This study was aimed to analyse the lower limb kinematics during the change of direction (COD) performance with the dominant (DL) and non-dominant (NDL) leg using linear (traditional kinematics) and nonlinear (Self Organising Map-based cluster analysis) approaches. Three 5-0-5 COD performances with the DL and three with the NDL were performed by 23 (aged 21.6 ± 2.3 years) collegiate athletes. No significant difference was observed between the COD duration, and approach speed of DL and NDL. Significantly greater ankle abductions, knee and hip external rotations were identified in COD with DL, compared to NDL (p < .001, d > 0.8). Self Organising Maps portrayed a completely different coordination pattern profile during change of direction performance with the DL and NDL. The cluster analysis illustrated similar inter-individual coordination patterning when participants turned with their DL or NDL. No visible relationship was observed in the cluster analysis of the lower limb joint angles and angular velocities. Outcomes of this study portrayed that coordination patterning (combination of joint angles and the rate of change of angles) could portray the movement patterning differences in different tasks, while a sole investigation on the joint angles or angular velocities may not reveal the underlying mechanisms of movement patterning.

• MeSH
• bérec * fyziologie   MeSH
• biomechanika MeSH
• dolní končetina * fyziologie   MeSH
• funkční lateralita * fyziologie   MeSH
• kotník fyziologie   MeSH
• lidé MeSH
• mladý dospělý MeSH
• motorické dovednosti * fyziologie   MeSH
• nelineární dynamika MeSH
• pohyb fyziologie   MeSH
• shluková analýza MeSH
• sportovní výkon * fyziologie   MeSH
• Check Tag
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

This study aimed to develop a vancomycin population pharmacokinetic model in obese adult patients treated with intermittent haemodialysis and propose a model-based loading dose strategy ensuring attainment of newly recommended AUC-based PK/PD target. Retrospective cross-sectional analysis was performed among obese haemodialysis dependent adult patients treated with intravenous vancomycin. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were used to identify the optimal loading dose for PK/PD target attainment during the first 48 h of treatment. Therapeutic drug monitoring data from 27 patients with a BMI of 30.2-52.9 kg/m2 were analysed. Among all tested variables, only LBM as a covariate of vancomycin Vd significantly improved the model, while vancomycin CL did not correlate with any of the tested variables. The median (IQR) value from the conditional mean of individual estimates of Vd and CL was 68.4 (56.6-84.2) L and 0.86 (0.79-0.90) L/h, respectively. To ensure optimal vancomycin exposure during the first 48 h of therapy, the vancomycin loading dose of 1500, 1750, 2000, 2250, 2500 and 2750 mg should be administered to obese patients with a lean body mass of ˂50, 50-60, 60-70, 70-80, 80-85 and >85 kg, respectively.

• MeSH
• antibakteriální látky * farmakokinetika   aplikace a dávkování   MeSH
• biologické modely MeSH
• dialýza ledvin * MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv MeSH
• obezita * komplikace   MeSH
• průřezové studie MeSH
• retrospektivní studie MeSH
• senioři MeSH
• vankomycin * farmakokinetika   aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: The objective of this study was to investigate the relationship between both short-term and long-term tacrolimus exposure and overall survival after allogeneic stem cell transplantation and to propose individualized tacrolimus dosing based on the population pharmacokinetic model. STUDY DESIGN: Tacrolimus exposure during the first 3 months of therapy after transplantation was calculated using therapeutic drug monitoring data from all patients who underwent allogeneic stem cell transplantation from 2016 to 2018. The optimal upper level was determined using ROC analysis, and the impact of cutoff tacrolimus exposure values on overall survival of patients was assessed together with other transplant variables using multivariate analysis. The population pharmacokinetic model was developed using a nonlinear mixed-effects modeling method, and the optimal tacrolimus dose was proposed. RESULTS: A total of 86 patients were included in the outcome analyses. Except for the disease risk category, age ≥55 years, and female-to-male donor, tacrolimus exposures of the area under the curve of trough concentrations (AUCtc) ≥ 222 ng h/mL, ≥258 ng h/mL, and ≥160 ng h/mL during the whole three-month period, second month, and third month of therapy, respectively, were also found to be statistically significant for overall survival in univariate analysis. These AUCtc values were independent variables for overall survival in multivariate analysis, with RR of 3.01 (P = 0.0056), 3.22 (P = 0.0058), and 2.93 (P = 0.0184) for the whole three-month period, second month, and third month of therapy, respectively. The disease risk category (RR 7.11; P < 0.0001), age (RR 2.45; P = 0.0214), and non-myeloablative conditioning (RR 3.39; P = 0.0014) were also significant factors influencing survival in multivariate analysis. Tacrolimus volume of distribution was 127.1 L and was not affected by any of the tested covariates, whereas clearance decreased with age according to the equation CL=7.94×e-0.0085×age and was reduced by 23% in patients who underwent repeat transplantation. CONCLUSION: Except for the disease risk category, age, and non-myeloablative conditioning, exposure to tacrolimus is an independent predictor of overall survival and should not exceed trough levels of 10.7 ng/mL during the second month and 6.8 ng/mL during third month after transplantation. In order to reach this target, nomogram for estimation of the maximal initial tacrolimus daily dose was developed based on the population pharmacokinetic model.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: The hypothalamus (HT) plays a crucial role in regulating eating behaviors. Disruptions in its function have been linked to the development of weight-related disorders. Nevertheless, its characterization remains a challenge. OBJECTIVES: We assessed the structural alterations of individual HT nuclei related to eating behaviors in patients with weight-related disorders, and their association with body mass index (BMI) and severity of eating disorders. METHODS: Forty-four young females with normal weight (HC, n = 21), restrictive anorexia nervosa (AN, n = 13), and living with obesity (OB, n = 10) were explored in vivo using 7-T high-resolution (0.6 mm isotropic voxel) T1 quantitative magnetic resonance imaging (MRI). Volumes and quantitative T1 values of individual HT nuclei were compared after whole-brain normalization using nonparametric tests (corrected for multiple comparisons for groups and regions). We investigated the parameters associated with BMI and eating disorders, such as MRI parameters of HT nuclei, ghrelin and leptin levels, depression, and anxiety using multivariate nonlinear partial least square (NIPALS). RESULTS: Both AN and OB showed higher volumes of HT relative to HC (Zscores: 0.78 ± 1.06; 1.43 ± 1.51). AN showed significantly higher volumes and T1 values of the right paraventricular nucleus (PaVN) (volume Zscore: 1.82 ± 1.45; T1 Zscore: 3.76 ± 4.67), and higher T1 values of the left PaVN (Zscore: 2.25 ± 2.37) and right periventricular nuclei (Zscore: 3.73 ± 4.81). NIPALS models showed that lower BMI in AN was associated with structural alterations of the bilateral PaVN, right anterior commissure, and left fornix (FX). Higher BMI in OB was associated with structural alterations within the right PaVN, bilateral FX, left posterior hypothalamic nucleus, right lateral HT, and right anterior hypothalamic area. Finally, the severity of eating disorders was associated with larger structural alterations within the bilateral PaVN, bilateral arcuate hypothalamic nuclei, right bed nucleus of stria terminalis, left medial preoptic nucleus, and right tubero-mammillary hypothalamic nucleus. CONCLUSIONS: Weight-related disorders are associated with significant micro and macrostructural alterations in HT nuclei involved in eating behaviors.

• MeSH
• dospělí MeSH
• hypothalamus * diagnostické zobrazování   patologie   MeSH
• index tělesné hmotnosti MeSH
• leptin krev   MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• mentální anorexie * diagnostické zobrazování   patologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• obezita * diagnostické zobrazování   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: While COVID-19 continues to challenge the world, meteorological variables are thought to impact COVID-19 transmission. Previous studies showed evidence of negative associations between high temperature and absolute humidity on COVID-19 transmission. Our research aims to fill the knowledge gap on the modifying effect of vaccination rates and strains on the weather-COVID-19 association. METHODS: Our study included COVID-19 data from 439 cities in 22 countries spanning 3 February 2020 - 31 August 2022 and meteorological variables (temperature, relative humidity, absolute humidity, solar radiation, and precipitation). We used a two-stage time-series design to assess the association between meteorological factors and COVID-19 incidence. For the exposure modeling, we used distributed lag nonlinear models with a lag of up to 14 days. Finally, we pooled the estimates using a random effect meta-analytic model and tested vaccination rates and dominant strains as possible effect modifiers. RESULTS: Our results showed an association between temperature and absolute humidity on COVID-19 transmission. At 5 °C, the relative risk of COVID-19 incidence is 1.22-fold higher compared to a reference level at 17 °C. Correlated with temperature, we observed an inverse association for absolute humidity. We observed a tendency of increased risk on days without precipitation, but no association for relative humidity and solar radiation. No interaction between vaccination rates or strains on the weather-COVID-19 association was observed. CONCLUSIONS: This study strengthens previous evidence of a relationship of temperature and absolute humidity with COVID-19 incidence. Furthermore, no evidence was found that vaccinations and strains significantly modify the relationship between environmental factors and COVID-19 transmission.

• Publikační typ
• časopisecké články MeSH

AIMS: Abiraterone treatment requires regular drug intake under fasting conditions due to pronounced food effect, which may impact patient adherence. The aim of this prospective study was to evaluate adherence to abiraterone treatment in patients with prostate cancer. To achieve this aim, an abiraterone population pharmacokinetic model was developed and patients' adherence has been estimated by comparison of measured levels of abiraterone with population model-based simulations. METHODS: A total of 1469 abiraterone plasma levels from 83 healthy volunteers collected in a bioequivalence study were analysed using a nonlinear mixed-effects model. Monte Carlo simulation was used to describe the theoretical distribution of abiraterone pharmacokinetic profiles at a dose of 1000 mg once daily. Adherence of 36 prostate cancer patients treated with abiraterone was then evaluated by comparing the real abiraterone concentration measured in each patient during follow-up visit with the theoretical distribution of profiles based on simulations. Patients whose abiraterone levels were ˂5th or ˃95th percentile of the distribution of simulated profiles were considered to be non-adherent. RESULTS: Based on this evaluation, 13 patients (36%) have been classified as non-adherent. We observed significant association (P = .0361) between richness of the breakfast and rate of non-adherence. Adherent patients reported significantly better overall condition in self-assessments (P = .0384). A trend towards a higher occurrence of adverse effects in non-adherent patients was observed. CONCLUSIONS: We developed an abiraterone population pharmacokinetic model and proposed an advanced approach to medical adherence evaluation. Due to the need for administration under fasting conditions, abiraterone therapy is associated with a relatively high rate of non-adherence.

• MeSH
• adherence k farmakoterapii * statistika a číselné údaje   MeSH
• androsteny * farmakokinetika   aplikace a dávkování   terapeutické užití   MeSH
• biologické modely * MeSH
• dospělí MeSH
• interakce mezi potravou a léky MeSH
• lidé středního věku MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• nádory prostaty * farmakoterapie   MeSH
• omezení příjmu potravy MeSH
• prospektivní studie MeSH
• protinádorové látky farmakokinetika   aplikace a dávkování   MeSH
• senioři MeSH
• terapeutická ekvivalence MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The association between nonoptimal temperatures and cardiovascular mortality risk is recognized. However, a comprehensive global assessment of this burden is lacking. OBJECTIVES: The goal of this study was to assess global cardiovascular mortality burden attributable to nonoptimal temperatures and investigate spatiotemporal trends. METHODS: Using daily cardiovascular deaths and temperature data from 32 countries, a 3-stage analytical approach was applied. First, location-specific temperature-mortality associations were estimated, considering nonlinearity and delayed effects. Second, a multivariate meta-regression model was developed between location-specific effect estimates and 5 meta-predictors. Third, cardiovascular deaths associated with nonoptimal, cold, and hot temperatures for each global grid (55 km × 55 km resolution) were estimated, and temporal trends from 2000 to 2019 were explored. RESULTS: Globally, 1,801,513 (95% empirical CI: 1,526,632-2,202,831) annual cardiovascular deaths were associated with nonoptimal temperatures, constituting 8.86% (95% empirical CI: 7.51%-12.32%) of total cardiovascular mortality corresponding to 26 deaths per 100,000 population. Cold-related deaths accounted for 8.20% (95% empirical CI: 6.74%-11.57%), whereas heat-related deaths accounted for 0.66% (95% empirical CI: 0.49%-0.98%). The mortality burden varied significantly across regions, with the highest excess mortality rates observed in Central Asia and Eastern Europe. From 2000 to 2019, cold-related excess death ratios decreased, while heat-related ratios increased, resulting in an overall decline in temperature-related deaths. Southeastern Asia, Sub-Saharan Africa, and Oceania observed the greatest reduction, while Southern Asia experienced an increase. The Americas and several regions in Asia and Europe displayed fluctuating temporal patterns. CONCLUSIONS: Nonoptimal temperatures substantially contribute to cardiovascular mortality, with heterogeneous spatiotemporal patterns. Effective mitigation and adaptation strategies are crucial, especially given the increasing heat-related cardiovascular deaths amid climate change.

• MeSH
• celosvětové zdraví * MeSH
• kardiovaskulární nemoci * mortalita   MeSH
• lidé MeSH
• nízká teplota škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

• MeSH
• celogenomová asociační studie * MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• mendelovská randomizace MeSH
• rizikové faktory MeSH
• strojové učení MeSH
• syndrom neklidných nohou * genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

This study aimed to explore pharmacokinetics of voriconazole and its covariates in lung transplant recipients using population approach in order to propose dosing individualization. Data from routine therapeutic drug monitoring in adult lung transplant recipients treated with oral voriconazole were analysed with a three-stage population pharmacokinetic model using nonlinear mixed-effects modelling. Monte Carlo simulations based on final voriconazole pharmacokinetic model were used to generate the theoretical distribution of pharmacokinetic profiles at various dosing regimens. A total of 78 voriconazole serum concentrations collected from 40 patients were included in pharmacokinetic analysis. The only significant covariate was age for voriconazole clearance. Population voriconazole apparent clearance started at 32.26 L/h and decreased by 0.021 L/h with each year of patient's age, while population apparent volume of distribution was 964.46 L. Based on this model, we have proposed an easy-to-use dosing regimen consisting of a loading dose of 400 mg every 12 h for the first 48 h of treatment followed by maintenance dose of 300 mg every 12 h in patients aged up to 59 years, or by maintenance dose of 200 mg every 12 h in patients aged above 59 years.

• MeSH
• biologické modely MeSH
• dospělí MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv * MeSH
• plíce MeSH
• příjemce transplantátu * MeSH
• senioři MeSH
• vorikonazol farmakokinetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

Applications of causal techniques to neural time series have increased extensively over last decades, including a wide and diverse family of methods focusing on electroencephalogram (EEG) analysis. Besides connectivity inferred in defined frequency bands, there is a growing interest in the analysis of cross-frequency interactions, in particular phase and amplitude coupling and directionality. Some studies show contradicting results of coupling directionality from high frequency to low frequency signal components, in spite of generally considered modulation of a high-frequency amplitude by a low-frequency phase. We have compared two widely used methods to estimate the directionality in cross frequency coupling: conditional mutual information (CMI) and phase slope index (PSI). The latter, applied to infer cross-frequency phase-amplitude directionality from animal intracranial recordings, gives opposite results when comparing to CMI. Both metrics were tested in a numerically simulated example of unidirectionally coupled Rössler systems, which helped to find the explanation of the contradictory results: PSI correctly estimates the lead/lag relationship which, however, is not generally equivalent to causality in the sense of directionality of coupling in nonlinear systems, correctly inferred by using CMI with surrogate data testing.

• MeSH
• elektroencefalografie * metody   MeSH
• lidé MeSH
• modely neurologické MeSH
• mozek fyziologie   MeSH
• nelineární dynamika * MeSH
• počítačová simulace MeSH
• počítačové zpracování signálu MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH