Interindividual Variability In Response Research Articles

Cytochrome P450 2B6 6 distribution among patients living with HIV in Burkina Faso

The function of cytochrome P450 (CYP) enzymes, one of the major catalysts in drug metabolism, is significantly influenced by genetic polymorphisms leading to substantial inter-individual variability in drug response and/ or adverse reactions activity. The aim of this study was to determine the frequency of the CYP2B6 516G>T allele in patients living with HIV receiving treatment at the Medical Center of Camp General Aboubacar Sangoule Lamizana for whom the treatment was changed after the initiation of treatment because of the appearance of side effects. 155 HIV-positive patients were enrolled. Genomic Deoxyribonucleic acid (DNA) extraction from blood was performed using the GenJET® Genomic DNA according to the manufacturer’s instructions. Genotyping for the cytochrome P450 variant alleles was performed using predesigned primers. The amplification was carried out by Polymerase Chain Reaction (PCR), while the differentiation between the alleles was carried out after digestion with restriction enzymes by electrophoresis. The results obtained showed. Among these patients, 61 changed treatments during their follow-up. The majority of the 61 patients, 32 patients, received an initial treatment regimen based on the AZT (3'-Azido-3'-Deoxythymidine)/3TC (Lamivudine)/ NVP(Nevirapine) combination, followed by 18 patients for the TDF (tenofovir)/3TC (lamivudine)/ EFV(Efavirenz) regimens. Currently, the majority of patients, 48 patients, have benefited from a therapeutic regimen based on the TDF (tenofovir)/3TC (lamivudine) /DTG(Dolutegravir) combination, followed by 11 patients for the TDF (tenofovir)/3TC (lamivudine)/EFV(Efavirenz) regimens. The distribution of the major allele CYP2B6*T was 68%, and the minor CYP2B6*G allele was 32%. Heterozygote (GT genotype) and Homozygous mutants (TT genotype) and Heterozygote were 31% and 52,5%. Studies could be continued to set up cytochrome mutation detection kits to anticipate the onset of side effects and adapt treatments.

Response to visual and mechano-acoustic predator cues is robust to ocean warming and acidification and is highly variable in European sea bass

Predator-prey interactions and, especially, the success of anti-predator responses are modulated by the sensory channels of vision, olfaction, audition and mechanosensation. If climate change alters fish sensory ability to avoid predation, community dynamics can be affected. We investigated whether mid-duration exposure to warming and/or acidification alters behavioural response to visual or mechano-acoustic predator cues in juvenile Dicentrarchus labrax. We measured kinematic variables before and after a visual or a mechano-acoustic challenge which mimicked an overflying bird shadow or a bird swoop attack, respectively. Due to large interindividual variability in responses before cue presentation, fish were categorized as slow and fast to account for baseline individual variability. Treatment did not impact kinematic variables as both slow and fast fish of every treatment elicited precautionary and escape responses. Interestingly, even slow fish swam as fast as fast fish after the cue, suggesting that regardless of initial category, fish managed to escape facing a danger. Anti-predator response varied according to the level of threat to survival with greater responses elicited after the swoop attack. Although wild juvenile sea bass aggregate in schools, school dynamics rely on single leaders which highlights the importance of the variability in individual behaviours. We demonstrated that anti-predator response in juvenile D. labrax is robust to mid-duration exposure to independent and combined effects of warming and acidification. If robustness is confirmed over long-duration, it could provide D. labrax with an evolutionary advantage in the future ocean, where cue transmission through changing environments can further modulate cue perception and predator-prey interactions.

At the Head and Heart of Oxytocin’s Stress-Regulatory Neural and Cardiac Effects: A Chronic Administration RCT in Children with Autism

Introduction: Intranasal administration of oxytocin presents a promising new approach to reduce disability associated with an autism spectrum disorder diagnosis. Previous investigations have emphasized the amygdala as the neural foundation for oxytocin’s acute effects. However, to fully understand oxytocin’s therapeutic potential, it is crucial to gain insight into the neuroplastic changes in amygdala circuitry induced from chronic oxytocin administrations, particularly in pediatric populations. Objective: We aimed to examine the impact of a 4-week course of intranasal oxytocin on amygdala functional connectivity in children with autism, compared to placebo. Additionally, we investigated whether oxytocin improves cardiac autonomic arousal, as indexed by high-frequency heart rate variability. Methods: Fifty-seven children with autism aged 8–12 years (45 boys, 12 girls) participated in a double-blind, randomized pharmaco-neuroimaging trial involving twice-daily administrations of intranasal oxytocin or placebo. Resting-state fMRI scans and simultaneous, in-scanner heart rate recordings were obtained before, immediately after, and 4 weeks after the nasal spray administration period. Results: Significant reductions in intrinsic amygdala-orbitofrontal connectivity were observed, particularly at the 4-week follow-up session. These reductions were correlated with improved social symptoms and lower cardiac autonomic arousal. Further, oxytocin’s neural and cardiac autonomic effects were modulated by epigenetic modifications of the oxytocin receptor gene. The effects were more pronounced in children with reduced epigenetic methylation, signifying heightened expression of the oxytocin receptor. Conclusion: These findings underscore that a 4-week oxytocin administration course decreases amygdala connectivity and improves cardiac autonomic balance. Epigenetic modulators may explain inter-individual variation in responses to oxytocin.

Combining pharmacokinetic and electrophysiological models for early prediction of drug-induced arrhythmogenicity

Background and ObjectiveIn silico methods are gaining attention for predicting drug-induced Torsade de Pointes (TdP) in different stages of drug development. However, many computational models tended not to account for inter-individual response variability due to demographic covariates, such as sex, or physiologic covariates, such as renal function, which may be crucial when predicting TdP. This study aims to compare the effects of drugs in male and female populations with normal and impaired renal function using in silico methods. MethodsPharmacokinetic models considering sex and renal function as covariates were implemented from data published in pharmacokinetic studies. Drug effects were simulated using an electrophysiologically calibrated population of cellular models of 300 males and 300 females. The population of models was built by modifying the endocardial action potential model published by O'Hara et al. (2011) according to the experimentally measured gene expression levels of 12 ion channels. ResultsFifteen pharmacokinetic models for CiPA drugs were implemented and validated in this study. Eight pharmacokinetic models included the effect of renal function and four the effect of sex. The mean difference in action potential duration (APD) between male and female populations was 24.9 ms (p<0.05). Our simulations indicated that women with impaired renal function were particularly susceptible to drug-induced arrhythmias, whereas healthy men were less prone to TdP. Differences between patient groups were more pronounced for high TdP-risk drugs. The proposed in silico tool also revealed that individuals with impaired renal function, electrophysiologically simulated with hyperkalemia (extracellular potassium concentration [K+]o = 7 mM) exhibited less pronounced APD prolongation than individuals with normal potassium levels. The pharmacokinetic/electrophysiological framework was used to determine the maximum safe dose of dofetilide in different patient groups. As a proof of concept, 3D simulations were also run for dofetilide obtaining QT prolongation in accordance with previously reported clinical values. ConclusionsThis study presents a novel methodology that combines pharmacokinetic and electrophysiological models to incorporate the effects of sex and renal function into in silico drug simulations and highlights their impact on TdP-risk assessment. Furthermore, it may also help inform maximum dose regimens that ensure TdP-related safety in a specific sub-population of patients.

Introduction to the Theme "Pharmacological Individuality: New Insights and Strategies for Personalized and Precise Drug Treatment".

The reviews in Volume 64 of the Annual Review of Pharmacology and Toxicology cover diverse topics. A common theme in many of the reviews is the interindividual variability in the clinical response to drugs. Highlighted areas include emerging developments in pharmacogenomics that can predict the personal risk for drug inefficacy and/or adverse drug reactions. Other reviews focus on the use of circulating biomarkers to define drug metabolism phenotypes and the effect of circadian regulation on drug response. Another emerging technology, digital twins that model individual patients, is used to generate computational simulations of drug effects and identify optimal personalized treatments. Another variable that may affect clinical outcomes, the nocebo response (an adverse reaction to a placebo), complicates clinical trials. These reviews further document that pharmacological individuality is an essential component of the concepts of personalized medicine and precision medicine and will likely have an important impact on patient care. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Heritability of amygdala reactivity to angry faces and its replicable association with the schizophrenia risk locus of miR-137.

Among healthy participants, the interindividual variability of brain response to facial emotions is associated with genetic variation, including common risk variants for schizophrenia, a heritable brain disorder characterized by anomalies in emotion processing. We aimed to identify genetic variants associated with heritable brain activity during processing of facial emotions among healthy participants and to explore the impact of these identified variants among patients with schizophrenia. We conducted a data-driven stepwise study including samples of healthy twins, unrelated healthy participants and patients with schizophrenia. Participants approached or avoided pictures of faces with negative emotional valence during functional magnetic resonance imaging (fMRI). We investigated 3 samples of healthy participants - including 28 healthy twin pairs, 289 unrelated healthy participants (genome-wide association study [GWAS] discovery sample) and 90 unrelated healthy participants (replication sample) - and 1 sample of 48 patients with schizophrenia. Among healthy twins, we identified the amygdala as the brain region with the highest heritability during processing of angry faces (heritability estimate 0.54, p < 0.001). Subsequent GWAS in both discovery and replication samples of healthy non-twins indicated that amygdala activity was associated with a polymorphism in the miR-137 locus (rs1198575), a micro-RNA strongly involved in risk for schizophrenia. A significant effect in the same direction was found among patients with schizophrenia (p = 0.03). The limited sample size available for GWAS analyses may require further replication of results. Our data-driven approach shows preliminary evidence that amygdala activity, as evaluated with our task, is heritable. Our genetic associations preliminarily suggest a role for miR-137 in brain activity during explicit processing of facial emotions among healthy participants and patients with schizophrenia, pointing to the amygdala as a brain region whose activity is related to miR-137.

Association of ADME gene polymorphisms on toxicity to CDK4/6 inhibitors in patients with HR+ HER2- metastatic breast cancer

A wide interindividual variability in therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) palbociclib, ribociclib and abemaciclib, among patients with HR+/HER2- metastatic breast cancer has been reported. This study explored the impact of genetic polymorphisms in ADME genes (responsible for drug absorption, distribution, metabolism, and elimination) on CDKis safety profiles in 230 patients. Selected endpoints include grade 3/4 neutropenia at day 14 of the first treatment cycle, early dose-limiting toxicities (DLTs), and dose reductions within the initial three cycles. Our analysis revealed associations between these endpoints and polymorphisms in CYP3A4, CYP3A5, ABCB1, and ABCG2 genes. Their impact on CDKis plasma concentrations (Ctrough) was also examined. Specifically, ABCB1 c.1236C>T and c.2677C>T polymorphisms correlated significantly with grade 3/4 neutropenia at day 14 (OR 3.94, 95% CI 1.32–11.75; p = 0.014 and OR 3.32, 95% CI 1.12-9.85; p = 0.030). Additionally, ABCB1 c.3435C>T was associated with an elevated risk of early DLTs and dose reductions (OR 3.28, 95% CI 1.22–8.84, p = 0.019; OR 2.60, 95% CI 1.20–5.60, p = 0.015). Carriers of the CYP3A4*22 allele also demonstrated in univariate a higher risk of early DLTs (OR 3.10, 95% CI 1.01–9.56, p = 0.049). Furthermore, individuals with the ABCB1 1236T–3435T–2677T(A) variant haplotype exhibited significant associations with grade 3/4 neutropenia at day 14 (OR 3.36, 95% CI 1.20–9.41; p = 0.021) and early DLTs in univariate (OR 3.08, 95% CI 1.19–7.95; p = 0.020). Homozygous carriers of the ABCB1 T-T-T(A) haplotype tended to have a higher mean ribociclib Ctrough (934.0 ng/mL vs. 752.0 ng/mL and 668.0 ng/mL). Regardless preliminary, these findings offer promising insights into the role of pharmacogenetic markers in CDKis safety profiles, potentially contributing to address the interindividual variability in CDKis responses.

A comprehensive review of machine learning algorithms and their application in geriatric medicine: present and future.

The increasing access to health data worldwide is driving a resurgence in machine learning research, including data-hungry deep learning algorithms. More computationally efficient algorithms now offer unique opportunities to enhance diagnosis, risk stratification, and individualised approaches to patient management. Such opportunities are particularly relevant for the management of older patients, a group that is characterised by complex multimorbidity patterns and significant interindividual variability in homeostatic capacity, organ function, and response to treatment. Clinical tools that utilise machine learning algorithms to determine the optimal choice of treatment are slowly gaining the necessary approval from governing bodies and being implemented into healthcare, with significant implications for virtually all medical disciplines during the next phase of digital medicine. Beyond obtaining regulatory approval, a crucial element in implementing these tools is the trust and support of the people that use them. In this context, an increased understanding by clinicians of artificial intelligence and machine learning algorithms provides an appreciation of the possible benefits, risks, and uncertainties, and improves the chances for successful adoption. This review provides a broad taxonomy of machine learning algorithms, followed by a more detailed description of each algorithm class, their purpose and capabilities, and examples of their applications, particularly in geriatric medicine. Additional focus is given on the clinical implications and challenges involved in relying on devices with reduced interpretability and the progress made in counteracting the latter via the development of explainable machine learning.

At last, empirical elicitations of the magnitudes of those risks (and costs!) too small to matter and those too large to abide

Scholars, decision-makers, and pundits have long tossed around words and numbers meant to demarcate those health/safety risks that are too small to matter at all (called, variously, “trivial” or “de minimis” or “insignificant”), or risks that are so large as to be abhorrent (“unacceptable,” “intolerable,” and the like). But there has been nothing approaching a consensus about how large or small these important probabilities are, and worse, there have been no serious attempts to explore these concepts via any carefully-elicited preferences from laypeople themselves. Perhaps even more concerning, the dominant paradigm—cost-benefit analysis (CBA)—requires balancing of (monetized) risks against the costs of controlling them, but the parallel concepts of de minimis costs and intolerable costs have never been formally considered. As a result of these lapses, all attempts to consider equity or justice in the distribution of how risks and costs are borne are an absurdity, despite claims to the contrary. This article reports on a pair of elicitations involving 1350 laypeople. In one elicitation, a careful set of background and contextual explanations and a structured series of questions probed where each subject perceived lifetime excess mortality risk (from involuntary exposure) to become “so small you would not spend a moment thinking about it,” and where it becomes so large that “you would strongly object, as an ethical matter, to ever having to face it.” With a separate sample, we asked the parallel questions with regard to regulatory costs imposed by the government in the name of risk reduction. Although there was significant interindividual variation in responses, the central tendency of each of these four science-policy-values “goalposts” was as follows: (1) de minimis risk—a lifetime excess chance of premature death of 1 in 770,000; (2) intolerable risk—1 chance in 570; (3) de minimis cost—$25 per year; and (4) intolerable cost—$775 per year. These results offer, for the first time, a principled and evidence-based starting point for further refinement of which risks or costs to individuals can/should be disregarded in setting policy, and which must dominate policies regardless of how total “monetized lives saved” and total dollar costs compare to each other when viewed simplistically. We offer several prescriptions for how CBA might change, and how environmental/health/safety policy might improve, to take account of these fundamental thresholds in how risks and costs actually impose burdens on citizens. Both those interventions that impose intolerable costs while only reducing diffuse and trivially small risks, and those failures to intervene (sufficiently) that perpetuate intolerable risks for the sake of avoiding trivial and eminently manageable costs, are inefficient, unjust, and are thus unethical.

Inter-individual Variability In Astronaut Strength Response To Long-duration Spaceflight May Be Dictated By In-flight Exercise

Inter-individual Variability In Astronaut Strength Response To Long-duration Spaceflight May Be Dictated By In-flight Exercise

Are there Interindividual Responses of Cardiovascular Disease Risk Markers to Acute Exercise? A Replicated Crossover Study.

Using a replicated crossover design, we quantified the response heterogeneity of postprandial cardiovascular disease (CVD) risk marker responses to acute exercise. Twenty men (mean (SD) age, 26 (6) years; BMI, 23.9 (2.4) kg·m-2) completed four, 2-day conditions (two control, two exercise) in randomised orders. On days 1 and 2, participants rested and consumed two high-fat meals over 9-h. Participants ran for 60-mins (61 (7)% of peak oxygen uptake) on day 1 (6.5-7.5 h) of both exercise conditions. Time-averaged total-area-under-the-curve (TAUC) for triacylglycerol (TAG), glucose and insulin were calculated from 11 venous blood samples on day 2. Arterial stiffness and blood pressure responses were calculated from measurements at baseline on day 1 and at 2.5-h on day 2. Consistency of individual differences was explored by correlating the two replicates of control-adjusted exercise responses for each outcome. Within-participant covariate-adjusted linear mixed models quantified participant-by-condition interactions and individual-response SDs. Acute exercise reduced mean TAUC-TAG (-0.27 mmol·L-1 h; Cohen's d = 0.29, P = 0.017) and TAUC-insulin (-24.45 pmol·L-1 h; Cohen's d = 0.35, P = 0.022) vs. control, but led to negligible changes in TAUC-glucose and the vascular outcomes (Cohen's d ≤ 0.41, P ≥ 0.106). Small-to-moderate, but nonsignificant, correlations were observed between the two response replicates (r = -0.40 to 0.15, P ≥ 0.066). We did not detect any individual response heterogeneity. All participant-by-condition interactions were P ≥ 0.137, and all individual-response SDs were small with wide 95% confidence intervals overlapping zero. Large trial-to-trial within-subject variability inhibited detection of consistent inter-individual variability in postprandial metabolic and vascular responses to acute exercise.

Role of SGLT2 Inhibitors in Diabetes Management: Focus on HbA1c Levels, Weight Loss and Genetic Variation

Sodium Glucose Co-transporters-2 (SGLT2) inhibitors are the recent addition to treatment strategies for Type 2 Diabetes Mellitus (T2DM). It is a non-insulin dependent anti-diabetic therapeutic approach that eliminates plasma glucose by urination. The study was carried out with the aim of evaluating the effect of SGLT2 inhibitors on HbA1c levels and weight loss in responders and non-responders. In addition, the role of two significant variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), affecting the inter-individual variation in response to SGLT2 inhibitors was evaluated in the study population. 200 confirmed T2DM patients on SGLT2 inhibitors were enrolled for the study. Patients with decreased HbA1c levels and body weight were categorized as responders, whereas the ones who did not show a significant decrease in these two parameters after treatment were categorised as non-responders. Association of HbA1c levels and weight loss before as well as after treatment with responders and non-responders was evaluated. Patients were screened for two significant variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), affecting the inter-individual variation in response to SGLT2 inhibitors by Sanger Sequencing. A significant difference in HbA1c levels and weight was found in responders and non-responders before and after the treatment. However, both of the variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), were not found to be significantly associated with the drug response. In conclusion, SGLT2 inhibitors reduced HbA1c levels and weight effectively in responders. However, the targeted gene variants need not to be involved in genetic testing before prescribing this class of drugs to T2DM patients from Malwa region of Punjab. Highlights: Treatment of Type 2 diabetes mellitus (T2DM) with Sodium Glucose co-transporter-2 (SGLT2) inhibitors is an insulin-independent method of reducing blood glucose levels by lowering renal tubular glucose reabsorption. Significant decrease in HbA1c levels and weight loss in responders was observed after the treatment with SGLT2 inhibitors. Pharmacogenetic analysis was carried out for two gene variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), reported to be involved in inter-individual response to SGLT2 inhibitors. None of the tested variants were found to be significantly associated with inter-individual response to SGLT2 inhibitors. Pharmacogenetic testing for the two most commonly reported variants is not required for the T2DM patients on SGLT2 inhibitors from the Malwa region of Punjab.

Association between plasma rituximab concentration and the risk of major relapse in antineutrophil cytoplasmic antibody-associated vasculitides during rituximab maintenance therapy.

Interindividual variability in response to rituximab remains unexplored in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Rituximab pharmacokinetics (PK) and pharmacodynamics (PD) as well as genetic polymorphisms could contribute to variability. This ancillary study of the MAINRITSAN 2 trial aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in PK/PD candidate genes, and clinical outcomes. Patients included in the MAINRITSAN2 trial (NCT01731561) were randomized to receive a 500 mg fixed-schedule RTX infusion or an individually-tailored regimen. Rituximab plasma concentrations at month 3 (CM3 ) were assessed. DNA samples (n=53) were genotyped for single nucleotide polymorphisms within 88 putative PK/PD candidate genes. The relationship between PK/PD outcomes and genetic variants was investigated using logistic linear regression in additive and recessive genetic models. One hundred and thirty-five patients were included. The frequency of underexposed patients (<4 μg/mL) in the fixed-schedule group was statistically lower compared to that in the tailored-infusion group (2.0% vs. 18.0%; p=0.02, respectively). Low RTX plasma concentration at 3 months (CM3 <4 μg/mL) was an independent risk factor for major relapse (odds ratio=6.56; 95% CI 1.26-34.09; p=0.025) at month 28 (M28). A sensitivity survival analysis also identified CM3 <4 μg/mL as an independent risk factor for major relapse (Hazard ratio [HR] = 4.81; 95% CI 1.56-14.82; p=0.006) and relapse (HR=2.70; 95% CI 1.02-7.15; p=0.046). STAT4 rs2278940 and PRKCA rs8076312 were significantly associated with CM3 but not with major relapse onset at M28. These results suggest that drug monitoring could be useful to individualize the schedule of rituximab administration within the maintenance phase. This article is protected by copyright. All rights reserved.

The relationship between the brain-derived neurotrophic factor and neurocognitive response to physical exercise in individuals with schizophrenia

ObjectivePhysical exercise can improve neurocognition in individuals with schizophrenia, presumably by facilitating neuroplasticity. There is, however, large inter-individual variation in response. The brain-derived neurotrophic factor (BDNF) has been proposed to mediate these effects. The current aim was to investigate the sparsely studied relationship between peripheral resting BDNF and neurocognitive response to physical exercise in individuals with schizophrenia. MethodThe current study reports secondary analyses of data from a randomized controlled trial (RCT), ClinicalTrials.gov number 02205684, recently reported according to the CONSORT guidelines. Eighty-two individuals with schizophrenia (mean age 37 ± 14 years old, 61% men) were randomly allocated to high-intensity interval training (HIIT) or a comparison group performing low-intensity active video gaming (AVG). Both interventions consisted of 2 sessions/week for 12 weeks. In previously published primary RCT analyses, HIIT and AVG showed comparable small to moderate improvements in neurocognition. We now address the inter-individual variability in neurocognitive response. We apply mediation and moderation analyses for repeated measures designs (MEMORE) and mixed effects models. ResultsBaseline neurocognition was not significantly correlated with baseline levels of mature BDNF (baseline-mBDNF) or the precursor proBDNF. Nonetheless, baseline-mBDNF, but not baseline proBDNF, moderated the effect of exercise on neurocognition (p = 0.025) and explained 7% of the variance. The neurocognitive improvement increased with increasing baseline-mBDNF values. The moderating effect of baseline-mBDNF remained significant in a more complex model adding the moderating effects of exercise mode, sex, age, duration of illness and baseline VO2max on the outcome (neurocognition). Mean baseline-mBDNF significantly decreased from baseline to post-intervention (p = 0.036), regardless of exercise mode, differing by sex and associated with improved VO2max but not with change in neurocognition. A mediating role of mBDNF on the effect of physical exercise on neurocognition was not supported. Values of proBDNF mainly remained stable from baseline to post-intervention. ConclusionWe found that baseline-mBDNF moderated the effect of physical exercise on neurocognition in individuals with schizophrenia and explained a small part of the inter-individual variation in neurocognitive response. Mean mBDNF decreased from baseline to post-intervention, regardless of exercise mode. A mediating role of mBDNF on the effect of exercise on neurocognition was not supported. The inter-individual variation in neurocognitive response and the complex role of peripheral BDNF in physical exercise is still to be elucidated.

Pharmacometabolomic Approach to Investigate the Response to Metformin in Patients with Type 2 Diabetes: A Cross-Sectional Study.

Metformin constitutes the foundation therapy in type 2 diabetes (T2D). Despite its multiple beneficial effects and widespread use, there is considerable inter-individual variability in response to metformin. Our objective is to identify metabolic signatures associated with poor and good responses to metformin, which may improve our ability to predict outcomes for metformin treatment. In this cross-sectional study, clinical and metabolic data for 119 patients with type 2 diabetes taking metformin were collected from the Qatar Biobank. Patients were empirically dichotomized according to their HbA1C levels into good and poor responders. Differences in the level of metabolites between these two groups were compared using orthogonal partial least square discriminate analysis (OPLS-DA) and linear models. Good responders showed increased levels of sphingomyelins, acylcholines, and glutathione metabolites. On the other hand, poor responders showed increased levels of metabolites resulting from glucose metabolism and gut microbiota metabolites. The results of this study have the potential to increase our knowledge of patient response variability to metformin and carry significant implications for enabling personalized medicine.

Acute Physiological Effects of Drop Set on IGF and GH in the Quadriceps Femoris Among Males in Kakamega County, Kenya

Background: Resistance training (RT) for muscle growth (hypertrophy training – HT) theoretically optimizes the mechanical tension placed on the working muscle, which may be key to activating hypertrophic mechanisms. After prolonged HT, specialized weightlifting techniques like drop set training (DS) – or lifting progressively reduced loads without recovery – may help overcome plateaus in strength and re-stimulate hypertrophy, but physiological evidence to potentially support this hypothesis or the efficacy of implementing an acute drop set protocol in comparison to maintaining a standard hypertrophy training program is lacking. Objective: This objective of this study was to assess the levels of plasma growth hormone, and IGF during drop set and concentric exercises. Methods: The study used a randomized controlled, counterbalanced, repeated measures design. A repeated measures design was used to minimize the inter-individual variability of the hypertrophic response to resistance training. Thirty young males participated in a randomized, counterbalanced, within-subjects design, a DS protocol (4 sets, 4 loads/set, 75-30% 1RM, minimal recovery between loads, 3-minute recovery intervals between sets) and, separated by at least 7 days, a HT protocol (4 sets, 75% 1RM, 3-minute recovery intervals between sets). Data was analyzed using a 2 (Training Type: DS, HT, levels of quadriceps muscle hypertrophy) ´ 2 (Time: pre-exercise, post-exercise) repeated measures ANOVA to test the differences in concentrations of IGF-1 and GH during DS and HT at the specified time points. Results: The study found that there was a significant difference in IGF 1 levels before and after the exercise for both groups (Drop set and concentric exercise), with a p-value of .007. The interaction effect between the within-subjects factor (IGF 1 pre and post) and group was also significant. The results showed that there was a significant difference in GH levels before and after the exercise for both groups (Drop set and concentric exercise), with a p-value of &lt; .001. For the Drop set group, GH pre was also significantly lower than GH post. It can be concluded that both the drop set and concentric exercise techniques have an impact on the levels of IGF 1, and GH in the quadriceps femoris. The study recommends that physical trainers and fitness professionals should consider using the Drop set exercise technique in their training programs for clients who are looking to improve their performance.

Effects of Endurance Exercise and Vitamin D Supplementation on Insulin Resistance and Plasma Lipidome in Middle-Aged Adults with Type 2 Diabetes.

(1) Background: We investigated the effects of a 12-week exercise intervention with or without vitamin D supplementation on insulin resistance and the plasma lipidome of participants with type 2 diabetes. We further explored whether the effects of the intervention on glycemic parameters could be associated with the baseline lipidome. (2) Methods: Sixty-one participants were randomly allocated to control (Con), exercise (EX), vitamin D (VD), and EX + VD groups. Multiple glycemic and anthropometric parameters were evaluated before and after intervention. The homeostasis model assessment of insulin resistance (HOMA-IR) was the primary outcome. The plasma lipidome was analyzed before, after, and at an additional 12-week follow-up. Machine learning was applied to establish prediction models for responsiveness of glycemic control. (3) Results: Our interventions failed to improve the HOMA-IR index while fasting glucose was reduced in the EX + VD group (change%, -11.9%; effect size, 0.65; p < 0.05). Both EX and VD interventions altered the plasma lipidome, with EX + VD intervention considerably affecting levels of lyso-phosphatidylcholines and triglycerols containing long-chain unsaturated fatty acids. Such effects could last until 12 weeks after intervention. Notably, there was high inter-individual variability in glycemic parameters including HOMA-IR in response to the interventions, which could be predicted with great accuracy using an optimal panel of baseline lipid predictors alone or in combination with clinical indices, as assessed by an area under the receiver operating characteristic curve value of over 0.9. (4) Conclusions: Although substantial alterations were observed in the plasma lipidome related to glycemic control, our intervention failed to improve HOMA-IR scores, which may have been predominately due to the large inter-individual variability in responses. Basal plasma lipid levels could potentially predict an individual's response to intervention, highlighting the necessity of personalized nutrition.

Pharmacogenomics and the Concept of Personalized Medicine for the Management of Hypertension

Pharmacogenomics and the Concept of Personalized Medicine for the Management of Hypertension

A pilot exome sequencing study suggests that germline variants influence methotrexate-induced toxicities in pediatric patients with localized osteosarcoma.

Osteosarcoma (OS) is a rare pediatric cancer for which therapeutic approaches, including chemotherapy and surgery, show a wide interindividual variability in patient response, both in terms of adverse events and therapy efficacy. There is growing evidence that this individual variable response to therapies is also influenced by inherited genetic variations. However, the results obtained to date in these pediatric cancers have been contradictory and often lack validation in independent series. Additionally, these studies frequently focused only on a limited number of polymorphisms in candidate genes. In order to identify germline coding variations associated with individual differences in adverse events occurrence in pediatric patients affected by localized OS, we carried out an exome-wide association study in 24 OS patients treated with methotrexate, cisplatin, and doxorubicin, using the SNP-Set (Sequence) Kernel Association Test (SKAT), optimized for small sample size. Gene sets significantly associated (FDR<.05) with neutropenia and hepatotoxicity induced by methotrexate were identified. Some of the identified genes map in loci previously associated with similar phenotypes (e.g., leukocyte count, alkaline phosphatase levels). Further studies in larger series and with functional characterization of the identified associations are needed; nonetheless, this pilot study prompts the relevance of broadly investigating variants along the whole genome, to identify new potential pharmacogenes, beyond drug metabolism, transport, and receptor candidate genes.

Functional MRI responses to naturalistic stimuli are increasingly typical across early childhood

While findings show that throughout development, there are child- and age-specific patterns of brain functioning, there is also evidence for significantly greater inter-individual response variability in young children relative to adults. It is currently unclear whether this increase in functional “typicality” (i.e., inter-individual similarity) is a developmental process that occurs across early childhood, and what changes in BOLD response may be driving changes in typicality. We collected fMRI data from 81 typically developing 4–8-year-old children during passive viewing of age-appropriate television clips and asked whether there is increasing typicality of brain response across this age range. We found that the “increasing typicality” hypothesis was supported across many regions engaged by passive viewing. Post hoc analyses showed that in a priori ROIs related to language and face processing, the strength of the group-average shared component of activity increased with age, with no concomitant decline in residual signal or change in spatial extent or variability. Together, this suggests that increasing inter-individual similarity of functional responses to audiovisual stimuli is an important feature of early childhood functional brain development.