Interindividual Differences In Response Research Articles

Repeatability and reproducibility of changes in thoracoabdominal compartmental volumes and breathing pattern during low-, moderate- and heavy-intensity exercise.

To determine how repeatable thoracoabdominal compartmental contributions to tidal volume (VT) are across different intensities of exercise, and to examine if the pattern of breathing for a given minute ventilation (V̇E) is reproducible between constant-load and ramp exercise tests. Ten healthy adults (age: 27 ± 6yr, peak oxygen uptake: 42 ± 5mLmin-1kg-1) completed a 25W·min-1 ramp cycling test to exhaustion and two repetitions of a step cycling test on separate days. VT, breathing rate (BR), and V̇E were assessed using a bi-directional turbine, and thoracic and abdominal contributions to VT were measured using respiratory inductance plethysmography. Repeatability (step vs. step) and reproducibility (step vs. ramp) of responses were assessed using the intra-class correlation coefficient (ICC). The relative compartment contributions to VT during step exercise were highly repeatable for low (ICC = 0.87, p = 0.003), moderate (ICC = 0.89, p = 0.002) and heavy (ICC = 0.93, p = 0.001) exercise. Inter-individual differences in response to higher intensity exercise were observed, as two participants had significant relationships between VT and their percent compartmental contributions to VT, but five others did not. No differences were identified between ramp and step exercise tests for VT (main effect: p = 0.61) or BR (main effect: p = 0.77) at matched V̇E for each intensity, and the pattern of breathing was reproducible for each intensity. These findings suggest the way young healthy adults breathe for a given V̇E is repeatable day-to-day and reproducible between different exercise protocols.

Fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs), but not gluten, elicit modest symptoms of irritable bowel syndrome: a double-blind, placebo-controlled, randomized three-way crossover trial

ABSTRACTBackgroundIrritable bowel syndrome (IBS) has been associated with diets rich in fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs), and gluten. Most previous studies have been single-blind and have focused on the elimination of FODMAPs or provocation with single FODMAPs. The effect of gluten is unclear, large trials isolating the effect of gluten from that of FODMAPs are needed.ObjectivesThe aims of this study were to ensure high intakes of a wide range of FODMAPs, gluten, or placebo, and to evaluate the effects on IBS symptoms using the IBS-severity scoring system (IBS-SSS).MethodsThe study was carried out with a double-blind, placebo-controlled, randomized 3-way crossover design in a clinical facility in Uppsala from September 2018 to June 2019. In all, 110 participants fulfilling the IBS Rome IV criteria, with moderate to severe IBS, were randomly assigned; 103 (90 female, 13 male) completed the trial. Throughout, IBS participants maintained a diet with minimal FODMAP content and no gluten. Participants were block-randomly assigned to 1-wk interventions with FODMAPs (50 g/d), gluten (17.3 g/d), or placebo, separated by 1-wk washout. All participants who completed ≥1 intervention were included in the intention-to-treat analysis.ResultsIn participants with IBS (n = 103), FODMAPs caused higher IBS-SSS scores (mean 240 [95% CI: 222, 257]) than placebo (198 [180, 215]; P = 0.00056) or gluten (208 [190, 226]; P = 0.013); no differences were found between the placebo and gluten groups (P = 1.0). There were large interindividual differences in IBS-SSS scores associated with treatment. No adverse events were reported.ConclusionIn participants with IBS, FODMAPs had a modest effect on typical IBS symptoms, whereas gluten had no effect. The large interindividual differences in responses to the interventions warrant further detailed studies to identify possible underlying causes and enable individual prediction of responses. This trial was registered at www.clinicaltrials.gov as NCT03653689.

Taking the chance!-Interindividual differences in rule-breaking.

While some individuals tend to follow norms, others, in the face of tempting but forbidden options, tend to commit rule-breaking when this action is beneficial for themselves. Previous studies have neglected such interindividual differences in rule-breaking. The present study fills this gap by investigating cognitive characteristics of individuals who commit spontaneous deliberative rule-breaking (rule-breakers) versus rule-followers. We developed a computerised task, in which 133 participants were incentivised to sometimes violate set rules which would-if followed-lead to a loss. While 52% of participants tended to break rules to obtain a benefit, 48% tended to follow rules even if this behaviour led to loss. Although rule-breakers experienced significantly more cognitive conflict (measured via response times and mouse movement trajectories) than rule-followers, they also obtained higher payoffs. In rule-breakers, cognitive conflict was more pronounced when violating the rules than when following them, and mainly during action planning. This conflict increased with frequent, recurrent, and early rule-breaking. Our results were in line with the Decision-Implementation-Mandatory switch-Inhibition model and thus extend the application of this model to the interindividual differences in rule-breaking. Furthermore, personality traits such as extroversion, disagreeableness, risk propensity, high impulsiveness seem to play a role in the appreciation of behaviours and cognitive characteristics of rule-followers and rule-breakers. This study opens the path towards the understanding of the cognitive characteristics of the interindividual differences in responses towards rules, and especially in spontaneous deliberative rule-breaking.

Sensory processing sensitivity predicts performance in an emotional antisaccade paradigm

Sensory Processing Sensitivity (SPS) is a common, heritable, and evolutionarily conserved trait, describing inter-individual differences in responsiveness and a more cautious approach to novel stimuli. It is associated with increased activation of brain regions involved in awareness, integration of sensory information, and empathy during processing of emotional faces. Furthermore, SPS is related to better performance in a visual detection task. Even though SPS is conceptualized to be closely related to traits characterized by pausing before acting, no study to date has assessed the relation between SPS and inhibitory control in a behavioral inhibition task. The present study fills this gap by investigating how SPS influences individual performance on two different antisaccade paradigms including emotional face stimuli. In addition, we assessed self-reported mood, anxiety, and depressiveness. Results showed that SPS was related to faster processing speed on the emotional, but not the classic antisaccade paradigm. Moreover, SPS predicted inhibitory control speed above mood and depressiveness. Our results provide evidence that higher SPS participants show superior inhibitory abilities, especially during the processing of emotional stimuli. This is in line with earlier findings showing better performance in a visual detection task as well as increased brain activation during emotional face processing.

Regulatory regions in natural transposable element insertions drive interindividual differences in response to immune challenges in Drosophila

BackgroundVariation in gene expression underlies interindividual variability in relevant traits including immune response. However, the genetic variation responsible for these gene expression changes remains largely unknown. Among the non-coding variants that could be relevant, transposable element insertions are promising candidates as they have been shown to be a rich and diverse source of cis-regulatory elements.ResultsIn this work, we use a population genetics approach to identify transposable element insertions likely to increase the tolerance of Drosophila melanogaster to bacterial infection by affecting the expression of immune-related genes. We identify 12 insertions associated with allele-specific expression changes in immune-related genes. We experimentally validate three of these insertions including one likely to be acting as a silencer, one as an enhancer, and one with a dual role as enhancer and promoter. The direction in the change of gene expression associated with the presence of several of these insertions is consistent with an increased survival to infection. Indeed, for one of the insertions, we show that this is the case by analyzing both natural populations and CRISPR/Cas9 mutants in which the insertion is deleted from its native genomic context.ConclusionsWe show that transposable elements contribute to gene expression variation in response to infection in D. melanogaster and that this variation is likely to affect their survival capacity. Because the role of transposable elements as regulatory elements is not restricted to Drosophila, transposable elements are likely to play a role in immune response in other organisms as well.

Treatment Response to SGLT2 Inhibitors: From Clinical Characteristics to Genetic Variations.

SGLT2 (sodium-glucose cotransporter 2) inhibitors are a new class of antihyperglycaemic drugs that act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes mellitus type 2 and their cardiovascular and renal safety have been extensively investigated and confirmed in clinical trials. However, inter-individual differences in response to treatment with SGLT2 inhibitors may present in everyday clinical practice, and good predictors of glycemic response and the risk for adverse events in an individual patient are lacking. As genetic variability of SGLT2 may influence the treatment response, pharmacogenetic information could support the choice of the most beneficial treatment strategy in an individual patient. This review focuses on the clinical and genetic factors that may influence the treatment response to SGLT2 inhibitors in type 2 diabetes patients with comorbid conditions.

Positive psychology interventions in in-patients with depression: influences of comorbidity and subjective evaluation of the training programme.

Studies on positive psychology interventions (PPIs) have frequently demonstrated benefits for healthy participants and patients. However, effect sizes are moderate, and underlying inter-individual differences in responses were rarely investigated. We investigated whether severity of depression and subjective evaluation of PPIs are relevant sources of variance in this respect. A 4-week group PPI programme (one 45-min session per week) was offered to 38 in-patients with depression. The control group (n = 38) was carefully matched and received treatment as usual. In the PPI group, emotional states were recorded before and after each session (responsiveness). Beck Depression Inventory-II scores at hospital admission and discharge were used to evaluate clinical effectiveness. The number of comorbidities (as an indicator of severity of disease) and patients' evaluations of the PPI sessions were used as additional independent factors for overall treatment outcome. The PPI induced a highly significant improvement in positive emotional state and decrease in negative emotional state, indicating responsiveness. Moreover, positive affectivity increased from week to week only in patients with a low number of comorbidities (indicating effectiveness). With respect to overall treatment outcome (Beck Depression Inventory-II scores), positive attitude toward the PPI resulted in the largest improvement. The results partly explain the variance in the effectiveness of PPIs. Moreover, they support the idea of personalised psychotherapy, and may inform discussion on whether patients with depression should be included in PPIs. However, additional individual characteristics should increase knowledge about individual predictors for effectiveness.

Abstract MP12: Proteomic Predictors Of High-density Lipoprotein Cholesterol Response To Regular Exercise

Introduction: Regular exercise beneficially increases plasma HDL-C levels at the group level. However, variation in individual HDL-C responses to exercise highlight a need for predictive biomarkers of exercise response. Hypothesis: We hypothesized that baseline abundance of circulating proteins is predictive of HDL-C response to exercise and that identified proteins are part of a complex biological network of exercise response. Methods: We measured over 5,000 circulating proteins using an aptamer-affinity based platform (SomaScan) in 667 black and white adults from the HERITAGE Family Study. Fasting plasma HDL-C was measured at baseline and following 20 weeks of supervised endurance exercise training. To predict exercise induced changes in HDL-C using baseline abundance of circulating proteins, models were created using LASSO regression and a 70/30 training test data split with 10-fold cross validation. Biological pathways, networks, and functions involving proteins identified in predictive modeling were investigated by ingenuity pathway analysis (IPA) and integrated molecular pathway level analysis (IMPaLA). Results: Regular exercise significantly increased HDL-C in the sample by 1.5 ± 4.6 mg/dL (p<0.0001), however marked inter-individual differences in response were present (range: -19.5 to +17.4 mg/dL). LASSO regression of circulating proteins only yielded a model of 120 proteins with similar but stronger predictive power to a model of 19 clinical traits (root mean square error = 4.52 and 5.3 mg/dL respectively). LASSO regression of both clinical and proteomic predictors resulted in a final model of baseline HDL-C and 116 circulating proteins, with an improved root mean square error of 4.11 mg/dL. Furthermore, this panel of 116 proteins was able to explain 40.0% of the variance in exercise induced changes in plasma HDL-C, while clinical predictors alone (including baseline HDL-C) explained only 3.9%. Pathway analysis of these 116 proteins identified several biological processes including pathways involved in the progression towards atherosclerosis, angiogenesis, mTOR signaling, and mitochondrial fatty acid synthesis. Conclusions: Circulating proteins may allow for prediction of exercise induced changes in HDL-C. Additionally, proteins predictive of HDL-C response to exercise are associated with important biological pathways and may provide insights into the molecular mechanisms of the benefits of regular exercise.

Individual variation of follicular phase changes in endothelial function across two menstrual cycles.

What is the central question of this study? The purpose of this study was to determine intra-individual reproducibility of follicular phase changes in endothelial function (flow-mediated dilatation) over two menstrual cycles in healthy, premenopausal women. What is the main finding and its importance? Phase changes in endothelial function were not consistent at the individual level across two menstrual cycles, which challenges the utility of interpreting individual responses over one cycle. Evidence regarding the impact of menstrual phase on endothelial function is conflicting, and studies to date have examined responses only over a single cycle. It is unknown whether the observed inter-individual variability of phase changes in endothelial function reflects stable, inter-individual differences in responses to oestrogen (E2 ; a primary female sex hormone). The purpose of this study was to examine changes in endothelial function from the early follicular (EF; low-E2 ) phase to the late follicular (LF; high-E2 ) phase over two consecutive cycles. Fourteen healthy, regularly menstruating women [22±3years of age (mean±SD)] participated in four visits (EFVisit1 , LFVisit2 , EFVisit3 and LFVisit4 ) over two cycles. Ovulation testing was used to determine the time between the LF visit and ovulation. During each visit, endothelial function [brachial artery flow-mediated dilatation (FMD)], E2 and progesterone were assessed. At the group level, there was no impact of phase or cycle on FMD (P=0.48 and P=0.65, respectively). The phase change in FMD in cycle1 did not predict the phase change in cycle2 (r=0.03, P=0.92). Using threshold-based classification (2×typical error threshold), four of 14 participants (29%) exhibited directionally consistent phase changes in FMD across cycles. Oestrogen was not correlated between cycles, and this might have contributed to variability in the FMD response. The intra-individual variability in follicular fluctuation in FMD between menstrual cycles challenges the utility of interpreting individual responses to phase over a single menstrual cycle.

Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes.

One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived of oxygen. To study inter-individual differences in response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels in four culturing conditions that correspond to normoxia, hypoxia, and short- or long-term re-oxygenation. We characterized thousands of gene regulatory changes as the cells transition between conditions. Using available genotypes, we identified 1,573 genes with a cis expression quantitative locus (eQTL) in at least one condition, as well as 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of genes with dynamic eQTLs is associated with complex traits and disease. Our data demonstrate how dynamic genetic effects on gene expression, which are likely relevant for disease, can be uncovered under stress.

Genetic Variants of ANGPT1, CD39, FGF2 and MMP9 Linked to Clinical Outcome of Bevacizumab Plus Chemotherapy for Metastatic Colorectal Cancer.

Angiogenesis pathway genes show substantial genetic variability causing inter-individual differences in responses to anti-angiogenic drugs. We examined 20 single nucleotide polymorphisms (SNPs) in 13 of these genes to predict tumour response and clinical outcome measured as progression free survival (PFS) and overall survival (OS) in 57 patients with metastatic colorectal cancer (mCRC) given bevacizumab plus chemotherapy. SNPs were detected (iPLEX® Assay) in genomic DNA extracted from formalin-fixed paraffin-embedded tumour specimens. The variant allele CD39 rs11188513 was associated with a good tumour response (p = 0.024). Patients homozygous for the wild-type allele FGF2 rs1960669 showed a median PFS of 10.95 months versus 5.44 months for those with at least one variant allele-A (HR 3.30; 95% CI: 1.52–7.14; p = 0.001). Patients homozygous for wild-type MMP9 rs2236416 and rs2274755 showed a median PFS of 9.48 months versus 6 and 6.62 months, respectively, for those with at least one variant allele (p = 0.022, p = 0.043, respectively). OS was also lengthened to 30.92 months (p = 0.034) in carriers of wild-type ANGPT1 rs2445365 versus 22.07 months for those carrying at least one variant allele-A. These gene variants were able to predict clinical outcome and tumour response in mCRC patients given bevacizumab-based therapy.

Group and individual level variations between symmetric and asymmetric DLPFC montages for tDCS over large scale brain network nodes

Two challenges to optimizing transcranial direct current stimulation (tDCS) are selecting between, often similar, electrode montages and accounting for inter-individual differences in response. These two factors are related by how tDCS montage determines current flow through the brain considered across or within individuals. MRI-based computational head models (CHMs) predict how brain anatomy determines electric field (EF) patterns for a given tDCS montage. Because conventional tDCS produces diffuse brain current flow, stimulation outcomes may be understood as modulation of global networks. Therefore, we developed a network-led, rather than region-led, approach. We specifically considered two common “frontal” tDCS montages that nominally target the dorsolateral prefrontal cortex; asymmetric “unilateral” (anode/cathode: F4/Fp1) and symmetric “bilateral” (F4/F3) electrode montages. CHMs of 66 participants were constructed. We showed that cathode location significantly affects EFs in the limbic network. Furthermore, using a finer parcellation of large-scale networks, we found significant differences in some of the main nodes within a network, even if there is no difference at the network level. This study generally demonstrates a methodology for considering the components of large-scale networks in CHMs instead of targeting a single region and specifically provides insight into how symmetric vs asymmetric frontal tDCS may differentially modulate networks across a population.

Assessing True Variability And Mean Changes To Two Distinct Resistance Training Protocols

Millions of dollars are spent analyzing inter-individual differences in response to resistance exercise, but the lack of a non-exercise control group makes it possible that these studies may simply be examining random error. Furthermore, it has been hypothesized that the magnitude of variability may differ depending upon the exercise protocol employed, but this yet to be appropriately tested. PURPOSE: To determine differences in two distinct resistance training protocols and whether true variability could be detected after accounting for random error. METHODS: Individuals (n=151) were randomly assigned to one of three groups: (1) a traditional exercise group performing four sets of elbow flexion exercise to failure; (2) a one-repetition maximum (1RM) performing a 1RM elbow flexion test; and (3) a time-matched non-exercise control group. Both exercise groups performed 18 sessions over six weeks. A Bayesian ANCOVA was used to test for mean changes across groups while adjusting for pre-values. To assess whether the variability in response to each exercise intervention differed from that of the control group, Bayesian Levene’s tests were computed. Bayes Factors (BF10) were used to quantify evidence for or against the null hypothesis. RESULTS: Both 1RM (2.3kg; BF10 = 4.791e+6) and traditional training groups (2.4kg; BF10 = 11,915) increased 1RM strength similarly (BF10 = 0.21), but only the 1RM group increased untrained arm 1RM strength (1.5kg; BF10 = 271). Only the traditional exercise group increased ultrasound measured muscle thickness (~0.23 cm across all sites; all BF10 ≥ 224). Across both training groups, the only differential responses were found in the change in 1RM strength of the trained arm in the traditional training group (BF10 = 5.381). This resulted in a true variability of 1.8 kg after the removal of random error. CONCLUSION: These findings demonstrate the importance of taking into consideration the magnitude of random error when determining response heterogeneity, as many studies may be classifying individuals based on random error. Additionally, our mean results demonstrate that strength is largely driven by task specificity, and the cross-over effect of strength may be load dependent.

Inter-individual differences in the responses to aerobic exercise in Alzheimer's disease: Findings from the FIT-AD trial

BackgroundDespite the strong evidence of aerobic exercise as a disease-modifying treatment for Alzheimer's disease (AD) in animal models, its effects on cognition are inconsistent in human studies. A major contributor to these findings is inter-individual differences in the responses to aerobic exercise, which was well documented in the general population but not in those with AD. The purpose of this study was to examine inter-individual differences in aerobic fitness and cognitive responses to a 6-month aerobic exercise intervention in community-dwelling older adults with mild-to-moderate dementia due to AD. MethodsThis study was a secondary analysis of the Effects of Aerobic Exercise for Treating Alzheimer's Disease (FIT-AD) trial data. Aerobic fitness was measured by the shuttle walk test (SWT), the 6-min walk test (6MWT), and the maximal oxygen consumption (VO2max) test, and cognition by the AD Assessment Scale-Cognition (ADAS-Cog). Inter-individual differences were calculated as the differences in the standard deviation of 6-month change (SDR) in the SWT, 6MWT, VO2max, and ADAS-Cog between the intervention and control groups. ResultsSeventy-eight participants were included in this study (77.4 ± 6.3 years old, mean ± SD; 15.7 ± 2.8 years of education; 41% were female). VO2max was available for 26 participants (77.7 ± 7.1 years old; 14.8 ± 2.6 years of education; 35% were female). The SDR was 37.0, 121.1, 1.7, and 2.3 for SWT, 6MWT, VO2max, and ADAS-Cog, respectively. ConclusionThere are true inter-individual differences in aerobic fitness and cognitive responses to aerobic exercise in older adults with mild-to-moderate dementia due to AD. These inter-individual differences likely underline the inconsistent cognitive benefits in human studies.

Are There Inter-Individual Differences in Fat Mass and Percent Body Fat as a Result of Aerobic Exercise Training in Overweight and Obese Children and Adolescents? A Meta-Analytic Perspective.

Background: Determine whether inter-individual response differences exist with respect to changes in fat mass and percent body fat as a result of aerobic exercise training in overweight and obese children and adolescents. Methods: Using the meta-analytic approach, randomized controlled trials that examined the effects of aerobic exercise training on fat mass and percent body fat in overweight and obese children and adolescents were included. Change outcome standard deviations for fat mass and percent body fat were used to calculate true inter-individual differences from each study. The inverse variance heterogeneity model was used to pool results. Results: Pooled changes for inter-individual response differences in fat mass (16 studies, 575 participants) were 0.9 kg (95% confidence interval [CI], -1.4 to 1.8 kg) while tau ([Formula: see text]) was 2.9. For percent body fat, inter-individual differences (27 studies, 1035 participants) were 0.6% (95% CI, -0.6% to 1.0%, [Formula: see text] = 0.7). The 95% prediction interval for true inter-individual responses in a future study was -4.9 to 5.5 kg for fat mass and -0.7% to 1.7% for percent body fat. The percent chance, that is, probability, of a clinically meaningful difference in variability was 47% for fat mass and 26% for percent body fat, both of which were considered as only possibly clinically important. Conclusions: There is a lack of convincing evidence to suggest that true inter-individual response differences exist with respect to aerobic exercise training and changes in fat mass and percent body fat in overweight and obese children and adolescents.

Hypercytokinemia and Pathogen-Host Interaction in COVID-19.

Severe acute respiratory syndrome (SARS) coronavirus (CoV)-2 (SARS-CoV-2) is a novel coronavirus identified as the cause of coronavirus disease-2019 (COVID-19) that began in Wuhan, China in late 2019 and spread now in 210 countries and territories around the world. Many people are asymptomatic or with mild symptoms. However, in some cases (usually the elderly and those with comorbidities) the disease may progress to pneumonia, acute respiratory distress syndrome and multi-organ dysfunction that can lead to death. Such wide interindividual differences in response to SARS-CoV-2 infection may relate to several pathogen- and host-related factors. These include the different levels of the ubiquitously present human angiotensin I converting enzyme 2 (ACE2) receptors gene expression and its variant alleles, the different binding affinities of ACE2 to the virus spike (S) protein given its L- and S-subtypes and the subsequent extent of innate immunity-related hypercytokinemia. The extensive synthesis of cytokines and chemokines in coronavirus diseases was suggested as a major factor in exacerbating lung damage and other fatal complications. The polymorphisms in genes coding for pro-inflammatory cytokines and chemokines have been associated with mediating the response and susceptibility to a wide range of infections and their severe outcomes. Understanding the nature of pathogen–host interaction in COVID-19 symptomatology together with the role of hypercytokinemia in disease severity may permit developing new avenues of approach for prevention and treatment and can delineate public health measures to control the spread of the disease.

RETRACTED ARTICLE: Dietary metabotype modelling predicts individual responses to dietary interventions.

Habitual consumption of poor quality diets is linked directly to risk factors for many non-communicable diseases. This has resulted in the vast majority of countries and the World Health Organization developing policies for healthy eating to reduce the prevalence of non-communicable diseases in the population. However, there is mounting evidence of variability in individual metabolic responses to any dietary intervention. We have developed a method for applying a pipeline for understanding interindividual differences in response to diet, based on coupling data from highly controlled dietary studies with deep metabolic phenotyping. In this feasibility study, we create an individual Dietary Metabotype Score (DMS) that embodies interindividual variability in dietary response and captures consequent dynamic changes in concentrations of urinary metabolites. We find an inverse relationship between the DMS and blood glucose concentration. There is also a relationship between the DMS and urinary metabolic energy loss. Furthermore, we use a metabolic entropy approach to visualize individual and collective responses to dietary interventions. Potentially, the DMS offers a method to target and to enhance dietary response at the individual level, thereby reducing the burden of non-communicable diseases at the population level.

Inter-individual differences in the nutrition response: from research to recommendations.

The 2019 Nutrition Society Spring Conference, which convened in Dundee, focused on the challenges presented by inter-individual differences in the responses to nutrition and in conducting nutritional research. The programme brought together national and international experts to discuss the collective evidence on inter-individual nutritional responses and impacts on health. Speakers and delegates from across the UK, Europe and the USA debated new methods of conducting research in nutrition and discussed the development of appropriate dietary interventions to maintain health and prevent disease in diverse populations. Symposium 1 focused on the effects of ethnicity on nutrient availability and type 2 diabetes and cardio-metabolic disease. Symposium 2 explored sex differences in nutrient availability and health and metabolism. The final symposium examined genetic and phenotypic variation, nutrition and health. The meeting ended with a panel discussion about how we take research to recommendations and concluded with a need to consider inter-individual differences in planning, conducting and analysing nutritional research.

Interindividual Heterogeneity of SGLT2 Expression and Function in Human Pancreatic Islets.

Studies implicating sodium-glucose cotransporter 2 (SGLT2) inhibitors in glucagon secretion by pancreatic α-cells reported controversial results. We hypothesized that interindividual heterogeneity in SGLT2 expression and regulation may affect glucagon secretion by human α-cells in response to SGLT2 inhibitors. An unbiased RNA-sequencing analysis of 207 donors revealed an unprecedented level of heterogeneity of SLC5A2 expression. To determine heterogeneity of SGLT2 expression at the protein level, the anti-SGLT2 antibody was first rigorously evaluated for specificity, followed by Western blot and immunofluorescence analysis on islets from 10 and 12 donors, respectively. The results revealed a high interdonor variability of SGLT2 protein expression. Quantitative analysis of 665 human islets showed a significant SGLT2 protein colocalization with glucagon but not with insulin or somatostatin. Moreover, glucagon secretion by islets from 31 donors at low glucose (1 mmol/L) was also heterogeneous and correlated with dapagliflozin-induced glucagon secretion at 6 mmol/L glucose. Intriguingly, islets from three donors did not secrete glucagon in response to either 1 mmol/L glucose or dapagliflozin, indicating a functional impairment of the islets of these donors to glucose sensing and SGLT2 inhibition. Collectively, these data suggest that heterogeneous expression of SGLT2 protein and variability in glucagon secretory responses contribute to interindividual differences in response to SGLT2 inhibitors.

Constructing a control-ready model of EEG signal during general anesthesia in humans

Significant effort toward the automation of general anesthesia has been made in the past decade. One open challenge is in the development of control-ready patient models for closed-loop anesthesia delivery. Standard depth-of-anesthesia tracking does not readily capture inter-individual differences in response to anesthetics, especially those due to age, and does not aim to predict a relationship between a control input (infused anesthetic dose) and system state (commonly, a function of electroencephalography (EEG) signal). In this work, we developed a control-ready patient model for closed-loop propofol-induced anesthesia using data recorded during a clinical study of EEG during general anesthesia in ten healthy volunteers. We used principal component analysis to identify the low-dimensional state-space in which EEG signal evolves during anesthesia delivery. We parameterized the response of the EEG signal to changes in propofol target-site concentration using logistic models. We note that inter-individual differences in anesthetic sensitivity may be captured by varying a constant cofactor of the predicted effect-site concentration. We linked the EEG dose-response with the control input using a pharmacokinetic model. Finally, we present a simple nonlinear model predictive control in silico demonstration of how such a closed-loop system would work.