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UNLABELLED: The aim of this study was to identify parameters influencing DNA extraction and PCR amplification efficiencies in an attempt to standardize Mucorales qPCR. The Fungal PCR Initiative Mucorales Laboratory Working Group distributed two panels of simulated samples to 26 laboratories: Panel A (six sera spiked with Mucorales DNA and one negative control serum) and Panel B (six Mucorales DNA extracts). Panel A underwent DNA extraction in each laboratory according to the local procedure and were sent to a central laboratory for testing using three different qPCR techniques: one in-house qPCR assay and two commercial assays (MucorGenius and Fungiplex). Panel B DNA extracts were PCR amplified in each laboratory using local procedures: nine in-house qPCR assays and two commercial kits (MucorGenius and MycoGENIE). All data were compiled and anonymously analyzed at the central laboratory. For Panel A, a total of six different automated platforms and five manual extraction methods were used. Positive rates were 64%, 70%, and 89%, for the MucorGenius, Fungiplex, and the in-house qPCR assay, respectively. Using a large volume of serum for DNA extraction provided the highest analytical sensitivity (82.5% for 1 mL compared with 62.7% for smaller volumes, P < 0.01). For Panel B, five in-house qPCR assays and two commercial kits had >78% positivity. Using larger PCR input volumes (≥7 μL) was associated with the highest sensitivity at 95.5% compared to 58.3% when lower input volumes were used (P < 0.01). Using larger sample volumes for nucleic acid extraction and DNA template volumes for PCR amplification significantly improves the performance of Mucorales qPCR when testing serum. IMPORTANCE: Mucormycosis is a life-threatening mold infection affecting immunosuppressed patients but also other patients with diabetes or trauma. Better survival is linked to shorter delays in diagnosis and treatment initiation. Detection of Mucorales-free DNA in serum or plasma using quantitative PCR allows a prompt diagnosis and earlier treatment. Several techniques and protocols of quantitative Mucorales PCR are used in Europe, and improving performance remains a common objective of laboratories participating in the fungal PCR Initiative Working Group. This study, which combined results from 26 laboratories in Europe, showed that the main parameters underpinning sensitivity are the preanalytical variables (volume of serum used for DNA extraction and DNA template volume), irrespective of the extraction platforms and qPCR assay/platform.
- MeSH
- diagnostické techniky molekulární normy metody MeSH
- DNA fungální * krev genetika MeSH
- kvantitativní polymerázová řetězová reakce * normy metody MeSH
- lidé MeSH
- Mucorales * genetika izolace a purifikace MeSH
- mukormykóza * diagnóza mikrobiologie krev MeSH
- senzitivita a specificita * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
OBJECTIVE: We comprehensively characterized a large pediatric cohort with focal cortical dysplasia (FCD) type 1 to expand the phenotypic spectrum and to identify predictors of postsurgical outcomes. METHODS: We included pediatric patients with histopathological diagnosis of isolated FCD type 1 and at least 1 year of postsurgical follow-up. We systematically reanalyzed clinical, electrophysiological, and radiological features. The results of this reanalysis served as independent variables for subsequent statistical analyses of outcome predictors. RESULTS: All children (N = 31) had drug-resistant epilepsy with varying impacts on neurodevelopment and cognition (presurgical intelligence quotient [IQ]/developmental quotient scores = 32-106). Low presurgical IQ was associated with abnormal slow background electroencephalographic (EEG) activity and disrupted sleep architecture. Scalp EEG showed predominantly multiregional and often bilateral epileptiform activity. Advanced epilepsy magnetic resonance imaging (MRI) protocols identified FCD-specific features in 74.2% of patients (23/31), 17 of whom were initially evaluated as MRI-negative. In six of eight MRI-negative cases, fluorodeoxyglucose-positron emission tomography (PET) and subtraction ictal single photon emission computed tomography coregistered to MRI helped localize the dysplastic cortex. Sixteen patients (51.6%) underwent invasive EEG. By the last follow-up (median = 5 years, interquartile range = 3.3-9 years), seizure freedom was achieved in 71% of patients (22/31), including seven of eight MRI-negative patients. Antiseizure medications were reduced in 21 patients, with complete withdrawal in six. Seizure outcome was predicted by a combination of the following descriptors: age at epilepsy onset, epilepsy duration, long-term invasive EEG, and specific MRI and PET findings. SIGNIFICANCE: This study highlights the broad phenotypic spectrum of FCD type 1, which spans far beyond the narrow descriptions of previous studies. The applied multilayered presurgical approach helped localize the epileptogenic zone in many previously nonlesional cases, resulting in improved postsurgical seizure outcomes, which are more favorable than previously reported for FCD type 1 patients.
- MeSH
- dítě MeSH
- elektroencefalografie * metody MeSH
- epilepsie MeSH
- fokální kortikální dysplazie MeSH
- kohortové studie MeSH
- kojenec MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- malformace mozkové kůry, skupina I * chirurgie komplikace diagnostické zobrazování MeSH
- malformace mozkové kůry chirurgie komplikace diagnostické zobrazování MeSH
- mladiství MeSH
- pozitronová emisní tomografie MeSH
- předškolní dítě MeSH
- refrakterní epilepsie * chirurgie diagnostické zobrazování patofyziologie MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: Liver cytochromes (CYPs) play an important role in drug metabolism but display a large interindividual variability resulting both from genetic and environmental factors. Most drug dose adjustment guidelines are based on genetics performed in healthy volunteers. However, hospitalized patients are not only more likely to be the target of new prescriptions and drug treatment modifications than healthy volunteers, but will also be more subject to polypharmacy, drug-drug interactions, or to suffer from disease or inflammation affecting CYP activities. METHODS: We compared predicted phenotype based on genetic data and measured phenotype using the Geneva cocktail to determine the extent of drug metabolizing enzyme variability in a large population of hospitalized patients (>500) and healthy young volunteers (>300). We aimed to assess the correlation between predicted and measured phenotype in the two populations. RESULTS: We found that, even in cases where the genetically predicted metabolizer group correlates well with measured CYP activity at group level, this prediction lacks accuracy for the determination of individual metabolizer capacities. Drugs can have a profound impact on CYP activity, but even after combining genetic and drug treatment information, the activity of a significant proportion of extreme metabolizers could not be explained. CONCLUSIONS: Our results support the use of measured metabolic ratios in addition to genotyping for accurate determination of individual metabolic capacities to guide personalized drug prescription.
- MeSH
- dospělí MeSH
- fenotyp MeSH
- genotyp MeSH
- hospitalizace MeSH
- léčivé přípravky metabolismus MeSH
- lékové interakce MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- senioři MeSH
- systém (enzymů) cytochromů P-450 * genetika metabolismus MeSH
- zdraví dobrovolníci pro lékařské studie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Penile squamous cell carcinoma (pSCC) represents an uncommon malignancy characterized by stagnant mortality, psychosexual distress, and a highly variable prognosis. Currently, the World Health Organization distinguishes between human papillomavirus (HPV)-related and HPV-independent pSCC. Recently, there has been an evolving line of research documenting the enrichment of HPV-independent pSCC with a high tumor mutational burden (TMB) and programmed death ligand-1 expression, as well as clusters of genes associated with HPV status. In this study, we conducted comprehensive next-generation sequencing DNA profiling of 146 pSCC samples using a panel consisting of 355 genes associated with tumors. This profiling was correlated with immunohistochemical markers and prognostic clinical data. A survival analysis of recurrent genomic events (found in ≥10 cases) was performed. TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR alterations were associated with significantly shortened overall survival in univariate and multivariate analysis. HPV positivity, diagnosed through both p16 immunohistochemistry and HPV DNA analysis, displayed no impact on survival but was associated with high-grade, lymphatic invasion, programmed death ligand-1 negativity/weak expression, and low TMB. FAT1, TP53, CDKN2A, CASP8, and HRAS were more often mutated in HPV-independent pSCC. In contrast, HPV-associated pSCCs were enriched by EPHA7, ATM, GRIN2A, and CHEK1 mutations. PIK3CA, FAT1, FBXW7, and KMT2D mutations were associated with high TMB. NOTCH1, TP53, CDKN2A, POT1, KMT2D, ATM, CHEK1, EPHA3, and EGFR alterations were related to adverse clinicopathologic signs, such as advanced stage, high tumor budding, and lymphovascular invasion. We detected 160 alterations with potential treatment implications, with 21.2% of samples showing alterations in the homologous recombination repair pathway. To the best of our knowledge, this study describes the largest cohort of pSCC with complex molecular pathologic, clinical, and prognostic analysis correlating with prognosis.
- MeSH
- ATM protein genetika MeSH
- dospělí MeSH
- erbB receptory genetika MeSH
- infekce papilomavirem MeSH
- inhibitor p16 cyklin-dependentní kinasy genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- nádorové biomarkery * genetika analýza MeSH
- nádorový supresorový protein p53 genetika MeSH
- nádory penisu * genetika mortalita patologie virologie MeSH
- prognóza MeSH
- proteiny vázající telomery MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- shelterinový komplex MeSH
- spinocelulární karcinom * genetika mortalita patologie virologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
Pathogenic alterations, namely, fusions and amplifications, of the GLI1 gene have been identified in various mesenchymal tumors, including pericytoma with t(7;12), plexiform fibromyxoma, gastroblastoma, and other malignant mesenchymal neoplasms arising in the soft tissues, as well as in various visceral organs. However, only three cases of GLI1-rearranged renal tumors have been reported to date, comprising two low-grade spindle cell tumors with GLI1::FOXO4 fusion along with one GLI1-rearranged case with an unknown fusion partner. In this study, we analyzed three cases with GLI1::FOXO4 fusion and overlapping morphology. One of the cases was reported previously, but an extended clinical and immunohistochemical information is provided. The studied cases occurred in 2 female and 1 male patients aged 35, 55, and 62 years (mean 51 years). All three tumors affected the renal parenchyma and grew as unencapsulated but well-circumscribed solid masses containing occasional entrapped and dilated renal tubules. The tumor cells were organized in cords, nests, or fascicles, had a round to spindled shape, and exhibited only mild nuclear atypia and minimal mitotic activity. They had a sparse eosinophilic to clear cytoplasm and were embedded in myxocollagenous stroma. Immunohistochemically, all cases expressed GLI1 (albeit with variable intensity) and harbored GLI1::FOXO4 fusion. All three patients were treated solely by complete surgical excision. Case 1 was alive with unknown disease status, case 2 was alive without evidence of disease, and case 3 died of unrelated causes. Our study doubles the number of reported cases with GLI1::FOXO4 fusion. The so far absolute predilection of this fusion for renal tumors, coupled with the absence of reports of other GLI1 fusions in tumors of the kidney, might indicate the potential existence of a distinct renal subtype with morphological features similar to other GLI1-altered tumors. All four reported cases had an uneventful follow-up which, together with their low-grade morphological features, suggests that these tumors might have a favorable prognosis.
- MeSH
- dospělí MeSH
- forkhead transkripční faktory * genetika MeSH
- genová přestavba * MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery * genetika analýza MeSH
- nádory ledvin * genetika patologie MeSH
- protein Gli1 * genetika MeSH
- proteiny buněčného cyklu * genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Global obesity rates have risen dramatically, now exceeding deaths from starvation. Metabolic and bariatric surgery (MBS), initially for severe obesity (BMI ≥35 kg/m2), is performed globally over 500 000 times annually, offering significant metabolic benefits beyond weight loss. However, varying eligibility criteria globally impact patient care and healthcare resources. Updated in 2022, ASMBS and IFSO guidelines aim to standardise MBS indications, reflecting current understanding and emphasising comprehensive preoperative assessments. Yet, clinical variability persists, necessitating consensus-based recommendations. This modified Delphi study engaged 45 global experts to establish consensus on perioperative management in MBS. Experts selected from bariatric societies possessed expertise in MBS and participated in a two-round Delphi protocol. Consensus was achieved on 90 of 169 statements (53.3%), encompassing multidisciplinary team composition, patient selection criteria, preoperative testing, and referral pathways. The agreement highlighted the critical role of comprehensive preoperative assessments and the integration of healthcare professionals in MBS. These findings offer essential insights to standardise perioperative practices and advocate for evidence-based guidelines in MBS globally. The study underscores the need for unified protocols to optimise outcomes and guide future research in MBS.
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.
- MeSH
- bendamustin hydrochlorid * aplikace a dávkování terapeutické užití MeSH
- chronická lymfatická leukemie * farmakoterapie mortalita MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- piperidiny terapeutické užití aplikace a dávkování škodlivé účinky MeSH
- protokoly protinádorové kombinované chemoterapie * terapeutické užití škodlivé účinky MeSH
- pyrazoly * terapeutické užití aplikace a dávkování škodlivé účinky MeSH
- pyrimidiny * terapeutické užití aplikace a dávkování škodlivé účinky MeSH
- rituximab * aplikace a dávkování terapeutické užití škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři 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
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
PURPOSE: TACE induces variable systemic effects by producing factors that promote inflammation, oncogenesis, and angiogenesis. Here we compare concentrations of microRNAs (miR-21, miR-210 and miR-34a) and vascular endothelial growth factor (VEGF) in hepatocellular carcinoma (HCC) patients undergoing TACE with degradable (DSM) and nondegradable (DEB) particles and potential use of these biomarker changes for prediction of patient outcomes. MATERIALS AND METHODS: Overall, 52 patients with HCC treated with DSM TACE (24 patients) and DEB TACE (28 patients) were included in this prospective study. Concentrations of studied biomarkers were measured from blood plasma preprocedurally, immediately (< 90 min) postprocedurally, and 24-h after TACE. Levels were compared between DSM and DEB TACE and correlated with treatment response six and 12 months after the first TACE. RESULTS: Both DSM and DEB TACE elevated plasma levels of miR-21, miR-34a, and miR-210 at 24 h post-procedure compared to baseline levels (FC 1.25-4.0). MiR-34a elevation immediately after TACE was significantly associated with nonprogressive disease compared to those with progressive disease at both six months (FCa: p = 0.014) and 12 months (FCa: p = 0.029) post-TACE. No significant biomarker changes were found between the embolization particle groups. However, VEGF levels showed a decrease only in the DSM TACE group (FC24: p = < 0.001). CONCLUSION: Embolization particle type did not significantly impact miRNA or VEGF changes post-TACE. However, miR-34a elevation immediately after the procedure predicts better patient outcome and may prove useful as a biomarkers for the monitoring of clinical outcomes. LEVEL OF EVIDENCE: Level 3 Prospective cohort study.
- MeSH
- biologické markery krev MeSH
- chemoembolizace * metody MeSH
- hepatocelulární karcinom * terapie krev genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA * krev MeSH
- nádorové biomarkery * krev MeSH
- nádory jater * terapie genetika krev MeSH
- prospektivní studie MeSH
- senioři MeSH
- vaskulární endoteliální růstový faktor A * krev 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
INTRODUCTION: Plantar fasciitis (PF) is one of the most common running-related injuries. PURPOSE: The aim of this prospective study was to determine the incidence of PF and identify potential risk or protective factors for PF in runners and non-runners. METHODS: Data from 1206 participants from the 4HAIE cohort study (563 females/643 males; 715 runners/491 non-runners; 18-65 yr of age) were included in the analysis. We collected biomechanical data during overground running using a three-dimensional motion capture system at the baseline and running distance data via retrospective questionnaires and followed the participants for 12 months following the baseline data collection. Participants were asked weekly about any sports-related injury (including PF). A binary logistic regression was performed to reveal potential associations between running distance and biomechanical risk factors and PF while controlling for running distance, sex, and age. RESULTS: The total incidence of PF was 2.3% (28 PF from 1206 participants), 2.5% in runners and 2.0% in non-runners ( P = 0.248). Runners who ran more than 40 km·wk -1 had six times higher odds of suffering PF than individuals who ran 6-20 km·wk -1 ( P = 0.009). There was a significant association between maximal ankle adduction and PF; that is, runners with a lower abduction angle during the stance period had higher risk of PF ( P = 0.024). No other biomechanical variables indicated significant associations with PF. CONCLUSIONS: Regular running with a moderate weekly volume and more toeing out of the foot relative to the shank may reduce the risk against PF in runners, which may be useful for researchers, runners, coaches, and health professionals to minimize PF injury risk.
- MeSH
- běh * fyziologie zranění MeSH
- biomechanika MeSH
- dospělí MeSH
- fasciitida plantární * epidemiologie patofyziologie MeSH
- incidence MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- prospektivní studie MeSH
- rizikové faktory MeSH
- senioři 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
INTRODUCTION: A variable proportion of non-responders to cardiac resynchronization therapy (CRT) warrants the search for new approaches to optimize the position of the left ventricular (LV) lead and the CRT device programming. CineECG is a novel ECG modality proposed for the spatial visualization and quantification of myocardial depolarization and repolarization sequences. OBJECTIVE: The present study aimed to evaluate CineECG-derived parameters in different pacing modes and to test their associations with acute hemodynamic responses in CRT patients. METHODS AND RESULTS: CineECG was used to construct the average electrical path within the cardiac anatomy from the 12-lead ECG. CineECG and LV dP/dt max were tested in 15 patients with nonischemic dilated cardiomyopathy and left bundle branch block (QRS: 170 ± 17 ms; LVEF: 26 ± 5.5%) under pacing protocols with different LV lead localizations. The CineECG-derived path directions were computed for the QRS and ST-T intervals for the anteroposterior (Xh), interventricular (Yh), and apicobasal (Zh) axes. In a multivariate linear regression analysis with adjustment for the pacing protocol type, the ST-T path direction Yh was independently associated with the increase in dP/dt max during CRT, [regression coefficient 639.4 (95% confidence interval: 187.9-1090.9), p = 0.006]. In ROC curve analysis, the ST-T path direction Yh was associated with the achievement of a 10% increase in dP/dt max (AUC: 0.779, p = 0.002) with the optimal cut-off > 0.084 (left-to-right direction) with sensitivity 0.67 and specificity 0.92. CONCLUSION: The acute hemodynamic response in CRT patients was associated with specific CineECG repolarization sequence parameters, warranting their further testing as potential predictors of clinical outcomes.
- MeSH
- akční potenciály MeSH
- blokáda Tawarova raménka * patofyziologie terapie diagnóza MeSH
- časové faktory MeSH
- dilatační kardiomyopatie patofyziologie terapie diagnóza MeSH
- elektrokardiografie * MeSH
- funkce levé komory srdeční * MeSH
- hemodynamika * MeSH
- lidé středního věku MeSH
- lidé MeSH
- prediktivní hodnota testů * MeSH
- prostředky srdeční resynchronizační terapie MeSH
- senioři MeSH
- srdeční frekvence MeSH
- srdeční resynchronizační terapie * MeSH
- srdeční selhání patofyziologie terapie diagnóza 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
