Interindividual Variability Research Articles

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.

Inter-strain variability in responses to a single administration of the cannabidiol-rich cannabis extract in mice

Cannabidiol (CBD) has gained widespread popularity; however, its pharmacological and toxicological profiles in the context of human genetic diversity remain largely unexplored. Here, we investigated the variability in metabolism and toxicity of CBD-rich cannabis extract (CRCE) in genetically diverse mouse models: C57BL/6J, B6C3F1/J, and NZO/HlLtJ strains. Mice received a single dose of CRCE containing 57.9% CBD at dosages of 0, 246, 738, and 2460 mg/kg of CBD. At 24 h after treatment, no appreciable histomorphological changes were detected in the liver. Plasma bilirubin levels increased markedly in all strains at the highest CBD dose. Mice in all treatment groups displayed significant but distinct increases in ALT and AST levels. While B6C3F1/J and NZO/HlLtJ mice had negligible plasma CBD levels at 738 mg/kg, C57BL/6J mice exhibited levels exceeding 7000 ng/mL. At 2460 mg/kg, high CBD concentrations were found in B6C3F1/J and C57BL/6J mice, but markedly lower levels were seen in NZO/HlLtJ mice. Gene expression profiling showed significant increases in Cyp2b10 across all strains but varying responses in Cyp1a1 expression, indicating strain-specific CYP dysregulation. Genetically diverse mice exhibited differential pharmacological and toxicological responses to CRCE, suggesting a high potential for inter-individual variability in the pharmacology and toxicology of CBD in humans.

Age and interpulse interval relation from newborn to adult sperm whale (Physeter macrocephalus) off Mauritius

Sperm whales (Physeter macrocephalus) have been studied for decades, but the development of their clicks during the animal growth is not yet well known. The click they emit during socialization and echolocation contains information about the length of their acoustic organs and, therefore the length of the body through the interpulse interval (IPI). This paper provides the first IPI/age relationship for juvenile male and female sperm whales (Physeter macrocephalus) based on field recordings of individuals whose age is largely known. Across 9 years, audiovisual recordings of a Mauritian sperm whale social unit were carried out. Adult female and juvenile sperm whales were identified and aged. The dataset made from those recordings is publicly available. The interpulse interval was measured for individuals whose ages ranged from 7 days to around 38 years. The growth of the acoustic organ of juveniles showed an early inter-individual variability as well as sexual dimorphism. Usual growth models were also fitted, predicting a mean IPI∞\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$IPI_\\infty$$\\end{document} of 3.5 ms for adults and a physical maturity reached at around 30 years old. The use of passive acoustic monitoring (PAM) is one of the main tools used to study sperm whales. This IPI-age relationship may aid demographic studies on sperm whales by enabling PAM to assess the ages of recorded sperm whales.

Pharmacokinetic modeling of sulfamethoxazole-trimethoprim and sulfadiazine-trimethoprim combinations in broilers

Sulfonamides (S) are old bacteriostatic antibiotics which are widely prescribed in combination with trimethoprim (TMP) for the treatment of various diseases in food-producing animals such as poultry. Nowadays, the 1:5 dose ratio of TMP/S used in broilers is a direct transposition of the ratio determined in Human decades ago for TMP/sulfamethoxazole (SMX), aiming to obtain a supposed synergistic plasma concentration ratio of 1:19. However, major pharmacokinetics (PK) differences exist according to the sulfonamide used in the combination. Here, we generated new PK data in broilers after a cross-over design with IV and the oral administration of 2 major sulfonamides, sulfadiazine (SDZ) and SMX, in combination with TMP, and analyzed the data via a population pharmacokinetic (popPK) modeling approach. Results showed that TMP has a greater plasma to tissue distribution than both sulfonamides with a higher volume of distribution (0.51 L/kg for SDZ, 0.62 L/kg for SMX and 3.14 L/kg for TMP). SMX has the highest elimination half-life (2.83 h) followed by SDZ and TMP (2.01 h and 1.49 h, respectively). The oral bioavailability of the 3 molecules was approximately 100%. Bodyweight could explain some of the inter-individual variability in the volume of distribution of SDZ and SMX and the clearance of SDZ and TMP, as heavier broilers have higher typical values. Monte Carlo simulations of a large virtual broiler population (n = 1,000) showed that the targeted plasma ratio of TMP:S of 1:19 was rarely or never reached at the individual level for both combinations at the marketed doses and greatly varies over time and between individuals, questioning the relevance of the 1:5 dose ratio for current formulations of TMP/S.

Real-World Application of a Quantitative Systems Pharmacology (QSP) Model to Predict Potassium Concentrations from Electronic Health Records: A Pilot Case towards Prescribing Monitoring of Spironolactone.

Quantitative systems pharmacology (QSP) models are rarely applied prospectively for decision-making in clinical practice. We therefore aimed to operationalize a QSP model for potas-sium homeostasis to predict potassium trajectories based on spironolactone administrations. For this purpose, we proposed a general workflow that was applied to electronic health records (EHR) from patients treated in a German tertiary care hospital. The workflow steps included model exploration, local and global sensitivity analyses (SA), identifiability analysis (IA) of model parameters, and specification of their inter-individual variability (IIV). Patient covariates, selected parameters, and IIV then defined prior information for the Bayesian a posteriori prediction of individual potassium trajectories of the following day. Following these steps, the successfully operationalized QSP model was interactively explored via a Shiny app. SA and IA yielded five influential and estimable parameters (extracellular fluid volume, hyperaldosteronism, mineral corticoid receptor abundance, potassium intake, sodium intake) for Bayesian prediction. The operationalized model was validated in nine pilot patients and showed satisfactory performance based on the (absolute) average fold error. This provides proof-of-principle for a Prescribing Monitoring of potassium concentrations in a hospital system, which could suggest preemptive clinical measures and therefore potentially avoid dangerous hyperkalemia or hypokalemia.

Maternal rejection but not protectiveness predicts juvenile Japanese macaque behavior without direct maternal influence.

Primates show large interindividual variability in the character and quantity of interactions between mothers and their immature offspring. Multiple studies have documented associations between maternal behavior and the occurrence or frequency of certain behaviors among offspring, but it remains unclear whether and how early maternal interactions generally affect behavioral development in offspring. We followed two wild groups of Japanese macaques on Yakushima island and investigated the relationship between maternal behavior and several types of behavior performed by 35 juvenile offspring. We further asked if the impact of maternal behavior on juvenile behavior persists regardless of the distance between mother and offspring, testing whether the influence extends beyond cases when the mother is nearby. We found that juveniles whose mothers frequently rejected them approached and played with others more often, independent of their mother's presence. Juveniles of more protective mothers were in proximity to fewer other individuals and played less, but only if their mothers were nearby. Maternal rejection appears to exert a generalized effect on offspring behavior that endures when mothers are absent. In contrast, effects of maternal protectiveness may be temporary and/or reflect direct maternal influences, such as active intervention in offspring interactions, or effects of the mother's own social relationships on offspring interactions. Our results suggest that understanding how maternal behavior affects offspring development requires paying attention to the context of juvenile behavior, including the mother's distance from her offspring.

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.

Multiscale heterogeneity of white matter morphometry in psychiatric disorders.

Inter-individual variability in neurobiological and clinical characteristics in mental illness is often overlooked by classical group-mean case-control studies. Studies using normative modelling to infer person-specific deviations of grey matter volume have indicated that group means are not representative of most individuals. The extent to which this variability is present in white matter morphometry, which is integral to brain function, remains unclear. We applied Warped Bayesian Linear Regression normative models to T1-weighted magnetic resonance imaging data and mapped inter-individual variability in person-specific white matter volume deviations in 1,294 cases (58% male) diagnosed with one of six disorders (attention-deficit/hyperactivity, autism, bipolar, major depressive, obsessive-compulsive and schizophrenia) and 1,465 matched controls (54% male) recruited across 25 scan sites. We developed a framework to characterize deviation heterogeneity at multiple spatial scales, from individual voxels, through inter-regional connections, specific brain regions, and spatially extended brain networks. The specific locations of white matter volume deviations were highly heterogeneous across participants, affecting the same voxel in fewer than 8% of individuals with the same diagnosis. For autism and schizophrenia, negative deviations (i.e., areas where volume is lower than normative expectations) aggregated into common tracts, regions and large-scale networks in up to 35% of individuals. The prevalence of white matter volume deviations was lower than previously observed in grey matter, and the specific location of these deviations was highly heterogeneous when considering voxel-wise spatial resolution. Evidence of aggregation within common pathways and networks was apparent in schizophrenia and autism but not other disorders.

Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P≤ 5 × 10-6). While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

Identification of Amino Acids and Polyphenolic Metabolites in Human Plasma by UHPLC-ESI-QTOF-MS/MS, after the Chronic Intake of a Functional Meal in an Elderly Population.

Novel foods especially formulated and targeted for the elderly population should provide sufficient nutrients and bioactive ingredients to counteract the natural age-related deterioration of various organs and tissues. Dietary protein and phenolic compounds achieve this goal; however, older adults have alterations in their gastrointestinal system that may impact their bioavailability and few studies have been aimed at this population. Since phenolic compounds are the subject of multiple biotransformations by host and microbiome enzymes during the digestion process, identification of their bioavailable forms in human plasma or tissues represents a considerable analytical challenge. In this study, UHPLC-ESI-QTOF/MS-MS, chemometrics, and multivariate statistical methods were used to identify the amino acids and phenolic compounds that were increased in the plasma of elderly adults after a 30-day intervention in which they had consumed an especially formulated muffin and beverage containing Brosimum alicastrum Sw. seed flour. A large interindividual variation was observed regarding the amino acids and phenolic metabolites identified in the plasma samples, before and after the intervention. Three phenolic metabolites were significantly increased in the population after the intervention: protocatechuic acid, 5-(methoxy-4'-hydroxyphenyl) valerolactone, and phloretic acid. These metabolites, as well as others that were not significantly increased (although they did increase in several individuals), are probably the product of the microbiota metabolism of the major phenolic compounds present in the B. alicastrum Sw. seed flour and other food ingredients. A significant decrease in 4-ethyl-phenol, a biomarker of stress, was observed in the samples. Results showed that the incorporation of foods rich in phenolic compounds into the regular diet of older adults contributes to the increase in bioactive compounds in plasma, that could substantially benefit their mental, cardiovascular, and digestive health.

Recruitment-to-inflation ratio to assess response to PEEP during laparoscopic surgery: A physiologic study

Study objectiveDuring laparoscopic surgery, the role of PEEP to improve outcome is controversial. Mechanistically, PEEP benefits depend on the extent of alveolar recruitment, which prevents ventilator-induced lung injury by reducing lung dynamic strain. The hypotheses of this study were that pneumoperitoneum-induced aeration loss and PEEP-induced recruitment are inter-individually variable, and that the recruitment-to-inflation ratio (R/I) can identify patients who benefit from PEEP in terms of strain reduction. DesignSequential study. SettingOperating room. PatientsSeventeen ASA I-III patients receiving robot-assisted prostatectomy during Trendelenburg pneumoperitoneum. Interventions and measurementsPatients underwent end-expiratory lung volume (EELV) and respiratory/lung/chest wall mechanics (esophageal manometry and inspiratory/expiratory occlusions) assessment at PEEP = 0 cmH2O before and after pneumoperitoneum, at PEEP = 4 and 12 cmH2O during pneumoperitoneum. Pneumoperitoneum-induced derecruitment and PEEP-induced recruitment were assessed through a simplified method based on multiple pressure-volume curve. Dynamic and static strain changes were evaluated. R/I between 12 and 4 cmH2O was assessed from EELV. Inter-individual variability was rated with the ratio of standard deviation to mean (CoV). Main resultsPneumoperitoneum reduced EELV by (median [IqR]) 410 mL [80–770] (p < 0.001) and increased dynamic strain by 0.04 [0.01–0.07] (p < 0.001), with high inter-individual variability (CoV = 70% and 88%, respectively). Compared to PEEP = 4 cmH2O, PEEP = 12 cmH2O yielded variable amount of recruitment (139 mL [96–366] CoV = 101%), causing different extent of dynamic strain reduction (median decrease 0.02 [0.01–0.04], p = 0.002; CoV = 86%) and static strain increases (median increase 0.05 [0.04–0.07], p = 0.01, CoV = 33%). R/I (1.73 [0.58–3.35]) estimated the decrease in dynamic strain (p ≤0.001, r = −0.90) and the increase in static strain (p = 0.009, r = −0.73) induced by PEEP, while PEEP-induced changes in respiratory and lung mechanics did not. ConclusionsTrendelenburg pneumoperitoneum yields variable derecruitment: PEEP capability to revert these phenomena varies significantly among individuals. High R/I identifies patients in whom higher PEEP mostly reduces dynamic strain with limited static strain increases, potentially allowing individualized settings.

Assessing how individuals conceptualize numeric pain ratings: validity and reliability of the Pain Schema Inventory (PSI-6) Short Form.

While numeric scales to represent pain intensity have been well validated, individuals use various conceptualizations when assigning a number to pain intensity, referred to as pain rating schema. The 18-item Pain Schema Inventory (PSI-18) quantifies pain rating schema by asking for numeric values for multiple mild, moderate or severe pain conditions. This study aimed to assess the validity and reliability of a shortened form of the PSI, using only 6 items (PSI-6). A secondary analysis was performed on two existing datasets. The first (n = 641) involved a community-based population that completed the PSI-18. The second (n = 182) included participants with chronic pain who completed the PSI-6 twice, one week apart. We assessed face validity, convergent validity, offset biases, test-retest reliability, and internal consistency of the PSI-6 compared to the PSI-18. Both the PSI-18 and PSI-6 demonstrated excellent face validity. The PSI-6 demonstrated excellent convergent validity relative to the PSI-18, with correlations from r = 0.88 to 0.92. Bland-Altman plots revealed offset biases near zero (< 0.22 on 0-10 scale) across all categories of mild, moderate, severe and average pain. Internal consistency was excellent, with Cronbach's Alpha = 0.91 and 0.80, for PSI-18 and PSI-6 respectively. Test-retest reliability of the PSI-6 was high with correlations from r = 0.70-0.76. The PSI-6 is a valid and reliable tool to assess pain rating schema with reduced subject burden, to better interpret individuals' pain ratings and adjust for inter-individual variability.

Is There an Interplay between Environmental Factors, Microbiota Imbalance, and Cancer Chemotherapy-Associated Intestinal Mucositis?

Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes. While pharmacogenetics and pharmacogenomics have long been considered the primary causes of such heterogeneous responses, pharmacomicrobiomics has recently gained attention. The microbiome, a community of microorganisms living in or on the human body, is a critical determinant of drug response and toxicity. Factors such as diet, lifestyle, exposure to xenobiotics, antibiotics use, illness, and genetics can influence the composition of the microbiota. Changes in the intestinal microbiota are particularly influential in drug responsiveness, especially in cancer chemotherapy. The microbiota can modulate an individual's response to a drug, affecting its bioavailability, clinical effect, and toxicity, affecting treatment outcomes and patient quality of life. For instance, the microbiota can convert drugs into active or toxic metabolites, influencing their efficacy and side effects. Alternatively, chemotherapy can also alter the microbiota, creating a bidirectional interplay. Probiotics have shown promise in modulating the microbiome and ameliorating chemotherapy side effects, highlighting the potential for microbiota-targeted interventions in improving cancer treatment outcomes. This opinion paper addresses how environmental factors and chemotherapy-induced dysbiosis impact cancer chemotherapy gastrointestinal toxicity.

PBPK model-based gender-specific risk assessment of N-nitrosodimethylamine (NDMA) using human biomonitoring data.

Despite several screening levels for NDMA reported in water, soil, air, and drugs, the human risk assessment using biomonitoring concentrations has not been performed. In this study, gender-specific exposure guidance values were determined in humans, then biomonitoring measurements in healthy Korean subjects (32 men and 40 women) were compared to the exposure guidance values to evaluate the current exposure level to NDMA. For the human risk assessment of NDMA, the gender-specific physiologically based pharmacokinetic (PBPK) model was developed in humans using proper physiological parameters, partition coefficients, and biochemical parameters. Using the PBPK model, a Monte Carlo simulation was performed to describe the magnitudes of inter-individual variability and uncertainty on the single model predictions. The PBPK modeling and Monte Carlo simulation allowed the estimation of the relationship between external dose and blood concentration for the risk assessment. The procedure for the human risk assessment was summarized as follows: (1) estimating a steady-state blood concentration (Cavg) corresponding to the daily no observed adverse effect level (NOAEL) administration in rats; (2) applying uncertainty factors (UFs) for deriving the human Cavg; (3) determining the exposure guidance values as screening criteria; (4) interpreting the human biomonitoring measurements by forward and reverse dosimetry approaches. Using the biomonitoring concentrations, current daily exposures to NDMA were estimated to be 3.95μg/day/kg for men and 10.60μg/day/kg for women, respectively. The result of the study could be used as a basis for implementing further risk management and regulatory decision-making for NDMA.

Genetic Factors Contributing to Interindividual Variability of α-Tocopherol Levels in Subcutaneous Adipose Tissue among Healthy Adult Males.

In humans, α-tocopherol (α-TOC) is mainly stored in adipose tissue, where it participates in preventing damages induced by inflammation and reactive oxygen species. Factors, including genetic ones, that explain adipose tissue α-TOC concentration remain poorly understood. This study, therefore, aimed to characterize the interindividual variability of adipose tissue α-TOC concentration in healthy individuals and to identify single nucleotide polymorphisms (SNPs) associated with it. The study used a randomized cross-over design with 42 healthy adult males. α-TOC concentration was measured in fasting plasma and periumbilical adipose tissue samples, both at fast and 8 h after consumption of three standard meals. Partial least squares (PLS) regression was performed to identify SNPs associated with the interindividual variability of adipose tissue α-TOC concentration. Adipose tissue α-TOC concentration was not associated with fasting plasma concentration (Pearson's r = 0.24, 95% CI: [-0.08, 0.51]). There was a high interindividual variability of adipose tissue α-TOC concentration (CV = 61%). A PLS regression model comprising 10 SNPs in five genes (PPARG, ABCA1, BUD13, CD36, and MGLL) explained 60% (adjusted R2) of the variability of this concentration. The interindividual variability of adipose tissue α-TOC concentration in humans is due, at least partly, to SNPs in genes involved in α-TOC and triglyceride metabolism.

Behavior and Activity Patterns of the Critically Endangered Mangshan Pit Viper (Protobothrops mangshanensis) Determined Using Remote Monitoring.

This study focuses on understanding the behavior and activity patterns of the critically endangered Protobothrops mangshanensis in China in order to better provide scientific data for upcoming artificial breeding and propagation efforts. We conducted a long-term observation of 15 Mangshan pit vipers at different sites in Hunan Province during the summer and autumn of 2021. Our methods involved analyzing the influence of environmental factors such as temperature, relative humidity, and light condition on the snakes' day and night activity and behaviors. The results revealed that the wild behaviors of Protobothrops mangshanensis include resting, sunbathing, crawling, and exploring, with distinct rhythms in their diel behavior. The snakes' diel activity exhibits three peak periods which may be related to food activity and sunbathing. This study also highlights the complex interplay of environmental factors on the activity of Protobothrops mangshanensis. Relative humidity was identified as a critical factor accounting for the difference in activity between observation groups. There was little inter-individual variation among the 15 Protobothrops mangshanensis, even though these snakes used terrestrial and arboreal habitats under different environmental conditions. These findings enhance our understanding of Protobothrops mangshanensis behavior and provide a basis for effective conservation measures for this rare and critically endangered species.

Abstract Mo043: Advanced waveform analysis of the electrocardiogram signals using complementary signal processing techniques to investigate the response to a QTc prolonging drug vs control including food effect.

Background: Thorough QT studies using Electrocardiogram data, are a well-established method for testing the pro-arrhythmic propensity of drugs performed during drug development. ECG analysis is currently reduced to simplified biomarkers, such as rate, intervals and amplitudes. However, ECG waveforms are complex and generally sampled with high fidelity 125-1000 Hz. Our novel mathematical method, Symmetric Projection Attractor Reconstruction analyses the morphology and variability of such waveforms, using every data point to generate a new, faithful 2D waveform representation termed an attractor. Moxifloxacin know QT prolonging medicine and has been shown to cause a mean increase of the QTc interval of 10–14 mS after a single dose of 400 mg. Separately, studies have shown that meals can alter QT interval as well as altering the pharmacokinetic profile of moxifloxacin itself with gender and ethnicity impacting individual responses. In-depth knowledge of these physiological factors could support safer medicines development and clinical use. Purpose: This project investigated the feasibility of SPAR analysis of ECG signals to detect drug induced changes which a higher degree of sensitivity, to support safety evaluation during medicines development Methods: High resolution triplicate 12 lead ECG time-series data from a Phase one study of healthy human volunteers cross over of placebo, moxifloxacin or moxifloxacin + food was retrospectively analysed using SPAR at 0,1 and 6 hours. MATLAB bespoke software tool was used to perform SPAR analyses to transform ECG time-series into corresponding attractors. Corresponding single point measurements were previously obtained as part of the original Phase one study. Results: Initial evaluation of attractors revealed high inter-individual variation, consistent with previous SPAR ECG analysis. Nevertheless, we identified changes in subjects receiving Moxifloxacin +/- food vs placebo control. These changes were not as evident in previously obtained QT intervals. Conclusion: This pilot study illustrates that SPAR is highlighting changes on the ECG in fasted and fed states that are less obvious from QT data alone. Further evaluation of the whole dataset to identify generalisable SPAR features, and their comparison with existing markers is now necessary. The individualised nature of ECGs and corresponding attractors indicates the method may have highest utility in personalised medicine.

Harmonization of experimental procedures to assess mitochondrial respiration in human permeabilized skeletal muscle fibers

AimHigh-resolution respirometry in human permeabilized muscle fibers is extensively used for analysis of mitochondrial adaptions to nutrition and exercise interventions, and is linked to athletic performance. However, the lack of standardization of experimental conditions limits quantitative inter- and intra-laboratory comparisons. MethodsIn our study, an international team of investigators measured mitochondrial respiration of permeabilized muscle fibers obtained from three biopsies (vastus lateralis) from the same healthy volunteer to avoid inter-individual variability. High-resolution respirometry assays were performed together at the same laboratory to assess whether the heterogenity in published results are due to the effects of respiration media (MiR05 versus Z) with or without the myosin inhibitor blebbistatin at low- and high-oxygen regimes. ResultsOur findings reveal significant differences between respiration media for OXPHOS and ETcapacities supported by NADH&succinate-linked substrates at different oxygen concentrations. Respiratory capacities were approximately 1.5-fold higher in MiR05 at high-oxygen regimes compared to medium Z near air saturation. The presence or absence of blebbistatin in human permeabilized muscle fiber preparations was without effect on oxygen flux. ConclusionOur study constitutes a basis to harmonize and establish optimum experimental conditions for respirometric studies of permeabilized human skeletal muscle fibers to improve reproducibility.

Evaluation of intra- and inter-individual variations in plasma belimumab concentrations in adult patients with systemic lupus erythematosus.

In this study, plasma belimumab concentrations were measured over the course of treatment in systemic lupus erythematosus (SLE) patients on belimumab therapy, and intra- and interindividual variations in plasma belimumab concentration were evaluated. A single-center prospective study was conducted at Oita University Hospital to evaluate trough plasma concentrations over the course of treatment in 13 SLE patients treated with intravenous belimumab. Plasma belimumab concentrations were measured by a validated ultra-high performance liquid chromatography with tandem mass spectrometry method. The median age of the patients was 40 (interquartile range: 35-51) years and the median weight was 51.8 (47.0-58.1) kg. A mean of 9.4 (range: 1-13) blood samples was collected per patient at routine visits. The mean (± SD) plasma belimumab concentration was 33.4 ± 11.9 μg/mL in the patient with the lowest concentration and 170.0 ± 16.6 μg/mL in the patient with the highest concentration, indicating a 5-fold difference between patients. On the other hand, the within-patient coefficient of variation ranged from 7.1% to 35.7%, showing no large variations. No significant correlation was observed between plasma belimumab concentration and belimumab dose (mg/kg) (Spearman's rank correlation coefficient = 0.22, p = .54). Examinations of trough plasma belimumab concentrations over the course of treatment in patients with SLE showed small intraindividual variation but large interindividual variation. Plasma belimumab trough concentration varied widely among patients administered the approved dose.

Inter-individual variability (but intra-individual stability) of overt versus covert rehearsal strategies in a digital Corsi task.

The Corsi (block-tapping) paradigm is a classic and well-established visuospatial working memory task in humans involving internal computations (memorizing of item sequences, organizing and updating the memorandum, and recall processes), as well as both overt and covert shifts of attention to facilitate rehearsal, serving to maintain the Corsi sequences during the retention phase. Here, we introduce a novel digital version of a Corsi task in which i) the difficulty of the memorandum (using sequence lengths ranging from 3 to 8) was controlled, ii) the execution of overt and/or covert attention as well as the visuospatial working memory load during the retention phase was manipulated, and iii) shifts of attention were quantified in all experimental phases. With this, we present behavioral data that demonstrate, characterize, and classify the individual effects of overt and covert strategies used as a means of encoding and rehearsal. In a full within-subject design, we tested 28 participants who had to solve three different Corsi conditions. While in condition A neither of the two strategies were restricted, in condition B the overt and in condition C the overt as well as the covert strategies were suppressed. Analyzing Corsi span, (eye) exploration index, and pupil size (change), data clearly show a continuum between overt and covert strategies over all participants (indicating inter-individual variability). Further, all participants showed stable strategy choice (indicating intra-individual stability), meaning that the preferred strategy was maintained in all three conditions, phases, and sequence lengths of the experiment.