Interindividual Variations Research Articles

New Insights into Colorectal Cancer through the Lens of Precision Oncology and Personalized Medicine: Multi-Omics Helps Aging of Predisposed People.

Recently, there has been a significant evolution in our understanding of the molecular pathways causing the genesis and progression of cancer via the inter-individual variations. Thus, one-size-fits-all methods for cancer treatment have been replaced by precision oncology (PO) targeting individual cancer symptoms, offering increased effectiveness, and decreased safety concerns and cost load. The identification of novel actionable indications, rapid, precise, and comprehensive detection of complex phenotypes in every individual, pioneering clinical trial projects with enhanced response feedback, and widespread availability of innovative targeted anticancer management for every patient are vital for the effective implementation of next-generation precision oncology. Additionally, the emergence of precision medicine has altered the perspective of oncologic biomarkers, drug discovery, drug development, and, improvements for cancer patients. This paper narratively reviewed to identify actionable abnormalities, Genomic profiling of tumors employing clinical next-generation sequencing (NGS) from both tumor tissues and liquid biopsies along with the multi-omics strategies as the key component of PO. Our increasing information on tumor biology, specifically microenvironment and heterogeneity- associated data, would improve our understanding of the resistance of targeted drugs and specific mechanisms of action, as well as help enhance existing metastatic colorectal cancer (mCRC) treatment strategies. Collectively, this paper indicated the current and innovative strategies for prognosis, diagnosis, and treatment of various cancer types based on PO overview with a groundbreaking emphasis on CRC suggesting the integrations of multi-omics, highlighting Genomics, and utilizing AL and ML algorithms with targeted therapies. Notably, these findings can help improve the life-span and ageing of the predisposed people.

Gut microbiome and inflammation in cardiovascular drug response: trends in therapeutic success and commercial focus.

The intricate Gut microbiome is evolving as an important system and is hypothesized to be a "metabolic organ" within the host. Alterations in Gut microbiota and inflammation associated with several diseases play acrucial role in drug transformation through microbiota-host co-metabolism, modified pharmacokinetic and pharmacodynamics profiles, and may result in the formation of toxic metabolites with interference in drug response. In recent studies, a large number of drugs are reported that are co-metabolized by the host and the Gut microbial enzymes. we summarize thedirect and indirect involvement of Gut microbiome promotion or inhibition of cardiovascular diseases, mechanisms on bioavailability, and therapeutic outcomes of cardiovascular drugs, particularly pharmacokinetics and pharmacodynamics profiles in light of AUC, Tmax, Cmax, and bioavailability and drug transportation via immune cells, inter-individual variations in intestinal microbial taxonomy, influence of drugs on diversity and richness of microflora, high lightening limitations and significance of in personalized medicine. Recent advances in target-drug delivery by nanoparticles with limitations and challenges in application are discussed. The cross-talk between Gut microbiota and cardiovascular drugs signifies abetter understanding and rationale fortargeting the Gut microbiota to improve the therapeutic outcome for cardiovascular diseases, with present-day limitations.

Spatiotemporal dynamics during niche remodeling by super-colonizing microbiota in the mammalian gut.

While fecal microbiota transplantation (FMT) has been shown to be effective in reversing gut dysbiosis, we lack an understanding of the fundamental processes underlying microbial engraftment in the mammalian gut. Here, we explored a murine gut colonization model leveraging natural inter-individual variations in gut microbiomes to elucidate the spatiotemporal dynamics of FMT. We identified a natural "super-donor" consortium that robustly engrafts into diverse recipients and resists reciprocal colonization. Temporal profiling of the gut microbiome showed an ordered succession of rapid engraftment by early colonizers within 72 h, followed by a slower emergence of late colonizers over 15-30days. Moreover, engraftment was localized to distinct compartments of the gastrointestinal tract in a species-specific manner. Spatial metagenomic characterization suggested engraftment was mediated by simultaneous transfer of spatially co-localizing species from the super-donor consortia. These results offer a mechanism of super-donor colonization by which nutritional niches are expanded in a spatiotemporally dependent manner. A record of this paper's transparent peer review process is included in the supplemental information.

Personalized blood pressure estimation using multiview fusion information of wearable physiological signals and transfer learning

Continuous blood pressure (BP) monitoring is crucial for individual health management, yet the significant inter-individual variations among patients pose challenges to achieving precision medicine. In response to this issue, we propose a parallel cross-hybrid architecture that integrates a convolutional neural network backbone and a Mix-Transformer backbone. This model, grounded in multi-view physiological signals and personalized fine-tuning strategies, aims to estimate BP, facilitating the capture of physiological information across diverse receptive fields and enhancing network expressive capabilities. Our proposed architecture exhibits superior performance in estimating systolic blood pressure and diastolic blood pressure, with average absolute errors of 3.94 mmHg and 2.24 mmHg, respectively. These results surpass existing baseline models and align with the standards set by the British Hypertension Society, the Association for the Advancement of Medical Instrumentation, and the Institute of Electrical and Electronics Engineers for BP measurement. Additionally, this study explores a personalized model fine-tuning strategy by adjusting specific layers and incorporating individual information, presenting an optimal solution. The model's generalization ability is validated through transfer learning across databases (public and self-made). To enhance the proposed architecture's usability in wearable devices, this study employs a knowledge distillation strategy for model lightweighting, with preliminary application in our designed real-time BP estimation system. This study provides an efficient and accurate solution for personalized BP estimation, exhibiting broad potential applications.

Early Supraspinal Influences on Human Embryonic Posture.

Knowledge of embryonic body posture as a reflection of neurodevelopment is limited. Here, we investigate embryonic body posture, preference, symmetry, and lateralization during periods of rest using virtual reality (VR) and four-dimensional (4D) ultrasound techniques to enhance our knowledge of neurodevelopment. It is hypothesized that lateralization and asymmetry in embryonic posture are absent. Embryos from low-risk pregnancies at 9 weeks gestational age (GA) were analyzed using a 30-min 4D ultrasound and VR techniques. In the middle of an embryonic resting period, the total body posture was determined by combining joint positions. Interindividual and intraindividual postures were analyzed over time to identify posture preferences, asymmetry, and lateralization. Sixteen embryos (N=210 middle frames out of 210 resting periods) displayed 27 different embryonic body postures. Interindividual and intraindividual variations in postures were seen. Asymmetry was noted in upper extremities, whereas lateralization of the head and spine was observed in nine embryos. Intraindividual and interindividual variation in embryonic posture at 9 weeks' GA is seen, suggesting the presence of supraspinal influences on body posture this early. Future interdisciplinary longitudinal studies on embryonic posture may provide further insights into embryonic central nervous system development, contributing to our understanding of embryonic health.

Modulation of gut microbiome in response to the combination of Escherichia coli Nissle 1917 and sugars: a pilot study using host-free system reflecting impact on interpersonal microbiome.

The differential effects of probiotic, prebiotic, and synbiotic formulations on human health are dictated by the inter-individual gut microbial profile. The effects of probiotics such as Escherichia coli Nissle 1917 (ECN) on gut microbiota may vary according to the microbiome profiles of individuals and may be influenced by the presence of certain carbohydrates, which can impact microbial community structure and treatment results. Processed fecal samples from donors having contrasting lifestyles, dietary patterns, and disease histories were mixed with 5 × 106 CFU/mL ECN with or without 1% (w/v) sugars (glucose, galactose, or rice starch) in a host-free system. Post-incubation, 16 s rRNA sequencing was performed. Microbial diversity and taxonomic abundance were computed in relation to the probiotic, prebiotic, and synbiotic treatment effects and interpersonal microbiome variance. Baseline gut microbial profiles showed significant inter-individual variations. ECN treatment alone had a limited impact on the inter-personal gut microbial diversity and abundance. Prebiotics caused a substantial enrichment in Actinobacteria, but there were differences in the responses at the order and genus levels, with enrichment shown in Bifidobacterium, Collinsella, and Megasphaera. Subject B exhibited enrichment in Proteobacteria and Cyanobacteria, but subject A showed more diversified taxonomic alterations as a consequence of the synbiotic treatments. Despite negligible difference in the α-diversity, probiotic, prebiotic, and synbiotic treatments independently resulted in distinct segregation in microbial communities at the β-diversity level. The core microbiota was altered only under prebiotic and synbiotic treatment. Significant correlations primarily for minor phyla were identified under prebiotic and synbiotic treatment. The interindividual microbiome composition strongly influences the effectiveness of personalized diet and treatment plans. The responsiveness to dietary strategies varies according to individual microbiome profiles influenced by health, diet, and lifestyle. Therefore, tailored approaches that consider individual microbiome compositions are crucial for maximizing gut health and treatment results.

Progression of cyclosporine A-blood levels in experimental cats receiving a high-dose treatment protocol.

Cyclosporine A (CsA) is used as a steroid-sparing or alternative immunosuppressing agent in cats with various immune-mediated diseases such as immune-mediated hemolytic anemia. Daily treatment dosages of 5-20 mg/kg have been described. Interindividual variations in CsA blood levels are known to occur. To determine when steady-state conditions are reached and thus the earliest advisable time for monitoring CsA blood levels during the course of treatment, a prospective experimental study was conducted in six healthy adult Domestic Shorthair cats. Cats were treated with an oral dosage of 7 mg/kg CsA q 12 h for 10 days. On days 1, 2, 3, 5, 7, and 10 after the start of CsA administration (i.e., after 1, 3, 5, 9, 13, and 19 CsA administrations), EDTA blood was collected to measure the CsA level 12 h after the CsA administration (trough values) using high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS/MS). Statistical analysis revealed a significant increase in mean CsA blood levels up to day 5 (2,050 ± 964.2 ng/mL [mean ± SD], 832-3,203 ng/mL [minimum-maximum]; repeated-measures ANOVA: p = 0.0021), while values on days 5 and 7 did not differ significantly from CsA concentrations on day 10. CsA concentrations showed markedly interindividual variability. Cyclosporine A blood levels reached a steady state on day 5 of high dosages of CsA q 12 h (i.e., after nine CsA administrations), indicating that this time point is suitable for monitoring blood levels in clinical patients. Results confirmed the well-known remarkable interindividual variability of CsA, indicating the need for treatment monitoring. The assessed treatment regime resulted in significantly higher mean CsA trough levels than the target range for immunosuppressive therapy (200-600 ng/mL).

Sub- and supratherapeutic efavirenz plasma concentrations with risk for HIV therapy failure are mainly genetically explained in Ugandan children: The prospective GENEFA cohort study.

Interindividual variations in efavirenz (EFV) plasma concentrations are extensive, but paediatric data on its consequences for viral control are scarce. The aim of this study was to explore the role of genetic variation in achieving therapeutic efavirenz plasma concentrations in a cohort of Ugandan children and the linkage between genetic CYP2B6 variants, EFV plasma variability, viral resistance and viral outcome. Ninety-nine treatment-naïve children, aged 3-12 years and living with HIV, were followed for 24 weeks after ART initiation assessing mid-dose efavirenz plasma concentrations, HIV RNA, HIV drug resistance and adherence. Polymorphisms in genes coding for drug-metabolizing enzymes were genotyped. Efavirenz concentrations were determined by liquid chromatography coupled with high-resolution tandem mass spectrometry. Metabolizer phenotype was predicted from composite genotypes of CYP2B6 (c.516G>T and c.983 T>C). A mixed effects restricted maximum likelihood regression model was used to identify important factors for efavirenz exposure. Efavirenz plasma concentrations were below the therapeutic interval (1000-4000 mg/mL) in 12-17% and above in 21-24% of measurements. Eight children had persisting subtherapeutic concentrations, five of which failed virologically and three acquired at least one new resistant mutation. Multivariate modelling explained 70% of interindividual variation in plasma concentration, with treatment duration, adherence, CYP2B6c.136A>G, and metabolizer phenotype as independent predictors of EFV concentration. In univariate analysis, metabolizer phenotype explained 50% of interindividual variation. Metabolizer phenotype explained 50% of interindividual variation in efavirenz plasma concentration. Autoinduction was not confirmed and >33% of the concentrations were outside the therapeutic interval. Subtherapeutic concentrations worsened virological resistance and outcomes. Genotype-based dosing may help avert both sub- and supratherapeutic efavirenz plasma concentrations in Ugandan children.

Early wave reflection of carotid artery is associated with 18F-FDG PET hypometabolism in Alzheimer's brain areas of cognitively normal adults.

Arterial stiffening likely plays a role in Alzheimer disease (AD) pathogenesis. The current study investigated whether inter-individual variations in arterial stiffness and pressure wave parameters were associated with 18F-FDG positron emission tomography (PET) metabolism in AD-associated brain areas throughout adulthood, independently of age and before the onset of any neuropsychological disorders. A prospective, large age-range population of 67 patients (17 young, 16 middle-aged, and 34 older adults; 37 women) underwent a: brain 18F-FDG PET, blood pressure recording, and carotid/femoral pulse wave-based measurements, including the time-to-peak of the reflected backward carotid pulse wave (bT), on the same day. Multivariable and quantitative voxel-to-voxel analyses (P-voxel < 0.005, corrected for cluster volumes) were conducted to assess associations between vascular parameters and 18F-FDG PET metabolism in AD-associated brain areas. In the multivariable analysis, only increased age and decreased bT were independently associated with the decline of metabolic activity in AD-associated brain areas (P < 0.001). In the voxel-to-voxel analysis with age as a covariate, bT was strongly associated with the metabolic activity of 40 clusters in AD-associated brain areas (clusters cumulative volume: 63 cm3; T score max: 5.7). In a large age-range population of adult patients, who are still unaffected by neuropsychological disorders, an early reflected arterial pressure wave, as evidenced by a decreased bT value, is strongly associated with hypometabolic activity of AD-associated brain areas, independently of age.

Zygosity Effects on Human Voice: Fundamental Frequency Analysis of Brazilian Twins' Speech.

Voice production can be influenced by interindividual variations related to genetic, physiological, behavioral, and several environmental factors. Here we examined the effect of zygosity on speaking fundamental frequency (F0) statistical descriptors. Our aims were: (1) to determine whether the genetic similarity between monozygotic (MZ) and dizygotic (DZ) twins affects F0 characteristics, and (2) to quantify the contribution of genetic factors to these characteristics. The study involved 79 same-sex twin pairs of Brazilian Portuguese speakers, comprising 65 MZ and 14 DZ twins, aged 18 to 66 years (31.7 ± 11.6 years), with 21 male and 58 female pairs. Participants were recorded while uttering a greeting phrase and the Brazilian Portuguese version of the 'Happy Birthday to You' song. Speech segments were analyzed using Praat free software, and F0 measures were automatically extracted in both Hertz and semitone scales. Statistical descriptors, including centrality, dispersion, and extreme values of F0 were examined, and the ACE model (i.e., total genetic effects, A; shared environmental influences, C; and nonshared environmental influences, E) was employed to estimate the additive effect;ts of monozygosity. As anticipated, we observed a zygosity effect on several F0 parameters, with more similarity between MZ twins compared to DZ twins. We discuss the genetic influences on F0 parameters and the absence of a monozygosity effect in two of them. Additionally, we briefly address potential biases associated with the selected measurement scale for statistical modeling. Finally, we explore the influence of genetic factors on F0 patterns, as well as environmental, life history and linguistic factors, particularly concerning F0 variation in speech.

The Amount and Pattern of Reciprocal Compensations Predict Performance Stability in a Visually Guided Finger Force Production Task.

Previous work suggests that synergistic activity among motor elements implicated in force production tasks underlies enhanced performance stability associated with visual feedback. A hallmark of synergistic activity is reciprocal compensation, that is, covariation in the states of motor elements that stabilizes critical performance variables. The present study examined if characteristics of reciprocal compensation are indicators of individuals' capacity to respond adaptively to variations in the resolution of visual feedback about criterion performance. Twenty healthy adults (19.25 ± 1.25years; 15 females and five males) pressed two sensors with their index fingers to produce a total target force equivalent to 20% of their maximal voluntary contraction under nine conditions that differed in the spatial resolution of real-time feedback about their performance. By combining within-trial uncontrolled manifold and sample entropy analyses, we quantified the amount and degree of irregularity (i.e.,non-repetitiveness) of reciprocal compensations over time. We found a U-shaped relationship between performance stability and gain. Importantly, this relationship was moderated by the degree of irregularity of reciprocal compensation. Lower irregularity in reciprocal compensation patterns was related to individuals' capacity to maintain (or minimize losses in) performance under changes in feedback resolution. Results invite future investigation into how interindividual variations in reciprocal compensation patterns relate to differences in control strategies supporting adaptive responses in complex, visually guided motor tasks.

Right Ventricular Hypertrophy in Spontaneously Hypertensive Rats (SHR/NHsd) Is Associated with Inter-Individual Variations of the Pulmonary Endothelin System.

Spontaneously hypertensive rats (SHRs) develop severe hypertension and subsequently left ventricular hypertrophy. Whether they also develop right ventricular hypertrophy is not clear. We analyzed 76 female SHRs (strain SHR/NHsd) and observed severe right ventricular hypertrophy in 7% of these rats (SHR-RVH). Right ventricular hypertrophy did not correlate with the age of the rats and was already seen in one rat at the pre-hypertensive state. The current study investigated the molecular fingerprint of the lung and right ventricle from SHR-RVH and compared this first to SHRs that did develop left but not right ventricular hypertrophy, and second to normotensive rats without hypertrophy. Rats with right ventricular hypertrophy had a decreased expression of the endothelin-B receptor (EDNRB) in the lung, together with an increased protein content of endothelin-1 and an increased expression of ACTA2A. Furthermore, in the right ventricle, a down-regulation of the endothelin-A receptor (EDNRA) was found, consistent with a mild phenotype. The data suggest that in a sub-group of SHR/NHsd rats, low expression of the endothelin clearance receptor (endothelin-B receptor) in the lung triggers an increase in vascular resistance to the right ventricle that then triggers hypertrophy. Our study is the first description of a genetic variant in a defined SHR strain.

Comparison of different group-level templates in gradient-based multimodal connectivity analysis

Abstract The study of large-scale brain connectivity is increasingly adopting unsupervised approaches that derive low-dimensional spatial representations from high-dimensional connectomes, referred to as gradient analysis. When translating this approach to study interindividual variations in connectivity, one technical issue pertains to the selection of an appropriate group-level template to which individual gradients are aligned. Here, we compared different group-level template construction strategies using functional and structural connectome data from neurotypical controls and individuals with autism spectrum disorder (ASD) to identify between-group differences. We studied multimodal magnetic resonance imaging data obtained from the Autism Brain Imaging Data Exchange (ABIDE) Initiative II and the Human Connectome Project (HCP). We designed six template construction strategies that varied in whether (1) they included typical controls in addition to ASD; or (2) they mapped from one dataset onto another. We found that aligning a combined subject template of the ASD and control subjects from the ABIDE Initiative onto the HCP template exhibited the most pronounced effect size. This strategy showed robust identification of ASD-related brain regions for both functional and structural gradients across different study settings. Replicating the findings on focal epilepsy demonstrated the generalizability of our approach. Our findings will contribute to improving gradient-based connectivity research.

Gut phageome in Mexican Americans: a population at high risk for metabolic dysfunction-associated steatotic liver disease and diabetes.

Mexican Americans are disproportionally affected by metabolic dysfunction-associated steatotic liver disease (MASLD), which often co-occurs with diabetes. Despite extensive evidence on the causative role of the gut microbiome in MASLD, studies determining the involvement of the gut phageome are scarce. In this cross-sectional study, we characterized the gut phageome in Mexican Americans of South Texas by stool shotgun metagenomic sequencing of 340 subjects, concurrently screened for liver steatosis by transient elastography. Inter-individual variations in the phageome were associated with gender, country of birth, diabetes, and liver steatosis. The phage signatures for diabetes and liver steatosis were subsequently determined. Enrichment of Inoviridae was associated with both diabetes and liver steatosis. Diabetes was further associated with the enrichment of predominantly temperate Escherichia phages, some of which possessed virulence factors. Liver steatosis was associated with the depletion of Lactococcus phages r1t and BK5-T, and enrichment of the globally prevalent Crassvirales phages, including members of genus cluster IX (Burzaovirus coli, Burzaovirus faecalis) and VI (Kahnovirus oralis). The Lactococcus phages showed strong correlations and co-occurrence with Lactococcus lactis, while the Crassvirales phages, B. coli, B. faecalis, and UAG-readthrough crAss clade correlated and co-occurred with Prevotella copri. In conclusion, we identified the gut phageome signatures for two closely linked metabolic diseases with significant global burden. These phage signatures may have utility in risk modeling and disease prevention in this high-risk population, and identification of potential bacterial targets for phage therapy.IMPORTANCEPhages influence human health and disease by shaping the gut bacterial community. Using stool samples from a high-risk Mexican American population, we provide insights into the gut phageome changes associated with diabetes and liver steatosis, two closely linked metabolic diseases with significant global burden. Common to both diseases was an enrichment of Inoviridae, a group of phages that infect bacterial hosts chronically without lysis, allowing them to significantly influence bacterial growth, virulence, motility, biofilm formation, and horizontal gene transfer. Diabetes was additionally associated with the enrichment of Escherichia coli-infecting phages, some of which contained virulence factors. Liver steatosis was additionally associated with the depletion of Lactococcus lactis-infecting phages, and enrichment of Crassvirales phages, a group of virulent phages with high global prevalence and persistence across generations. These phageome signatures may have utility in risk modeling, as well as identify potential bacterial targets for phage therapy.

Methyltransferase Like-3-Mediated N6-Methyladenosine Modification of Long Noncoding RNA Hepatocyte Nuclear Factor 1a Antisense RNA 1/Hepatocyte Nuclear Factor 4a Antisense RNA 1 Regulates Cytochrome P450 Enzyme Expression.

Interindividual variations in the expression and activity of cytochrome P450 enzymes (CYPs) led to lower therapeutic efficacy or adverse drug events. We previously demonstrated that CYPs are regulated by the long noncoding RNAs (lncRNAs) hepatocyte nuclear factor 1a antisense RNA 1 (HNF1A-AS1) and HNF4A-AS1 via transcription factors (TFs) including hepatocyte nuclear factor 1a (HNF1A), hepatocyte nuclear factor 4a (HNF4A), and pregnane X receptor (PXR). However, the upstream mechanisms regulating HNF1A-AS1 and HNF4A-AS1 are poorly understood. N6-methyladenosine (m6A) is a prevalent epitranscriptomic modification in mammalian RNA. Therefore, the aim of this study was to investigate whether m6A modification regulates the expression of HNF1A-AS1 and HNF4A-AS1 and affects CYP expression in HepG2 and Huh7 cells. The methyltransferase-like 3 (METTL3) inhibitor, STM2457, significantly suppressed the expression of HNF1A-AS1 and induced HNF4A-AS1 expression. Consistent with this, a loss-of-function assay of METTL3 in the cell lines resulted in the downregulation of HNF1A-AS1 and its downstream HNF1A, PXR, and CYPs at the RNA level, as well as the downregulation of some CYPs proteins, and upregulation of HNF4A-AS1. The results of gain-of-function experiments showed the opposite trend. Mechanistically, subsequent RNA stability experiments confirmed that METTL3 affected the stability of both lncRNAs, but in opposite ways; that is, METTL3 reduced HNF1A-AS1 stability and increased HNF4A-AS1 stability. Rescue experiments confirmed that the regulation of METTL3 on TFs and CYPs may require the involvement of these two lncRNAs. Altogether, our study demonstrates that METTL3 is involved in TFs-mediated CYP expression by affecting HNF1A-AS1/HNF4A-AS1 stability. SIGNIFICANCE STATEMENT: Although the impact of long noncoding RNAs (lncRNAs) including hepatocyte nuclear factor 1a antisense RNA 1 (HNF1A-AS1) and hepatocyte nuclear factor 4a antisense RNA 1 (HNF4A-AS1) on the downstream transcription factor (TF) and cytochrome P450 enzyme (CYP) expression is well studied, the upstream regulation of these two lncRNAs by methyltransferase-like 3 (METTL3) remains unexplored. This study reveals that METTL3 is involved in the regulation of lncRNA-TF-CYP expression by affecting the stability of HNF1A-AS1 and HNF4A-AS1 in HepG2 and Huh7 cells.

Interindividual Variability in Postprandial Plasma Fructose Patterns in Adults.

High fructose consumption is associated with an increased risk of cardiometabolic disease, and fructose feeding dose-dependently induces markers reflective of poor metabolic health. However, unlike glucose, surprisingly little is known about person-to-person differences in postprandial plasma fructose patterns. Herein, we performed post hoc analyses of two published studies to address this question. In the first cohort, 16 participants' all-day plasma fructose concentration patterns (08:00-23:30) were determined (8 women and 8 men) while consuming mixed meals (breakfast, lunch, and dinner) with a fructose-sweetened beverage at each meal (30% of calories). Individually plotted results demonstrate remarkably disparate fructose patterns with respect to peak concentration and timing. A secondary study confirmed substantial interindividual variability in plasma fructose patterns over 240 min in 16 adults consuming Ensure®, a commercially available mixed macronutrient drink containing a low dose of fructose. The health ramifications of interindividual variations in postprandial fructose metabolism and the underlying physiological mechanisms driving differences in post-meal blood patterns remain to be explored. Future research is warranted to determine if interindividual variability in fructose digestion, metabolism, and postprandial blood concentration patterns is associated with cardiometabolic health phenotypes and disease risk.

Orthostatic testing for heart rate and heart rate variability monitoring in exercise science and practice.

Orthostatic testing, involving the transition from different body positions (e.g., from lying or sitting position to an upright or standing position), offers valuable insights into the autonomic nervous system (ANS) functioning and cardiovascular regulation reflected through complex adjustments in, e.g., measures of heart rate (HR) and heart rate variability (HRV). This narrative review explores the intricate physiological mechanisms underlying orthostatic stress responses and evaluates its significance for exercise science and sports practice. Into this matter, active orthostatic testing (e.g., active standing up) challenges the cardiovascular autonomic function in a different way than a passive tilt test. It is well documented that there is a transient reduction in blood pressure while standing up, leading to a reflex increase in HR and peripheral vasoconstriction. After that acute response systolic and diastolic blood pressures are usually slightly increased compared to supine lying body position. The ANS response to standing is initiated by instantaneous cardiac vagal withdrawal, followed by sympathetic activation and vagal reactivation over the first 25-30 heartbeats. Thus, HR increases immediately upon standing, peaking after 15-20 beats, and is less marked during passive tilting due to the lack of muscular activity. Standing also decreases vagally related HRV indices compared to the supine position. In overtrained endurance athletes, both parasympathetic and sympathetic activity are attenuated in supine and standing positions. Their response to standing is lower than in non-overtrained athletes, with a tendency for further decreased HRV as a sign of pronounced vagal withdrawal and, in some cases, decreased sympathetic excitability, indicating a potential overtraining state. However, as a significant main characteristic, it could be noted that additional pathophysiological conditions consist in a reduced responsiveness or counter-regulation of neural drive in ANS according to an excitatory stimulus, such as an orthostatic challenge. Hence, especially active orthostatic testing could provide additional information about HR(V) reactivity and recovery giving valuable insights into athletes' training status, fatigue levels, and adaptability to workload. Measuring while standing might also counteract the issue of parasympathetic saturation as a common phenomenon especially in well-trained endurance athletes. Data interpretation should be made within intra-individual data history in trend analysis accounting for inter-individual variations in acute responses during testing due to life and physical training stressors. Therefore, additional measures (e.g., psychometrical scales) are required to provide context for HR and HRV analysis interpretation. However, incidence of orthostatic intolerance should be evaluated on an individual level and must be taken into account when considering to implement orthostatic testing in specific subpopulations. Recommendations for standardized testing procedures and interpretation guidelines are developed with the overall aim of enhancing training and recovery strategies. Despite promising study findings in the above-mentioned applied fields, further research, thorough method comparison studies, and systematic reviews are needed to assess the overall perspective of orthostatic testing for training monitoring and fine-tuning of different populations in exercise science and training.

Addressing the Ethnicity Gap in Catechol O-Methyl Transferase Inhibitor Trials in Parkinson's Disease: A Review of Available Global Data.

Catechol-O-methyltransferase inhibitors (COMT-Is) have significantly improved the quality of life and symptom management for those at advanced stages of Parkinson's Disease (PD). Given that PD is one of the fastest-growing neurodegenerative diseases worldwide, there is a need to establish a clear framework for the systematic distribution of COMT-Is, considering inter-individual and intra-individual variations in patient response. One major barrier to this is the underrepresentation of ethnic minority participants in clinical trials investigating COMT-Is. To investigate this, we performed a narrative review. We searched PubMed for clinical trials investigating COMT-Is in patients with PD and examined the ethnic diversity of cohorts. A total of 63 articles were identified, with 34 trials found to match our inclusion criteria. Among the 34 trials meeting our inclusion criteria, only 8 reported participants' ethnic backgrounds. Our findings reveal a consistent underrepresentation of ethnic minority groups in trials investigating COMT-Is in PD cohorts-a trend that reflects broader concerns across clinical research. In this review, we explore potential reasons for the underrepresentation of ethnic minorities in clinical trials and propose strategies to address this issue.

Advancements in the use of nanopharmaceuticals for cancer treatment.

Advances in nanotechnology make it possible to specifically target therapies to cancer cells and neoplasms, guide the surgical resection of tumors, and optimize the effectiveness of radiological treatments. This research article provides a concise synthesis of current knowledge in the field of galenic pharmacy focused on targeted drug delivery in oncology. This research article synthesizes current knowledge in galenic pharmacy, focusing on targeted drug delivery in oncology and reviewing recent advancements in nanopharmaceuticals for cancer treatment. The data for this review are derived from a comprehensive analysis of the most cited scientific literature (Pubmed). Recent studies, clinical trials, and technological breakthroughs related to nanopharmaceuticals have been rigorously examined. This diverse source ensures a comprehensive representation of the latest developments in the field. The results highlight the emergence of nanopharmaceuticals as a promising approach to cancer treatment. The most common in oncology remain liposomes, nanopolymers, and nanocrystals. From a galenic point of view, these three forms offer a wide range of improvements compared to conventional forms such as improvement in solubility as well as stability. The same observation is in the clinic where treatment response rates are significantly improved. The most advantageous form will depend on the specific characteristics of each patient and each type of cancer. The precise design of nanocarriers allows for targeted drug delivery, enhancing therapeutic efficacy while reducing side effects. Concrete examples of clinical applications are presented, illustrating the practical potential of these advancements. In conclusion, this review provides a holistic overview of recent developments in galenic pharmacy for targeted drug delivery in oncology. The stability of nanocarriers is a crucial challenge because it conditions the effectiveness and safety of the drugs transported. Environmental and biological variations encountered in the body can compromise this stability, jeopardizing the therapeutic effectiveness and safety of treatments. Likewise, personalized approaches are essential to address interindividual variations in treatment response, as well as patients' pharmacogenomic profiles, in order to optimize therapeutic effectiveness and minimize adverse effects.

Cells and Molecules Underpinning Cannabis-Related Variations in Cortical Thickness during Adolescence.

During adolescence, cannabis experimentation is common, and its association with interindividual variations in brain maturation well studied. Cellular and molecular underpinnings of these system-level relationships are, however, unclear. We thus conducted a three-step study. First, we exposed adolescent male mice to Δ-9-tetrahydrocannabinol (THC) or a synthetic cannabinoid WIN 55,212-2 (WIN) and assessed differentially expressed genes (DEGs), spine numbers, and dendritic complexity in their frontal cortex. Second, in human (male) adolescents, we examined group differences in cortical thickness in 34 brain regions, using magnetic resonance imaging, between those who experimented with cannabis before age 16 (n = 140) and those who did not (n = 327). Finally, we correlated spatially these group differences with gene expression of human homologs of mouse-identified DEGs. The spatial expression of 13 THC-related human homologs of DEGs correlated with cannabis-related variations in cortical thickness, and virtual histology revealed coexpression patterns of these 13 genes with cell-specific markers of astrocytes, microglia, and a type of pyramidal cells enriched in dendrite-regulating genes. Similarly, the spatial expression of 18 WIN-related human homologs of DEGs correlated with group differences in cortical thickness and showed coexpression patterns with the same three cell types. Gene ontology analysis indicated that 37 THC-related human homologs are enriched in neuron projection development, while 33 WIN-related homologs are enriched in processes associated with learning and memory. In mice, we observed spine loss and lower dendritic complexity in pyramidal cells of THC-exposed animals (vs controls). Experimentation with cannabis during adolescence may influence cortical thickness by impacting glutamatergic synapses and dendritic arborization.