BACKGROUND: Neuromuscular diseases (NMDs) are rare disorders characterized by progressive muscle fibre loss, leading to replacement by fibrotic and fatty tissue, muscle weakness and disability. Early diagnosis is critical for therapeutic decisions, care planning and genetic counselling. Muscle magnetic resonance imaging (MRI) has emerged as a valuable diagnostic tool by identifying characteristic patterns of muscle involvement. However, the increasing complexity of these patterns complicates their interpretation, limiting their clinical utility. Additionally, multi-study data aggregation introduces heterogeneity challenges. This study presents a novel multi-study harmonization pipeline for muscle MRI and an AI-driven diagnostic tool to assist clinicians in identifying disease-specific muscle involvement patterns. METHODS: We developed a preprocessing pipeline to standardize MRI fat content across datasets, minimizing source bias. An ensemble of XGBoost models was trained to classify patients based on intramuscular fat replacement, age at MRI and sex. The SHapley Additive exPlanations (SHAP) framework was adapted to analyse model predictions and identify disease-specific muscle involvement patterns. To address class imbalance, training and evaluation were conducted using class-balanced metrics. The model's performance was compared against four expert clinicians using 14 previously unseen MRI scans. RESULTS: Using our harmonization approach, we curated a dataset of 2961 MRI samples from genetically confirmed cases of 20 paediatric and adult NMDs. The model achieved a balanced accuracy of 64.8% ± 3.4%, with a weighted top-3 accuracy of 84.7% ± 1.8% and top-5 accuracy of 90.2% ± 2.4%. It also identified key features relevant for differential diagnosis, aiding clinical decision-making. Compared to four expert clinicians, the model obtained the highest top-3 accuracy (75.0% ± 4.8%). The diagnostic tool has been implemented as a free web platform, providing global access to the medical community. CONCLUSIONS: The application of AI in muscle MRI for NMD diagnosis remains underexplored due to data scarcity. This study introduces a framework for dataset harmonization, enabling advanced computational techniques. Our findings demonstrate the potential of AI-based approaches to enhance differential diagnosis by identifying disease-specific muscle involvement patterns. The developed tool surpasses expert performance in diagnostic ranking and is accessible to clinicians worldwide via the Myo-Guide online platform.

• MeSH
• dospělí MeSH
• internet MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie * metody   MeSH
• neuromuskulární nemoci * diagnóza   diagnostické zobrazování   MeSH
• strojové učení * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BackgroundOn 29 January 2024, the European Centre for Disease Prevention and Control distributed an alert about a metronidazole-resistant Clostridioides difficile outbreak of PCR ribotype (RT) 955 in England.AimWe aimed to investigate the presence of RT955 in Czech, Slovak and Polish C. difficile isolates and evaluate different culture media for detecting its metronidazole resistance.MethodsIsolates with binary toxin genes identified as 'unknown' by the WEBRIBO PCR ribotyping database up to 2023 were re-analysed after adding the RT955 profile to the database. The RT955 isolates were characterised by whole genome sequencing and tested for susceptibility to 15 antimicrobials.ResultsWe did not find RT955 in Czech (n = 6,661, 2012-2023) and Slovak (n = 776, 2015-2023) isolates, but identified 13 RT955 cases (n = 303, 2021-2023) in three hospitals in Poland. By whole genome multilocus sequence typing, 10 isolates clustered into one clonal complex including a sequence of United Kingdom strain ERR12670107, and shared similar antimicrobial resistance genes/mutations. All 13 isolates were resistant to ciprofloxacin/moxifloxacin, erythromycin/clindamycin and ceftazidime. All isolates had a mutation in the nimB gene promoter and in NimB (Tyr130Ser and Leu155Ile). The metronidazole resistance was detected in all isolates using brain-heart-infusion agar supplemented with haemin and Chocolate agar. Results were discrepant with the European Committee on Antimicrobial Susceptibility Testing-recommended Fastidious anaerobe agar and Brucella blood agar.ConclusionThe identification of clonally related haem-dependent metronidazole-resistant C. difficile RT955 in multiple hospitals indicates a need for prospective surveillance to estimate its prevalence in Europe.

• MeSH
• antibakteriální látky * farmakologie   MeSH
• bakteriální léková rezistence * genetika   MeSH
• Clostridioides difficile * genetika   účinky léků   izolace a purifikace   klasifikace   MeSH
• epidemický výskyt choroby MeSH
• klostridiové infekce * epidemiologie   mikrobiologie   farmakoterapie   MeSH
• lidé MeSH
• metronidazol * farmakologie   MeSH
• mikrobiální testy citlivosti MeSH
• multilokusová sekvenční typizace MeSH
• polymerázová řetězová reakce MeSH
• ribotypizace * MeSH
• sekvenování celého genomu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Polsko MeSH
• Slovenská republika MeSH

Purine de novo purine synthesis involves 10 reactions catalysed by six enzymes, including phosphoribosylformyglycinamidine synthase (PFAS). To date, genetic defects of three of these enzymes, namely ATIC, ADSL and PAICS, have been characterised in humans. Here, we report for the first time two individuals with PFAS deficiency. Probands were identified through metabolic and genetic screening of neurologically impaired individuals. The pathogenicity of the variants was established by structural and functional studies. Probands C1 and C2 presented with prematurity, short stature, recurrent seizures and mild neurological impairment. C1 had elevated urinary levels of formylglycineamide riboside (FGAr) and bi-allelic PFAS variants encoding the NP_036525.1:p.Arg811Trp substitution and the NP_036525.1:p.Glu228_Ser230 in-frame deletion. C2 is a 20-year-old female with a homozygous NP_036525.1:p.Asn264Lys substitution. These amino acid changes are predicted to affect the structural stability of PFAS. Accordingly, C1 skin fibroblasts showed decreased PFAS content and activity, with impaired purinosome formation that was restored by transfection with pTagBFP_PFAS_wt. The enzymatic activities of the corresponding recombinant mutant PFAS proteins were also reduced, and none of them, after transfection, corrected the elevated FGAR/r levels in PFAS-deficient HeLa cells. While genetic defects in purine de novo synthesis are typically considered in patients with severe neurological impairment, these disorders, especially PFAS deficiency, should also be considered in milder phenotypes.

• MeSH
• lidé MeSH
• ligasy tvořící vazby C-N s glutaminem jako amidovým donorem * genetika   nedostatek   metabolismus   MeSH
• mladý dospělý MeSH
• mutace MeSH
• poruchy metabolismu purinů a pyrimidinů * genetika   MeSH
• předškolní dítě MeSH
• puriny * biosyntéza   MeSH
• Check Tag
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Atherosclerosis is a chronic inflammatory disease of the blood vessels caused by elevated levels of lipoproteins. The hyperlipoproteinemia triggers a series of cellular changes, particularly the activation of the macrophages, which play a crucial role in the development and progression of atherosclerosis. The presence of free cholesterol (FC) in lipoproteins may contribute to macrophage stimulation. However, the mechanisms linking the accumulation of FC in macrophages to their pro-inflammatory activation remain poorly understood. Our research found a positive correlation between the number of pro-inflammatory macrophages (CD14 + CD16 + CD36high) in visceral adipose tissue and the levels of LDL-C and cholesterol remnant particles in 56 healthy people. In contrast, the proportion of anti-inflammatory, alternatively activated macrophages (CD14 + CD16-CD163+) correlated negatively with HDL-C. Additionally, our in vitro study demonstrated that macrophages accumulating FC promoted a pro-inflammatory response, activating the TNF-α and chemokine CCL3 genes. Furthermore, the accumulation of FC in macrophages alters the surface receptors on macrophages (CD206 and CD16) and increases cellular granularity. Notably, the CD36 surface receptor and the ACAT and CD36 genes did not show a response. These results suggest a link between excessive FC accumulation and systemic inflammation to underlie the development of atherosclerosis.

• MeSH
• aktivace makrofágů MeSH
• antigeny CD36 metabolismus   MeSH
• ateroskleróza metabolismus   MeSH
• CD antigeny metabolismus   MeSH
• cholesterol * metabolismus   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• makrofágy * metabolismus   imunologie   účinky léků   MeSH
• nitrobřišní tuk metabolismus   MeSH
• TNF-alfa metabolismus   genetika   MeSH
• zánět * metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Although chronic inflammation is implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL), the mechanisms responsible are unknown. We demonstrate that the overexpression of the collagen receptor, DDR1, correlates with reduced expression of spindle checkpoint genes, with three transcriptional signatures of aneuploidy and with a higher frequency of copy number alterations, pointing to a potential role for DDR1 in the acquisition of aneuploidy in DLBCL. In support of this, we found that collagen treatment of primary germinal centre B cells transduced with DDR1, not only partially recapitulated the aberrant transcriptional programme of DLBCL but also downregulated the expression of CENPE, a mitotic spindle that has a crucial role in preventing chromosome mis-segregation. CENPE expression was also downregulated following DDR1 activation in two B-cell lymphoma lines and was lost in most DDR1-expressing primary tumours. Crucially, the inhibition of CENPE and the overexpression of a constitutively activated DDR1 were able to induce aneuploidy in vitro. Our findings identify a novel mechanistic link between DDR1 signalling and chromosome instability in B cells and provide novel insights into factors driving aneuploidy in DLBCL.

• MeSH
• aneuploidie * MeSH
• B-lymfocyty metabolismus   MeSH
• chromozomální nestabilita * genetika   MeSH
• difúzní velkobuněčný B-lymfom * genetika   patologie   metabolismus   MeSH
• kolagen farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• receptor DDR1 * genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Rational prescribing in geriatrics represents an important ethical as well as socio-economic issue. The aim of this project was to analyze the drug-related problems (DRPs) among the Czech nursing home residents and increase public awareness of further possible employment of clinical pharmacists in social care. The project was designed as a multicenter observational study. A total of 16 nursing homes and 800 participants with an average age of 84.6 ± 7.3 years were included in the study. Of them, a DRP was noted in 93.3% of people. The total amount of DRPs identified was 2215, which means an average of 2.8 ± 1.6 DRPs per patient. The most common DRPs identified were 'overtreatment' (19.5%), 'undertreatment' (12.8%), inappropriate dose (10.6%), recommendations for laboratory monitoring (10.4%) and adverse effects (10.3%). Of different drug classes, BZDs (OR 16.6, 95% CI 1.0-270.2), PPIs (OR 2.5, 95% CI 1.1-5.6) and NSAIDs (OR 4.4, 95% CI 1.1-18.3) were identified to be most commonly associated with DRPs. The risk of DRP identification clearly increased with the number of drugs used, with seven drugs demonstrated as the best cut-off for predicting DRP identification (AUC 0.842, sensitivity 0.602; specificity 0.796). 'SENIOR' project has confirmed a high rate of excessive polypharmacy among nursing home residents in the Czech republic resulting in high risk of potential and manifested DRPs. The project emphasized the role of clinical pharmacists in optimizing safety and effectiveness of treatment among older nursing home residents.

• MeSH
• domovy pro seniory * statistika a číselné údaje   MeSH
• farmaceuti MeSH
• farmaceutické služby * organizace a řízení   MeSH
• lidé MeSH
• nevhodné předepisování * statistika a číselné údaje   prevence a kontrola   MeSH
• nežádoucí účinky léčiv * epidemiologie   diagnóza   prevence a kontrola   MeSH
• pečovatelské domovy * statistika a číselné údaje   MeSH
• polypharmacy MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Geografické názvy
• Česká republika MeSH

Hyponatremia is a crucial complication of therapy with thiazide diuretics. This study compares the epidemiological and biochemical profiles and hospital course of patients using hydrochlorothiazide (HCTZ), indapamide (INDA), and chlorthalidone (CTD) admitted with thiazide-associated hyponatremia (TAH). Data were obtained retrospectively from the hospital's digital registries. The epidemiological and biochemical parameters between the HCTZ, INDA, and CTD groups were compared. The correlation between dose and biochemical parameters in each group was performed. The thiazide groups without diuretic co-medication were compared (HCTZ vs. INDA), and the correlation between dose and biochemical parameters in each group was examined. A comparison of the HCTZ (n = 135), INDA (n = 125), and CTD (n = 27) groups identified differences in serum potassium (s-K; p = 0.03). The hyponatremia correction rate was slower in the CTD group at 96 h after admission (p < 0.001). After the exclusion of diuretic co-medication, the HCTZ group (n = 64/135) showed a higher prevalence of ARBs, s-K (both p < 0.001), and a lower median (IQR) equipotent dose (12.5 (o) mg vs. 2.5 (1.2) mg), prevalence of ACE-I (p < 0.001), and eGFR (p = 0.03), when compared to the INDA group (n = 109/125). In conclusion, except for s-K, we observed no significant difference in biochemical and epidemiological profiles between HCTZ, INDA, and CTD. After excluding the influence of other diuretics, we observed higher s-K in the HCTZ group compared to the INDA group, potentially explained by the lower equipotent dose of HCTZ. The CTD group showed a statistically significant trend of slower hyponatremia correction.

• MeSH
• antihypertenziva škodlivé účinky   MeSH
• chlorthalidon * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• diuretika škodlivé účinky   MeSH
• draslík krev   MeSH
• hydrochlorthiazid * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• hypertenze * farmakoterapie   MeSH
• hyponatremie * chemicky indukované   epidemiologie   krev   MeSH
• indapamid * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• inhibitory symportérů pro chlorid sodný škodlivé účinky   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Although sodium-glucose cotransporter 2 inhibitors reduce the risk of cardiovascular death or worsening heart failure (HF) in patients with chronic HF, there are limited data on initiation in hospitalized patients with HF. DAPA ACT HF-TIMI 68 (Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure - Thrombolysis in Myocardial Infarction 68) is an international, randomized, double-blind trial evaluating the initiation of dapagliflozin (10 mg daily) vs placebo in 2,401 patients hospitalized for acute HF. Patients were enrolled irrespective of left ventricular ejection fraction, type 2 diabetes status, or chronicity of HF (de novo and worsening chronic HF). Randomized participants receive blinded treatment for 2 months. The primary efficacy endpoint is time to first occurrence of cardiovascular death or worsening HF (worsening HF during the index admission, rehospitalization for worsening HF, or urgent HF visit). Key safety endpoints include symptomatic hypotension and worsening kidney function. This is the first cardiovascular outcomes trial designed specifically to evaluate the efficacy and safety of in-hospital initiation of dapagliflozin in patients hospitalized for the management of acute HF. (Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure - Thrombolysis in Myocardial Infarction 68 [DAPA ACT HF-TIMI 68]; NCT04363697; EudraCT # 2022-001262-35).

• MeSH
• akutní nemoc MeSH
• benzhydrylové sloučeniny * terapeutické užití   aplikace a dávkování   MeSH
• diabetes mellitus 2. typu komplikace   farmakoterapie   MeSH
• dvojitá slepá metoda MeSH
• glifloziny * terapeutické užití   MeSH
• glukosidy * terapeutické užití   aplikace a dávkování   MeSH
• hospitalizace MeSH
• lidé středního věku MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• randomizované kontrolované studie jako téma MeSH
• senioři MeSH
• srdeční selhání * farmakoterapie   patofyziologie   MeSH
• tepový objem MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• protokol klinické studie MeSH

BACKGROUND: Severe combined immunodeficiency (SCID) is a fatal but treatable inborn error of immunity (IEI). Newborn screening (NBS) using T-cell receptor excision circles (TREC) has been adopted globally, with very few countries incorporating kappa recombination excision circles (KREC) to also detect early B-cell development disorders, such as X-linked agammaglobulinemia (XLA). OBJECTIVE: To evaluate the effectiveness of a 2-year pilot SCID NBS program in the Czech Republic, emphasising the utility of combined TREC/KREC screening. METHODS: Between January 2022 and December 2023, a dual TREC/KREC NBS pilot was conducted across the Czech Republic, alongside spinal muscular atrophy (SMA) screening. Approximately 200,000 newborns were screened using quantitative real-time PCR on dried blood spots collected 48-72 h after birth. RESULTS: The pilot referred 58 newborns, identifying 21 cases of IEI, including two SCID cases, with an overall incidence of TREC/KREC screenable IEI of 10.5/100,000 newborns. SCID incidence was 1/100,000. KREC screening proved invaluable, detecting 10 cases of congenital agammaglobulinemia including novel non-XLA forms, which increased the estimated incidence of agammaglobulinemia in the Czech Republic sixfold. Over one-third of low KREC results were linked to maternal immunosuppression. CONCLUSION: The Czech pilot demonstrated the effectiveness of integrated TREC/KREC NBS in detecting both T- and B-cell immunodeficiencies. As of 2024, SCID and SMA screening are included in the nationwide NBS, with KREC screening significantly improving early detection of B-cell disorders.

• MeSH
• agamaglobulinemie diagnóza   MeSH
• B-lymfocyty imunologie   MeSH
• genetické nemoci vázané na chromozom X MeSH
• lidé MeSH
• novorozenec MeSH
• novorozenecký screening * metody   MeSH
• pilotní projekty MeSH
• receptory antigenů T-buněk * genetika   MeSH
• těžká kombinovaná imunodeficience * diagnóza   genetika   epidemiologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: Emerging evidence suggests that tumour morphological heterogeneity may influence mutational profiles relevant to therapy response. In this pilot study, we aimed to assess whether mutations identified within specific morphological patterns or at the invasion front correlate with shorter time to progression after anti-EGFR therapy, as compared to whole-tissue analysis. METHODS: We investigated genetic mutations in 142 samples from primary tumours of 39 KRAS wild-type metastatic colorectal cancer (CRC) patients receiving anti-EGFR therapy. Deep next-generation sequencing was performed on whole-tumour sections and six morphology-defined tumour regions. RESULTS: Mutations in genes linked to anti-EGFR therapy response (KRAS, BRAF, NRAS, PTEN and PI3KCA) were found uniquely in the non-responder group, with substantial variability across morphological sub-regions. BRAF mutations were aligned with serrated and mucinous morphologies, while KRAS mutations (p.Lys147Glu and p.Ala146Thr) were associated with mucinous and desmoplastic morphologies. In all cases, the cumulative mutational profile from sub-regions provided more details than that of the whole-tumour profile. CONCLUSION: Our findings highlight that comprehensive analysis, considering morphological heterogeneity, is crucial for personalised CRC treatment strategies.

• MeSH
• chemorezistence * genetika   MeSH
• dospělí MeSH
• erbB receptory antagonisté a inhibitory   MeSH
• fosfohydroláza PTEN genetika   MeSH
• GTP-fosfohydrolasy genetika   MeSH
• inhibitory proteinkinas * terapeutické užití   MeSH
• kolorektální nádory * genetika   farmakoterapie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• pilotní projekty MeSH
• protinádorové látky * terapeutické užití   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování 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