BACKGROUND: Corticosteroids are among the few effective treatments for knee osteoarthritis, but short duration of action limits their utility. EP-104IAR, a long-acting formulation of fluticasone propionate for intra-articular injection, optimises the action of fluticasone propionate through novel diffusion-based extended-release technology. The SPRINGBOARD trial assessed the efficacy, safety, and pharmacokinetics of EP-104IAR in people with knee osteoarthritis. METHODS: SPRINGBOARD was a randomised, vehicle-controlled, double-blind, phase 2 trial done at 12 research sites in Denmark, Poland, and Czech Republic. We recruited adults aged 40 years or older with primary knee osteoarthritis (Kellgren-Lawrence grade 2-3) who reported Western Ontario and McMaster Universities Osteoarthritis Arthritis Index (WOMAC) pain scores of at least 4 and no more than 9 out of 10. Participants were randomly assigned (1:1) to receive one intra-articular dose of 25 mg EP-104IAR or vehicle control. Randomisation was done via interactive web-based access to a central predefined computer-generated list with block size of six (allocated by clinical site). Participants and assessors were masked to treatment allocation. Participants were followed up for 24 weeks. The primary outcome was the difference between groups in change in WOMAC pain score from baseline to week 12, analysed in all participants who were randomly assigned and received treatment. Safety, including laboratory analyses, and pharmacokinetics from quantification of fluticasone propionate in peripheral blood were assessed in all participants who received a dose of randomly assigned treatment. A person with lived experience of knee osteoarthritis was involved in study interpretation and writing of the report. This trial is registered with ClinicalTrials.gov, NCT04120402, and the EU Clinical Trials Register, EudraCT 2021-000859-39, and is complete. FINDINGS: Between Sept 10, 2021, and Nov 16, 2022, 1294 people were screened for eligibility, and 319 were randomly assigned to EP-104IAR (n=164) or vehicle control (n=155). One participant in the EP-104IAR group was excluded from all analyses because treatment was not administered due to an adverse event. 318 participants (135 [42%] male and 183 [58%] female, 315 [99%] White) received randomly assigned treatment and were included in the primary analysis and safety analysis (EP-104IAR, n=163; vehicle control, n=155). At week 12, least squares mean change in WOMAC pain score from baseline was -2·89 (95% CI -3·22 to -2·56) in the EP-104IAR group and -2·23 (-2·56 to -1·89) in the vehicle control group, with a between-group difference of -0·66 (-1·11 to -0·21; p=0·0044); a significant between-group difference persisted to week 14. 106 (65%) of 163 participants in the EP-104IAR group had one or more treatment-emergent adverse event compared with 89 (57%) of 155 participants in the vehicle control group. Effects on serum glucose and cortisol concentrations were minimal and transient. There were no treatment-emergent deaths or treatment-related serious adverse events. Plasma concentrations of fluticasone propionate showed a blunted initial peak with terminal half-life of approximately 18-20 weeks. INTERPRETATION: These phase 2 results suggest that EP-104IAR has the potential to offer clinically meaningful pain relief in knee osteoarthritis for an extended period of up to 14 weeks, longer than published data for currently marketed corticosteroids. There were minimal effects on glucose and cortisol, and stable fluticasone propionate concentrations in plasma. The safety and efficacy of EP-104IAR will be further evaluated in phase 3 trials, including the possibility of bilateral and repeat dosing with EP-104IAR. FUNDING: Eupraxia Pharmaceuticals. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

• MeSH
• artróza kolenních kloubů * farmakoterapie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• flutikason * aplikace a dávkování   farmakokinetika   terapeutické užití   škodlivé účinky   MeSH
• injekce intraartikulární MeSH
• léky s prodlouženým účinkem MeSH
• lidé středního věku MeSH
• lidé MeSH
• měření bolesti MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Geografické názvy
• Česká republika MeSH
• Dánsko MeSH
• Polsko MeSH

Hemolytic uremic syndromes (HUSs) are a heterogeneous group of conditions, only some of which are mediated by complement (complement-mediated HUS). We report the outcome of the 2023 International Society of Nephrology HUS International Forum where a global panel of experts considered the current state of the art, identified areas of uncertainty, and proposed optimal solutions. Areas of uncertainty and areas for future research included the nomenclature of HUS, novel complement testing strategies, identification of biomarkers, genetic predisposition to atypical HUS, optimal dosing and withdrawal strategies for C5 inhibitors, treatment of kidney transplant recipients, disparity of access to treatment, and the next generation of complement inhibitors in complement-mediated HUS. The current rationale for optimal patient management is described.

• MeSH
• atypický hemolyticko-uremický syndrom genetika   imunologie   terapie   farmakoterapie   diagnóza   MeSH
• biologické markery krev   MeSH
• hemolyticko-uremický syndrom * terapie   imunologie   diagnóza   MeSH
• inhibitory komplementu terapeutické užití   MeSH
• komplement imunologie   MeSH
• lidé MeSH
• nefrologie * normy   metody   MeSH
• společnosti lékařské normy   MeSH
• transplantace ledvin škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The aim was to evaluate the performance of the Peritoneal Cancer Index (PCI) using imaging (ultrasound, contrast-enhanced computed tomography (CT), and whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) in assessing peritoneal carcinomatosis and predicting non-resectability in tubo-ovarian carcinoma patients. METHODS: This was a prospective multicenter observational study. We considered all patients with suspected primary ovarian/tubal/peritoneal cancer who underwent preoperative ultrasound, CT, and WB-DWI/MRI (if available). The optimal cut off value for assessing the performance of the methods in predicting non-resectability was identified at the point at which the sensitivity and specificity were most similar. The reference standard to predict non-resectability was surgical outcome in terms of residual disease >1 cm or surgery not feasible. Agreement between imaging methods and surgical exploration in assessing sites included in the PCI score was evaluated using the Intraclass Correlation Coefficient (ICC). RESULTS: 242 patients were included from January 2020 until November 2022. The optimal PCI cut-off for predicting non-resectability for surgical exploration was >12, which achieved the best AUC of 0.87, followed by ultrasound with a cut-off of >10 and AUC of 0.81, WB-DWI/MRI with a cut-off of >12 and AUC of 0.81, and CT with a cut-off of >11 and AUC of 0.74. Using ICC, ultrasound had very high agreement (0.94) with surgical PCI, while CT and WB-DWI/MRI had high agreement (0.86 and 0.87, respectively). CONCLUSION: Ultrasound performed by an expert operator had the best agreement with surgical findings compared to WB-DWI/MRI and CT in assessing radiological PCI. In predicting non-resectability, ultrasound was non-inferior to CT, while its non-inferiority to WB-DWI/MRI was not demonstrated.

• MeSH
• difuzní magnetická rezonance metody   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory vaječníků * diagnostické zobrazování   patologie   chirurgie   MeSH
• nádory vejcovodů diagnostické zobrazování   patologie   chirurgie   MeSH
• peritoneální nádory * diagnostické zobrazování   MeSH
• počítačová rentgenová tomografie * metody   MeSH
• prediktivní hodnota testů MeSH
• prospektivní studie MeSH
• senioři MeSH
• ultrasonografie * metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH

BACKGROUND AND PURPOSE: Centers for training in autonomic nervous system (ANS) disorders are not widely available and the recent coronavirus 2019 pandemic temporarily reduced training opportunities in autonomic medicine across European countries. Here we evaluated the current state of education, clinical skills and postgraduate educational preferences on ANS disorders of European neurology residents and consultants. METHODS: A 23-item questionnaire was developed and distributed online amongst European neurology residents and consultants via mailing lists of the European Academy of Neurology. The questions assessed demographics, current training opportunities and learning preferences in ANS disorders. Six multiple-choice questions were used to self-evaluate knowledge of ANS disorders. RESULTS: In all, 285 individuals answered the survey (60% female, mostly 25-34 years of age). All respondents considered clinical autonomic skills necessary for good clinical neurological practice, and 92% would like to increase their ANS knowledge. Female respondents and those who trained in Southern/Eastern/Greater Europe more frequently judged ANS skills important for clinical practice than male respondents (p = 0.012) and respondents from Northern/Western Europe (p = 0.011). Female and younger respondents felt less confident in managing ANS disorders (p = 0.001 and p < 0.001, respectively). Respondents below 45 years of age (p < 0.001) and those with lower confidence in managing ANS disorders (p = 0.004) were more likely to recommend that ANS education is embedded in the residency curriculum. CONCLUSIONS: Most European neurology residents and consultants reported a need for more autonomic education, with additional gender, age and regional differences. These findings underscore the importance of increasing the educational content on autonomic medicine in European medical and postgraduate curricula.

• MeSH
• autonomní nervový systém patofyziologie   fyziologie   MeSH
• dospělí MeSH
• klinické kompetence * MeSH
• konzultanti MeSH
• kurikulum * MeSH
• kurzy a stáže v nemocnici * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci autonomního nervového systému terapie   MeSH
• neurologie * výchova   MeSH
• průzkumy a dotazníky MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH

This study investigates the risk of head injuries, specifically concussions, from falling objects in workplace accidents. A case study focuses on a construction worker who sustained a head injury despite wearing a protective helmet. Utilizing finite element (FE) analysis, the helmet-head system was modeled to assess impact forces and head accelerations. The helmet, made of High-Density Polyethylene with a 6-point suspension system, was tested against falling objects of 332 g and 665 g. Simulations, conducted from heights of 5 to 25 m, revealed that objects weighing as little as 332 g could cause severe concussions from a 10-meter fall. These findings demonstrate that helmets, while mitigating some impact, absorb significantly less energy than the kinetic energy of falling objects. The analyses carried out confirmed the worker's statement that his injury was caused by a foreign object falling on his head, which was protected by a helmet.

• MeSH
• analýza metodou konečných prvků MeSH
• biomechanika MeSH
• komoce mozku * prevence a kontrola   MeSH
• lidé MeSH
• pracovní nehody * prevence a kontrola   MeSH
• prostředky k ochraně hlavy * MeSH
• úrazy pádem * prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Electroencephalography (EEG) has emerged as a primary non-invasive and mobile modality for understanding the complex workings of the human brain, providing invaluable insights into cognitive processes, neurological disorders, and brain-computer interfaces. Nevertheless, the volume of EEG data, the presence of artifacts, the selection of optimal channels, and the need for feature extraction from EEG data present considerable challenges in achieving meaningful and distinguishing outcomes for machine learning algorithms utilized to process EEG data. Consequently, the demand for sophisticated optimization techniques has become imperative to overcome these hurdles effectively. Evolutionary algorithms (EAs) and other nature-inspired metaheuristics have been applied as powerful design and optimization tools in recent years, showcasing their significance in addressing various design and optimization problems relevant to brain EEG-based applications. This paper presents a comprehensive survey highlighting the importance of EAs and other metaheuristics in EEG-based applications. The survey is organized according to the main areas where EAs have been applied, namely artifact mitigation, channel selection, feature extraction, feature selection, and signal classification. Finally, the current challenges and future aspects of EAs in the context of EEG-based applications are discussed.

• MeSH
• algoritmy * MeSH
• artefakty MeSH
• elektroencefalografie * metody   MeSH
• lidé MeSH
• mozek * fyziologie   MeSH
• rozhraní mozek-počítač MeSH
• strojové učení MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Health literacy is a core public health issue in relation to children and adolescents associated with multiple health behaviours and health outcomes. The aim of the study is to test the direct associations between health literacy, physical activity behaviour, health outcomes of body composition and cardiorespiratory fitness among Slovak adolescents and possible indirect effect of health literacy on health outcomes of body composition and cardiorespiratory fitness mediated by adolescents' physical activity behaviour. METHODS: Data from the Slovak Health Behaviour in School-aged Children (HBSC) study conducted in 2022 were used. For the purposes of this study, a subsample of the adolescents (n = 508; mean age = 14.50; SD = 0.82; 54.3% boys) which provided HBSC questionnaire data on health literacy, moderate-to-vigorous physical activity and vigorous physical activity and participated in body composition (InBody 230) and cardiorespiratory fitness (20-m shuttle run test) measurements. Data were analysed using linear regression analysis. RESULTS: The findings showed that higher health literacy of the adolescents was directly associated with higher frequency of physical activity represented by moderate-to-vigorous physical activity and vigorous physical activity and only with the visceral fat area in the crude model. Furthermore, there was an indirect effect of health literacy on cardiorespiratory fitness and most of the body composition variables (except the Body Mass Index) which was mediated by physical activity of the respondents. CONCLUSIONS: Health literacy is indirectly associated to body composition and cardiorespiratory fitness through higher frequency of physical activity. It seems that health literacy as cognitive and social competencies need behavioural components to be involved in the proposed causal pathway between health literacy and health outcomes. Our findings may contribute to the process of creating a framework for future health literacy interventions in adolescents.

• MeSH
• cvičení * fyziologie   MeSH
• kardiorespirační zdatnost * fyziologie   MeSH
• lidé MeSH
• mladiství MeSH
• průzkumy a dotazníky MeSH
• složení těla * MeSH
• zdravotní gramotnost * statistika a číselné údaje   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Slovenská republika MeSH

Citizens play a crucial role in attaining the United Nations 2030 sustainable development goals (SDGs). There is growing awareness of the importance of understanding citizen perspectives on environmental issues, in relation to developing and maintaining sustainable lifestyles, and in addressing perceived threats to protection and restoration of ecosystems and biodiversity. This analysis sought to understand people's attitudes towards environmental conservation, how they relate to perceived threats to the countryside, and to determine how attitudes and perceived threats vary demographically and between countries. A survey was administered to citizens (quota sampled on age, gender, education, and split between rural and urban residency) across five countries representative of differing biogeographical regions (N = 3,190): Czech Republic (n = 649) (Continental); Spain (Mediterranean) (n = 623); Sweden (Boreal) (n = 645); Switzerland (Alpine) (n = 641); United Kingdom (UK) (Atlantic) (n = 632). Attitudes were measured using the Environmental Attitudes Inventory (EAI-24) on 2 factors (utilization; preservation) and perceived threat to the countryside on 1-factor (15 items). Multigroup regression analysis indicated that preservationist attitudes were associated with greater perceived threat to the countryside in all five countries. Higher perceived threat was associated with activities linked to environmental degradation, socio-economic uncertainty and risks in agri-food supply chains in all countries. The "bad behaviour of visitors" was the greatest perceived threat in the Czech Republic, Switzerland and the UK, while "lack of young farmers taking over farming" was the greatest perceived threat in Spain and Sweden. To promote pro-environmental attitudes and obtain greater public support for policies and interventions targeting environmental conservation, communication about environmental threats is needed, together with threat mitigation measures. Raising peoples' awareness of threats to the countryside through targeted communications could promote pro-environment attitudes and potentially result in pro-environmental behaviours.

• MeSH
• biodiverzita MeSH
• dospělí MeSH
• ekosystém MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• postoj * MeSH
• průzkumy a dotazníky MeSH
• senioři MeSH
• zachování přírodních zdrojů * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Evropa MeSH
• Španělsko MeSH

PML, a multifunctional protein, is crucial for forming PML-nuclear bodies involved in stress responses. Under specific conditions, PML associates with nucleolar caps formed after RNA polymerase I (RNAPI) inhibition, leading to PML-nucleolar associations (PNAs). This study investigates PNAs-inducing stimuli by exposing cells to various genotoxic stresses. We found that the most potent inducers of PNAs introduced topological stress and inhibited RNAPI. Doxorubicin, the most effective compound, induced double-strand breaks (DSBs) in the rDNA locus. PNAs co-localized with damaged rDNA, segregating it from active nucleoli. Cleaving the rDNA locus with I-PpoI confirmed rDNA damage as a genuine stimulus for PNAs. Inhibition of ATM, ATR kinases, and RAD51 reduced I-PpoI-induced PNAs, highlighting the importance of ATM/ATR-dependent nucleolar cap formation and homologous recombination (HR) in their triggering. I-PpoI-induced PNAs co-localized with rDNA DSBs positive for RPA32-pS33 but deficient in RAD51, indicating resected DNA unable to complete HR repair. Our findings suggest that PNAs form in response to persistent rDNA damage within the nucleolar cap, highlighting the interplay between PML/PNAs and rDNA alterations due to topological stress, RNAPI inhibition, and rDNA DSBs destined for HR. Cells with persistent PNAs undergo senescence, suggesting PNAs help avoid rDNA instability, with implications for tumorigenesis and aging.

• MeSH
• buněčné jadérko * metabolismus   MeSH
• dvouřetězcové zlomy DNA MeSH
• lidé MeSH
• poškození DNA MeSH
• protein promyelocytické leukemie * metabolismus   genetika   MeSH
• ribozomální DNA * genetika   metabolismus   MeSH
• RNA-polymerasa I metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. Although genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations, and copy-neutral loss of heterozygosity were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91%, 43%, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and loss of heterozygosity at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow (BM) blast percentage across groups ranged from 1.5% to 10%, and the median overall survival ranged from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of BM blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and might inform future classification schemas and translational therapeutic research.

• MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• myelodysplastické syndromy * genetika   klasifikace   patologie   MeSH
• prognóza MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• variabilita počtu kopií segmentů DNA MeSH
• ztráta heterozygozity 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