Interindividual Variability In Response Research Articles

Precision pharmacotherapy of atomoxetine in children with ADHD: how to ensure the right dose for the right person?

Non-stimulant atomoxetine is recognized in various current clinical guidelines as an important alternative to stimulants for the pharmacological treatment of attention deficit/hyperactivity disorder (ADHD) in children. While its efficacy and tolerability for core symptoms are established, there is considerable inter-individual variability in response and exposure, highlighting the need for personalized dosing. In this review, we evaluated existing studies and summarized comprehensive evidence supporting the clinical implementation of therapeutic drug monitoring (TDM) and personalized dosing of atomoxetine, organized around a series of logically structured questions. Although there are notable gaps in achieving personalized dosing across multiple critical elements, the available evidence is helpful to endorse personalized dose adjustments based on TDM and CYP2D6 genotyping “whenever possible.” We advocate for ongoing improvement and enhancement in clinical practice. Future advancements will rely on a deeper understanding of ADHD, facilitating more precise diagnoses and personalized treatment strategies.

Pharmacogenomics of CRP response to statins: a GIST consortium study

Abstract Introduction Statins are first line treatments in the primary and secondary prevention of cardiovascular disease. Prior clinical studies have shown that statins act independently of lipid lowering mechanisms to decrease C-reactive protein (CRP), a marker of inflammation. Purpose To elucidate genetic loci associated with CRP response to statins. Methods CRP response was specified as the change from baseline in log CRP after at least 4 weeks of statin therapy. Cohort level Genome-wide Association Studies (GWAS) of this CRP response was performed by linear regression analysis adjusted for baseline CRP, age, sex and BMI covariates using genetic data imputed to 1000 Genomes, testing ~10 million single nucleotide polymorphisms (SNPs) of minor allele frequency (MAF) >2%. Following quality control with EasyQC, a meta-analysis was conducted with METAL to combine GWAS results from six different cohorts of European ancestry (CARDS, FHS, JUPITER, MESA, PARC, PROSPER) within the GIST consortium. 1Mb loci regions were defined, centred +/-500kb around the lead SNP. Conditional analysis was performed using GCTA. Results There were 11,075 statin-treated individuals. The meta-analysis results revealed two loci achieving genome wide significance (P<5e-8): APOE (chr 19) and HNF1A (chr 12) (Figure 1). A signal at the CRP locus was highly suggestive (P=2.3e-7). All three loci are known to be associated with CRP levels in the absence of statin. Conditional analysis did not reveal secondary signals. The most associated variant at the APOE locus was the missense SNP rs429358, which contributes to the APOE E4 haplotype and is a risk locus for both dyslipidaemia and Alzheimer’s dementia. It is a C>T missense variant of MAF 0.12 leading to a R/C amino acid change, more common in African ancestry populations (MAF 0.27), and least common in Asian populations (MAF 0.09). A nominally significant association (P=0.09) for interaction with randomized allocation to statin v. placebo within samples derived from clinical trials supports this pharmacogenetic effect at APOE beyond genetic effects on baseline CRP levels. The most associated variant at the HNF1A locus was the intronic SNP rs11065384, which is in strong LD with the HNF1A missense SNP (rs1169288). The HNF1A locus is associated with diabetes, cholesterol levels, and coronary artery disease. There was no between-study heterogeneity at the top three loci (P>0.1), and forest plots show contribution to these signals from all 6 studies within the meta-analysis (Figure 2 A,B,C). Conclusions APOE and HNF1A are associated with CRP response to statins at the level of genome-wide significance. TheAPOE E4 signal is also known to be associated with LDL-Cholesterol response to statins, whereas the HNF1A locus is identified here for the first time as a pharmacogenetic determinant of statin response. The effect of this interindividual variability in CRP response on non-cardiovascular clinical outcomes should be elucidated.Figure 1Figure 2 A,B,C

Rapid modulation in music supports attention in listeners with attentional difficulties

Background music is widely used to sustain attention, but little is known about what musical properties aid attention. This may be due to inter-individual variability in neural responses to music. Here we find that music with amplitude modulations added at specific rates can sustain attention differentially for those with varying levels of attentional difficulty. We first tested the hypothesis that music with strong amplitude modulation would improve sustained attention, and found it did so when it occurred early in the experiment. Rapid modulations in music elicited greater activity in attentional networks in fMRI, as well as greater stimulus-brain coupling in EEG. Finally, to test the idea that specific modulation properties would differentially affect listeners based on their level of attentional difficulty, we parametrically manipulated the depth and rate of amplitude modulations inserted in otherwise-identical music, and found that beta-range modulations helped more than other modulation ranges for participants with more ADHD symptoms. Results suggest the possibility of an oscillation-based neural mechanism for targeted music to support improved cognitive performance.

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

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

6527 Genetic variants may influence the glycemic response to sodium-glucose cotransporter-2 inhibitors in the Mass General Brigham Biobank

Abstract Disclosure: J.H. Li: None. A. Barry: None. A. Huerta-Chagoya: None. L. Szczerbinski: None. J.M. Mercader: None. J.C. Florez: Consulting Fee; Self; AstraZeneca. Grant Recipient; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Merck. A. Leong: None. Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are increasingly prescribed for the treatment of type 2 diabetes, but there is interindividual variability in glycemic response. We investigated whether two genetic variants, rs33954001, a missense variant (p.His615Gln) in SLC5A1 encoding SGLT1, and rs8050500 near SLC5A2 encoding SGLT2, previously associated with glycemic traits in genome-wide association studies, had any influence on short-term glycated hemoglobin (HbA1c) lowering in patients on SGLT2i treatment. Methods: We identified 1,961 ancestrally diverse, genotyped individuals with documented exposure to a SGLT2i in the Mass General Brigham Biobank, a hospital-based biobank linked with patient medical records. Of these, 736 individuals had a baseline HbA1c ≥ 6% within 6 months of the index appearance of an SGLT2i and a follow-up HbA1c measured 6-12 months after. Genotyping was performed on the Illumina Multi-Ethnic Genotyping Array and the Illumina Global Screening Array. Variants were imputed with the TOPMed reference panel. Using linear regression models, we evaluated the additive effect of the genetic variants on HbA1c reduction, defined as baseline HbA1c minus follow-up HbA1c, adjusted for age, sex, 10 genetic ancestry principal components to account for population stratification, the number of concomitant glucose-lowering drug classes, and three covariates accounting for potential genotyping batch effects. To determine whether genetic effects varied by pretreatment glycemic control, we tested for a genotype × baseline HbA1c interaction and performed stratified analysis by baseline HbA1c (≥ 8% vs. < 8%). Results: The mean age of participants was 63.7 years and 41% were female. The baseline HbA1c was 8.0 ± 1.9%. The mean HbA1c reduction was 0.6% over a mean follow-up time of 8.7 ± 1.6 months. None of the variants were associated with HbA1c reduction (p > 0.05) in the whole dataset. However, in stratified analyses, among those with baseline HbA1c ≥ 8% (n = 382), we observed that carriers of the G allele at rs33954001 had a 0.5% greater HbA1c reduction (p = 0.048) compared to those with CC genotype. Further adjustment for baseline renal function did not modify results. In the Genotype-Tissue Expression (GTEx) portal, the G allele was associated with higher SLC5A1 expression in nerve (p = 1 × 10-8), esophageal mucosa (p = 4 × 10-5) and stomach (p = 9 × 10-5), but not kidney. In the Translational human pancreatic Islet Genotype tissue-Expression Resource (TIGER), the G allele was associated with SLC5A1 expression in pancreatic islets (p = 2 × 10-6). Conclusion: Genetic variation in SLC5A1 may partly explain heterogeneity in SGLT2i treatment effects among people with sub-optimally controlled diabetes, possibly due to differences in SLC5A1 tissue-specific expression. These findings require validation in large hospital-based biobanks or dedicated clinical trials. Presentation: 6/2/2024

Drivers of Wolf Activity in a Human-Dominated Landscape and Its Individual Variability Toward Anthropogenic Disturbance.

Wolves (Canis lupus) exhibit contrasted activity patterns along their distribution range. The shift from diurnal to nocturnal habits within and among populations appears to be primarily driven by localized levels of human activity, with ambivalent responses toward such disturbance reported among populations. Yet, the drivers and the underlying individual variability of temporal avoidance patterns toward human remains unexplored. We equipped 26 wolves with GPS-GSM collars, obtaining 54,721 locations. We used step lengths, turning angles, and accelerometer data from recorded locations to infer activity through hidden Markov models (Conners, M. G., T. Michelot, E. I. Heywood, et al. 2021. "Hidden Markov Models Identify Major Movement Modes in Accelerometer and Magnetometer Data From Four Albatross Species." Movement Ecology 9, no. 1: 1-16.). We further explored the probability of activity as a function of a set of proxies of anthropogenic disturbance at different spatial scales and its interaction with different periods of the day by fitting population-level and individual-based hidden Markov models. Wolves were predominantly active during dusk and night, yet variations in activity emerged among individuals across day periods. We did not find clear population-level effects of anthropogenic disturbance predictors, as these were masked by a wide range of individual-specific responses, which varied from positive to negative, with inter-individual variability in responses changing according to different predictors and periods of the day. Our results suggest a non-uniform strategy of wolves in adapting their behavior to human-dominated environments, further underscoring the role of vegetation patches acting as functional refuge cover for buffering the effects of anthropogenic disturbance and boosting the persistence of the species in human-dominated landscapes. This study, for the first time, reveals the individual variability in wolf responses to human disturbance. By fitting hidden Markov models to data from GPS-GSM collars deployed on 26 wolves, we found significant variation between individuals in their responses to different levels of anthropogenic pressure and across different times of day, highlighting a non-uniform strategy for coping with perturbations in human-dominated landscapes. Our findings underscore the diverse behavioral adjustments employed by wolves to persist in these environments and highlight the critical importance of vegetation patches serving as refuge cover.

Preserved Spontaneous Mentalizing amid Reduced Intersubject Variability in Autism during a Movie Narrative

While individuals with autism often face challenges in everyday social interactions, they may demonstrate proficiency in structured Theory of Mind (ToM) tasks that assess their ability to infer others' mental states. Using functional MRI and pupillometry, we investigated whether these discrepancies stem from diminished spontaneous mentalizing or broader difficulties in unstructured contexts. Fifty-two adults diagnosed with autism and 52 neurotypical controls viewed 'Partly Cloudy', a nonverbal animated film with a dynamic social narrative known to engage the ToM brain network during specific scenes. Analysis focused on comparing brain and pupil responses to these ToM events. Additionally, dynamic intersubject correlations explored the variability of these responses throughout the film. Both groups showed similar brain and pupil responses to ToM events and provided comparable descriptions of the characters' mental states. However, participants with autism exhibited significantly stronger correlations in their responses across the film's social narrative, indicating reduced inter-individual variability. This distinct pattern emerged well before any ToM events and involved brain regions beyond the ToM network. Our findings provide functional evidence of spontaneous mentalizing in autism, demonstrating this capacity in a context affording but not requiring mentalizing. Rather than responses to ToM events, a novel neurocognitive signature - inter-individual variability in brain and pupil responses to evolving social narratives - differentiated neurotypical individuals from those with autism. These results suggest that idiosyncratic narrative processing in unstructured settings, a common element of everyday social interactions, may offer a more sensitive scenario for understanding the autistic mind.

The repeatability of a cycling exercise-heat stress test in a male population

IntroductionThere is considerable inter-individual variability in the physiological responses to environmental stressors and so to accurately assess and monitor changes in an individual's ability to cope with exercise-heat stress, a reliable protocol is required. The aim of this study was to examine the repeatability of a 90-min steady-state heat exercise bout with physiological and subjective variables, and performance during an incremental test to exhaustion post 90-min steady-state exercise. MethodSixteen mixed ability males (Age: 39 ± 15yrs; Height: 176.5 ± 4.8 cm; BM: 79.7 ± 10.3 kg; V˙O2peak: 46.2 ± 8.6 ml/kg/min; PPO: 309 ± 39W) who trained at least three times a week undertook two 90-min steady-state – followed by an incremental protocol to exhaustion – cycling heat stress tests (HSTs) in a hot-humid environment (35 °C, 60%RH). Heart rate (HR), rectal (T‾re) and skin temperature (T‾sk), rating of perceived exertion (RPE), thermal sensation (TS), and thermal comfort (TC) were measured throughout. Data was analysed using Intraclass Correlation Coefficients (ICC), technical error of measurement (TEM), Bland-Altman plots, t-tests, and Cohen's d to indicate magnitude of change. ResultsPhysiological variables indicated good repeatability evident through moderate to strong ICC ratings, low magnitudes of change (d), lower mean biases compared to their respective calculated TEMs, and statistical non-significance, except HR90, ₸sk90, and ₸sk. Hydration status showed good repeatability except for urine osmolality (osmu90) and resting urine colour (colu). Perceptual variables showed encouraging repeatability apart from resting TS and mean TS. Performance data showed good repeatability overall, however 11 participants progressed to the incremental test to exhaustion in the second visit compared to 7 in the first. ConclusionCurrent data demonstrated favourable physiological, perceptual, and performance repeatability during repeated cycling HSTs in hot-humid conditions. However, given more participants progressed to the incremental trial to exhaustion protocol in the second visit, at least one familiarisation trial may improve the reliability of exercise capacity assessment.

Hematological and performance adaptations to altitude training (2,320m) in elite middle-distance and distance swimmers.

Elite swimmers often schedule altitude training camps ahead of major events in an attempt to maximize performance. However, the relationships between altitude-induced hematological changes, markers of training adaptation, and performance changes in such context are unclear. This study assessed hematological status, markers of daily adaptation, and swimming performance in elite middle-distance and distance swimmers during a 22-day altitude training camp at 2,320m, 2weeks prior to World Championship qualification competition. Venous blood was obtained and total hemoglobin mass (tHbmass) measured (CO rebreathing) in 7 elite swimmers (4 females, 3 males) 8days before and on day 22 of the altitude camp. Resting heart rate, peripheral oxygen saturation, urinary specific gravity, body mass, fatigue and self-reported sleep duration and quality were monitored daily during the altitude camp. Swimming performance was assessed through a standardized set (6 sets of 4 maximal repetitions of 100m front crawl) on days 3, 10 and 17 of the camp, and at sea level competitions (200m-1,500m) immediately after the camp, and 2weeks later. tHbmass (+5.6 ± 3.3%; range: 2.1%-11.0%; p < 0.05), red blood cell count, hemoglobin concentration, hematocrit increased at the end of the training camp (p < 0.05). Performance at altitude improved throughout the camp (+1.4 ± 0.4%; range: 0.7%-2.5%; p < 0.05). No significant relationship was noted between hematological changes, the change in altitude performance and any of the monitored daily markers of adaptation during the camp. Compared to the swimmers' previous personal best, competition performances did not improve immediately (2.5% ± 1.9% slower times) and 2weeks after altitude (1.2% ± 1.4% slower times). The 22-day altitude training camp at 2,320m was beneficial for elite swimmers' tHbmass, hematological status and performance at altitude, but these benefits did not clearly translate into enhanced sea level performance immediately after or 2weeks later. The present study confirms the large inter-individual variability in hematological responses to altitude training, and that the improvement in performance at altitude and sea level may depend on factors other than the increase in tHbmass alone.

Characterizing PFAS hazards and risks: a human population-based in vitro cardiotoxicity assessment strategy

Per- and poly-fluoroalkyl substances (PFAS) are emerging contaminants of concern because of their wide use, persistence, and potential to be hazardous to both humans and the environment. Several PFAS have been designated as substances of concern; however, most PFAS in commerce lack toxicology and exposure data to evaluate their potential hazards and risks. Cardiotoxicity has been identified as a likely human health concern, and cell-based assays are the most sensible approach for screening and prioritization of PFAS. Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes are a widely used method to test for cardiotoxicity, and recent studies showed that many PFAS affect these cells. Because iPSC-derived cardiomyocytes are available from different donors, they also can be used to quantify human variability in responses to PFAS. The primary objective of this study was to characterize potential human cardiotoxic hazard, risk, and inter-individual variability in responses to PFAS. A total of 56 PFAS from different subclasses were tested in concentration-response using human iPSC-derived cardiomyocytes from 16 donors without known heart disease. Kinetic calcium flux and high-content imaging were used to evaluate biologically-relevant phenotypes such as beat frequency, repolarization, and cytotoxicity. Of the tested PFAS, 46 showed concentration-response effects in at least one phenotype and donor; however, a wide range of sensitivities were observed across donors. Inter-individual variability in the effects could be quantified for 19 PFAS, and risk characterization could be performed for 20 PFAS based on available exposure information. For most tested PFAS, toxicodynamic variability was within a factor of 10 and the margins of exposure were above 100. This study identified PFAS that may pose cardiotoxicity risk and have high inter-individual variability. It also demonstrated the feasibility of using a population-based human in vitro method to quantify population variability and identify cardiotoxicity risks of emerging contaminants.

Prevalence of actionable pharmacogenetic variants and high-risk drug prescriptions: A Swiss hospital-based cohort study.

Drug type and dosing recommendation have been designed and optimized based on average response in the general population. Yet, there is significant inter-individual variability in drug response, which results in treatment inefficacy or adverse drug reactions in a subset of patients. This is partly due to genetic factors that typically affect drug metabolism or clearance. To verify the relevance and applicability of international pharmacogenetic guidelines in the Swiss population, we genotyped 1533 patients from a hospital-based biobank who received at least 30 different drugs, as documented in their electronic health record. We then assessed the prevalence of clinically actionable variants in 13 high-risk pharmacogenes. We compared the allele frequencies obtained in the hospital-based cohort with those of a Swiss population-based cohort of 4791 individuals. The prevalence of clinically actionable variants was comparable between the two cohorts, with most study participants (97.3%) carrying at least one actionable pharmacogenetic variant. We then assessed the frequency of high-risk prescriptions due to actionable gene-drug interactions and observed that 31% of patients in the hospital-based cohort were prescribed at least one drug for which they carried a high-risk variant, and for which international guidelines recommend a change of drug or dosage. Our analysis confirms the high prevalence of actionable pharmacogenetic variants in the Swiss population. It also shows that a substantial minority of patients are exposed to drugs for which they carry potentially problematic variants. Implementing a genetically informed approach to drug prescribing could have a positive impact on the quality of healthcare delivery.

Surgicogenomics: The Role of Genetics in Deep Brain Stimulation in Parkinson's Disease Patients.

Parkinson's disease (PD) is the second-most common neurodegenerative disease, affecting 1% of people aged over 60. Currently, there is only symptomatic relief for PD patients, with levodopa being the gold standard of PD treatment. Deep brain stimulation (DBS) is a surgical option to treat PD patients. DBS improves motor functions and may also allow a significant reduction in dopaminergic medication. Important parameters for DBS outcomes are the disease duration, the age of disease onset, responsiveness to levodopa and cognitive or psychiatric comorbidities. Emerging data also highlight the need to carefully consider the genetic background in the preoperative assessment of PD patients who are candidates for DBS, as genetic factors may affect the effectiveness of DBS in these patients. This review article discusses the role of genetics in DBS for PD patients, in an attempt to better understand inter-individual variability in DBS response, control of motor PD symptoms and appearance of non-motor symptoms, especially cognitive decline.

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

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

Variation of LDL cholesterol in response to the replacement of saturated with unsaturated fatty acids: a nonrandomized, sequential dietary intervention; the Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention (“RISSCI”-1) study

BackgroundSerum low density lipoprotein (LDL) cholesterol shows marked interindividual variation in response to the replacement of saturated fatty acids (SFAs) with unsaturated fatty acids (UFAs). ObjectivesTo demonstrate the efficacy of United Kingdom guidelines for exchanging dietary SFAs for UFAs, to reduce serum LDL cholesterol and other cardiovascular disease (CVD) risk factors, and to identify determinants of the variability in LDL cholesterol response. MethodsHealthy males (n = 109, mean ± SD age 48 ± 11 y; BMI 25.1 ± 3.3 kg/m2), consumed a higher-SFA/lower-UFA diet for 4 wk, followed by an isoenergetic, lower-SFA/higher-UFA diet for 4 wk (achieved intakes SFA:UFA as % total energy 19.1:14.8 and 8.9:24.5, respectively). Serum LDL cholesterol, CVD risk markers, peripheral blood mononuclear cell (PBMC) gene expression, and dietary intakes were assessed at baseline and the end of each diet. ResultsTransition from a higher-SFA/lower-UFA to a lower-SFA/higher-UFA diet significantly reduced fasting blood lipids: LDL cholesterol (−0.50 mmol/L; 95% confidence interval [CI]: −0.58, −0.42), high-density lipoprotein (HDL) cholesterol (−0.11 mmol/L; 95% CI: −0.14, −0.08), and total cholesterol (TC) (−0.65 mmol/L; 95% CI:−0.75, −0.55). The dietary exchange also reduced apolipoprotein (apo)B, TC:HDL cholesterol ratio, non-HDL cholesterol, E-selectin (P < 0.0001), and LDL subfraction composition (cholesterol [LDL-I and LDL-II], apoB100 [LDL-I and LDL-II], and TAG [LDL-II]) (P < 0.01). There was also an increase in plasma biomarkers of cholesterol intestinal absorption (β-sitosterol, campesterol, cholestanol), and synthesis (desmosterol) (P < 0.0001) and fold change in PBMC LDL-receptor mRNA expression relative to the higher-SFA/lower-UFA diet (P = 0.035). Marked interindividual variation in the change in serum LDL cholesterol response (−1.39 to +0.77 mmol/L) to this dietary exchange was observed, with 33.7% of this variation explained by serum LDL cholesterol before the lower-SFA/higher-UFA diet and reduction in dietary SFA intake (adjusted R2 27% and 6.7%, respectively). APOE genotype was unrelated to serum LDL cholesterol response to SFA. ConclusionsThese findings support the efficacy of United Kingdom SFA dietary guidelines for the overall lowering of serum LDL cholesterol but showed marked variation in LDL cholesterol response. Further identification of the determinants of this variation will facilitate targeting and increasing the efficacy of these guidelines.The RISSCI-1 study was registered with ClinicalTrials.Gov (No. NCT03270527).

Pharmacogenomic Polygenic Model of Clopidogrel Predicts Recurrent Ischemic Events in Chinese Patients With Coronary Artery Disease

Patients with coronary artery disease (CAD) need to take antiplatelet drugs regularly in order to prevent thrombosis; however, there is existing inter-individual variability in drug response. Pharmacogenomic studies indicate that drug response may also be influenced by genetic variants, and multiple genetic variants may work together. We assumed that patients carrying more risk alleles might have a worse clopidogrel drug response and that a polygenic model integrated different single variants might have the potential to explain clopidogrel drug response variability better. We aimed to investigate whether the polygenic model could be used to predict clopidogrel drug response. A total of 935 CAD patients were enrolled in the study. We investigated the association between 19 clopidogrel-related single-nucleotide polymorphisms (SNPs) and the incidence of recurrent ischemic events. Additionally, a polygenic model was constructed to assess the risk of ischemic events. There were only 2 SNPs of CYP2C8 gene (rs1934980 and rs17110453) that were nominally associated with incidence of recurrent ischemic events. We constructed a polygenic model integrated with 6 clopidogrel-related SNPs. When compared with patients carrying 6 or fewer risk alleles, patients with 7 or more risk alleles had a higher risk of ischemic events (hazard ratio = 1.87; P = 0.04). The polygenetic model may be useful for clopidogrel drug response prediction in patients with CAD.

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

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

Trajectories of improvement with repetitive transcranial magnetic stimulation for treatment-resistant major depression in the BRIGhTMIND trial

Repetitive transcranial magnetic stimulation (rTMS) is an established non-invasive brain stimulation treatment for major depressive disorder, but there is marked inter-individual variability in response. Using latent class growth analysis with session-by-session patient global impression ratings from the recently completed BRIGhTMIND trial, we identified five distinct classes of improvement trajectory during a 20-session treatment course. This included a substantial class of patients noticing delayed onset of improvement. Contrary to prior expectations, members of a class characterised by early and continued improvement showed greatest inter-session variability in stimulated location. By relating target locations and inter-session variability to a well-studied atlas, we estimated an average of 3.0 brain networks were stimulated across the treatment course in this group, compared to 1.1 in a group that reported symptom worsening (p < 0.001, d = 0.893). If confirmed, this would suggest that deliberate targeting of multiple brain networks could be beneficial to rTMS outcomes.

Exploring the contribution of inter-individual factors to the development of physiological heat strain in older adults exposed to simulated indoor overheating.

Older adults are at elevated risk of heat-related mortality due to age-associated declines in thermoregulatory and cardiovascular function. However, the inter-individual factors that exacerbate physiological heat strain during heat exposure remain unclear, making it challenging to identify more heat-vulnerable subgroups. We therefore explored factors contributing to inter-individual variability in physiological responses of older adults exposed to simulated hot weather. Thirty-seven older adults (61-80 years, 16 females) rested for 8 h in 31 and 36 °C (45% relative humidity). Core (rectal) temperature, heart rate (HR), HR variability, mean arterial pressure (MAP), and cardiac autonomic responses to standing were measured at baseline and end-exposure. Bootstrapped least absolute shrinkage and selection operator regression was used to evaluate whether variation in these responses was related to type 2 diabetes (T2D, n=10), hypertension (n=18), age, sex, body morphology, habitual physical activity levels, and/or heat-acclimatization. T2D was identified as a predictor of end-exposure HR (with vs. without: 13 beats/min (bootstrap 95% confidence interval: 6, 23)), seated MAP (-7mmHg (-18, 1)), and the systolic pressure response to standing (20mmHg (4, 36)). HR was also influenced by sex (female vs. male: 8 beats/min (1, 16)). No other predictors were identified. The inter-individual factors explored did not meaningfully contribute to the variation in body temperature responses in older adults exposed to simulated indoor overheating. By contrast, cardiovascular responses were exacerbated in females and individuals with T2D. These findings improve understanding of how inter-individual differences contribute to heat-induced physiological strain in older persons.

Optimal Prescription for Superior Outcomes: A Comparative Analysis of Inter-Individual Variability in Adaptations to Small-Sided Games and Short Sprint Interval Training in Young Basketball Players.

This study compared the inter-individual variability in adaptive responses to six weeks of small-sided games (SSG) and short sprint interval training (sSIT) in young basketball players. Thirty well-trained young athletes (age: 16.4 ± 0.6 years; stature: 190 ± 8.4 cm; weight: 84.1 ± 8.2 kg) voluntarily participated and were randomly assigned to SSG (3 sets of 5 min 3v3 on full length (28 m) and half-width (7.5 m) court, with 2 minutes of passive recovery in-between), sSIT (3 sets of 12 × 5 s sprinting with 20 s recovery between efforts and 2 min of rest between sets), or CON (routine basketball-specific technical and tactical drills) groups, each of ten. Before and after the training period, participants underwent a series of laboratory- and field-based measurements to evaluate their maximum oxygen uptake (V̇O2max), first and second ventilatory threshold (VT1 and VT2), oxygen pulse, peak and average power output (PPO and APO), linear speed, change of direction (COD), countermovement jump (CMJ), and vertical jump (VJ). Both SSG and sSIT sufficiently stimulated adaptive mechanisms involved in enhancement of the mentioned variables (p < 0.05). However, sSIT resulted in lower residuals in percent changes in V̇O2max (p = 0.02), O2pulse (p = 0.005), VT1 (p = 0.001), PPO (p = 0.03), and linear speed (p = 0.01) across athletes compared to the SSG. Moreover, sSIT resulted in more responders than SSG in V̇O2max (p = 0.02, φ = 0.500), O2pulse (p = 0.003, φ = 0.655), VT1 (p = 0.003, φ = 0.655), VT2 (p = 0.05, φ = 0.436), and linear speed (p = 0.05, φ = 0.420). Our results indicate that sSIT creates a more consistent level of mechanical and physiological stimulus than SSG, potentially leading to more similar adaptations across team members.

Landscape of TPMT and NUDT15 Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients.

Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups. Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations. Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively). These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.