We have developed a method to longitudinally classify subjects into two or more prognostic groups using longitudinally observed values of markers related to the prognosis. We assume the availability of a training data set where the subjects' allocation into the prognostic group is known. The proposed method proceeds in two steps as described earlier in the literature. First, multivariate linear mixed models are fitted in each prognostic group from the training data set to model the dependence of markers on time and on possibly other covariates. Second, fitted mixed models are used to develop a discrimination rule for future subjects. Our method improves upon existing approaches by relaxing the normality assumption of random effects in the underlying mixed models. Namely, we assume a heteroscedastic multivariate normal mixture for random effects. Inference is performed in the Bayesian framework using the Markov chain Monte Carlo methodology. Software has been written for the proposed method and it is freely available. The methodology is applied to data from the Dutch Primary Biliary Cirrhosis Study.

• MeSH
• biliární cirhóza farmakoterapie   MeSH
• biologické markery analýza   MeSH
• cholagoga a choleretika terapeutické užití   MeSH
• diskriminační analýza MeSH
• interpretace statistických dat MeSH
• kyselina ursodeoxycholová terapeutické užití   MeSH
• lidé MeSH
• lineární modely MeSH
• longitudinální studie MeSH
• počítačová simulace MeSH
• progrese nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• statistika jako téma MeSH

• Konspekt
• Statistika
• NLK Obory
• statistika, zdravotnická statistika

BACKGROUND: Evidence regarding the effectiveness of allergen immunotherapy (AIT) on allergic rhinitis has been provided mostly by randomised controlled trials, with little data from real-life studies. OBJECTIVE: To compare the reported control of allergic rhinitis symptoms in three groups of users of the MASK-air® app: those receiving sublingual AIT (SLIT), those receiving subcutaneous AIT (SCIT), and those receiving no AIT. METHODS: We assessed the MASK-air® data of European users with self-reported grass pollen allergy, comparing the data reported by patients receiving SLIT, SCIT and no AIT. Outcome variables included the daily impact of allergy symptoms globally and on work (measured by visual analogue scales-VASs), and a combined symptom-medication score (CSMS). We applied Bayesian mixed-effects models, with clustering by patient, country and pollen season. RESULTS: We analysed a total of 42,756 days from 1,093 grass allergy patients, including 18,479 days of users under AIT. Compared to no AIT, SCIT was associated with similar VAS levels and CSMS. Compared to no AIT, SLIT-tablet was associated with lower values of VAS global allergy symptoms (average difference = 7.5 units out of 100; 95% credible interval [95%CrI] = -12.1;-2.8), lower VAS Work (average difference = 5.0; 95%CrI = -8.5;-1.5), and a lower CSMS (average difference = 3.7; 95%CrI = -9.3;2.2). When compared to SCIT, SLIT-tablet was associated with lower VAS global allergy symptoms (average difference = 10.2; 95%CrI = -17.2;-2.8), lower VAS Work (average difference = 7.8; 95%CrI = -15.1;0.2), and a lower CSMS (average difference = 9.3; 95%CrI = -18.5;0.2). CONCLUSION: In patients with grass pollen allergy, SLIT-tablet, when compared to no AIT and to SCIT, is associated with lower reported symptom severity. Future longitudinal studies following internationally-harmonised standards for performing and reporting real-world data in AIT are needed to better understand its 'real-world' effectiveness.

• Publikační typ
• časopisecké články MeSH

Metabotropic glutamate receptors (mGluRs) represent a potential therapeutic target. Possible anticonvulsant action of AMN 082, an agonist of mGluR7 subtype, was studied in immature rats using pentylenetetrazol (PTZ)-induced seizures as a model. Five age groups of rats (7-, 12-, 18-, 25-day-old and adult animals) were pretreated with AMN 082 in doses of 0.5, 1, 2, and 5 mg/kg i.p. and 30 min later PTZ was administered (100 mg/kg s.c.). Controls received saline instead of the agonist. AMN 082 did not exhibit clear anticonvulsant action with the exception of suppression of the tonic phase of generalized tonic-clonic seizures (GTCS) in 12-day-old rats. Shorter latencies of GTCS after AMN 082 pretreatment indicate a proconvulsant action. Involuntary movements (mostly tremor) appeared after AMN 082 before PTZ administration, therefore we performed another experimental series with AMN 082 only (1, 2, 5, and 10 mg/kg i.p.). During 60-min observation period tremor appeared in all age groups; sensitivity to this action decreased with age from the 2 mg/kg dose in 7- and 12-day-old rats to the 10 mg/kg dose in adult rats. Mixed anti- and proconvulsant actions of AMN 082 together with unwanted motor effects makes clinical use of this drug highly improbable.

• Klíčová slova
• Seizures, Rat, Ontogeny, mGluR7, Unwanted motor effects,
• MeSH
• agonisté excitačních aminokyselin toxicita   MeSH
• antikonvulziva toxicita   MeSH
• benzhydrylové sloučeniny toxicita   MeSH
• financování organizované MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• pentylentetrazol MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Wistar MeSH
• reakční čas MeSH
• receptory metabotropního glutamátu agonisté   metabolismus   MeSH
• stárnutí MeSH
• věkové faktory MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• záchvaty chemicky indukované   metabolismus   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

Public support of training in firms corresponds to the long-term importance of the quality of human capital in the competitiveness of firms and nations. Thus, the EU supports such training via the European Social Fund (ESF). The evaluation community evaluates the support by using either qualitative or quantitative methods. The simultaneous application of these two approaches is rare. The purpose of this paper is to combine quantitative (counterfactual impact evaluation) and qualitative (qualitative comparative analysis) methods in order to fill the methodological gap. Based on the combination of both approaches, it explores their strengths, complementarity and disadvantages to evaluate public support for employee training in the Czech Republic. The combination of methods makes it possible to identify not only the impacts but also their causes. Linking the ESF support to corporate competitiveness is crucial for demonstrating the effectiveness of public spending.

• MeSH
• doškolování organizace a řízení   MeSH
• financování vládou ekonomika   organizace a řízení   MeSH
• hodnocení programu metody   MeSH
• kauzalita MeSH
• lidé MeSH
• případové studie organizací MeSH
• výzkumný projekt * MeSH
• zaměstnanost organizace a řízení   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika 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

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

OBJECTIVE: To develop a preoperative risk model, using endometrial biopsy results and clinical and ultrasound variables, to predict the individual risk of lymph-node metastases in women with endometrial cancer. METHODS: A mixed-effects logistic regression model for prediction of lymph-node metastases was developed in 1501 prospectively included women with endometrial cancer undergoing transvaginal ultrasound examination before surgery, from 16 European centers. Missing data, including missing lymph-node status, were imputed. Discrimination, calibration and clinical utility of the model were evaluated using leave-center-out cross validation. The predictive performance of the model was compared with that of risk classification from endometrial biopsy alone (high-risk defined as endometrioid cancer Grade 3/non-endometrioid cancer) or combined endometrial biopsy and ultrasound (high-risk defined as endometrioid cancer Grade 3/non-endometrioid cancer/deep myometrial invasion/cervical stromal invasion/extrauterine spread). RESULTS: Lymphadenectomy was performed in 691 women, of whom 127 had lymph-node metastases. The model for prediction of lymph-node metastases included the predictors age, duration of abnormal bleeding, endometrial biopsy result, tumor extension and tumor size according to ultrasound and undefined tumor with an unmeasurable endometrium. The model's area under the curve was 0.73 (95% CI, 0.68-0.78), the calibration slope was 1.06 (95% CI, 0.79-1.34) and the calibration intercept was 0.06 (95% CI, -0.15 to 0.27). Using a risk threshold for lymph-node metastases of 5% compared with 20%, the model had, respectively, a sensitivity of 98% vs 48% and specificity of 11% vs 80%. The model had higher sensitivity and specificity than did classification as high-risk, according to endometrial biopsy alone (50% vs 35% and 80% vs 77%, respectively) or combined endometrial biopsy and ultrasound (80% vs 75% and 53% vs 52%, respectively). The model's clinical utility was higher than that of endometrial biopsy alone or combined endometrial biopsy and ultrasound at any given risk threshold. CONCLUSIONS: Based on endometrial biopsy results and clinical and ultrasound characteristics, the individual risk of lymph-node metastases in women with endometrial cancer can be estimated reliably before surgery. The model is superior to risk classification by endometrial biopsy alone or in combination with ultrasound. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

• MeSH
• dospělí MeSH
• endometroidní karcinom diagnostické zobrazování   sekundární   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• lineární modely MeSH
• lymfatické metastázy MeSH
• lymfatické uzliny MeSH
• nádory endometria diagnostické zobrazování   patologie   MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• staging nádorů MeSH
• ultrasonografie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVES: The objective of this study was to develop a population pharmacokinetic model of meropenem in a heterogeneous population of patients with a serious bacterial infection in order to propose dosing optimisation leading to improved achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target. METHODS: A total of 174 meropenem serum levels obtained from 144 patients during therapeutic drug monitoring were analysed using a non-linear mixed-effects modelling approach and Monte Carlo simulation was then used to compare various dosing regimens in order to optimise PK/PD target attainment. RESULTS: The meropenem volume of distribution of the patient population was 54.95 L, while clearance started at 3.27 L/hour and increased by 0.91 L/hour with each 1 mL/s/1.73 m2 of estimated glomerular filtration rate. Meropenem clearance was also 0.31 L/hour higher in postoperative patients with central nervous system infection. Meropenem administration by continuous infusion showed a significantly higher probability of attaining the PK/PD target than a standard 30 min infusion (95.3% vs 49.5%). CONCLUSIONS: A daily meropenem dose of 3 g, 6 g and 10.5 g administered by continuous infusion was shown to be accurate for patients with moderate to severe renal impairment, normal renal function to mild renal impairment and augmented renal clearance, respectively.

• MeSH
• antibakteriální látky * farmakokinetika   aplikace a dávkování   MeSH
• bakteriální infekce * farmakoterapie   MeSH
• biologické modely * MeSH
• dospělí MeSH
• intravenózní infuze MeSH
• lidé středního věku MeSH
• lidé MeSH
• meropenem * farmakokinetika   aplikace a dávkování   MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv metody   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• epidemiologická měření MeSH
• infekční nemoci MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• infekční lékařství
• epidemiologie