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INTRO: Viruses, including SARS-CoV-2, which causes COVID-19, are constantly changing. These genetic changes (aka mutations) occur over time and can lead to the emergence of new variants that may have different characteristics. After the first SARS-CoV-2 genome was published in early 2020, scientists all over the world soon realized the immediate need to obtain as much genetic information from as many strains as possible. However, understanding the functional significance of the mutations harbored by a variant is important to assess its impact on transmissibility, disease severity, immune escape, and the effectiveness of vaccines and therapeutics.METHODS: Here in Canada, we have developed an interactive framework for visualizing and reporting mutations in SARS-CoV-2 variants. This framework is composed of three stand-alone yet connected components; an interactive visualization (COVID-MVP), a manually curated functional annotation database (pokay), and a genomic analysis workflow (nf-ncov-voc). Findings: COVID-MVP provides (i) an interactive heatmap to visualize and compare mutations in SARS-CoV-2 lineages classified across different VOCs, VOIs, and VUMs; (ii) mutation profiles including the type, impact, and contextual information; (iii) annotation of biological impacts for mutations where functional data is available in the literature; (iv) summarized information for each variant and/or lineage in the form of a surveillance report; and (v) the ability to upload raw genomic sequence(s) for rapid processing and annotating for real-time classification.DISCUSSION: This comprehensive comparison allows microbiologists and public health practitioners to better predict how the mutations in emerging variants will impact factors such as infection severity, vaccine resistance, hospitalization rates, etc.CONCLUSION: This framework is cloud-compatible & standalone, which makes it easier to integrate into other genomic surveillance tools as well. COVID-MVP is integrated into the Canadian VirusSeq data portal (https://virusseqdataportal.ca) - a national data hub for SARS-COV-2 genomic data. COVID-MVP is also used by the CanCOGeN and CoVaRR networks in national COVID-19 genomic surveillance.

Embaràs i malaltia cardíaca; Resultats de l’embaràs; Transposició de les grans artèries Embarazo y enfermedad cardíaca; Resultados del embarazo; Transposición de las grandes arterias Pregnancy and cardiac disease; Pregnancy outcomes, Transposition of the great arteries Background In the past 3 decades, the arterial switch procedure has replaced the atrial switch procedure as treatment of choice for transposition of the great arteries. Although survival is superior after the arterial switch procedure, data on pregnancy outcomes are scarce and transposition of the great arteries after arterial switch is not yet included in the modified World Health Organization classification of maternal cardiovascular risk. Methods and Results The ROPAC (Registry of Pregnancy and Cardiac disease) is an international prospective registry of pregnant women with cardiac disease, part of the European Society of Cardiology EURObservational Research Programme. Pregnancy outcomes in all women after an arterial switch procedure for transposition of the great arteries are described. The primary end point was a major adverse cardiovascular event, defined as combined end point of maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischemic coronary events, and thromboembolic events. Altogether, 41 pregnant women (mean age, 26.7±3.9 years) were included, and there was no maternal mortality. A major adverse cardiovascular event occurred in 2 women (4.9%): heart failure in one (2.4%) and ventricular tachycardia in another (2.4%). One woman experienced fetal loss, whereas no neonatal mortality was observed. Conclusions Women after an arterial switch procedure for transposition of the great arteries tolerate pregnancy well, with a favorable maternal and fetal outcome. During counseling, most women should be reassured that the risk of pregnancy is low. Classification as modified World Health Organization risk class II seems appropriate. Funding from “Zabawas Foundation” and “De Hoop Foundation” in addition to the support from EURObservational Research Programme (EORP) is greatly acknowledged. Since the start of EORP, the following companies have supported the program: Abbott Vascular Int (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer AG (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2019), Daiichi Sankyo Europe GmbH (2011–2020), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2014–2017), Edwards (2016–2019), Gedeon Richter Plc (2014–2016), Menarini Int Op (2009–2012), MSD‐Merck & Co (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2009–2021), and Vifor (2019–2022).

Bevezetés: A krónikus obstruktív tüdőbetegség (COPD) gyakori krónikus gyulladásos betegség, nagy mortalitással. Célkitűzés: A vizsgálat célja a COPD-ben szenvedő betegek paraméterei – életkor, nemi megoszlás, kockázati tényezők (dohányzás, foglalkozási expozíció), a COPD súlyossága, testtömegindex, tüdőfunkció, társbetegségek és szövődmények – közötti összefüggések feltárása volt dohányzó és foglalkozási ártalomnak kitett betegeknél. Módszer: 209 beteg adatait elemeztük, akiket 2019-ben a marosvásárhelyi Tüdőgyógyászati Klinikára COPD-exacerbatio miatt vettek fel. Eredmények: A tápláltsági állapot alapján 4 csoportba soroltuk a betegeket: 50 alultáplált, 53 normál testsúlyú, 53 túlsúlyos, valamint 53 elhízott páciens. A férfi : nő arány 2,48 volt. Az esetek 67%-a aktív, keresőkorban levő páciens, 55,98%-a 55–65 év közötti volt. A betegek 10,5%-a volt 75 év feletti. A páciensek jelentős része (76,55%) dohányzott, a férfiak 91,9%-a és a nők 33,8%-a. A foglalkozási ártalom az esetek 30,62%-ában a dohányzással társult. A nem dohányzóknál a foglalkozási expozíció volt a fő tényező a COPD patogenezisében (81,6%). A „biomassza-tüzelőanyagoknak” vagy a passzív dohányzásnak való expozíció is főleg a nem dohányzó nőknél volt megfigyelhető (78,9%). A FEV1 átlagértékei alacsonyabbak voltak a túlsúlyos, elhízott és alultáplált betegekben, mint a normál testsúlyúaknál. Az elhízott és túlsúlyos COPD-s betegek körében gyakrabban fordult elő ischaemiás szívbetegség (41,5%, illetve 43,4%), mint a normál súlyú, illetve sovány betegeknél (24%, illetve 20%). Megbeszélés: Adataink rávilágítanak a károsodott tüdőfunkció súlyosságára mind a cachexiás, mind az elhízott betegeknél, és alátámasztják a testmozgás, a táplálkozás-ellenőrzés, a légzőfunkciók szűrése és az általános rehabilitáció szükségességét a COPD-s betegek tüdőkapacitásának javítása érdekében. Következtetés: A COPD multidiszciplináris megközelítése mind diagnosztikai módszerként, mind a COPD-társbetegségek helyes kezeléséhez szükséges. Orv Hetil. 2022; 163(40): 1597–1605.

Tuberculosis (TB) is a leading cause of global child mortality. Until the turn of the 21st century, Mycobacterium bovis bacille Calmette-Guerin (BCG) was the only vaccine to prevent TB. The pediatric TB vaccine pipeline has advanced in the past decade to include the evaluation of novel whole cell vaccines to replace infant BCG and investigation of subunit and whole cell vaccines to boost TB immunity during adolescence. We describe the history of BCG, current TB vaccine candidates in clinical trials, and the challenges and opportunities for future TB vaccine research in children. Children are a critical target population for TB vaccines, and expansion of the pediatric TB vaccine pipeline is urgently needed to end the TB pandemic.

The immune reconstitution inflammatory syndrome (IRIS) can be a complication of anti-retroviral therapy (ART) in patients with advanced HIV, but its pathogenesis is uncertain. In tuberculosis (TB) endemic countries, IRIS is often associated with mycobacterial infections or Bacille Calmette-Guerin (BCG) vaccination in children. With no predictive or confirmatory tests at present, IRIS remains a diagnosis of exclusion. We tested whether RISK6 and Sweeney3, validated immune-based blood transcriptomic signatures for TB, could predict or diagnose IRIS in HIV+ children and adults. Transcripts were measured by RT-qPCR in BCG-vaccinated children and by microarray in HIV+ adults with TB, including TB meningitis (TBM). Signature scores before ART initiation and up to IRIS diagnosis were compared between participants who did or did not develop IRIS. In children, RISK6 and Sweeney3 discriminated IRIS cases from non-IRIS controls before ART, and at diagnosis. In adults with TB, RISK6 discriminated IRIS cases from controls after half-week on ART. In adults with TBM, only Sweeney3 discriminated IRIS cases from controls before ART, while both signatures distinguished cases from controls at TB-IRIS onset. Parsimonious whole blood transcriptomic signatures for TB showed potential to predict and diagnose IRIS in HIV+ children and adults. This article is protected by copyright. All rights reserved.

Identification of novel therapeutics and risk assessment in early stages of Alzheimer's disease (AD) is a crucial aspect of addressing this complex disease. We characterized gene-expression patterns at the mild cognitive impairment (MCI) stage to identify critical mRNA measures and gene clusters associated with AD pathogenesis.We used a transcriptomics approach, integrating magnetic resonance imaging (MRI) and peripheral blood-based gene expression data using persistent homology (PH) followed by kernel-based clustering.We identified three clusters of genes significantly associated with diagnosis of amnestic MCI. The biological processes associated with each cluster were mitochondrial function, NF-kB signaling, and apoptosis. Cluster-level associations with cortical thickness displayed canonical AD-like patterns. Driver genes from clusters were also validated in an external dataset for prediction of amyloidosis and clinical diagnosis.We found a disease-relevant transcriptomic signature sensitive to prodromal AD and identified a subset of potential therapeutic targets associated with AD pathogenesis.

Our aim was to investigate whether the previously observed higher contrast-to-noise ratio (CNR) and better image quality of Digital Variance Angiography (DVA) - compared to Digital Subtraction Angiography (DSA) - can be used to reduce radiation exposure in lower limb X-ray angiography. This prospective study enrolled 30 peripheral artery disease patients (mean ± SD age 70 ± 8 years) undergoing diagnostic angiography. In all patients, both normal (1.2 µGy/frame; 100%) and low-dose (0.36 µGy/frame; 30%) protocols were used for the acquisition of images in three anatomical regions (abdominal, femoral, crural). The CNR of DSA and DVA images were calculated, and the visual quality was evaluated by seven specialists using a 5-grade Likert scale. For investigating non-inferiority, the difference of low-dose DVA and normal dose DSA scores (DVA30-DSA100) was analyzed. DVA produced two- to three-fold CNR and significantly higher visual score than DSA. DVA30 proved to be superior to DSA100 in the crural region (difference 0.25 ± 0.07, p p = 0.435) and abdominal (− 0.10 ± 0.09, p = 0.350) regions. Our data show that DVA allows about 70% reduction of DSA-related radiation exposure in lower limb X-ray angiography, providing a potential new radiation protection tool for the patients and the medical staff.

Peer reviewed: True, Objectives: To assess the risk of new-onset or worsening hyperglycaemia, hypertension, weight gain and hyperlipidaemia with systemic corticosteroid therapy (CST) as reported in published randomised control trial (RCT) studies. Data sources: Literature search using MEDLINE, EMBASE, Cochrane library, Web of Science and Scopus Study eligibility criteria: Published articles on results of RCT with a systemic CST arm with numerical data presented on adverse effect (AE). Participants and interventions: Reports of hyperglycaemia, hypertension, weight gain and hyperlipidaemia associated with systemic CST in patients or healthy volunteer’s ≥17 years of age. Study appraisal methods: Risk of bias tool, assessment at the level of AE and key study characteristics. Results: A total of 5446 articles were screened to include 118 studies with 152 systemic CST arms (total participants=17 113 among which 8569 participants treated with CST). Pooled prevalence of hyperglycaemia in the CST arms within the studies was 10% (95% CI 7% to 14%), with the highest prevalence in respiratory illnesses at 22% (95% CI 9% to 35%). Pooled prevalence of severe hyperglycaemia, hypertension, weight gain and hyperlipidaemia within the corticosteroid arms was 5% (95% CI 2% to 9%), 6% (95% CI 4% to 8%), 13% (95% CI 8% to 18%), 8% (95% CI 4% to 17%), respectively. CST was significantly associated hyperglycaemia, hypertension and weight gain as noted in double-blinded placebo-controlled parallel-arms studies: OR of 2.13 (95% CI 1.66 to 2.72), 1.68 (95% CI 0.96 to 2.95) and 5.20 (95% CI 2.10 to 12.90), respectively. Intravenous therapy posed higher risk than oral therapy: OR of 2.39 (95% CI 1.16 to 4.91). Limitations: There was significant heterogeneity in the AE definitions and quality of AE reporting in the primary studies and patient populations in the studies. The impact of cumulative dose effect on incidental AE could not be calculated. Conclusions and implications of key findings: Systemic CST use is associated with increased risk of metabolic AEs, which differs for each disease group and route of administration. PROSPERO registration number: CRD42020161270.

One of the most important possible complications determining long-term graft survival after kidney transplant is antibody-mediated rejection (ABMR). The criterion standard approach to recognize ABMR is currently the kidney biopsy with histopathologic analysis. However, this test has limitations because of difficulties in timing of sampling, the evaluability of histology because of the questionable representativeness of specimens, and the limited number of this intervention. Hence, new reliable, noninvasive biomarkers are required to detect the development of ABMR in time.In this study, we analyzed the clinical data of 45 kidney transplant patients (mean age of 44.51 years, 20 male and 25 female subjects). These participants were recruited into 5 subcohorts based on their clinical status, histologic findings, and level of donor-specific anti-HLA antibodies. Circulating microRNAs (miR-21, miR-181b, miR-146a, miR-223, miR-155, miR-150) in plasma samples were quantified by quantitative polymerase chain reaction and their levels were correlated with the clinical characteristics in different subgroups.The relative expression of plasma miR-155 (P = .0003), miR-223 (P = .0316), and miR-21 (P = .0147) were significantly higher in patients who had subsequent histology-approved ABMR with donor-specific anti-HLA antibody positivity (n = 10) than in the "triple negative" group (n = 21), and miR-155 showed the highest sensitivity (90%) and specificity (81%) to indicate ABMR development based on receiver operating characteristic analysis.According to our preliminary data, plasma miR-155, miR-21, and miR-223 can indicate the development of ABMR after kidney transplant in correlation with classic clinical parameters. However, future studies with larger number of participants are necessary to further evaluate the diagnostic properties of blood miRNAs in prediction of this life-threatening condition.

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Objective The multicenter proximal upper limb artery (PULA) Registry was created to study the optimal puncture sites for the interventions involving the subclavian, axillary, and innominate arteries. Background Little is known about the optimal vascular access for PULA interventions, despite the well-known technical complexity of these procedures. Methods We performed the retrospective analysis of consecutive patients treated for symptomatic steno-occlusive disease of the proximal upper limb arteries between January 2015 and December 2019 in three high-volume centers. Acute thrombotic occlusions were excluded from the study. Results Two hundred and seventy-two patients were treated for significant stenosis and 108 for total occlusion. The baseline patient's characteristics were similar, except for the higher median age of the stenotic patients: 68.5 years (31.1; 90.0) versus 64 years (38.0; 86.0) p = 0.0015. Successful revascularization rate was higher in the stenotic group 93.75% (255/272) versus 86.11% (93/108) p = 0.0230, while the procedure length 27 min (8; 133) versus 46 min (7; 140) p = 0.0001 and fluoroscopy times 439 s (92; 2993) versus 864 s (86; 4176) p = 0.0001 were higher in the occlusion group. The main adverse event rate was similarly low. Dual access was used more often to treat occlusions (60.19% (65/108) vs. 11.40% (31/272) p = 0.0001) without significantly increasing the complication rate. The safest access was ultrasound-guided distal radial artery puncture, significantly better than conventional radial access with 0% (0/31) versus 13.6% (18/131) p = 0.0253 complication. Conclusions The percutaneous revascularization of proximal upper limb arteries is a safe and effective. Dual access can be applied to increase treatment efficacy, without significantly compromising safety.

Pigment epithelium-derived factor (PEDF) is a serin protease inhibitor and a potent inhibitor of angiogenesis. Its serum level has significant associations with metabolic parameters. However, little is known about the association between PEDF levels and lipid parameters in renal transplanted (TX) patients. Therefore, our aim was to investigate the relationship between PEDF level and lipid parameters in TX patients.Seventy TX patients (47 males, 23 females, mean age 51.7 ± 12.4 years) and 34 healthy controls were enrolled. We examined the serum creatinine, C-reactive protein, fasting glucose and lipid parameters right before, then 1 and 6 months after TX. High-density lipoprotein (HDL)-associated paraoxonase-1 (PON1) activities were measured spectrophotometrically. Lipoprotein subfractions were determined by Lipoprint. PEDF and oxidized low-density liporotein (oxLDL) levels were measured by ELISA.Before transplantation, patients had had a significantly higher PEDF level compared to control subjects (PEDF may play an important role in the increased oxidative stress and enhanced atherogenesis in renal transplant patients.

The problems caused by the COVID-19 epidemic have the worst impact on chronic patient populations. People with chronic pain are one of the most vulnerable groups due to stress, disruption of daily routine, family problems, illness and difficulty in hospital care. It is therefore essential to assess the situation and mental well-being of this group. The aim of this survey was to assess chronic pain patients during the COVID-19 pandemic, addressing psychological background factors that might affect pain symptoms, such as depression, emotion regulation, alexithymia, well-being, health literacy and social support.158 people participated in the survey, reporting pain for at least 3 months but had not received medical treatment. Data was collected at two dates: February and December 2021. Participants completed an online questionnaire due to the pandemic situation. The following six psychological questionnaires were used in the survey: Toronto Alexithymia Scale, Beck Depression Inventory 9-item version, Difficulty in Emotion Regulation Scale, Multidimensional Scale of Perceived Social Support, Chew-questions measuring health literacy, WHO Well-being Index.The participants ranged from 20 to 80 years in age, of whom 140 (88%) were female. 42 participants (27%) achieved severe alexithymia. 118 people (75%) had depression, of which 72 people (46%) had mild depression, 26 (16%) had moderate depression, and 20 (13%) had severe depression. The degree of pain and alexithy-mia (r(158) = 0.16, p = 0.004), depression (r(158) = 0.41, p0.001), difficulties in emotion regulation (r(158) = 0.26, p = 0.004), and health literacy, and difficulties in emotion regulation (r(158) = 0.25, p = 0.001) were positively and significantly related.In addition to the characteristic comorbidities of people living with pain (e.g. anxiety, emotion disorder, sleep disorder), the epidemic-induced prolonged social isolation, stress and fear of illness may explain the proportion of high depression, emotion regulation difficulties or health literacy problems in the study sample which exacerbate alexithymia and the degree of pain. Based on these results it is important to draw the attention of professionals to the appropriate health care and educational needs of those affected.A Covid-19-járvánnyal járó problémák a krónikusbeteg-populációkra vannak a legrosszabb hatással. A stressz, a mindennapi rutin felbomlása, családi problémák, a megbetegedés és az ellátás nehezítettsége miatt a krónikus fájdalommal élők az egyik kiemelkedően veszélyeztetett csoport. Ezért elengedhetetlen felmérni ennek a csoportnak a helyzetét, pszichés jóllétét. A jelen kérdőíves felmérés célja a következő volt: a krónikus fájdalommal élő személyek felmérése a Covid-19-pan­dé­mia alatt, kitérve a fájdalommal összefüggésbe hozható pszichés háttértényezőkre, mint a depresszió, az érzelemszabályozás, az alexithymia, a jóllét, az egészségértés és a társas támogatás.A felmérés 158 főt vizsgált, akiknél legalább 3 hónapja állt fenn valamilyen fájdalom, de orvosi ellátásban nem részesültek. Az adatfelvétel két időpontban zaj­lott: 2021. februárban és decemberben. A pandémiára való tekintettel a felmérés online, kérdőíves módszerrel zajlott. A felmérés során a következő hat pszichológiai tesztet alkalmaztuk: Torontói Alexithymia Skála, Beck Dep­resszió Kérdőív rövidített változata, Érzelemszabályozási Nehézségek Kérdőív, Multidimenzionális Észlelt Társas Támogatás Kérdőív, az egészségértést mérő Chew-kér­dé­sek és a WHO Jóllét Kérdőív.A vizsgálati személyek életkora 20–80 év közötti, 140 (88%) nő. Negyvenkét fő (27%) érte el a súlyos alexithymia mértékét. Depresszió 118 főnél (75%) volt kimutatható, melyből 72 fő (46%) enyhe, 26 fő (16%) közepesen súlyos és 20 fő (13%) súlyos depresszióval érintett. A fájdalom mértéke és az alexithymia [r(158) = 0,16, p = 0,004], a depresszió [r(158) = 0,41, p0,001], az érzelemszabályozási nehézségek [r(158) = 0,26, p = 0,004], az egészségértési és érzelemszabályozási nehézségek [r(158) = 0,25, p = 0,001] között pozitív, szignifikáns korreláció volt kimutatható.A fájdalommal élő személyeket jellemző komorbiditások (szorongás, hangulatzavar, alvászavar) mellett a járvány indukálta hosszan tartó szociális izoláció, stressz és a félelem magyarázhatja a depresszió, az ér­ze­lemszabályozási nehézségek és az egészségértési problémák magas arányát a vizsgált mintában, amik tovább súlyosbítják az alexithymia és a fájdalom mértékét. Ezek alapján fontos felhívni a szakemberek figyelmét az érintett személyek megfelelő egészségügyi ellátására és edukációs szükségleteire.

Turmeric has been used for decades for its antioxidant and anti-inflammatory effect, which is due to an active ingredient isolated from the plant, called curcumin. However, the extremely poor water-solubility of curcumin often limits the bioavailability of the drug. The aim of our experimental work was to improve the solubility and thus bioavailability of curcumin by developing self-nano/microemulsifying drug delivery systems (SN/MEDDS). Labrasol and Cremophor RH 40 as nonionic surfactants, Transcutol P as co-surfactant and isopropyl myristate as the oily phase were used during the formulation. The average droplet size of SN/MEDDS containing curcumin was between 32 and 405 nm. It was found that the higher oil content resulted in larger particle size. The drug loading efficiency was between 93.11% and 99.12% and all formulations were thermodynamically stable. The curcumin release was studied at pH 6.8, and the release efficiency ranged between 57.3% and 80.9% after 180 min. The results of the MTT cytotoxicity assay on human keratinocyte cells (HaCaT) and colorectal adenocarcinoma cells (Caco-2) showed that the curcumin-containing preparations were non-cytotoxic at 5

Aims Lower body half compression of bilateral secondary leg lymphoedema (LE) without relevant cardiac insufficiency gives rise to whether external leg compression may influence left ventricular (LV) function. Patients with LE were subjected to baseline two‐dimensional transthoracic echocardiography (2DTTE) for general assessment then three‐dimensional speckle‐tracking echocardiography (3DSTE) before and 1 h after lower body half external compression for LV torsion analysis. Methods and results Baseline 2DTTE was performed in the cohort of 25 LE patients, and the results were compared with those of age‐ and gender‐matched 52 healthy controls (mean age: 47.8 ± 12.8 vs. 40.7 ± 14.0 years, 24 women/1 man vs. 49 women/3 men, respectively). 3DSTE was conducted for the assessment of LV rotational mechanics where apical (AR), and basal rotations (BR) were measured before and 1 h after the use of compression class 2 (ccl 2) flat‐knitted medical compression pantyhoses (pressure range: 23–32 mmHg). 2DTTE showed significantly larger LV end‐diastolic volume and ejection fraction among LE patients compared with control subjects (108.3 ± 20.1 vs. 98.5 ± 21.7 mL, 69.8 ± 4.8 vs. 65.5 ± 4.3%, respectively) and notably smaller LV end‐systolic diameter and posterior wall thickness (28.9 ± 3.5 vs. 31.2 ± 3.4 mm, 8.1 ± 1.0 vs. 9.0 ± 1.7 mm, respectively). The results of 20 patients with LE were considered in 3DSTE examinations due to the drop‐out of five probands with technical failures. The data of four LE patients showing significant LV rotational abnormalities were managed separately, and the rotational parameters of the remaining sixteen patients did not differ significantly from those of matched controls except significant reduction of LV BR following the application of medical compression stockings (MCS) (−2.70 ± 1.26 degrees after 1 h use of pantyhose in patient group vs. −4.28 ± 2.18 degrees of the control group; P

Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1 ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4 ) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1 , ECRTSMARCA4 , and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1 ; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1 , potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Objectives The aim of the present work was to assess the knowledge and attitudes of different health care workers and laypeople toward the donation and transplantation procedure. Subjects and methods A survey consisting of questions regarding brain death diagnosis, legal organization or organ donation, and the transplantation procedure were sent to participants: 56 intensive care unit (ICU) doctors, 76 ICU nurses, 188 sixth-year medical students, and 320 general practitioners (GPs). Laypeople were also asked to complete the survey. Results The majority of participants reported being aware of legal regulations for organ donation in Hungary (88.5%). Roughly 25% of GPs and 60% of laypeople were unaware of the opt-out system effective in the country. Less than one-third of ICU physicians (26.9%) and nurses (34.7%) were able to list the organs that may be transplanted from a deceased donor; GPs (22.4%) and medical students (20%) performed even worse on this item. The willingness of ICU specialists (57%) and ICU nurses (45%) to support donating their own organs was moderate. Conclusions The results of this survey indicate a need for graduate and postgraduate education and regular teaching programs regarding organ donation and transplantation. More active use of modern media is proposed to improve public awareness and acceptance of organ donation.

Introduction The usage of extended-criteria donors (ECD) became a routinely accepted manner in the last decade. ECD is a potential risk factor for antibody-mediated rejection. Analysis of lymphocyte subsets might be a complementary diagnostic toolkit because there is limited knowledge about this term. Method Between May 12, 2016, and September 4, 2019, a total of 130 patients who had undergone kidney transplant were investigated. Patients were divided in ECD and standard criteria donor (SCD) groups. Blood samples were collected before the operation, then in the first week and after 30, 60, 180, and 365 days. Besides routine laboratory tests, multicolor flow cytometry was performed for lymphocyte subsets. Results ECD grafts were transplanted to older recipients. The number of CD4+ cells increased in the SCDs from the first week to until the end of first month, and then decreased. The number of CD4+ cells decreased from the beginning of the study until the end of first year to 66% of its original value in ECDs. At the first month, the number of CD19+ cells was higher in SCD compared with ECD cases; the number then decreased in both groups. T-regulatory cells had a drop at the first week that lasted until the first month. A bigger increase in SCD and a moderate increase in ECD group were then observed. The kinetics of CD19+ and CD19+ naive cells are similar in the ECD and SCD groups. In the SCD group, cell count decreased in both CD19+ (13%) and CD19+ naive (12%) between third and sixth month. The count of CD19+ cells decreased by 9%, but the count of CD19+ naive cells increased by 11% between the sixth month and first year. Discussion The prolonged postoperative uremic state caused by the poorer initial function, together with an aging immune system, explains the weaker immune response in ECD patients, which may be the cause of the decreased number of memory and regulatory T cells. Older patients with an ECD graft need a tailored, personalized, and less aggressive immunosuppressive treatment.

Adequate knowledge is needed to make the correct decision regarding kidney transplantation. The purpose of this study was to measure the demographic, sociologic, economic, and cultural factors that may influence patients' decision-making regarding kidney transplantation and to explore patients' knowledge of renal replacement therapies. A total of 254 end-stage renal disease patients (predialysis, peritoneal dialysis, and hemodialysis) from 8 dialysis centers in eastern Hungary participated in our study. We developed a questionnaire that measures patients' knowledge of renal replacement therapies and the role of sociodemographic, economic, and cultural factors that may influence their knowledge. Factors influencing the knowledge scores were evaluated using a multivariate linear regression adjusted for 8 factors. We found a significant correlation between education level and knowledge score, where patients with greater education (greater than high school: β = 3.003; P.001; high school: β = 1.906; P.001) achieved higher knowledge scores than those without. Moreover, patients with a previous kidney transplant (β = -2.111; P.001) had greater knowledge in the field. Our study identified a risk group where targeted, personalized patient education is essential.

Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E−10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E−7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated β-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations.

Objectives: The aim of the study was to present the results obtained in our experiment regarding the management of postoperative enterocutaneous fistulas (PECF). Materials and Methods: We conducted a retrospective study on 64 PECF registered after 2030 abdominal surgeries (1525 digestive tract surgeries and 505 extra-digestive ones) over a period of 7 years (1st of January 2014–31th of December 2020) in the 1st and 2nd Surgery Clinics, Clinical County Emergency Hospital of Craiova, Romania. The group included 41 men (64.06%) and 23 women (35.34%), aged between 21–94 years. Of the cases, 71.85% occurred in elderly patients over 65 years old. Spontaneous fistulas in Crohn’s disease, intestinal diverticulosis, or specific inflammatory bowel disease were excluded. Results: The overall incidence of 3.15% varied according to the surgery type: 6.22% after gastroduodenal surgery, 1.78% after enterectomies, 4.30% after colorectal surgery, 4.28% after bilio-digestive anastomoses, and 0.39% after extra-digestive surgery. We recorded a 70.31% fistula closure rate, 78.94% after exclusive conservative treatment and 57.61% after surgery; morbidity was 79.68%, mortality was 29.68%. Conclusion: PECF management requires a multidisciplinary approach and is carried out according to an algorithm underlying well-established objectives and priorities. Conservative treatment including resuscitation, sepsis control, output control, skin protection, and nutritional support is the first line treatment; surgery is reserved for complications or permanent repair of fistulas that do not close under conservative treatment. The therapeutic strategy is adapted to topography, morphological characteristics and fistula output, age, general condition, and response to therapy.

Background: Malnutrition predicts a worse outcome for critically ill patients. However, quick, easy-to-use nutritional risk assessment tools have not been adequately validated. Aims and Methods: The study aimed to evaluate the role of four biological nutritional risk assessment instruments (the Prognostic Nutritional Index—PNI, the Controlling Nutritional Status Score—CONUT, the Nutrition Risk in Critically Ill—NUTRIC, and the modified NUTRIC—mNUTRIC), along with CT-derived fat tissue and muscle mass measurements in predicting in-hospital mortality in a consecutive series of 90 patients hospitalized in the intensive care unit for COVID-19-associated ARDS. Results: In-hospital mortality was 46.7% (n = 42/90). Non-survivors had a significantly higher nutritional risk, as expressed by all four scores. All scores were independent predictors of mortality on the multivariate regression models. PNI had the best discriminative capabilities for mortality, with an area under the curve (AUC) of 0.77 for a cut-off value of 28.05. All scores had an AUC above 0.72. The volume of fat tissue and muscle mass were not associated with increased mortality risk. Conclusions: PNI, CONUT, NUTRIC, and mNUTRIC are valuable nutritional risk assessment tools that can accurately predict mortality in critically ill patients with COVID-19-associated ARDS.

Introduction and Objective: Acromegaly is a rare, chronic and slowly developing endocrine disorder caused by hypersecretion of human growth hormone and consequently of insulin-like growth factor-1 during adulthood. The present study was conducted to assess mitral annular (MA) size and function between acromegalic patients and age- and gender-matched healthy controls by three-dimensional speckle-tracking echocardiography (3D-STE). It also aimed to examine whether activity of the disease has any effect on MA parameters. Methods: This study included 27 patients with acromegaly, three of whom were excluded due to inferior image quality. The mean age of the remaining 24 patients was 55.7±14.0 years and seven were male. Complete two-dimensional Doppler echocardiography and 3D-STE were performed in all cases. Results: Significantly increased end-diastolic and end-systolic MA diameter (2.81±0.36 cm vs. 2.44±0.34 cm and 2.00±0.32 cm vs. 1.65±0.37 cm, respectively), area (9.67±2.33 cm2 vs. 7.38±1.93 cm2 and 5.14±1.62 cm2 vs. 3.74±1.19 cm2, respectively) and perimeter (11.76±1.42 cm vs. 10.27±1.33 cm and 8.61±1.23 cm vs. 7.36±1.10 cm, respectively) were demonstrated in acromegalic patients compared with control subjects. MA functional parameters were not significantly altered compared to those of healthy individuals. Conclusions: MA dilation could be seen in acromegaly regardless of its activity. Acromegaly is not associated with MA functional impairment. Resumo: Introdução e Objectivo: A acromegalia é uma doença endócrina rara, crónica e de desenvolvimento lento, causada pela hipersecreção da hormona do crescimento humano e, consequentemente, do fator de crescimento semelhante à insulina-1 durante a idade adulta. O presente estudo foi conduzido para avaliar o tamanho e a função do anel mitral (MA) nos doentes com acromegalia e controles saudáveis emparelhados por idade e sexo, por meio de ecocardiografia tridimensional com speckle-tracking (3DSTE). O objetivo foi também examinar se a atividade da doença tem algum efeito nos parâmetros da MA. Métodos: Este estudo incluiu 27 pacientes com acromegalia, três dos quais tiveram de ser excluídos devido à qualidade inferior de imagem. A média de idade dos 24 pacientes restantes foi de 55,7 ± 14,0 anos (7 homens). Foram realizados em todos os casos uma ecocardiografia Doppler bidimensional completa e um 3DSTE. Resultados: Quando comparados com os controlos, os doentes acromegálicos apresentaram diâmetros diastólico e sistólico finais significativamente dilatados (2,81 ± 0,36 cm versus 2,44 ± 0,34 cm e 2,00 ± 0,32 cm versus 1,65 ± 0,37 cm, respetivamente), assim como a área valvular (9,67 ± 2,33 cm2 versus 7,38 ± 1,93 cm2 e 5,14 ± 1,62 cm2 versus 3,74 ± 1,19 cm2, respetivamente) e o perímetro (11,76 ± 1,42 cm versus 10,27 ± 1,33 cm e 8,61 ± 1,23 cm versus 7,36 ± 1,10 cm, respetivamente) Os parâmetros funcionais da MA não estavam significativamente alterados em comparação com indivíduos saudáveis. Conclusões: A dilatação do MA pode ser observada na acromegalia, independentemente de sua atividade. A acromegalia não está associada ao comprometimento funcional da MA.

The JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway.

The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.

Szolnoky, G, Gavallér, H, Gönczy, A, Bihari, I, Kemény, L, Forster, T, and Nemes, A. The effects of below-knee medical compression stockings on pulse wave velocity of young healthy volunteers. J Strength Cond Res 35(1): 275-279, 2021-The effects of graduated medical compression stockings (MCS) on cardiovascular responses are poorly investigated. A simple study was undertaken to investigate whether the application of below-knee leg MCSs with different pressures could influence aortic pulse wave velocity (PWV) as the gold standard for aortic stiffness measurement evaluated by arteriography. Ten volunteers underwent PWV measurement at baseline, then in below-knee compression class (ccl) 1 (18-21 mm Hg), 2 (23-32 mm Hg) and 3 (34-46 mm Hg) MCSs in a consecutive manner. Baseline PWV (mean value: 7.86 ± 1.70 m·s-1) was significantly reduced by ccl 1 MCSs (mean value: 6.55 ± 0.88 m·s-1, p = 0.04). ccl 2 and ccl 3 stockings also notably decreased baseline PWV (mean values: 6.63 ± 0.65 m·s-1, p = 0.058 and 6.62 ± 1.00 m·s-1, p = 0.067; respectively). The application of low compression MCSs (ccl 1) leads to a significant decrease in PWV indicating a beneficial cardiovascular influence.

Introduction A number of studies defined normal reference values of three-dimensional (3D) speckle-tracking echocardiography (3DSTE)-derived left ventricular (LV) strains. The present study aimed to quantify normal reference values of LV strains in healthy adult population in real clinical world settings in different age groups, and to determine age- and gender-dependence of these variables in a high volume single center. Methods The present prospective study included 296 healthy adult subjects. Among them, 124 were excluded due to inferior image quality during the 6-year recruitment period (2011-2017). The remaining population was further divided into four subgroups based on age decades. Results While global radial (RS) strain showed an increase-decrease-increase pattern with age, circumferential, longitudinal, and area strains (CS, LS, AS, respectively) were nonsignificantly lower in older ages. Only global LV-LS showed gender-dependency with higher values in females. Although moderately higher RS and 3DS and lower LS, and AS were observed in males, clear gender-dependency could not be detected in different age decades. Conclusions This study provides normal reference values of 3DSTE-derived global, segmental, mean segmental, and regional LV strains in healthy adult subjects based on real-life clinical experience. Age-, gender-, and functional nonuniformity of LV strains were also defined.

PURPOSE Rhabdoid tumor of the kidney (RTK) is one of the most aggressive childhood renal tumors. Overall survival ranges from 22% to 47%. The indication for radiation therapy (RT) in usually very young patients is an ongoing discussion. Recent protocols recommend RT independent of local stage, the latter being a good discriminator in other childhood kidney tumors. In this study, we analyze the evidence for RT in regard to risk factors, including tumor stage. METHODS AND MATERIALS This study analyzed 58 patients with RTK from Austria, Switzerland, and Germany treated in the framework of 4 consecutive, prospective renal/rhabdoid tumor studies from 1991 to 2014. All treatment protocols included multimodality treatment, including high-intensity chemotherapy, surgery, and RT. RESULTS Local stage distribution was not applicable, I, II, and III in 1, 6, 11, and 40, respectively. Twenty-nine (50%) patients had stage IV disease at diagnosis. Thirty-seven patients (64%) achieved complete remission, and 49% (18/37) relapsed. Thirty-four patients (60%) patients had progressive disease and died, 17 had local disease, 10 had combined disease, and 7 had distant disease; 2 treatment-related deaths were reported (3%). Twenty-one patients received RT during first-line treatment, 18 of them to all involved sites. Eight of the 34 cases of progressive disease occurred in irradiated patients. The local failure rate of treated patients with local stage II or III disease was 29% (6/18) in patients irradiated to all sites compared with 68% (15/22) in nonirradiated patients. One of 6 stage I patients received RT, and 1 patient experienced distant relapse (2-year progression-free and overall survival both 83% ± 15%). Progression-free survival for local stage II and III disease treated with RT, adjusted for early relapse or treatment abandonment, was 67% ± 11%, compared with 15% ± 7% without RT (P < .0001). CONCLUSION The 68% local failure rate in nonirradiated patients underlines the importance of local treatment. Our experience supports the use of RT for local control in higher stage disease. In contrast, no local relapse in 6 local stage I patients, including 5 nonirradiated patients, suggests omission of RT in this favorable subset of usually infant patients with RTK.

The next frontier in hemophilia A management has arrived. However, questions remain regarding the broader applicability of new and emerging hemophilia A therapies, such as the long-term safety and efficacy of non-factor therapies and optimal regimens for individual patients. With an ever-evolving clinical landscape, it is imperative for physicians to understand how available and future hemophilia A therapies could potentially be integrated into real-life clinical practice to improve patient outcomes. Against this background, nine hemophilia experts from Central European countries participated in a pre-advisory board meeting survey. The survey comprised 11 multiple-choice questions about current treatment practices and future factor and non-factor replacement therapies. The survey questions were developed to reflect current unmet needs in hemophilia management reflected in the literature. The experts also took part in a follow-up advisory board meeting to discuss the most important unmet needs for hemophilia management as well as the pre-meeting survey results. All experts highlighted the challenge of maintaining optimal trough levels with prophylaxis as their most pressing concern. Targeting trough levels of ≥30–50 IU/L or even higher to achieve less bleeding was highlighted as their preferred strategy. However, the experts had an equal opinion on how this could be achieved (i.e., more efficacious non-factor therapies or factor therapy offering broader personalization possibilities such as targeting trough levels to individual pharmacokinetic data). In summary, our study favors personalized prophylaxis to individual pharmacokinetic data rather than a "one-size-fits-all" approach to hemophilia A management to maintain optimal trough levels for individual patients.

New tuberculosis vaccine candidates that are in the development pipeline need to be studied in people with HIV, who are at high risk of acquiring Mycobacterium tuberculosis infection and tuberculosis disease and tend to develop less robust vaccine-induced immune responses. To address the gaps in developing tuberculosis vaccines for people with HIV, a series of symposia was held that posed six framing questions to a panel of international experts: What is the use case or rationale for developing tuberculosis vaccines? What is the landscape of tuberculosis vaccines? Which vaccine candidates should be prioritised? What are the tuberculosis vaccine trial design considerations? What is the role of immunological correlates of protection? What are the gaps in preclinical models for studying tuberculosis vaccines? The international expert panel formulated consensus statements to each of the framing questions, with the intention of informing tuberculosis vaccine development and the prioritisation of clinical trials for inclusion of people with HIV.

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT–TYR, ATRT–MYC and ATRT–SHH. ATRT–SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT–SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT–SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT–SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT–SHH has prognostic relevance and might aid to stratify patients within future clinical trials.

Background and Objectives: Malignant neoplasms are common causes of acute pleuropericardial effusion. Pleuropericarditis denotes poor patient prognosis, is associated with shortened average survival time, and represents a surgical emergency. Materials and Methods: We analyzed the impact of two minimally invasive surgical approaches, the type of cancer, and other clinical variables on the mortality of 338 patients with pleuropericarditis admitted to an emergency hospital in Romania between 2009 and 2020. All patients underwent minimally invasive surgeries to prevent the recurrence of the disease and to increase their life expectancy. Log-rank tests were used to check for survival probability differences by surgical approach. We also applied univariate and multivariate Cox proportional hazard models to assess the effect of each covariate. Results: No significant differences were found in the 2-year overall survival rate between patients who underwent the two types of surgery. The multivariate Cox proportional regression model adjusted for relevant covariates showed that age, having lung cancer, and a diagnosis of pericarditis and right pleural effusion increased the mortality risk. The surgical approach was not associated with mortality in these patients. Conclusion: These findings open up avenues for future research to advance the understanding of survival among patients with pleuropericarditis.

Given the rising popularity of robotics, student-driven robot development projects are playing a key role in attracting more people towards engineering and science studies. This article presents the early development process of an open-source mobile robot platform—named PlatypOUs—which can be remotely controlled via an electromyography (EMG) appliance using the MindRove brain–computer interface (BCI) headset as a sensor for the purpose of signal acquisition. The gathered bio-signals are classified by a Support Vector Machine (SVM) whose results are translated into motion commands for the mobile platform. Along with the physical mobile robot platform, a virtual environment was implemented using Gazebo (an open-source 3D robotic simulator) inside the Robot Operating System (ROS) framework, which has the same capabilities as the real-world device. This can be used for development and test purposes. The main goal of the PlatypOUs project is to create a tool for STEM education and extracurricular activities, particularly laboratory practices and demonstrations. With the physical robot, the aim is to improve awareness of STEM outside and beyond the scope of regular education programmes. It implies several disciplines, including system design, control engineering, mobile robotics and machine learning with several application aspects in each. Using the PlatypOUs platform and the simulator provides students and self-learners with a firsthand exercise, and teaches them to deal with complex engineering problems in a professional, yet intriguing way.

A paragangliomák a szimpatikus vagy paraszimpatikus ganglionokból kiinduló, többségükben jóindulatú daganatok, de rosszindulatú formájuk is ismert. A fej-nyak régióban, a glomus caroticumban, illetve a vegetatív idegrendszer dúcláncának megfelelően a hasüregben, illetve a mellüregben is előfordulhatnak. A 39 éves férfi beteg kivizsgálása extrém magas vérnyomásértékek, éjszakai izzadás és 10 kg-os fogyás miatt kezdődött. A mellkas-CT-vizsgálat a jobb oldali tüdőkapuban óriási térfoglalást írt le, a bronchoszkópos mintavétel sikertelen volt. Jobb oldali thoracotomiából mintavétel történt, reszekcióra a kifejezett adhéziók, illetve a szívérintettség miatt nem volt lehetőség. A szövettani vizsgálat eredménye paraganglioma lett, ezt a laborvizsgálatok is támogatták. Ennek megfelelőn szomatosztatinanalóg-terápiát kezdtünk, majd 131I-MIBG-kezelést alkalmaztunk, jó klinikai eredménnyel. A koronarográfia során észleltük, hogy a jobb coronaria két marginális ággal hozzájárul a mellkasi terime vérellátásához. Megfelelő előkészítést követően, szív- és mellkassebészeti beavatkozással a tumor eltávolíthatónak bizonyult, ennek eredményeként a posztoperatív szakban a beteg vérnyomáscsökkentőit elhagytuk. A kontrollok során tumormaradványra utaló jel nem volt. A vérnyomáskiugrások okának keresésekor merüljön fel bennünk a paraganglioma lehetősége is. Ezen esetekben az invazív beavatkozások, amennyiben nem előzi meg őket gyógyszeres előkészítés, akár fatális kimenetellel járhatnak. Az egyre szélesedő terápiás lehetőségek kihasználásával és az intézetek közötti kooperációval az óriás-paragangliomában szenvedő betegek is tumormentessé tehetők. Orv Hetil. 2022; 163(31): 1243–1249.

B cells express various ion channels, but the presence of voltage-gated sodium (Na

Summary: Background: Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CD1, MR1, and butyrophilin 3A1. Such T cells, referred to as donor unrestricted T (DURT) cells, typically express stereotypic T cell receptors. The near-unrestricted nature of DURT cell antigen recognition is of particular interest for vaccine development, and we sought to define the roles of DURT cells, including MR1-restricted MAIT cells, CD1b-restricted glucose monomycolate (GMM)-specific T cells, CD1d-restricted NKT cells, and γδ T cells, in vaccination against Mycobacterium tuberculosis. Methods: We compared and characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in a cohort of vaccinated and unvaccinated infants, as well as before and after BCG-revaccination in adults. Findings: BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CD1b-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CD1d-restricted NKT cells. By contrast, primary BCG vaccination was associated with increased frequencies of γδ T cells as well as a novel subset of CD26+CD161+TRAV1-2− IFN-γ-expressing CD4+ T cells in infants. Interpretation: Our findings, that most DURT cell populations were not modulated by BCG, do not preclude a role of BCG in modulating other qualitative aspects of DURT cells. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies. Funding: Aeras, the National Institutes of Health, and the Bill and Melinda Gates Foundation.

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

Background Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection. Methods We hypothesized that TruCulture, an immunomonitoring method for whole-blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from patients with active TB and compared with LTBI donors. Mtb-specific antigens and live bacillus Calmette-Guérin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital enzyme-linked immunosorbent assay (ELISA), as well as Luminex. Results TruCulture showed discrimination of active TB cases from LTBI (P < .0001, AUC = .81) compared with QFT (P = .45, AUC = .56), based on an interferon γ (IFNγ) readout after Mtb antigen (Ag) stimulation. This result was replicated in an independent cohort (AUC = .89). In exploratory analyses, TB stratification could be further improved by the Mtb antigen to BCG IFNγ ratio (P < .0001, AUC = .91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with patients with TB, suggesting the possibility to identify subclinical disease. Conclusions TruCulture offers a next-generation solution for whole-blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection., We tested TruCulture, an immunomonitoring tool, to identify active disease from latent Mtb infection. TruCulture showed improved discrimination of tuberculosis cases from LTBI as compared with QuantiFERON. Tuberculosis stratification could be further improved by the Mtb Ag:BCG IFNγ ratio.

Patients with degenerative hip and lumbar spine disorders requiring surgery in both locations is fairly common in clinical practice. We investigated if the order of total hip replacement (THR) and lumbar spinal stenosis surgery (LSSS) influences patient-reported outcomes (PROs). We used data from the Swedish Hip Arthroplasty Register (SHAR) and the Swedish Spine Register (Swespine), on patients operated with THR and LSSS in years 2002 to 2012. To increase the probability of having symptomatic disorders in both locations at the time of the first surgery, we only included patients with both LSSS and THR performed within 2 years. Linear and logistic regression analyses adjusted for age, sex, preoperative PROs, and time between surgeries were used to investigate the association between order of surgeries and the generic PRO measurements EQ-5D and EQ VAS. Eighty-four patients had THR prior to LSSS and 171 patients LSSS prior to THR. Linear regression showed that LSSS prior to THR was associated with higher EQ-5D index (B = 0.09, 95% confidence interval [CI] 0.03-0.16) and EQ VAS (B = 5.6, 95% CI 0.4-10.9) 1 year after the last surgery. Logistic regression showed that the odds ratio [OR] for not having any problems in the "pain" (OR = 3.0, 95% CI 1.5-6.3) and "anxiety/depression" (OR = 2.3, 95% CI 1.3-4.1) dimensions were higher for LSSS before THR. In our cohort, LSSS before THR was associated with better health-related quality of life outcomes compared to the reverse order. The results from our cohort can be helpful in a clinical situation where the physician gives advice to an individual patient when choosing the order of procedures. However, further studies are necessary in order to confirm these results in other cohorts. At present, standard of care remains that order of surgery should be individualized for each patient, with guidance from the operating surgeons.

Purpose: To compare the acute success and complication rates of distal radial (DR) vs proximal radial (PR) artery access for superficial femoral artery (SFA) interventions. Materials and Methods: Between 2016 and 2019, 195 consecutive patients with symptomatic SFA stenosis were treated via DR (n=38) or PR (n=157) access using a sheathless guide. Secondary access was achieved through the pedal artery when necessary. The main outcomes were technical success, major adverse events (MAEs), and access site complications. Secondary outcomes were treatment success, fluoroscopy time, radiation dose, procedure time, and crossover rate to another puncture site. Results: Overall technical success was achieved in 188 patients (96.4%): 37 of 38 patients (97.3%) in the DR group and 151 of 157 patients (96.2%) in the PR group (p=0.9). Dual (transradial and transpedal) access was used in 14 patients (36.8%) in the DR group and 28 patients (18.9%) in the PR group (pConclusion: SFA interventions can be safely and effectively performed using PR or DR access with acceptable morbidity and a high technical success rate. DR access is associated with few access site complications.

Vγ9Vδ2 T cells are a major human blood γδ T cell population that respond in a T cell receptor (TCR)-dependent manner to phosphoantigens which are generated by a variety of microorganisms. It is not clear how Vγ9Vδ2 T cells react toward the sudden microbial exposure early after birth. We found that human Vγ9Vδ2 T cells with a public/shared fetal-derived TCR repertoire expanded within 10 wk postpartum. Such an expansion was not observed in non-Vγ9Vδ2 γδ T cells, which possessed a private TCR repertoire. Furthermore, only the Vγ9Vδ2 T cells differentiated into potent cytotoxic effector cells by 10 wk of age, despite their fetal origin. Both the expansion of public fetal Vγ9Vδ2 T cells and their functional differentiation were not affected by newborn vaccination with the phosphoantigen-containing bacillus Calmette-Guérin (BCG) vaccine. These findings suggest a strong and early priming of the public fetal-derived Vγ9Vδ2 T cells promptly after birth, likely upon environmental phosphoantigen exposure., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction There is a limited number of echocardiographic studies determining mitral annular (MA) dimensions in healthy subjects. The present study aimed to establish normal reference values of three-dimensional speckle-tracking echocardiography-derived MA dimensions and functional properties in healthy adults in relation with age and gender. Methods The present study comprised 298 healthy adult subjects. From this population, 94 subjects were excluded due to inadequate image quality. Therefore the remaining group consisted of 204 subjects with the mean age of 33.88 ± 12.97 years (107 males). The population sample was further divided into age categories: 18-29 years (n = 105; mean age: 24.11 ± 2.98 years, 51 males), 30-39 years (n = 44; mean age: 33.80 ± 2.39 years, 31 males), 40-49 years (n = 19; mean age: 43.47 ± 3.18 years, 11 males) and ≥50 years of age (n = 36, mean age: 57.42 ± 6.11 years, 14 males). Results End-diastolic MA dimensions did not change significantly during the decades. End-systolic MA diameter, area, and perimeter were larger over the age of 50 years than in the 18-29 year-old group. MA fractional area change was found smaller over the age of 50 years than in 18-29-year-old group. While end-diastolic MA variables did not show gender-differences, end-systolic MA area and perimeter were lower in females in the 18-29-year-old group. Conclusions End-systolic MA dimensions change over decades, resulting in a special pattern of MA functional properties with significant reduction over the age of 50 years.

Purpose In retrospective clinical studies digital variance angiography (DVA) provided higher contrast-to-noise ratio and better image quality than digital subtraction angiography (DSA). Our aim was to verify the clinical usefulness and benefits of DVA in carbon dioxide (CO2)-assisted lower limb interventions. Materials and Methods A workstation running the DVA software was integrated into a Siemens Artis Zee with Pure angiography system, and this new image processing technology was used in four patients (3 male, 1 female, age: 76.2 ± 4.2 years) with peripheral artery disease (PAD, Rutherford 2–3) and impaired renal function (average eGFR 25.5 ± 11.2 ml/min/1.73 m2). The DSA and DVA images of 46 CO2-assisted runs were visually evaluated by five experts in single-image evaluation using a 5-grade Likert scale and in paired comparisons. Results DVA images received significantly higher score (3.84 ± 0.10) than DSA images (3.31 ± 0.10, p 2 angiography (4–6 FPS). No adverse events were recorded during or after the procedures. Conclusions Our initial experience shows that DVA might facilitate the correct diagnostic and therapeutic decisions, and potentially help to reduce radiation exposure in lower limb CO2 angiography. Although the dose management capabilities of DVA have to be validated in further clinical studies, this technology might be a useful new tool in the operating room and contributes to the safety and efficacy of CO2-enhanced endovascular interventions. Level of Evidence Level IV.

Introduction Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half‐life developed for prophylaxis, treatment of bleeds and perioperative management in patients with haemophilia A. Aim Evaluate the efficacy and safety of turoctocog alfa pegol treatment for major and minor surgeries in the pathfinder 3 and 5 phase III trials. Methods Adults/adolescents aged ≥12 years with severe haemophilia A (FVIII 80% during major surgery (pathfinder 3). The primary end point was haemostatic efficacy during surgery; secondary end points were blood loss, haemostatic effect postsurgery, consumption, transfusions, safety and health economics. Children (0‐11 years) undergoing minor surgeries received 20‐75 IU/kg turoctocog alfa pegol at Investigator's discretion (pathfinder 5). Results pathfinder 3 included 35 patients undergoing 49 major surgeries. Haemostasis was successful in 47/49 (95.9%) surgeries; two had moderate haemostatic responses. Median (mean) blood loss during major surgery was 75 (322.6) mL. Four bleeds were reported postsurgery; three were successfully treated with turoctocog alfa pegol (one was not evaluated). On the day of surgery, overall mean (median) dose was 75.5 (74.5) IU/kg and mean (median) number of doses was 1.7 (2.0). Five procedures required 11 transfusions on the day of surgery or days 1‐6. No safety concerns or inhibitors were identified. Forty‐five minor surgeries in 23 children were performed without complications. Conclusion Turoctocog alfa pegol was effective for perioperative haemostatic management of major and minor surgeries in patients across age groups with severe haemophilia A.

Background and purpose — To better detect small changes in postoperative outcome following total hip replacement (THR), the Swedish Hip Arthroplasty Register (SHAR) has decided to change from the EQ-5D-3L (3L) to the EQ-5D-5L (5L). To enable comparison of results obtained with use of the 2 versions of EQ-5D, transferal of results between the questionnaires used is necessary. We assessed the measurement properties of the EQ-5D-5L compared with the EQ-5D-3L, preoperatively and 1-year postoperatively in a Swedish THR population. Patients and methods — Patients eligible for elective THR during 2015 in Western Sweden were invited to the study. With a 2-week separation, the 3L and 5L questionnaires were administered to patients before and 1 year after surgery. Comparing the 2 versions of the EQ-5D, we investigated redistribution of responses, ceiling and floor effects, EQ VAS correlations (Spearman’s rank correlation coefficient, rs), and EQ VAS scores for different severity levels by dimension (univariable ordinary least square regression). Results — The additional severity levels of the 5L version were frequently used on both measurement occasions (preoperative mobility 5%, self-care 17%, usual activities 20%, pain 5% and anxiety 3%, postoperative mobility 6%, self-care 5%, usual activities 8%, pain 9%, and anxiety 5%). Ceiling effects of the 3L version diminished overall by 7% using the 5L version. The correlations between the 2 EQ VAS scores obtained with the 3L and 5L instruments were strong both pre- (rs = 0.71) and postoperatively (rs = 0.87). Estimated EQ VAS scores for different levels of severity were consistent for all dimensions except for the mobility dimension of the preoperative 5L version and the anxiety dimension in the postoperative 5L version. Interpretation — Our findings support that the 5L has a higher resolution than the 3L version regarding description of health-related quality of life in patients undergoing THR in Sweden. The EQ VAS scores for different levels of severity agree well between the EQ-5D versions. This could potentially be used to develop a crosswalk value set for transforming 3L to 5L responses in this patient group.

Introduction: Acromegaly is a relatively rare chronic hormonal disease resulting in disfigurement. In 90% of cases, acromegaly is caused by a benign pituitary monoclonal human growth hormone-secreting tumor. The aim of the present study was to determine the presence of left ventricular (LV) deformation abnormalities using three-dimensional speckle-tracking echocardiography in a group of acromegalic patients. Methods: Thirty-eight acromegalic patients were involved in the study. Thirteen patients were excluded due to inadequate image quality. The mean age of the remaining patients was 57.2±13.6 years and seven were male. Their data were compared to an age- and gender-matched control population, which consisted of 34 healthy volunteers (mean age: 52.7±4.9 years, 15 male). Results: Global and mean segmental LV radial strain (RS) (33.2±13.4% vs. 25.2±10.8%, p=0.01 and 36.0±12.1% vs. 28.2±10.0%, p=0.009, respectively) proved to be significantly higher in acromegaly compared to controls. Active acromegalic patients had significantly higher global and mean segmental LV-RS (35.5±14.4% vs. 25.2±10.8%, p=0.03 and 37.9±13.3% vs. 28.2±10.0%, p=0.03, respectively) compared to controls. Between the active and inactive acromegaly groups, only basal LV circumferential strain (-30.2±4.8% vs. -26.7±4.1%, p=0.02) was found to be significantly different. Conclusion: The presented clinical, demographic, therapeutic and echocardiographic features demonstrate that active acromegaly is associated with enhanced LV RS as compared to healthy controls and those with inactive acromegaly. Resumo: Introdução: A acromegalia é uma doença hormonal crónica relativamente rara, associada a dismorfismos somáticos. Em 90% dos casos, ela é causada por um tumor benigno monoclonal da hipófise, secretor de hormona do crescimento. O objetivo do presente estudo foi detetar a presença de alterações da deformação miocárdica do ventrículo esquerdo (VE) através de ecocardiografia tridimensional por speckle tracking num grupo de doentes portadores de acromegalia. Métodos: Foram incluídos 38 doentes portadores de acromegalia. Treze foram excluídos devido à má qualidade de imagem. A idade média dos restantes foi de 57,2±13,6 anos (7 homens). Os seus dados foram comparados com uma população controlo emparelhada por idade e género, que compreendeu 34 voluntários saudáveis (idade média: 52,7±4,9 anos, sendo 15 indivíduos do sexo masculino). Resultados: O strain radial (SR) global e segmentar VE (respetivamente 33,2±13,4% versus 25,2±10,8%, p=0,01 e 36,0±12,1% versus 28,2±10,0%, p=0,009) foi significativamente superior nos casos de acromegalia em relação aos casos controlo. Os doentes portadores de acromegalia ativa tiveram um SR global e segmentar significativamente superior (35,5±14,4% versus 25,2±10,8%, p=0,03 e 37,9±13,3% versus 28,2±10,0%, p=0,03, respetivamente), quando comparados com os grupos controlo. Entre os grupos portadores de acromegalia ativos e inativos, só foi considerado significativamente diferente o strain circunferencial basal VE (-30,2±4,8% versus -26,7±4,1%, p=0,02). Conclusões: Com base nas características clínicas, demográficas, terapêuticas e ecocardiográficas apresentadas, a acromegalia ativa apresenta SR-VE aumentado em relação à população saudável e ao grupo de portadores de acromegalia inativa.