With the incorporation of effective therapies for myelofibrosis (MF), accurately predicting outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) is crucial for determining the optimal timing for this procedure. Using data from 5183 patients with MF who underwent first allo-HCT between 2005 and 2020 at European Society for Blood and Marrow Transplantation centers, we examined different machine learning (ML) models to predict overall survival after transplant. The cohort was divided into a training set (75%) and a test set (25%) for model validation. A random survival forests (RSF) model was developed based on 10 variables: patient age, comorbidity index, performance status, blood blasts, hemoglobin, leukocytes, platelets, donor type, conditioning intensity, and graft-versus-host disease prophylaxis. Its performance was compared with a 4-level Cox regression-based score and other ML-based models derived from the same data set, and with the Center for International Blood and Marrow Transplant Research score. The RSF outperformed all comparators, achieving better concordance indices across both primary and postessential thrombocythemia/polycythemia vera MF subgroups. The robustness and generalizability of the RSF model was confirmed by Akaike information criterion and time-dependent receiver operating characteristic area under the curve metrics in both sets. Although all models were prognostic for nonrelapse mortality, the RSF provided better curve separation, effectively identifying a high-risk group comprising 25% of patients. In conclusion, ML enhances risk stratification in patients with MF undergoing allo-HCT, paving the way for personalized medicine. A web application (https://gemfin.click/ebmt) based on the RSF model offers a practical tool to identify patients at high risk for poor transplantation outcomes, supporting informed treatment decisions and advancing individualized care.
- MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Survival Rate MeSH
- Primary Myelofibrosis * therapy mortality MeSH
- Prognosis MeSH
- Aged MeSH
- Machine Learning * MeSH
- Hematopoietic Stem Cell Transplantation * mortality MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Pressure Ulcer diagnosis nursing therapy MeSH
- Home Nursing MeSH
- Nursing Assessment MeSH
- Home Care Services MeSH
- Publication type
- Case Reports MeSH
Developmental remodeling shapes neural circuits via activity-dependent pruning of synapses and axons. Regulation of the cytoskeleton is critical for this process, as microtubule loss via enzymatic severing is an early step of pruning across many circuits and species. However, how microtubule-severing enzymes, such as spastin, are activated in specific neuronal compartments remains unknown. Here, we reveal that polyglutamylation, a post-translational tubulin modification enriched in neurons, plays an instructive role in developmental remodeling by tagging microtubules for severing. Motor neuron-specific gene deletion of enzymes that add or remove tubulin polyglutamylation-TTLL glutamylases vs. CCP deglutamylases-accelerates or delays neuromuscular synapse remodeling in a neurotransmission-dependent manner. This mechanism is not specific to peripheral synapses but also operates in central circuits, e.g., the hippocampus. Thus, tubulin polyglutamylation acts as a cytoskeletal rheostat of remodeling that shapes neuronal morphology and connectivity.
- MeSH
- Hippocampus metabolism cytology MeSH
- Polyglutamic Acid * metabolism MeSH
- Microtubules * metabolism MeSH
- Motor Neurons * metabolism MeSH
- Mice MeSH
- Neuromuscular Junction metabolism MeSH
- Synaptic Transmission MeSH
- Neurons * metabolism MeSH
- Neuronal Plasticity * physiology MeSH
- Peptide Synthases metabolism genetics MeSH
- Protein Processing, Post-Translational MeSH
- Spastin metabolism MeSH
- Synapses metabolism MeSH
- Tubulin metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Dyslipidaemia is a key risk factor for atherosclerotic cardiovascular disease (ASCVD), necessitating effective statin therapy. Despite statins' proven safety and efficacy, adherence remains suboptimal, with significant gaps between clinical practice and guideline recommendations. METHODS: This retrospective cohort study analysed anonymized health administrative claims data from six employee health funds in the Czech Republic, covering approximately 40% of the insured population from January 1, 2017, to December 31, 2020. We identified statin-incident as well as prevalent cohort of patients. Adherence to statin therapy was assessed using the proportion of days covered (PDC) metric, with factors such as age, gender, sequence of use, and treatment intensity considered as modifiers. RESULTS: Among the statin-prevalent cohort (SP, n = 890,180), 83.5% achieved a PDC ≥ 50%, and 61.0% reached a PDC ≥ 80%. In the statin-incident cohort (SI, n = 287,871), a clear trend of increasing adherence with age and medication sequence was observed: in adults aged 18-39 median PDC rose from 84.1% (IQR: 57-100) in the first to 94.7% (IQR: 75.6-100) in the third sequence; in those aged 80 + median PDC rose from 95.0% (IQR: 68.9-100) in the first to 100% (IQR: 78.3-100) in the third sequence. Logistic regression identified age (OR=1.011 per year), female gender (OR=0.896), high-intensity treatment (OR=0.975), and second (OR=1.267) or later treatment sequences (OR=1.704) as significant predictors of adherence (all p < 0.001). CONCLUSION: Adherence to statin therapy improves with subsequent treatment sequences and age. These findings highlight the need for targeted interventions to enhance adherence, particularly among younger patients. The PDC metric is recommended for integration into clinical practice to monitor and improve medication adherence.
- MeSH
- Medication Adherence * MeSH
- Adult MeSH
- Dyslipidemias * drug therapy MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors * therapeutic use MeSH
- Age Factors MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
Previous research has studied the extent to which men are the default members of social groups in terms of memory, categorization, and stereotyping, but not attitudes which is critical because of attitudes' relationship to behavior. Results from our survey (N > 5000) collected via a globally distributed laboratory network in over 40 regions demonstrated that attitudes toward Black people and politicians had a stronger relationship with attitudes toward the men rather than the women of the group. However, attitudes toward White people had a stronger relationship with attitudes toward White women than White men, whereas attitudes toward East Asian people, police officers, and criminals did not have a stronger relationship with attitudes toward either the men or women of each respective group. Regional agreement with traditional gender roles was explored as a potential moderator. These findings have implications for understanding the unique forms of prejudice women face around the world.
- MeSH
- White People MeSH
- Black People MeSH
- Adult MeSH
- Humans MeSH
- Attitude * MeSH
- Prejudice * MeSH
- Sex Factors MeSH
- Stereotyping MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
N-Methyl-d-aspartate receptors (NMDARs) play a crucial role in excitatory neurotransmission, with numerous pathogenic variants identified in the GluN subunits, including their ligand-binding domains (LBDs). The prevailing hypothesis postulates that the endoplasmic reticulum (ER) quality control machinery verifies the agonist occupancy of NMDARs, but this was tested in a limited number of studies. Using microscopy and electrophysiology in the human embryonic kidney 293 (HEK293) cells, we found that surface expression of GluN1/GluN2A receptors containing a set of alanine substitutions within the LBDs correlated with the measured EC50 values for glycine (GluN1 subunit mutations) while not correlating with the measured EC50 values for l-glutamate (GluN2A subunit mutations). The mutant cycle of GluN1-S688 residue, including the pathogenic GluN1-S688Y and GluN1-S688P variants, showed a correlation between relative surface expression of the GluN1/GluN2A receptors and the measured EC50 values for glycine, as well as with the calculated ΔGbinding values for glycine obtained from molecular dynamics simulations. In contrast, the mutant cycle of GluN2A-S511 residue did not show any correlation between the relative surface expression of the GluN1/GluN2A receptors and the measured EC50 values for l-glutamate or calculated ΔGbinding values for l-glutamate. Coexpression of both mutated GluN1 and GluN2A subunits led to additive or synergistic alterations in the surface number of GluN1/GluN2A receptors. The synchronized ER release by ARIAD technology confirmed the altered early trafficking of GluN1/GluN2A receptors containing the mutated LBDs. The microscopical analysis from embryonal rat hippocampal neurons (both sexes) corroborated our conclusions from the HEK293 cells.
- MeSH
- Glycine metabolism MeSH
- HEK293 Cells MeSH
- Hippocampus cytology metabolism MeSH
- Rats MeSH
- Glutamic Acid metabolism MeSH
- Humans MeSH
- Ligands MeSH
- Mutation genetics MeSH
- Protein Domains MeSH
- Nerve Tissue Proteins MeSH
- Receptors, N-Methyl-D-Aspartate * metabolism genetics chemistry MeSH
- Protein Transport physiology genetics MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Polymorphisms in thiopurine methyltransferase (TPMT) are a predominant cause of azathioprine-induced leucopenia in Western countries. The exact role of these polymorphisms in the Indian population with dermatological disorders is uncertain. OBJECTIVES: To evaluate the frequency of genetic polymorphism of TPMT and its impact on the safety of azathioprine in dermatological disorders. METHODS: We included consecutive patients on azathioprine who were initiated for dermatological disorders from South India. Three TPMT polymorphisms (c.238G>C, c.460G>A and c.719A>G) were assessed. The proportions of adverse events to azathioprine, especially myelosuppression, were compared between those with the wildtype genotype and those with TPMT polymorphisms. RESULTS: Of the 123 patients (61 male and 62 female, mean age 46 years), 65% had an autoimmune blistering disorder. Adverse events to azathioprine were noted in 25 (20.3%), of whom 16 (13.0%) had myelosuppression and 4 (3.2%) each had hepatotoxicity and gastrointestinal intolerance. TPMT polymorphisms were detected in 13 (10.6%), of whom 5 had experienced adverse events. The polymorphisms could explain 25% (4 of 16) of the cases of leucopenia. The odds of developing leucopenia in patients with TPMT polymorphism were not significant (odds ratio 3.63, 95% confidence interval 0.96-13.6; P = 0.06). CONCLUSIONS: The tested TPMT polymorphisms could not predict the adverse events of azathioprine, particularly the haematological toxicity, in dermatological use among the South Indian population.
- MeSH
- Azathioprine * adverse effects therapeutic use MeSH
- Adult MeSH
- Genotype MeSH
- Immunosuppressive Agents * adverse effects therapeutic use MeSH
- Clinical Relevance MeSH
- Skin Diseases * drug therapy genetics MeSH
- Leukopenia chemically induced genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Methyltransferases * genetics MeSH
- Adolescent MeSH
- Young Adult MeSH
- Polymorphism, Genetic MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- India MeSH
xviii, 190 stran : portrét ; 21 cm
Štúdia, ktorá sa zameriava na vývojovú psychológiu, konkrétne na formovanie vzťahovej väzby v priebehu života človeka. Určené odbornej verejnosti.
- MeSH
- Interpersonal Relations MeSH
- Object Attachment MeSH
- Family Relations MeSH
- Psychology, Developmental MeSH
- Conspectus
- Vývojová psychologie. Individuální psychologie
- NML Fields
- psychologie, klinická psychologie
- NML Publication type
- studie
