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Flavonoids exert vasculoprotective effects in humans, but interindividual variability in their action has also been reported. This study aims to identify genes that are associated with vascular health effects of flavonoids and whose polymorphisms could explain interindividual variability in response to their intake. Applying the predetermined literature search criteria, we identified five human intervention studies reporting positive effects of flavonoids on vascular function together with global genomic changes analyzed using microarray methods. Genes involved in vascular dysfunction were identified from genome-wide association studies (GWAS). By extracting data from the eligible human intervention studies, we obtained 5807 differentially expressed genes (DEGs). The number of identified upstream regulators (URs) varied across the studies, from 227 to 1407. The search of the GWAS Catalog revealed 493 genes associated with vascular dysfunction. An integrative analysis of transcriptomic data with GWAS genes identified 106 candidate DEGs and 42 candidate URs, while subsequent functional analyses and a search of the literature identified 20 top priority candidate genes: ALDH2, APOE, CAPZA1, CYP11B2, GNA13, IL6, IRF5, LDLR, LPL, LSP1, MKNK1, MMP3, MTHFR, MYO6, NCR3, PPARG, SARM1, TCF20, TCF7L2, and TNF. In conclusion, this integrated analysis identifies important genes to design future nutrigenetic studies for development of precision nutrition for polyphenols.

Background Decades of research have firmly established that cognitive health and cognitive treatment services are a key need for people living with psychosis. However, many current clinical programs do not address this need, despite the essential role that an individual's cognitive and social cognitive capacities play in determining their real-world functioning. Preliminary practice-based research in the Early Psychosis Intervention Network early psychosis intervention network shows that it is possible to develop and implement tools that delineate an individuals' cognitive health profile and that help engage the client and the clinician in shared decision-making and treatment planning that includes cognitive treatments. These findings signify a promising shift toward personalized cognitive health. Study Design Extending upon this early progress, we review the concept of interindividual variability in cognitive domains/processes in psychosis as the basis for offering personalized treatment plans. We present evidence from studies that have used traditional neuropsychological measures as well as findings from emerging computational studies that leverage trial-by-trial behavior data to illuminate the different latent strategies that individuals employ. Study Result We posit that these computational techniques, when combined with traditional cognitive assessments, can enrich our understanding of individual differences in treatment needs, which in turn can guide evermore personalized interventions. Conclusion As we find clinically relevant ways to decompose maladaptive behaviors into separate latent cognitive elements captured by model parameters, the ultimate goal is to develop and implement approaches that empower clients and their clinical providers to leverage individual's existing learning capacities to improve their cognitive health and well-being. [ABSTRACT FROM AUTHOR]

Summary: Trace elements and heavy metals play pivotal roles in health status by regulating a myriad of vital biological functions. Abnormal metal homeostasis has been linked to a constellation of pathogenic complications, including oxidative stress, inflammatory processes, dyslipidemia, and impaired insulin‐mediated metabolism of carbohydrates, thereby increasing the odds of developing childhood obesity and related comorbidities. Herein, we provide a comprehensive revision of recent literature on the association between childhood obesity, trace elements, and heavy metals. Further, we emphasize on the crucial importance of addressing the influence that interindividual variability factors (e.g., sex, age, genetic determinants, concomitance of comorbidities, and environmental factors) may have in modulating the susceptibility to disease development. Altogether, this review article represents a concise guide to better understand the involvement of metals in childhood obesity pathogenesis and discusses future needs with the aim of establishing robust biomarkers in the context of precision medicine. [ABSTRACT FROM AUTHOR]

Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anticancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for exploring the interindividual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intraindividual variability of iPSC-CM-related assays and presented a proof of concept to prospectively predict doxorubicin (DOX)-induced cardiotoxicity (DIC) using donor-specific iPSC-CMs. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intraindividual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice and largely replicated the reported mechanisms. By categorizing iPSC-CMs into resistant and sensitive cell lines based on their time- and concentration-related phenotypic responses to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we identified a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. Our results support the utilization of donor-specific iPSC-CMs in assessing interindividual differences in DIC. Further studies will encompass a large panel of donor-specific iPSC-CMs to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Interindividual variability, influenced by patient-specific factors including age, weight, gender, race, and genetics, among others, contributes to variations in therapeutic response. Population pharmacokinetic (popPK) modeling is an essential tool for pinpointing measurable factors affecting dose-concentration relationships and tailoring dosage regimens to individual patients. Herein, we developed a popPK model for salbutamol, a short-acting β2-agonist (SABA) used in asthma treatment, to identify key patient characteristics that influence treatment response. To do so, synthetic data from physiologically-based pharmacokinetic (PBPK) models was employed, followed by an external validation using real patient data derived from an equivalent study. Thirty-two virtual patients were included in this study. A two-compartment model, with first-order absorption (no delay), and linear elimination best fitted our data, according to diagnostic plots and selection criteria. External validation demonstrated a strong agreement between individual predicted and observed values. The incorporation of covariates into the basic structural model identified a significant impact of age on clearance (Cl) and intercompartmental clearance (Q); gender on Cl and the constant rate of absorption (ka); race on Cl; and weight on Cl in the volume of distribution of the peripheral compartment (V2). This study addresses critical challenges in popPK modeling, particularly data scarcity, incompleteness, and homogeneity, in traditional clinical trials, by leveraging synthetic data from PBPK modeling. Significant associations between individual characteristics and salbutamol's PK parameters, here uncovered, highlight the importance of personalized therapeutic regimens for optimal treatment outcomes. [ABSTRACT FROM AUTHOR]

Major epigenetic changes are associated with carcinogenesis, including aberrant DNA methylations and post-translational modifications of histone. Indeed evidence accumulated in recent years indicates that inactivating DNA hypermethylation preferentially targets the subset of polycomb group (PcG) genes that are regulators of developmental processes. Conversely, activating DNA hypomethylation targets oncogenic signaling pathway genes, but outcomes of both events lead in the overexpression of oncogenic signaling pathways that contribute to the stem-like state of cancer cells. On the basis of recent evidence from population-basedclinical and experimental studies, we hypothesize that factors associated with risk for developing a hematologic malignancy (HM), such as metabolic syndrome and chronic inflammation, may trigger epigenetic mechanisms to increase the transcriptional expression of oncogenes and activate oncogenic signaling pathways. Signaling pathways associated with such risk factors include but are not limited to pro-inflammatory nuclear factor κB (NF-κB) and mitogenic, growth, and survival Janus kinase (JAK) intracellular non-receptor tyrosine kinase-triggered pathways. The latter includes signaling pathways such as transducer and activator of transcription (STAT), Ras GTPases/mitogen-activated protein kinases (MAPKs)/extracellular signal-related kinases (ERKs), phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and β-catenin pathways. Recent findings on epigenetic mechanisms at work in the biology of cancer and in HMs and their importance in the etiology and pathogenesis of these diseases are herein summarized and discussed. Furthermore, the role of epigenetic processes in the determination of biological identity, the consequences for interindividual variability in disease clinical profile, and the potential of epigenetic drugs in HMs are also considered.

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. [ABSTRACT FROM AUTHOR]

Introduction: Approximately four million people worldwide die annually because of obesity. Weight loss is commonly recommended as a first-line therapy in overweight and obese patients. Although many individuals attempt to lose weight, not everyone achieves optimal success. Few studies point out that weight loss eventually slows down, stagnates or reverses in 85% of the cases. Research question: What could be the reasons for not losing weight even after following a weight loss program? Methods: A scoping review of the literature was performed using weight loss-related search terms such as 'Obesity,' 'Overweight,' 'Lifestyle,' 'weight loss,' 'Basal Metabolism,' 'physical activity,' 'adherence,' 'energy balance,' 'Sleep' and 'adaptations. The search involved reference tracking and database and web searches (PUBMED, Science Direct, Elsevier, Web of Science and Google Scholar). Original articles and review papers on weight loss involving human participants and adults aged > 18 years were selected. Approximately 231 articles were reviewed, and 185 were included based on the inclusion criteria. Design: Scoping review. Results: In this review, the factors associated with not losing weight have broadly been divided into five categories. Studies highlighting each subfactor were critically reviewed and discussed. A wide degree of interindividual variability in weight loss is common in studies even after controlling for variables such as adherence, sex, physical activity and baseline weight. In addition to these variables, variations in factors such as previous weight loss attempts, sleep habits, meal timings and medications can play a crucial role in upregulating or downregulating the association between energy deficit and weight loss results. Conclusion: This review identifies and clarifies the role of several factors that may hinder weight loss after the exploration of existing evidence. Judging the effectiveness of respective lifestyle interventions by simply observing the 'general behavior of the groups' is not always applicable in clinical practice. Each individual must be monitored and advised as per their requirements and challenges. [ABSTRACT FROM AUTHOR]

Background: Establishing reference intervals (RIs) in clinical laboratories is essential, as these can vary due to inter-individual variability as well as the analytical methods used. The purpose of this study was to determine RIs for markers and ratios biochemical in apparently healthy Chilean adults. Methods: A sample of 1,143 data was selected from the Universidad Católica de Temuco, Clinical Laboratory database, La Araucanía Region, Chile, which were analysed by sex. The Tukey's Fences was used to detect outliers and the RIs were established using the non-parametric method. Results: The RIs obtained for the female sex were: Urea 2.48-7.35 mmol/L, AST 0.20-0.69 mkat/L, ALT 0.13-1.12 mkat/L, Alkaline Phosphatase 0.83-2.5 mkat/L, Total Bilirubin 3.5-17.3 mmol/L, Direct Bilirubin 1.5-4.9 mmol/L, Uric Acid 148-362 mmol/L and Total Proteins 66.3-80.3 g/L and for males: Urea 3.28-8.17 mmol/L, AST 0.22-0.80 mkat/L, ALT 0.18-1.9 mkat/L, Alkaline Phosphatase 0.93-2.33 mkat/L, Total Bilirubin 4.58-24.0 mmol/L, Direct Bilirubin 1.9-7.5 mmol/L, Uric Acid 202-458 mmol/L and Total Proteins 67.4-83 g/L. The FIB-4 and APRI index presented a range of 0.2-1.6 and 0.12-0.5 respectively (in both genders) and the AST/ALT index was 0.5-2 in women and 0.38-1.66 in men. Conclusion: A panel of RIs for locally-relevant biochemical parameters has been established, this study being the first to be carried out in our country. When comparing these results with other studies and those reported by reagent manufacturers, some differences were observed. This study thus contributes to increase the reliability in the interpretation of laboratory results and therefore to the clinical management of patients.

Objective: Interindividual similarity refers to how similarly individuals respond when receiving the same stimulus or intervention. In this study, we aimed to examine interindividual similarity in adults with ADHD. Method: We used the cosine similarity index of ex-Gaussian reaction time (RT) vectors of mu, sigma, and tau parameters during a Stroop task. Results: Our results demonstrate that the ADHD group exhibits a reduced interindividual similarity index in their ex-Gaussian RT vectors for congruent stimuli compared to the healthy control group. Importantly, we did not find significant differences in the interindividual similarity index to incongruent stimuli between both groups, thus suggesting that this reduced index was selective for congruent stimuli. Conclusion: Our findings highlight that ADHD adults exhibit more significant interindividual differences in cognitive functioning when processing congruent stimuli than healthy controls. These results provide new insights into the selective mechanisms underlying ADHD and may contribute to developing new targeted interventions for this disorder. [ABSTRACT FROM AUTHOR]

Background: High-definition transcranial direct current stimulation (HD-tDCS) holds promise for therapeutic use in psychiatric disorders. One obstacle for the implementation into clinical practice is response variability. One way to tackle this obstacle is the use of Individualized head models. Objective: This study investigated the variability of HD-tDCS induced electric fields (EFs) and its impact on resting-state functional connectivity (rsFC) during different time windows. Methods: In this randomized, double-blind, and sham controlled study, seventy healthy males underwent 20 min of 1.5 mA HD-tDCS on the right inferior frontal gyrus (rIFG) while undergoing resting-state functional magnetic resonance imaging (rs-fMRI). Individual head models and EF simulations were created from anatomical images. The effects of HD-tDCS on rsFC were assessed using a seed-to-voxel analysis. A subgroup analysis explored the relationship between EF magnitude and rsFC during different stimulation time windows. Results: Results highlighted significant variability in HD-tDCS-induced EFs. Compared to the sham group, the active group showed increased rsFC between the rIFG and the left prefrontal cortex, during and after stimulation. During active stimulation, EF magnitude correlated positively with rsFC between the rIFG and the left hippocampus initially, and negatively during the subsequent period. Conclusion: This study indicated an HD-tDCS induced increase of rsFC between left and right prefrontal areas. Furthermore, an interaction between the magnitude and the duration of HD-tDCS on rsFC was observed. Due to the high EF variability that was apparent, these findings highlight the need for individualized HD-tDCS protocols and the creation of head models to optimize effects and reduce response heterogeneity.

Citrus fruits and juices are a major source of dietary flavanones, and the regular consumption of these foods is inversely associated with the development of cardiometabolic diseases. However, the biological benefits depend on the bioavailability of these compounds, and previous studies have reported a large interindividual variability in the absorption and excretion of these compounds. Different factors, such as age, gender or genetic polymorphism of genes coding enzymes involved in the metabolism and transport of the flavanones, may explain this heterogeneity. This study aimed to assess the impact of single nucleotide polymorphism of sulfotransferases SULT1A1 and SULT1C4, and ABCC2 transporter genes on excretion of phase II flavanone metabolites in volunteers after 24 h of orange juice intake. Forty-six volunteers ingested a single dose of 500 mL of orange juice and 24-h urine was collected. The hesperetin and naringenin phase II metabolites were quantified in urine, and SNPs in SULT1A1, SULT1C4 and ABCC2 genes were genotyped. A significant (p < 0.05) relationship between the SNPs in these genes and the high excretion of phase II flavanone metabolites were observed. These results identified novel polymorphisms associated with higher absorption of flavanones, which may provide bases for future personalized nutritional guidelines for consuming flavanone-rich foods rich in these nutrients for better benefit from their health properties.

Interindividual variability, influenced by patient-specific factors including age, weight, gender, race, and genetics, among others, contributes to variations in therapeutic response. Population pharmacokinetic (popPK) modeling is an essential tool for pinpointing measurable factors affecting dose-concentration relationships and tailoring dosage regimens to individual patients. Herein, we developed a popPK model for salbutamol, a short-acting β2-agonist (SABA) used in asthma treatment, to identify key patient characteristics that influence treatment response. To do so, synthetic data from physiologically-based pharmacokinetic (PBPK) models was employed, followed by an external validation using real patient data derived from an equivalent study. Thirty-two virtual patients were included in this study. A two-compartment model, with first-order absorption (no delay), and linear elimination best fitted our data, according to diagnostic plots and selection criteria. External validation demonstrated a strong agreement between individual predicted and observed values. The incorporation of covariates into the basic structural model identified a significant impact of age on clearance (Cl) and intercompartmental clearance (Q); gender on Cl and the constant rate of absorption (ka); race on Cl; and weight on Cl in the volume of distribution of the peripheral compartment (V2). This study addresses critical challenges in popPK modeling, particularly data scarcity, incompleteness, and homogeneity, in traditional clinical trials, by leveraging synthetic data from PBPK modeling. Significant associations between individual characteristics and salbutamol’s PK parameters, here uncovered, highlight the importance of personalized therapeutic regimens for optimal treatment outcomes.

Areas of the dorsolateral prefrontal cortex (DLPFC) are part of the frontoparietal control, default mode, salience, and ventral attention networks. The DLPFC is involved in executive functions, like working memory, value encoding, attention, decision-making, and behavioral control. This functional heterogeneity is not reflected in existing neuroanatomical maps. For example, previous cytoarchitectonic studies have divided the DLPFC into two or four areas. Macroanatomical parcellations of this region rely on gyri and sulci, which are not congruent with cytoarchitectonic parcellations. Therefore, this study aimed to provide a microstructural analysis of the human DLPFC and 3D maps of cytoarchitectonic areas to help address the observed functional variability in studies of the DLPFC. We analyzed ten human post-mortem brains in serial cell-body stained brain sections and mapped areal boundaries using a statistical image analysis approach. Five new areas (i.e., SFG2, SFG3, SFG4, MFG4, and MFG5) were identified on the superior and middle frontal gyrus, i.e., regions corresponding to parts of Brodmann areas 9 and 46. Gray level index profiles were used to determine interregional cytoarchitectural differences. The five new areas were reconstructed in 3D, and probability maps were generated in commonly used reference spaces, considering the variability of areas in stereotaxic space. Hierarchical cluster analysis revealed a high degree of similarity within the identified DLPFC areas while neighboring areas (frontal pole, Broca's region, area 8, and motoric areas) were separable. Comparisons with functional imaging studies revealed specific functional profiles of the DLPFC areas. Our results indicate that the new areas do not follow a simple organizational gradient assumption in the DLPFC. Instead, they are more similar to those of the ventrolateral prefrontal cortex (Broca's areas 44, 45) and frontopolar areas (Fp1, Fp2) than to the more posterior areas. Within the DLPFC, the cytoarchitectonic similarities between areas do not seem to follow a simple anterior-to-posterior gradient either, but cluster along other principles. The new maps are part of the publicly available Julich Brain Atlas and provide a microstructural reference for existing and future imaging studies. Thus, our study represents a further step toward deciphering the structural-functional organization of the human prefrontal cortex.

High-definition transcranial direct current stimulation (HD-tDCS) holds promise for therapeutic use in psychiatric disorders. One obstacle for the implementation into clinical practice is response variability. One way to tackle this obstacle is the use of Individualized head models. This study investigated the variability of HD-tDCS induced electric fields (EFs) and its impact on resting-state functional connectivity (rsFC) during different time windows. In this randomized, double-blind, and sham controlled study, seventy healthy males underwent 20 min of 1.5 mA HD-tDCS on the right inferior frontal gyrus (rIFG) while undergoing resting-state functional magnetic resonance imaging (rs-fMRI). Individual head models and EF simulations were created from anatomical images. The effects of HD-tDCS on rsFC were assessed using a seed-to-voxel analysis. A subgroup analysis explored the relationship between EF magnitude and rsFC during different stimulation time windows. Results highlighted significant variability in HD-tDCS-induced EFs. Compared to the sham group, the active group showed increased rsFC between the rIFG and the left prefrontal cortex, during and after stimulation. During active stimulation, EF magnitude correlated positively with rsFC between the rIFG and the left hippocampus initially, and negatively during the subsequent period. This study indicated an HD-tDCS induced increase of rsFC between left and right prefrontal areas. Furthermore, an interaction between the magnitude and the duration of HD-tDCS on rsFC was observed. Due to the high EF variability that was apparent, these findings highlight the need for individualized HD-tDCS protocols and the creation of head models to optimize effects and reduce response heterogeneity. • HD-tDCS induced electric fields show substantial variability. • Resting-state functional connectivity of the ROI was increased for active over sham. • E-field magnitude correlates with changes in functional connectivity. • The influence of E-field magnitude on connectivity varies with stimulation time. [ABSTRACT FROM AUTHOR]

Blood pressure (BP) responses to recommended aerobic training can vary widely between individuals. Although studies demonstrate the role of exercise training in regulating BP responsiveness, predictive models are still unknown. This study aimed to identify hemodynamic predictive markers for the diagnosis of BP responsiveness based on baseline characteristics and postexercise ambulatory blood pressure (ABP) before an aerobic training program in postmenopausal women. Sixty-five postmenopausal women with essential hypertension were randomly allocated into the continuous aerobic training (CAT, n = 51) and nonexercising control (CON, n = 14) groups. CAT group cycled at moderate intensity three times a week for 12 weeks. Individuals who failed to decrease systolic blood pressure (SBP) were classified as nonresponders (NRs; n = 34) based on typical error of measurement. Baseline anthropometric, metabolic, cardiovascular, hemodynamic variables, and postexercise ABP was measured to predict BP responsiveness. A logistic regression model based on Baseline SBP [odds ratio (OR) = 1.202; 95% confidence interval (CI) = 1.080–1.338], SBP Nighttime (OR = 0.889; 95% CI = 0.811–0.975), and heart rate (HR) Nighttime (OR = 1.127; 95% CI = 1.014–1.254) were able to diagnose responders and NR individuals to BP reduction in response to CAT with 92.6% accuracy (P < 0.001; Sensitivity = 94.1%; Specificity = 79.4%). The findings highlight the potential value of baseline clinical characteristics as Baseline SBP, SBP, and HR Nighttime as markers for diagnosing BP responsiveness to recommended CAT in hypertension postmenopausal women. Clinical Trial Registration number: RBR-3xnqxs8. [ABSTRACT FROM AUTHOR]

Simple Summary: To adapt to a new environment, people must choose between using strategies that previously produced the expected effect in a similar context and trying new strategies with no certainty of achieving the expected effect. This is known as the exploration/exploitation trade-off. Its underlying brain mechanisms and factors accounting for interindividual differences have been overlooked. Resting-state functional connectivity highlights the synchronicity of different brain regions at rest, i.e., basal or intrinsic connectivity. Here, we investigated the evolution of this synchronicity before/after a task involving environmental uncertainty. To study the trade-off, we introduced uncertainty and cheated participants by introducing false feedbacks during an associative learning task. We examined the associations among the participants' behaviors, changes in the brain intrinsic functional connectivity, and psychological factors. The sensitivity to uncertainty was used to create two groups. The groups displayed different patterns of evolution of regional connectivity from before to after the task. We also found a trend whereby higher scores of anxiety and greater propensity to doubt about actions were positively linked to these patterns. These results provide additional arguments in favor of short-term plasticity in basal brain connectivity and clues about the interindividual factors influencing neural and behavioral adaptation. To adapt to a new environment, individuals must alternate between exploiting previously learned "action–consequence" combinations and exploring new actions for which the consequences are unknown: they face an exploration/exploitation trade-off. The neural substrates of these behaviors and the factors that may relate to the interindividual variability in their expression remain overlooked, in particular when considering neural connectivity patterns. Here, to trigger environmental uncertainty, false feedbacks were introduced in the second phase of an associative learning task. Indices reflecting exploitation and cost of uncertainty were computed. Changes in the intrinsic connectivity were determined using resting-state functional connectivity (rFC) analyses before and after performing the "cheated" phase of the task in the MRI. We explored their links with behavioral and psychological factors. Dispersion in the participants' cost of uncertainty was used to categorize two groups. These groups showed different patterns of rFC changes. Moreover, in the overall sample, exploitation was correlated with rFC changes between (1) the anterior cingulate cortex and the cerebellum region 3, and (2) the left frontal inferior gyrus (orbital part) and the right frontal inferior gyrus (triangular part). Anxiety and doubt about action propensity were weakly correlated with some rFC changes. These results demonstrate that the exploration/exploitation trade-off involves the modulation of cortico-cerebellar intrinsic connectivity. [ABSTRACT FROM AUTHOR]

Warfarin is the most commonly prescribed anti-coagulant medication. Warfarin's pharmacokinetics (PK) in its enantiomeric form have been reported to be highly variable. Five population pharmacokinetic model studies for warfarin were identified in this systematic review. This review summarized these studies and reported on various factors affecting warfarin PK. Most studies reported a one-compartment model with first-order absorption and elimination for both S-warfarin and R-warfarin. Warfarin disposition has been reported to be influenced by various factors, including gender, age, genetic variation, body surface area (BSA), concurrent drug, weight, and ethnicity. So, all of these factors must be considered when addressing this pharmacokinetic variability. These models should undergo an external evaluation to confirm their generalizability and to support model-informed dosing in clinical settings. [ABSTRACT FROM AUTHOR]

We expand the usually cross-sectional perspective on dual-tasking performance to include both intra- and interpersonal variability, which should capture within-person dynamics and psychological processes better. Two simple tasks, first as single-, then as dual-tasks, were performed by 58 participants over 20 sessions. We found positive relationships between (1) single- and dual-tasking performance and (2) the dual-task component tasks both inter- and intrapersonally. Better single-taskers were better dual-taskers and better single-tasking sessions were better dual-tasking sessions. This implies shared capacities that covary both inter- and intraindividually. We conclude that taking intra- and interpersonal variability into account is a promising future perspective.

Many observations have demonstrated great heterogeneity in the magnitude of the response to the physical exercise stimulus. Only a few studies have investigated the effects of high-intensity interval training (HIIT) on the prevalence of non-responders (NRs) in adolescents while considering health-related fitness measurements and other co-variables. Therefore, the aim of the current work was twofold: (1) to assess the effects of ten weeks of school-based HIIT on the prevalence of responders (Rs) and NRs for body composition, resting blood pressure (BP), cardiorespiratory and musculoskeletal fitness, and (2) to assess the relationship of this prevalence with sex, body mass category, and biological maturation status, while estimating the likelihood of a response. Adolescents aged 16 years (n = 73) were included in the study. Waist-to-hip ratio, body fat percentage (BFP), skeletal muscle mass (SMM), BP, cardiorespiratory fitness (CRF), and musculoskeletal fitness were the primary outcomes. Co-variables included sex, body mass index (BMI), and maturity offset. The percentages of the Rs and NRs were analyzed based on changes (Δ) between post-intervention and pre-intervention values. The typical error (TE) method was used to identify Rs and NRs. Results showed a variation in the relative size of changes (% of changes) depending on the variable and sex. The greatest changes were observed in females' abdomen muscle strength (Δ% = 23.89%), and the difference from that of males (Δ% = 5.98%) was statistically significant (p < 0.001) with very large effect size of (Cohen's d = 0.941). Similar significant differences in relative changes were observed in body composition, but in the reverse direction. Males gained more from HIIT in the decrease in the body fat percentage (Δ% = −8.24%) and increase in skeletal muscle mass (Δ% = 3.38%) comparing to females (Δ% = 0.46, p = 0.040 and Δ% = 1.06%, p = 0.007, respectively). Effect size for body fat was small (Cohen's d = 0.469), and for skeletal muscle mass it was moderate (Cohen's d = −0.659). The results also showed positive significant differences in the prevalence of Rs compared to NRs in BFP, SMM, systolic BP (SBP), diastolic BP (DBP), CRF, and abdominal muscular strength (ABS) (p = 0.047, p = 0.047, p < 0.001, p = 0.003, p = 0.014, and p = 0.014, respectively). The effect was greatest and largest for SBP (Cohen's ω = 0.67). Sex was related to the prevalence of Rs for ABS and close to significance for SMM. More males than females benefited from HIIT in SMM (p = 0.058), but more females than males had ABS benefits (p = 0.050). Males were more likely (2.5-fold) to be Rs than females in SMM. BMI was not related to the prevalence of Rs and NRs. Biological maturation was related to the prevalence of Rs and NRs in SMM (p = 0.036) and SBP (p = 0.016). In SBP, 100% of the early matured derived benefit from HIIT, but the effect size was small (Cramer's V = 0.27). Those who maturated later were more likely (almost 70%) to be Rs. Thus, the HIIT program introduced to a typical physical education (PE) lesson can be considered partially effective. Therefore, there is a need to continue the search for an optimal and effective program for all health-related parameters. The close relationship between analyzed values and sex and biological maturation, but not BMI, indicates that the intervention programs should be tailored specifically for males and females. [ABSTRACT FROM AUTHOR]

Background: Procalcitonin (PCT) is a well‐established biomarker for bacterial infection in human patients. Objectives: We aimed to analyze the kinetics of plasma PCT (pPCT) in healthy dogs and dogs with canine cranial cruciate ligament (CCL) rupture undergoing tibial plateau leveling osteotomy (TPLO). Methods: This prospective, longitudinal study included 15 healthy dogs and 25 dogs undergoing TPLO. Hematology, pPCT, and C‐reactive protein (CRP) were assessed on 3 consecutive days in healthy dogs and 1 day preoperatively and days 1, 2, 10, and 56 postoperatively. Inter‐ and intraindividual variability of pPCT were assessed in healthy dogs. Median pPCT concentrations of dogs with CCL rupture preoperatively were compared with healthy controls, and median pPCT concentrations, as well as percentage change post anesthesia, arthroscopy, and TPLO, were compared with baseline. For the correlation analysis, the Spearman rank correlation test was used. Results: Inter‐ and intraindividual variabilities of pPCT in healthy dogs were 36% and 15%, respectively. Median baseline pPCT concentrations were not significantly different between healthy dogs (118.9 pg/mL; IQR: 75.3‐157.3 pg/mL) and dogs undergoing TPLO (95.9 pg/mL; IQR: 63.8‐117.0 pg/mL). Plasma PCT concentrations were significantly lower immediately post‐ than preoperatively (P < 0.001). CRP, WBC, and neutrophil concentrations increased significantly on post‐OP day 2 and had normalized by day 10. Conclusions: These results indicate that CCL rupture, as well as anesthesia, arthroscopy, and TPLO combined, are not associated with increased pPCT concentrations in dogs with uncomplicated recovery. Considering the high intraindividual variability, individual serial measurements rather than a population‐based reference interval should be considered. [ABSTRACT FROM AUTHOR]

Background/Objective: Considerable attention has been paid to interindividual differences in the cardiorespiratory fitness (CRF) response to exercise. However, the complex multifactorial nature of CRF response variability poses a significant challenge to our understanding of this issue. We aimed to explore whether unsupervised clustering can take advantage of large amounts of clinical data and identify latent subgroups with different CRF exercise responses within a healthy population. Methods: 252 healthy participants (99 men, 153 women; 36.8 ± 13.4 yr) completed moderate endurance training on 3 days/week for 4 months, with exercise intensity prescribed based on anaerobic threshold (AT). Detailed clinical measures, including resting vital signs, ECG, cardiorespiratory parameters, echocardiography, heart rate variability, spirometry and laboratory data, were obtained before and after the exercise intervention. Baseline phenotypic variables that were significantly correlated with CRF exercise response were identified and subjected to selection steps, leaving 10 minimally redundant variables, including age, BMI, maximal oxygen uptake (VO2max), maximal heart rate, VO2 at AT as a percentage of VO2max, minute ventilation at AT, interventricular septal thickness of end-systole, E velocity, root mean square of heart rate variability, and hematocrit. Agglomerative hierarchical clustering was performed on these variables to detect latent subgroups that may be associated with different CRF exercise responses. Results: Unsupervised clustering revealed two mutually exclusive groups with distinct baseline phenotypes and CRF exercise responses. The two groups differed markedly in baseline characteristics, initial fitness, echocardiographic measurements, laboratory values, and heart rate variability parameters. A significant improvement in CRF following the 16-week endurance training, expressed by the absolute change in VO2max, was observed only in one of the two groups (3.42 ± 0.4 vs 0.58 ± 0.65 ml⋅kg−1⋅min−1, P = 0.002). Assuming a minimal clinically important difference of 3.5 ml⋅kg−1⋅min−1 in VO2max, the proportion of population response was 56.1% and 13.9% for group 1 and group 2, respectively (P

Apply It!: • Understand the importance of accurate measures of heart rate during submaximal exercise testing to estimate the client's V̇O2max. • Delineate the most appropriate formula to estimate maximal heart rate for a given population to provide more accurate exercise intensity prescriptions. • Identify ways to reduce the error in estimating V̇O2max when using submaximal exercise testing. [ABSTRACT FROM AUTHOR]

A genetic risk score (GRS) predictive of the plasma triglyceride (TG) response to an omega-3 fatty acid (n-3 FA) supplementation has been previously developed in the Fatty Acid Sensor (FAS) Study. Recently, novel single nucleotide polymorphisms (SNPs) interacting with a fish oil supplementation and associated with plasma lipid levels have been identified in the UK Biobank. The aim of this study was to verify whether the addition of SNPs identified in the UK Biobank to the GRS built in the FAS Study improves its capacity to predict the plasma TG response to an n-3 FA supplementation. SNPs interacting with fish oil supplementation in the modulation of plasma lipid levels in the UK Biobank and associated with plasma TG levels have been genotyped in participants of the FAS Study (n = 141). Participants have been supplemented with 5 g fish oil/day for six weeks. Plasma TG concentrations were measured before and after the supplementation. Based on the initial GRS of 31 SNPs (GRS31), we computed three new GRSs by adding new SNPs identified in the UK Biobank: GRS32 (rs55707100), GRS38 (seven new SNPs specifically associated with plasma TG levels), and GRS46 (all 15 new SNPs associated with plasma lipid levels). The initial GRS31 explained 50.1% of the variance in plasma TG levels during the intervention, whereas GRS32, GRS38, and GRS46 explained 49.1%, 45.9%, and 45%, respectively. A significant impact on the probability of being classified as a responder or a nonresponder was found for each of the GRSs analyzed, but none of them outperformed the predictive capacity of GRS31 in any of the metrics analyzed, i.e., accuracy, area under the response operating curve (AUC-ROC), sensitivity, specificity and McFadden's pseudo R2. The addition of SNPs identified in the UK Biobank to the initial GRS31 did not significantly improve its capacity to predict the plasma TG response to an n-3 FA supplementation. Thus, GRS31 still remains the most precise tool so far by which to discriminate the individual responsiveness to n-3 FAs. Further studies are needed in the field to increase our knowledge of factors underlying the heterogeneity observed in the metabolic response to an n-3 FA supplementation. [ABSTRACT FROM AUTHOR]

The gut microbiota is increasingly implicated in the health and metabolism of its human host. The host's diet is a major component influencing the composition and function of the gut microbiota, and mounting evidence suggests that the composition and function of the gut microbiota influence the host's metabolic response to diet. This effect of the gut microbiota on personalized dietary response is a growing focus of precision nutrition research and may inform the effort to tailor dietary advice to the individual. Because the gut microbiota has been shown to be malleable to some extent, it may also allow for therapeutic alterations of the gut microbiota in order to alter response to certain dietary components. This article is the second in a 2-part review of the current research in the field of precision nutrition incorporating the gut microbiota into studies investigating interindividual variability in response to diet. Part I reviews the methods used by researchers to design and carry out such studies as well as analyze the results subsequently obtained. Part II reviews the findings of these studies and discusses the gaps in our current knowledge and directions for future research. The studies reviewed provide the current understanding in this field of research and a foundation from which we may build, utilizing and expanding upon the methods and results they present to inform future studies.

Health care is increasingly focused on health at the individual level. In the rapidly evolving field of precision nutrition, researchers aim to identify how genetics, epigenetics, and the microbiome interact to shape an individual's response to diet. With this understanding, personalized responses can be predicted and dietary advice can be tailored to the individual. With the integration of these complex sources of data, an important aspect of precision nutrition research is the methodology used for studying interindividual variability in response to diet. This article stands as the first in a 2-part review of current research investigating the contribution of the gut microbiota to interindividual variability in response to diet. Part I reviews the methods used by researchers to design and carry out such studies as well as the statistical and bioinformatic methods used to analyze results. Part II reviews the findings of these studies, discusses gaps in our current knowledge, and summarizes directions for future research. Taken together, these reviews summarize the current state of knowledge and provide a foundation for future research on the role of the gut microbiome in precision nutrition.

Poor and variable oral bioavailability of furosemide (FUR) presents critical challenges in pharmacotherapy. We investigated the interplay of breast cancer resistance protein (Bcrp)-mediated transport, sex, and fed state on FUR pharmacokinetics (PK) in rats. A crossover PK study of FUR (5 mg/kg, oral) was performed in Sprague-Dawley rats (3 males and 3 females), alone or with a Bcrp inhibitor, novobiocin (NOV) (20 mg/kg, oral), in both fed and fasted states. Co-administration of NOV significantly increased FUR extent (AUC) and rate (Cmax) of exposure by more than two-fold, which indicates efficient Bcrp inhibition in the intestine. The female rats showed two-fold higher AUC and Cmax, and two-fold lower renal clearance of FUR compared to the male rats. The latter was correlated with higher renal abundance of Bcrp and organic anion transporters (Oats) in the male rats compared to age-matched female rats. These findings suggest that the PK of Bcrp and/or Oat substrates could be sex-dependent in rats. Moreover, allometric scaling of rat PK and toxicological data of Bcrp substrates should consider species and sex differences in Bcrp and Oat abundance in the kidney. Considering that Bcrp is abundant in the intestine of rats and humans, a prospective clinical study is warranted to evaluate the effect of Bcrp inhibition on FUR PK. The potential confounding effect of the Bcrp transporter should be considered when FUR is used as a clinical probe of renal organic anion transporter-mediated drug–drug interactions. Unlike human data, no food-effect was observed on FUR PK in rats. [ABSTRACT FROM AUTHOR]

Considerable attention has been paid to interindividual differences in the cardiorespiratory fitness (CRF) response to exercise. However, the complex multifactorial nature of CRF response variability poses a significant challenge to our understanding of this issue. We aimed to explore whether unsupervised clustering can take advantage of large amounts of clinical data and identify latent subgroups with different CRF exercise responses within a healthy population. 252 healthy participants (99 men, 153 women; 36.8 ± 13.4 yr) completed moderate endurance training on 3 days/week for 4 months, with exercise intensity prescribed based on anaerobic threshold (AT). Detailed clinical measures, including resting vital signs, ECG, cardiorespiratory parameters, echocardiography, heart rate variability, spirometry and laboratory data, were obtained before and after the exercise intervention. Baseline phenotypic variables that were significantly correlated with CRF exercise response were identified and subjected to selection steps, leaving 10 minimally redundant variables, including age, BMI, maximal oxygen uptake (VO 2max), maximal heart rate, VO 2 at AT as a percentage of VO 2max , minute ventilation at AT, interventricular septal thickness of end-systole, E velocity, root mean square of heart rate variability, and hematocrit. Agglomerative hierarchical clustering was performed on these variables to detect latent subgroups that may be associated with different CRF exercise responses. Unsupervised clustering revealed two mutually exclusive groups with distinct baseline phenotypes and CRF exercise responses. The two groups differed markedly in baseline characteristics, initial fitness, echocardiographic measurements, laboratory values, and heart rate variability parameters. A significant improvement in CRF following the 16-week endurance training, expressed by the absolute change in VO 2max , was observed only in one of the two groups (3.42 ± 0.4 vs 0.58 ± 0.65 ml⋅kg−1⋅min−1, P = 0.002). Assuming a minimal clinically important difference of 3.5 ml⋅kg−1⋅min−1 in VO 2max , the proportion of population response was 56.1% and 13.9% for group 1 and group 2, respectively (P< 0.001). Although group 1 exhibited no significant improvement in CRF at group level, a significant decrease in diastolic blood pressure (70.4 ± 7.8 vs 68.7 ± 7.2 mm Hg, P = 0.027) was observed. Unsupervised learning based on dense phenotypic characteristics identified meaningful subgroups within a healthy population with different CRF responses following standardized aerobic training. Our model could serve as a useful tool for clinicians to develop personalized exercise prescriptions and optimize training effects. [ABSTRACT FROM AUTHOR]

Flavonoid consumption has beneficial effects on human health, however, clinical evidence remains often inconclusive due to high interindividual variability. Although this high interindividual variability has been consistently observed in flavonoid research, the potential underlying reasons are still poorly studied. Especially the knowledge on the impact of health status on flavonoid responsiveness is limited and merits more investigation. Here, we aim to highlight the bidirectional interplay between flavonoids and cellular stress. First, the state-of-the-art concerning inflammatory stress and mitochondrial dysfunction is reviewed and a comprehensive overview of recent in vitro studies investigating the impact of flavonoids on cellular stress, induced by tumor necrosis factor α, lipopolysaccharide and mitochondrial stressors, is given. Second, we critically discuss the influence of cellular stress on flavonoid uptake, accumulation, metabolism and cell responses, which has, to our knowledge, never been extensively reviewed before. Next, we advocate the innovative insight that stratification of the general population based on health status can reveal subpopulations that benefit more from flavonoid consumption. Finally, suggestions are given for the development of future cell models that simulate the physiological micro-environment, including interindividual variability, since more mechanistic research is needed to establish scientific-based personalized food recommendations for specific subpopulations. [ABSTRACT FROM AUTHOR]

While anti-PD-1 and anti-PD-L1 [anti-PD-(L)1] monotherapies are effective treatments for many types of cancer, high variability in patient responses is observed in clinical trials. Understanding the sources of response variability can help prospectively identify potential responsive patient populations. Preclinical data may offer insights to this point and, in combination with modeling, may be predictive of sources of variability and their impact on efficacy. Herein, a quantitative systems pharmacology (QSP) model of anti-PD-(L)1 was developed to account for the known pharmacokinetic properties of antiPD-(L)1 antibodies, their impact on CD8+ T cell activation and influx into the tumor microenvironment, and subsequent anti-tumor effects in CT26 tumor syngeneic mouse model. The QSP model was sufficient to describe the variability inherent in the anti-tumor responses post anti-PD-(L)1 treatments. Local sensitivity analysis identified tumor cell proliferation rate, PD-1 expression on CD8+ T cells, PD-L1 expression on tumor cells, and the binding affinity of PD1:PD-L1 as strong influencers of tumor growth. It also suggested that treatment-mediated tumor growth inhibition is sensitive to T cell properties including the CD8+ T cell proliferation half-life, CD8+ T cell half-life, cytotoxic T-lymphocyte (CTL)-mediated tumor cell killing rate, and maximum rate of CD8+ T cell influx into the tumor microenvironment. Each of these parameters alone could not predict anti-PD-(L)1 treatment response but they could shift an individual mouse’s treatment response when perturbed. The presented preclinical QSP modeling framework provides a path to incorporate potential sources of response variability in human translation modeling of anti-PD-(L)1. [ABSTRACT FROM AUTHOR]

Abstract Background Precision nutrition is highly topical. However, no studies have explored the interindividual variability in response to nutrition interventions for sarcopenia. The purpose of this study was to determine the magnitude of interindividual variability in response to two nutrition supplementation interventions for sarcopenia and metabolic health, after accounting for sources of variability not attributable to supplementation. Methods A 24 week, randomized, double‐blind, placebo‐controlled trial tested the impact of leucine‐enriched protein (LEU‐PRO), LEU‐PRO plus long‐chain n‐3 PUFA (LEU‐PRO+n‐3) or control (CON) supplementation in older adults (n = 83, 71 ± 6 years) at risk of sarcopenia. To estimate the true interindividual variability in response to supplementation (free of the variability due to measurement error and within‐subject variation), the standard deviation of individual responses (SDR) was computed and compared with the minimally clinically important difference (MCID) for appendicular lean mass (ALM), leg strength, timed up‐and‐go (TUG), and serum triacylglycerol (TG) concentration. Clinically meaningful interindividual variability in response to supplementation was deemed to be present when the SDR positively exceeded the MCID. The probability that individual responses were clinically meaningful, and the phenotypic, dietary, and behavioural determinants of response to supplementation were examined. Results The SDR was below the MCID for ALM (LEU‐PRO: −0.12 kg [90% CI: −0.38, 0.35], LEU‐PRO+n‐3: −0.32 kg [−0.45, 0.03], MCID: 0.21 kg), TUG (LEU‐PRO: 0.58 s [0.18, 0.80], LEU‐PRO+n‐3: 0.73 s [0.41, 0.95], MCID: 0.9 s) and TG (LEU‐PRO: −0.38 mmol/L [−0.80, 0.25], LEU‐PRO+n‐3: −0.44 mmol/L [−0.63, 0.06], MCID: 0.1 mmol/L), indicating no meaningful interindividual variability in response to either supplement. The SDR exceeded the MCID (19 Nm) for strength in response to LEU‐PRO (25 Nm [−29, 45]) and LEU‐PRO+n‐3 (23 Nm [−29, 43]) supplementation but the effect was uncertain, evidenced by wide confidence intervals. In the next stage of analysis, similar proportions of participant responses were identified as very likely, likely, possibly, unlikely, and very unlikely to represent clinically meaningful improvements across the LEU‐PRO, LEU‐PRO+n‐3, and CON groups (P > 0.05). Baseline LC n‐3 PUFA status, habitual protein intake, and numerous other phenotypic and behavioural factors were not determinants of response to LEU‐PRO or LEU‐PRO+n‐3 supplementation. Conclusions Applying a novel, robust methodological approach to precision nutrition, we show that there was minimal interindividual variability in changes in ALM, muscle function, and TG in response to LEU‐PRO and LEU‐PRO+n‐3 supplementation in older adults at risk of sarcopenia.

To adapt to a new environment, individuals must alternate between exploiting previously learned “action–consequence” combinations and exploring new actions for which the consequences are unknown: they face an exploration/exploitation trade-off. The neural substrates of these behaviors and the factors that may relate to the interindividual variability in their expression remain overlooked, in particular when considering neural connectivity patterns. Here, to trigger environmental uncertainty, false feedbacks were introduced in the second phase of an associative learning task. Indices reflecting exploitation and cost of uncertainty were computed. Changes in the intrinsic connectivity were determined using resting-state functional connectivity (rFC) analyses before and after performing the “cheated” phase of the task in the MRI. We explored their links with behavioral and psychological factors. Dispersion in the participants’ cost of uncertainty was used to categorize two groups. These groups showed different patterns of rFC changes. Moreover, in the overall sample, exploitation was correlated with rFC changes between (1) the anterior cingulate cortex and the cerebellum region 3, and (2) the left frontal inferior gyrus (orbital part) and the right frontal inferior gyrus (triangular part). Anxiety and doubt about action propensity were weakly correlated with some rFC changes. These results demonstrate that the exploration/exploitation trade-off involves the modulation of cortico-cerebellar intrinsic connectivity.

Diffuse low-grade glioma (LGG) is a rare cerebral cancer, mostly involving young adults with an active life at diagnosis. If left untreated, LGG widely invades the brain and becomes malignant, generating neurological worsening and ultimately death. Early and repeat treatments for this incurable tumor, including maximal connectome-based surgical resection(s) in awake patients, enable postponement of malignant transformation while preserving quality of life owing to constant neural network reconfiguration. Due to considerable interindividual variability in terms of LGG course and consecutive cerebral reorganization, a multistage longitudinal strategy should be tailored accordingly in each patient. It is crucial to predict how the glioma will progress (changes in growth rate and pattern of migration, genetic mutation, etc.) and how the brain will adapt (changes in patterns of spatiotemporal redistribution, possible functional consequences such as epilepsy or cognitive decline, etc.). The goal is to anticipate therapeutic management, remaining one step ahead in order to select the optimal (re-)treatment(s) (some of them possibly kept in reserve), at the appropriate time(s) in the evolution of this chronic disease, before malignization and clinical worsening. Here, predictive tumoral and non-tumoral factors, and their ever-changing interactions, are reviewed to guide individual decisions in advance based on patient-specific markers, for the treatment of LGG. [ABSTRACT FROM AUTHOR]

(Poly)phenols have anti-diabetic properties that are mediated through the regulation of the main biomarkers associated with type 2 diabetes mellitus (T2DM) (fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), insulin resistance (IR)), as well as the modulation of other metabolic, inflammatory and oxidative stress pathways. A wide range of human and pre-clinical studies supports these effects for different plant products containing mixed (poly)phenols (e.g., berries, cocoa, tea) and for some single compounds (e.g., resveratrol). We went through some of the latest human intervention trials and pre-clinical studies looking at (poly)phenols against T2DM to update the current evidence and to examine the progress in this field to achieve consistent proof of the anti-diabetic benefits of these compounds. Overall, the reported effects remain small and highly variable, and the accumulated data are still limited and contradictory, as shown by recent meta-analyses. We found newly published studies with better experimental strategies, but there were also examples of studies that still need to be improved. Herein, we highlight some of the main aspects that still need to be considered in future studies and reinforce the messages that need to be taken on board to achieve consistent evidence of the anti-diabetic effects of (poly)phenols. [ABSTRACT FROM AUTHOR]

Background: Office workers represent one of the most sedentary groups. Alarmingly, more than a third of their sitting time during workdays occurs in prolonged bouts. Sit-stand desk (SSD) interventions have been found to be effective in reducing sitting time, but heterogeneity exists amongst studies, which may be due to compensations outside the workplace. This study aimed to assess the impact of a 6-month SSD intervention on office workers' sitting and standing times during the work shift and outside work (leisure time)., Methods: A two-arm (1:1) clustered randomized controlled trial was conducted with 38 participants randomly assigned to either the intervention or control group. The intervention included a psychoeducational session, motivational prompts, and environmental modification (SSD implemented in the workplace). The waiting-list control group maintained the usual work conditions and only received the initial session. We employed repeated measures ANCOVA to compare changes between groups while adjusting for relevant covariates, with significance set at 5%., Results: In the intervention group, there was a significant reduction in sitting time at work by 32.97 min, along with a notable increase in standing time by 27.88 min (p<0.05). Although not significant (p>0.05), there was an increase in sitting time in the leisure context of about 23.07 min., Conclusions: This study underscores the effectiveness of SSD as a key strategy to mitigate sitting time among office workers. However, future interventions should consider integrating comprehensive behavioral strategies beyond the workplace to sustain potential increases in sitting time during the leisure time and avoid compensatory behaviors. What is already known on this topic: Sedentary behavior, particularly in the workplace, is associated with increased risks of non-communicable diseases and premature mortality. Previous studies have shown that sit-stand desk (SSD) interventions can significantly reduce sitting time at work. However, uncertainties remain about whether these effects persist outside of the workplace and if compensatory behaviors occur during leisure time., What This Study Adds: This study demonstrated that a 6-month SSD intervention resulted in a significant reduction of 32.97 minutes in sitting time during work hours and a corresponding increase in standing time. However, a non-significant increase of 23.07 minutes in sitting time during leisure was observed, suggesting potential compensatory behaviors outside of work. Additionally, the response to the intervention varied among participants, highlighting the influence of individual factors. How this study might affect research, practice, or policy: The findings emphasize the importance of extending behavioral interventions beyond the workplace to maintain sustainable reductions in sedentary behavior. To maximize health benefits, future interventions should consider personalized strategies that address sedentary behavior in the workplace and during leisure time. Moreover, the variability in individual responses suggests that more tailored interventions may be necessary to ensure widespread effectiveness., (© The Author(s) [2024]. Published by Oxford University Press.)

Major epigenetic changes are associated with carcinogenesis, including aberrant DNA methylations and post-translational modifications of histone. Indeed evidence accumulated in recent years indicates that inactivating DNA hypermethylation preferentially targets the subset of polycomb group (PcG) genes that are regulators of developmental processes. Conversely, activating DNA hypomethylation targets oncogenic signaling pathway genes, but outcomes of both events lead in the overexpression of oncogenic signaling pathways that contribute to the stem-like state of cancer cells. On the basis of recent evidence from population-basedclinical and experimental studies, we hypothesize that factors associated with risk for developing a hematologic malignancy (HM), such as metabolic syndrome and chronic inflammation, may trigger epigenetic mechanisms to increase the transcriptional expression of oncogenes and activate oncogenic signaling pathways. Signaling pathways associated with such risk factors include but are not limited to pro-inflammatory nuclear factor κB (NF-κB) and mitogenic, growth, and survival Janus kinase (JAK) intracellular non-receptor tyrosine kinase-triggered pathways. The latter includes signaling pathways such as transducer and activator of transcription (STAT), Ras GTPases/mitogen-activated protein kinases (MAPKs)/extracellular signal-related kinases (ERKs), phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and β-catenin pathways. Recent findings on epigenetic mechanisms at work in the biology of cancer and in HMs and their importance in the etiology and pathogenesis of these diseases are herein summarized and discussed. Furthermore, the role of epigenetic processes in the determination of biological identity, the consequences for interindividual variability in disease clinical profile, and the potential of epigenetic drugs in HMs are also considered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nwabo Kamdje, Dongmo Fogang and Mimche.)

The neural face perception network is distributed across both hemispheres. However, the dominant role in humans is virtually unanimously attributed to the right hemisphere. Interestingly, there are, to our knowledge, no imaging studies that systematically describe the distribution of hemispheric lateralization in the core system of face perception across subjects in large cohorts so far. To address this, we determined the hemispheric lateralization of all core system regions (i.e., occipital face area - OFA, fusiform face area - FFA, posterior superior temporal sulcus - pSTS) in 108 healthy subjects using functional magnetic resonance imaging (fMRI). We were particularly interested in the variability of hemispheric lateralization across subjects and explored how many subjects can be classified as right-dominant based on the fMRI activation pattern. We further assessed lateralization differences between different regions of the core system and analyzed the influence of handedness and sex on the lateralization with a generalized mixed effects regression model. As expected, brain activity was on average stronger in right-hemispheric brain regions than in their left-hemispheric homologues. This asymmetry was, however, only weakly pronounced in comparison to other lateralized brain functions (such as language and spatial attention) and strongly varied between individuals. Only half of the subjects in the present study could be classified as right-hemispheric dominant. Additionally, we did not detect significant lateralization differences between core system regions. Our data did also not support a general leftward shift of hemispheric lateralization in left-handers. Only the interaction of handedness and sex in the FFA revealed that specifically left-handed men were significantly more left-lateralized compared to right-handed males. In essence, our fMRI data did not support a clear right-hemispheric dominance of the face perception network. Our findings thus ultimately question the dogma that the face perception network – as measured with fMRI – can be characterized as “typically right lateralized”.

This review collects and critically examines data on the levels of tumour necrosis factor-alpha (TNF-α) in lean, overweight and obese subjects, and the effects of intervention with different foods and food products containing bioactive constituents in overweight/obese individuals. We additionally explore the influence of different single nucleotide polymorphisms (SNPs) on TNF-α levels and compare the response to food products with that to some anti-obesity drugs. Our aim was to provide an overview of the variability, consistency, and magnitude of the reported effects of dietary factors on TNF-α, and to envisage the reliability of measuring changes in the levels of this cytokine as a biomarker responsive to food intervention in association with the reduction in body weight. Regarding the circulating levels of TNF-α, we report: (i) a large intra-group variability, with most coefficients of variation (CV%) values being ≥30% and, in many cases, >100%; (ii) a large between-studies variability, with baseline TNF-α values ranging from <1.0 up to several hundred pg/mL; (iii) highly variable effects of the different dietary approaches with both statistically significant and not significant decreases or increases of the protein, and the absolute effect size varying from <0.1 pg/mL up to ≈50 pg/mL. Within this scenario of variability, it was not possible to discern clear differentiating limits in TNF-α between lean, overweight, and obese individuals or a distinct downregulatory effect on this cytokine by any of the different dietary approaches reviewed, i.e., polyunsaturated fatty acids (PUFAs), Vitamin-D (VitD), mixed (micro)nutrients, (poly)phenols or other phytochemicals. Further, there was not a clear relationship between the TNF-α responses and body weight changes. We found similarities between dietary and pharmacological treatments in terms of variability and limited evidence of the TNF-α response. Different factors that contribute to this variability are discussed and some specific recommendations are proposed to reinforce the need to improve future studies looking at this cytokine as a potential biomarker of response to dietary approaches. [ABSTRACT FROM AUTHOR]