BACKGROUND: This study develops a deep learning-based automated lesion segmentation model for whole-body 3D18F-fluorodeoxyglucose (FDG)-Position emission tomography (PET) with computed tomography (CT) images agnostic to disease location and site. METHOD: A publicly available lesion-annotated dataset of 1014 whole-body FDG-PET/CT images was used to train, validate, and test (70:10:20) eight configurations with 3D U-Net as the backbone architecture. The best-performing model on the test set was further evaluated on 3 different unseen cohorts consisting of osteosarcoma or neuroblastoma (OS cohort) (n = 13), pediatric solid tumors (ST cohort) (n = 14), and adult Pheochromocytoma/Paraganglioma (PHEO cohort) (n = 40). Both lesion-level and patient-level statistical analyses were conducted to validate the performance of the model on different cohorts. RESULTS: The best performing 3D full resolution nnUNet model achieved a lesion-level sensitivity and DISC of 71.70 % and 0.40 for the test set, 97.83 % and 0.73 for ST, 40.15 % and 0.36 for OS, and 78.37 % and 0.50 for the PHEO cohort. For the test set and PHEO cohort, the model has missed small volume and lower uptake lesions (p < 0.01), whereas no statistically significant differences (p > 0.05) were found in the false positive (FP) and false negative lesions volume and uptake for the OS and ST cohort. The predicted total lesion glycolysis is slightly higher than the ground truth because of FP calls, which experts can easily check and reject. CONCLUSION: The developed deep learning-based automated lesion segmentation AI model which utilizes 3D_FullRes configuration of the nnUNet framework showed promising and reliable performance for the whole-body FDG-PET/CT images.

• Klíčová slova
• Artificial intelligence, Deep learning, FDG PET/CT, Oncology,
• MeSH
• celotělové zobrazování * metody   MeSH
• deep learning * MeSH
• dítě MeSH
• dospělí MeSH
• fluorodeoxyglukosa F18 * MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• nádory * diagnostické zobrazování   MeSH
• PET/CT * metody   MeSH
• počítačové zpracování obrazu * metody   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• validační studie MeSH
• Názvy látek
• fluorodeoxyglukosa F18 * MeSH

• Klíčová slova
• Bleeding, Children, Emicizumab, Haemophilia, Inhibitors, Survey,
• Publikační typ
• dopisy MeSH

• Publikační typ
• tisková chyba MeSH

BACKGROUND: In this trial, we previously showed per-oral endoscopic myotomy (POEM) to be non-inferior to laparoscopic Heller's myotomy (LHM) plus Dor fundoplication in managing symptoms in patients with idiopathic achalasia 2 years post-procedure. However, post-procedural gastro-oesophageal reflux was more common after POEM at 2 years. Here we report 5-year follow-up data. METHODS: This study is a multicentre, randomised, open-label, non-inferiority trial performed at eight centres in six European countries (Germany, Italy, Czech Republic, Sweden, the Netherlands, and Belgium). Patients with symptomatic primary achalasia were eligible for inclusion if they were older than 18 years and had an Eckardt symptom score higher than 3. Patients were randomly assigned (1:1; randomly permuted blocks of sizes 4, 8, or 12) to undergo either POEM or LHM plus Dor fundoplication. The primary endpoint was clinical success, defined by an Eckardt symptom score of 3 or less without the use of additional treatments, at 2 years, and was reported previously. Prespecified secondary endpoints at 5 years were clinical success; Eckardt symptom score; Gastrointestinal Quality of Life Index score; lower oesophageal sphincter function by high-resolution manometry; and parameters of post-procedural reflux (reflux oesophagitis according to the Los Angeles classification; pH-metry, and DeMeester clinical score). We hypothesised that POEM would be non-inferior (with a non-inferiority margin of -12·5 percentage points) to LHM plus Dor fundoplication with regards to clinical success. All analyses were performed on a modified intention-to-treat (mITT) population, which included all patients who underwent the assigned procedure. This study is registered with ClinicalTrials.gov (NCT01601678) and is complete. FINDINGS: Between Dec 7, 2012, and Oct 9, 2015, 241 patients were randomly assigned (120 to POEM and 121 to LHM) and 221 had the assigned treatment (112 POEM and 109 LHM; mITT). 5-year follow up data were available for 90 (80%) patients in the POEM group and 87 (80%) patients in the LHM group. Clinical success rate at 5 years was 75·0% (95% CI 66·2 to 82·1) after POEM and 70·8% (61·7 to 78·5) after LHM (difference 4·2 percentage points [95% CI -7·4 to 15·7]). The mean Eckardt symptom score decreased from baseline to 5 years in both groups and the overall difference in mean scores was -0·29 (95% CI -0·62 to 0·05). Change in Gastrointestinal Quality of Life Index scores, as well as in integrated relaxation pressure on manometry, from baseline to 5 years, did not differ significantly between the groups. At 5 years, 26 (41%) of 63 patients after POEM and 18 (31%) of 58 patients after LHM had reflux oesophagitis (difference 10·2 percentage points [95% CI -7·0 to 26·8]). Significant oesophagitis (Los Angeles classification grade B, C, or D) was observed in nine (14%) of 63 patients after POEM and in four (7%) of 58 patients after LHM. pH-metry was performed in 81 (37%) of 221 patients, with higher mean acid exposure time for POEM (10·2% [95% CI 7·6 to 14·2]) than for LHM (5·5% [3·1 to 11·8]). Significantly more patients in the POEM than in the LHM group had abnormal acid exposure time at 5 years (>4·5%; 28 [62%] of 45 vs 11 [31%] of 36; difference 31·7 percentage points [95% CI 9·8 to 50·5]). The presence of reflux symptoms at 5 years was similar in both groups, with a mean DeMeester clinical score of 1·3 (95% CI 1·0 to 1·6) after POEM and 1·1 (0·9 to 1·4) after LHM. The complications of peptic stricture, Barrett's oesophagus, and oesophageal adenocarcinoma were not reported. INTERPRETATION: Our long-term results support the role of POEM as a less invasive myotomy approach that is non-inferior to LHM in controlling symptoms of achalasia. Gastro-oesophageal reflux was common in both groups, but with a tendency towards higher rates in the POEM group. Thus, patients should be provided with the advantages and disadvantages of each approach in decision making. FUNDING: European Clinical Research Infrastructure Network, Hamburgische Stiftung für Wissenschaften, Entwicklung und Kultur Helmut und Hannelore Greve, Dr med Carl-August Skröder Stiftung, Dr Gerhard Büchtemann Stiftung, Agnes-Graefe Stiftung, Georg und Jürgen Rickertsen Stiftung, Reinhard Frank Stiftung, Johann Max Böttcher Stiftung, Richard und Annemarie Wolf Stiftung, Olympus Europa, German Society for Gastroenterology and Metabolism and Olympus Europe Foundation, United European Gastroenterology Week, Olympus EuroNOTES Research Fund Program, Harvard Catalyst, the Harvard Clinical and Translational Science Center, and Harvard University and its affiliated academic health-care centres.

• MeSH
• achalázie jícnu * chirurgie   MeSH
• dospělí MeSH
• fundoplikace * metody   škodlivé účinky   MeSH
• gastroezofageální reflux etiologie   MeSH
• Hellerova myotomie * metody   škodlivé účinky   MeSH
• kvalita života MeSH
• laparoskopie * metody   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• pooperační komplikace epidemiologie   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
• hodnocení ekvivalence MeSH
• multicentrická studie MeSH
• srovnávací studie MeSH
• Geografické názvy
• Evropa MeSH

Dry deposition is the primary pathway for tropospheric ozone (O3) removal, with forests playing a critical role. However, environmental stressors such as drought can reduce this removal capacity by limiting stomatal O3 uptake due to stomata closure. Here we test the hypothesis that combined soil and atmospheric drought reduces the O3 sink capacity of forest ecosystems by diminishing stomatal O3 flux. For stomatal O3 flux estimation, we applied a single-layer resistance model, which estimates stomatal O3 flux based on evaporative resistance method complemented by aerodynamic and laminar sublayer resistances calculation. The model was complemented by detailed sap flow monitoring within the forest footprint, to calculate stomatal O3 flux, using long-term eddy covariance measurements of total water vapour and O3 fluxes over four growing seasons (2017-2020), including an unprecedented drought period. The results revealed that non-stomatal O3 flux compensated for the reduction in stomatal flux in a temperate Norway spruce forest at the Bílý Kříž experimental site in the mountainous region of the Czech Republic, Central Europe. Ozone consumption through interactions with volatile organic compounds, quantified by the MEGAN (Model of Emissions of Gases and Aerosols from Nature) model, contributed only marginally to the non-stomatal flux. These findings suggest that surface reactions, where O3 interacts with plant surfaces, cuticular layers, and soil particles, likely constitute a dominant non-stomatal O3 sink during drought. To our knowledge, this is the first report of severe drought influencing O3 fluxes in temperate mountainous regions, which were previously considered less affected by drought stress.

• Klíčová slova
• Eddy covariance, MEGAN, Ozone flux, Picea abies, Stomatal conductance, Volatile organic compounds,
• MeSH
• látky znečišťující vzduch * metabolismus   analýza   MeSH
• lesy * MeSH
• monitorování životního prostředí metody   MeSH
• období sucha * MeSH
• ozon * MeSH
• průduchy rostlin * fyziologie   metabolismus   MeSH
• smrk * metabolismus   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• látky znečišťující vzduch * MeSH
• ozon * MeSH

INTRODUCTION: This study explored patient and clinician perspectives on a new fixed-dose combination of macitentan and tadalafil (M/T FDC) in a once-daily single tablet for treatment of pulmonary arterial hypertension (PAH). METHODS: Qualitative semi-structured interviews were conducted during the open-label period of the global, phase 3 A DUE clinical trial that evaluated M/T FDC. A subset of enrolled patients (N = 26) and site investigators (N = 18 clinicians) were interviewed. Patients received four tablets during double-blind treatment and could be in one of three arms (macitentan + placebo; tadalafil + placebo; M/T FDC + placebo) followed by M/T FDC (one tablet) during the open-label period. Patients and clinicians were asked to share their experience of pre-trial PAH medication, double-blind treatment, and open-label M/T FDC. Thematic analysis was conducted on blinded data. RESULTS: Patients preferred the M/T FDC tablet (open-label) over the four tablets during double-blind treatment. Patients were satisfied with M/T FDC, highlighting its positive impact on their psychological well-being, through reducing stress associated with managing multiple pills. All patients indicated that having a single, once-a-day pill for PAH was more convenient and associated with greater treatment adherence. Clinicians highlighted that their patients have a high daily pill burden for PAH and other comorbidities, and prefer treatments with an oral mode of administration that reduce the number of daily pills required. Clinicians felt that M/T FDC would be well received in clinical practice and potentially assist in implementing guideline-recommended combination treatment of PAH. CONCLUSIONS: In this qualitative analysis, all 26 patients and 18 clinicians provided positive feedback on M/T FDC treatment, which was consistent across countries. Reducing the number of pills needed to treat PAH, through use of single-tablet M/T FDC, is highly valued by patients and endorsed by clinicians, who both felt the single-tablet combination therapy could have a positive effect on patients' well-being and increase treatment adherence.

• Klíčová slova
• Clinician interview, Fixed-dose combination, Patient interview, Patient perspective, Polypharmacy, Pulmonary arterial hypertension, Treatment adherence,
• MeSH
• adaptivní klinické zkoušky jako téma MeSH
• antihypertenziva * aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• fixní kombinace léků MeSH
• inhibitory fosfodiesterasy 5 aplikace a dávkování   terapeutické užití   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• kvalitativní výzkum MeSH
• lidé středního věku MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• plicní arteriální hypertenze * farmakoterapie   MeSH
• plicní hypertenze * farmakoterapie   MeSH
• pyrimidiny * aplikace a dávkování   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• rozhovory jako téma MeSH
• senioři MeSH
• spokojenost pacientů MeSH
• sulfonamidy * aplikace a dávkování   terapeutické užití   MeSH
• tablety MeSH
• tadalafil * aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antihypertenziva * MeSH
• fixní kombinace léků MeSH
• inhibitory fosfodiesterasy 5 MeSH
• macitentan MeSH Prohlížeč
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil * MeSH

AIMS: To assess the efficacy and safety of switching from premixed insulin to a once-daily, fixed-ratio combination of insulin glargine 100 U/mL + lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D). METHODS: In this phase 4, 24-week, single-arm study, participants switched from once-daily or twice-daily premixed insulin to iGlarLixi (EudraCT number 2021-003711-25). Key inclusion criteria: ≥18 years; premixed insulin therapy for ≥3 months and < 10 years; ± 1-2 oral antidiabetic drugs (OADs); HbA1c ≥7.5% to ≤10.0%. The primary endpoint was the change in HbA1c from baseline to Week 24. Secondary endpoints included: participants achieving HbA1c <7% and change in body weight at Week 24, and safety. RESULTS: Overall, 162 participants switched to iGlarLixi (89.5% from twice-daily premixed insulin); mean duration of diabetes was 15.7 (standard deviation [SD]: 8.3) years. Mean baseline HbA1c (8.5%) reduced by least squares (LS) mean of 1.2% (95% confidence interval [CI]: -1.4, -1.1) at Week 24, and 37.6% of participants had achieved an HbA1c target of <7% (95% CI: 30.0, 45.7). LS mean body weight change from baseline to Week 24 was -1.0 kg (95% CI: -1.6, -0.5). Fasting and post-prandial plasma glucose decreased from baseline to Week 24 by 45.6 mg/dL (SD ± 52.4) and 67.6 mg/dL (SD ± 65.1), respectively. Confirmed symptomatic hypoglycaemia occurred in 38.3% of participants (ADA level 1: 35.8%; level 2: 15.4%; level 3: 0.0%). CONCLUSIONS: iGlarLixi initiation was associated with improved glycaemic control, without body weight gain or increased hypoglycaemia over 24 weeks.

• Klíčová slova
• clinical trial, iGlarLixi, insulin glargine, lixisenatide, phase IV study, type 2 diabetes,
• MeSH
• diabetes mellitus 2. typu * farmakoterapie   krev   MeSH
• dospělí MeSH
• fixní kombinace léků MeSH
• glykovaný hemoglobin analýza   MeSH
• hypoglykemie chemicky indukované   MeSH
• hypoglykemika * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• inzulin glargin * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• krevní glukóza účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhrada léků * MeSH
• peptidy * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• receptor pro glukagonu podobný peptid 2 MeSH
• rozvrh dávkování léků 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 IV MeSH
• multicentrická studie MeSH
• Názvy látek
• fixní kombinace léků MeSH
• glykovaný hemoglobin MeSH
• hemoglobin A1c protein, human MeSH Prohlížeč
• hypoglykemika * MeSH
• inzulin glargin * MeSH
• krevní glukóza MeSH
• lixisenatide MeSH Prohlížeč
• peptidy * MeSH
• receptor pro glukagonu podobný peptid 2 MeSH

BACKGROUND: The open-label, single-arm, multicentre ORZORA trial (NCT02476968) evaluated maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) with a germline (g) or somatic (s) BRCA1 and/or BRCA2 mutation (BRCAm) or a non-BRCA homologous recombination repair mutation (non-BRCA HRRm). METHODS: Patients were in response to platinum-based chemotherapy after ≥2 prior lines of treatment and underwent prospective central screening for tumour BRCA status, then central gBRCAm testing to determine sBRCAm or gBRCAm status. An exploratory cohort evaluated non-BRCA HRRm in 13 predefined genes. Patients received olaparib 400 mg (capsules) twice daily until investigator-assessed disease progression. Secondary endpoints included overall survival (OS) and safety. RESULTS: 177 patients received olaparib. At the final data cutoff (25 June 2021), median OS from study enrolment was 46.8 (95% confidence interval [CI] 37.9-54.4), 43.2 (31.7-NC [not calculated]), 47.4 (37.9-NC) and 44.9 (28.9-NC) months in the BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts, respectively. No new safety signals were identified. CONCLUSION: Maintenance olaparib showed consistent clinical activity in the BRCAm and sBRCAm cohorts; exploratory analysis suggested similar activity in the non-BRCA HRRm cohort. These findings highlight that patients with PSR OC, beyond those with gBRCAm, may benefit from maintenance olaparib.

• MeSH
• dospělí MeSH
• ftalaziny * aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru * farmakoterapie   genetika   MeSH
• nádory vaječníků * farmakoterapie   genetika   mortalita   patologie   MeSH
• PARP inhibitory * aplikace a dávkování   terapeutické užití   MeSH
• piperaziny * aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• protein BRCA1 * genetika   MeSH
• protein BRCA2 * genetika   MeSH
• rekombinační oprava DNA genetika   MeSH
• senioři MeSH
• zárodečné mutace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze IV MeSH
• multicentrická studie MeSH
• Názvy látek
• BRCA1 protein, human MeSH Prohlížeč
• BRCA2 protein, human MeSH Prohlížeč
• ftalaziny * MeSH
• olaparib MeSH Prohlížeč
• PARP inhibitory * MeSH
• piperaziny * MeSH
• protein BRCA1 * MeSH
• protein BRCA2 * MeSH

Social withdrawal and deficits in social cognition are hallmarks of Alzheimer's disease (AD). While early deficits in social behavior and memory have been documented in mouse AD models, they remain understudied in rat models. Early-stage AD is accompanied by dysfunction of parvalbumin-positive (PV+) interneurons, implicating their potential connection to early symptoms. In this study, we employed a 5-trial social memory task to investigate early deficits in social cognition in 6-month-old TgF344-AD male and female rats. We counted the number of PV+ interneurons and recorded local field potentials during social interactions in the hippocampal CA2 - a region critical for social information processing. Our results show decreased social interest and novelty preference in TgF344-AD male and female rats. However, reduced PV+ interneuron numbers were observed only in female rats and specific to the CA2 area. The electrophysiological recordings revealed reduced theta-gamma phase-amplitude coupling in the CA2 during direct social interactions. We conclude that deficits in social cognition accompany early-stage AD in TgF344-AD rats and are potentially linked to PV+ interneuron and brain oscillatory dysfunction in the CA2 region of the hippocampus.

• Klíčová slova
• Alzheimer's disease, CA2, Hippocampus, Parvalbumin-positive interneurons, Social memory, TgF344-AD,
• MeSH
• Alzheimerova nemoc * patofyziologie   patologie   metabolismus   MeSH
• hipokampální oblast CA2 * patofyziologie   metabolismus   patologie   MeSH
• interneurony * metabolismus   patologie   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• parvalbuminy * metabolismus   MeSH
• pohlavní dimorfismus MeSH
• potkani inbrední F344 MeSH
• potkani transgenní MeSH
• sociální chování * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• parvalbuminy * MeSH

Cuticle function can be pivotal to plant success in different environments. Yet, the occurrence of intraspecific adjustments in cuticle traits resulting from acclimation or adaptation to different habitats remains poorly understood. Here, we used genetically well-characterised populations of Arabidopsis arenosa to investigate whether cuticle traits were adjusted as part of the parallel evolution from a foothill to an alpine ecotype. Six alpine and six foothill populations, representing at least three independent evolutionary origins of an alpine ecotype, were used in reciprocal transplantation experiments, to investigate cuticle traits at the eco-physiological, biochemical and structural levels. The genetic basis behind these traits was assessed by combining selection scans and differential gene expression analysis. Overall, alpine populations showed reduced cuticular transpiration in conjunction with consistently altered cuticular wax composition, with higher accumulation of two fatty alcohols and two iso-alkanes. Genomic analysis unravelled nine genes associated with cuticular wax metabolism showing allelic differentiation in alpine compared to lowland populations. In silico gene expression analysis revealed differences between ecotypes for several genes related to cuticle metabolism. Repeated ecotypic differentiation in cuticle traits together with the genetic architecture of the alpine ecotype points at an adaptive value of cuticle adjustments for the colonisation of alpine habitats.

• Klíčová slova
• Alpine habitat, Arabidopsis arenosa, adaptation, cuticle, cuticular wax composition, ecotype, parallel evolution,
• MeSH
• Arabidopsis * genetika   fyziologie   MeSH
• ekosystém * MeSH
• ekotyp MeSH
• epidermis rostlin * fyziologie   genetika   MeSH
• fenotyp MeSH
• kvantitativní znak dědičný * MeSH
• listy rostlin * fyziologie   genetika   anatomie a histologie   MeSH
• regulace genové exprese u rostlin MeSH
• rostlinné geny MeSH
• vosky metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• vosky MeSH