PURPOSE: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome, or panel sequencing data sets aligned to a GRCh37, GRCh38, or T2T reference genome. METHODS: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs. It uses these reads to determine whether an individual most likely has 0 functional copies of SMN1. RESULTS: We developed SMA Finder and evaluated it on 16,626 exomes and 3911 genomes from the Broad Institute Center for Mendelian Genomics, 1157 exomes and 8762 panel samples from Tartu University Hospital, and 198,868 exomes and 198,868 genomes from the UK Biobank. SMA Finder's false-positive rate was below 1 in 200,000 samples, its positive predictive value was greater than 96%, and its true-positive rate was 29 out of 29. Most of these SMA diagnoses had initially been clinically misdiagnosed as limb-girdle muscular dystrophy. CONCLUSION: Our extensive evaluation of SMA Finder on exome, genome, and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, and the existence of treatment options, we propose that it is time to add SMN1 to the American College of Medical Genetics list of genes with reportable secondary findings after genome and exome sequencing.

• MeSH
• algoritmy MeSH
• exom genetika   MeSH
• genom lidský genetika   MeSH
• genomika metody   MeSH
• lidé MeSH
• protein přežití motorických neuronů 1 genetika   MeSH
• protein přežití motorických neuronů 2 genetika   MeSH
• sekvenční analýza DNA metody   MeSH
• sekvenování exomu MeSH
• spinální svalová atrofie * genetika   diagnóza   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The intertumoral and intratumoral heterogeneity of colorectal adenocarcinoma (CRC) at the morphologic level is poorly understood. Previously, we identified morphological patterns associated with CRC molecular subtypes and their distinct molecular motifs. Here we aimed to evaluate the heterogeneity of these patterns across CRC. Three pathologists evaluated dominant, secondary, and tertiary morphology on four sections from four different FFPE blocks per tumor in a pilot set of 22 CRCs. An AI-based image analysis tool was trained on these tumors to evaluate the morphologic heterogeneity on an extended set of 161 stage I-IV primary CRCs (n = 644 H&E sections). We found that most tumors had two or three different dominant morphotypes and the complex tubular (CT) morphotype was the most common. The CT morphotype showed no combinatorial preferences. Desmoplastic (DE) morphotype was rarely dominant and rarely combined with other dominant morphotypes. Mucinous (MU) morphotype was mostly combined with solid/trabecular (TB) and papillary (PP) morphotypes. Most tumors showed medium or high heterogeneity, but no associations were found between heterogeneity and clinical parameters. A higher proportion of DE morphotype was associated with higher T-stage, N-stage, distant metastases, AJCC stage, and shorter overall survival (OS) and relapse-free survival (RFS). A higher proportion of MU morphotype was associated with higher grade, right side, and microsatellite instability (MSI). PP morphotype was associated with earlier T- and N-stage, absence of metastases, and improved OS and RFS. CT was linked to left side, lower grade, and better survival in stage I-III patients. MSI tumors showed higher proportions of MU and TB, and lower CT and PP morphotypes. These findings suggest that morphological shifts accompany tumor progression and highlight the need for extensive sampling and AI-based analysis. In conclusion, we observed unexpectedly high intratumoral morphological heterogeneity of CRC and found that it is not heterogeneity per se, but the proportions of morphologies that are associated with clinical outcomes.

• MeSH
• adenokarcinom * patologie   genetika   mortalita   MeSH
• dospělí MeSH
• kolorektální nádory * patologie   genetika   mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů 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

Navrhovaná studie proveditelnosti využívá aplikaci „OCD dům“, vytvořenou v prostředí virtuální reality (VR) pro expoziční terapii u pacien- tů s obsedantně-kompulzivní poruchou (OCD). Metoda byla vyvinuta na základě dimenzionálního přístupu k symptomatologii OCD, který vyčleňuje čtyři podtypy: „kontaminace/čištění“, „symetrie/uspořádání“, „strach z poškození/kontrola“ a „hromadění“. Cílem probíhající studie proveditelnosti je ověřit účinnosti již dříve validované expoziční metody ve spojení s čichovou stimulací. Předpokládáme, že čichová stimulace během expozice ve VR zvýší vnímanou realističnost a potenciálně také intenzitu symptomů vyvolaných touto čichově obohacenou simulací.

The proposed feasibility study uses the application "OCD house" created in a virtual reality (VR) environment for exposure therapy in pati- ents with obsessive-compulsive disorder (OCD). The method was designed based on a dimensional approach to OCD symptomatology, which distinguishes four subtypes: 'contamination/cleaning', 'symmetry/ordering', 'fear of harm/checking' and 'hoarding'. An ongoing feasibility study aims to test the previously validated exposure method in combination with olfactory stimulation. We hypothesize that olfactory stimu- lation during exposure in VR will increase the perceived level of immersion in the environment and potentially also the assessed intensity of symptoms induced by this olfactory-enriched simulation.

• MeSH
• čichová percepce MeSH
• dospělí MeSH
• implozivní terapie metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• obsedantně kompulzivní porucha * terapie   MeSH
• software MeSH
• statistika jako téma MeSH
• studie proveditelnosti MeSH
• terapie pomocí virtuální reality * metody   MeSH
• úzkost terapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

BACKGROUND: Liver glycogen storage disorders (GSDs) are rare inherited disorders of carbohydrate metabolism that are clinically characterized by hepatomegaly and fasting intolerance. This group of disorders comprises GSD Ia and Ib as well as the so-called ketotic GSDs including GSD III, VI, IX, XI and 0a. Although clinical practice guidelines exist for most GSD subtypes, diagnostics, treatment and monitoring differ significantly among metabolic centres. The aim of this study was to gain insight into current clinical practice for liver GSDs. METHODS: An international web-based survey was performed among health care professionals involved in the care of individuals with liver GSDs. RESULTS: Sixty-seven respondents from 28 different countries caring for approximately 2650 liver GSD patients completed the survey. While the diagnostic approach was generally consistent, significant differences among metabolic centres are still observed with respect to monitoring parameters and treatment approaches. Reasons for these differences are local availability of management tools and treatment options, the rarity of the different GSD subtypes, the experiences of health care professionals, and the existence of extreme phenotypes. CONCLUSION: The development of a standard set of outcomes for patients with liver GSDs is warranted as a reference for both daily care and the evaluation of safety and efficacy of future therapies. For various parameters that serve as valuable outcome measures, tools and target values should be better defined.

• MeSH
• glykogenóza * terapie   diagnóza   MeSH
• játra metabolismus   patologie   MeSH
• lidé MeSH
• management nemoci MeSH
• nemoci jater * terapie   diagnóza   MeSH
• průzkumy a dotazníky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND OBJECTIVES: Frontotemporal lobar degeneration (FTLD) as the second most common dementia encompasses a range of syndromes and often shows overlapping symptoms with other subtypes or neurodegenerative diseases, which poses a significant clinical diagnostic challenge. Recent advancements in artificial intelligence (AI), specifically the application of machine learning (ML) algorithms to neuroimaging, have significantly progressed in addressing this challenge. This study aims to assess the diagnostic and predictive efficacy of neuroimaging feature-based AI algorithms for FTLD. METHODS: We conducted a systematic review and meta-analysis following PRISMA guidelines. We searched Pubmed, Scopus, and Web of Science for English-language, peer-reviewed studies using the following three umbrella terms: artificial intelligence, frontotemporal lobar degeneration, and neuroimaging modality. Our survey focused on computer-aided diagnosis for FTLD, employing machine/deep learning with neuroimaging radiomic features. RESULTS: The meta-analysis includes 75 articles with 20,601 subjects, including 8,051 FTLD patients. The results reveal that FTLD can be automatically classified against healthy controls (HC) with pooled sensitivity and specificity of 86% and 89%, respectively. Likewise, FTLD versus Alzheimer's disease (AD) classification exhibits pooled sensitivity and specificity of 84% and 81%, while FTLD versus Parkinson's disease (PD) demonstrates pooled sensitivity and specificity of 84% and 75%, respectively. Classification performance distinguishing FTLD from atypical Parkinsonian syndromes (APS) showed pooled sensitivity and specificity of 84% and 79%, respectively. Multiclass classification sensitivity ranges from 42% to 100%, with lower sensitivity occurring in higher class distinctions (e.g., 5-class and 11-class). DISCUSSION: Our study demonstrates the effectiveness of utilizing neuroimaging features to distinguish FTLD from HC, AD, APS, and PD in binary classification. Utilizing deep learning with multimodal neuroimaging data to differentiate FTLD subtypes and perform multiclassification among FTLD and other neurodegenerative disease holds promise for expediting diagnosis. In sum, the meta-analysis supports translation of machine learning tools in combination with imaging to clinical routine paving the way to precision medicine.

• MeSH
• frontotemporální lobární degenerace * diagnostické zobrazování   MeSH
• lidé MeSH
• neurozobrazování * metody   normy   MeSH
• strojové učení MeSH
• umělá inteligence * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH

INTRODUCTION: Idiopathic inflammatory myopathies (IIM) are a group of rare systemic autoimmune diseases characterized by muscle weakness, histopathological signs of inflammation in muscle tissues, elevated serum levels of muscle-associated enzymes, inflammatory mononuclear cells infiltrating muscle tissue and progressive symmetrical proximal muscle weakness. The current view is that they begin by immune activation in response to environmental factors in genetically predisposed people, but despite the number of investigations into the genetic background, the detailed etiopathogenesis remains unknown. The aim of this study was to examine the relationship between select polymorphisms located in the human major histocompatibility complex (MHC) and IIM. These genetic markers may take part in the onset of the autoimmune process, and their identification could aid in the diagnosis and classification of IIM subtypes. MATERIAL AND METHODS: One hundred and fifty-two adult patients suffering from IIM (82 dermatomyositis and 70 polymyositis) and 150 healthy controls were analyzed in this study. All were from the Czech Republic. SNPs of the HSP70 genes HSPA1A (rs1008438, rs1043618), HSPA1B (rs1061581, rs539689, pentanucleotide tandem duplication rs9281590) and HSPA1L (rs2227956) were analyzed in all patients and controls. For the detection of HLA polymorphisms, we used commercial kits from CareDx. Haplotypes were created using Arlequin 3.5. RESULTS: Our results confirm the association of IIM with the ancestral haplotype HLA-DRB1*03-DQB1*02. The most important MHC haplotype related to IIM and covering all polymorphisms was HLA-DQB1*02-DRB1*03:01-T-C-C-G-C-INS (p < 0.05, OR = 1.90, 95% CI: 1.15-3.13). This haplotype is associated with the risk of IIM development. CONCLUSIONS: Our results show that polymorphism typing within the MHC might be a very strong tool for recognition of IIM.

• Publikační typ
• časopisecké články MeSH

Presence of minimal residual disease (MRD), detected by flow cytometry, is an important prognostic biomarker in the management of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, data-analysis remains mainly expert-dependent. In this study, we designed and validated an Automated Gating & Identification (AGI) tool for MRD analysis in BCP-ALL patients using the two tubes of the EuroFlow 8-color MRD panel. The accuracy, repeatability, and reproducibility of the AGI tool was validated in a multicenter study using bone marrow follow-up samples from 174 BCP-ALL patients, stained with the EuroFlow BCP-ALL MRD panel. In these patients, MRD was assessed both by manual analysis and by AGI tool supported analysis. Comparison of MRD levels obtained between both approaches showed a concordance rate of 83%, with comparable concordances between MRD tubes (tube 1, 2 or both), treatment received (chemotherapy versus targeted therapy) and flow cytometers (FACSCanto versus FACSLyric). After review of discordant cases by additional experts, the concordance increased to 97%. Furthermore, the AGI tool showed excellent intra-expert concordance (100%) and good inter-expert concordance (90%). In addition to MRD levels, also percentages of normal cell populations showed excellent concordance between manual and AGI tool analysis. We conclude that the AGI tool may facilitate MRD analysis using the EuroFlow BCP-ALL MRD protocol and will contribute to a more standardized and objective MRD assessment. However, appropriate training is required for the correct analysis of MRD data.

• MeSH
• dítě MeSH
• dospělí MeSH
• imunofenotypizace metody   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• pre-B-buněčná leukemie * patologie   diagnóza   MeSH
• předškolní dítě MeSH
• průtoková cytometrie * metody   MeSH
• reprodukovatelnost výsledků MeSH
• reziduální nádor * patologie   diagnóza   MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

Bazocelulárny karcinóm je najčastejší typ rakoviny kože a zároveň najčastejšia forma malignity vôbec. Vzhľadom na významnú heterogenitu závažnosti bazocelulárneho karcinómu ale aj širokú škálu dostupných liečebných modalít je efektívna subtypizácia kľúčová pre optimalizáciu terapeutického plánovania. Z hľadiska diagnostickej výťažnosti dermatoskopie pri subtypizácii bazocelulárneho karcinómu výsledky viacerých štúdií nasvedčujú, že ide o spoľahlivú metódu, čo je reflektované aj v odporúčaniach významných odborných spoločností. Dermatoskopické hodnotenie nadobúda význam najmä pri voľbe nechirurgických liečebných modalít ako aj pri selekcii nádorov, ktoré je nevyhnutné ďalej verifikovať histopatologicky. Cieľom príspevku bolo stručne zhrnúť praktické aspekty hodnotenia nádoru z hľadiska stratifikácie rizika, a to na klinickej aj dermatoskopickej úrovni. V oblasti lokálnej liečby bazocelulárneho karcinómu prebieha v súčasnosti rozsiahly výskum, a preto je pravdepodobné, že hodnotenie za použitia neinvazívnych diagnostických modalít nadobudne v budúcnosti ešte väčší význam ako doposiaľ.

Basal cell carcinoma is the most common type of skin cancer and also the most common form of malignancy overall. Given the significant heterogeneity in the severity of basal cell carcinoma as well as the wide range of available treatment modalities, effective subtyping is crucial for optimizing therapeutic planning. In terms of the diagnostic yield of dermoscopy for the subtyping of basal cell carcinoma, results from several studies suggest its reliability, which is reflected in the guidelines of most professional societies.Dermoscopic evaluation becomes particularly important when choosing non-surgical treatment modalities as well as in the selection of tumors that require further histopathological verification. The aim of this article was to briefly summarize the practical aspects of tumor evaluation in terms of risk stratification at both the clinical and dermoscopic level. With extensive research ongoing in local treatments, non-invasive diagnostic tools are poised to play an even greater role in the future.

• MeSH
• bazocelulární karcinom * diagnostické zobrazování   klasifikace   ultrastruktura   MeSH
• dermatoskopie MeSH
• lidé MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

INTRODUCTION: In silico tools capable of predicting the functional consequences of genomic differences between individuals, many of which are AI-driven, have been the most effective over the past two decades for non-synonymous single nucleotide variants (nsSNVs). When appropriately selected for the purpose of the study, a high predictive performance can be expected. In this feasibility study, we investigate the distribution of nsSNVs with an allele frequency below 5%. To classify the putative functional consequence, a tier-based filtration led by AI-driven predictors and scoring system was implemented to the overall decision-making process, resulting in a list of prioritised genes. METHODS: The study has been conducted on breast cancer patients of homogeneous ethnicity. Germline rare variants have been sequenced in genes that influence pharmacokinetic parameters of anticancer drugs or molecular signalling pathways in cancer. After AI-driven functional pathogenicity classification and data mining in pharmacogenomic (PGx) databases, variants were collapsed to the gene level and ranked according to their putative deleterious role. RESULTS: In breast cancer patients, seven of the twelve genes prioritised based on the predictions were found to be associated with response to oncotherapy, histological grade, and tumour subtype. Most importantly, we showed that the group of patients with at least one rare nsSNVs in cystic fibrosis transmembrane conductance regulator (CFTR) had significantly reduced disease-free (log rank, p = 0.002) and overall survival (log rank, p = 0.006). CONCLUSION: AI-driven in silico analysis with PGx data mining provided an effective approach navigating for functional consequences across germline genetic background, which can be easily integrated into the overall decision-making process for future studies. The study revealed a statistically significant association with numerous clinicopathological parameters, including treatment response. Our study indicates that CFTR may be involved in the processes influencing the effectiveness of oncotherapy or in the malignant progression of the disease itself.

• MeSH
• dospělí MeSH
• frekvence genu MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu * genetika   farmakoterapie   patologie   MeSH
• protein CFTR * genetika   MeSH
• senioři MeSH
• studie proveditelnosti * MeSH
• umělá inteligence * MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Yohimbine, a natural indole alkaloid and a nonselective adrenoceptor antagonist, possesses potential benefits in treating inflammatory disorders and sepsis. Nevertheless, its broader clinical use faces challenges due to its low receptor selectivity. A structure-activity relationship study of novel yohimbine analogues identified amino esters of yohimbic acid as potent and selective ADRA2A antagonists. Specifically, amino ester 4n, in comparison to yohimbine, showed a 6-fold higher ADRA1A/ADRA2A selectivity index (SI > 556 for 4n) and a 25-fold higher ADRA2B/ADRA2A selectivity index. Compound 4n also demonstrated high plasma and microsomal stability, moderate-to-low membrane permeability determining its limited ability to cross the blood-brain barrier, and negligible toxicity on nontumor normal human dermal fibroblasts. Compound 4n represents an important complementary pharmacological tool to study the involvement of adrenoceptor subtypes in pathophysiologic conditions such as inflammation and sepsis and a novel candidate for further preclinical development to treat ADRA2A-mediated pathologies.

• MeSH
• alfa-2-adrenergní receptory - antagonisté * farmakologie   chemie   chemická syntéza   MeSH
• alfa-2-adrenergní receptory * metabolismus   MeSH
• lidé MeSH
• racionální návrh léčiv * MeSH
• vztahy mezi strukturou a aktivitou MeSH
• yohimbin * farmakologie   chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH