Large Interindividual Variability Research Articles

Magnitude and timescales of Ca isotope variability in human urine: implications for bone mass balance monitoring.

Calcium (Ca) isotopes in blood/urine are emerging biomarkers of bone mineral balance (BMB) in the human body. While multiple studies have investigated Ca isotopes in patients suffering from diseases affecting BMB, comparatively little effort has been devoted to understanding the homeostasis of Ca isotopes in healthy individuals. Here, we report on a longitudinal study of the urine Ca isotope composition (δ44/42CaUrine) from 22 healthy participants (age 19 to 60) over timescales ranging from days to months. Data from a single participant collected over a 30-day period show that morning urine is an excellent proxy for 24 hr pooled urine fractions. Data from all participants reveal large inter-individual variability in δ44/42CaUrine (up to 2.2 ‰), which is partly due to anthropometric differences, as shown by a correlation between the participants' body mass index (BMI) and δ44/42CaUrine values. In contrast, intra-individual data reveal encouraging stability (within ∼ ±0.2-0.3 ‰) over timescales>160 days, indicating that self-referencing approaches for BMB monitoring hold greater promise than cross sectional ones. Our data confirm that intra-individual δ44/42CaUrine variations are mainly a function of Ca reabsorption in the kidney, but also reveal the impact of other (and at times equally important) drivers, such as diet, alcohol consumption, physical exercise, or fasting. We also find that a magnetic resonance imaging contrast agent (gadolinium) can lead to artifacts during Ca isotope analysis. Based on our results, a series of practical considerations for the use of Ca isotopes in urine as tracers of BMB is presented.

Muscle fatigue, pedalling technique and the slow component during cycling.

Above the first lactate threshold, the steady-state is delayed or prevented due to the slow component ( ). This phenomenon has been associated with muscle fatigue, but evidence for a causal relationship is equivocal. Moreover, little is known about the contribution of pedalling technique adjustments to during fatiguing cycling exercise. Eleven participants completed constant power trials at 10% above the second lactate threshold. Muscle fatigue was assessed, utilizing femoral nerve stimulation and instrumented pedals, while , quadriceps oxygenation, electromyography (EMG) and pedal force components were measured. Correlations between physiological and mechanical variables were estimated at group and individual levels. Group correlations revealed moderate values for with quadriceps twitch force (r=-0.51) and muscle oxygenation (r=-0.52), while weak correlations were observed for EMG amplitude (r=0.26) and EMG mean power frequency (r=-0.16), and with pedalling mechanical variables such as peak total downstroke force (r=-0.16), minimum total upstroke force (r=-0.16) and upstroke index of effectiveness (r=0.16). The findings here align with prior literature reporting significant correlations between the magnitude of muscle fatigue and that of , although there was large interindividual variability for all the reported correlations. Considering the heterogeneity in the data, it is difficult to determine therelative impact of pedalling technique adjustments on overall, but the present study opens the possibility that in some cases, increases in secondary to technical adjustments may be 'superimposed' on the underlying .

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.

Pharmacokinetics and Pharmacodynamics of Systemic Corticosteroids in Autoimmune and Inflammatory Diseases: A Review of Current Evidence.

Systemic corticosteroids have a long history of use in the treatment of autoimmune and inflammatory diseases. Both efficacy and safety show large interindividual variability (IIV), suggesting that corticosteroids may have the potential for individualised dosing strategies to optimise therapy. This systematic review aims to provide an overview of current evidence on the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of systemic corticosteroids in patients with autoimmune and inflammatory diseases. A systematic literature search was conducted in PubMed and Embase for PK/PD studies of systemic corticosteroids in autoimmune and inflammatory diseases in humans published until December 2023. Studies were scored from 1 to 5 according to criteria for the levels of evidence, as inspired by the Oxford Centre for Evidence-Based Medicine. Twelve studies (1981-2016) were included. The majority of these studies had a small sample size. The corticosteroids involved were prednisone, prednisolone, methylprednisolone and budesonide. Substantial IIV of corticosteroid PK was described in all studies. Evidence for a relationship between the PK of corticosteroids and efficacy was inconclusive and limited. However, there was some evidence for a relationship between the PK of prednisolone and the severity of Cushingoid features. There is insufficient evidence to draw firm conclusions on the potential associations between PK and clinical outcome of systemic corticosteroid treatment in autoimmune and inflammatory diseases. This is remarkable given the many decades that steroid drugs have been used in clinical care. Prospective research is recommended with robust and well-defined cohorts to fully quantify the PK/PD associations of corticosteroids.

Influence of surprise on reinforcement learning in younger and older adults.

Surprise is a key component of many learning experiences, and yet its precise computational role, and how it changes with age, remain debated. One major challenge is that surprise often occurs jointly with other variables, such as uncertainty and outcome probability. To assess how humans learn from surprising events, and whether aging affects this process, we studied choices while participants learned from bandits with either Gaussian or bi-modal outcome distributions, which decoupled outcome probability, uncertainty, and surprise. A total of 102 participants (51 older, aged 50-73; 51 younger, 19-30 years) chose between three bandits, one of which had a bimodal outcome distribution. Behavioral analyses showed that both age-groups learned the average of the bimodal bandit less well. A trial-by-trial analysis indicated that participants performed choice reversals immediately following large absolute prediction errors, consistent with heightened sensitivity to surprise. This effect was stronger in older adults. Computational models indicated that learning rates in younger as well as older adults were influenced by surprise, rather than uncertainty, but also suggested large interindividual variability in the process underlying learning in our task. Our work bridges between behavioral economics research that has focused on how outcomes with low probability affect choice in older adults, and reinforcement learning work that has investigated age differences in the effects of uncertainty and suggests that older adults overly adapt to surprising events, even when accounting for probability and uncertainty effects.

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.

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.

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.

Usability of a novel Hounsfield units measurement procedure to quantify intercorporal bone graft remodeling in patients after posterior lumbar interbody fusion: a case series

BackgroundThere is a lack of knowledge about the biological process of intercorporal bone graft remodeling after posterior lumbar interbody fusion surgery and whether this process is associated with changes in back pain and intercorporal fusion status. As an alternative to the commonly used but unreliable fusion criteria, Hounsfield units can be used to quantify biological activity and changes in bone mineral content. However, studies assessing Hounsfield units conducted to date do not provide sufficient details about how the bone grafts were segmented to measure the Hounsfield units to allow for replication, and did not assess individual patient trends in graft changes over time. Using the data of nine patients after posterior lumbar interbody fusion, a novel Hounsfield units measurement procedure was developed and used to explore its usability to quantify the bone graft remodeling process.Case detailsWe report a case series of nine patients (six male, three female, mean age 64 years, all Caucasian) who all had computed tomography scans performed at 1 and 2 years after posterior lumbar interbody fusion surgery. Overall, seven out of the nine (78%) cases had a 3–41% increase in their bone grafts’ Hounsfield units between 1 and 2 years after surgery. The cases showed large interindividual variability in their Hounsfield units values over time, which coincided with varying levels of back pain and intercorporal fusion status.ConclusionThe Hounsfield units measurement procedure used for this case series may be useful to quantify intercorporal bone graft remodeling in patients after posterior lumbar interbody fusion, and may be used as an adjunct diagnostic measure to monitor bone graft remodeling over time. Future research is warranted to explore how to interpret bone graft Hounsfield units-values and Hounsfield units trajectories in light of clinical variables or intercorporal fusion status.

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.

Labetalol Dosing in Pregnancy: PBPK/PD and CYP2C19 Polymorphisms.

As detailed information on the pharmacokinetics (PK) of labetalol in pregnant people are lacking, the aims of this study were: (1) to build a physiologically based PK (PBPK) model of labetalol in non-pregnant individuals that incorporates different CYP2C19 genotypes (specifically, *1/*1, *1/*2 or *3, *2/*2, and *17/*17); (2) to translate this model to the second and third trimester of pregnancy; and (3) to combine the model with a previously published direct pharmacodynamic (PD) model to predict the blood pressure lowering effect of labetalol in the third trimester. Clinical data for model evaluation was obtained from the scientific literature. In non-pregnant populations, the mean ratios of simulated versus observed peak concentration (Cmax), time to reach Cmax (Tmax), and exposure (area under the plasma concentration-time curve, AUC) were 0.94, 0.82, and 1.16, respectively. The pregnancy PBPK model captured the observed PK adequately, but clearance was slightly underestimated with mean ratios of simulated versus observed Cmax, Tmax, and AUC of 1.28, 1.30, and 1.39, respectively. The results suggested that pregnant people with CYP2C19 *2/*2 alleles have similar labetalol exposure and trough levels compared to non-pregnant controls, whereas those with other alleles were found to have increased exposure and trough concentrations. Importantly, the pregnancy PBPK/PD model predicted that, despite increased exposure in some genotypes, the blood pressure lowering effect was broadly comparable across all genotypes. In view of the large inter-individual variability and the potentially increasing blood pressure during pregnancy, patients may need to be closely monitored for achieving optimal therapeutic effects and avoiding adverse events.

Transcriptome changes in humans acutely exposed to nanoparticles during grinding of dental nanocomposites.

Aim: Today, there is a lack of research studies concerning human acute exposure to nanoparticles (NPs). Our investigation aimed to simulate real-world acute inhalation exposure to NPs released during work with dental nanocomposites in a dental office or technician laboratory. Methods: Blood samples from female volunteers were processed before and after inhalation exposure. Transcriptomic mRNA and miRNA expression changes were analyzed. Results: We detected large interindividual variability, 90 significantly deregulated mRNAs, and 4 miRNAs when samples of participants before and after dental nanocomposite grinding were compared. Conclusion: The results suggest that inhaled dental NPs may present an occupational hazard to human health, as indicated by the changes in the processes related to oxidative stress, synthesis of eicosanoids, and cell division.

Quantitative summary on the human pharmacokinetic properties of cannabidiol to accelerate scientific clinical application of cannabis.

Cannabidiol (CBD) is a non-psychoactive substance that exerts numerous pharmacological benefits, including anti-inflammatory and antioxidant properties. It has received attention as a useful substance for the treatment of intractable pain, seizures, and anxiety, and related clinical trials have continued. However, the CBD pharmacokinetic results between reports are highly variable, making it difficult to clearly identify the pharmacokinetic properties of CBD. The main purpose of this study was to identify CBD clinical pharmacokinetic properties through meta-analysis. In particular, we sought to derive valid, interpretable independent variables and interpret their pharmacokinetic parameter correlations in relation to the large inter-individual and inter-study variability in CBD pharmacokinetics. For this study, CBD-related clinical trial reports were extensively screened and intercomparisons were performed between internal data sets through systematic classification and extraction of pharmacokinetic parameter values. The candidate independent variables associated with interpretation of CBD pharmacokinetic diversity established and explored in this study were as follows: diet, tetrahydrocannabinol (THC) combination, sample matrix type, liver and renal function, exposure route, dosage form, CBD exposure dose, cannabis smoking frequency, multiple exposure. The results of this study showed that CBD pharmacokinetics were influenced (increased plasma exposure by approximately 2-5 times) by diet immediately before or during CBD exposure, and that THC was not expected to have an antagonistic effect on the CBD absorption. The influence of changes in liver function would be significant in CBD pharmacokinetic diversity. Due to decreased liver function, the plasma exposure of CBD increased 2.57-5.15 times compared to healthy adults, and the half-life and clearance showed a 2.58-fold increase and a 5.15-fold decrease, respectively. CBD can be rapidly absorbed into the body (time to reach maximum concentration within 3.18h) by oral, transdermal, and inhalation exposures, and lipid emulsification and nanoformulation of CBD will greatly improve CBD bioavailability (up to approximately 2 times). The pharmacokinetics of CBD generally follow linear kinetic characteristics. The importance of this study is that it suggests key factors that should be considered in terms of pharmacokinetics in further clinical trials and formulations of CBD in the future.

Crop use structures resource selection strategies for African elephants in a human-dominated landscape.

To conserve wide-ranging species in degraded landscapes, it is essential to understand how the behavior of animals changes in relation to the degree and composition of modification. Evidence suggests that large inter-individual variation exists in the propensity for use of degraded areas and may be driven by both behavioral and landscape factors. The use of cultivated lands by wildlife is of particular interest, given the importance of reducing human-wildlife conflicts and understanding how such areas can function as biodiversity buffers. African elephant space use can be highly influenced by human activity and the degree to which individuals crop-raid. We analyzed GPS data from 56 free-ranging elephants in the Serengeti-Mara Ecosystem using resource selection functions (RSFs) to assess how crop use may drive patterns of resource selection and space use within a population. We quantified drivers of similarity in resource selection across individuals using proximity analysis of individual RSF coefficients derived from random forest models. We found wide variation in RSF coefficient values between individuals indicating strongly differentiated resource selection strategies. Proximity assessment indicated the degree of crop use in the dry season, individual repeatability, and time spent in unprotected areas drove similarity in resource selection patterns. Crop selection was also spatially structured in relation to agricultural fragmentation. In areas with low fragmentation, elephants spent less time in crops and selected most strongly for crops further from protected area boundaries, but in areas of high fragmentation, elephants spent twice as much time in crops and selected most strongly for crops closer to the protected area boundary. Our results highlight how individual differences and landscape structure can shape use of agricultural landscapes. We discuss our findings in respect to the conservation challenges of human-elephant conflict and incorporating behavioral variation into human-wildlife coexistence efforts.

Preliminary results of classifying otosclerosis and disarticulation using a convolutional neural network trained with simulated wideband acoustic immittance data

Current noninvasive methods of clinical practice often do not identify the causes of conductive hearing loss due to pathologic changes in the middle ear with sufficient certainty. Wideband acoustic immittance (WAI) measurement is noninvasive, inexpensive and objective. It is very sensitive to pathologic changes in the middle ear and therefore promising for diagnosis. However, evaluation of the data is difficult because of large interindividual variations. Machine learning methods like Convolutional neural networks (CNN) which might be able to deal with this overlaying pattern require a large amount of labeled measurement data for training and validation. This is difficult to provide given the low prevalence of many middle-ear pathologies. Therefore, this study proposes an approach in which the WAI training data of the CNN are simulated with a finite-element ear model and the Monte-Carlo method. With this approach, virtual populations of normal, otosclerotic, and disarticulated ears were generated, consistent with the averaged data of measured populations and well representing the qualitative characteristics of individuals. The CNN trained with the virtual data achieved for otosclerosis an AUC of 91.1 %, a sensitivity of 85.7 %, and a specificity of 85.2 %. For disarticulation, an AUC of 99.5 %, sensitivity of 100 %, and specificity of 93.1 % was achieved. Furthermore, it was estimated that specificity could potentially be increased to about 99 % in both pathological cases if stapes reflex threshold measurements were used to confirm the diagnosis. Thus, the procedures’ performance is comparable to classifiers from other studies trained with real measurement data, and therefore the procedure offers great potential for the diagnosis of rare pathologies or early-stages pathologies. The clinical potential of these preliminary results remains to be evaluated on more measurement data and additional pathologies.

Inter-individual variability of aerobic capacity after rehabilitation exercise training in children with severe burn injury

IntroductionSevere burn trauma damages resting and exercise cardiac function that may affect long term cardiovascular health. The implementation of rehabilitation exercise training (RET) soon after hospital discharge improves cardiorespiratory fitness; however, it does not fully restore aerobic capacity and presents large inter-individual variability. We tested the hypothesis that the inter-individual variability of aerobic capacity for responders (R) compared to nonresponders (NR) would differ for exercise frequency and intensity. MethodsThirty-three children (11 female, [mean±SD] 12 ± 3 years, 145 ± 18 cm, 40 ± 11 kg, 49 ± 31 BMI percentile) with severe burns (49 ± 15 % total body surface area burned, with 35 ± 22 % third-degree burns) completed a 6-week RET program. Cardiorespiratory fitness (peak VO2) was measured before and after RET. Frequency (session days/week), intensity (% peak heart rate), time (min/session), and volume (min/week) were compared between responders and non-responders. Significance was set at p < 0.05. ResultsSixty-four percent of the study population improved peak VO2 after RET whereas 36 % showed no improvements. Using a 2-way factorial ANOVA (group [G] × week [WK]), we found that exercise frequency and session time were similar and increased slightly over 6 weeks between R and NR (main effect for WK; P < 0.002). Exercise volume was significantly lower on week 2 for NR compared to R (G × WK interaction, P < 0.028). Exercise intensity over 6-weeks was significantly lower in the NR compared to the R group (G × WK interaction, P < 0.022). ConclusionsExercise intensity and volume may be important contributors for improving the interindividual response to exercise training for peak VO2. These data suggest that the appropriate dose-response requirement for exercise intensity may be > 80 % peak heart rate and exercise volume of > 150 min per week. Further understanding of the exercise prescription will provide insights important for cardiovascular rehabilitation in children with severe burns. Subject codeInter-individual Variability, Exercise, Pediatrics, Exercise Training

Large inter-individual variability in force-velocity profile changes in response to acute high-load resistance training.

While the acute effects of high-load resistance training on the force generating capacity of muscles have been widely examined, limited data exist on the relationship with the force-velocity profile (FV). Evidence suggests high sensitivity of the vertical FV profile to monitor changes in the muscle's mechanical properties according to the type of the exercise protocol. However, the interpretation of the findings seems not as straightforward. Therefore, the purpose of this study was to examine the effects of a high-load resistance training protocol on the muscle's mechanical properties during loaded jumps and on the vertical force-velocity profile (FV) in relation to maximal strength. 29 resistance-trained male (mean age±SD: 35.4 ± 7.8 years) and 29 female athletes (mean age±SD: 32.5 ± 7.0 years) participated in the study. Five-repetition maximum (5RM) in back squat, unloaded countermovement jump (CMJ) and FV profile were assessed. Loaded jumps were performed against 25, 50, 75, and 100 percent of body mass. Participants performed exercise protocols corresponding to their 5RM. Immediately after, unloaded CMJ and FV profile measurements were repeated. A significant decrease in CMJ height (∼5-6%) and in average power (∼4%) was recorded for both men and women. The FV profile did not change after the exercise protocol; however, there was a significant decrease in theoretical maximal power (from 4 to 5%) and in theoretical maximal velocity (∼3%). Maximal strength was not associated with the changes in FV profile. Findings suggest that an acute high-load exercise decreased vertical jump performance and maximal power output, but without a concomitant change in FV profile. The large interindividual variability in FV measures indicates a less straightforward connection of the applied exercise with the acute response in the FV profile, highlighting the complexity of the FV profile to monitor changes in response to an acute training load.

Talent development in female soccer: Developmental activities of professional players in England

ABSTRACT The activities soccer players engage in during their formative years are thought to significantly contribute to the acquisition of expert performance. Whilst this area has seen great interest in male players, there has been little research in females. The study examined developmental activities engaged in by professional female soccer players in England. 56 female soccer players that had either progressed to professional status in adulthood (professional), or did not (ex-academy), completed the Participant History Questionnaire. Professional players started engaging in soccer at an earlier age than their ex-academy counterparts, resulting in greater engagement in practice and play during childhood. During adolescence, professional players engaged in higher amounts of practice than ex-academy players. Engagement in competition and practice was rated as high in physical and cognitive effort by all, yet ex-academy players reported higher levels of physical effort during early adolescence, and cognitive effort during late adolescence. Findings provide an illustration of the talent pathways of professional female soccer players in England and may inform future talent development systems. Large interindividual variation in soccer-specific and other-sport activity data highlight the importance of further understanding the environments of individual soccer nations and their potential impact on the talent identification and development processes.

Optimal exposure of mycophenolic acid for induction therapy of childhood lupus nephritis patients: an observational cohort study.

Mycophenolic acid (MPA) is recommended for lupus nephritis (LN) treatment, but with large inter-individual variability in pharmacokinetics (PK). The aim of this study is to reveal the relationship between MPA exposure and disease response and adverse drug reactions in pediatric LN patients. This was a population-based observational cohort study. A total of 86 pediatric LN patients treated with mycophenolate mofetil (MMF) for induction therapy were enrolled. The area-under the concentration-time curve (AUC) was calculated using MPA concentrations according to a limited sampling strategy. Receiver operating characteristic analysis was performed to assess the MPA-AUC threshold values. The cumulative incidence of renal remission and inactive systemic lupus erythematosus (SLE) over time was evaluated by Kaplan-Meier's analysis. MPA-AUC was identified as an independent factor associated with renal remission and lupus activity at 6 and 12 months after MMF treatment, and the improved renal remission rates were correlated with higher MPA-AUC, with thresholds of 29.81 and 30.63 μg·h·mL-1 at 6months and 12 months, respectively. Furthermore, the thresholds for maintaining the hypoactive state of LN were 30.96 and 31.19 μg·h·mL-1at 6 months and 12 months, respectively. Patients reaching target thresholds for MPA-AUC achieved renal response or stable disease earlier. In addition, the MPA-AUC threshold for decreasing MMF-related adverse reactions was 50.80 μg·h·mL-1. The initial and long-term treatments of pediatric LN patients with MMF should be individualized according to the MPA-AUC, and the recommended MPA exposure is 31.19-50.80 μg·h·mL-1.

Transcranial Alternating Current Stimulation over Frontal Eye Fields Mimics Attentional Modulation of Visual Processing.

Attentional control over sensory processing has been linked to neural alpha oscillations and related inhibition of cerebral cortex. Despite the wide consensus on the functional relevance of alpha oscillations for attention, precise neural mechanisms of how alpha oscillations shape perception and how this top-down modulation is implemented in cortical networks remain unclear. Here, we tested the hypothesis that alpha oscillations in frontal eye fields (FEFs) are causally involved in the top-down regulation of visual processing in humans (male and female). We applied sham-controlled, intermittent transcranial alternating current stimulation (tACS) over bilateral FEF at either 10 Hz (alpha) or 40 Hz (gamma) to manipulate attentional preparation in a visual discrimination task. Under each stimulation condition, we measured psychometric functions for contrast perception and introduced a novel linear mixed modeling approach for statistical control of neurosensory side effects of the electric stimulation. tACS at alpha frequency reduced the slope of the psychometric function, resulting in improved subthreshold and impaired superthreshold contrast perception. Side effects on the psychometric functions were complex and showed large interindividual variability. Controlling for the impact of side effects on the psychometric parameters by using covariates in the linear mixed model analysis reduced this variability and strengthened the perceptual effect. We propose that alpha tACS over FEF mimicked a state of endogenous attention by strengthening a fronto-occipitoparietal network in the alpha band. We speculate that this network modulation enhanced phasic gating in occipitoparietal cortex leading to increased variability of single-trial psychometric thresholds, measurable as a reduction of psychometric slope.