical changes of these materials induced by the manufacturing steps-that is, solid-solid mixing involving grinding (trituration) and slurry mixing involving impact (succussion), followed by dilution-are still unknown. METHODS: We subjected cupric oxide and zinc oxide nanoparticles (NPs) to the homeopathic processes of trituration and succussion, followed by dilution up to 6 cH. Particle image velocimetry was employed to analyze the fluid motion during succussion and its effect on the NPs. The resulting microstructural and chemical changes at different dilution steps were determined by X-ray photoelectron spectroscopy, Fourier-transform infrared spectroscopy and transmission electron microscopy. RESULTS: The succussion triggered multi-sized bubble generation and turbulent fluid motion up to a duration of 400 ms, with maximum average velocity of 0.23 m/s. Due to 1% transfer of kinetic energy from a moving eddy with this velocity, upon collision, the rate of temperature change in a particle of size 1 µm and 1 nm was predicted to rise by approximately 102 K/s and 106 K/s respectively. During trituration, the oxide NPs reduced to metals and did not aggregate by remaining within lactose, but they converted to oxidized finer NPs after impact. Silicate chains leached from the vial cross-linked after third dilution, forming large macro-particles and encapsulating the NPs that were retained and carried at higher dilution steps. CONCLUSION: The results showed that the NPs sustained significant rate of temperature change due to energy transfer from moving eddies during succussion. Different physico-chemical changes, such as size reduction, successive reduction and oxidation of NPs, and morphological changes, were achieved through trituration and succussion. The retention of NPs within cross-linked poly-siloxane chains reveals the importance of both the borosilicate glass vial and the ethanol solution during preparation of homeopathic medicines.

Ontogeny of Hepatic Sulfotransferases and Prediction of Age-Dependent Fractional Contribution of Sulfation in Acetaminophen Metabolism.

Cytosolic sulfotransferases (SULTs), including SULT1A, SULT1B, SULT1E, and SULT2A isoforms, play noteworthy roles in xenobiotic and endobiotic metabolism. We quantified the protein abundances of SULT1A1, SULT1A3, SULT1B1, and SULT2A1 in human liver cytosol samples (n = 194) by liquid chromatography-tandem mass spectrometry proteomics. The data were analyzed for their associations by age, sex, genotype, and ethnicity of the donors. SULT1A1, SULT1B1, and SULT2A1 showed significant age-dependent protein abundance, whereas SULT1A3 was invariable across 0-70 years. The respective mean abundances of SULT1A1, SULT1B1, and SULT2A1 in neonatal samples was 24%, 19%, and 38% of the adult levels. Interestingly, unlike UDP-glucuronosyltransferases and cytochrome P450 enzymes, SULT1A1 and SULT2A1 showed the highest abundance during early childhood (1 to <6 years), which gradually decreased by approx. 40% in adolescents and adults. SULT1A3 and SULT1B1 abundances were significantly lower in African Americans compared with Caucasians. Multiple linear regression analysis further confirmed the association of SULT abundances by age, ethnicity, and genotype. To demonstrate clinical application of the characteristic SULT ontogeny profiles, we developed and validated a proteomics-informed physiologically based pharmacokinetic model of acetaminophen. The latter confirmed the higher fractional contribution of sulfation over glucuronidation in the metabolism of acetaminophen in children. The study thus highlights that the ontogeny-based age-dependent fractional contribution (fm) of individual drug-metabolizing enzymes has better potential in prediction of drug-drug interactions and the effect of genetic polymorphisms in the pediatric population.

Effects of Caffeinated Gum on a Battery of Soccer-Specific Tests in Trained University-Standard Male Soccer Players.

The purpose of this study was to determine whether caffeinated gum influenced performance in a battery of soccer-specific tests used in the assessment of performance in soccer players. In a double-blind, randomized, crossover design, 10 male university-standard soccer players (age: 19 ± 1 years, stature: 1.80 ± 0.10 m, body mass: 75.5 ± 4.8 kg) masticated a caffeinated (200 mg; caffeine) or control (0 mg; placebo) gum on two separate occasions. After a standardized warm-up, gum was chewed for 5 min and subsequently expectorated 5 min before players performed a maximal countermovement jump, a 20-m sprint test, and the Yo-Yo Intermittent Recovery Test Level 1. Performance on 20-m sprints was not different between trials (caffeine: 3.2 ± 0.3 s, placebo: 3.1 ± 0.3 s; p = .567; small effect size: d = 0.33), but caffeine did allow players to cover 2.0% more distance during Yo-Yo Intermittent Recovery Test Level 1 (caffeine: 1,754 ± 156 m, placebo: 1,719 ± 139 m; p = .016; small effect size: d = 0.24) and increase maximal countermovement jump height by 2.2% (caffeine: 47.1 ± 3.4 cm, placebo: 46.1 ± 3.2 cm; p = .008; small effect size: d = 0.30). Performance on selected physical tests (Yo-Yo Intermittent Recovery Test Level 1 and countermovement jump) was improved by the chewing of caffeinated gum in the immediate period before testing in university-standard soccer players, but the sizes of such effects were small. Such findings may have implications for the recommendations made to soccer players about to engage with subsequent exercise performance.

Antioxidants for preventing and reducing muscle soreness after exercise.

BACKGROUND: Muscle soreness typically occurs after intense exercise, unaccustomed exercise or actions that involve eccentric contractions where the muscle lengthens while under tension. It peaks between 24 and 72 hours after the initial bout of exercise. Many people take antioxidant supplements or antioxidant-enriched foods before and after exercise in the belief that these will prevent or reduce muscle soreness after exercise. OBJECTIVES: To assess the effects (benefits and harms) of antioxidant supplements and antioxidant-enriched foods for preventing and reducing the severity and duration of delayed onset muscle soreness following exercise. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, SPORTDiscus, trial registers, reference lists of articles and conference proceedings up to February 2017. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials investigating the effects of all forms of antioxidant supplementation including specific antioxidant supplements (e.g. tablets, powders, concentrates) and antioxidant-enriched foods or diets on preventing or reducing delayed onset muscle soreness (DOMS). We excluded studies where antioxidant supplementation was combined with another supplement. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, assessed risk of bias and extracted data from included trials using a pre-piloted form. Where appropriate, we pooled results of comparable trials, generally using the random-effects model. The outcomes selected for presentation in the 'Summary of findings' table were muscle soreness, collected at times up to 6 hours, 24, 48, 72 and 96 hours post-exercise, subjective recovery and adverse effects. We assessed the quality of the evidence using GRADE. MAIN RESULTS: Fifty randomised, placebo-controlled trials were included, 12 of which used a cross-over design. Of the 1089 participants, 961 (88.2%) were male and 128 (11.8%) were female. The age range for participants was between 16 and 55 years and training status varied from sedentary to moderately trained. The trials were heterogeneous, including the timing (pre-exercise or post-exercise), frequency, dose, duration and type of antioxidant supplementation, and the type of preceding exercise. All studies used an antioxidant dosage higher than the recommended daily amount. The majority of trials (47) had design features that carried a high risk of bias due to selective reporting and poorly described allocation concealment, potentially limiting the reliability of their findings.We tested only one comparison: antioxidant supplements versus control (placebo). No studies compared high-dose versus low-dose, where the low-dose supplementation was within normal or recommended levels for the antioxidant involved.Pooled results for muscle soreness indicated a small difference in favour of antioxidant supplementation after DOMS-inducing exercise at all main follow-ups: up to 6 hours (standardised mean difference (SMD) -0.30, 95% confidence interval (CI) -0.56 to -0.04; 525 participants, 21 studies; low-quality evidence); at 24 hours (SMD -0.13, 95% CI -0.27 to 0.00; 936 participants, 41 studies; moderate-quality evidence); at 48 hours (SMD -0.24, 95% CI -0.42 to -0.07; 1047 participants, 45 studies; low-quality evidence); at 72 hours (SMD -0.19, 95% CI -0.38 to -0.00; 657 participants, 28 studies; moderate-quality evidence), and little difference at 96 hours (SMD -0.05, 95% CI -0.29 to 0.19; 436 participants, 17 studies; low-quality evidence). When we rescaled to a 0 to 10 cm scale in order to quantify the actual difference between groups, we found that the 95% CIs for all five follow-up times were all well below the minimal important difference of 1.4 cm: up to 6 hours (MD -0.52, 95% CI -0.95 to -0.08); at 24 hours (MD -0.17, 95% CI -0.42 to 0.07); at 48 hours (MD -0.41, 95% CI -0.69 to -0.12); at 72 hours (MD -0.29, 95% CI -0.59 to 0.02); and at 96 hours (MD -0.03, 95% CI -0.43 to 0.37). Thus, the effect sizes suggesting less muscle soreness with antioxidant supplementation were very unlikely to equate to meaningful or important differences in practice. Neither of our subgroup analyses to examine for differences in effect according to type of DOMS-inducing exercise (mechanical versus whole body aerobic) or according to funding source confirmed subgroup differences. Sensitivity analyses excluding cross-over trials showed that their inclusion had no important impact on results.None of the 50 included trials measured subjective recovery (return to previous activities without signs or symptoms).There is very little evidence regarding the potential adverse effects of taking antioxidant supplements as this outcome was reported in only nine trials (216 participants). From the studies that did report adverse effects, two of the nine trials found adverse effects. All six participants in the antioxidant group of one trial had diarrhoea and four of these also had mild indigestion; these are well-known side effects of the particular antioxidant used in this trial. One of 26 participants in a second trial had mild gastrointestinal distress. AUTHORS' CONCLUSIONS: There is moderate to low-quality evidence that high dose antioxidant supplementation does not result in a clinically relevant reduction of muscle soreness after exercise at up to 6 hours or at 24, 48, 72 and 96 hours after exercise. There is no evidence available on subjective recovery and only limited evidence on the adverse effects of taking antioxidant supplements. The findings of, and messages from, this review provide an opportunity for researchers and other stakeholders to come together and consider what are the priorities, and underlying justifications, for future research in this area.

Nutritional Considerations for Bouldering.

Bouldering competitions are held up to International level and governed by the International Federation of Sport Climbing. Bouldering has been selected to feature at the 2020 Olympic Games in Tokyo, however, physiological qualities and nutritional requirements to optimize performance remain inadequately defined due to large gaps in the literature. The primary goals of training include optimizing the capacity of the anaerobic energy systems and developing sport-specific strength, with emphasis on the isometric function of the forearm flexors responsible for grip. Bouldering athletes typically possess a lean physique, similar to the characteristics of sport climbers with reported body fat values of 6-12%. Athletes strive for a low body weight to improve power to weight ratio and limit the load on the extremities. Specialized nutritional support is uncommon and poor nutritional practices such as chronic carbohydrate restriction are prevalent, compromising the health of the athletes. The high intensity nature of bouldering demands a focus on adequate carbohydrate availability. Protein intake and timing should be structured to maximize muscle protein synthesis and recovery, with the literature suggesting 0.25-0.3 g/kg in 3-4 hr intervals. Supplementing with creatine and b-alanine may provide some benefit by augmenting the capacity of the anaerobic systems. Boulderers are encouraged to seek advice from nutrition experts to enhance performance, particularly important when weight loss is the desired outcome. Further research is warranted across all nutritional aspects of bouldering which is summarized in this review.