Interindividual Response Research Articles

Inter-individual differences in muscle damage following a single bout of high-intense whole-body electromyostimulation

PurposeThis brief report aimed to characterize inter-individual training responses following a single session of high-intense whole-body electromyostimulation (WB-EMS) using markers of muscle damage over a period of 72 h.MethodsTwelve healthy individuals (5 men, 7 women; 32.0 ± 7 years) participated in a single 20-minute high-intensity WB-EMS training session. Markers of muscle damage, creatine kinase (CK) and myoglobin (Mb), were assessed before and immediately after training, as well as at 1.5, 3, 24, 48 and 72 h post-exercise. Lactate levels were determined pre- and post-exercise.ResultsOverall, WB-EMS induced significant CK elevations, peaking at 72 h (18.358 ± 21.380 U/L; p < 0.01), and correlating Mb levels peaking at 48 h (1.509 ± 1.394 ng/dl, p < 0.01). Despite significant inter-individual variability in CK levels, both slow (SR) and fast responders (FR) were identified. FR showed significant increases in CK at all time points post WB-EMS (p < 0.05), whereas CK in SR significantly elevated after 48 h. Post-WB-EMS lactate concentration was identified to predict peak CK and Mb levels (r ≥ 0.65, both p < 0.05).ConclusionHigh-intensity WB-EMS has the potential to induce severe muscle damage, as indicated by elevated levels of CK and Mb. We identified two distinct groups of individuals, SR and FR, indicating variability in response to WB-EMS. Furthermore, we suggest that individual responses to WB-EMS can be predicted based on post-WB-EMS lactate concentration.

A Multivariate Phenotypical Approach of Sepsis and Septic Shock—A Comprehensive Narrative Literature Review

Despite medical advances, sepsis and septic shock remain some of the leading causes of mortality worldwide, with a high inter-individual variability in prognosis, clinical manifestations and response to treatment. Evidence suggests that pulmonary sepsis is one of the most severe forms of sepsis, while liver dysfunction, left ventricular dysfunction, and coagulopathy impact the prognostic. Sepsis-related hypothermia and a hypoinflammatory state are related to a poor outcome. Given the heterogeneity of sepsis and recent technological progress amongst machine learning analysis techniques, a new, personalized approach to sepsis is being intensively studied. Despite the difficulties when tailoring a targeted approach, with the use of artificial intelligence-based pattern recognition, more and more publications are becoming available, highlighting novel factors that may intervene in the high heterogenicity of sepsis. This has led to the devise of a phenotypical approach in sepsis, further dividing patients based on host and trigger-related factors, clinical manifestations and progression towards organ deficiencies, dynamic prognosis algorithms, and patient trajectory in the Intensive Care Unit (ICU). Host and trigger-related factors refer to patients’ comorbidities, body mass index, age, temperature, immune response, type of bacteria and infection site. The progression to organ deficiencies refers to the individual particularities of sepsis-related multi-organ failure. Finally, the patient’s trajectory in the ICU points out the need for a better understanding of interindividual responses to various supportive therapies. This review aims to identify the main sources of variability in clustering septic patients in various clinical phenotypes as a useful clinical tool for a precision-based approach in sepsis and septic shock.

Precision or Personalized Nutrition: A Bibliometric Analysis.

Food systems face the challenge of maintaining adequate nutrition for all populations. Inter-individual responses to the same diet have made precision or personalized nutrition (PN) an emerging and relevant topic. The aim of this study is to analyze the evolution of the PN field, identifying the principal actors and topics, and providing a comprehensive overview. Therefore, a bibliometric analysis of the scientific research available through the Web of Science (WOS) database was performed, revealing 2148 relevant papers up to June 2024. VOSviewer and the WOS platform were employed for the processing and analysis, and included an evaluation of diverse data such as country, author or most frequent keywords, among others. The analysis revealed a period of exponential growth from 2015 to 2023, with the USA, Spain, and England as the top contributors. The field of "Nutrition and Dietetics" is particularly significant, comprising nearly 33% of the total publications. The most highly cited institutions are the universities of Tufts, College Dublin, and Navarra. The relationship between nutrition, genetics, and omics sciences, along with dietary intervention studies, has been a defining factor in the evolution of PN. In conclusion, PN represents a promising field of research with significant potential for further advancement and growth.

Effect of Advanced Footwear Technology Spikes on Sprint Acceleration: A Multiple N-of-1 Trial

BackgroundIn contrast with Advanced Footwear Technology-AFT running shoes for long-distance, little is known about AFT sprint spikes on performance and acceleration parameters. However, their use has become widespread since the Tokyo 2020 Olympics, and knowledge of their effects would seem to be an essential starting point before any clinical or socio-economic considerations.ObjectivesOur objectives were to determine intra- and inter-subject sprinting performance modifications with Nike® AFT spikes (NAS) compared to standard spiked-shoes (SS).MethodsHealthy regional to national sprint athletes (n = 21, ≥ 750 pts World Athletics) performed 16 repetitions of 30-m sprints with either the NAS or SS condition during a single session, based on the multiple N-of-1 method, with pairwise randomisation and double-blind procedure. Time on 30-m sprints (Stalker radar), force-velocity profile (F0, V0, Vmax, Pmax, RF, DRF and FVP slope), and confounding factors (wind and shoe mass) were measured. Statistical analyses included a mixed linear regression model for group analyses, and randomisation test inversion and non-overlap-of-all-pair (NAP) methods for intra-individual analysis.ResultsNAS improved 30-m time by a mean of − 0.02 s (SMD = 0.4, p = 0.014), with no interaction with any confounding factors. Significant changes were seen in velocity (Vmax : SMD = 0.9, p < 0.001; V0: SMD = 0.7, p < 0.001) and the horizontal ratio of force (RFmax: SMD = 0.5, p = 0.043), with no changes observed in force production. Whatever the footwear, one unit of positive wind (+ 1 m.s− 1 ) improved performance by − 0.03 s (p < 0.001). At an individual level, four athletes improved (NAP ≥ 0.69), and one had a statistical decrease in performance. Changes in F-V profiles were largely individual.ConclusionsA positive effect on sprint acceleration characteristics was observed when using Nike® AFT spikes, due to an increase in velocity and the horizontal ratio of force. A major variability in inter-individual response justifies single-case experimental designs for research on the topic.Trial Registration NumberNCT05881148.

The Ex-Timing trial: evaluating morning, afternoon, and evening exercise on the circadian clock in individuals with type 2 diabetes and overweight/obesity—a randomized crossover study protocol

BackgroundExercise is known to provide multiple metabolic benefits such as improved insulin sensitivity and glucose control in individuals with type 2 diabetes mellitus (T2DM) and those at risk. Beyond the traditional exercise dose, exercise timing is perceived as a contemporary hot topic, especially in the field of T2DM; however, the number of intervention studies assessing exercise timing and glucose metabolism is scarce. Our aim is to test the effect of exercise timing (i.e., morning, afternoon, or evening) on the inter-individual response variability in glycemic control and related metabolic health parameters in individuals with T2DM and those at risk during a 12-week intervention.MethodsA randomized crossover exercise intervention will be conducted involving two groups: group 1, individuals with T2DM; group 2, age-matched older adults with overweight/obesity. The intervention will consist of three 2-week blocks of supervised post-prandial exercise using high-intensity interval training (HIIT). Between each training block, a 2-week washout period, where participants avoid structured exercise, will take place. Assessments will be conducted in both groups before and after each exercise block. The primary outcomes include the 24-h area under the curve continuous glucose monitoring-based glucose. The secondary outcomes include body composition, resting energy expenditure, insulin response to a meal tolerance test, maximal aerobic capacity, peak power output, physical activity, sleep quality, and insulin and glucose levels. All primary and secondary outcomes will be measured at each assessment point.DiscussionOutcomes from this trial will provide us additional insight into the role of exercise timing on the inter-individual response variability in glycemic control and other related metabolic parameters in two distinct populations, thus contributing to the development of more effective exercise prescription guidelines for individuals with T2DM and those at risk.Trial registrationClinicalTrials.gov NCT06136013. Registered on November 18, 2023.

Characteristics associated with responsiveness to isometric handgrip training in medicated hypertensive patients: secondary data analysis.

Isometric handgrip training (IHT) has been shown to reduce blood pressure (BP) in hypertensive patients. However, factors that predict responsiveness to IHT are largely unknown. The aim of this study was to investigate the patient characteristics associated with the antihypertensive response to IHT using a recommended statistical approach for evaluating interindividual responses. Data from four randomized controlled trials were combined, totaling 81 patients undergoing IHT (48.8% women; 60 ± 11 years) and 90 control patients (45.6% women; 62 ± 12 years). IHT consisted of 4 × 2 min isometric contractions at 30% of maximal voluntary contraction, performed three times/week for 8-12 weeks. BP was measured at baseline and following IHT and control interventions. The interindividual variation was assessed by the standard deviation of the individual responses (SD ir ), and linear regression analyses were conducted to explore response predictors. IHT significantly decreased both SBP (-5.4; 95% confidence interval (CI) -9.5 to -1.3 mmHg) and DBP (-2.8; 95% CI -5.1 to -0.6 mmHg). The interindividual variation of BP change was moderate for systolic (SD ir = 5.2 mmHg, 0.30 standardized units) and low for diastolic (SD ir = 1.7 mmHg, 0.15 standardized units). Sex, age, and BMI were not associated with the antihypertensive effect of IHT. However, a higher baseline SBP ( b = -0.467, P < 0.001) and absence of dihydropyridine calcium channel blockers use ( b = 0.340, P = 0.001) were associated with greater BP reductions. IHT reduced BP in medicated hypertensive patients regardless of age, sex, and BMI. Patients with a higher baseline SBP and those not prescribed dihydropyridine calcium channel blockers were more responsive to IHT.

Inter-individual variability in neural response to low doses of LSD

The repeated use of small doses of psychedelics (also referred to as “microdosing”) to facilitate benefits in mental health, cognition, and mood is a trending practice. Placebo-controlled studies however have largely failed to demonstrate strong benefits, possibly because of large inter-individual response variability. The current study tested the hypothesis that effects of low doses of LSD on arousal, attention and memory depend on an individual’s cognitive state at baseline. Healthy participants (N = 53) were randomly assigned to receive repeated doses of LSD (15 mcg) or placebo on 4 occasions divided over 2 weeks. Each treatment condition also consisted of a baseline and a 1-week follow-up visit. Neurophysiological measures of arousal (resting state EEG), pre-attentive processing (auditory oddball task), and perceptual learning and memory (visual long-term potentiation (LTP) paradigm) were assessed at baseline, dosing session 1 and 4, and follow-up. LSD produced stimulatory effects as reflected by a reduction in resting state EEG delta, theta, and alpha power, and enhanced pre-attentive processing during the acute dosing sessions. LSD also blunted the induction of LTP on dosing session 4. Stimulatory effects of LSD were strongest in individuals with low arousal and attention at baseline, while inhibitory effects were strongest in high memory performers at baseline. Decrements in delta EEG power and enhanced pre-attentive processing in the LSD treatment condition were still present during the 1-week follow-up. The current study demonstrates across three cognitive domains, that acute responses to low doses of LSD depend on the baseline state and provides some support for LSD induced neuroadaptations that sustain beyond treatment.

Ensuring optimal lipid oxidation during physical activity in overweight and obese patients using a capillary glycerol sensor

AimTo describe lipid oxidation during physical activity (PA) in overweight and obese patients using a real-time capillary glycerol sensor and to propose a personalized strategy to optimize lipolysis. MethodsHealthy adult volunteers with a BMI >25 kg/m2 were recruited. All participants performed 27 sessions of 30-minute PA covering all possible combinations of exercises (low, moderate, high intensities) and pre-exercise meals (high-carbohydrate, high-fat, or fasting) with 3 replicates. Glycerol measurements were performed five times during each session: at T0, T20, T30, T45, and T60. The evolution of capillary glycerolemia during PA was modeled by a nonlinear mixed-effects model. We developed a personalized PA recommendation based on the first 2 glycerolemia measurements that indicates whether a change in activity type is preferable. ResultsThirteen patients were included in the study and 1232 capillary glycerolemia measurements were performed. Hyperglycemic and hyperlipidemic meals were associated with lower baseline glycerolemia (p<0.0001 for both) compared to fasting. In contrast, the type of meal was not significantly associated with PA-induced lipolysis (p=0.52 and p=0.76 for high-carbohydrate and hyperlipidemic meal respectively). Compared with exercises done at low and moderate intensities, high intensity exercises were associated with a higher PA-induced lipolysis (p=0.0002). Specific strength exercises were associated with a lower PA-induced lipolysis (p<0.0001). The 2 initial glycerolemia measurements appeared to be a pertinent criterion which help the personalization of PA programs for such individuals (c-index 0.67). ConclusionThe inter-individual lipolysis responses to PA and the availability of a real-time capillary blood glycerol sensor may enable the personalization of PA programs, thus promoting optimal lipolysis in subjects with overweight and obesity.

Brain dopamine responses to ultra-processed milkshakes are highly variable and not significantly related to adiposity in humans.

Ultra-processed foods high in fat and sugar may be addictive, in part, due to their purported ability to induce an exaggerated postingestive brain dopamine response akin to drugs of abuse. Using standard [11C]raclopride positron emission tomography (PET) displacement methods used to measure brain dopamine responses to addictive drugs, we measured postingestive striatal dopamine responses to an ultra-processed milkshake high in fat and sugar in 50 young, healthy adults over a wide body mass index range (BMI 20-45 kg/m2). Surprisingly, milkshake consumption did not result in significant postingestive dopamine response in the striatum (p=0.62) nor any striatal subregion (p>0.33) and the highly variable interindividual responses were not significantly related to adiposity (BMI: r=0.076, p=0.51; %body fat: r=0.16, p=0.28). Thus, postingestive striatal dopamine responses to an ultra-processed milkshake were likely substantially smaller than many addictive drugs and below the limits of detection using standard PET methods.

Genetic and environmental interactions contribute to immune variation in rewilded mice

The relative and synergistic contributions of genetics and environment to interindividual immune response variation remain unclear, despite implications in evolutionary biology and medicine. Here we quantify interactive effects of genotype and environment on immune traits by investigating C57BL/6, 129S1 and PWK/PhJ inbred mice, rewilded in an outdoor enclosure and infected with the parasite Trichuris muris. Whereas cellular composition was shaped by interactions between genotype and environment, cytokine response heterogeneity including IFNγ concentrations was primarily driven by genotype with consequence on worm burden. In addition, we show that other traits, such as expression of CD44, were explained mostly by genetics on T cells, whereas expression of CD44 on B cells was explained more by environment across all strains. Notably, genetic differences under laboratory conditions were decreased following rewilding. These results indicate that nonheritable influences interact with genetic factors to shape immune variation and parasite burden.

Inter-individual variability of aerobic capacity after rehabilitation exercise training in children with severe burn injury

IntroductionSevere burn trauma damages resting and exercise cardiac function that may affect long term cardiovascular health. The implementation of rehabilitation exercise training (RET) soon after hospital discharge improves cardiorespiratory fitness; however, it does not fully restore aerobic capacity and presents large inter-individual variability. We tested the hypothesis that the inter-individual variability of aerobic capacity for responders (R) compared to nonresponders (NR) would differ for exercise frequency and intensity. MethodsThirty-three children (11 female, [mean±SD] 12 ± 3 years, 145 ± 18 cm, 40 ± 11 kg, 49 ± 31 BMI percentile) with severe burns (49 ± 15 % total body surface area burned, with 35 ± 22 % third-degree burns) completed a 6-week RET program. Cardiorespiratory fitness (peak VO2) was measured before and after RET. Frequency (session days/week), intensity (% peak heart rate), time (min/session), and volume (min/week) were compared between responders and non-responders. Significance was set at p < 0.05. ResultsSixty-four percent of the study population improved peak VO2 after RET whereas 36 % showed no improvements. Using a 2-way factorial ANOVA (group [G] × week [WK]), we found that exercise frequency and session time were similar and increased slightly over 6 weeks between R and NR (main effect for WK; P < 0.002). Exercise volume was significantly lower on week 2 for NR compared to R (G × WK interaction, P < 0.028). Exercise intensity over 6-weeks was significantly lower in the NR compared to the R group (G × WK interaction, P < 0.022). ConclusionsExercise intensity and volume may be important contributors for improving the interindividual response to exercise training for peak VO2. These data suggest that the appropriate dose-response requirement for exercise intensity may be > 80 % peak heart rate and exercise volume of > 150 min per week. Further understanding of the exercise prescription will provide insights important for cardiovascular rehabilitation in children with severe burns. Subject codeInter-individual Variability, Exercise, Pediatrics, Exercise Training

Inter-individual responses to a hybrid walking program in patients with peripheral arterial disease - an exploratory analysis of the PROSECO study

Inter-individual responses to a hybrid walking program in patients with peripheral arterial disease - an exploratory analysis of the PROSECO study

Identification of carbohydrate gene clusters obtained from in vitro fermentations as predictive biomarkers of prebiotic responses

BackgroundPrebiotic fibers are non-digestible substrates that modulate the gut microbiome by promoting expansion of microbes having the genetic and physiological potential to utilize those molecules. Although several prebiotic substrates have been consistently shown to provide health benefits in human clinical trials, responder and non-responder phenotypes are often reported. These observations had led to interest in identifying, a priori, prebiotic responders and non-responders as a basis for personalized nutrition. In this study, we conducted in vitro fecal enrichments and applied shotgun metagenomics and machine learning tools to identify microbial gene signatures from adult subjects that could be used to predict prebiotic responders and non-responders.ResultsUsing short chain fatty acids as a targeted response, we identified genetic features, consisting of carbohydrate active enzymes, transcription factors and sugar transporters, from metagenomic sequencing of in vitro fermentations for three prebiotic substrates: xylooligosacharides, fructooligosacharides, and inulin. A machine learning approach was then used to select substrate-specific gene signatures as predictive features. These features were found to be predictive for XOS responders with respect to SCFA production in an in vivo trial.ConclusionsOur results confirm the bifidogenic effect of commonly used prebiotic substrates along with inter-individual microbial responses towards these substrates. We successfully trained classifiers for the prediction of prebiotic responders towards XOS and inulin with robust accuracy (≥ AUC 0.9) and demonstrated its utility in a human feeding trial. Overall, the findings from this study highlight the practical implementation of pre-intervention targeted profiling of individual microbiomes to stratify responders and non-responders.

Hypotensive effects of exercise training: are postmenopausal women with hypertension non-responders or responders?

We tested the hypothesis that increasing the exercise dose or changing the exercise mode would augment hypotensive effects when traditional aerobic exercise training failed to produce it in postmenopausal women. Sixty-five postmenopausal women with essential hypertension were randomly allocated into the continuous aerobic training (CAT) and non-exercising control (CON) groups. CAT group cycled at moderate intensity 3 times a week for 12 weeks. Individuals who failed to decrease systolic blood pressure (BP) were classified as non-responders (n = 34) and performed an additional 12 weeks of exercise training with either increasing the exercise dose or changing the exercise mode. The 3 follow-up groups were continuous aerobic training 3 times a week, continuous aerobic training 4 times a week, and high-intensity interval training. After the first 12 weeks of exercise training, systolic BP decreased by 1.5 mmHg (NS) with a wide range of inter-individual responses (-23 to 23 mmHg). Sixty-seven percent of women who were initially classified as non-responders participated in the second training period. Sixty percent of women who participated in continuous exercise training 3 or 4 times a week at greater exercise intensities reduced systolic BP. All (100%) of the women who performed high-intensity interval training experienced significant reductions in systolic BP. Traditional aerobic exercise was not sufficient to decrease BP significantly in the majority of postmenopausal women. However, those women who were not sensitive to recommended exercise may reduce BP if they were exposed to continuous aerobic exercise at higher intensities and/or volumes or a different mode of exercise.

Gut microbial β-glucuronidases influence endobiotic homeostasis and are modulated by diverse therapeutics

Hormones and neurotransmitters are essential to homeostasis, and their disruptions are connected to diseases ranging from cancer to anxiety. The differential reactivation of endobiotic glucuronides by gut microbial β-glucuronidase (GUS) enzymes may influence interindividual differences in the onset and treatment of disease. Using multi-omic, invitro, and invivo approaches, we show that germ-free mice have reduced levels of active endobiotics and that distinct gut microbial Loop 1 and FMN GUS enzymes drive hormone and neurotransmitter reactivation. We demonstrate that a range of FDA-approved drugs prevent this reactivation by intercepting the catalytic cycle of the enzymes in a conserved fashion. Finally, we find that inhibiting GUS in conventional mice reduces free serotonin and increases its inactive glucuronide in the serum and intestines. Our results illuminate the indispensability of gut microbial enzymes in sustaining endobiotic homeostasis and indicate that therapeutic disruptions of this metabolism promote interindividual response variabilities.

Exercise-based interventions targeting balance and falls in people with COPD: a systematic review and meta-analysis.

This review quantifies the mean treatment effect of exercise-based interventions on balance and falls risk in people with COPD. A structured search strategy (2000-2023) was applied to eight databases to identify studies evaluating the impact of exercise-based interventions (≥14 days in duration) on balance or falls in people with COPD. Pooled mean treatment effects (95% confidence intervals (CIs), 95% prediction intervals (PIs)) were calculated for outcomes reported in five or more studies. Inter-individual response variance and the promise of behaviour change techniques (BCTs) were explored. 34 studies (n=1712) were included. There were greater improvements in balance post intervention compared to controls for the Berg Balance Scale (BBS) (mean 2.51, 95% CI 0.22-4.80, 95% PI -4.60-9.63), Timed Up and Go (TUG) test (mean -1.12 s, 95% CI -1.69- -0.55 s, 95% PI -2.78-0.54 s), Single-Leg Stance (SLS) test (mean 3.25 s, 95% CI 2.72-3.77 s, 95% PI 2.64-3.86 s) and Activities-specific Balance Confidence (ABC) scale (mean 8.50%, 95% CI 2.41-14.58%, 95% PI -8.92-25.92%). Effect on falls remains unknown. Treatment effects were larger in male versus mixed-sex groups for the ABC scale and SLS test, and in balance training versus other exercise-based interventions for the BBS and TUG test. Falls history was not associated with changes in balance. Meta-analysis of individual response variance was not possible and study-level results were inconclusive. Eleven promising BCTs were identified (promise ratio ≥2). Evidence for the effect of exercise-based interventions eliciting clinically important improvements in balance for people with COPD is weak, but targeted balance training produces the greatest benefits. Future exercise interventions may benefit from inclusion of the identified promising BCTs.

Contribution of genetic polymorphism in ABCB1 to individual variations of imatinib plasma levels in patients with gastrointestinal stromal tumor.

Imatinib mesylate (IM) is a first-line treatment option for the majority of patients diagnosed with gastrointestinal stromal tumors (GISTs). Although the clinical benefit is high, interindividual response is variable. This study thus aimed to assess how genetic polymorphisms can affect the blood levels of IM and treatment outcomes in patients with GIST. A total of 31 single-nucleotide polymorphisms (SNPs) in selected cytochrome P450 (P450), ATP-binding cassette transporter (ABC), solute carrier family (SLC), interleukin-4 receptor (IL4R), and vascular endothelial growth factor (VEGF) genes were genotyped using an SNP mass array platform. A total of 192 consecutive patients with GIST who received 400 mg of IM daily were enrolled into the study, with 1,485 blood samples being analyzed. According to genotypes, IM trough concentrations were tested and compared. Progression-free survival (PFS) and overall survival (OS) were also assessed. With a mean follow-up of 75.99 months, trough concentrations of imatinib were examined at average time points of 7.73 for each patient. Polymorphism in ABCB1 rs1045642 was found to be associated with steady-state IM trough plasma levels (P=0.008). Patients with the C genotype (CT + CC) of rs1045642 exhibited higher IM trough concentrations (1,271.09±306.69 ng/mL) compared to those with the TT genotype (1,106.60±206.05 ng/mL). No statistically significant differences in IM plasma concentration were observed for the other SNPs tested. None of the tested SNPs displayed a significant association with patients' survival in this study. This is the largest cohort study evaluating the associations of SNP and imatinib blood trough levels. The ABCB1 rs1045642 genetic polymorphism may exert an effect on the pharmacokinetics of imatinib. The presence of the C allele in ABCB1 rs1045642 is predictive of a higher plasma concentration of IM.

Very important pharmacogenetic variants landscape and potential clinical relevance in the Zhuang population from Yunnan province

The gradual evolution of pharmacogenomics has shed light on the genetic basis for inter-individual drug response variations across diverse populations. This study aimed to identify pharmacogenomic variants that differ in Zhuang population compared with other populations and investigate their potential clinical relevance in gene-drug and genotypic-phenotypic associations. A total of 48 variants from 24 genes were genotyped in 200 Zhuang subjects using the Agena MassARRAY platform. The allele frequencies and genotype distribution data of 26 populations were obtained from the 1000 Genomes Project, followed by a comparison and statistical analysis. After Bonferroni correction, significant differences in genotype frequencies were observed of CYP3A5 (rs776746), ACE (rs4291), KCNH2 (rs1805123), and CYP2D6 (rs1065852) between the Zhuang population and the other 26 populations. It was also found that the Chinese Dai in Xishuangbanna, China, Han Chinese in Beijing, China, and Southern Han Chinese, China showed least deviation from the Zhuang population. The Esan in Nigeria, Gambian in Western Division, The Gambia, and Yoruba in Ibadan, Nigeria exhibited the largest differences. This was also proved by structural analysis, Fst analysis and phylogenetic tree. Furthermore, these differential variants may be associated with the pharmacological efficacy and toxicity of Captopril, Amlodipine, Lisinopril, metoclopramide, and alpha-hydroxymetoprolol in the Zhuang population. Our study has filled the gap of pharmacogenomic information in the Zhuang population and has provided a theoretical framework for the secure administration of drugs in the Zhuang population.

Predicting interindividual response to theta burst stimulation in the lower limb motor cortex using machine learning.

Using theta burst stimulation (TBS) to induce neural plasticity has played an important role in improving the treatment of neurological disorders. However, the variability of TBS-induced synaptic plasticity in the primary motor cortex prevents its clinical application. Thus, factors associated with this variability should be explored to enable the creation of a predictive model. Statistical approaches, such as regression analysis, have been used to predict the effects of TBS. Machine learning may potentially uncover previously unexplored predictive factors due to its increased capacity for capturing nonlinear changes. In this study, we used our prior dataset (Katagiri et al., 2020) to determine the factors that predict variability in TBS-induced synaptic plasticity in the lower limb motor cortex for both intermittent (iTBS) and continuous (cTBS) TBS using machine learning. Validation of the created model showed an area under the curve (AUC) of 0.85 and 0.69 and positive predictive values of 77.7 and 70.0% for iTBS and cTBS, respectively; the negative predictive value was 75.5% for both patterns. Additionally, the accuracy was 0.76 and 0.72, precision was 0.82 and 0.67, recall was 0.82 and 0.67, and F1 scores were 0.82 and 0.67 for iTBS and cTBS, respectively. The most important predictor of iTBS was the motor evoked potential amplitude, whereas it was the intracortical facilitation for cTBS. Our results provide additional insights into the prediction of the effects of TBS variability according to baseline neurophysiological factors.

Resveratrol and vascular health: evidence from clinical studies and mechanisms of actions related to its metabolites produced by gut microbiota.

Cardiovascular diseases are among the leading causes of mortality worldwide, with dietary factors being the main risk contributors. Diets rich in bioactive compounds, such as (poly)phenols, have been shown to potentially exert positive effects on vascular health. Among them, resveratrol has gained particular attention due to its potential antioxidant and anti-inflammatory action. Nevertheless, the results in humans are conflicting possibly due to interindividual different responses. The gut microbiota, a complex microbial community that inhabits the gastrointestinal tract, has been called out as potentially responsible for modulating the biological activities of phenolic metabolites in humans. The present review aims to summarize the main findings from clinical trials on the effects of resveratrol interventions on endothelial and vascular outcomes and review potential mechanisms interesting the role of gut microbiota on the metabolism of this molecule and its cardioprotective metabolites. The findings from randomized controlled trials show contrasting results on the effects of resveratrol supplementation and vascular biomarkers without dose-dependent effect. In particular, studies in which resveratrol was integrated using food sources, i.e., red wine, reported significant effects although the resveratrol content was, on average, much lower compared to tablet supplementation, while other studies with often extreme resveratrol supplementation resulted in null findings. The results from experimental studies suggest that resveratrol exerts cardioprotective effects through the modulation of various antioxidant, anti-inflammatory, and anti-hypertensive pathways, and microbiota composition. Recent studies on resveratrol-derived metabolites, such as piceatannol, have demonstrated its effects on biomarkers of vascular health. Moreover, resveratrol itself has been shown to improve the gut microbiota composition toward an anti-inflammatory profile. Considering the contrasting findings from clinical studies, future research exploring the bidirectional link between resveratrol metabolism and gut microbiota as well as the mediating effect of gut microbiota in resveratrol effect on cardiovascular health is warranted.