BACKGROUND: Pulsed field ablation (PFA) of atrial fibrillation is a new method in clinical practice. Despite a favorable safety profile of PFA in atrial fibrillation ablation, rare cases of renal failure, probably due to hemolysis, have recently been reported. OBJECTIVE: The aim of this study was to determine the rate of hemolysis and cardiac cell death during in vitro PFA with different electric field intensities. METHODS: Blood samples from healthy volunteers and mouse HL-1 cardiomyocyte cell lines were subjected to in vitro irreversible electroporation using 216 bipolar pulses, each lasting 2 μs with intervals of 5 μs, repeated 20 times at a frequency of 1 Hz. These pulses varied from 500 V to 1500 V. Cell-free hemoglobin levels were assessed spectrophotometrically, and red blood cell microparticles were evaluated by flow cytometry. Cardiomyocyte death was quantified with propidium iodide. RESULTS: Pulsed field energy (1000 V/cm, 1250 V/cm, and 1500 V/cm) was associated with a significant increase in cell-free hemoglobin (0.32 ± 0.16 g/L, 2.2 ± 0.96 g/L, and 5.7 ± 0.39 g/L; P < .01) and similar increase in the concentration of red blood cell microparticles. Significant rates of cardiomyocyte death were observed at electric field strengths of 750 V/cm, 1000 V/cm, 1250 V/cm, and 1500 V/cm (26.5% ± 5.9%, 44.3% ± 6.2%, 55.5% ± 6.9%, and 74.5% ± 17.8% of cardiomyocytes; P < .01). CONCLUSION: The most effective induction of cell death in vitro was observed at 1500 V/cm. This intensity was also associated with a significant degree of hemolysis.
- MeSH
- elektroporace * metody MeSH
- fibrilace síní patofyziologie chirurgie MeSH
- hemolýza * fyziologie MeSH
- kardiomyocyty * metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- myši MeSH
- průtoková cytometrie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Pancreas is a vital gland of gastrointestinal system with exocrine and endocrine secretory functions, interweaved into essential metabolic circuitries of the human body. Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies, with a 5-year survival rate of 11%. This poor prognosis is primarily attributed to the absence of early symptoms, rapid metastatic dissemination, and the limited efficacy of current therapeutic interventions. Despite recent advancements in understanding the etiopathogenesis and treatment of PDAC, there remains a pressing need for improved individualized models, identification of novel molecular targets, and development of unbiased predictors of disease progression. Here we aim to explore the concept of precision medicine utilizing 3-dimensional, patient-specific cellular models of pancreatic tumors and discuss their potential applications in uncovering novel druggable molecular targets and predicting clinical parameters for individual patients.
- MeSH
- duktální karcinom slinivky břišní * patologie genetika metabolismus MeSH
- individualizovaná medicína * metody MeSH
- lidé MeSH
- nádory slinivky břišní * patologie genetika MeSH
- techniky 3D buněčné kultury metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BackgroundCOVID-19 remains a major infectious disease with substantial implications for individual and public health including the risk of a post-infection syndrome, long COVID. The continuous changes in dominant variants of SARS-CoV-2 necessitate a careful study of the effect of preventative strategies.AimWe aimed to estimate the effectiveness of post-vaccination, post-infection and hybrid immunity against severe cases requiring oxygen support caused by infections with SARS-CoV-2 variants BA1/2 and BA4/5+, and against long COVID in the infected population and their changes over time.MethodsWe used a Cox regression analysis with time-varying covariates and calendar time and logistic regression applied to national-level data from Czechia from December 2021 until August 2023.ResultsRecently boosted vaccination, post-infection and hybrid immunity provide significant protection against a severe course of COVID-19, while unboosted vaccination more than 10 months ago has a negligible protective effect. The post-vaccination immunity against the BA1/2 or BA4/5+ variants, especially based on the original vaccine types, appears to wane rapidly compared with post-infection and hybrid immunity. Once infected, however, previous immunity plays only a small protective role against long COVID.ConclusionVaccination remains an effective preventative measure against a severe course of COVID-19 but its effectiveness wanes over time thus highlighting the importance of booster doses. Once infected, vaccines may have a small protective effect against the development of long COVID.
- MeSH
- COVID-19 * imunologie prevence a kontrola epidemiologie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- postakutní syndrom COVID-19 MeSH
- SARS-CoV-2 * imunologie MeSH
- sekundární imunizace MeSH
- senioři MeSH
- vakcinace MeSH
- vakcíny proti COVID-19 * imunologie 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
- Geografické názvy
- Česká republika MeSH
Iron and copper chelation therapy plays a crucial role in treating conditions associated with metal overload, such as hemochromatosis or Wilson's disease. However, conventional chelators face challenges in reaching the core of iron and copper metabolism - the mitochondria. Mitochondria-targeted chelators can specifically target and remove metal ions from mitochondria, showing promise in treating diseases linked to mitochondrial dysfunction, including neurodegenerative diseases and cancer. Additionally, they serve as specific mitochondrial metal sensors. However, designing these new molecules presents its own set of challenges. Depending on the chelator's intended use to prevent or to promote redox cycling of the metals, the chelating moiety must possess different donor atoms and an optimal value of the electrode potential of the chelator-metal complex. Various targeting moieties can be employed for selective delivery into the mitochondria. This review also provides an overview of the current progress in the design of mitochondria-targeted chelators and their biological activity investigation.
- MeSH
- chelátory železa farmakologie MeSH
- chelátory * terapeutické užití metabolismus MeSH
- chelátová terapie metody MeSH
- lidé MeSH
- měď * metabolismus MeSH
- mitochondrie * metabolismus účinky léků MeSH
- železo * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- jazyk (prostředek komunikace) MeSH
- lidé MeSH
- software trendy MeSH
- studium lékařství * metody MeSH
- umělá inteligence * trendy MeSH
- vzdělávací modely MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
Triphenylphosphonium (TPP) derivatives are commonly used to target chemical into mitochondria. We show that alkyl-TPP cause reversible, dose- and hydrophobicity-dependent alterations of mitochondrial morphology and function and a selective decrease of mitochondrial inner membrane proteins including subunits of the respiratory chain complexes, as well as components of the mitochondrial calcium uniporter complex. The treatment with alkyl-TPP resulted in the cleavage of the pro-fusion and cristae organisation regulator Optic atrophy-1. The structural and functional effects of alkyl-TPP were found to be reversible and not merely due to loss of membrane potential. A similar effect was observed with the mitochondria-targeted antioxidant MitoQ.
- MeSH
- antioxidancia * farmakologie MeSH
- kationty metabolismus farmakologie MeSH
- membránové proteiny metabolismus MeSH
- membránový potenciál mitochondrií MeSH
- mitochondriální membrány metabolismus MeSH
- mitochondrie * metabolismus MeSH
- organofosforové sloučeniny farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Short-term forecasts of infectious disease burden can contribute to situational awareness and aid capacity planning. Based on best practice in other fields and recent insights in infectious disease epidemiology, one can maximise the predictive performance of such forecasts if multiple models are combined into an ensemble. Here, we report on the performance of ensembles in predicting COVID-19 cases and deaths across Europe between 08 March 2021 and 07 March 2022. METHODS: We used open-source tools to develop a public European COVID-19 Forecast Hub. We invited groups globally to contribute weekly forecasts for COVID-19 cases and deaths reported by a standardised source for 32 countries over the next 1-4 weeks. Teams submitted forecasts from March 2021 using standardised quantiles of the predictive distribution. Each week we created an ensemble forecast, where each predictive quantile was calculated as the equally-weighted average (initially the mean and then from 26th July the median) of all individual models' predictive quantiles. We measured the performance of each model using the relative Weighted Interval Score (WIS), comparing models' forecast accuracy relative to all other models. We retrospectively explored alternative methods for ensemble forecasts, including weighted averages based on models' past predictive performance. RESULTS: Over 52 weeks, we collected forecasts from 48 unique models. We evaluated 29 models' forecast scores in comparison to the ensemble model. We found a weekly ensemble had a consistently strong performance across countries over time. Across all horizons and locations, the ensemble performed better on relative WIS than 83% of participating models' forecasts of incident cases (with a total N=886 predictions from 23 unique models), and 91% of participating models' forecasts of deaths (N=763 predictions from 20 models). Across a 1-4 week time horizon, ensemble performance declined with longer forecast periods when forecasting cases, but remained stable over 4 weeks for incident death forecasts. In every forecast across 32 countries, the ensemble outperformed most contributing models when forecasting either cases or deaths, frequently outperforming all of its individual component models. Among several choices of ensemble methods we found that the most influential and best choice was to use a median average of models instead of using the mean, regardless of methods of weighting component forecast models. CONCLUSIONS: Our results support the use of combining forecasts from individual models into an ensemble in order to improve predictive performance across epidemiological targets and populations during infectious disease epidemics. Our findings further suggest that median ensemble methods yield better predictive performance more than ones based on means. Our findings also highlight that forecast consumers should place more weight on incident death forecasts than incident case forecasts at forecast horizons greater than 2 weeks. FUNDING: AA, BH, BL, LWa, MMa, PP, SV funded by National Institutes of Health (NIH) Grant 1R01GM109718, NSF BIG DATA Grant IIS-1633028, NSF Grant No.: OAC-1916805, NSF Expeditions in Computing Grant CCF-1918656, CCF-1917819, NSF RAPID CNS-2028004, NSF RAPID OAC-2027541, US Centers for Disease Control and Prevention 75D30119C05935, a grant from Google, University of Virginia Strategic Investment Fund award number SIF160, Defense Threat Reduction Agency (DTRA) under Contract No. HDTRA1-19-D-0007, and respectively Virginia Dept of Health Grant VDH-21-501-0141, VDH-21-501-0143, VDH-21-501-0147, VDH-21-501-0145, VDH-21-501-0146, VDH-21-501-0142, VDH-21-501-0148. AF, AMa, GL funded by SMIGE - Modelli statistici inferenziali per governare l'epidemia, FISR 2020-Covid-19 I Fase, FISR2020IP-00156, Codice Progetto: PRJ-0695. AM, BK, FD, FR, JK, JN, JZ, KN, MG, MR, MS, RB funded by Ministry of Science and Higher Education of Poland with grant 28/WFSN/2021 to the University of Warsaw. BRe, CPe, JLAz funded by Ministerio de Sanidad/ISCIII. BT, PG funded by PERISCOPE European H2020 project, contract number 101016233. CP, DL, EA, MC, SA funded by European Commission - Directorate-General for Communications Networks, Content and Technology through the contract LC-01485746, and Ministerio de Ciencia, Innovacion y Universidades and FEDER, with the project PGC2018-095456-B-I00. DE., MGu funded by Spanish Ministry of Health / REACT-UE (FEDER). DO, GF, IMi, LC funded by Laboratory Directed Research and Development program of Los Alamos National Laboratory (LANL) under project number 20200700ER. DS, ELR, GG, NGR, NW, YW funded by National Institutes of General Medical Sciences (R35GM119582; the content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS or the National Institutes of Health). FB, FP funded by InPresa, Lombardy Region, Italy. HG, KS funded by European Centre for Disease Prevention and Control. IV funded by Agencia de Qualitat i Avaluacio Sanitaries de Catalunya (AQuAS) through contract 2021-021OE. JDe, SMo, VP funded by Netzwerk Universitatsmedizin (NUM) project egePan (01KX2021). JPB, SH, TH funded by Federal Ministry of Education and Research (BMBF; grant 05M18SIA). KH, MSc, YKh funded by Project SaxoCOV, funded by the German Free State of Saxony. Presentation of data, model results and simulations also funded by the NFDI4Health Task Force COVID-19 (https://www.nfdi4health.de/task-force-covid-19-2) within the framework of a DFG-project (LO-342/17-1). LP, VE funded by Mathematical and Statistical modelling project (MUNI/A/1615/2020), Online platform for real-time monitoring, analysis and management of epidemic situations (MUNI/11/02202001/2020); VE also supported by RECETOX research infrastructure (Ministry of Education, Youth and Sports of the Czech Republic: LM2018121), the CETOCOEN EXCELLENCE (CZ.02.1.01/0.0/0.0/17-043/0009632), RECETOX RI project (CZ.02.1.01/0.0/0.0/16-013/0001761). NIB funded by Health Protection Research Unit (grant code NIHR200908). SAb, SF funded by Wellcome Trust (210758/Z/18/Z).
- MeSH
- COVID-19 * diagnóza epidemiologie MeSH
- epidemie * MeSH
- infekční nemoci * MeSH
- lidé MeSH
- předpověď MeSH
- retrospektivní studie MeSH
- statistické modely MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
Bisphenol S (BPS), the main replacement for bisphenol A (BPA), is thought to be toxic, but limited information is available on the effects of Bisphenol S on ovarian follicles. In our study, we demonstrated the presence of Bisphenol S in the follicular fluid of women at a concentration of 22.4 nM. The effect of such concentrations of Bisphenol S on oocyte maturation and subsequent embryo development is still unknown. Therefore, we focused on the effect of Bisphenol S on in vitro oocyte maturation, fertilization, and embryo development. As a model, we used porcine oocytes, which show many physiological similarities to human oocytes. Oocytes were exposed to Bisphenol S concentrations similar to those detected in female patients in the ART clinic. We found a decreased ability of oocytes to successfully complete meiotic maturation. Mature oocytes showed an increased frequency of meiotic spindle abnormalities and chromosome misalignment. Alarming associations of oocyte Bisphenol S exposure with the occurrence of aneuploidy and changes in the distribution of mitochondria and mitochondrial proteins were demonstrated for the first time. However, the number and quality of blastocysts derived from oocytes that successfully completed meiotic maturation under the influence of Bisphenol S was not affected.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Contact tracing is one of the most effective non-pharmaceutical interventions in the COVID-19 pandemic. This study uses a multi-agent model to investigate the impact of four types of contact tracing strategies to prevent the spread of COVID-19. METHODS: In order to analyse individual contact tracing in a reasonably realistic setup, we construct an agent-based model of a small municipality with about 60.000 inhabitants (nodes) and about 2.8 million social contacts (edges) in 30 different layers. Those layers reflect demographic, geographic, sociological and other patterns of the TTWA (Travel-to-work-area) Hodonín in Czechia. Various data sources such as census, land register, transport data or data reflecting the shopping behaviour, were employed to meet this purpose. On this multi-graph structure we run a modified SEIR model of the COVID-19 dynamics. The parameters of the model are calibrated on data from the outbreak in the Czech Republic in the period March to June 2020. The simplest type of contact tracing follows just the family, the second tracing version tracks the family and all the work contacts, the third type finds all contacts with the family, work contacts and friends (leisure activities). The last one is a complete (digital) tracing capable of recalling any and all contacts. We evaluate the performance of these contact tracing strategies in four different environments. First, we consider an environment without any contact restrictions (benchmark); second with strict contact restriction (replicating the stringent non-pharmaceutical interventions employed in Czechia in the spring 2020); third environment, where the measures were substantially relaxed, and, finally an environment with weak contact restrictions and superspreader events (replicating the situation in Czechia in the summer 2020). FINDINGS: There are four main findings in our paper. 1. In general, local closures are more effective than any type of tracing. 2. In an environment with strict contact restrictions there are only small differences among the four contact tracing strategies. 3. In an environment with relaxed contact restrictions the effectiveness of the tracing strategies differs substantially. 4. In the presence of superspreader events only complete contact tracing can stop the epidemic. INTERPRETATION: In situations, where many other non-pharmaceutical interventions are in place, the specific extent of contact tracing may not have a large influence on their effectiveness. In a more relaxed setting with few contact restrictions and larger events the effectiveness of contact tracing depends heavily on their extent.
- MeSH
- COVID-19 * epidemiologie MeSH
- epidemický výskyt choroby prevence a kontrola MeSH
- lidé MeSH
- pandemie prevence a kontrola MeSH
- SARS-CoV-2 MeSH
- trasování kontaktů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Studies demonstrating the waning of post-vaccination and post-infection immunity against covid-19 generally analyzed a limited range of vaccines or subsets of populations. Using Czech national health data from the beginning of the covid-19 pandemic till November 20, 2021 we estimated the risks of reinfection, breakthrough infection, hospitalization and death by a Cox regression adjusted for sex, age, vaccine type and vaccination status. Vaccine effectiveness against infection declined from 87% at 0-2 months after the second dose to 53% at 7-8 months for BNT162b2 vaccine, from 90% at 0-2 months to 65% at 7-8 months for mRNA-1273, and from 83% at 0-2 months to 55% at 5-6 months for the ChAdOx1-S. Effectiveness against hospitalization and deaths declined by about 15% and 10%, respectively, during the first 6-8 months. Boosters (third dose) returned the protection to the levels observed shortly after dose 2. In unvaccinated, previously infected individuals the protection against infection declined from 97% after 2 months to 72% at 18 months. Our results confirm the waning of vaccination-induced immunity against infection and a smaller decline in the protection against hospitalization and death. Boosting restores the original vaccine effectiveness. Post-infection immunity also decreases over time.
- MeSH
- COVID-19 * prevence a kontrola MeSH
- hospitalizace MeSH
- lidé MeSH
- pandemie MeSH
- vakcína BNT162 MeSH
- vakcinace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
